1.1 Cough and Upper Respiratory Allergy Symptoms

Hydrocodone bitartrate and chlorpheniramine maleate oral solution is indicated for relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 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)].

2.1 Adults 18 Years of Age and Older

5 mL every 4 to 6 hours as needed, not to exceed 4 doses (20 mL) in 24 hours.

5.1 Respiratory Depression

Hydrocodone bitartrate, one of the active ingredients in hydrocodone bitartrate and chlorpheniramine maleate oral solution, produces dose-related respiratory depression by directly acting on brain stem respiratory centers. Overdose of hydrocodone bitartrate in adults has been associated with fatal respiratory depression, and the use of hydrocodone bitartrate in children less than 6 years of age has been associated with fatal respiratory depression. Exercise caution when administering Hydrocodone bitartrate and chlorpheniramine maleate oral solution because of the potential for respiratory depression. If respiratory depression occurs, discontinue hydrocodone bitartrate and chlorpheniramine maleate oral solution and use naloxone hydrochloride when indicated to antagonize the effect and other supportive measures as necessary [see Overdosage (10)].

5.2 Drug Dependence

Hydrocodone can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of hydrocodone bitartrate and chlorpheniramine maleate oral solution. Prescribe and administer hydrocodone bitartrate and chlorpheniramine maleate with the same degree of caution appropriate to the use of other opioid drugs [see Drug Abuse and Dependence (9.2, 9.3)].

5.3 Head Injury and Increased Intracranial Pressure

The respiratory depression effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, opioids produce adverse reactions which may obscure the clinical course of patients with head injuries. The use of hydrocodone bitartrate and chlorpheniramine maleate oral solution should be avoided in these patients.

5.4 Activities Requiring Mental Alertness

Hydrocodone bitartrate and chlorpheniramine maleate, the active ingredients in hydrocodone bitartrate and chlorpheniramine maleate oral solution, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of hydrocodone bitartrate and chlorpheniramine maleate oral solution. Concurrent use of hydrocodone bitartrate and chlorpheniramine maleate oral solution with alcohol or other central nervous system depressants should be avoided because additional impairment of central nervous system performance may occur.

5.5 Acute Abdominal Conditions

Hydrocodone bitartrate and chlorpheniramine maleate oral solution should be used with caution in patients with acute abdominal conditions since the administration of hydrocodone may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of other anticholinergics with hydrocodone may produce paralytic ileus [see Drug Interactions (7.3)].

5.6 Co-administration with Anticholinergics

The concurrent use of anticholinergics with hydrocodone may produce paralytic ileus. Exercise caution when using hydrocodone bitartrate and chlorpheniramine maleate oral solution in patients taking anticholinergic medications [see Drug Interactions (7.3)].

5.7  Co-administration with MAOIs or Tricyclic Antidepressants

Hydrocodone bitartrate and chlorpheniramine maleate oral solution should not be used in patients receiving MAOI therapy or within 14 days of stopping such therapy. The use of MAOIs or tricyclic antidepressants with hydrocodone bitartrate, one of the active ingredients in hydrocodone bitartrate and chlorpheniramine maleate oral solution, may increase the effect of either the antidepressant or hydrocodone [see Contraindications (4) and Drug Interactions (7.2)].

5.8  Dosing

Patients should be advised to measure hydrocodone bitartrate and chlorpheniramine maleate oral solution with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions [see Overdosage (10)]. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose.

5.9  Coexisting Conditions

Hydrocodone bitartrate and chlorpheniramine maleate oral solution should be used with caution in patients with thyroid disease, Addison’s disease, prostatic hypertrophy, urethral stricture, or asthma.

5.10  Renal Impairment

Hydrocodone bitartrate and chlorpheniramine maleate oral solution should be used with caution in patients with severe renal impairment [see Use in Specific Populations (8.6)].

5.11  Hepatic Impairment

Hydrocodone bitartrate and chlorpheniramine maleate oral solution should be used with caution in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

7.1 Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)

The use of opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with hydrocodone bitartrate and chlorpheniramine maleate oral solution may cause an additive CNS depressant effect and should be avoided.

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

Do not prescribe hydrocodone bitartrate and chlorpheniramine maleate oral solution if the patient is taking a prescription MAOI (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping a MAOI drug. The use of MAOIs or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone [see Warnings and Precautions (5.7)].

