Chlorpheniramine Drug Information

Important Dosage and

Administration Instructions Administer Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension by the oral route only. Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension can be taken with or without food. Shake well before using.

Do not mix Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension with other liquids or medicines. Mixing may change how Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension works. Always use an accurate milliliter measuring device when administering Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension to ensure that the dose is measured and administered accurately.

A household teaspoon is not an accurate measuring device and could lead to overdosage. The dosing cup is provided with the 3 oz (70 mL) and 4 oz (115 mL) packaged product. The dosing cup fills for 2.5 mL dose and for 5 mL dose.

Instruct the patient to fill to the line that the dose has been prescribed. Do not fill over the dose prescribed. Rinse the measuring cup with water after each use.

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 Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension because serious adverse events such as respiratory depression may occur with overdosage. The dosage of Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology .

Recommended Dosage Adults 18 years of age and older : 5 mL

every 12 hours as needed, not to exceed 2 doses (10 mL) in 24 hours

Monitoring, Maintenance, and Discontinuation of Therapy Prescribe Hydrocodone Polistirex and Chlorpheniramine Polistirex

Extended-Release Suspension for the shortest duration that is consistent with individual patient treatment goals. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy. Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease.

If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse. Do not abruptly discontinue Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension in a physically-dependent patient. When a patient who has been taking Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension regularly and may bephysically dependent no longer requires therapy with Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension, taper the dose gradually, by25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal.

If the patientdevelops these signs or symptoms, raise the dose to the previous level and taper more slowly, either byincreasing the interval between decreases, decreasing the amount of change in dose, or both.

• 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 , 5.8 ), Overdosage (10) ]
• Accidental overdose and death due to medication errors [ see Warnings and Precautions (5.5) ]
• Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions (5.6) ]
• Interactions with benzodiazepines and other CNS depressants [ see Warnings and Precautions (5.8) , Drug Interactions (7.1 , 7.5 ) ]
• Paralytic ileus, gastrointestinal adverse reactions [ see Warnings and Precautions (5.9) ]
• Increased intracranial pressure [ see Warnings and Precautions (5.10 ) ]
• Obscured clinical course in patients with head injuries [ see Warnings and Precautions (5.10) ]
• Seizures [ see Warnings and Precautions (5.11) ]
• Severe hypotension [ see Warnings and Precautions (5.12) ]
• Neonatal Opioid Withdrawal Syndrome [ see Warnings and Precautions (5.13) ]
• Adrenal insufficiency [ see Warnings and Precautions (5.14) ] The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone 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 Hydrocodone Polistirex and Chlorpheniramine Polistirex include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation. Other reactions include: Anaphylaxis : Anaphylaxis has been reported with hydrocodone, one of the ingredients in Hydrocodone Polistirex and Chlorpheniramine Polistirex. 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, migraine, increased intracranial pressure, 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, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, upper respiratory tract infection, thickening of bronchial secretions, tightness of chest and wheezing, dry nose, dry throat. Other : Drug abuse, drug dependence, opioid withdrawal syndrome. Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation (6) To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc. at 1-732-940-0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Alcohol

Concomitant use of alcohol with Hydrocodone Polistirex and Chlorpheniramine Polistirex can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on Hydrocodone Polistirex and Chlorpheniramine Polistirex therapy.

Inhibitors of

CYP3A4 and CYP2D6 The concomitant use of Hydrocodone Polistirex and Chlorpheniramine Polistirex and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Hydrocodone Polistirex and Chlorpheniramine Polistirex and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Polistirex and Chlorpheniramine Polistirex is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.

Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

CYP3A4 Inducers

The concomitant use of Hydrocodone Polistirex and Chlorpheniramine Polistirex and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking CYP3A4 inducers.

If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

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 Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking phenytoin.

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 Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking benzodiazepines or other CNS depressants, and instruct patients to avoid consumption of alcohol while on Hydrocodone Polistirex and Chlorpheniramine Polistirex.

