Promethazine Hydrochloride and Codeine Phosphate

Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate Oral Solution is a combination of codeine, an opioid agonist; and promethazine, a phenothiazine, indicated for the temporary relief of cough and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older. ( 1 ) Important Limitations of Use ( 1 ) Not indicated for pediatric patients under 18 years of age. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Promethazine HCl and Codeine Phosphate 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.

Oral solution: Each 5 mL contains codeine phosphate, 10 mg and promethazine hydrochloride 6.25 mg, in a flavored syrup base [ see Description (11) ]. Oral solution: Each 5 mL contains codeine phosphate, 10 mg and promethazine hydrochloride 6.25 mg, in a clear, purple red, peach-mint flavor syrup. ( 3 )

Promethazine HCl and Codeine Phosphate Oral Solution is contraindicated for: All children younger than 12 years of age [ see Warnings and Precautions (5.2 , 5.3 , 5.5 ), Use in Specific Populations (8.4) ]. Postoperative pain management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Warnings and Precautions (5.2 , 5.3 ) ]. Promethazine HCl and Codeine Phosphate Oral Solution is also contraindicated in patients with: Significant respiratory depression [ see Warnings and Precautions (5.2) ]. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [ see Warnings and Precautions (5.6) ] . Known or suspected gastrointestinal obstruction, including paralytic ileus [ see Warnings and Precautions (5.11) ]. A history of an idiosyncratic reaction to promethazine or to other phenothiazines [ see Warnings and Precautions (5.14) ]. Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days [ see Warnings and Precautions (5.16) , Drug Interactions (7.6) ]. Hypersensitivity to codeine, promethazine, or any of the inactive ingredients in Promethazine HCl and Codeine Phosphate Oral Solution [ see Adverse Reactions (6) ]. Persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine. Children younger than 12 years of age. ( 4 ) Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Concurrent use of monoamine oxidase inhibitor (MAOI) therapy or within the last 14 days. ( 4 ) History of an idiosyncratic reaction to promethazine or to other phenothiazines. ( 4 ) Hypersensitivity to codeine or other opiates, promethazine, or any of the inactive ingredients in Promethazine HCl and Codeine Phosphate Oral Solution. ( 4 )

See Boxed WARNINGS Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients : Monitor closely, particularly during initiation of therapy. ( 5.6 ) Activities requiring mental alertness : Avoid engaging in hazardous tasks requiring mental alertness such as driving or operating machinery. ( 5.8 ) Risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors : Avoid use. May increase intracranial pressure and obscure the clinical course of head injuries. ( 5.12 ) Neuroleptic Malignant Syndrome : Monitor during therapy. ( 5.13 ) Paradoxical Reactions : Monitor during therapy. ( 5.14 ) Seizures in patients with seizure disorders : Monitor during therapy. ( 5.15 ) Bone marrow depression : Use with caution in patients with bone marrow depression. ( 5.17 ) Severe hypotension : Monitor during initiation of therapy. Avoid use in patients with circulatory shock. ( 5.18 ) Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.20 )

5.1 Addiction, Abuse, and Misuse Promethazine HCl and Codeine Phosphate Oral Solution contains codeine, a Schedule V controlled substance. As an opioid, Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate Oral Solution, prescribe Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 (CO 2 ) 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 HCl and Codeine Phosphate Oral Solution, the risk is greatest during the initiation of therapy, when Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate Oral Solution is contraindicated in all children younger than 12 years of age [ see Contraindications (4) ] . Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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) ]. […]

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, abuse, and misuse [ see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.3) ] Life-threatening respiratory depression [ see Warnings and Precautions (5.2, 5.3 , 5.4 , 5.5 , 5.6 ), Overdosage (10) ] Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children [ see Warnings and Precautions (5.3) ] Accidental overdose and death due to medication errors [ see Warnings and Precautions (5.7) ] Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions (5.8) ] Interactions with benzodiazepines and other CNS depressants [ see Warnings and Precautions (5.10) ] Paralytic ileus, gastrointestinal adverse reactions [ see Warnings and Precautions (5.11) ] Increased intracranial pressure [ see Warnings and Precautions (5.12) ] Obscured clinical course in patients with head injuries [ see Warnings and Precautions (5.12) ] Neuroleptic Malignant Syndrome [ see Warnings and Precautions (5.13) ] Paradoxical reactions, including dystonias [ see Warnings and Precautions (5.14) ] Seizures [ see Warnings and Precautions (5.15) ] Interactions with MAOI [ see Warnings and Precautions (5.16) ] Bone marrow suppression [ see Warnings and Precautions (5.17) ] Severe hypotension [ see Warnings and Precautions (5.18) ] Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions (5.19) ] Adrenal insufficiency [ see Warnings and Precautions (5.20) ] The following adverse reactions have been identified during clinical studies, in the literature, or during postapproval use of codeine and/or promethazine. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions to Promethazine HCl and Codeine Phosphate Oral Solution include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, sweating. Other reactions include: Anaphylaxis : Anaphylaxis has been reported with codeine, one of the ingredients in Promethazine HCl and Codeine Phosphate Oral Solution. Body as a whole : Coma, death, fatigue, falling injuries, lethargy. Cardiovascular : Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush. Central Nervous System : Ataxia, diplopia, facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tinnitus, tremor, vertigo. Dermatologic : Flushing, hyperhidrosis, photosensitivity, pruritus, rash, urticaria. Endocrine/Metabolic : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology (12.2) ]. Gastrointestinal : Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, dry mouth, GERD, indigestion, jaundice, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi). Genitourinary : Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention. Hematologic : Bone marrow suppression, agranulocytosis, aplastic anemia, and thrombocytopenia have been reported. Laboratory : Increases in serum amylase. Musculoskeletal : Arthralgia, backache, muscle spasm. Ophthalmic : Blurred vision, miosis (constricted pupils), visual disturbances. Paradoxical Reactions : Dystonias, torticollis, tongue protrusion, hyperexcitability, and abnormal movements have been reported following a single administration of promethazine. Psychiatric : Agitation, anxiety, confusion, fear, dysphoria, depression, hallucinations. Reproductive : Hypogonadism, infertility. Respiratory : Apnea, bronchitis, cough, dry nose, dry throat, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, thickening of bronchial secretions, tightness of chest and wheezing, upper respiratory tract infection. Other : Drug abuse, drug dependence, Neuroleptic Malignant Syndrome, opioid withdrawal syndrome. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, and sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

