INFUMORPH 500 Dailymed

• INFUMORPH should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (2.1)
• Should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration. (2.1)
• Patients should be observed in a fully equipped and staffed environment for at least 24 hours after each test dose and, as indicated, for the first several days after surgery. (2.1)
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of INFUMORPH for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5)
• Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.2)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with INFUMORPH. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.3)
• Initial Dosage: Must be individualized, based upon in-hospital evaluation of the response to serial single dose epidural bolus injections of regular DURAMORPH (morphine sulfate injection, USP) 0.5 mg/mL or 1 mg/mL, with close observation for analgesic efficacy and adverse effects prior to surgery involving the continuous microinfusion device. (2.2)
• Dosage for Epidural Administration: Initial dose range of 3.5 to 7.5 mg/day for patients with no tolerance to opioids. The usual starting dose for continuous epidural infusion in patients with some degree of opioid tolerance is 4.5 to 10 mg/day and may increase significantly during treatment to 20-30 mg/day. (2.3)
• Dosage for Intrathecal Administration: Initial dose range of 0.2 to 1 mg/day for patients with no tolerance to opioids. The range of doses for patients with some degree of opioid tolerance varies from 1 to 10 mg/day. Doses above 20 mg/day should be employed with caution. (2.4)
• Do not abruptly discontinue INFUMORPH in a physically-dependent patient. (2.6)

2.1 Important Dosage and Administration Instructions

INFUMORPH should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration and familiar with the patient management problems associated with epidural or intrathecal drug administration.

• INFUMORPH should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
• Because of the risk of delayed respiratory depression, patients should be observed in a fully equipped and staffed environment for at least 24 hours after each test dose and, as indicated, for the first several days after surgery.
• Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible.
• For safety reasons, it is recommended that administration of INFUMORPH 200 and 500 (10 and 25 mg/mL, respectively) by the intrathecal route be limited to the lumbar area.
• INFUMORPH 200 and 500 (10 and 25 mg/mL, respectively) should not be used for single-dose neuraxial injection because lower doses can be more reliably administered with the standard preparation of DURAMORPH (0.5 and 1 mg/mL). Candidates for neuraxial administration of INFUMORPH in a continuous microinfusion device should be hospitalized to provide for adequate patient monitoring during assessment of response to single doses of intrathecal or epidural morphine. Hospitalization should be maintained for several days after surgery involving the infusion device for additional monitoring and adjustment of daily dosage. The facility must be equipped with resuscitative equipment, oxygen, naloxone injection and other resuscitative drugs. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir. Before discharge, the patient and attendant(s) should receive instruction in the proper home care of the device and insertion site and in the recognition and practical treatment of an overdose of neuraxial morphine. Familiarization with the continuous microinfusion device is essential. The desired amount of morphine should be withdrawn from the ampul through a microfilter. To minimize risk from glass or other particles, the product must be filtered through a 5 μ (or smaller) microfilter before injecting into the microinfusion device. If dilution is required, 0.9% Sodium Chloride Injection is recommended. Reservoir filling must be performed by fully trained and qualified personnel, following the directions provided by the device manufacturer. Care should be taken in selecting the proper refill frequency to prevent depletion of the reservoir, which would result in exacerbation of severe pain, onset of opioid withdrawal symptoms, and/or reflux of cerebrospinal fluid into some devices. Strict aseptic technique is required to avoid bacterial contamination and serious infection. Extreme care must be taken to ensure that the needle is properly inserted into the filling port of the device before attempting to refill the reservoir. Injecting the solution into the tissue around the device or (in the case of devices that have more than one port) attempting to inject the refill dose into the direct injection port will result in a large, clinically significant, overdosage to the patient. Safety and Handling Instructions: INFUMORPH is supplied in sealed ampuls. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water. Inspect parenteral drug products for particulate matter before opening the amber ampul and again for color after removing contents from the ampul. Do not use if the solution in the unopened ampul contains a precipitate which does not disappear upon shaking. After removal, do not use unless the solution is colorless or pale yellow. INFUMORPH is intended for single-use only. Protect from light, discard any unused portion. Do not heat-sterilize.

2.2 Initial Dosage

The starting dose of INFUMORPH must be individualized, based upon in-hospital evaluation of the response to serial single-dose epidural or intrathecal bolus injections of regular DURAMORPH (morphine sulfate injection,) 0.5 mg/mL or 1 mg/mL, with close observation for analgesic efficacy and adverse effects prior to surgery involving the continuous microinfusion device.

• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of INFUMORPH for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with INFUMORPH. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

2.3 Dosage for Epidural Administration

The recommended initial epidural dose in patients who are not tolerant to opioids ranges from 3.5 to 7.5 mg/day. The usual starting dose for continuous epidural infusion, based upon limited data in patients who have some degree of opioid tolerance, is 4.5 to 10 mg/day. The dose requirements may increase significantly during treatment, frequently to 20-30 mg/day. The upper daily limit for each patient must be individualized.

