Tuxarin
codeine phosphate and chlorpheniramine maleate · Tablet, Extended Release · Oral
Uses
1 INDICATIONS AND USAGE TUXARIN ER is 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. TUXARIN ER is a combination of codeine, an opioid agonist; and chlorpheniramine, a histamine-1 (H 1 ) receptor antagonist, 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 TUXARIN ER 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. Important Limitations of Use Not indicated for pediatric patients under 18 years of age [see Use in Specific Population (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 TUXARIN ER 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.
Dosage and administration
Adults 18 years of age and older : 1 tablet every 12 hours as needed, not to exceed 2 tablets in 24 hours. ( 2.2 ) 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 TUXARIN ER by the oral route only. Advise patients not to increase the dose or dosing frequency of TUXARIN ER because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions (5.2) , Overdosage (10) ]. The dosage of TUXARIN ER 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 (5.5) ]. 2.2 Recommended Dosage Adults 18 years of age and older: one tablet every 12 hours as needed, not to exceed 2 tablets in 24 hours. 2.3 Monitoring, Maintenance, and Discontinuation of Therapy Prescribe TUXARIN ER 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 (5.5) ]. If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with TUXARIN ER, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [ see Warnings and Precautions (5.1) ]. Do not abruptly discontinue TUXARIN ER in a physically-dependent patient [ see Drug Abuse and Dependence (9.3) ]. When a patient who has been taking TUXARIN ER regularly and may be physically dependent no longer requires therapy with TUXARIN ER, 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.
Dosage forms and strengths
Extended-release tablets: Each tablet contains 54.3 mg of codeine phosphate (equivalent to 40 mg of codeine); and 8 mg of chlorpheniramine maleate (equivalent to 5.6 mg of chlorpheniramine). Each tablet is white to off-white, uncoated, round, debossed with MP on one side and CC on the other side [ see Description (11) ]. Extended-release (ER) tablet: contains 54.3 mg of codeine phosphate; and 8 mg of chlorpheniramine maleate. ( 3 )
Contraindications
4 CONTRAINDICATIONS TUXARIN ER is contraindicated for: All children younger than 12 years of age [ see Warnings and Precautions (5.2 , 5.3 , 5.4) , Use in Specific Populations (8.4) ]. Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Warnings and Precautions (5.2 , 5.3) ]. TUXARIN ER 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 (5.5) ]. Known or suspected gastrointestinal obstruction, including paralytic ileus [ see Warnings and Precautions (5.10) ]. Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days [ see Warnings and Precautions (5.13) , Drug Interactions (7.7) ]. Hypersensitivity to codeine, chlorpheniramine, or any of the inactive ingredients in TUXARIN ER [ 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 ) Hypersensitivity to codeine or other opiates, chlorpheniramine, or any of the inactive ingredients in TUXARIN ER. ( 4 )
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. ( 5.5 ) Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring mental alertness such as driving or operating machinery. ( 5.7 ) 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. ( 5.11 ) Seizures in patients with seizure disorders: Monitor during therapy. ( 5.12 ) Severe hypotension: Monitor during initiation of therapy. Avoid use in patients with circulatory shock. ( 5.14 ) Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.16 ) 5.1 Addiction, Abuse, and Misuse TUXARIN ER contains codeine, a Schedule III controlled substance. As an opioid, TUXARIN ER 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 TUXARIN ER 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 TUXARIN ER, prescribe TUXARIN ER 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 TUXARIN ER. 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 TUXARIN ER. 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 TUXARIN ER. 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) ]. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of TUXARIN ER, 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 TUXARIN ER, the risk is greatest during the initiation of therapy, when TUXARIN ER is used concomitantly with other drugs that may cause respiratory depression [ see Warnings and Precautions (5.9) ], 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 (5.5) ]. To reduce the risk of respiratory depression, proper dosing of TUXARIN ER is essential [see Dosage and Administration (2.1) , Warnings and Precautions (5.6) ]. 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 TUXARIN ER, 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.
