Dyural 80 LM-C Dailymed
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Warning: Risks With Inadvertent Intrathecal Administration Omnipaque Injection, 140 And 350 Mg Iodine/ml
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Warning: Risk Of Cardiac Arrest With Use Of Bupivacaine Hydrochloride Injection In Obstetrical Anesthesia
There have been reports of cardiac arrest with difficult resuscitation or death during use of Bupivacaine Hydrochloride Injection for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of Bupivacaine Hydrochloride Injection is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary [see Warnings and Precautions (5.1)].
WARNING: RISK OF CARDIAC ARREST WITH USE OF BUPIVACAINE HYDROCHLORIDE INJECTION IN OBSTETRICAL ANESTHESIA
See full prescribing information for complete boxed warning.
There have been reports of cardiac arrest with difficult resuscitation or death during use of Bupivacaine Hydrochloride Injection for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of Bupivacaine Hydrochloride Injection is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary (5.1 ).
1 Indications And Usage
Bupivacaine Hydrochloride Injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations of Bupivacaine Hydrochloride Injection are recommended for each type of block indicated to produce local or regional anesthesia or analgesia [see Dosage and Administration (2.2)].
Bupivacaine Hydrochloride Injection contains bupivacaine, an amide local anesthetic. Bupivacaine Hydrochloride Injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended. (1 ,2.2 )
Limitations of Use
Not all blocks are indicated for use with Bupivacaine Hydrochloride Injection given clinically significant risks associated with use. (1 ,2.2 ,4 ,5.1 ,5.4 ,5.5 ,5.7 ,5.9 )
Limitations of Use
Not all blocks are indicated for use with Bupivacaine Hydrochloride Injection given clinically significant risks associated with use [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1, 5.4, 5.5, 5.7, 5.9)] .
2 Dosage And Administration
- Not for intrathecal use. (
2.1 )- Avoid use of solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia. (
2.1 ,5.4 )- Three mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. (
2.4 )- See full prescribing information for:
- Recommended concentrations and dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection according to type of block. (
2.2 )- Additional dosage and administration information pertaining to use in epidural anesthesia, test dose for caudal and lumbar epidural blocks, use in dentistry, and use in ophthalmic surgery. (
2.3 ,2.4 ,2.5 ,2.6 )2.1 Important Dosage and Administration Information
- Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not for intrathecal use.
- Avoid use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.4)] .
- Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use.
- Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection are clear, colorless solutions. Do not administer solutions which are discolored or contain particulate matter.
- Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures.
Administration Precautions
- Bupivacaine Hydrochloride Injection Injection/Bupivacaine Hydrochloride and Epinephrine Injection are to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed.
- Use Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions (5.2), Adverse Reactions (6), Overdosage (10)] .
- The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection [see Warnings and Precautions (5.2), Drug Interactions (7.1), Overdosage (10)] .
- Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [see Warnings and Precautions (5.9)] .
- Avoid rapid injection of a large volume of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection and use fractional (incremental) doses when feasible.
- During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.
- Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient's level of consciousness after each local anesthetic injection.
- Use Bupivacaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions (5.12)] .
2.2 Recommended Concentrations and Dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection
The dosage of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration required to produce the desired result.
The types of block and recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection concentrations are shown in Table 1.
Table 1. Types of Block and Recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentrations Type of Block Bupivacaine Hydrochloride Bupivacaine Hydrochloride and Epinephrine 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) 0.75% (7.5 mg/mL) Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) is not recommended for nonobstetrical surgical procedures in pregnant patients. 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) âś“= indicated use [see Warnings and Precautions (5.1)]. Local infiltration âś“ âś“ Peripheral nerve block âś“ âś“ âś“ âś“ Retrobulbar block âś“ Sympathetic block âś“ Caudal block Avoid use of multiple-dose vials of Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection for caudal or epidural anesthesia [see Warnings and Precautions (5.4)] . âś“ âś“ âś“ âś“ Lumbar epidural block âś“ âś“ âś“ (not for obstetrical anesthesia) âś“ âś“ Epidural test dose âś“ Dental block âś“
At recommended dosages, Bupivacaine Hydrochloride/Bupivacaine Hydrochloride and Epinephrine produces complete sensory block, but the effect on motor function differs among the three concentrations. Table 2 provides information on the expected effect on motor function for the three concentrations.
Table 2. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentration vs. Motor Function Bupivacaine Hydrochloride Injection Concentration Motor Function 0.25% (2.5 mg/mL) These products include Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection [the epinephrine concentration (1:200,000) is not included in the table]. When used for caudal, epidural, or peripheral nerve block, produces incomplete motor block. Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. Onset of action may be slower than with the 0.5% (5 mg/mL) or 0.75% (7.5 mg/mL) solutions. 0.5% (5 mg/mL) Provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75% (7.5 mg/mL) These are only Bupivacaine Hydrochloride Injection products [there is no 0.75% (7.5 mg/mL) concentration for Bupivacaine Hydrochloride and Epinephrine Injection]. Produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia.
The duration of anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is such that for most indications, a single-dose is sufficient.
The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site.
The dosages in Table 3 are recommended as a guide for use in the average adult. These doses may be repeated once every three hours. Do not exceed a total daily dosage of 400 mg in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine.
Table 3. Recommended Concentrations and Doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in Adults Type of Block Concentration of Bupivacaine Hydrochloride Injection Each Dose Motor Block With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% (5 mg/mL) may produce complete motor block. Intercostal nerve block with 0.25% (2.5 mg/mL) also may produce complete motor block for intra-thoracic and upper intra-abdominal surgery. mL mg of Bupivacaine Hydrochloride Injection Local infiltration 0.25% (2.5 mg/mL) Solutions with or without epinephrine (i.e., applies to Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection). The Bupivacaine Hydrochloride and Epinephrine Injection products include epinephrine (1:200,000). Up to 70 (without epinephrine) Up to 175 (without epinephrine) ― Up to 90 (with epinephrine) Up to 225 (with epinephrine) Peripheral nerve block 0.5% (5 mg/mL) 5–35 (without epinephrine) 25–175 (without epinephrine) moderate to complete 5–45 (with epinephrine) 25–225 (with epinephrine) 0.25% (2.5 mg/mL) 5–70 (without epinephrine) 12.5–175 (without epinephrine) moderate to complete 5–90 (with epinephrine) 12.5–225 (with epinephrine) Retrobulbar block [see Dosage and Administration (2.6)] 0.75% (7.5 mg/mL) 2–4 15–30 complete Sympathetic block 0.25% (2.5 mg/mL) 20–50 50–125 ― Caudal block [see Dosage and Administration (2.4)] 0.5% (5 mg/mL) 15–30 75–150 moderate to complete 0.25% (2.5 mg/mL) 15–30 37.5–75 moderate Lumbar epidural block [see Dosage and Administration (2.3)] 0.75% (7.5 mg/mL) For single-dose use; not for intermittent epidural technique. Not for obstetrical anesthesia. 10–20 75–150 complete 0.5% (5 mg/mL) 10–20 50–100 moderate to complete 0.25% (2.5 mg/mL) 10–20 25–50 partial to moderate Epidural test dose [see Dosage and Administration (2.4)] 0.5% (5 mg/mL) with epinephrine 2–3 10–15 (10–15 micrograms epinephrine) ― Dental [see Dosage and Administration (2.5)] 0.5% (5 mg/mL) with epinephrine 1.8–3.6 per site 9–18 per site ― 2.3 Use in Epidural Anesthesia
During the administration of epidural anesthesia, it is recommended that a test dose of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given. When using a "continuous" catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura [see Dosage and Administration (2.4)] .
During epidural administration, administer Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, 0.5% (5 mg/mL) and Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. In obstetrics, use ONLY the 0.5% (5 mg/mL) and 0.25% (2.5 mg/mL) concentrations of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection [see Warnings and Precautions (5.1)]; incremental doses of 3 mL to 5 mL of the 0.5% (5 mg/mL) solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by a test dose containing epinephrine if not clinically contraindicated. Use only the single-dose vials for caudal or epidural anesthesia; avoid use of the multiple-dose vials for these procedures, which contain a preservative [see Dosage and Administration (2.1, 2.4), Warnings and Precautions (5.4, 5.9)] .
2.4 Test Dose for Caudal and Lumbar Epidural Blocks
Three mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. This test dose may serve as a warning of unintended intravascular or intrathecal injection. Closely monitor for early clinical signs of toxicity following each test dose [see Warnings and Precautions (5.9)] . Allot adequate time for onset of spinal block to detect possible intrathecal injection. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal, or cardiovascular effects from the epinephrine [see Warnings and Precautions (5.2, 5.9), Overdosage (10)].
2.5 Use in Dentistry
Bupivacaine Hydrochloride and Epinephrine Injection 0.5% (5 mg/mL) is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthesia is desired, such as for procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after allowing 2 to 10 minutes for block onset [see Clinical Pharmacology (12.2)]. Use the lowest effective dose and allow time between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, not exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% (5 mg/mL) Bupivacaine Hydrochloride and Epinephrine Injection). Inject slowly and with frequent aspirations.
2.6 Use in Ophthalmic Surgery
When Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery [see Warnings and Precautions (5.15)] .
3 Dosage Forms And Strengths
Bupivacaine Hydrochloride Injection, USP is a clear, colorless solution available as:
- 0.25% (25 mg/10 mL) (2.5 mg/mL) in single-dose teartop vials.
- 0.25% (75 mg/30 mL) (2.5 mg/mL) in single-dose teartop vials.
- 0.25% (125 mg/50 mL) (2.5 mg/mL) in multiple-dose fliptop vials.
- 0.5% (50 mg/10 mL) (5 mg/mL) in single-dose teartop vials.
- 0.5% (150 mg/30 mL) (5 mg/mL) in single-dose teartop vials.
- 0.5% (250 mg/50 mL) (5 mg/mL) in multiple-dose fliptop vials.
- 0.75% (75 mg/10 mL) (7.5 mg/mL) in single-dose teartop vials.
- 0.75% (225 mg/30 mL) (7.5 mg/mL) in single-dose teartop vials.
Bupivacaine Hydrochloride Injection, USP are available in multiple concentrations. See full prescribing information for detailed description of each formulation. (3 )
4 Contraindications
Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated in:
- obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death.
- intravenous regional anesthesia (Bier Block) [see Warnings and Precautions (5.7)].
- patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.
- Obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. (
4 )- Intravenous regional anesthesia (Bier Block). (
4 )- Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. (
4 )
5 Warnings And Precautions
- Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient's state of consciousness after injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. (
5.2 )- Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. See full prescribing information for more detail on managing these risks. (
5.3 )- Chondrolysis with Intra-Articular Infusion: Intra-articular infusions of local anesthetics including Bupivacaine Hydrochloride Injection following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. (
5.5 )- Risk of Cardiac Arrest with Intravenous Regional Anesthesia Use (Bier Block): There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). (
5.7 )- Allergic-Type Reactions to Sulfites in Bupivacaine Hydrochloride and Epinephrine Injection: Bupivacaine Hydrochloride and Epinephrine Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. (
5.8 )- Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection: Unintended intravascular or intrathecal injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Aspirate for blood or cerebrospinal fluid (where applicable) prior to each dose and consider using a test dose of Bupivacaine Hydrochloride and Epinephrine Injection. (
5.9 )5.1 Risk of Cardiac Arrest with Use of Bupivacaine Hydrochloride Injection in Obstetrical Anesthesia
There have been reports of cardiac arrest with difficult resuscitation or death during use of Bupivacaine Hydrochloride Injection for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of Bupivacaine Hydrochloride Injection is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary.
5.2 Dose-Related Toxicity
The safety and effectiveness of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection solutions.
Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.
During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. Use the lowest dosage of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of Bupivacaine. Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection solution and administer fractional (incremental) doses when feasible.
Injection of repeated doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status.
5.3 Methemoglobinemia
Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition [see Drug Interactions (7.5)] . If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.
Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
5.4 Antimicrobial Preservatives in Multiple-Dose Vials
Avoid use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose vials, for epidural or caudal anesthesia because safety has not been established with such use.
5.5 Chondrolysis with Intra-Articular Infusion
Intra-articular infusions of local anesthetics including Bupivacaine Hydrochloride Injection following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are associated with chondrolysis. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2 ndmonth after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.
5.6 Risk of Adverse Reactions Due to Drug Interactions with Bupivacaine Hydrochloride and Epinephrine Injection
Risk of Severe, Persistent Hypertension Due to Drug Interactions Between Bupivacaine Hydrochloride and Epinephrine Injection and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
Administration of Bupivacaine Hydrochloride and Epinephrine Injection (containing a vasoconstrictor) in patients receiving monoamine oxidase inhibitors (MAOI), or tricyclic antidepressants may result in severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's hemodynamic status is essential [see Drug Interactions (7.2)].
Risk of Severe, Persistent Hypertension or Cerebrovascular Accidents Due to Drug Interactions Between Bupivacaine Hydrochloride and Epinephrine Injection and Ergot-Type Oxytocic Drugs
Concurrent administration of Bupivacaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Bupivacaine Hydrochloride and Epinephrine Injection concomitantly with ergot-type oxytocic drugs [see Drug Interactions (7.3)] .
Risk of Hypertension and Bradycardia Due to Drug Interactions Between Bupivacaine Hydrochloride and Epinephrine Injection and Nonselective Beta-Adrenergic Antagonists
Administration of Bupivacaine Hydrochloride and Epinephrine Injection (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's blood pressure and heart rate is essential [see Drug Interactions (7.4)] .
5.7 Risk of Cardiac Arrest with Intravenous Regional Anesthesia Use (Bier Block)
There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of Bupivacaine Hydrochloride Injection in this procedure is lacking. Therefore, Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated for use with this technique [see Contraindications (4)] .
5.8 Allergic-Type Reactions to Sulfites in Bupivacaine Hydrochloride and Epinephrine Injection
Bupivacaine Hydrochloride and Epinephrine Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Bupivacaine Hydrochloride Injection without epinephrine does not contain sodium metabisulfite.
5.9 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection
Unintended intravascular or intrathecal injection of. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in underventilation or apnea ("Total or High Spinal"). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia [see Adverse Reactions (6)] .
Aspirate for blood or cerebrospinal fluid (where applicable) before injecting Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection.
Use of Test Dose with Epidural Anesthesia
To serve as a warning of unintended intravascular or intrathecal injection, 3 mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see Dosage and Administration (2.4)] . Three mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) contains 15 mg bupivacaine and 15 mcg epinephrine. An intravascular or intrathecal injection is still possible even if results of the test dose are negative.
Signs/symptoms of unintended intravascular or intrathecal injection of the test dose of Bupivacaine Hydrochloride and Epinephrine Injection and monitoring recommendations are described below.