2.4 Dosage for Intrathecal Administration

The recommended initial lumbar intrathecal dose range in patients with no tolerance to opioids is 0.2 to 1 mg/day. The published range of doses for individuals who have some degree of opioid tolerance varies from 1 to 10 mg/day. The upper daily dosage limit for each patient must be individualized.

• Intrathecal dosage is usually 1/10 that of epidural dosage.

2.5 Titration and Maintenance of Therapy

Individually titrate INFUMORPH to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving INFUMORPH to assess the maintenance of pain control, signs and symptoms for opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.3, 5.16)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of the increased pain before increasing the INFUMORPH dosage. If after increasing the dosage, unacceptable opioid related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Limited experience with continuous intrathecal infusion of morphine has shown that the daily doses have to be increased over time. Although the rate of increase, over time, in the dose required to sustain analgesia is highly variable, an estimate of the expected rate of increase is shown in the following Figure.

 

Doses above 20 mg/day should be employed with caution since they may be associated with a higher likelihood of serious side effects [see Warnings and Precautions (5.2, 5.7) and Adverse Reactions (6)].

If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.6 Discontinuation of INFUMORPH

When a patient who has been taking INFUMORPH regularly and may be physically dependent or no longer requires therapy with INFUMORPH, taper the dose gradually while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not stop INFUMORPH abruptly in a physically dependent patient [see Warnings and Precautions (5.15), Drug Abuse and Dependence (9.3)].

3 Dosage Forms And Strengths

Injection: 200 mg per 20 mL (10 mg/mL) Preservative-free amber glass ampuls Injection: 500 mg per 20 mL (25 mg/mL) Preservative-free amber glass ampuls


Injection: 200 mg/20 mL (10 mg/mL) Preservative-free amber glass ampuls Injection: 500 mg/20 mL (25 mg/mL) Preservative-free amber glass ampuls (3)

4 Contraindications

INFUMORPH is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.10), Drug Interactions (7)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)]
• Hypersensitivity to morphine (e.g., anaphylaxis) [see Adverse Reactions (6)]

Neuraxial administration of INFUMORPH is contraindicated in patients with:

• Infection at the injection microinfusion site [see Warnings and Precautions (5.1)]
• Concomitant anticoagulant therapy [see Warnings and Precautions (5.1)]
• Uncontrolled bleeding diathesis [see Warnings and Precautions (5.1)]
• The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous.

• Significant respiratory depression (4)
• Acute or severe bronchial asthma in an unmonitored setting in absence of resuscitative equipment (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4)
• Known or suspected gastrointestinal obstruction, including paralytic ileus (4)
• Hypersensitivity or intolerance to morphine (4)

Neuraxial administration of INFUMORPH is contraindicated in patients with:

• Infection at the injection microinfusion site (4)
• Concomitant anticoagulant therapy (4)
• Uncontrolled bleeding diathesis (4)
• The presence of any other concomitant therapy or medical condition which would render epidural or
• intrathecal administration of medication especially hazardous. (4) 

5 Warnings And Precautions

• Risk of Inflammatory Masses: Monitor patients receiving continuous infusion of INFUMORPH via indwelling intrathecal catheter for new signs or symptoms of neurologic impairment. (5.6)
• Risk of Tolerance and Myoclonic Activity: Monitor patients for unusual acceleration of neuraxial morphine, which may cause myoclonic-like spasm of lower extremities. Detoxification may be required. (5.7)
• Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. (5.8)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.9)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.11)
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of INFUMORPH in patients with circulatory shock. (5.12)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of INFUMORPH in patients with impaired consciousness or coma. (5.13)

5.1 Risks with Neuraxial Administration

Control of pain by neuraxial opiate delivery, using a continuous microinfusion device, is always accompanied by considerable risk to the patients and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care.

INFUMORPH should be administered by or under the direction of a physician experienced in the techniques of epidural or intrathecal administration and familiar with the patient management problems associated with epidural or intrathecal drug administration. The physician should be familiar with patient conditions (such as infection at the injection site, bleeding diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk potential.

Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose.

The facility must be equipped to resuscitate patients with severe opioid overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases.

For safety reasons, it is recommended that administration of INFUMORPH 200 and 500 (10 and 25 mg/mL, respectively) by the intrathecal route be limited to the lumbar area.

