Promethazine with Codeine (Page 3 of 11)

5.4 Promethazine and Respiratory Depression

Children

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients. Concomitant administration with other respiratory depressants may increase the risk of respiratory depression. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine [see Warnings and Precautions (5.3, 5.5, 5.10) ].

Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death [see Overdosage (10) ].

Concomitant Conditions and Other Risk Factors

Avoid use of promethazine in patients at risk for respiratory depression. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions (5.6, 5.10) ].

5.5 Risks with Use in Pediatric Populations

Children are particularly sensitive to the respiratory depressant effects of codeine [see Warnings and Precautions (5.2, 5.3) ] and promethazine [see Warnings and Precautions (5.4) ]. Because of the risk of life-threatening respiratory depression and death, Promethazine with Codeine Oral Solution is contraindicated in children less than 12 years of age, and in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ].

Use of Promethazine with Codeine Oral Solution in children also exposes them to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ], which can lead to overdose and death [see Warnings and Precautions (5.1), Overdosage (10)]. Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of codeine in pediatric patients, Promethazine with Codeine Oral Solution is not indicated for use in patients younger than 18 years of age [see Indications (1), Use in Specific Populations (8.4)].

5.6 Risks with Use in Other At-Risk Populations

Unresponsive Cough

The dosage of Promethazine with Codeine Oral Solution should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Dosage and Administration (2.3) ].

Asthma and Other Pulmonary Disease

The use of Promethazine with Codeine Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [see Contraindications (4) ].

Opioid analgesics and antitussives, including codeine, one of the active ingredients in Promethazine with Codeine Oral Solution, should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function.

Promethazine with Codeine Oral Solution-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 Promethazine with Codeine Oral Solution [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) ].

Because of the risk of respiratory depression, avoid the use of opioid antitussives, including Promethazine with Codeine Oral Solution in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If Promethazine with Codeine Oral Solution is prescribed, monitor such patients closely, particularly when initiating Promethazine with Codeine Oral Solution and when Promethazine with Codeine Oral Solution is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.10) ].

5.7 Risk of Accidental Overdose and Death due to Medication Errors

Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of Promethazine with Codeine Oral Solution is communicated clearly and dispensed accurately [see Dosage and Administration (2.1) ].

Advise patients to always use an accurate milliliter measuring device when measuring and administering Promethazine with Codeine Oral Solution. Inform patients that a household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [see Overdosage (10) ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

5.8 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery

Codeine and promethazine, two of the active ingredients in Promethazine with Codeine Oral Solution, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of Promethazine with Codeine Oral Solution. Avoid concurrent use of Promethazine with Codeine Oral Solution with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.10) ].

5.9 Risks of 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 Promethazine with Codeine Oral Solution requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.

Cytochrome P450 3A4 Interaction

The concomitant use of Promethazine with Codeine Oral Solution 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 Promethazine with Codeine Oral Solution 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.

Avoid the use of Promethazine with Codeine Oral Solution in patients who are taking a CYP3A4 inhibitor or CYP3A4 inducer. If concomitant use of Promethazine with Codeine Oral Solution with inhibitors and inducers of CYP3A4 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [see Drug Interactions (7.1, 7.2) ].

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

The concomitant use of Promethazine with Codeine Oral Solution 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.

Avoid the use of Promethazine with Codeine Oral Solution in patients who are taking a CYP2D6 inhibitor. If concomitant use of Promethazine with Codeine Oral Solution with inhibitors of CYP2D6 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [see Drug Interactions (7.3) ].

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