Side effects
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 , 5.9) , 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 (5.6) ] Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions (5.7) ] Interactions with benzodiazepines and other CNS depressants [ see Warnings and Precautions (5.9) ] Paralytic ileus, gastrointestinal adverse reactions [ see Warnings and Precautions (5.10) ] Increased intracranial pressure [ see Warnings and Precautions (5.11) ] Obscured clinical course in patients with head injuries [ see Warnings and Precautions (5.11) ] Seizures [ see Warnings and Precautions (5.12) ] Interactions with MAOI [ see Warnings and Precautions (5.13) ] Severe hypotension [ see Warnings and Precautions (5.14) ] Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions (5.15) ] Adrenal insufficiency [ see Warnings and Precautions (5.16) ] The following adverse reactions have been identified during clinical studies, or during post-approval use of codeine and/or chlorpheniramine. 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 TUXARIN ER include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, and sweating. Other reactions include: Anaphylaxis : Anaphylaxis has been reported with codeine, one of the ingredients in TUXARIN ER. 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, facial dyskinesia, insomnia, increased intracranial pressure, migraine, seizure, tremor, tinnitus, vertigo. Dermatologic : Flushing, hyperhidrosis, pruritus, rash. 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, GERD, indigestion, 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 : Agranulocytosis, aplastic anemia, and thrombocytopenia have been reported. Laboratory: Increases in serum amylase. Musculoskeletal : Arthralgia, backache, muscle spasm. Ophthalmic : Blurred vision, diplopia, miosis (constricted pupils), visual disturbances. Psychiatric : Agitation, anxiety, confusion, fear, dysphoria, depression, hallucinations. Reproductive : Hypogonadism, infertility. Respiratory : 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, 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 of TUXARIN ER 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 MainPointe Pharmaceuticals, LLC at 502-709-7544 or go to mainpointepharmaceuticals.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug interactions
No specific drug interaction studies have been conducted with TUXARIN ER. Phenytoin : Avoid concomitant use; may increase phenytoin levels. ( 7.4 ) Serotonergic drugs : Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is suspected. ( 7.6 ) Muscle relaxants : Avoid concomitant use. ( 7.8 ) Diuretics: Codeine may reduce the efficacy of diuretics. Monitor for reduced effect. ( 7.9 ) Anticholinergic drugs : Concurrent use may cause paralytic ileus. ( 5.10 , 7.10 ) 7.1 Inhibitors of CYP3A4 The concomitant use of TUXARIN ER 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 TUXARIN ER is achieved [ see Warnings and Precautions (5.8) ]. 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 TUXARIN ER 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 TUXARIN ER 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 (5.8) ]. 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 TUXARIN ER in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy. 7.3 Phenytoin Adverse event reports in the literature suggest a possible drug interaction involving increased serum phenytoin levels and phenytoin toxicity when chlorpheniramine and phenytoin are co-administered. The exact mechanism for this interaction is not known, however it is believed that chlorpheniramine may inhibit the hepatic metabolism of phenytoin. Avoid the use of TUXARIN ER while taking phenytoin. 7.4 Inhibitors of CYP2D6 Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of TUXARIN ER 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 TUXARIN ER in patients who are taking inhibitors of CYP2D6. 7.5 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 TUXARIN ER in patients who are taking benzodiazepines or other CNS depressants. [ see Warnings and Precautions (5.9) ] . 7.6 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 TUXARIN ER if serotonin syndrome is suspected. 7.7 Monoamine Oxidase Inhibitors (MAOIs) TUXARIN ER 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 (5.13) ] . 7.8 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 TUXARIN ER in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected. 7.9 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. 7.10 Anticholinergic Drugs The concomitant use of anticholinergic drugs with TUXARIN ER may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [ see Warnings and Precautions (5.10) ].