5.2 Addiction, Abuse, and Misuse

INFUMORPH contains morphine, a Schedule II controlled substance. As an opioid, INFUMORPH exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed INFUMORPH. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing INFUMORPH, and monitor all patients receiving INFUMORPH for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as INFUMORPH but use in such patients necessitates intensive counseling about the risks and proper use of INFUMORPH along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing INFUMORPH. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Each ampul of INFUMORPH contains a large amount of a potent narcotic which has been associated with abuse and dependence among health care providers. Due to the limited indications for this product, the risk of overdosage and the risk of its diversion and abuse, it is recommended that special measures must be taken to control this product within the hospital or clinic. INFUMORPH should be subject to rigid accounting, rigorous control of wastage, and restricted access.

5.3 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of INFUMORPH, the risk is greatest during the initiation of therapy or following a dosage increase. This respiratory depression and/or respiratory arrest may be severe and could require intervention.

• Because of the risk of severe adverse effects, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial (single) test dose and, as appropriate, for the first several days after catheter implantation. The facility must be equipped to resuscitate patients with severe opioid overdosage, and the personnel must be familiar with the use and limitations of specific narcotic antagonists (naloxone, naltrexone) in such cases
• Severe respiratory depression up to 24 hours following epidural or intrathecal administration has been reported.
• Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.
• Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.

To reduce the risk of respiratory depression, proper dosing and titration of INFUMORPH are essential [see Dosage and Administration (2)]. Overestimating the INFUMORPH dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. IMPROPER OR ERRONEOUS SUBSTITUTION OF INFUMORPH 200 or 500 (10 or 25 mg/mL, respectively) FOR REGULAR DURAMORPH (0.5 or 1 mg/mL) IS LIKELY TO RESULT IN SERIOUS OVERDOSAGE, LEADING TO SEIZURES, RESPIRATORY DEPRESSION, AND DEATH. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.6)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from concomitant use of INFUMORPH with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation.

5.5 Neonatal Opioid Withdrawal Syndrome

Use of INFUMORPH for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)].

5.6 Risk of Inflammatory Masses

Inflammatory masses such as granulomas, some of which have resulted in serious neurologic impairment including paralysis, have been reported to occur in patients receiving continuous infusion of opioid analgesics including INFUMORPH via indwelling intrathecal catheter. Patients receiving continuous infusion of INFUMORPH via indwelling intrathecal catheter should be carefully monitored for new neurologic signs or symptoms. Further assessment or intervention should be based on the clinical condition of the individual patient.

5.7 Risk of Tolerance and Myoclonic Activity

Patients sometimes manifest unusual acceleration of neuraxial morphine requirements, which may cause concern regarding systemic absorption and the hazards of large doses; these patients may benefit from hospitalization and detoxification. Two cases of myoclonic-like spasm of the lower extremities have been reported in patients receiving more than 20 mg/day of intrathecal morphine.

After detoxification, it might be possible to resume treatment at lower doses, and some patients have been successfully changed from continuous epidural morphine to continuous intrathecal morphine.

Repeat detoxification may be indicated at a later date. The upper daily dosage limit for each patient during continuing treatment must be individualized.

5.8 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics.

Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safety switching the patient to a different opioid moiety) [see Dosage and Administration (2), Warnings and Precautions (5.16)].

5.9Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of INFUMORPH in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended doses of INFUMORPH [see Warnings and Precautions (5.3)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)]. Monitor such patients closely, particularly when initiating and titrating INFUMORPH and when INFUMORPH is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3, 5.4), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.10 Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphine Sulfate Injection should not be used in patients taking MAOIs or within 14 days of stopping such treatment [see Drug Interactions (7)].

5.11 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include nonspecific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.12 Severe Hypotension

INFUMORPH may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of INFUMORPH. In patients with circulatory shock, INFUMORPH may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of INFUMORPH in patients with circulatory shock.

5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO retention (e.g., those with evidence of increased intracranial pressure or brain tumors), INFUMORPH may reduce respiratory drive, and the resultant CO retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with INFUMORPH. INFUMORPH should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events [see Warnings and Precautions (5.7)]. Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of INFUMORPH in patients with impaired consciousness or coma.

5.14 Risks of Use in Patients with Gastrointestinal Conditions

INFUMORPH is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The morphine in INFUMORPH may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. As significant morphine is released into the systemic circulation from neuraxial administration, the ensuing smooth muscle hypertonicity may result in biliary colic.

5.15 Increased Risk of Seizures in Patients with Seizure Disorders

The morphine in INFUMORPH may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical setting associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during INFUMORPH therapy.

5.16 Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including INFUMORPH. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [Drug Interactions (7)] .

When discontinuing INFUMORPH, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue INFUMORPH [see Drug Abuse and Dependence (9.3)] .

5.17 Risks of Driving and Operating Machinery

INFUMORPH may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of INFUMORPH and know how they will react to the medication.

5.18 Risks of Use in Patients with Urinary System Disorders

Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male patients than female patients. Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters.

5.19 Risks of Use in Ambulatory Patients

Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.