Acetaminophen, Caffeine, Dihydrocodeine Bitartrate (Page 4 of 7)

Drug Interactions

CYP2D6 Inhibitors

Dihydrocodeine in Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate is metabolized by CYP2D6 to form dihydromorphine. The concomitant use of Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate and CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, paroxetine bupropion) can increase the plasma concentration of dihydrocodeine, but can decrease the plasma concentration of active metabolite dihydromorphine which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate is achieved.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the dihydrocodeine plasma concentration will decrease but the active metabolite dihydromorphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

If concomitant use with a CYP2D6 inhibitor is necessary or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate 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, Caffeine, and Dihydrocodeine Bitartrate as needed.

After stopping use of a CYP2D6 inhibitor, consider reducing the Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate and monitor the patient for signs and symptoms of respiratory depression or sedation.

CYP3A4 Inhibitors

The concomitant use of Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate with 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 dihydrocodeine plasma concentration with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater dihydromorphine 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, Caffeine, and Dihydrocodeine Bitartrate is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower dihydrocodeine plasma levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihydromorphine levels, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to dihydrocodeine. If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate 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, Caffeine, and Dihydrocodeine Bitartrate dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

CYP3A4 Inducers

The concomitant use of Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin), can result in lower dihydrocodeine levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihydromorphine levels, resulting in decreased efficacy or a withdrawal syndrome in patients who had developed physical dependence to dihydrocodeine.

After stopping a CYP3A4 inducer, as the effects of the inhibitor decline, the dihydrocodeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater dihydromorphine levels, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use with CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate dosage as needed.

If a CYP3A4 inducer is discontinued, consider Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate 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, and 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (used to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see PRECAUTIONS; Information for Patients].

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate immediately if serotonin syndrome is suspected.

Dihydrocodeine with Monoamine Oxidase Inhibitors

Dihydrocodeine, like all opioid analgesics, interacts with monoamine oxidase inhibitors causing central nervous system excitation and hypertension.

Dihydrocodeine with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) may reduce the analgesic effect of this combination product.

Acetaminophen Drug Interactions

Chronic and excessive consumption of alcohol may increase the hepatotoxic risk of Acetaminophen. The potential for hepatotoxicity with Acetaminophen also may be increased in patients receiving anticonvulsants that induce hepatic microsomal enzymes (including phenytoin, barbiturates, and carbamazepine) or isoniazide. Chronic ingestion of large doses of Acetaminophen may slightly potentiate the effects of warfarin-and indandione-derivative anticoagulants. Severe hypothermia is possible in patients receiving Acetaminophen concomitantly with phenothiazines.

Caffeine Drug Interactions

Caffeine may enhance the cardiac inotropic effects of beta-adrenergic stimulating agents. Co-administration of caffeine and disulfiram may lead to a substantial decrease in caffeine clearance. Caffeine may increase the metabolism of other drugs such as phenobarbital and aspirin. Caffeine accumulation may occur when products or foods containing caffeine are consumed concomitantly with quinolones such as ciprofloxacin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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].

Pregnancy:

Teratogenic Effects – Pregnancy Category C.

Animal reproduction studies have not been conducted with Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate capsules. It is also not known whether this combination product can cause fetal harm when administered to pregnant women or can affect reproduction capacity in males and females. This combination product should be given to pregnant women only if clearly needed, especially during the first trimester.

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].

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