Use in specific populations
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 TUXARIN ER 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 (5.15) and Clinical Considerations ]. There are no available data with TUXARIN ER 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 TUXARIN ER; 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 15 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity ( see Data ). Chlorpheniramine administered by the oral route to mice throughout pregnancy was embryolethal at a dose approximately 9 times the MRHD and decreased postnatal survival when dosing was continued after parturition. Chlorpheniramine administered by the oral route to male and female rats prior to mating produced embryolethality at a dose approximately 9 times the MRHD ( 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 (5.15) ]. 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 TUXARIN ER, 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 No new primary pharmacodynamic studies were conducted. Codeine is a well-established antitussive and chlorpheniramine maleate is a recognized antihistamine. Both drugs have been used at these strengths in combination for several years. Codeine 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. 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. Chlorpheniramine The majority of studies examining the use of chlorpheniramine in pregnancy did not find an association with an increased risk of congenital anomalies. In the few studies reporting an association, there was no consistent pattern of malformations noted. Animal Data Reproductive toxicity studies have not been conducted with TUXARIN ER; 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 15 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 7 and 35 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). Chlorpheniramine In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, chlorpheniramine produced no adverse developmental effects at oral doses up to approximately 35 and 45 times, respectively, the MRHD on a mg/m 2 basis.
Pregnancy
8.1 Pregnancy Risk Summary TUXARIN ER 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 (5.15) and Clinical Considerations ]. There are no available data with TUXARIN ER 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 TUXARIN ER; 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 15 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity ( see Data ). Chlorpheniramine administered by the oral route to mice throughout pregnancy was embryolethal at a dose approximately 9 times the MRHD and decreased postnatal survival when dosing was continued after parturition. Chlorpheniramine administered by the oral route to male and female rats prior to mating produced embryolethality at a dose approximately 9 times the MRHD ( 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 (5.15) ]. 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 TUXARIN ER, 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 No new primary pharmacodynamic studies were conducted. Codeine is a well-established antitussive and chlorpheniramine maleate is a recognized antihistamine. Both drugs have been used at these strengths in combination for several years. Codeine 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. 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. Chlorpheniramine The majority of studies examining the use of chlorpheniramine in pregnancy did not find an association with an increased risk of congenital anomalies. In the few studies reporting an association, there was no consistent pattern of malformations noted. Animal Data Reproductive toxicity studies have not been conducted with TUXARIN ER; 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 15 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 7 and 35 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). Chlorpheniramine In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, chlorpheniramine produced no adverse developmental effects at oral doses up to approximately 35 and 45 times, respectively, the MRHD on a mg/m 2 basis. However, in a reproduction study with pregnant mice dosed throughout pregnancy, chlorpheniramine produced embryolethality at a dose approximately 9 times the MRHD (on a mg/m 2 basis with a maternal oral dose of 20 mg/kg/day) and decreased postnatal survival when dosing was continued after parturition.
Pediatric use
8.4 Pediatric Use TUXARIN ER 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 (5.4) ]. 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. Because of the risk of life-threatening respiratory depression and death: TUXARIN ER is contraindicated in all children younger than 12 years of age [see Contraindications (4) ] . TUXARIN ER 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 TUXARIN ER 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) ] .
Geriatric use
8.5 Geriatric Use Clinical studies have not been conducted with TUXARIN ER in geriatric populations. Use caution when considering the use of TUXARIN ER 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 (5.5) ]. Respiratory depression is the chief risk for elderly patients treated with opioids, including TUXARIN ER. 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 (5.5 , 5.9) ]. 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.