No specific drug interaction studies have been conducted with Promethazine HCl and Codeine Phosphate Oral Solution. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is suspected. ( 7.5 ) Muscle relaxants : Avoid concomitant use. ( 7.7 ) Diuretics : Codeine may reduce the efficacy of diuretics. Monitor for reduced effect. ( 7.8 ) Anticholinergic drugs : Concurrent use may cause paralytic ileus. ( 5.11 , 7.9 )

7.1 Inhibitors of CYP3A4 The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Promethazine HCl and Codeine Phosphate Oral Solution is achieved [ see Warnings and Precautions (5.9) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels [ see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution while taking a CYP3A4 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals. 7.2 CYP3A4 Inducers The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution and CYP3A4 inducers, such as rifampin, carbamazepine, or phenytoin, can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [ see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [ see Warnings and Precautions (5.9) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, codeine plasma concentrations may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [ see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.3 Inhibitors of CYP2D6 Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate Oral Solution in patients who are taking inhibitors of CYP2D6.

7.4 Benzodiazepines, and Other CNS 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate Oral Solution if serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs) Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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.

7.8 Diuretics 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 HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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].

7.1 Inhibitors of CYP3A4 The concomitant use of Promethazine HCl and Codeine Phosphate Oral Solution with CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Promethazine HCl and Codeine Phosphate Oral Solution is achieved [ see Warnings and Precautions (5.9) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels [ see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Avoid the use of Promethazine HCl and Codeine Phosphate Oral Solution while taking a CYP3A4 inhibitor. […]

Pregnancy : Avoid use in pregnant women. May cause fetal harm. ( 8.1 ) Lactation : Breastfeeding not recommended. ( 8.2 ) Renal Impairment : Use with caution in patients with severe renal impairment. ( 8.6 ) Hepatic Impairment : Use with caution in patients with severe hepatic impairment. ( 8.7 )

8.1 Pregnancy Risk Summary Promethazine HCl and Codeine Phosphate Oral Solution is not recommended for use in pregnant women, including during or immediately prior to labor. Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [ see Warnings and Precautions (5.19) , Clinical Considerations ]. There are no available data with Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate 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. Clinical Considerations 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 HCl and Codeine Phosphate 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. Data Human Data 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. Animal Data Reproductive toxicity studies have not been conducted with Promethazine HCl and Codeine Phosphate Oral Solution; however, studies are available with individual active ingredients. Codeine 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/m 2 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/m 2 basis with maternal oral doses of 30 mg/kg/day in rabbits and 600 mg/kg/day in mice). Promethazine 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/m 2 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/m 2 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/m 2 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/m 2 basis with maternal oral doses up to 10 mg/kg/day). The relevance of these findings to humans is unclear.

8.2 Lactation Risk Summary 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 HCl and Codeine Phosphate Oral Solution [ see Warnings and Precautions (5.3) ]. There are no data on the presence of Promethazine HCl and Codeine Phosphate Oral Solution in human milk, the effects of Promethazine HCl and Codeine Phosphate Oral Solution on the breastfed infant, or the effects of Promethazine HCl and Codeine Phosphate Oral Solution on milk production; however, data are available with codeine and promethazine. Codeine 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. Promethazine There are no data on the presence of promethazine in human milk. […]

Codeine Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic and antitussive properties of codeine have been speculated to come from its conversion to morphine. The precise mechanism of action of codeine and other opiates is not known; however, codeine is believed to act centrally on the cough center. In excessive doses, codeine will depress respiration. Promethazine Promethazine is a phenothiazine derivative, which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. Promethazine possesses antihistamine (H 1 receptor antagonist), antiemetic, sedative, and anticholinergic effects. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.