Acetaminophen and Codeine (Page 6 of 10)

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of acetaminophen and codeine phosphate tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see WARNINGS; Pregnancy).

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that acetaminophen and codeine phosphate tablets can cause fetal harm and to inform the prescriber of a known or suspected pregnancy (see PRECAUTIONS; Pregnancy).

Lactation

Advise women that breastfeeding is not recommended during treatment with acetaminophen and codeine phosphate tablets (see PRECAUTIONS; Nursing Mothers).

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Driving or Operating Heavy Machinery

Inform patients that acetaminophen and codeine phosphate tablets may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery and to avoid such tasks while taking this product, until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention (see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY).

Drug Interactions

CYP2D6 Inhibitors

Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of acetaminophen and codeine phosphate tablets and CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion, quinidine) 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 acetaminophen and codeine phosphate tablets are achieved (see CLINICAL PHARMACOLOGY).

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).

If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of acetaminophen and codeine phosphate tablets 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 acetaminophen and codeine phosphate tablets as needed.

After stopping use of a CYP2D6 inhibitor, consider reducing the acetaminophen and codeine phosphate tablets and monitor the patient for signs and symptoms of respiratory depression or sedation.

CYP3A4 Inhibitors

The concomitant use of acetaminophen and codeine phosphate tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), 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 acetaminophen and codeine phosphate tablets is achieved (see WARNINGS).

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), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine.

If concomitant use of CYP3A4 inhibitor is necessary, consider dosage reduction of acetaminophen and codeine 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 acetaminophen and codeine phosphate tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

CYP3A4 Inducers

The concomitant use of acetaminophen and codeine phosphate tablets and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels (see CLINICAL PHARMACOLOGY), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence (see WARNINGS).

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), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the acetaminophen and codeine phosphate tablets dosage as needed.

If a CYP3A4 inducer is discontinued, consider acetaminophen and codeine phosphate tablets dosage reduction and monitor for signs of respiratory depression and sedation at frequent intervals.

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

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).

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome (see PRECAUTIONS; Information for Patients).

If concomitant use is warranted, carefully follow the patient, particularly during treatment initiation and dose adjustment. Discontinue acetaminophen and codeine phosphate tablets if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, linezolid, may manifest as serotonin syndrome or opioid toxicity.

Advise patients taking acetaminophen and codeine phosphate tablets not to use 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 or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of acetaminophen and codeine phosphate tablets and/or precipitate withdrawal symptoms.

Advise patient to avoid concomitant use of these drugs.

Muscle Relaxants

Acetaminophen and codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

If concomitant use is warranted, monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of acetaminophen and codeine phosphate tablets and/or the muscle relaxant as necessary.

Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

If concomitant use is warranted, monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

If concomitant use is warranted, monitor patients for signs of urinary retention or reduced gastric motility when acetaminophen and codeine phosphate tablets are used concomitantly with anticholinergic drugs.

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