chlorpheniramine/hydrocodone (Rx)

Frequency Not Defined

Chest tightness

Syncope

Agitation

Coma

Depression

Dizziness

Dysphoria

Euphoria

Faintness

Mental clouding

Nervousness

Restlessness

Sedation

Seizures

Flushing

Pruritus

Sweating

Urticaria

Warmness of the face/neck/upper thorax

Constipation

Dry mouth

Nausea

Vomiting

Respiratory/circulatory depression

Shock

Urinary retention

Blurred vision

Visual disturbances

Diplopia

Xerostomia

Dysuria

Ureteral spasm

Contraindications

Hypersensitivity to opioids or chlorpheniramine

Use of extended release in children < 6 years

Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment

Known or suspected gastrointestinal obstruction, including paralytic ileus

Cautions

Ingredients and dosage could change; ALWAYS check label

Use with caution in acute pancreatitis, Addison disease, cardiac arrhythmias, emotional lability, gallbladder disease, pseudomembranous colitis, GI surgery, myxedema, toxic psychosis, urethral stricture, seizures, acute alcoholism, emphysema, narrow-angle glaucoma, asthma, prostatic hypertrophy, hypercapnia, renal/hepatic impairment, elderly debilitated patients

Use with caution extended-release suspension in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral stricture for possibility of respiratory depression

The two active ingredients in the drug combination may produce marked drowsiness and impair mental and/or physical abilities required for 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 medication; avoid concurrent use with alcohol or other central nervous system depressants as additional impairment of central nervous system performance may occur

Dosage should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease

Dosing errors can result in accidental overdose and death; to reduce risk of overdose and respiratory depression, ensure that the dose is communicated clearly and dispensed accurately; advise patients to always use accurate milliliter measuring device when measuring and administering drug; inform patients that household teaspoon is not accurate measuring device and could lead to overdosage and serious adverse reactions; for prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and provide instructions for measuring correct dose

Hydrocodone and chlorpheniramine in drug combination may increase frequency of seizures in patients with seizure disorders, and may increase risk of seizures occurring in other clinical settings associated with seizures; monitor patients with a history of seizure disorders for worsened seizure control during therapy

Therapy may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics); monitor these patients for signs of hypotension after initiating therapy; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid use of drug in patients with circulatory shock

Respiratory depression

• Hydrocodone produces dose-related respiratory depression (risk increased in children) by directly acting on brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing; respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death
• Management of respiratory depression includes discontinuation of therapy, close observation, supportive measures, and use of opioid antagonists (eg, naloxone), depending on patient’s clinical status; carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate sedating effects of opioids
• While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy, when drug is used concomitantly with other drugs that may cause respiratory depression in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (eg, elderly, cachectic, or debilitated patients)
• To reduce risk of respiratory depression, proper dosing of is essential; monitor patients closely, especially within first 24-72 hr of initiating therapy or when used in patients at higher risk
• Overdose of hydrocodone in adults has been associated with fatal respiratory depression, and use of hydrocodone in children < 6 years of age associated with fatal respiratory depression when used as recommended; accidental ingestion of even one dose of drug combination especially by children, can result in respiratory depression and death

Addiction, abuse, and misuse

• Exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death; prescribe for shortest duration consistent with individual patient treatment goals, monitor all patients regularly for development of addiction or abuse, and refill only after reevaluation of need for continued treatment
• Addiction can occur at recommended dosages and if drug is misused or abused; risks are increased in patients with personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression); strategies to reduce risks include prescribing drug in smallest appropriate quantity and advising patient on proper disposal of unused drug

Asthma and other pulmonary diseases

• Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages
• Should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on patient’s respiratory function
• Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients
• Because of risk of respiratory depression, avoid use of opioid antitussives, in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients if prescribed, monitor such patients closely, particularly when initiating therapy and when given concomitantly with other drugs that depress respiration

Concomitant use with other CNS depressants

• Concomitant use of opioids, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death; because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol
• Advise both patients and caregivers about risks of respiratory depression and sedation if drug is used with benzodiazepines, alcohol, or other CNS depressants
• Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on therapy; co-ingestion of alcohol with drug combination may result in increased plasma levels and a potentially fatal overdose of hydrocodone

