Codeineinteractions

No specific drug interaction studies have been conducted with Promethazine HCl and Codeine Phosphate Oral Solution.

Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is suspected.

Muscle relaxants: Avoid concomitant use.

Diuretics: Codeine may reduce the efficacy of diuretics. Monitor for reduced effect.

Anticholinergic drugs: Concurrent use may cause paralytic ileus.

7.1 Inhibitors of CYP3A4

The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or 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 Promethazine HCl and Codeine Phosphate Oral Solution is achieved. 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, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution while taking a CYP3A4 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

7.2 CYP3A4 Inducers

The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution and CYP3A4 inducers, such as rifampin, carbamazepine, or phenytoin, can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. 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, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.3 Inhibitors of CYP2D6

Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution and CYP2D6 inhibitors, such as paroxetine, fluoxetine, bupropion, or quinidine, can increase the plasma concentration of codeine, but can decrease the plasma concentration of active metabolite morphine, which could result in reduced efficacy. 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. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking inhibitors of CYP2D6.

7.4 Benzodiazepines, and

Other 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. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking benzodiazepines or other CNS depressants..

7.5 Serotonergic

Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue Promethazine HCl and Codeine Phosphate Oral Solution if serotonin syndrome is suspected.

7.6 Monoamine

Oxidase Inhibitors (MAOIs) Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients who are taking MAOIs (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease) or have taken MAOIs within 14 days. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.

7.7 Muscle Relaxants

Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.8 Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.9 Anticholinergic

Drugs The concomitant use of anticholinergic drugs with Promethazine HCl and Codeine Phosphate Oral Solution may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when Promethazine HCl and Codeine Phosphate Oral Solution is used concomitantly with anticholinergic drugs. Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with promethazine].

7.1 Inhibitors of CYP3A4

The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or 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 Promethazine HCl and Codeine Phosphate Oral Solution is achieved. 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, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution while taking a CYP3A4 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

7.2 CYP3A4 Inducers

The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution and CYP3A4 inducers, such as rifampin, carbamazepine, or phenytoin, can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. 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, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.3 Inhibitors of CYP2D6

Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution and CYP2D6 inhibitors, such as paroxetine, fluoxetine, bupropion, or quinidine, can increase the plasma concentration of codeine, but can decrease the plasma concentration of active metabolite morphine, which could result in reduced efficacy. 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. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking inhibitors of CYP2D6.

7.4 Benzodiazepines, and

Other 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. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking benzodiazepines or other CNS depressants..

7.5 Serotonergic

Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue Promethazine HCl and Codeine Phosphate Oral Solution if serotonin syndrome is suspected.

7.6 Monoamine

Oxidase Inhibitors (MAOIs) Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated in patients who are taking MAOIs (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease) or have taken MAOIs within 14 days. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.

7.7 Muscle Relaxants

Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.8 Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.9 Anticholinergic

Drugs The concomitant use of anticholinergic drugs with Promethazine HCl and Codeine Phosphate Oral Solution may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when Promethazine HCl and Codeine Phosphate Oral Solution is used concomitantly with anticholinergic drugs. Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with promethazine].