Codeine sulfate (codeine sulfate 30 mg) Dailymed

• •Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1)
• •Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)
• •Initiate treatment with 15 to 60 mg every 4 hours as needed. (2.2)
• •Do not stop Codeine Sulfate Tablets abruptly in a physically dependent patient. (2.4)

2.1 Important Dosage and Administration Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].

Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Codeine Sulfate Tablets and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

2.2 Initial Dosage

Initiating Treatment with Codeine Sulfate Tablets

Initiate treatment with Codeine Sulfate Tablets in a dosing range of 15 to 60 mg every 4 hours as needed for pain.

Adult doses of Codeine Sulfate Tablets higher than 60 mg provide no further efficacy but are associated with greater adverse reactions. The maximum 24 hour dose is 360 mg.

Conversion from Other Opioids to Codeine Sulfate Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Codeine Sulfate Tablets. It is safer to underestimate a patient’s 24-hour Codeine Sulfate Tablets dosage than to overestimate the 24-hour Codeine Sulfate Tablets dosage and manage an adverse reaction due to overdose.

2.3 Titration and Maintenance of Therapy

Individually titrate Codeine Sulfate Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving codeine sulfate to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. 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 increased pain before increasing the Codeine Sulfate Tablets dosage. 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.

2.4 Discontinuation of Codeine Sulfate Tablets

When a patient who has been taking Codeine Sulfate Tablets regularly and may be physically dependent no longer requires therapy with Codeine Sulfate Tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, 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 abruptly discontinue Codeine Sulfate Tablets in a physically-dependent patient [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)].

3 Dosage Forms And Strengths

Each 15 mg tablet for oral administration contains 15 mg of codeine sulfate USP. It is a white to off-white biconvex tablet with “15” debossed on the scored side and “54 613” debossed on the other side.

Each 30 mg tablet for oral administration contains 30 mg of codeine sulfate USP. It is a white to off-white biconvex tablet with “30” debossed on the scored side and “54 783” debossed on the other side.

Each 60 mg tablet for oral administration contains 60 mg of codeine sulfate USP. It is a white to off-white biconvex tablet with “60” debossed on the scored side and “54 412” debossed on the other side.


Tablets: 15 mg, 30 mg and 60 mg (3)

4 Contraindications

Codeine Sulfate Tablets are contraindicated in patients with:

• •Significant respiratory depression [see Warnings and Precautions (5.2)].
• •Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.4)].
• •Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)].
• • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.8), Drug Interactions (7)].
• •Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12)].
• •Hypersensitivity to codeine (e.g., anaphylaxis) [see Adverse Reactions (6)].

• •Significant respiratory depression. (4)
• •Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy. (4)
• •Acute or severe bronchial asthma in an unmonitored setting or 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 to codeine. (4)

5 Warnings And Precautions

• • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.7)
• • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.9)
• • Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Codeine Sulfate Tablets in patients with circulatory shock. (5.10)
• • 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 Codeine Sulfate Tablets in patients with impaired consciousness or coma. (5.11)

5.1 Addiction, Abuse, and Misuse

Codeine Sulfate Tablets contain codeine, a Schedule II controlled substance. As an opioid, Codeine Sulfate Tablets 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 Codeine Sulfate Tablets. 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 Codeine Sulfate Tablets, and monitor all patients receiving Codeine Sulfate Tablets 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 Codeine Sulfate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Codeine Sulfate Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Codeine Sulfate Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. 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.

5.2 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 (CO2) 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 Codeine Sulfate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Codeine Sulfate Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Codeine Sulfate Tablets are essential [see Dosage and Administration (2.2, 2.3)]. Overestimating the Codeine Sulfate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of Codeine Sulfate Tablets, especially by children, can result in respiratory depression and death due to an overdose of codeine.

5.3 Neonatal Opioid Withdrawal Syndrome

Prolonged use of Codeine Sulfate Tablets 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

5.4 Death Related to Ultra-Rapid Metabolism of Codeine to Morphine

Codeine Sulfate Tablets are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications (4)].

Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine [see Use in Specific Populations (8.4)].

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5% to 1% in Chinese and Japanese, 0.5% to 1% in Hispanics, 1% to 10% in Caucasians, 3% in African Americans, and 16% to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage (10)].

Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine.

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Codeine Sulfate Tablets requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Codeine Sulfate Tablets with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

The concomitant use of Codeine Sulfate Tablets with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Follow patients receiving Codeine Sulfate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codeine Sulfate Tablets are used in conjunction with inhibitors and inducers of CYP3A4.

If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Codeine Sulfate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Codeine Sulfate Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal [Drug Interactions (7)].

Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of Codeine Sulfate Tablets with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

Follow patients receiving Codeine Sulfate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Codeine Sulfate Tablets are used in conjunction with inhibitors of CYP2D6.

If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the Codeine Sulfate Tablets dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Codeine Sulfate Tablets dosage and follow the patient for signs and symptoms of respiratory depression or sedation [see Drug Interactions (7)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Codeine Sulfate Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

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. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Codeine Sulfate Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs

[see Drug Interactions (7), Patient Counseling Information (17)].

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

The use of Codeine Sulfate Tablets 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

Codeine Sulfate Tablets-treated 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 dosages of Codeine Sulfate Tablets [see Warnings and Precautions (5.2)].

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 (5.2)].

Monitor such patients closely, particularly when initiating and titrating Codeine Sulfate Tablets and when Codeine Sulfate Tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.6)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.8 Interaction with Monoamine Oxidase Inhibitors

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

5.9 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 non-specific 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.

5.10 Severe Hypotension

Codeine Sulfate Tablets 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 Codeine Sulfate Tablets. In patients with circulatory shock, Codeine Sulfate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Codeine Sulfate Tablets in patients with circulatory shock.

5.11 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 CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Codeine Sulfate Tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Codeine Sulfate Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Codeine Sulfate Tablets in patients with impaired consciousness or coma.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

Codeine Sulfate Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The codeine in Codeine Sulfate Tablets 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.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The codeine in Codeine Sulfate Tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occuring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Codeine Sulfate Tablets therapy.

5.14 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 Codeine Sulfate Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing Codeine Sulfate Tablets in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue Codeine Sulfate Tablets in these patients [see Drug Abuse and Dependence (9.3)].

5.15 Risks of Driving and Operating Machinery

Codeine Sulfate Tablets 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 Codeine Sulfate Tablets and know how they will react to the medication [see Patient Counseling Information (17)].

6 Adverse Reactions

The following serious adverse reactions are described, or described in greater detail, in other sections:

• •Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• •Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• •Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
• •Death Related to Ultra-rapid Metabolizers of Codeine [see Warnings and Precautions (5.4)]
• •Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.6)]
• •Adrenal Insufficiency [see Warnings and Precautions (5.9)]
• •Severe Hypotension [see Warnings and Precautions (5.10)]
• •Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12)]
• •Seizures [see Warnings and Precautions (5.13)]
• •Withdrawal [see Warnings and Precautions (5.14)]
  The following adverse reactions associated with the use of codeine were identified in clinical studies or postmarketing reports. Because some 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.
  
  Serious adverse reactions associated with codeine were respiratory depression and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.
  

The most frequently observed adverse reactions with codeine administration included drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation.

Other adverse reactions included allergic reactions, euphoria, dysphoria, abdominal pain, and pruritis.

Other less frequently observed adverse reactions expected from opioid analgesics, including Codeine Sulfate Tablets, include: 

Cardiovascular System: faintness, flushing, hypotension, palpitations, syncope

Digestive System: abdominal cramps, anorexia, diarrhea, dry mouth, gastrointestinal distress, pancreatitis

Nervous System: anxiety, drowsiness, fatigue, headache, insomnia, nervousness, shakiness, somnolence, vertigo, visual disturbances, weakness

Skin and Appendages: rash, sweating, urticaria

Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

<sup>Anaphylaxis:Anaphylaxis has been reported with ingredients contained in Codeine Sulfate Tablets.

Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].</sup>


The most common adverse reactions include: drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 Drug Interactions

Table 1 includes clinically significant drug interactions with Codeine Sulfate Tablets.

Table 1: Clinically Significant Drug Interactions with Codeine Sulfate Tablets

Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of Codeine Sulfate Tablets with CYP3A4 inhibitors, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Codeine Sulfate Tablets is achieved [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine.
Intervention:	If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of Codeine Sulfate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Codeine Sulfate Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of Codeine Sulfate Tablets and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, codeine plasma concentrations may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the Codeine Sulfate Tablets dosage as needed. If a CYP3A4 inducer is discontinued, consider Codeine Sulfate tablets dosage reduction and monitor for signs of respiratory depression and sedation at frequent intervals.
Examples:	Rifampin, carbamazepine, phenytoin
Inhibitors of CYP2D6
Clinical Impact:	Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Codeine Sulfate Tablets and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentration of active metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Codeine Sulfate Tablets is achieved [see Clinical Pharmacology (12.3)]. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Codeine Sulfate Tablet and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Codeine Sulfate Tablets as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the Codeine Sulfate Tablets and monitor the patient for signs and symptoms of respiratory depression or sedation.
Examples	Paroxetine, fluoxetine, bupropion, quinidine.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Codeine Sulfate Tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.8)].
Intervention:	Do not use Codeine Sulfate Tablets in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	Phenelzine, tranylcypromine, linezolid.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Codeine Sulfate Tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:	Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Codeine Sulfate Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Codeine Sulfate Tablets are used concomitantly with anticholinergic drugs.

• • Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue codeine sulfate if serotonin syndrome is suspected. (7)
• • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Codeine Sulfate Tablets because they may reduce analgesic effect of Codeine Sulfate Tablets or precipitate withdrawal symptoms. (7)

8 Use In Specific Populations

• • Pregnancy: May cause fetal harm. (8.1)
• • Lactation: The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and the baby. (8.2)

8.1 Pregnancy

Pregnancy Category C

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Codeine Sulfate Tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 1.4 times maximum recommended human dose (MRHD) of 360 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 2 to 3 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD [see Data ].

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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions: Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Codeine Sulfate Tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Codeine Sulfate Tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data: Studies on the reproductive and developmental effects of codeine have been reported in the published literature in hamsters, rats, mice and rabbits.

In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 7 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 2 to 8 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (oral; approximately 3 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 1.4 times the recommended daily dose of 360 mg/day for adults on a mg/mg² basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring.

No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 2 times the maximum recommended daily dose of 360 mg/day for adults on a mg/m² basis) of codeine during organogenesis.

Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 0.8 times the maximum recommended human dose of 360 mg/day on a body surface area comparison.

8.2 Lactation

Risk Summary

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Codeine Sulfate Tablets and any potential adverse effects on the breastfed infant from Codeine Sulfate Tablets or from the underlying maternal condition.

Clinical Considerations

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and the baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Infants exposed to codeine sulfate through breast milk should be monitored for excess sedation and respiratory depression. Mothers using Codeine Sulfate Tablets should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breast-feeding.

Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6)].

8.4 Pediatric Use

The safety and effectiveness and the pharmacokinetics of Codeine Sulfate Tablets in pediatric patients below the age of 18 have not been established.

Respiratory depression and death have occurred in children with obstructive sleep apnea who received Codeine Sulfate Tablets in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications (4)].

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to codeine. In general, use caution when selecting a dosage for an elderly patient, 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.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Codeine Sulfate Tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7)].

Codeine 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.

8.6 Hepatic Impairment

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of codeine in this patient population are unknown. Start these patients with a lower than normal dosage of Codeine Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.

8.7 Renal Impairment

Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients with a lower than normal dosage of Codeine Sulfate Tablets or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.