Hydrocodone and Chlorpheniramine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 12 Hour, Oral:

TussiCaps: Hydrocodone polistirex [equivalent to hydrocodone bitartrate 5 mg] and chlorpheniramine polistirex [equivalent to chlorpheniramine maleate 4 mg] [DSC], Hydrocodone polistirex [equivalent to hydrocodone bitartrate 10 mg] and chlorpheniramine polistirex [equivalent to chlorpheniramine maleate 8 mg] [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #10 (quinoline yellow), fd&c yellow #10 aluminum lake]

Solution, Oral:

Vituz: Hydrocodone bitartrate 5 mg and chlorpheniramine maleate 4 mg per 5 mL (480 mL [DSC]) [contains methylparaben, propylene glycol, propylparaben, saccharin sodium; grape flavor]

Suspension Extended Release, Oral:

Tussionex Pennkinetic ER: Hydrocodone polistirex [equivalent to hydrocodone bitartrate 10 mg] and chlorpheniramine polistirex [equivalent to chlorpheniramine maleate 8 mg] per 5 mL (115 mL [DSC]) [contains fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow), methylparaben, polyethylene glycol, polysorbate 80, propylene glycol, propylparaben]

Generic: Hydrocodone polistirex [equivalent to hydrocodone bitartrate 10 mg] and chlorpheniramine polistirex [equivalent to chlorpheniramine maleate 8 mg] per 5 mL (70 mL, 115 mL, 118 mL, 473 mL)

Pharmacology

Mechanism of Action

Hydrocodone: Binds to opiate receptors in the CNS, altering the perception of and response to pain; suppresses cough in medullary center; produces generalized CNS depression.

Chlorpheniramine: Competes with histamine for H₁-receptor sites on effector cells in the GI tract, blood vessels, and respiratory tract.

Pharmacokinetics/Pharmacodynamics

Metabolism

Hydrocodone: Hepatic; O-demethylation via primarily CYP2D6 to hydromorphone (major, active metabolite with ~10- to 33-fold higher or as much as a >100-fold higher binding affinity for the mu-opioid receptor than hydrocodone); N-demethylation via CYP3A4 to norhydrocodone (major metabolite); and ~40% of metabolism/clearance occurs via other non-CYP pathways, including 6-ketosteroid reduction to 6-alpha-hydrocol and 6-beta-hydrocol, and other elimination pathways (eg, fecal, biliary, intestinal, renal) (Hutchinson 2004; Volpe 2011; Zhou 2009)

Excretion

Hydrocodone: Urine (26% of single dose in 72 hours, with ~12% as unchanged drug, 5% as norhydrocodone, 4% as conjugated hydrocodone, 3% as 6-hydrocodol, and 0.21% as conjugated 6-hydromorphol (Zhou 2009)

Time to Peak

Hydrocodone: Plasma: ~1 to 2 hours (solution); ~3 hours (capsules, suspension)

Duration of Action

Hydrocodone: 4 to 8 hours

Half-Life Elimination

Hydrocodone: ~4 to 5 hours

Use: Labeled Indications

Cough and upper respiratory tract symptoms: Temporary relief of cough and upper respiratory tract symptoms associated with allergy or the common cold

Limitations of use: Reserve for use in 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.

Contraindications

Hypersensitivity to hydrocodone, chlorpheniramine, or any component of the formulation; pediatric patients <6 years of age (ER formulations).

Oral solution and ER suspension: Additional contraindications: Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected); significant respiratory depression

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosage and Administration

Dosing: Adult

Note: Vituz has been discontinued in the US for more than 1 year.

Cough and upper respiratory tract symptoms: Oral: Note: Dosage units vary based on product formulation (extended release vs immediate release); use caution when verifying dose with product formulation.

Extended release:

Capsules (hydrocodone 10 mg and chlorpheniramine 8 mg per capsule): 1 capsule every 12 hours; maximum: 2 capsules (hydrocodone 20 mg/chlorpheniramine 16 mg) per day

Suspension (hydrocodone 10 mg and chlorpheniramine 8 mg per 5 mL): 5 mL every 12 hours; maximum: 10 mL (hydrocodone 20 mg/chlorpheniramine 16 mg) per day

Immediate release: Oral solution (hydrocodone 5 mg and chlorpheniramine 4 mg per 5 mL): 5 mL every 4 to 6 hours as needed; maximum: 20 mL (hydrocodone 20 mg/chlorpheniramine 16 mg) per day

Discontinuation of therapy: For patients on long term opioid therapy, decrease dose by 25% to 50% every 2 to 4 days; monitor carefully for signs/symptoms of withdrawal. If patient displays withdrawal symptoms, increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both.