Overdosage
Clinical Presentation Codeine Acute overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, partial or complete airway obstruction, atypical snoring, hypotension, hypoglycemia, circulatory collapse, cardiac arrest, and death. Codeine may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [ see Clinical Pharmacology (12.2) ]. Chlorpheniramine Signs and symptoms of chlorpheniramine overdosage may vary from central nervous system depression to stimulation. Central toxic effects are characterized by agitation, anxiety, delirium, disorientation, hallucinations, hyperactivity, sedation, and seizures. Severe overdosage may produce coma, medullary paralysis, and death. Peripheral toxicity includes hypertension, tachycardia, dysrhythmias, vasodilation, hyperpyrexia, mydriasis, urinary retention, and diminished gastrointestinal motility. Atropine-like signs and symptoms (dry mouth, fixed dilated pupils, flushing, tachycardia, hallucinations, gastrointestinal symptoms, convulsions, urinary retention, cardiac arrhythmias and coma) may be observed. Impaired secretion from sweat glands following toxic doses of drugs with anticholinergic side effects may predispose to hyperthermia. Toxic psychosis, a possible class effect from overdose of sedating antihistamines, has been reported. Treatment of Overdose Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of TUXARIN ER together with institution of appropriate therapy. Give primary attention to the reestablishment of adequate respiratory exchange through provision of a patent and protected airway and the institution of assisted or controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Gastric emptying may be useful in removing unabsorbed drug. The opioid antagonists, naloxone and nalmefene, are specific antidotes for respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to codeine overdose, administer an opioid antagonist. An antagonist should not be administered in the absence of clinically significant respiratory depression. Because the duration of opioid reversal is expected to be less than the duration of action of codeine in TUXARIN ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. TUXARIN ER will continue to release codeine and add to the codeine load for 4 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information. Hemodialysis is not routinely used to enhance the elimination of codeine or chlorpheniramine from the body. Urinary excretion of chlorpheniramine is increased when the pH of the urine is acidic; however, acid diuresis is NOT recommended to enhance elimination in overdose, as the risks of acidemia and acute tubular necrosis in patients with rhabdomyolysis far outweigh any potential benefits.
Description
(codeine phosphate and chlorpheniramine maleate) extended-release tablets, contains codeine, an opioid agonist; and chlorpheniramine, a histamine-1 (H 1 ) receptor antagonist. Each tablet of TUXARIN ER contains 54.3 mg of codeine phosphate and 8 mg of chlorpheniramine maleate for oral administration. TUXARIN ER are white to off-white, uncoated, standard round extended-release matrix tablets. TUXARIN ER also contains the following inactive ingredients: hypromellose, lactose monohydrate, cellulose microcrystalline, polysorbate 80, magnesium stearate, and colloidal silicon dioxide. Codeine Phosphate The chemical name for codeine phosphate is [morphine3methyl ether phosphate (1:1) (salt)] hemihydrate. It has the following structural formula: Chemical Structure Chlorpheniramine Maleate The chemical name for chlorpheniramine maleate is 2-pyridinepropanamine, γ-(4-chlorophenyl)- N,N -dimethyl-, ( Z )-2-butenedioate (1:1). It has the following structural formula: Chemical Structure
Mechanism of action
12.1 Mechanism of Action 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. Chlorpheniramine Chlorpheniramine is a propylamine derivative antihistamine (H 1 -receptor antagonist) of the alkylamine class that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.
How supplied
(codeine phosphate and chlorpheniramine maleate) 54.3 mg/ 8 mg extended-release tablets, are white to off-white, uncoated, standard round tablets, debossed with MP on one side and CC on the other side. Supplied in bottles of 30 tablets (NDC 71269-040-30) and 100 tablets (NDC 71269-040-10). Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. Keep this and all medicine out of reach of children.
