Promethazine Hydrochloride and Codeine Phosphate

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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. ( 2.2 ) Measure Promethazine HCl and Codeine Phosphate Oral Solution with an accurate milliliter measuring device. ( 2.1 , 5.7 ) Do not increase the dose or dosing frequency. ( 2.1 ) Prescribe for the shortest duration consistent with treatment goals. ( 2.3 ) Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology. ( 2.3 ) Reevaluate patient prior to refilling. (2.3) 2.1 Important Dosage and Administration Instructions Administer Promethazine HCl and Codeine Phosphate Oral Solution by the oral route only. Always use an accurate milliliter measuring device when administering Promethazine HCl and Codeine Phosphate Oral Solution to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [ see Warnings and Precautions (5.7) ] . For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. Do not overfill. Rinse the measuring device with water after each use. Advise patients not to increase the dose or dosing frequency of Promethazine HCl and Codeine Phosphate Oral Solution because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions (5.1) , Overdosage (10) ]. The dosage of Promethazine HCl and Codeine Phosphate Oral Solution should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology [ see Dosage and Administration (2.3) , Warnings and Precautions (5.6) ]. 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 HCl and Codeine Phosphate 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 (5.6) ]. If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with Promethazine HCl and Codeine Phosphate 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 HCl and Codeine Phosphate Oral Solution in a physically-dependent patient [ see Drug Abuse and Dependence (9.3) ]. When a patient who has been taking Promethazine HCl and Codeine Phosphate Oral Solution regularly and may be physically dependent no longer requires therapy with Promethazine HCl and Codeine Phosphate 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. 2.1 Important Dosage and Administration Instructions Administer Promethazine HCl and Codeine Phosphate Oral Solution by the oral route only. Always use an accurate milliliter measuring device when administering Promethazine HCl and Codeine Phosphate Oral Solution to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [ see Warnings and Precautions (5.7) ] . For pre…

5 WARNINGS AND PRECAUTIONS 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 Warning…

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS 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, ant…

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 increas…

6 ADVERSE REACTIONS 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 prot…