- Unintended intravascularinjection: Likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for increases. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure.
- Unintended intrathecalinjection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk).
The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see Overdosage (10)] .
5.10 Risk of Toxicity in Patients with Hepatic Impairment
Because amide local anesthetics such as bupivacaine are metabolized by the liver, consider reduced dosing and increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see Use in Specific Populations (8.6)].
5.11 Risk of Use in Patients with Impaired Cardiovascular Function
Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection should be given in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, heartblock) because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. Monitor patients closely for blood pressure, heart rate, and ECG changes.
5.12 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply
Use Bupivacaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.
5.13 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation Anesthetics
Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Drug Interactions (7.6)] . In deciding whether to concurrently use Bupivacaine Hydrochloride and Epinephrine Injection with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account.
5.14 Risk of Adverse Reactions with Use in Head and Neck Area
Small doses of local anesthetics (e.g., Bupivacaine Hydrochloride Injection) injected into the head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Monitor circulation and respiration and constantly observe patients receiving Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2)].
5.15 Risk of Respiratory Arrest with Use in Ophthalmic Surgery
Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block (e.g., with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection), as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available [see Warnings and Precautions (5.14)]. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses.
A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva [see Indications and Usage (1)].
5.16 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental Applications
Because of the long duration of anesthesia, when Bupivacaine Hydrochloride and Epinephrine Injection [0.5% (5 mg/mL) of bupivacaine] is used for dental injections, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see Patient Counseling Information (17)] .
6 Adverse Reactions
The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling:
- Cardiac Arrest in Obstetrical Anesthesia [see Warnings and Precautions (5.1)]
- Dose-Related Toxicity [see Warnings and Precautions (5.2)]
- Methemoglobinemia [see Warnings and Precautions (5.3)]
- Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions (5.5)]
- Severe, Persistent Hypertension, Cerebrovascular Accidents, and Bradycardia Due to Drug Interactions [see Warnings and Precautions (5.6)]
- Cardiac Arrest with Intravenous Regional Anesthesia Use [see Contraindications (4), Warnings and Precautions (5.7)]
- Allergic-Type Reactions [see Warnings and Precautions (5.8)]
- Systemic Toxicities with Unintended Intravascular or Intrathecal Injection [see Warnings and Precautions (5.9)]
- Respiratory Arrest Following Retrobulbar Block [see Warnings and Precautions (5.15)]
The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine or bupivacaine and epinephrine. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions to Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation.
The most commonly encountered acute adverse reactions that demand immediate counter-measures were related to the CNS and the cardiovascular system. These adverse reactions were generally dose-related and due to high plasma levels which may have resulted from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional intrathecal injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) has resulted in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia have occurred. This has led to secondary cardiac arrest when untreated.
Most common adverse reactions are related to the central nervous system and the cardiovascular system. (6 )
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Nervous System Disorders
Adverse reactions were characterized by excitation and/or depression of the central nervous system and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction.
In the practice of caudal or lumbar epidural block, unintentional penetration of the subarachnoid space by the catheter or needle has occurred. Subsequent adverse effects may have depended partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia.
Neurologic effects following epidural or caudal anesthesia have included spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control, all of which had slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid.
Neurologic effects following other procedures or routes of administration have included persistent anesthesia, paresthesia, weakness, paralysis, all with slow, incomplete, or no recovery.
Convulsions: Incidence varied with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient.
Cardiac Disorders
High doses or unintentional intravascular injection have led to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest [see Warnings and Precautions (5.9)].
Immune System Disorders
Allergic-type reactions have occurred as a result of sensitivity to bupivacaine or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions were characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and severe hypotension. Cross sensitivity among members of the amide-type local anesthetic group has been reported [see Warnings and Precautions (5.8)] .
7 Drug Interactions
- Local Anesthetics: The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. (
7.1 )- Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: Administration of Bupivacaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. (
5.6 ,7.2 )- Ergot-Type Oxytocic Drugs: Concurrent administration of Bupivacaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. (
5.6 ,7.3 )- Nonselective Beta-Adrenergic Antagonists: Administration of Bupivacaine Hydrochloride and Epinephrine Injection (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. (
5.6 ,7.4 )- Drugs Associated with Methemoglobinemia: Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs. (
7.5 )- Potent Inhalation Anesthetics: Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics. (
5.13 ,7.6 )7.1 Local Anesthetics
The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1), Warnings and Precautions (5.2)] .
7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
The administration Bupivacaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors, or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's hemodynamic status is essential [see Warnings and Precautions (5.6)] .
7.3 Ergot-Type Oxytocic Drugs
Concurrent administration of Bupivacaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Bupivacaine Hydrochloride and Epinephrine concomitantly with ergot-type oxytocic drugs [see Warnings and Precautions (5.6)].
7.4 Nonselective Beta-Adrenergic Antagonists
Administration of Bupivacaine Hydrochloride and Epinephrine Injection (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's blood pressure and heart rate is essential [see Warnings and Precautions (5.6)].
7.5 Drugs Associated with Methemoglobinemia
Patients who are administered Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection are at increased risk of developing methemoglobinemia when concurrently exposed to following drugs, which could include other local anesthetics [see Warnings and Precautions (5.3)] .
Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics
Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13)] .
7.7 Phenothiazines and Butyrophenones
Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of Bupivacaine Hydrochloride and Epinephrine Injection and these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.
8 Use In Specific Populations
- Pediatric Use: Administration of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pediatric patients younger than 12 years is not recommended. (
8.4 )- Geriatric Use: Patients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. (
8.5 )- Moderate to Severe Hepatic Impairment: Consider increased monitoring for bupivacaine systemic toxicity. (
8.6 )8.1 Pregnancy
Risk Summary
Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated for obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death [see Contraindications (4), Warnings and Precautions (5.1)].
There are no available data on use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes.
In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses. Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risks to a fetus (see Data).
Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity [see Clinical Pharmacology (12.3)]. The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the CNS, peripheral vascular tone, and cardiac function.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations
Maternal Adverse Reactions
Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient's legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable.
Labor or Delivery
Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient's reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance.
The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine.
It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.
Data
Animal Data
Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses.
Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are comparable to the daily MRHD of 400 mg/day on a mg/m 2BSA basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 0.3 times the MRHD on a BSA basis.
In a rat pre-and post-natal developmental study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis.
8.2 Lactation
Risk Summary
Lactation studies have not been conducted with bupivacaine. Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection should be administered to lactating women only if clearly indicated. Studies assessing the effects of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in breastfed children have not been performed. Studies to assess the effect of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection on milk production or excretion have not been performed. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for bupivacaine and any potential adverse effects on the breastfed child from bupivacaine or from the underlying maternal condition.
8.4 Pediatric Use
Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is approved for use in adults. Administration of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pediatric patients younger than 12 years is not recommended.
Continuous infusions of bupivacaine in pediatric patients have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities.
8.5 Geriatric Use
Patients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.
In clinical studies of bupivacaine, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger adult patients.
Differences in various pharmacokinetic parameters have been observed between elderly and younger adult patients [see Clinical Pharmacology (12.3)].
This product is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients may require lower doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.
8.6 Hepatic Impairment
Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see Warnings and Precautions (5.10)] .
8.7 Renal Impairment
Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. This should be considered when selecting the Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection dosage [see Use in Specific Populations (8.5)] .
10 Overdosage
Clinical Presentation
Acute emergencies from use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection are generally related to high plasma levels encountered during therapeutic use or to unintended intrathecal injection [see Warnings and Precautions (5.2, 5.9), Adverse Reactions (6)].
If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of bupivacaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Hypoventilation or apnea due to unintentional intrathecal injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts.
Management
The first step in the management of systemic toxic reactions, as well as hypoventilation or apnea due to unintentional intrathecal injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, consists of immediateattention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated.
If necessary, use drugs to manage the convulsions. A bolus intravenous dose of a benzodiazepine will counteract CNS stimulation related to Bupivacaine Hydrochloride Injection. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advance Cardiac Life Support measures.
11 Description
Bupivacaine Hydrochloride Injection contains bupivacaine hydrochloride, an amide local anesthetic, as the active pharmaceutical ingredient. The route of administration for Bupivacaine Hydrochloride Injection (without epinephrine) is by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use. Multiple-dose vials contain methylparaben [see Warnings and Precautions (5.4)] .
Bupivacaine hydrochloride is 2-piperidinecarboxamide, 1-butyl- N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate. It is a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula:
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Bupivacaine Hydrochloride Injection, USP is a clear and colorless sterile isotonic solution. Each mL of single-dose vial contains 2.5 mg, 5 mg, or 7.5 mg of bupivacaine hydrochloride (equivalent to 2.22 mg, 4.44 mg, or 6.66 mg of bupivacaine, respectively), sodium chloride for isotonicity, sodium hydroxide or hydrochloric acid to adjust the pH between 4 and 6.5, in water for injection.
For the multiple-dose vials, each mL also contains 1 mg methylparaben as preservative.
12 Clinical Pharmacology
12.1 Mechanism of Action
Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.
Epinephrine is a vasoconstrictor added to bupivacaine to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration.
12.2 Pharmacodynamics
Systemic absorption of bupivacaine produces effects on the cardiovascular system and CNS. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. These cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine [see Warnings and Precautions (5.9)] .
Following systemic absorption, bupivacaine can produce CNS stimulation, CNS depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by CNS depression and coma progressing ultimately to respiratory arrest. However, bupivacaine has a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state.
The duration of local anesthesia after administration of Bupivacaine Hydrochloride Injection is longer than that observed after administration of other commonly used short-acting local anesthetics. There appears to be period of analgesia that persists after the resolution of the block and return of sensation.
The onset of action following dental injections is usually 2 to 10 minutes and may last up to 7 hours. The duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000.
12.3 Pharmacokinetics
Systemic plasma levels of bupivacaine following administration of Bupivacaine Hydrochloride Injection do not correlate with local efficacy.
Absorption
The rate of systemic absorption of bupivacaine is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000) usually reduces the rate of absorption and peak plasma concentration of bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action [see Dosage and Administration (2)] .
After injection of Bupivacaine Hydrochloride Injection for caudal, epidural, or peripheral nerve block, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours.
Distribution
Bupivacaine appears to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of bupivacaine appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.
Depending upon the route of administration, bupivacaine is distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
Pharmacokinetic studies on the plasma profile of bupivacaine after direct intravenous injection (Bupivacaine Hydrochloride Injection is not approved for intravenous use) suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat.
Elimination
The half-life of bupivacaine in adults is 2.7 hours.
Metabolism
Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecoloxylidine is the major metabolite of bupivacaine. The elimination of drug from tissue distribution depends largely upon the availability of binding sites in the circulation to carry it to the liver where it is metabolized.
Excretion
The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine.
Specific Populations
Geriatric Patients
Elderly patients exhibited higher peak plasma concentrations than younger patients following administration of Bupivacaine Hydrochloride Injection. The total plasma clearance was decreased in these patients [see Use in Specific Populations (8.5)] .
Patients with Hepatic Impairment
Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics [see Use in Specific Populations (8.6)] .
Patients with Renal Impairment
Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow [see Use in Specific Populations (8.5, 8.7)] .
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted.
Mutagenesis
The mutagenic potential of bupivacaine hydrochloride has not been determined.
Impairment of Fertility
The effect of bupivacaine on fertility has not been determined.
16 How Supplied/storage And Handling
STORAGE AND HANDLING SECTION
Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F). [See USP Controlled Room Temperature.]
Bupivacaine Hydrochloride Injection, USP─ Solutions of bupivacaine hydrochloride that do not contain epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121 °C (250 °F) for 15 minutes. This product is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate.
Unit of Sale Concentration NDC 0409-1159-01 Tray of 25 single-dose teartop vials 0.25% 25 mg/10 mL (2.5 mg/mL) NDC 0409-1159-02 Tray of 25 single-dose teartop vials 0.25% 75 mg/30 mL (2.5 mg/mL) NDC 0409-1160-01 Tray of 25 multiple-dose fliptop vials 0.25% 125 mg/50 mL (2.5 mg/mL) NDC 0409-1163-01 Tray of 25 multiple-dose fliptop vials 0.5% 250 mg/50 mL (5 mg/mL) NDC 0409-1162-01 Tray of 25 single-dose teartop vials 0.5% 50 mg/10 mL (5 mg/mL) NDC 0409-1162-02 Tray of 25 single-dose teartop vials 0.5% 150 mg/30 mL (5 mg/mL) NDC 0409-1165-01 Tray of 25 single-dose teartop vials 0.75% 75 mg/10 mL (7.5 mg/mL) NDC 0409-1165-02 Tray of 25 single-dose teartop vials 0.75% 225 mg/30 mL (7.5 mg/mL)
For single-dose vials: Discard unused portion.
17 Patient Counseling Information
Allergic-Type Reactions
Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see Contraindications (4), Warnings and Precautions (5.8), Adverse Reactions (6)].
Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia
When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia.
Instructions After Dental Injection of Bupivacaine Hydrochloride Injection
Advise patients receiving dental injections of Bupivacaine Hydrochloride Injection not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see Warnings and Precautions (5.16)].
Methemoglobinemia
Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.3)].
This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.
Distributed by Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1176-5.0
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FULL PRESCRIBING INFORMATION
Warning: Risks With Inadvertent Intrathecal Administration Omnipaque Injection, 140 And 350 Mg Iodine/ml
Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema [see Contraindications (4)and Warnings and Precautions (5.1)].