Use in patients with gastrointestinal conditions

• Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; hydrocodone may obscure diagnosis or clinical course of patients with acute abdominal conditions; concurrent use of anticholinergics with drug combination may produce paralytic ileus
• Hydrocodone may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders; use with caution in patients with underlying intestinal motility disorders
• Hydrocodone may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure; opioids may also cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms

Adrenal insufficiency

• Cases of adrenal insufficiency reported with opioid use, more often following greater than one month of use; presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure
• If adrenal insufficiency is suspected, confirm diagnosis with diagnostic testing as soon as possible; if adrenal insufficiency diagnosed, treat with physiologic replacement doses of corticosteroids; wean patient off of opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers
• Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency; information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency

Intracranial pressure

• Respiratory depressant effects of narcotics and capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure
• Avoid use in patients with head injury, intracranial lesions, or pre-existing increase in intracranial pressure; in patients who may be susceptible to intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), drug combination may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; furthermore, opioids produce adverse reactions that may obscure clinical course of patients with head injuries

Drug interaction overview

• Avoid use in patients who are taking a CYP3A4 inhibitor (increases plasma concentration of hydrocodone) or inducer (decreases plasma concentration of hydrocodone); if concomitant use of with a CYP3A4 inhibitor or inducer is necessary, monitor
• patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal
• Effects could be more pronounced with concomitant use of CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of drug combination is achieved
• MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone

Pregnancy

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 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

Reproductive toxicity studies have not been conducted with drug combination; however, studies are available with individual active ingredients or related active ingredients

Chronic use of opioids, such as hydrocodone, may cause reduced fertility in females and males of reproductive potential; it is not known whether these effects on fertility are reversible

Animal data

• In animal reproduction studies, hydrocodone administered by subcutaneous route to pregnant hamsters during period of organogenesis produced a teratogenic effect at dose approximately 70 times maximum recommended human dose (MRHD)
• Chlorpheniramine administered by oral route to mice throughout pregnancy was embryo lethal at a dose approximately 9 times MRHD and decreased postnatal survival when dosing was continued after parturition; chlorpheniramine administered by oral route to male and female rats prior to mating produced embryolethality at dose approximately 9 times MRHD

Lactation

Because of potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during therapy

There are no data on presence of drug in human milk, effects on breastfed infant, or on milk production; however, data are available with hydrocodone and chlorpheniramine

Hydrocodone is present in breast milk; published cases report variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in early post-partum period with relative infant doses of hydrocodone ranging between 1.4 and 3.7%; there are case reports of excessive sedation and respiratory depression in breastfed infants exposed to hydrocodone; no information is available on effects of hydrocodone on milk production

Chlorpheniramine is present in human milk; chlorpheniramine has not been reported to cause effects on breastfed infant; published literature suggests that chlorpheniramine may decrease milk production based on its anticholinergic effects

Infants exposed to drug combination through breast milk should be monitored for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Chlorpheniramine: Histamine-1 receptor antagonist on effector cells in blood vessels, gastrointestinal tract, and respiratory tract

Hydrocodone: Opioid agonist; elicits antitussive effect; suppresses cough in medullary center; alters perception and response to pain; produces generalized CNS depression

Absorption

Peak plasma time

• Chlorpheniramine: 6.3 hr
• Hydrocodone: 4-8 hr

Peak plasma concentration

• Chlorpheniramine: 58.4 ng/mL
• Hydrocodone: 22.8 ng/mL

Peak plasma time

• Hydrocodone: 1-2 hr (solution); 3 hr (capsules)
• Chlorpheniramine: 2-3 hr

Distribution

• Chlorpheniramine: 4-7 L/kg (children); 6-12 L/kg (adults)

Protein binding

• Chlorpheniramine: 33%

Elimination

Half-life

• Chlorpheniramine: 10-13 hr (children); 14-24 hr (adults)
• Hydrocodone: 4-5 hr

Excretion

• Hydrocodone: Urine