WOCKHARDT PROMETHAZINE WITH CODEINE
$300.00 – $600.00
Promethazine with Codeine Oral Solution contains codeine, an opioid agonist, and promethazine, a phenothiazine.
Each 5 mL of Promethazine with Codeine Oral Solution contains 10 mg of codeine phosphate and 6.25 mg of promethazine hydrochloride for oral administration.
Promethazine with Codeine Oral Solution has a pH between 4.8 and 5.4 and contains alcohol 7%.
Promethazine with Codeine Oral Solution also contains the following inactive ingredients: artificial and natural flavors, citric acid, D&C Red 33, FD&C Blue 1, FD&C Yellow 6, glycerin, saccharin sodium, sodium benzoate, sodium citrate, sodium propionate, water, and other ingredients.
The chemical name for codeine phosphate is 7,8-Didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate. Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy, it is classified pharmacologically as a narcotic analgesic. The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. The molecular weight is 406.37. Its molecular formula is C18H21NO3•H3PO4 • ½ H2O, and it has the following chemical structure.
The chemical name for promethazine hydrochloride, a phenothiazine derivative, is (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride. Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohol. The molecular weight is 320.88. Its molecular formula is C17H20N2S•HCl, and it has the following chemical structure.
Promethazine with Codeine Oral Solution is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older.
Important Limitations of Use
- Not indicated for pediatric patients under 18 years of age [SEE USE IN SPECIFIC POPULATIONS (8.4) ].
- Contraindicated in pediatric patients under 12 years of age [see CONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.4) ].
- Contraindicated in pediatric patients 12 to 18 years of age after tonsillectomy or adenoidectomy [see Contraindications (4), Use in Specific Populations (8.4) ].
- Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see WARNINGS AND PRECAUTIONS (5.1) ], 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.
Promethazine with Codeine Oral Solution is not recommended for use in pregnant women, including during or immediately prior to labor.
There are no available data with Promethazine with Codeine Oral Solution use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Published studies with codeine have reported inconsistent findings and have important methodological limitations (see DATA). There are reports of respiratory depression when codeine is used during labor and delivery (see CLINICAL CONSIDERATIONS).
Reproductive toxicity studies have not been conducted with Promethazine with Codeine Oral Solution; however, studies are available with individual active ingredients (see DATA).
In animal reproduction studies, codeine administered by the oral route to pregnant rats during the period of organogenesis increased resorptions and decreased fetal weights at a dose approximately 25 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity (see DATA).
For pregnant mice and rats that received promethazine at doses 0.2 and 3-6 times the MRHD, during various periods of gestation, there were findings of increased fetal resorptions and skeletal fragility, decreased pup weight, and developmental delays of pups (see DATA).
Based on the animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
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 AND PRECAUTIONS (5.19)].
Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including Promethazine with Codeine Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression.
Published data from case-control and observational studies on codeine use during pregnancy are inconsistent in their findings. Some studies of codeine exposure showed an increased risk of overall congenital malformations while others did not. An increased risk of specific malformations with codeine exposure such as respiratory malformations, spina bifida and congenital heart defects were reported in some studies.
The majority of studies examining the use of promethazine in pregnancy did not find an association with an increased risk of congenital anomalies. In the few studies reporting an association, no consistent pattern of malformations was noted.
Most of the studies, both positive and negative, were limited by small sample size, recall bias and lack of information regarding dose and timing of exposure.
Reproductive toxicity studies have not been conducted with Promethazine with Codeine Oral Solution; however, studies are available with individual active ingredients.
In an embryofetal development study in pregnant rats dosed throughout the period of organogenesis, codeine increased resorptions and decreased fetal weights at a dose approximately 25 times the MRHD (on a mg/m2 basis with a maternal oral dose of 120 mg/kg/day); however, these effects occurred in the presence of maternal toxicity. In embryofetal development studies with pregnant rabbits and mice dosed throughout the period of organogenesis, codeine produced no adverse developmental effects at doses approximately 15 and 65 times, respectively, the MRHD (on a mg/m2 basis with maternal oral doses of 30 mg/kg/day in rabbits and 600 mg/kg/day in mice).
In pregnant mice dosed during the period of implantation from gestation days 1 to 5, promethazine increased resorption at doses approximately 0.2 times the MRHD (on a mg/m2 basis with maternal intraperitoneal and subcutaneous doses up to 1 mg/kg/day).
In pregnant rats dosed during the period of organogenesis from gestation days 5 to 16, promethazine hydrochloride induced complete resorption at doses approximately 6 times the MRHD (on a mg/m2 basis with maternal oral doses up to 20 mg/kg/day).
In pregnant rats dosed during the period of organogenesis from gestation days 7 to 13, promethazine resulted in skeletal fragility of pups at doses approximately 3 times the MRHD (on a mg/m2 basis with maternal oral doses up to 10 mg/kg/day).
In pregnant rats dosed during the period of organogenesis from gestation days 10 to 12, promethazine resulted in decreased weight and delays in initial occurrence of behavioral/reflex of pups at doses approximately 3 times the MRHD (on a mg/m2 basis with maternal oral doses up to 10 mg/kg/day). The relevance of these findings to humans is unclear.
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.