1 Indications And Usage
1.1 Intrathecal Administration
Adults
OMNIPAQUE 180, 240, and 300
- Myelography (lumbar, thoracic, cervical, total columnar)
- Computerized Tomography (CT) (myelography, cisternography, ventriculography)
Pediatrics
OMNIPAQUE 180
- Myelography (lumbar, thoracic, cervical, total columnar)
- CT (myelography, cisternography)
1.2 Intravascular Administration
Adults
OMNIPAQUE 140
- Intra-arterial digital subtraction angiography of the head, neck, abdominal, renal and peripheral vessels
OMNIPAQUE 240
- CT head imaging
- Peripheral venography (phlebography)
OMNIPAQUE 300
- Aortography including studies of the aortic arch, abdominal aorta and its branches
- CT head and body imaging
- Cerebral arteriography
- Peripheral venography (phlebography)
- Peripheral arteriography
- Excretory urography
OMNIPAQUE 350
- Angiocardiography (ventriculography, selective coronary arteriography)
- Aortography including studies of the aortic root, aortic arch, ascending aorta, abdominal aorta and its branches
- CT head and body imaging
- Intravenous digital subtraction angiography of the head, neck, abdominal, renal and peripheral vessels
- Peripheral arteriography
- Excretory urography
Pediatrics
OMNIPAQUE 240
- CT head and body imaging
OMNIPAQUE 300
- Angiocardiography (ventriculography)
- Excretory urography
- CT head and body imaging
OMNIPAQUE 350
- Angiocardiography (ventriculography, pulmonary arteriography, venography, and studies of the collateral arteries)
- Aortography including the aortic root, aortic arch, ascending and descending aorta
1.3 Oral or Rectal Administration
Adults
OMNIPAQUE 350
- Oral radiographic examination of the gastrointestinal tract
Pediatrics
OMNIPAQUE 180, 240 and 300
- Oral and rectal radiographic examination of the gastrointestinal tract
1.4 Oral Administration in Conjunction with Intravenous Administration
Diluted OMNIPAQUE Injection
Adults
OMNIPAQUE 240, 300 and 350 diluted and administered orally in conjunction with OMNIPAQUE 300 administered intravenously
- CT of the abdomen
Pediatrics
OMNIPAQUE 240, 300 and 350 diluted and administered orally in conjunction with OMNIPAQUE 240 or OMNIPAQUE 300 administered intravenously
- CT of the abdomen
OMNIPAQUE Oral Solution
Adults
OMNIPAQUE oral solution 9 and 12 administered orally in conjunction with OMNIPAQUE 300 administered intravenously
- CT of the abdomen
Pediatrics
OMNIPAQUE oral solution 9 and 12 administered orally in conjunction with OMNIPAQUE 240 or OMNIPAQUE 300 administered intravenously
- CT of the abdomen
1.5 Intraarticular Administration
Adults
OMNIPAQUE 240, 300, and 350
- Arthrography
1.6 Body Cavity Administration
Adults
OMNIPAQUE 240
- Endoscopic retrograde pancreatography (ERP) and cholangiopancreatography (ERCP)
- Herniography
- Hysterosalpingography
OMNIPAQUE 300
- Hysterosalpingography
Pediatrics
OMNIPAQUE 240, 300 and 350 diluted
- Voiding cystourethrography (VCU)
2 Dosage And Administration
2.1 Important Dosage and Administration Instructions
- OMNIPAQUE 140, 180, 240, 300 and 350 are indicated for intravascular, oral, rectal, intraarticular, and body cavity administration. OMNIPAQUE 180, 240, and 300 are indicated for intrathecal administration [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].
- Use sterile technique for all handling and administration of OMNIPAQUE for intravascular, intrathecal, intraarticular, and body cavity administration.
- OMNIPAQUE oral solution 9 and 12 are indicated for oral use only [see Contraindications (4) and Warnings and Precautions (5.2)].
- Do not use if tamper-evident ring is broken or missing.
- OMNIPAQUE injection may be administered at either body (37°C, 98.6°F) or room temperature (20° to 25°C, 68° to 77°F).
- Inspect OMNIPAQUE injection for particulate matter or discoloration before administration, whenever solution and container permit. Do not administer if OMNIPAQUE injection contains particulate matter or is discolored.
- Do not mix OMNIPAQUE injection with, or inject in intravenous lines containing, other drugs or total nutritional admixtures.
- Use the lowest dose necessary to obtain adequate visualization.
- Individualize the volume, strength, and rate of administration of OMNIPAQUE injection. Consider factors such as age, body weight, vessel size, blood flow rate within the vessel, anticipated pathology, degree and extent of opacification required, structures or area to be examined, disease processes affecting the patient, and equipment and technique to be employed.
- Avoid extravasation when administering OMNIPAQUE injection intravascularly, especially in patients with severe arterial or venous disease [see Warnings and Precautions (5.6)] .
- Hydrate patients before and after intravascular administration of OMNIPAQUE injection [see Warnings and Precautions (5.4) ].
- Each bottle of OMNIPAQUE injection and oral solution is intended for one procedure only. Discard any unused portion.
2.2 Intrathecal Dosage and Administration
- Rate of injection: Injection should be made slowly over 1 to 2 minutes
- Repeat procedures: If sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body; at least 48 hours should be allowed before repeat examination; however, whenever possible, 5 days to 7 days is recommended.
- If computerized tomographic (CT) myelography follows myelography, delay imaging several hours to allow the degree of contrast to decrease.
TABLE 1 - INTRATHECAL ADULTS The usual recommended total doses for use in lumbar, thoracic, cervical, and total columnar myelography in adults are 1,200 mg iodine to 3,100 mg iodine (see below). STUDY TYPE INJECTION TYPE CONCENTRATION (mg iodine/mL) VOLUME (mL) * A total dose of 3,100 mg iodine or a concentration of 300 mg iodine/mL should not be exceeded in adults. LUMBAR MYELOGRAPHY LUMBAR OMNIPAQUE 180 OMNIPAQUE 240 10 to 17 7 to 12.5 THORACIC MYELOGRAPHY LUMBAR CERVICAL OMNIPAQUE 240 OMNIPAQUE 300 6 to 12.5 6 to 10 CERVICAL MYELOGRAPHY LUMBAR OMNIPAQUE 240 OMNIPAQUE 300 6 to 12.5 6 to 10 CERVICAL MYELOGRAPHY C1-2 OMNIPAQUE 180 OMNIPAQUE 240 OMNIPAQUE 300 7 to 10 6 to 12.5 4 to 10 TOTAL COLUMNAR MYELOGRAPHY LUMBAR OMNIPAQUE 240 OMNIPAQUE 300 6 to 12.5 6 to 10
TABLE 2 – INTRATHECAL PEDIATRICS The usual recommended total doses for lumbar, thoracic, cervical, and/or total columnar myelography by lumbar puncture in children are 360 mg iodine to 2700 mg iodine (see below). Actual volumes administered depend largely on patient age and the following guidelines are recommended. AGE STUDY TYPE INJECTION TYPE CONCENTRATION (mg iodine/mL) VOLUME (mL) *A total dose of 2,700 mg iodine or a concentration of 180 mg iodine/mL should not be exceeded in a single myelographic examination in pediatrics. 0 up to 3 mos. LUMBAR, THORACIC, CERVICAL AND/OR TOTAL COLUMNAR MYELOGRAPHY LUMBAR PUNCTURE OMNIPAQUE 180 2 to 4 3 up to 36 mos. OMNIPAQUE 180 4 to 8 3 up to 7 yrs. OMNIPAQUE 180 5 to 10 7 up to 13 yrs. OMNIPAQUE 180 5 to 12 13 to 18 yrs. OMNIPAQUE 180 6 to 15 2.3 Intravascular Dosage and Administration
Intra-arterial Procedures
TABLE 3 ANGIOCARDIOGRAPHIC PROCEDURES PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 350 VENTRICULOGRAPHY SELECTIVE CORONARY ARTERIOGRAPHY
- The recommended single dose is 40 mL (Range of 30 mL to 60 mL)
- May be combined with selective coronary arteriography
Doses may be repeated as necessary. Maximum volume with multiple injections should not exceed 250 mL.
- The recommended single dose is 5 mL (Range of 3 mL to 14 mL)
Pediatrics OMNIPAQUE 300 VENTRICULOGRAPHY The recommended single dose is 1.75 mL/kg (Range of 1.5 mL/kg to 2 mL/kg) Maximum dose with multiple injections should not exceed 6 mL/kg up to a total volume of 291 mL.
- May be repeated as necessary
OMNIPAQUE 350 VENTRICULOGRAPHY Recommended single dose is 1.25 mL/kg (Range of 1 mL/kg to 1.5 mL/kg). Maximum dose with multiple injections should not exceed 5 mL/kg up to a total volume of 250 mL. PULMONARY ANGIOGRAPHY (PULMONARY ARTERIOGRAPHY AND/OR PULMONARY VENOGRAPHY) The recommended single dose is 1 mL/kg.
- May be repeated as necessary
TABLE 4 AORTOGRAPHY PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 300 and 350 AORTOGRAPHY AND SELECTIVE VISCERAL ARTERIOGRAPHY The recommended single dose is: Injections may be repeated if indicated, but the total volume should not exceed:
- 50 mL to 80 mL for the aorta (aortic arch, ascending aorta)
- 30 mL to 60 mL for abdominal aorta and its branches (celiac, mesenteric, hepatic and splenic arteries)
- 5 mL to 15 mL for renal arteries
- 290 mL of OMNIPAQUE 300
- 250 mL of OMNIPAQUE 350
OMNIPAQUE 350 AORTIC ROOT AND ARCH STUDY WHEN USED ALONE The recommended single dose is 50 mL (Range of 20 mL to 75 mL) Pediatrics OMNIPAQUE 350 AORTOGRAPHY (AORTIC ROOT, AORTIC ARCH, AND DESCENDING AORTA) The recommended single dose is 1 mL/kg. Maximum dose should not exceed 5 mL/kg up to a total volume of 250 mL.
- May be repeated as necessary
TABLE 5 CEREBRAL ARTERIOGRAPHY PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 300 Single dose for cerebral arteriography is as follows:
- Common carotid artery (6 mL to 12 mL)
- Internal carotid artery (8 mL to 10 mL)
- External carotid artery (6 mL to 9 mL)
- Vertebral artery (6 mL to 10 mL)
TABLE 6 INTRA-ARTERIAL DIGITAL SUBTRACTION ANGIOGRAPHY HEAD, NECK, ABDOMINAL, RENAL AND PERIPHERAL VESSELS PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Mechanical or hand injection can be used to administer one or more bolus intra-arterial injections of OMNIPAQUE 140. Adults OMNIPAQUE 140 ARTERIES VOLUME/INJECTION (mL) RATE OF INJECTION (mL/sec) Aorta 20 to 45 8 to 20 Carotid 5 to 10 3 to 6 Femoral 9 to 20 3 to 6 Vertebral 4 to 10 2 to 8 Renal 6 to 12 3 to 6 Other branches of aorta (includes subclavian, axillary, innominate and iliac) 8 to 25 3 to 10
TABLE 7 PERIPHERAL ARTERIOGRAPHY PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 300 and 350 The recommended dose for use in peripheral angiography is as follows: Aortofemoral runoffs: Selective arteriograms:
- 30 mL to 90 mL of OMNIPAQUE 300
- 20 mL to 70 mL of OMNIPAQUE 350
- 10 mL to 60 mL of OMNIPAQUE 300
- 10 mL to 30 mL of OMNIPAQUE 350
Intravenous Procedures
TABLE 8 PERIPHERAL VENOGRAPHY (PHLEBOGRAPHY) PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 240 and 300 The recommended dose (per leg) is:
- 20 mL to 150 mL of OMNIPAQUE 240
- 40 mL to 100 mL of OMNIPAQUE 300
TABLE 9 EXCRETORY UROGRAPHY PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 300 and 350 The recommended dose is:
- 0.6 mL/kg to 1.2 mL/kg body weight
Pediatrics OMNIPAQUE 300 Dose ranging from 0.5 mL/kg to 3 mL/kg of body weight:
- The usual dose for children is 1 mL/kg to 1.5 mL/kg.
- The total administered dose should not exceed 3 mL/kg.
TABLE 10 DIGITAL SUBTRACTION ANGIOGRAPHY HEAD, NECK, ABDOMINAL, RENAL AND PERIPHERAL VESSELS PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) RATE OF INJECTION (mL/sec) Adults OMNIPAQUE 350 The usual dose for the intravenous digital technique is 30 mL to 50 mL. Frequently three or more doses may be required, up to a total volume not to exceed 250 mL 7.5 mL/second to 30 mL/second using a pressure injector
TABLE 11 CT SCANNING OF THE HEAD AND BODY PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME OMNIPAQUE may be used with an automated contrast injection system or contrast management system cleared for use with OMNIPAQUE [see Dosage and Administration (2.8)]. See device labeling for device indications, additional information, and instructions for use. (mL)Adults OMNIPAQUE 240, 300 and 350 Head and body imaging by rapid injection CT Imaging – Head: CT Imaging – Body:
- 70 mL to 150 mL of OMNIPAQUE 300
- 80 mL of OMNIPAQUE 350
Head imaging by infusion CT Imaging – Head:
- 50 mL to 200 mL of OMNIPAQUE 300
- 60 mL to 100 mL of OMNIPAQUE 350
- 120 mL to 250 mL of OMNIPAQUE 240
Pediatrics OMNIPAQUE 240 and 300 CT Imaging – Head and Body:
- 1 mL/kg to 2 mL/kg (with maximum = 3 mL/kg)
- Maximum single dose = 116 mL
2.4 Oral or Rectal Dosage and Administration
Oral and Rectal Administration – Undiluted OMNIPAQUE Injection for Radiographic Examination of the Gastrointestinal (GI) Tract
TABLE 12 DOSING FOR RADIOGRAPHIC EXAMINATION OF THE GI TRACT PATIENT POPULATION CONCENTRATION (mg iodine/mL) ORAL VOLUME (mL) RECTAL VOLUME When given rectally, larger volumes may be used. (mL)Adults OMNIPAQUE 350 The recommended dose is 50 mL to 100 mL - Pediatrics OMNIPAQUE 180, 240 and 300 The recommended dose is 5 mL to 100 mL The recommended dose is 5 mL to 100 mL Less than 3 months old OMNIPAQUE 180 5 mL to 30 mL - Three months to 3 years OMNIPAQUE 180, 240 and 300 Up to 60 mL - Four years to 10 years OMNIPAQUE 180, 240 and 300 Up to 80 mL - Greater than 10 years Up to 100 mL - 2.5 Oral Dosage and Administration in Conjunction with Intravenous Administration
See Table 16for concurrent intravenous dosing.
Oral Administration of Diluted OMNIPAQUE Injection in Conjunction with Intravenous Administration of OMNIPAQUE Injection for CT of the Abdomen
TABLE 13 DOSING OF DILUTED Dilutions of OMNIPAQUE should be prepared just prior to use and any unused portion discarded after the procedure. OMNIPAQUE INJECTION FOR ORAL ADMINISTRATIONPATIENT POPULATION ORAL CONCENTRATION (mg iodine/mL) ORAL VOLUME (mL) ADMINISTRATION INSTRUCTIONS Adults OMNIPAQUE 240, 300 and 350 DILUTED to 6 to 12 mg iodine/mL (See Table 14below) Recommended oral dose is:
- 500 mL to 1,000 mL
Smaller administered volumes can be given if the iodine concentration in final diluted product is increased (See Table 14below) The oral dosage may be given all at once or over a period of up to 45 minutes if there is difficulty in consuming the required volume. Pediatrics OMNIPAQUE 240, 300 and 350 DILUTED to 9 to 21 mg iodine/mL (See Table 14below) Recommended oral dose is: Do not exceed an oral dose of 5 grams iodine for patients less than 3 years old. Do not exceed an oral dose of 10 grams iodine for patients 3 to 18 years old.