7.3 Anticholinergic Drugs

Hydrocodone and chlorpheniramine should be administered cautiously to persons receiving other anticholinergic drugs in order to avoid paralytic ileus and excessive anticholinergic effects.

Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine [see Warnings and Precautions (5.6)].

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies of hydrocodone bitartrate and chlorpheniramine maleate oral solution in pregnant women. Reproductive toxicity studies have not been conducted with hydrocodone bitartrate and chlorpheniramine maleate oral solution; however, studies are available with individual active ingredients or related active ingredients. Hydrocodone was teratogenic in hamsters. Codeine, an opiate related to hydrocodone, increased resorptions and decreased fetal weight in rats. A single retrospective study reported that chlorpheniramine was teratogenic in humans; however, the significance of these findings was not known. Developmental toxicity was also evident with chlorpheniramine in mice and rats. Because animal reproduction studies are not always predictive of human response, hydrocodone bitartrate and chlorpheniramine maleate oral solution should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

Hydrocodone:

Hydrocodone has been shown to be teratogenic in hamsters when given in a dose approximately 35 times the maximum recommended human daily dose (MRHDD) (on a mg/m2 basis at a single subcutaneous dose of 102 mg/kg on gestation day 8). Reproductive toxicology studies were also conducted with codeine, an opiate related to hydrocodone. In a study in which pregnant rats were dosed throughout organogenesis, a dose of codeine approximately 50 times the MRHDD of hydrocodone (on a mg/m2 basis at an oral dose of 120 mg/kg/day of codeine) increased resorptions and decreased fetal weight; however, these effects occurred in the presence of maternal toxicity. In studies in which rabbits and mice were dosed throughout organogenesis, doses of codeine up to approximately 25 and 120 times, respectively, the MRHDD of hydrocodone (on a mg/m2 basis at oral doses of 30 and 600 mg/kg/day, respectively), produced no adverse developmental effects.

Chlorpheniramine:

A retrospective study found a small, but statistically significant, association between maternal use of chlorpheniramine and inguinal hernia and eye or ear anomalies in children. Other retrospective studies have found that the frequency of congenital anomalies, in general, was not increased among offspring of women who took chlorpheniramine during pregnancy. The significance of these findings to the therapeutic use of chlorpheniramine in human pregnancy is not known.

In studies with chlorpheniramine in which pregnant rats and rabbits were dosed throughout organogenesis, oral doses up to approximately 20 and 25 times the MRHDD on a mg/m2 basis, respectively, produced no adverse developmental effects. However, when mice were dosed throughout pregnancy, a dose approximately 5 times the MRHDD (on a mg/m2 basis at an oral dose of 20 mg/kg/day) was embryolethal, and postnatal survival was decreased when dosing was continued after parturition. Embryolethality was also observed when male and female rats were dosed with approximately 5 times the MRHDD (on a mg/m2 basis at an oral dose of 10 mg/kg/day) prior to mating.

Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose.

8.2 Labor and Delivery

As with all opioids, administration of hydrocodone bitartrate and chlorpheniramine maleate oral solution to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.

8.3 Nursing Mothers

Caution should be exercised when hydrocodone bitartrate and chlorpheniramine maleate is administered to nursing mothers. Hydrocodone and chlorpheniramine are excreted in human milk. The clinical significance is unknown; however, the anticholinergic action of chlorpheniramine may suppress lactation if taken prior to nursing. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from hydrocodone bitartrate and chlorpheniramine maleate oral solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of hydrocodone bitartrate and chlorpheniramine maleate oral solution in pediatric patients under 18 years of age have not been established. The use of hydrocodone in children less than 6 years of age has been associated with fatal respiratory depression [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Clinical studies have not been conducted with hydrocodone bitartrate and chlorpheniramine maleate oral solution. Other reported clinical experience with the individual active ingredients of hydrocodone bitartrate and chlorpheniramine maleate oral solution has not identified differences in responses between the elderly and patients younger than 65 years of age. In general, dose selection for an elderly patient should be made with caution, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Hydrocodone bitartrate and chlorpheniramine maleate oral solution should be given with caution in patients with severe impairment of renal function.

8.7 Hepatic Impairment

Hydrocodone bitartrate and chlorpheniramine maleate oral solution should be given with caution in patients with severe impairment of hepatic function.

