7.3 Inhibitors of CYP2D6
Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Promethazine with Codeine 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 [see Clinical Pharmacology (12.3) ].
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 [see Clinical Pharmacology (12.3) ].
Avoid the use of Promethazine with Codeine Oral Solution in patients who are taking inhibitors of CYP2D6.
7.4 Benzodiazepines, and Other 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 with Codeine Oral Solution in patients who are taking benzodiazepines or other CNS depressants. [see Warnings and Precautions (5.10)].
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 with Codeine Oral Solution if serotonin syndrome is suspected.
7.6 Monoamine Oxidase Inhibitors (MAOIs)
Promethazine with Codeine 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 [see Contraindications (4) ].
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.16) ].
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 with Codeine 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.
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 with Codeine Oral Solution may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [see Warnings and Precautions (5.11) ]. Monitor patients for signs of urinary retention or reduced gastric motility when Promethazine with Codeine 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].
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.
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