- 180 mL to 750 mL
Smaller administered volumes can be given if the iodine concentration in final diluted product is increased (See Table 14below) The oral dosage may be given all at once or over a period of up to 45 minutes if there is difficulty in consuming the required volume.
TABLE 14 PROCEDURE FOR PREPARATION OF DILUTED OMNIPAQUE INJECTION FOR ORAL ADMINISTRATION OMNIPAQUE to be mixed with liquid such as water, carbonated beverage, milk, infant formula, or juice to achieve one liter of oral contrast agent. Final Iodine Concentration of Diluted Contrast Agent (mg iodine/mL) OMNIPAQUE 240 OMNIPAQUE 300 OMNIPAQUE 350 Volume of Contrast Agent (mL) Volume of Liquid (mL) Volume of Contrast Agent (mL) Volume of Liquid (mL) Volume of Contrast Agent (mL) Volume of Liquid (mL) 6 25 975 20 980 17 983 9 38 962 30 970 26 974 12 50 950 40 960 35 965 15 63 937 50 950 43 957 18 75 925 60 940 52 948 21 88 912 70 930 60 940
Oral Administration of OMNIPAQUE Oral Solution in Conjunction with Intravenous Administration of OMNIPAQUE Injection for CT of the Abdomen
TABLE 15 DOSING AND ADMINISTRATION OF OMNIPAQUE ORAL SOLUTION PATIENT POPULATION ORAL CONCENTRATION (mg iodine/mL) ORAL VOLUME (mL) ADMINISTRATION INSTRUCTIONS Adults OMNIPAQUE oral solution 9 and 12 The recommended oral dose is:
- 500 mL to 1,000 mL
The oral dosage may be given all at once or over a period of up to 45 minutes if there is difficulty in consuming the required volume. Pediatrics OMNIPAQUE oral solution 9 and 12 The recommended oral dose is: Do not exceed an oral dose of 5 grams iodine for patients less than 3 years old. Do not exceed an oral dose of 10 grams iodine for patients 3 to 18 years old.
- 180 mL to 750 mL
The oral dosage may be given all at once or over a period of up to 45 minutes if there is difficulty in consuming the required volume.
TABLE 16 INTRAVENOUS ADMINISTRATION OF OMNIPAQUE INJECTION FOR CT OF THE ABDOMEN IN CONJUNCTION WITH ORALLY ADMINISTERED DILUTED OMNIPAQUE INJECTION OR OMNIPAQUE ORAL SOLUTION PATIENT POPULATION INTRAVENOUS CONCENTRATION (mg iodine/mL) INTRAVENOUS VOLUME OMNIPAQUE may be used with an automated contrast injection system or contrast management system cleared for use with OMNIPAQUE [see Dosage and Administration (2.8)]. See device labeling for device indications, additional information, and instructions for use. (mL)ADMINISTRATION INSTRUCTIONS Adults OMNIPAQUE 300 The recommended dose is:
- 100 mL to 150 mL
Administer up to 40 minutes AFTER consumption of the oral dose Pediatrics OMNIPAQUE 240 and 300 The recommended dose is:
- 2 mL/kg with a range of 1 mL/kg to 2 mL/kg (maximum 3 mL/kg)
Administer up to 60 minutes AFTER consumption of the oral dose 2.6 Intraarticular Dosage and Administration
TABLE 17 ARTHROGRAPHY PATIENT POPULATION LOCATION CONCENTRATION (mg iodine/mL) VOLUME (mL) DOUBLE CONTRAST/SINGLE CONTRAST Adults Knee Passive or active manipulation is used to disperse the medium throughout the joint space. OMNIPAQUE 240 5 to 15 Lower volumes recommended for double-contrast examinations; higher volumes recommended for single-contrast examinations. OMNIPAQUE 300 5 to 15 OMNIPAQUE 350 5 to 10 Adults Shoulder OMNIPAQUE 240 3 OMNIPAQUE 300 10 Adults Temporomandibular OMNIPAQUE 300 0.5 to 1 2.7 Body Cavity Dosage and Administration
Body Cavity Administration - Undiluted OMNIPAQUE Injection
TABLE 18 ENDOSCOPIC RETROGRADE PANCREATOGRAPHY (ERP) ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY (ECRP) PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 240 10 mL to 50 mL but may vary depending on individual anatomy and/or disease state.
TABLE 19 HYSTEROSALPINGOGRAPHY PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 240 and 300 15 mL to 20 mL but may vary depending on individual anatomy and/or disease state.
TABLE 20 HERNIOGRAPHY PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Adults OMNIPAQUE 240 50 mL but may vary depending on individual anatomy and/or disease state.
Body Cavity Administration - Diluted OMNIPAQUE Injection
TABLE 21 VOIDING CYSTOURETHROGRAPHY (VCU) (CAN BE PERFORMED IN CONJUNCTION WITH EXCRETORY UROGRAPHY) PATIENT POPULATION CONCENTRATION (mg iodine/mL) VOLUME (mL) Pediatrics The concentration may vary depending upon the patient's size and age and with the technique and equipment used. OMNIPAQUE injection may be diluted with Sterile Water for Injection. (See Table 22below). OMNIPAQUE injection may be diluted, utilizing aseptic technique, with Sterile Water for Injection to a concentration of 50 mg iodine/mL to 100 mg iodine/mL for voiding cystourethrography. Range:
- 50 mL to 300 mL of DILUTED OMNIPAQUE at a concentration of 100 mg iodine/mL
- 50 mL to 600 mL of DILUTED OMNIPAQUE at a concentration of 50 mg iodine/mL.
TABLE 22 PROCEDURE FOR PREPARATION OF DILUTED Dilutions of OMNIPAQUE should be prepared just prior to use and any unused portion discarded after the procedure. OMNIPAQUE INJECTION FOR VCUFinal Iodine Concentration of Diluted Contrast Agent (mg iodine/mL) Volume of OMNIPAQUE 240 (mL) Volume of Sterile Water for Injection (mL) Volume of OMNIPAQUE 300 (mL) Volume of Sterile Water for Injection (mL) Volume of OMNIPAQUE 350 (mL) Volume of Sterile Water for Injection (mL) 100 100 140 100 200 100 250 90 167 233 289 80 200 275 338 70 243 330 400 60 300 400 483 50 380 500 600 2.8 Instructions for Use with an Automated Contrast Injection System or Contrast Management System for CT of the Head and Body
- OMNIPAQUE may be used with an automated contrast injection system cleared for use with contrast media.
- See above Important Dosage and Administration Instructions for OMNIPAQUE (2.1).
- See device labeling for information on device indications, instructions for use, and techniques to help assure safe use.
- OMNIPAQUE 300 mg iodine/mL and 350 mg iodine/mL in 150 mL bottles may be used with a contrast media management system cleared for use with OMNIPAQUE 300 mg iodine/mL and 350 mg iodine/mL in 150 mL bottles.
- See device labeling for information on device indications, instructions for use, and techniques to help assure safe use.
- Use sterile technique for penetrating the container closure of OMNIPAQUE 300 and 350 and transferring OMNIPAQUE solution. The container closure may be penetrated only one time with a suitable sterile component of the contrast media management system cleared for use with OMNIPAQUE 300 and 350 in 150 mL bottles.
- Once the OMNIPAQUE 300 and 350 Injection is punctured, do not remove the bottle from the work area during the entire period of use.
- Maximum use time is 4 hours after initial puncture.
- Each bottle is for one procedure only. Discard unused portion.
3 Dosage Forms And Strengths
OMNIPAQUE (iohexol) Injection and Oral Solution
Sterile, pyrogen-free, gluten-free, colorless to pale yellow solution containing the nonionic, water-soluble x-ray contrast medium iohexol, and available in the following strengths and formats:
OMNIPAQUE (iohexol) Injection
- 140 mg of organically bound iodine per mL (302 mg iohexol/mL)
- Available in + PLUSPAK™ (polymer bottle)
- 180 mg of organically bound iodine per mL (388 mg iohexol/mL)
- Available in glass vials
- 240 mg of organically bound iodine per mL (518 mg iohexol/mL)
- 300 mg of organically bound iodine per mL (647 mg iohexol/mL)
- 350 mg of organically bound iodine per mL (755 mg iohexol/mL)
- Available in glass vials and bottles and + PLUSPAK™ polymer bottles.
OMNIPAQUE Oral Solution
- 9 mg of organically bound iodine per mL (19 mg iohexol/mL)
- 12 mg of organically bound iodine per mL (26 mg iohexol/mL)
- Available in + PLUSPAK™ polymer bottles.
4 Contraindications
- OMNIPAQUE 140 and OMNIPAQUE 350 are contraindicated for intrathecal use [ see Warnings and Precautions (5.1)]
- OMNIPAQUE oral solution 9 and 12 are contraindicated for parenteral administration [ see Warnings and Precautions (5.2)]
- OMNIPAQUE body cavity 240 and 300 for hysterosalpingography is contraindicated during pregnancy or suspected pregnancy, menstruation or when menstruation is imminent, within 6 months after termination of pregnancy, within 30 days after conization or curettage, when signs of infection are present in any portion of the genital tract including the external genitalia, and when reproductive tract neoplasia is known or suspected because of the risk of peritoneal spread of neoplasm.
5 Warnings And Precautions
5.1 Risks Associated with Inadvertent Intrathecal Administration
OMNIPAQUE injection 140 and 350 are contraindicated for intrathecal use [see Contraindications (4)and Dosage and Administration (2.1)]. Inadvertent intrathecal administration can cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema.
5.2 Risks Associated with Inadvertent Parenteral Administration
OMNIPAQUE oral solution 9 and 12 are contraindicated for parenteral administration [ see Contraindications (4)and Dosage and Administration (2.1)]. Adverse reactions such as hemolysis may occur if administered intravascularly. Do not administer OMNIPAQUE oral solution 9 and 12 parenterally.
5.3 Hypersensitivity Reactions
OMNIPAQUE can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Most severe reactions develop shortly after the start of the injection (within 3 minutes), but reactions can occur up to hours later. There is an increased risk in patients with a history of a previous reaction to contrast agent, and known allergies (i.e., bronchial asthma, drug, or food allergies) or other hypersensitivities. Premedication with antihistamines or corticosteroids does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.
Obtain a history of allergy, hypersensitivity, or hypersensitivity reactions to iodinated contrast agents and always have emergency resuscitation equipment and trained personnel available prior to OMNIPAQUE administration. Monitor all patients for hypersensitivity reactions.
5.4 Contrast-Induced Acute Kidney Injury
Acute kidney injury, including renal failure, may occur after parenteral administration of OMNIPAQUE. Risk factors include: pre-existing renal impairment, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma/paraproteinaceous diseases, repetitive and/or large doses of an iodinated contrast agent.
Use the lowest necessary dose of OMNIPAQUE in patients with renal impairment. Adequately hydrate patients prior to and following parenteral administration of OMNIPAQUE. Do not use laxatives, diuretics, or preparatory dehydration prior to OMNIPAQUE administration.
5.5 Cardiovascular Adverse Reactions
Life-threatening or fatal cardiovascular reactions including hypotension, shock, cardiac arrest have occurred with the parenteral administration of OMNIPAQUE. Most deaths occur during injection or five to ten minutes later, with cardiovascular disease as the main aggravating factor. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography.
Based upon clinical literature reported deaths from the administration of iodinated contrast agents range from 6.6 per million (0.00066%) to 1 in 10,000 (0.01%). Use the lowest necessary dose of OMNIPAQUE in patients with congestive heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions.
5.6 Thromboembolic Events
Angiocardiography
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke can occur during angiocardiography procedures with both ionic and nonionic contrast media. During these procedures, increased thrombosis and activation of the complement system occurs. Risk factors for thromboembolic events include: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications.
To minimize thromboembolic events, use meticulous angiographic techniques, and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing iodinated contrast agents, which increases the risk of clotting. Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism.
5.7 Extravasation and Injection Site Reactions
Extravasation of OMNIPAQUE during intravascular injection may cause tissue necrosis and/or compartment syndrome, particularly in patients with severe arterial or venous disease. Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms.
5.8 Thyroid Storm in Patients with Hyperthyroidism
Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of OMNIPAQUE.
5.9 Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age
Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast media (ICM) in pediatric patients 0 to 3 years of age.
Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after ICM exposure. Pediatric patients with congenital cardiac conditions may be at the greatest risk given that they often require high doses of contrast during invasive cardiac procedures.
An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to ICM, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates.
5.10 Hypertensive Crisis in Patients with Pheochromocytoma
Hypertensive crisis has occurred after the use of iodinated contrast agents in patient with pheochromocytoma. Monitor patients when administering OMNIPAQUE intravascularly if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of contrast necessary, assess the blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.
5.11 Sickle Cell Crisis in Patients with Sickle Cell Disease
Iodinated contrast agents when administered intravascularly may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following OMNIPAQUE administration and use OMNIPAQUE only if the necessary imaging information cannot be obtained with alternative imaging modalities.
5.12 Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of contrast agents; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering OMNIPAQUE to patients with a history of a severe cutaneous adverse reaction to OMNIPAQUE.
6 Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Risks Associated with Inadvertent Intrathecal Administration [see Warnings and Precautions (5.1)]
- Risks Associated with Inadvertent Parenteral Administration [see Warnings and Precautions (5.2)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
- Contrast-Induced Kidney Injury [see Warnings and Precautions (5.4)]
- Cardiovascular Adverse Reactions [see Warnings and Precautions (5.5)]
- Thromboembolic Events [see Warnings and Precautions (5.6) ]
- Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age [see Warnings and Precautions (5.9)]
- Severe Cutaneous Adverse Reactions [ see Warnings and Precautions (5.12)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Intrathecal Administration
Adults
TABLE 23 ADVERSE REACTIONS – INTRATHECAL ADMINISTRATION In controlled clinical studies involving 1531 patients using OMNIPAQUE the following adverse reactions were reported: System Organ Class Adverse Reaction Incidence Nervous System Headaches 18% Musculoskeletal and Connective Tissue Pain including backache, neckache, stiffness and neuralgia 8% Gastrointestinal System Nausea 6% Vomiting 3% Nervous System Dizziness 2% Other Reactions Feeling of heaviness, hypotension, hypertonia, sensation of heat, sweating, vertigo, loss of appetite, drowsiness, hypertension, photophobia, tinnitus, neuralgia, paresthesia, difficulty in micturition, and neurological changes <0.1%
Pediatric Patients
TABLE 24 ADVERSE REACTIONS – INTRATHECAL ADMINISTRATION In clinical studies involving 152 patients for pediatric myelography by lumbar puncture, adverse events following the use of OMNIPAQUE 180 were generally similar to those reported in adults. Procedure System Organ Class Adverse Reaction Incidence Myelography by Lumbar Puncture Nervous System Headache 9% Gastrointestinal System Vomiting 6% Musculoskeletal and Connective Tissue Backache 1.3% Other Reactions All were transient and mild with no clinical sequelae. Fever <0.7% Hives Stomachache Visual Hallucination Neurological Changes
Intravascular Administration
Immediately following intravascular injection of contrast medium, a transient sensation of mild warmth is not unusual. Warmth is less frequent with OMNIPAQUE than with ionic contrast media.