Dosing: Geriatric

Avoid use (Beers Criteria [AGS 2019]).

Dosing: Pediatric

Note: Due to risk of adverse effects (slowed or difficult breathing, misuse, abuse, addiction, overdose, and death), the FDA in January 2018 recommended against routine use of codeine/hydrocodone-containing cough/cold products for patients <18 years and that future manufacturer labeling for these products include a contraindication in this population (AAP 2018; FDA 2018a; FDA 2018b).

Cough (antitussive/antihistamine): Note: Oral liquid products (immediate-release solution and extended-release suspension) are NOT indicated for patients <18 years.

Extended-release capsules: Oral:

Children 6 to <12 years: Half-strength capsule (Hydrocodone 5 mg and chlorpheniramine 4 mg per capsule): One half-strength capsule every 12 hours; maximum daily dose: 2 capsules/24 hours

Children ≥12 years and Adolescents: Full-strength capsule (Hydrocodone 10 mg and chlorpheniramine 8 mg per capsule): One full-strength capsule every 12 hours; maximum daily dose: 2 capsules/24 hours

Administration

Capsule: Administer without regard to meals. Do not dilute with fluid or mix with other medications.

Oral solution, suspension: Use an accurate measuring device; a household teaspoon is not an accurate measuring device. Administer without regard to meals. Shake suspension well before administering dose; do not dilute with other fluids or mix with other medications.

Storage

ER capsules, oral solution: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

ER suspension: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Alcohol (Ethyl): May enhance the CNS depressant effect of HYDROcodone. Alcohol (Ethyl) may increase the serum concentration of HYDROcodone. Management: Patients using the Zohydro ER brand of extended-release hydrocodone must not consume alcohol or alcohol-containing products due to possibly fatal outcomes. Other hydrocodone products are also expected to interact, but to a less significant degree. Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Amezinium: Antihistamines may enhance the stimulatory effect of Amezinium. Monitor therapy

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Monitor therapy

Amphetamines: May diminish the sedative effect of Antihistamines. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Benzylpenicilloyl Polylysine: Antihistamines may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Suspend systemic H1 antagonists for benzylpenicilloyl-polylysine skin testing and delay testing until systemic antihistaminic effects have dissipated. A histamine skin test may be used to assess persistent antihistaminic effects. Consider therapy modification

Betahistine: Antihistamines may diminish the therapeutic effect of Betahistine. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of HYDROcodone. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of HYDROcodone. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of HYDROcodone. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of HYDROcodone. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Avoid combination

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosphenytoin-Phenytoin: Chlorpheniramine may increase the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Hyaluronidase: Antihistamines may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of HYDROcodone. Management: Consider alternatives to this combination when possible. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of HYDROcodone. Management: Reduce the hydrocodone dose by 50% during concurrent use of ombitasvir, paritaprevir, and ritonavir; monitor closely for both analgesic effectiveness and for signs of toxicity or withdrawal. Consider therapy modification

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of HYDROcodone. Management: Reduce the hydrocodone dose by 50% during concurrent use of ombitasvir, paritaprevir, ritonavir, and dasabuvir; monitor closely for both analgesic effectiveness and for signs of toxicity or withdrawal. Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

PHENobarbital: May enhance the CNS depressant effect of HYDROcodone. PHENobarbital may decrease the serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pitolisant: Antihistamines may diminish the therapeutic effect of Pitolisant. Avoid combination

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Primidone: May enhance the CNS depressant effect of HYDROcodone. Primidone may decrease the serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Consider therapy modification

QuiNINE: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Monitor therapy

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thioridazine: Chlorpheniramine may enhance the arrhythmogenic effect of Thioridazine. Thioridazine may increase the serum concentration of Chlorpheniramine. Management: Avoid this combination when possible. If used, monitor closely for arrhythmia as well as general toxicity of chlorpheniramine. Consider therapy modification

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Refer to individual agents.

Adverse Reactions

Also refer to Chlorpheniramine monograph. Frequency not defined.

