Promethazine with Codeine (Page 2 of 11)

2.2 Recommended Dosage

Adults 18 years of age and older: 5 mL every 4 to 6 hours as needed, not to exceed 6 doses (30 mL) in 24 hours.

2.3 Monitoring, Maintenance, and Discontinuation of Therapy

Prescribe Promethazine with Codeine Oral Solution for the shortest duration that is consistent with individual patient treatment goals [see Warnings and Precautions (5.1) ].

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy [see Warnings and Precautions (5.2) ].

Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Warnings and Precautions (5.5) ]. If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with Promethazine with Codeine Oral Solution, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1) ].

Do not abruptly discontinue Promethazine with Codeine Oral Solution in a physically-dependent patient [see Drug Abuse and Dependence (9.3) ]. When a patient who has been taking Promethazine with Codeine Oral Solution regularly and may be physically dependent no longer requires therapy with Promethazine with Codeine Oral Solution, 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.

3 DOSAGE FORMS AND STRENGTHS

Oral solution: Each 5 mL contains codeine phosphate, 10 mg and promethazine hydrochloride 6.25 mg, in a flavored syrup base [see Description (11) ].

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

Promethazine with Codeine Oral Solution contains codeine, a Schedule V controlled substance. As an opioid, Promethazine with Codeine Oral Solution exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ], which can lead to overdose and death [see Overdosage (10) ]. Reserve Promethazine with Codeine Oral Solution for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient’s risk prior to prescribing Promethazine with Codeine Oral Solution, prescribe Promethazine with Codeine Oral Solution for the shortest duration that is consistent with individual patient treatment goals, monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Promethazine with Codeine Oral Solution. Addiction can occur at recommended dosages and if the drug is misused or abused. 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).

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Promethazine with Codeine Oral Solution. 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, including codeine, one of the active ingredients in Promethazine with Codeine Oral Solution. Codeine produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to the active metabolite morphine [see Warnings and Precautions (5.3) ]. Promethazine exerts a depressant effect on the respiratory center that is independent of and additive to that of other respiratory depressants, including codeine [see Warnings and Precautions (5.4) ]. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of Promethazine with Codeine Oral Solution, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), 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 Promethazine with Codeine Oral Solution, the risk is greatest during the initiation of therapy, when Promethazine with Codeine Oral Solution is used concomitantly with other drugs that may cause respiratory depression [see Warnings and Precautions (5.10) ], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (e.g. elderly, cachectic, or debilitated patients) [see Warnings and Precautions (5.6) ].

To reduce the risk of respiratory depression, proper dosing of Promethazine with Codeine Oral Solution is essential [see Dosage and Administration (2.1), Warnings and Precautions (5.7)]. Monitor patients closely, especially within the first 24-72 hours of initiating therapy or when used in patients at higher risk.

Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children younger than 12 years of age has been associated with fatal respiratory depression when used as recommended [see Warnings and Precautions (5.3) ]. Accidental ingestion of even one dose of Promethazine with Codeine Oral Solution, especially by children, can result in respiratory depression and death.

5.3 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

  • Promethazine with Codeine Oral Solution is contraindicated in all children younger than 12 years of age [see Contraindications (4) ].
  • Promethazine with Codeine Oral Solution is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ].
  • Avoid the use of Promethazine with Codeine Oral Solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. 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 (5.10), Use in Specific Populations (8.4) ]
  • Healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see Warnings and Precautions (5.1), Overdosage (10) ].

Lactation

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Promethazine with Codeine Oral Solution [see Use in Specific Populations (8.2) ].

CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). 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) ]. Therefore, individuals who are ultra-rapid metabolizers should not use Promethazine with Codeine Oral Solution.

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