Adults
In controlled clinical studies involving 1485 patients, the following adverse reactions occurred (Table 25).
TABLE 25 ADVERSE REACTIONS – INTRAVASCULAR ADMINISTRATION System Organ Class Adverse Reaction Incidence Cardiovascular System Arrhythmias including PVCs and PACs 2% Hypotension 0.7% Others including cardiac failure, asystole, bradycardia, tachycardia, and vasovagal reaction ≤ 0.3% Nervous System Vertigo (including dizziness and lightheadedness) 0.5% Pain 3% Vision Abnormalities (including blurred vision and photomas) 2% Taste Perversion 1% Other Reactions Anxiety, fever, motor and speech dysfunction, convulsion, paresthesia, somnolence, stiff neck, hemiparesis, syncope, shivering, transient ischemic attack, cerebral infarction, and nystagmus Individual incidence of 0.3% or less Respiratory System Dyspnea, rhinitis, coughing, and laryngitis Individual incidence of 0.2% or less Gastrointestinal System Nausea 2% Vomiting 0.7% Others including diarrhea, dyspepsia, cramp, and dry mouth Individual incidence of less than 0.1%. Skin and Subcutaneous Tissues Urticaria 0.3% Purpura 0.1% Abscess 0.1% Pruritus 0.1%
Pediatric Patients
In controlled clinical studies involving 391 patients for pediatric angiocardiography, urography, and CT head imaging, adverse reactions following the use of OMNIPAQUE 240, 300, and 350 were generally similar in quality and frequency to those reported in adults (Table 26).
TABLE 26 ADVERSE REACTIONS – INTRAVASCULAR ADMINISTRATION System Organ Class Adverse Reaction Incidence Cardiovascular System Ventricular Tachycardia 0.5% 2:1 Heart Block 0.5% Hypertension 0.3% Anemia 0.3% General Disorders and Administration Site Conditions Pain 0.8% Fever 0.5% Nervous System Convulsion 0.3% Taste Abnormality 0.5% Respiratory System Congestion 0.3% Apnea 0.3% Gastrointestinal System Nausea 1% Vomiting 2% Endocrine System Hypoglycemia 0.3% Skin and Subcutaneous Tissue Rash 0.3%
Oral Administration for Examination of the Gastrointestinal Tract
Adults
Nausea, vomiting, and diarrhea have been most frequently reported following orally administered undiluted OMNIPAQUE for radiographic examination of the gastrointestinal tract. In controlled clinical studies involving 54 adult patients for oral radiographic examination of the gastrointestinal tract using undiluted OMNIPAQUE 350 the following adverse reactions were reported (Table 27).
TABLE 27 ADVERSE REACTIONS – ORAL ADMINISTRATION OF UNDILUTED OMNIPAQUE 350 System Organ Class Adverse Reaction Incidence Gastrointestinal System Diarrhea 42% Nausea 15% Vomiting 11% Abdominal Pain 7% Flatulence 2% Nervous System Headache 2%
Pediatrics Patients (Oral and Rectal Administration)
In clinical studies involving 58 pediatric patients, the adverse reactions were found to mostly affect the gastrointestinal system with diarrhea (36%), vomiting (9%), nausea (5%) and abdominal pain (2%). However, fever (5%), hypotension (2%) and urticaria (2%) were also reported.
Oral Administration for CT of the Abdomen in Conjunction with Intravenous Administration
Adults
In a controlled clinical study involving 44 adult patients receiving oral administration of diluted OMNIPAQUE (4-9 mg iodine/mL) in conjunction with intravenously injected OMNIPAQUE 300 for CT examination of the abdomen, adverse reactions were limited to a single report of vomiting.
Pediatric Patients
In clinical studies involving 69 pediatric patients receiving oral administration of diluted OMNIPAQUE (9-29 mg iodine/mL) in conjunction with intravenously administered OMNIPAQUE 240 and OMNIPAQUE 300 for CT examination of the abdomen, adverse reactions were limited to a single report of vomiting (1.4%).
Body Cavity Use
Adults
Arthrography : In controlled clinical studies involving 285 adult patients for various body cavity examinations using OMNIPAQUE 240, 300 and 350, the most frequent adverse reactions were administration site reactions: pain 26% and swelling 22%, were exclusively reported for arthrography and were generally related to the procedure rather than the contrast medium. Patients also experienced heat (7%). All other adverse reaction occurred at a rate less than or equal to 1%.
Pediatric Patients
No adverse reactions associated with the use of OMNIPAQUE for VCU procedures were reported in 51 pediatric patients studied.
6.2 Post-marketing Experience
The following additional reactions uled by indication have been identified during post-approval use of OMNIPAQUE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
General
Immune System Disorders:Hypersensitivity reactions, anaphylactic or anaphylactoid reactions, anaphylactic or anaphylactoid shock including life-threatening or fatal anaphylaxis
General Disorders and Administration Site Conditions:Pyrexia, chills, pain and discomfort, asthenia, administration site conditions including extravasation
Intrathecal Administration
Nervous System Disorders:Meningism, aseptic meningitis, seizures or status epilepticus, disorientation, coma, depressed or loss of consciousness, transient contrast-induced toxic encephalopathy (including amnesia, hallucination, paralysis, paresis, speech disorder, aphasia, dysarthria), restlessness, tremors, hypoesthesia
Musculoskeletal and Connective Tissue Disorders:Pain, muscle spasms or spasticity
Psychiatric Disorders:Confusional state, agitation, anxiety
Eye Disorders:Transient visual impairment including cortical blindness
Renal Reactions:Acute kidney injury
Intravascular Administration
Cardiovascular Disorders:Severe cardiac complications (including cardiac arrest, cardiopulmonary arrest), shock, peripheral vasodilatation, palpitations, vasospasm including spasm of coronary arteries, myocardial infarction, syncope, cyanosis, pallor, flushing, chest pain
Hemodynamic Reactions:Vasospasm and thrombophlebitis following intravenous injection
Blood and Lymphatic System Disorders:Neutropenia
Nervous System Disorders:Disorientation, coma, depressed or loss of consciousness, transient contrast-induced toxic encephalopathy (including amnesia, hallucination, paralysis, paresis, speech disorder, aphasia, dysarthria), restlessness, tremors, hypoesthesia
Psychiatric Disorders:Confusional state, agitation
Eye Disorders:Eye irritation or itchiness, periorbital edema, ocular or conjunctival hyperemia, lacrimation
Renal Reactions:Acute kidney injury, toxic nephropathy (CIN), transient proteinuria, oliguria or anuria, increased serum creatinine
Gastrointestinal Disorders:Abdominal pain, pancreatitis aggravated, salivary gland enlargement
Endocrine Reactions:Hyperthyroidism, hypothyroidism
Respiratory; Thoracic, and Mediastinal Disorders:Respiratory distress, respiratory failure, pulmonary edema, bronchospasm, laryngospasm, throat irritation, throat tightness, laryngeal edema, wheezing, chest discomfort, asthmatic attack
Skin and Subcutaneous Tissue Disorders:Contrast media reactions range from mild (e.g., pleomorphic rashes, drug eruption, erythema and skin discoloration, bulers, hyperhidrosis, angioedema, localized areas of edema) to severe: [e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), bullous or exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS)]
Oral Administration
Gastrointestinal Disorders:Dysphagia, abdominal pain
Body Cavity Administration
Gastrointestinal Disorders:Pancreatitis
Musculoskeletal and Connective Tissue Disorders:Arthritis (arthrography)
Hysterosalpingography: Injection of OMNIPAQUE for hysterosalpingography is associated with immediate, transient pain. Monitor injection pressure and volume instilled to minimize pain and to avoid disruptive distention of the uterus and fallopian tubes. Fluoroscopic monitoring is recommended.
Nervous system: Pain (49%), somnolence and fever each with an individual incidence of 3%.
Gastrointestinal system: Nausea (3%)
7 Drug Interactions
7.1 Drug-Drug Interactions
Metformin
In patients with renal impairment, metformin can cause lactic acidosis. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. Stop metformin at the time of, or prior to, OMNIPAQUE administration in patients with an eGFR between 30 and 60 mL/min/1.73 m 2; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and reinstitute metformin only after renal function is stable.
Radioactive Iodine
Administration of iodinated contrast agents may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy in patients with carcinoma of the thyroid. The decrease in efficacy lasts for 6 to 8 weeks.
Beta-adrenergic Blocking Agents
The use of beta-adrenergic blocking agents lowers the threshold for and increases the severity of contrast reactions and reduces the responsiveness of treatment of hypersensitivity reactions with epinephrine. Because of the risk of hypersensitivity reactions, use caution when administering OMNIPAQUE to patients taking beta-blockers.
Drugs that Lower Seizure Threshold
Drugs that lower seizure threshold, especially phenothiazine derivatives including those used for their antihistaminic or antinauseant properties, are not recommended for use with intrathecal administration of OMNIPAQUE.
CNS Active Drugs
Drugs such as monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, CNS stimulants, psychoactive drugs described as analeptics, major tranquilizers, or antipsychotic drugs. Such medications should be discontinued at least 48 hours before myelography, should not be used for the control of nausea or vomiting during or after myelography, and should not be resumed for at least 24 hours post procedure. In non-elective procedures in patients on these drugs, consider prophylactic use of anticonvulsants.
7.2 Drug-Laboratory Test Interactions
Effect on Thyroid Tests
If iodine-containing isotopes are to be administered for the diagnosis of thyroid disease, the iodine-binding capacity of thyroid tissue may be reduced for up to 2 weeks after contrast medium administration. Thyroid function tests that do not depend on iodine estimation, e.g., T 3resin uptake or direct thyroxine assays, are not affected.
8 Use In Specific Populations
8.1 Pregnancy
Risk Summary
Hysterosalpingography is contraindicated in pregnant women due to the potential risk to the fetus from an intrauterine procedure [see Contraindications (4)]. There are no data with iohexol use in pregnant women to inform any drug-associated risks. Iohexol crosses the placenta and reaches fetal tissues in small amounts (see Data) . In animal reproduction studies, no developmental toxicity occurred with intravenous iohexol administration to rats and rabbits at doses up to 0.4 (rat) and 0.5 (rabbit) times the maximum recommended human intravenous dose ( see Data ).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Human Data
Literature reports show that intravenously administered iohexol crosses the placenta and is visualized in the digestive tract of exposed infants after birth.
Animal Data
Iohexol was neither embryotoxic nor teratogenic in either rats or rabbits at the following dose levels tested: 1.0, 2.0, 4.0 g iodine/kg in rats, administered intravenously to 3 groups of 25 dams once daily during days 6 through 15 of pregnancy; 0.3, 1.0, 2.5 g iodine/kg in rabbits, administered intravenously to 3 groups of 18 rabbits dosed once a day during days 6 through 18 of pregnancy.
8.2 Lactation
Risk Summary
Published literature reports that breast feeding after intravenous iohexol administration to the mother would result in the infant receiving an oral dose of approximately 0.7% of the maternal intravenous dose; however, lactation studies have not been conducted with oral, intrathecal, or intracavity administration of iohexol. There is no information on the effects of the drug on the breastfed infant or on milk production. Iodinated contrast agents are excreted unchanged in human milk in very low amounts with poor absorption from the gastrointestinal tract of a breastfed infant. Exposure to iohexol to a breastfed infant can be minimized by temporary discontinuation of breastfeeding (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OMNIPAQUE and any potential adverse effects on the breastfed infant from OMNIPAQUE or from the underlying maternal condition.
Clinical Considerations
Interruption of breastfeeding after exposure to iodinated contrast agents is not necessary because the potential exposure of the breastfed infant to iodine is small. However, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 10 hours (approximately 5 elimination half-lives) after OMNIPAQUE administration to minimize drug exposure to a breastfed infant.
8.4 Pediatric Use
Intrathecal Use
The safety and effectiveness of OMNIPAQUE 180 have been established in pediatric patients 2 weeks to 17 years of age for myelography (lumbar, thoracic, cervical, total columnar) and for CT (myelography, cisternography). Use of OMNIPAQUE 180 is supported by controlled clinical studies in adults for myelography, in addition to clinical studies in pediatric patients undergoing myelography. The safety and effectiveness of OMNIPAQUE 180 have not been established for intrathecal use in patient pediatric patients less than 2 weeks of age. The safety and effectiveness of OMNIPAQUE 240 and 300 have not been established in pediatric patients for myelography (lumbar, thoracic, cervical, total columnar) and for CT (myelography, cisternography, or ventriculography).
Intravascular Use
Angiocardiography( Ventriculography, Pulmonary Arteriography, Venography, and Studies of the Collateral Arteries) and Aortography
The safety and effectiveness of OMNIPAQUE 300 have been established in pediatric patients from birth to 17 years of age for angiocardiography (ventriculography) and of OMNIPAQUE 350 in pediatric patients from birth to 17 years of age for angiocardiography (ventriculography, pulmonary arteriography, venography, and studies of the collateral arteries) and aortography. Use of OMNIPAQUE 300 and 350 is supported by controlled clinical studies in adults for angiocardiography and aortography, in addition to controlled clinical studies in pediatric patients undergoing angiocardiography, including aortography. The safety and effectiveness of OMNIPAQUE 300 have not been established in pediatric patients for aortography.
Intra-arterial Digital Subtraction Angiography, Intravenous Digital Subtraction Angiography, Cerebral Arteriography, or Peripheral Arteriography and Venography
The safety and effectiveness of OMNIPAQUE have not been established in pediatric patients for intra-arterial digital subtraction angiography, intravenous digital subtraction angiography, cerebral arteriography, or peripheral arteriography and venography.
CT of the Head and Body
The safety and effectiveness of OMNIPAQUE 240 and 300 have been established in pediatric patients from birth to 17 years of age for CT imaging of the head and body. Use of OMNIPAQUE 240 and 300 is supported by controlled clinical studies in adults for head and body CT, in addition to clinical studies in pediatric patients undergoing head CT and in 69 pediatric patients undergoing CT of the abdomen after oral administration of diluted OMNIPAQUE plus intravenous administration of OMNIPAQUE. The safety and effectiveness of OMNIPAQUE 350 have not been established in pediatric patients for CT imaging of the head and body.
