Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Promethazine with Codeine Oral Solution [see Warnings and Precautions (5.3) ].
There are no data on the presence of Promethazine with Codeine Oral Solution in human milk, the effects of Promethazine with Codeine Oral Solution on the breastfed infant, or the effects of Promethazine with Codeine Oral Solution on milk production; however, data are available with codeine and promethazine.
Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression and death (in one infant) in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. There is no information on the effects of the codeine on milk production.
There are no data on the presence of promethazine in human milk. However, direct oral administration of promethazine has been associated with respiratory depression, including fatalities, in pediatric patients [see Warnings and Precautions (5.4) ]. Promethazine has been shown to decrease basal prolactin levels in non-nursing women, and therefore may affect milk production.
Infants exposed to Promethazine with Codeine Oral Solution through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped.
8.8 Females and Males of Reproductive Potential
Chronic use of opioids, such as codeine, a component of Promethazine with Codeine Oral Solution, 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 (6), Clinical Pharmacology (12.2)].
8.9 Pediatric Use
Promethazine with Codeine Oral Solution is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of codeine in these patients [see Indications (1), Warnings and Precautions (5.5)].
Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions (5.2) ]. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine.
Life-threatening respiratory depression and death have also occurred in children who received 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 for 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 unless the benefits outweigh the risks. 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 (5.3, 5.6) ].
8.10 Geriatric Use
Use caution when considering the use of Promethazine with Codeine Oral Solution in patients 65 years of age or older. Elderly patients may have increased sensitivity to codeine; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [see Warnings and Precautions (5.6) ].
Respiratory depression is the chief risk for elderly patients treated with opioids, including Promethazine with Codeine Oral Solution. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration [see Warnings and Precautions (5.6, 5.10) ].
Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor these patients closely for respiratory depression, sedation, and hypotension.
8.11 Renal Impairment
The pharmacokinetics of Promethazine with Codeine Oral Solution has not been characterized in patients with renal impairment. Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Promethazine with Codeine Oral Solution should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.
8.12 Hepatic Impairment
No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of Promethazine with Codeine Oral Solution in this patient population are unknown. Promethazine with Codeine Oral Solution should be used with caution in patients with impairment of hepatic function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.
9.4 Controlled Substance
Promethazine with Codeine Oral Solution contains codeine, a substance with a high potential for abuse similar to other opioids including morphine and codeine. Promethazine with Codeine Oral Solution can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) ].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic and antitussive products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Promethazine with Codeine Oral Solution, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of Promethazine with Codeine Oral Solution
Promethazine with Codeine Oral Solution is for oral use only. Abuse of Promethazine with Codeine Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Promethazine with Codeine Oral Solution with alcohol and other central nervous system depressants [see Warnings and Precautions (5.10) ].
Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
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