Storage
Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. Keep this and all medicine out of reach of children.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Addiction, Abuse, and Misuse Inform patients that the use of TUXARIN ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [ see Warnings and Precautions (5.1) ] . Instruct patients not to share TUXARIN ER with others and to take steps to protect TUXARIN ER from theft or misuse. Important Dosing and Administration Instructions Advise patients take TUXARIN ER exactly as prescribed. Advise patients not to increase the dose or dosing frequency of TUXARIN ER because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions (5.2) , Overdosage (10) ]. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting TUXARIN ER and that it can occur even at recommended dosages [ see Warnings and Precautions (5.2) ]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [ see Warnings and Precautions (5.2) ]. Instruct patients to take steps to store TUXARIN ER securely and to properly dispose of unused TUXARIN ER in accordance with the local state guidelines and/or regulations. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Advise caregivers that TUXARIN ER is not indicated for pediatric patients under 18 years of age and is contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Activities Requiring Mental Alertness Advise patients to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as TUXARIN ER may produce marked drowsiness [ see Warnings and Precautions (5.7) ]. Interactions with Benzodiazepines and Other Central Nervous System Depressants, Including Alcohol Inform patients and caregivers that potentially fatal additive effects may occur if TUXARIN ER is used with benzodiazepines or other CNS depressants, including alcohol. Advise patients to avoid concomitant use of TUXARIN ER with benzodiazepines or other CNS depressants and to not use alcohol while taking TUXARIN ER [ see Warnings and Precautions (5.9) , Drug Interactions (7.5) ]. Constipation Advise patients of the potential for severe constipation [ see Warnings and Precautions (5.10) , Adverse Reactions (6) ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in TUXARIN ER. Advise patients how to recognize such a reaction and when to seek medical attention [ see Contraindications (4) , Adverse Reactions (6) ]. MAOI Interaction Inform patients not to take TUXARIN ER while using or within 14 days of stopping any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking TUXARIN ER [ see Warnings and Precautions (5.13) , Drug Interactions (7.7) ]. Hypotension Inform patients that TUXARIN ER may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [ see Warnings and Precautions (5.14) ]. Pregnancy Advise patients that use of TUXARIN ER is not recommended during pregnancy [ see Use in Specific Populations (8.1) ]. Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [ see Warnings and Precautions (5.15) , Use in Specific Populations (8.1) ] . Embryo-Fetal Toxicity Inform female patients of reproductive potential that TUXARIN ER can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [ see Use in Specific Populations (8.1) ] . Lactation Advise women that breastfeeding is not recommended during treatment with TUXARIN ER [ see Use in Specific Populations (8.2) ]. Infertility Inform patients that chronic use of opioids, such as codeine, a component of TUXARIN ER, may cause reduced fertility. It is not known whether these effects on fertility are reversible [ see Use in Specific Populations (8.3) ] . Adrenal Insufficiency Inform patients that TUXARIN ER could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [ see Warnings and Precautions (5.16) ]. Serotonin Syndrome Inform patients that TUXARIN ER could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [ see Adverse Reactions (6) , Drug Interactions (7.6) ]. Disposal of Unused TUXARIN ER Advise patients to properly dispose of unused TUXARIN ER. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs).
Label text from the FDA structured product label by Mainpointe Pharmaceuticals (revised Jan 10, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Codeine Phosphate in 1 product
- Chlorpheniramine Maleate in 1 product
Tuxarin NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 71269-040 | Codeine Phosphate 54.3 mg/1; Chlorpheniramine Maleate 8 mg/1 Tablet, Extended Release | Mainpointe Pharmaceuticals | NDA · DEA CIII |
Frequently asked questions
What is Tuxarin used for?
1 INDICATIONS AND USAGE TUXARIN ER is 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. TUXARIN ER is a combination of codeine, an opioid agonist; and chlorpheniramine, a histamine-1 (H 1 ) receptor antagonist, indicated for the temporary relief of cough and upper respiratory symptoms…
What are the side effects of Tuxarin?
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 , 5.9) , Overdosage (10) ] Ultra-rapid metabolism of codeine and other risk factors for… See the full label for the complete list.
Who makes Tuxarin?
Tuxarin is listed by 1 labeler in the FDA NDC directory, including Mainpointe Pharmaceuticals.