Urography
The safety and effectiveness of OMNIPQUE 300 have been established in pediatric patients from birth to 17 years of age for urography. Use of OMNIPAQUE 300 is supported by controlled clinical studies in adults for urography, in addition to controlled clinical studies in pediatric patients undergoing urography and clinical safety data in pediatric patients down to birth.
Oral or Rectal Use
Undiluted OMNIPAQUE Injection
The safety and effectiveness of OMNIPAQUE 180, 240, and 300 administered orally and rectally have been established in pediatric patients, from birth to 17 years of age for examination of the GI tract. Use of OMNIPAQUE 180, 240, and 300 administered orally and rectally is supported by controlled studies in adults for examination of the GI tract, in addition to clinical studies in pediatric patients undergoing examination of the GI tract.
Oral Use in Conjunction with Intravenous Use
Diluted OMNIPAQUE Injection
The safety and effectiveness of OMNIPAQUE injection diluted to concentrations from 9 to 21 mg iodine/mL administered orally in conjunction with OMNIPAQUE injection administered intravenously for CT of the abdomen have been established in pediatric patients from birth to 17 years of age. Use is supported by clinical trials in adults, in addition to clinical studies in 69 pediatric patients undergoing CT of the abdomen after oral administration of diluted OMNIPAQUE plus intravenous administration of OMNIPAQUE.
OMNIPAQUE Oral Solution
The safety and effectiveness of OMNIPAQUE oral solution 9 and 12 administered orally in conjunction with OMNIPAQUE injection administered intravenously for CT of the abdomen in pediatric patients have been established in pediatric patients from birth to 17 years of age. Use is supported by the data establishing safety and effectiveness for OMNIPAQUE injection diluted and administered orally in conjunction with OMNIPAQUE injection administered intravenously for CT of the abdomen in pediatric patients.
Intraarticular Use
The safety and effectiveness of OMNIPAQUE have not been established in pediatric patients for arthrography.
Body Cavity Use
OMNIPAQUE 240, 300, 350 diluted to concentrations from 50 mg iodine/mL to 100 mg iodine/mL is indicated for use in pediatric patients from birth to 17 years of age for voiding cystourethrography (VCU). The use for voiding cystourethrography is supported by clinical studies in 51 pediatric patients undergoing VCU. The safety and effectiveness of OMNIPAQUE have not been established in pediatric patients for ERCP, herniography, or hysterosalpingography.
In general, the frequency of adverse reactions in pediatric patients was similar to that seen in adults [see Adverse Reactions (6.1)] . Pediatric patients at higher risk of experiencing adverse events during contrast-medium administration may include those having asthma, a sensitivity to medication and/or allergens, congestive heart failure, a serum creatinine greater than 1.5 mg/dL or those less than 12 months of age.
Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates. Some patients were treated for hypothyroidism. After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients 0 to 3 years of age based on underlying risk factors, especially in term and preterm neonates [see Warnings and Precautions (5.9)and Adverse Reactions (6.2)] .
8.5 Geriatric Use
In clinical studies of OMNIPAQUE for CT, 52/299 (17%) of patients were 70 and over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
10 Overdosage
10.1 Intravascular Administration
The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. The symptoms included: cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma, and cardiac arrest. Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic therapy. Iohexol displays a low affinity for serum or plasma proteins and is poorly bound to serum albumin and can be dialyzed.
11 Description
11.1 Chemical Characteristics
OMNIPAQUE (iohexol) injection is a nonionic, x-ray or radiographic contrast medium for intrathecal, intravenous, oral, rectal and body cavity use. OMNIPAQUE oral solution is for oral use only.
OMNIPAQUE injection and OMNIPAQUE oral solution are both provided as sterile, pyrogen-free and gluten-free solutions. OMNIPAQUE injection and OMNIPAQUE oral solution are colorless to pale yellow solutions. The chemical name of iohexol is Bis(2,3-dihydroxypropyl)-5-[ N-(2,3-dihydroxypropyl)-acetamido]-2,4,6- triiodoisophthalamide with a molecular weight of 821.14 (iodine content 46.36%). Iohexol has the following structural formula:
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OMNIPAQUE injection is available in five strengths:
- OMNIPAQUE 140 mg iodine/mL (302 mg of iohexol/mL): Each mL contains 140 mg organically bound iodine, 1.21 mg tromethamine and 0.1 mg edetate calcium disodium
- OMNIPAQUE 180 mg iodine/mL (388 mg of iohexol/mL): Each mL contains 180 mg organically bound iodine, 1.21 mg tromethamine and 0.1 mg edetate calcium disodium
- OMNIPAQUE 240 mg iodine/mL (518 mg of iohexol/mL): Each mL contains 240 mg organically bound iodine, 1.21 mg tromethamine and 0.1 mg edetate calcium disodium
- OMNIPAQUE 300 mg iodine/mL (647 mg of iohexol/mL): Each mL contains 300 mg organically bound iodine, 1.21 mg tromethamine and 0.1 mg edetate calcium disodium
- OMNIPAQUE 350 mg iodine/mL (755 mg of iohexol/mL): Each mL contains 350 mg organically bound iodine, 1.21 mg tromethamine and 0.1 mg edetate calcium disodium
OMNIPAQUE oral solution is available in two strengths:
- OMNIPAQUE oral solution 9 mg iodine/mL (19 mg of iohexol/mL): Each mL contains 9 mg organically bound iodine, 1.21 mg tromethamine and 0.1 mg edetate calcium disodium
- OMNIPAQUE oral solution 12 mg iodine/mL (26 mg of iohexol/mL): Each mL contains 12 mg organically bound iodine, 1.21 mg tromethamine and 0.1 mg edetate calcium disodium
The pH is adjusted between 6.8 and 7.7 with hydrochloric acid or sodium hydroxide. OMNIPAQUE injection and OMNIPAQUE oral solution are sterilized by autoclaving and contain no preservatives.
11.2 Physical Characteristics
OMNIPAQUE injection and OMNIPAQUE oral solution have the following physical properties:
Presentation Concentration (mg iodine/mL) Osmolality By vapor-pressure osmometry. (mOsmol/kg water)Absolute Viscosity (cP) Specific Gravity 20°C 37°C 37°C OMNIPAQUE 140 140 322 2.3 1.5 1.164 OMNIPAQUE 180 180 408 3.1 2.0 1.209 OMNIPAQUE 240 240 520 5.8 3.4 1.280 OMNIPAQUE 300 300 672 11.8 6.3 1.349 OMNIPAQUE 350 350 844 20.4 10.4 1.406 OMNIPAQUE oral solution 9 9 38 1.1 0.8 1.011 OMNIPAQUE oral solution 12 12 45 1.1 0.8 1.014
OMNIPAQUE 140, OMNIPAQUE 180, OMNIPAQUE 240, OMNIPAQUE 300, and OMNIPAQUE 350 have osmolalities from approximately 1.1 to 3.0 times that of plasma (285 mOsmol/kg water) or cerebrospinal fluid (301 mOsmol/kg water) as shown in the above table and are hypertonic under conditions of use.
OMNIPAQUE oral solution 9 and OMNIPAQUE oral solution 12 are hypotonic under conditions of use (see tableabove).
12 Clinical Pharmacology
12.1 Mechanism of Action
The iodine atoms in iohexol provide attenuation of X-rays in direct proportion to the concentration of iohexol. Since concentration changes over time, iohexol provides time-dependent image contrast which may assist in visualizing body structures.
12.2 Pharmacodynamics
Intrathecal Administration
The initial concentration and volume of the contrast medium, in conjunction with patient manipulation and the volume of cerebrospinal fluid (CSF) into which the contrast medium is placed, will determine the extent of the contrast that can be achieved. Following intrathecal injection in conventional radiography, OMNIPAQUE 180, 240, and 300 will continue to provide contrast for at least 30 minutes. Slow diffusion of iohexol takes place throughout the CSF with subsequent absorption into the bloodstream. At approximately 1 hour following injection, contrast will no longer be sufficient for conventional myelography.
After administration into the lumbar subarachnoid space, computerized tomography shows the presence of contrast medium in the thoracic region in about 1 hour, in the cervical region in about 2 hours, and in the basal cisterns in 3 to 4 hours.
Intravascular Administration
Following intravascular administration of OMNIPAQUE, the degree of contrast enhancement is directly related to the iodine concentration of an administered dose; peak iodine blood concentrations occur immediately (15 seconds to 120 seconds) following rapid intravenous injection. The time to maximum contrast enhancement can vary, depending on the organ, from the time that peak blood iodine concentrations are reached to one hour after intravenous bolus administration. When a delay between peak blood iodine concentrations and peak contrast is present, it suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing agent within the lesion and outside the blood pool.
Oral Administration
Orally administered OMNIPAQUE produces visualization of the gastrointestinal tract. Less than 1% of orally administered iohexol is recovered in the urine, suggesting minimal amounts are absorbed from the normal gastrointestinal tract. This amount may increase in the presence of bowel perforation or bowel obstruction.
Intraarticular Administration
Visualization of the joint spaces can be accomplished by direct injection of contrast medium. For intraarticular cavities, the injected iohexol is absorbed into the surrounding tissue and subsequently absorbed into systemic circulation.
Body Cavity Administration
For most body cavities, the injected iohexol is absorbed into the surrounding tissue and subsequently absorbed into systemic circulation. Examinations of the uterus (hysterosalpingography) and bladder (voiding cystourethrography) involve the almost immediate drainage of contrast medium from the cavity upon conclusion of the radiographic procedure.
12.3 Pharmacokinetics
Following the intravenous administration of iohexol (between 500 mg iodine/kg to 1500 mg iodine/kg) to 16 adult human subjects, apparent first-order terminal elimination half-life was 12.6 hrs and total body clearance was 131 (98 to 165) mL/min. Clearance was not dose dependent.
Absorption
As evidenced by the amount recovered in urine, <1% of orally administered iohexol is absorbed from the normal gastrointestinal tract. This amount may increase in the presence of bowel perforation or bowel obstruction.
Distribution
In 16 adult subjects (receiving between 500 mg iodine/kg to 1500 mg iodine/kg intravenous iohexol) the plasma volume of distribution was165 (108 to 219) mL/kg.
In five adult patients receiving 16 mL to 18 mL of OMNIPAQUE (180 mg iodine/mL) by lumbar intrathecal injection the plasma volume of distribution was 559 (350 to 849) mL/kg.
Elimination
Metabolism
No significant metabolism, deiodination or biotransformation occurs.
Excretion
Following intravascular or intrathecal administration, iohexol is excreted unchanged by glomerular filtration. Approximately 90% of the intravenously injected iohexol dose is excreted within the first 24 hours. Following intravascular administration, peak urine concentration occurs in the first hour after injection.
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed with iohexol to evaluate carcinogenic potential. Iohexol was not genotoxic in a series of studies, including the Ames test, the mouse lymphoma TK locus forward mutation assay, and a mouse micronucleus assay. Iohexol did not impair the fertility of male or female rats when repeatedly administered at intravenous dosages up to 4 g iodine/kg.
16 How Supplied/storage And Handling
16.1 How Supplied
Volume/Concentration Configuration NDC OMNIPAQUE 140 (140 mg iodine/mL) – Boxes of 10 50 mL + PLUSPAK™ (polymer bottle) 0407-1401-52 OMNIPAQUE 180 (180 mg iodine/mL) – Boxes of 10 10 mL Glass Vial 0407-1411-10 OMNIPAQUE 240 (240 mg iodine/mL) – Boxes of 10 10 mL Glass Vial 0407-1412-10 20 mL Glass Vial 0407-1412-20 50 mL + PLUSPAK™ (polymer bottle) 0407-1412-30 100 mL + PLUSPAK™ (polymer bottle) 0407-1412-33 OMNIPAQUE 300 (300 mg iodine/mL) – Boxes of 10 10 mL Glass Vial 0407-1413-10 30 mL fill in 50 mL + PLUSPAK™ (polymer bottle) 0407-1413-59 50 mL + PLUSPAK™ (polymer bottle) 0407-1413-61 100 mL + PLUSPAK™ (polymer bottle) 0407-1413-63 125 mL fill in 150 mL Glass Bottle 0407-1413-53 150 mL fill in 200 mL + PLUSPAK™ (polymer bottle) 0407-1413-65 OMNIPAQUE 350 (350 mg iodine/mL) – Boxes of 10 50 mL + PLUSPAK™ (polymer bottle) 0407-1414-89 75 mL fill in 100 mL + PLUSPAK™ (polymer bottle) 0407-1414-90 100 mL + PLUSPAK™ (polymer bottle) 0407-1414-91 125 mL fill in 150 mL Glass Bottle 0407-1414-76 150 mL fill in 200 mL + PLUSPAK™ (polymer bottle) 0407-1414-93 200 mL + PLUSPAK™ (polymer bottle) 0407-1414-94 OMNIPAQUE Oral Solution 9 (9 mg iodine/mL) – Boxes of 10 500 mL + PLUSPAK™ (polymer bottle) 0407-1415-09 OMNIPAQUE Oral Solution 12 (12 mg iodine/mL) – Boxes of 10 500 mL + PLUSPAK™ (polymer bottle) 0407-1416-12
The container closure system components (bottle, vial, stopper and cap) of OMNIPAQUE injection and OMNIPAQUE oral solution are not made with natural rubber latex.
16.2 Storage and Handling
Protect OMNIPAQUE glass vials and bottles and + PLUSPAK™ polymer bottles from light. Do not freeze. Discard any product that is inadvertently frozen, as freezing may compromise the closure integrity of the immediate container.
OMNIPAQUE Injection 140, 180, 240, 300 and 350
Store at controlled room temperature, 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. May be stored in a contrast media warmer for up to one month at 36° to 38°C (96.8° to 100.4°F).
OMNIPAQUE Oral Solution 9 and 12
Store between 0° and 30°C (32° to 86°F).
17 Patient Counseling Information
Hypersensitivity Reactions
Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after OMNIPAQUE administration. Advise the patient to report any signs or symptoms of hypersensitivity reactions during the procedure and to seek immediate medical attention for any signs or symptoms experienced after discharge [see Warnings and Precautions (5.3)]
Advise patients to inform their physician if they develop a rash after receiving OMNIPAQUE [see Warnings and Precautions (5.12)].
Contrast-Induced Acute Kidney Injury
Advise the patient concerning appropriate hydration to decrease the risk of contrast-induced acute kidney injury [see Warnings and Precautions (5.4)] .
Extravasation
If extravasation occurs during injection, advise patients to seek medical care for progression of symptoms [see Warnings and Precautions (5.7)].