9.1  Controlled Substance

Hydrocodone bitartrate and chlorpheniramine maleate oral solution is a Schedule II controlled prescription containing hydrocodone bitartrate and should be prescribed and administered with caution.

9.2  Abuse

Hydrocodone can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of hydrocodone bitartrate and chlorpheniramine maleate oral solution, and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs.

9.3  Dependence

Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, hydrocodone bitartrate and chlorpheniramine maleate oral solution should be prescribed and administered with caution.

Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy.

12.1 Mechanism of Action

Hydrocodone is a semisynthetic narcotic antitussive and analgesic with multiple actions qualitatively similar to those of codeine. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act directly on the cough center. In excessive doses, hydrocodone will depress respiration. Hydrocodone can produce miosis, euphoria, and physical and physiological dependence.

Chlorpheniramine is an antihistamine drug (H1 receptor antagonist) that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa. 

12.3 Pharmacokinetics

Systemic exposure (in terms of peak plasma concentrations and area under plasma concentration versus time curve) of hydrocodone bitartrate and chlorpheniramine maleate after single dose administration of  5 mL hydrocodone bitartrate and chlorpheniramine maleate oral solution are equivalent to respective reference solutions of 5 mL hydrocodone bitartrate (5 mg/5 mL), and 5 mL chlorpheniramine maleate (4 mg/5 mL).

Hydrocodone had mean (SD) peak plasma concentration of 10.6 (2.63) ng/mL at 1.4 (0.55) hours. The mean plasma half-life of hydrocodone is approximately 4.9 hours. Chlorpheniramine had a mean (SD) plasma peak concentration of 7.20 (1.98) ng/mL at 3.5 (1.6) hours. The mean plasma half-life of chlorpheniramine is approximately 24 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with hydrocodone bitartrate and chlorpheniramine maleate oral solution; however, published information is available for the individual active ingredients or related active ingredients.

Hydrocodone:

Carcinogenicity studies were conducted with codeine, an opiate related to hydrocodone. In 2 year studies in F344/N rats and B6C3F1 mice, codeine showed no evidence of tumorigenicity at dietary doses up to 70 and 400 mg/kg/day, respectively (approximately 30 and 80 times, respectively, the MRHDD of hydrocodone on a mg/m2 basis).

Chlorpheniramine:

In 2 year studies in F344/N rats and B6C3F1 mice, chlorpheniramine maleate showed no evidence of tumorigenicity when administered 5 days/week at oral doses up to 30 and 50 mg/kg/day, respectively (approximately 15 times the MRHDD on a mg/m2 basis).

Chlorpheniramine maleate was not mutagenic in the in vitro bacterial reverse mutation assay or the in vitro mouse lymphoma forward mutation assay. Chlorpheniramine maleate was clastogenic in the in vitro CHO cell chromosomal aberration assay.

Chlorpheniramine maleate had no effects on fertility in rats and rabbits at oral doses approximately 20 and 25 times the MRHDD on a mg/m2 basis, respectively.

17.1 Overdosage

Patients should be advised not to increase the dose or dosing frequency of hydrocodone bitartrate and chlorpheniramine maleate oral solution because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.1); Overdosage (10)].

17.2 Dosing

Patients should be advised to measure hydrocodone bitartrate and chlorpheniramine maleate oral solution with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is measured. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose [see Warnings and Precautions (5.8)].

17.3 Concomitant Use of Alcohol and Other Central Nervous System Depressants

Patients should be advised to avoid the use of alcohol and other central nervous system depressants while taking hydrocodone bitartrate and chlorpheniramine maleate oral solution because additional reduction in mental alertness may occur [see Warnings and Precautions (5.4)].

17.4 Activities Requiring Mental Alertness

Patients should be advised to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as hydrocodone bitartrate and chlorpheniramine maleate oral solution may produce marked drowsiness [see Warnings and Precautions (5.4)].

17.5 Drug Dependence

Patients should be cautioned that hydrocodone bitartrate and chlorpheniramine maleate oral solution contains hydrocodone bitartrate and can produce drug dependence [see Warnings and Precautions (5.2)].

17.6 MAOIs

Patients should be informed that they should not use hydrocodone bitartrate and chlorpheniramine maleate oral solution with a MAOI or within 14 days of stopping use of an MAOI [see Warnings and Precautions (5.7)].

Manufactured by

Tris Pharma, Inc.

Monmouth Junction, NJ 08852

www.trispharma.com

LB8377

Rev 00

October 2014