Cardiovascular: Chest tightness

Central nervous system: Agitation, anxiety, confusion, decreased mental acuity, dizziness, drowsiness, drug dependence, dysphoria, euphoria, fear, headache, irritability, lethargy, mood changes, sedation

Dermatologic: Diaphoresis, erythema, pruritus, skin rash, urticaria

Gastrointestinal: Abdominal distention, abdominal pain, acute pancreatitis, constipation, decreased appetite, dyspepsia, epigastric distress, nausea, vomiting, xerostomia

Genitourinary: Dysuria, ureteral spasm, urinary frequency, urinary hesitancy, urinary retention

Neuromuscular & skeletal: Facial dyskinesia, tremor, vesicle sphincter spasm

Ophthalmic: Blurred vision, diplopia, visual disturbance

Respiratory: Dry throat, dyspnea, laryngismus, respiratory depression, wheezing

Postmarketing and/or case reports: Hypogonadism (Brennan 2013; Debono 2011)

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (codeine, hydromorphone, levorphanol, morphine, oxycodone, oxymorphone).
• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or when used in patients at higher risk. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease.
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO₂ retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Head trauma: Avoid use in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Increased intraocular pressure/glaucoma: Use with caution in patients with increased intraocular pressure or glaucoma. Oral solution is contraindicated in narrow angle glaucoma.
• Obesity: Use with caution in patients who are morbidly obese.
• Obstructive bowel disease: Use with caution in patients with obstructive bowel disease.
• Prostatic hyperplasia/urinary obstruction: Use with caution in patients with prostatic hyperplasia and/or urinary stricture. Oral solution is contraindicated in patients with urinary retention.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution in patients with severe renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy; critical respiratory depression may occur, even at therapeutic dosages.
• Seizures: Use with caution in patients with a history of seizure disorder; may cause or exacerbate preexisting seizures.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of hydrocodone/chlorpheniramine in patients taking benzodiazepines, other CNS depressants, or alcohol.
• CYP3A4 interactions: [US Boxed Warning]: Use with all CYP3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitant CYP3A4 inducer may result in increased hydrocodone concentrations. Avoid the use of hydrocodone /chlorpheniramine in patients taking a CYP3A4 inhibitor or inducer.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Ethanol use: [US Boxed Warning]: Do not consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking hydrocodone/chlorpheniramine. Coingestion of alcohol may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

Special populations:

• CYP2D6 "poor metabolizers": Due to the role of CYP2D6 in the metabolism of hydrocodone to hydromorphone (an active metabolite with higher binding affinity to mu-opioid receptors compared to hydrocodone), patients with genetic variations of CYP2D6, including "poor metabolizers" or "extensive metabolizers," may have decreased or increased hydromorphone formation, respectively. Variable effects in positive and negative opioid effects have been reported in these patients; however, limited data exists to determine if clinically significant differences of analgesia and toxicity can be predicted based on CYP2D6 phenotype (Hutchinson 2004; Otton 1993; Zhou 2009).
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages.
• Elderly: Use with caution in elderly patients; may be more sensitive to adverse effects.
• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
• Pediatric: Respiratory depression may occur even at therapeutic dosages; FDA and AAP recommend against use in pediatric patients <18 years due to risk of adverse effects.
• Pregnancy: [US Boxed Warning]: Use is not recommended in pregnant women.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Other warnings/precautions:

• Abuse/misuse/diversion: [US Boxed Warning]: Use exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Reserve for use in adults 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; prescribe for the shortest duration that is consistent with individual patient treatment goals; monitor all patients regularly for development of these behaviors or conditions; and refill only after reevaluation of the need for continued treatment. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use.
• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of hydrocodone.
• Cough: Appropriate use: Underlying cause of cough should be determined prior to prescribing. 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.
• Frequency of dosing: Appropriate use: Extended release capsules and suspension should not be given any more frequently than every 12 hours.
• Risk of medication errors: [US Boxed Warning]: Ensure accuracy when prescribing, dispensing, and administering hydrocodone/chlorpheniramine. Dosing errors can result in accidental overdose and death. Always use an accurate milliliter measuring device when measuring and administering dose. A household teaspoon is not an accurate measuring device and could lead to overdosage.

Monitoring Parameters

Relief of symptoms, respiratory and mental status; bowel function; signs/symptoms of misuse, abuse, and addiction

Pregnancy

Pregnancy Considerations

[US Boxed Warning]: Use is not recommended in pregnant women. Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate.

Refer to individual monographs for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience dry mouth or sweating a lot. Have patient report immediately to prescriber signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), signs of serotonin syndrome (dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), severe dizziness, passing out, chest pain, fast heartbeat, severe fatigue, difficulty breathing, slow breathing, shallow breathing, sexual dysfunction (males), no menstrual periods, decreased sex drive, trouble getting pregnant, confusion, abnormal heartbeat, sensing things that seem real but are not, mood changes, seizures, severe abdominal pain, severe headache, severe loss of strength and energy, severe constipation, difficult urination, tremors, vision changes, vomiting, or severe nausea (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.