LACTATION SECTION
Lactation
Advise a lactating woman that interruption of breastfeeding is not necessary. However, to avoid any exposure, a lactating woman may consider pumping and discarding breast milk for 10 hours after OMNIPAQUE administration [ see Use in Specific Populations (8.2)] .
Thyroid Dysfunction
Advise parents/caregivers about the risk of developing thyroid dysfunction after OMNIPAQUE administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function [see Warnings and Precautions (5.9)].
Distributed by GE Healthcare Inc., Marlborough, MA 01752 U.S.A.
Product of Norwegian Origin.
OMNIPAQUE is a trademark of GE HealthCare or one of its subsidiaries. GE is a trademark of General Electric Company used under trademark license.
© 2023 GE HealthCare
Methylprednisolone Acetate Injectable Suspension, USP 80 mg/mL (1 mL) Rx only Single-Dose Vial Not For Intravenous Use
Description
Methylprednisolone acetate injectable suspension, USP is an anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft tissue or intralesional injection. It is available as single-dose vials in 80 mg/mL strength
Each mL of these preparations contains:
##
80 mg/mL
Methylprednisolone Acetate, USP
80 mg
Polyethylene glycol 3350
28 mg
Myristyl-gamma-picolinium chloride
0.189 mg
Sodium chloride was added to adjust tonicity.
When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid.
The pH of the finished product remains within the USP specified range (e.g., 3.0 to 7.0).
The chemical name for methylprednisolone acetate is pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-11,17-dihydroxy-6-methyl-,(6α,11β)- and the molecular weight is 416.51. The structural formula is represented below:
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Methylprednisolone acetate injectable suspension, USP contains methylprednisolone acetate, USP which is the 6-methyl derivative of prednisolone. Methylprednisolone acetate, USP is a white or almost white crystalline powder which melts at about 213° with some decomposition. It is soluble in dioxane, sparingly soluble in acetone, alcohol, chloroform, and methanol, and slightly soluble in ether. It is practically insoluble in water.
Clinical Pharmacology
Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids.
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt retaining properties, are used in replacement therapy in adrenocortical deficiency states. Their synthetic analogs are used primarily for their anti-inflammatory effects in disorders of many organ systems.
Indications And Usage
A. For Intramuscular Administration
When oral therapy is not feasible and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intramuscular use of methylprednisolone acetate injectable suspension is indicated as follows:
Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, serum sickness, transfusion reactions.
Dermatologic Diseases: Bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).
Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsupportive thyroiditis.
Gastrointestinal Diseases: To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis.
Hematologic Disorders: Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond Blackfan anemia), pure red cell aplasia, select cases of secondary thrombocytopenia.
Miscellaneous: Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.
Neoplastic Diseases: For palliative management of: leukemias and lymphomas.
Nervous System: Cerebral edema associated with primary or metastatic brain tumor or craniotomy.
Ophthalmic Diseases: Sympathetic ophthalmia, temporal arteritis, uveitis, ocular inflammatory conditions unresponsive to topical corticosteroids.
Renal Diseases: To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome, or that due to lupus erythematosus.
Respiratory Diseases: Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis.
Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus.
B. For Intra-articular Or Soft Tissue Administration
(See WARNINGS)
Methylprednisolone acetate injectable suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis.
C. For Intralesional Administration
Methylprednisolone acetate injectable suspension is indicated for intralesional use in alopecia areata, discoid lupus erythematosus; keloids, localized hypertrophic, infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis) and psoriatic plaques; necrobiosis lipoidica diabeticorum.
Methylprednisolone acetate injectable suspension also may be useful in cystic tumors of an aponeurosis or tendon (ganglia).
Contraindications
Methylprednisolone acetate injectable suspension is contraindicated in patients with known hypersensitivity to the product and its constituents.
Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura. Methylprednisolone acetate injectable suspension is contraindicated for intrathecal administration. This formulation of methylprednisolone acetate has been associated with reports of severe medical events when administered by this route.
Methylprednisolone acetate injectable suspension is contraindicated in systemic fungal infections, except when administered as an intra-articular injection for localized joint conditions (see WARNINGS: Infections, Fungal Infections ).
Warnings
Serious Neurologic Adverse Reactions with Epidural Administration
Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.
General
This product is not suitable for multi-dose use. Following administration of the desired dose, any remaining suspension should be discarded.
Injection of methylprednisolone acetate may result in dermal and/or subdermal changes forming depressions in the skin at the injection site.
In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.
It is critical that, during administration of methylprednisolone acetate injectable suspension, appropriate technique be used and care taken to ensure proper placement of drug.
Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS ).
Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation.
Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including methylprednisolone acetate, should not be used for the treatment of traumatic brain injury.
Cardio-renal
Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.
Endocrine
Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing’s syndrome, and Hyperglycemia: Monitor patients for these conditions with chronic use.
Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.
Infections
General
Persons who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents.
These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Do not use intra-articularly, intrabursally, or for intratendinous administration for local effect in the presence of an acute infection. Corticosteroids may mask some signs of infection and new infections may appear during their use.
Fungal Infections
Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug interactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions, Amphotericin B injection and potassium-depleting agents).
Special Pathogens
Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis,and Toxoplasma.
It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.
Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides(threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloideshyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.
Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition.
Tuberculosis
The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary, as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
Vaccinations
Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted.
Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy (e.g., for Addison’s disease).
Viral Infections
Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents should be considered.
Ophthalmic
Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of systemic corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.
Precautions
General
This product, like many other corticosteroids, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial.
The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual.
Since complications of treatment with glucocorticosteroids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.
Karposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.
Cardio-renal
Caution is required in patients with systemic sclerosis because an increased incidence of scleroderma renal crisis has been observed with corticosteroids, including methylprednisolone.
As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure or renal insufficiency.
Endocrine
Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.
Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.
Gastrointestinal
Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of perforation.
Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.
There is an enhanced effect due to decreased metabolism of corticosteroids in patients with cirrhosis.
Parenteral Administration
Intra-articularly injected corticosteroids may be systemically absorbed.
Appropriate examination of any joint fluid present is necessary to exclude a septic process.
A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.
Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously infected joint is not usually recommended.
Musculoskeletal
Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (e.g., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to an inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e. postmenopausal women) before initiating corticosteroid therapy.
Neuro-psychiatric
An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.
Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.
Ophthalmic
Intraocular pressure may become elevated in some individuals. If steroid therapy is continued long-term, intraocular pressure should be monitored.
Corticosteroids should be used cautiously in patients with ocular herpes simplex for fear of corneal perforation.
Information for the Patient
Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop a fever or other signs of infection.
Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.
Drug Interactions
Aminoglutethimide: Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.
Amphotericin B injection and potassium-depleting agents:When corticosteroids are administered concomitantly with potassium depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.
Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see PRECAUTIONS: Drug Interactions, Hepatic Enzyme Inhibitors).
Anticholinesterases:Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
Anticoagulants, oral: Co-administration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.
Antidiabetics:Because corticosteroids may increase blood glucose concentration, dosage adjustments of antidiabetic agents may be required.
Antitubercular drugs:Serum concentrations of isoniazid may be decreased.
Cholestyramine:Cholestyramine may increase the clearance of oral corticosteroids.
Cyclosporine:Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.
Digitalis glycosides:Patients on digitalis glycosides may be at risk of arrhythmias due to hypokalemia.
Estrogens, including oral contraceptives:Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.
Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin):Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.
Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin):Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids.
Ketoconazole: Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.
Skin tests: Corticosteroids may suppress reactions to skin tests.
Vaccines: Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infections, Vaccinations ).
Carcinogenesis, Mutagenesis, Impairment of Fertility
No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis.
Steroids may increase or decrease motility and number of spermatozoa in some patients.
Corticosteroids have been shown to impair fertility in male rats.
Pregnancy: Teratogenic Effects
Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.
Nursing Mothers
Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephritic syndrome (patients > 2 years of age) and aggressive lymphomas and leukemias (patients > 1 month of age). Other indications for pediatric use of corticosteroids (e.g., severe asthma and wheezing) are based on adequate and well-controlled clinical trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.
The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS ). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e. cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.
Geriatric Use
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Adverse Reactions
The following adverse reactions have been reported with methylprednisolone acetate or other corticosteroids:
Allergic reactions :Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema.
Blood and lymphatic system disorders: Leukocytosis.
Cardiovascular :Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS ), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.
Dermatologic :Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.
Endocrine :Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.
Fluid and electrolyte disturbances : Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.
Gastrointestinal : Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible subsequent perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.
Metabolic : Negative nitrogen balance due to protein catabolism.
Musculoskeletal : Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intra-lesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.
Neurologic/Psychiatric : Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo.
Ophthalmic : Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts.
Other :Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see WARNINGS ), malaise, moon face, weight gain.
The following adverse reactions have been reported with the following routes of administration:
Intrathecal/Epidural : Arachnoiditis, bowel/bladder dysfunction, headache, meningitis, parapareisis/paraplegia, seizures, sensory disturbances.
Intranasal : Allergic reactions, rhinitis, temporary/permanent visual impairment including blindness.
Ophthalmic : Increased intraocular pressure, infection, ocular and periocular inflammation including allergic reactions, residue or slough at injection site, temporary/permanent visual impairment including blindness.
Miscellaneous injection sites (scalp, tonsillar fauces, sphenopalatine ganglion): Blindness.
To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Overdosage
Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced.
Dosage And Administration
Because of possible physical incompatibilities, methylprednisolone acetate injectable suspension should not be diluted or mixed with other solutions.
The initial dosage of parenterally administered methylprednisolone acetate injectable suspension will vary from 4 mg to 120 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.
It Should Be Emphasized that Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient.After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation, it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.
A. Administration for Local Effect
Therapy with methylprednisolone acetate injectable suspension does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation.
1. Rheumatoid Arthritis and Osteoarthritis.The dose for intra-articular administration depends upon the size of the joint and varies with the severity of the condition in the individual patient. In chronic cases, injections may be repeated at intervals ranging from one to five or more weeks, depending upon the degree of relief obtained from the initial injection. The doses in the following table are given as a general guide:
Size of
Joint
Examples
Range
of Dosage
Large
Knees
Ankles
Shoulders
20 mg to 80 mg
Medium
Elbows
Wrists
10 mg to 40 mg
Small
Metacarpophalangeal
Interphalangeal
Sternoclavicular
Acromioclavicular
4 mg to 10 mg
Procedure:It is recommended that the anatomy of the joint involved be reviewed before attempting intra-articular injection. In order to obtain the full anti-inflammatory effect, it is important that the injection be made into the synovial space. Employing the same sterile technique as for a lumbar puncture, a sterile 20 to 24 gauge needle (on a dry syringe) is quickly inserted into the synovial cavity. Procaine infiltration is elective. The aspiration of only a few drops of joint fluid proves the joint space has been entered by the needle. The injection site for each joint is determined by that location where the synovial cavity is most superficial and most free of large vessels and nerves.With the needle in place, the aspirating syringe is removed and replaced by a second syringe containing the desired amount of methylprednisolone acetate injectable suspension. The plunger is then pulled outward slightly to aspirate synovial fluid and to make sure the needle is still in the synovial space. After injection, the joint is moved gently a few times to aid mixing of the synovial fluid and the suspension. The site is covered with a small sterile dressing.
Suitable sites for intra-articular injection are the knee, ankle, wrist, elbow, shoulder, phalangeal, and hip joints. Since difficulty is not infrequently encountered in entering the hip joint, precautions should be taken to avoid any large blood vessels in the area. Joints not suitable for injection are those that are anatomically inaccessible such as the spinal joints and those like the sacroiliac joints that are devoid of synovial space. Treatment failures are most frequently the result of failure to enter the joint space. Little or no benefit follows injection into surrounding tissue. If failures occur when injections into the synovial spaces are certain, as determined by aspiration of fluid, repeated injections are usually futile.
If a local anesthetic is used prior to injection of methylprednisolone acetate injectable suspension, the anesthetic package insert should be read carefully and all the precautions observed.
2. Bursitis. The area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied.
3. Miscellaneous: Ganglion, Tendinitis, Epicondylitis.In the treatment of conditions such as tendinitis or tenosynovitis, care should be taken following application of a suitable antiseptic to the overlying skin to inject the suspension into the tendon sheath rather than into the substance of the tendon. The tendon may be readily palpated when placed on a stretch. When treating conditions such as epicondylitis, the area of greatest tenderness should be outlined carefully and the suspension infiltrated into the area. For ganglia of the tendon sheaths, the suspension is injected directly into the cyst. In many cases, a single injection causes a marked decrease in the size of the cystic tumor and may effect disappearance. The usual sterile precautions should be observed, of course, with each injection.
The dose in the treatment of the various conditions of the tendinous or bursal structures uled above varies with the condition being treated and ranges from 4 mg to 30 mg. In recurrent or chronic conditions, repeated injections may be necessary.
4. Injections for Local Effect in Dermatologic Conditions. Following cleansing with an appropriate antiseptic such as 70% alcohol, 20 mg to 60 mg is injected into the lesion. It may be necessary to distribute doses ranging from 20 mg to 40 mg by repeated local injections in the case of large lesions. Care should be taken to avoid injection of sufficient material to cause blanching since this may be followed by a small slough. One to four injections are usually employed, the intervals between injections varying with the type of lesion being treated and the duration of improvement produced by the initial injection.
B. Administration for Systemic Effect
The intramuscular dosage will vary with the condition being treated. When employed as a temporary substitute for oral therapy, a single injection during each 24-hour period of a dose of the suspension equal to the total daily oral dose of methylprednisolone tablets, USP is usually sufficient. When a prolonged effect is desired, the weekly dose may be calculated by multiplying the daily oral dose by 7 and given as a single intramuscular injection.
In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific disease entity being treated. Dosage must be individualized according to the severity of the disease and response of the patient. The recommended dosage may be reduced for pediatric patients, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight.
In patients with the adrenogenital syndrome, a single intramuscular injection of 40 mg every two weeks may be adequate. For maintenance of patients with rheumatoid arthritis, the weekly intramuscular dose will vary from 40 mg to 120 mg. The usual dosage for patients with dermatologic lesionsbenefited by systemic corticoid therapy is 40 mg to 120 mg of methylprednisolone acetate administered intramuscularly at weekly intervals for one to four weeks. In acute severe dermatitis due to poison ivy, relief may result within 8 to 12 hours following intramuscular administration of a single-dose of 80 mg to 120 mg. In chronic contact dermatitis, repeated injections at 5 to 10 day intervals may be necessary. In seborrheic dermatitis, a weekly dose of 80 mg may be adequate to control the condition.
Following intramuscular administration of 80 mg to 120 mg to asthmatic patients, relief may result within 6 to 48 hours and persist for several days to two weeks.
If signs of stress are associated with the condition being treated, the dosage of the suspension should be increased. If a rapid hormonal effect of maximum intensity is required, the intravenous administration of highly soluble methylprednisolone sodium succinate is indicated.