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 Hydrocodone Polistirex and Chlorpheniramine Polistirex if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs or tricyclic antidepressants with hydrocodone, one of the active ingredients in Hydrocodone Polistirex and Chlorpheniramine Polistirex, may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Muscle Relaxants Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle

relaxants and produce an increased degree of respiratory depression. Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

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 Hydrocodone Polistirex and Chlorpheniramine Polistirex may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.Monitor patients for signs of urinary retention or reduced gastric motility when Hydrocodone Polistirex and Chlorpheniramine Polistirex 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 chlorpheniramine.

Pregnancy Risk Summary Hydrocodone Polistirex and Chlorpheniramine Polistirex 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. There are no available data with Hydrocodone Polistirex and Chlorpheniramine Polistirex use in pregnant women to inform a drug-associated risk for adverse developmental outcomes.

Published studies with hydrocodone have reported inconsistent findings and have important methodological limitations ( see Data ). Reproductive toxicity studies have not been conducted with Hydrocodone Polistirex and Chlorpheniramine Polistirex; however, studies are available with individual active ingredients or related active ingredients ( see Data ). In animal reproduction studies, hydrocodone administered by the subcutaneous route to pregnant hamsters during the period of organogenesis produced a teratogenic effect at a dose approximately 70 times the maximum recommended human dose (MRHD) ( see Data ). Chlorpheniramine administered by the oral route to mice throughout pregnancy was embryo lethal 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.

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 Hydrocodone Polistirex and Chlorpheniramine Polistirex, 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 Hydrocodone A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing hydrocodone use during pregnancy.

However, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size and lack of details regarding dose, duration 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 Hydrocodone Polistirex and Chlorpheniramine Polistirex; however, studies are available with individual active ingredients or related active ingredients. Hydrocodone In an embryofetal development study in pregnant hamsters dosed on gestation day 8 during the period of organogenesis, hydrocodone induced cranioschisis, a malformation, at approximately 70 times the MRHD (on a mg/m 2 basis with a maternal subcutaneous dose of 102 mg/kg). Reproductive toxicology studies were also conducted with codeine, an opiate related to hydrocodone.

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 95 times the MRHD of hydrocodone (on a mg/m 2 basis with a maternal oral dose of codeine at 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 50 and 240 times, respectively, the MRHD of hydrocodone (on a mg/m 2 basis with maternal oral doses of codeine at 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.

In a fertility and reproduction study with male and female rats dosed prior to mating, chlorpheniramine produced embryolethality at a dose approximately 9 times the MRHD(on a mg/m 2 basis with an oral parental dose of 10 mg/kg/day).

Pediatric Use Hydrocodone Polistirex and Chlorpheniramine Polistirex 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 hydrocodone in these patients. Life-threatening respiratory depression and death have occurred in children who received hydrocodone. Because of the risk of life-threatening respiratory depression and death,Hydrocodone Polistirex and Chlorpheniramine Polistirex is contraindicated in children less than 6 years of age.

• Hydrocodone Polistirex and Chlorpheniramine Polistirex is contraindicated for: All children younger than 6 years of age. Hydrocodone Polistirex and Chlorpheniramine Polistirex is also contraindicated in patients with: Significant respiratory depression. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. Known or suspected gastrointestinal obstruction, including paralytic ileus. Hypersensitivity to hydrocodone, chlorpheniramine, or any of the inactive ingredients in Hydrocodone Polistirex and Chlorpheniramine Polistirex. Children younger than 6 years of age. Significant respiratory depression. Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. Known or suspected gastrointestinal obstruction, including paralytic ileus. Hypersensitivity to hydrocodone, chlorpheniramine, or any of the inactive ingredients in Hydrocodone Polistirex and Chlorpheniramine Polistirex.

Clinical Presentation Hydrocodone Acute overdose with hydrocodone 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, circulatory collapse, cardiac arrest, and death. Hydrocodone 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.

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 Hydrocodone Polistirex and Chlorpheniramine Polistirex together with institution of appropriate therapy. Give primary attention to 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 hydrocodone 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 hydrocodone in Hydrocodone Polistirex and Chlorpheniramine Polistirex, carefully monitor the patient until spontaneous respiration is reliably reestablished. Hydrocodone Polistirex and Chlorpheniramine Polistirex will continue to release hydrocodone and add to the hydrocodone load for 12 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 hydrocodone 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.