For the purpose of comparison, the following is the equivalent milligram dose of the various glucocorticoids:
Cortisone, 25
Triamcinolone, 4
Hydrocortisone, 20
Paramethasone, 2
Prednisolone, 5
Betamethasone, 0.75
Prednisone, 5
Dexamethasone, 0.75
Methylprednisolone, 4
These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.
How Supplied
Methylprednisolone Acetate Injectable Suspension, USP is supplied as a white to off-white homogenous suspension in single-dose vial available in the following strength and package size:
80 mg/mL (1 mL)
Single vial in a carton: NDC 70121-1574-1
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
This product’s label may have been updated. For current full prescribing information, please visit www.amneal.com.
Manufactured by:
Amneal Pharmaceuticals Pvt. Ltd.
Parenteral Unit
Ahmedabad 382213, INDIA
Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807
Rev. 07-2021-05
Lidocaine HCl Injection, USP
For Infiltration and Nerve Block Including Caudal and Epidural Use.
Preservative-Free
Rx only
Description
Lidocaine hydrochloride injection, USP is sterile, nonpyrogenic, aqueous solution that contains a local anesthetic agent and is administered parenterally by injection. See INDICATIONS AND USAGE section for specific uses. Lidocaine hydrochloride injection, USP contains lidocaine hydrochloride, which is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-, monohydrochloride and has the molecular weight 270.8. Lidocaine hydrochloride (C 14H 22N 2O • HCl) has the following structural formula:
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Lidocaine hydrochloride injection, USP is a sterile, nonpyrogenic, isotonic solution containing sodium chloride. The pH of the solution is adjusted to approximately 6.5 (5.0 to 7.0) with sodium hydroxide and/or hydrochloric acid.
Clinical Pharmacology
Mechanism of Action
Lidocaine hydrochloride stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action.
Hemodynamics
Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded.
Pharmacokinetics and Metabolism
Information derived from diverse formulations, concentrations and usages reveals that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending, for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. The plasma binding of lidocaine hydrochloride is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL 60 to 80 percent of lidocaine hydrochloride is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine hydrochloride crosses the blood-brain and placental barriers, presumably by passive diffusion. Lidocaine hydrochloride is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine hydrochloride. Approximately 90% of lidocaine hydrochloride administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2 hours. Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine hydrochloride kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine hydrochloride kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine hydrochloride required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6 mcg free base per mL. In the rhesus monkey arterial blood levels of 18 to 21 mcg/mL have been shown to be threshold for convulsive activity.
Indications And Usage
Lidocaine hydrochloride injection is indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks, when the accepted procedures for these techniques as described in standard textbooks are observed.
Contraindications
Lidocaine hydrochloride is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type.
Warnings
LIDOCAINE HYDROCHLORIDE INJECTION FOR INFILTRATION AND NERVE BLOCK SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER ENSURING THE IMMEDIATEAVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY EQUIPMENT AND THE PERSONNEL NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (see also ADVERSE REACTIONS and PRECAUTIONS ). DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue lidocaine hydrochloride and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2 ndmonth after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. To avoid intravascular injection, aspiration should be performed before the local anesthetic solution is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided. Anaphylactic reactions may occur following administration of lidocaine hydrochloride (see ADVERSE REACTIONS ). In the case of severe reaction, discontinue the use of the drug.
Precautions
General
The safety and effectiveness of lidocaine hydrochloride depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Standard textbooks should be consulted for specific techniques and precautions for various regional anesthetic procedures. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and ADVERSE REACTIONS ). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Syringe aspirations should also be performed before and during each supplemental injection when using indwelling catheter techniques. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and that the patient be monitored for central nervous system toxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions that contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Repeated doses of lidocaine hydrochloride may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical condition. Lidocaine hydrochloride should also be used with caution in patients with severe shock or heart block. Lumbar and caudal epidural anesthesia should be used with extreme caution in persons with the following conditions: existing neurological disease, spinal deformities, septicemia, and severe hypertension. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Preparations containing a vasoconstrictor should be used with caution in patients during or following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous system toxicity. Since amide-type local anesthetics are metabolized by the liver, lidocaine hydrochloride injection should be used with caution in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Lidocaine hydrochloride injection should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). Proper tourniquet technique, as described in publications and standard textbooks, is essential in the performance of intravenous regional anesthesia. Solutions containing epinephrine or other vasoconstrictors should not be used for this technique. Lidocaine hydrochloride should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to lidocaine hydrochloride.
Use in the Head and Neck Area
Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded (see DOSAGE AND ADMINISTRATION ).
Information for Patients
When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of epidural anesthesia. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.
Clinically Significant Drug Interactions
The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.
Drug/Laboratory Test Interactions
The intramuscular injection of lidocaine hydrochloride may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine hydrochloride. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:
Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants Phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies of lidocaine hydrochloride in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted.
Pregnancy
Teratogenic Effects
Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. General consideration should be given to this fact before administering lidocaine hydrochloride to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place.
Labor and Delivery
Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY , Pharmacokinetics and Metabolism ). The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine hydrochloride is administered to a nursing woman.
Pediatric Use
Dosages in children should be reduced, commensurate with age, body weight and physical condition, see DOSAGE AND ADMINISTRATION .
Adverse Reactions
Systemic
Adverse experiences following the administration of lidocaine hydrochloride are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported:
CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest.
Drowsiness following the administration of lidocaine hydrochloride is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption.
Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.
Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity to local anesthetic agents. Allergic reactions, including anaphylactic reactions, may occur as a result of sensitivity to lidocaine, but are infrequent. If allergic reactions do occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine.
The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In a prospective review of 10,440 patients who received lidocaine hydrochloride for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur. Subsequent adverse effects may depend partially on the amount of drug administered subdurally. These may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration.
Methemoglobinemia.
Overdosage
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS , WARNINGS , and PRECAUTIONS ).
Management of Local Anesthetic Emergencies
The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea due to unintended subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine hydrochloride. The oral LD 50of lidocaine hydrochloride in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214 (159 to 324) mg/kg (as the salt) in fasted female rats.
Dosage And Administration
Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of lidocaine hydrochloride injection for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Lidocaine hydrochloride injection is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION ). These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient. In all cases the lowest concentration and smallest dose that will produce the desired result should be given. Dosages should be reduced for children and for the elderly and debilitated patients and patients with cardiac and/or liver disease. The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Thus, an increase in volume and concentration of lidocaine hydrochloride injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia. However, increasing the volume and concentration of lidocaine hydrochloride injection may result in a more profound fall in blood pressure when used in epidural anesthesia. Although the incidence of side effects with lidocaine hydrochloride is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected.
Epidural Anesthesia
For epidural anesthesia the following dosage form of lidocaine hydrochloride injection is recommended: 1% without epinephrine 30 mL single dose vials Although this solution is intended specifically for epidural anesthesia, it may also be used for infiltration and peripheral nerve block, provided it is employed as a single dose unit. This solution contains no bacteriostatic agent. In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).
Caudal and Lumbar Epidural Block
As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine hydrochloride should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of lidocaine hydrochloride injection through the catheter should be avoided, and, when feasible, fractional doses should be administered. In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.
Maximum Recommended Dosages
Adults
For normal healthy adults, the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight, and in general it is recom mended that the max i m um t otal dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, more drug may be administered if required to produce adequate anesthesia. The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One half of the total dose is usually administered to each side. Inject slowly, five minutes between sides (see also discussion of paracervical block in PRECAUTIONS ). For intravenous regional anesthesia, the dose administered should not exceed 4 mg/kg in adults.
Children
It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight. For example, in a child of 5 years weighing 50 lbs the dose of lidocaine hydrochloride should not exceed 75 to 100 mg (1.5 to 2 mg/lb). The use of even more dilute solutions (i.e., 0.25 to 0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children. In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if solution is discolored or contains a precipitate.
Table 1: Recommended Dosages Procedure Lidocaine Hydrochloride Injection (without epinephrine) Conc (%) Vol (mL) Total Dose (mg) *Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome). Infiltration Percutaneous 0.5 or 1 1 to 60 5 to 300 Intravenous regional 0.5 10 to 60 50 to 300 Peripheral Nerve Blocks, e.g., Brachial 1.5 15 to 20 225 to 300 Dental 2 1 to 5 20 to 100 Intercostal 1 3 30 Paravertebral 1 3 to 5 30 to 50 Pudendal (each side) 1 10 100 Paracervical Obstetrical analgesia (each side) 1 10 100 Sympathetic Nerve Blocks, e.g., Cervical (stellate ganglion) 1 5 50 Lumbar 1 5 to 10 50 to 100 Central Neural Blocks Epidural* Thoracic 1 20 to 30 200 to 300 Lumbar Analgesia 1 25 to 30 250 to 300 Anesthesia 1.5 15 to 20 225 to 300 2 10 to 15 200 to 300 Caudal Obstetrical analgesia 1 20 to 30 200 to 300 Surgical anesthesia 1.5 15 to 20 225 to 300
THE ABOVE SUGGESTED CONCENTRATIONS AND VOLUMES SERVE ONLY AS A GUIDE. OTHER VOLUMES AND CONCENTRATIONS MAY BE USED PROVIDED THE TOTAL MAXIMUM RECOMMENDED DOSE IS NOT EXCEEDED.
Sterilization, Storage And Technical Procedures
Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection as they have been related to incidents of swelling and edema.
How Supplied
Lidocaine Hydrochloride Injection, USP is supplied as follows: Lidocaine Hydrochloride Injection USP, 1% (10 mg/mL) 5 mL Single Dose Vials in a Carton of 10 NDC 55150-162-05 Sterile, Nonpyrogenic
Discard unused portion Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] The vial stopper is not made with natural rubber latex. Distributed by: AuroMedics Pharma LLC
279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited
Hyderabad - 500038 India Revised: February 2020
Chloraprep One-step
Active Ingredients
Chlorhexidine gluconate 2% w/v
Isopropyl alcohol 70% v/v
Purposes
Antiseptic
Antiseptic
Use
for the preparation of the patient’s skin prior to surgery. Helps to reduce
bacteria that potentially can cause skin infection.
Warnings
For external use only. Flammable, keep away from fire or flame. To reduce risk of fire, PREP CAREFULLY:
- solution contains alcohol and gives off flammable vapors
- avoid getting solution into hairy areas. Hair may take up to 1 hour to dry. Wet hair is flammable.•
- do not drape or use ignition source (e.g., cautery, laser) until solution is completely dry (minimum of 3 minutes on hairless skin; up to 1 hour in hair)
- do not allow solution to pool
- remove wet materials from prep area
Allergy Alert:
This product may cause a severe allergic reaction. Symptoms may include:
• wheezing/difficulty breathing • shock • facial swelling • hives • rash
If an allergic reaction occurs, stop use and seek medical help right away.
Do Not Use
• on patients allergic to chlorhexidine gluconate or any other ingredient in this product
• for lumbar puncture or in contact with the meninges
• on open skin wounds or as a general skin cleanser
When Using This Product
keep out of eyes, ears, and mouth. May cause serious or
permanent injury if permitted to enter and remain. If contact occurs, rinse with cold
water right away and contact a doctor.
Stop Use And Ask A Doctor If
irritation, sensitization, or allergic reaction occurs. These
may be signs of a serious condition.
Keep Out Of Reach Of Children.
If swallowed, get medical help or contact a Poison
Control Center right away.
Directions
• use with care in premature infants or infants under 2 months of age.
These products may cause irritation or chemical burns. • use in a well ventilated area
• maximal treatment area for one applicator is approximately 4 in. x 5 in. (130 cm2)
• remove applicator from package; do not touch sponge • hold the applicator with the
sponge down. Pinch wings only onceto activate the ampule and release the antiseptic.
• wet the sponge by pressing and releasing the sponge against the treatment area until liquid
is visible on the skin • completely wet the treatment area with antiseptic • dry surgical
sites(e.g., abdomen or arm): use gentle repeated back-and-forth strokes of the sponge for
approximately 30 seconds Allow solution to air dry for approximately 30 seconds. Do not blot
or wipe away. • moist surgical sites(e.g., inguinal fold): use gentle repeated back-and-forth
strokes for approximately 2 minutes. • Allow solution to air dry for approximately
1 minute. Do not blot or wipe away. • if using an ignition source, allow the solution to
completely dry (minimum of 3 minutes on hairless skin; up to 1 hour in hair).Do not blot
or wipe away. • discard the applicator after a single use along with any portion of the solution
not required to cover the prep area. It is not necessary to use the entire amount available.
Other Information
• store between 15-30 oC (59-86 oF) • avoid freezing
and excessive heat above 40 oC (104 oF)
Inactive Ingredient
USP purified water
Questions?
www.chloraprep.com• call 1-800-523-0502(M-F 8 a.m.-5 p.m. CST)
Isopropyl Alcohol 70% Prep Pads
Active Ingredient
Isopropyl Alcohol 70% v/v
Purpose
Antiseptic
Uses
For first aid to decrease germs in
- minor cuts
- scrapes
- burns
For preparation of the skin prior to injection
Warnings
For external use only
Flammable - keep away from fire or flame
Do not use
with electrocautery procedures
When using this product do not
- get into eyes
- apply over large areas of the body
- in case of deep or puncture wounds, animal bites or serious burns consult a doctor
Stop use and ask a doctor if
- condition persists or gets worse or lasts for more than 72 hours
- do not use longer than 1 week unless directed by a doctor
Keep out of reach of children.
If swallowed, get medical help or contact a Poison Control Center right away.
Directions
- apply to skin as needed
- discard after single use
Other Information
Protect from freezing and avoid excessive heat
Inactive Ingredient
Water
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL
NDC: 76420-745-01
Rx Only
Dyural 80 LM-C™
Kit Contains
1Â MethylPREDNISolone Acetate Injectable Suspension, USP 80mg/mL Single Dose Vial (1mL)
1 Bupivacaine HCl 0.25% Single Dose Vial (10mL)
1 Lidocaine HCl Injection, USP 1%Â Single Dose Vial (5mL)
1 Omnipaque™ (iohexol) Injection 240mg/mL Single Dose Bottle (10mL)
1 BD ChloraPrep™ Clear (3mL Applicator)
4 Isopropyl Alcohol 70% Prep Pads
1 Pair Nitrile Powder Free Sterile Gloves (M)
1 Drape with Fenestration
1 Adhesive Bandage
5 Non Sterile 4x4 Gauze
Needles and Syringes Not Included
1 Dose
Single Use Only
Distributed by:
Enovachem™
PHARMACEUTICALS
Torrance, CA 90501
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DISCLAIMER:
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"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
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