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Hydrocodone and pseudoephedrine (United States: Not available): Drug information

Hydrocodone and pseudoephedrine (United States: Not available): Drug information
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For additional information see "Hydrocodone and pseudoephedrine (United States: Not available): Patient drug information"

For abbreviations, symbols, and age group definitions show table
ALERT: US Boxed Warning
Addiction, abuse, and misuse:

Hydrocodone/pseudoephedrine exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Reserve for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient's risk prior to prescribing, prescribe for the shortest duration that is consistent with individual patient treatment goals, monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use. Monitor for respiratory depression, especially during initiation of therapy or when used in patients at higher risk.

Accidental ingestion:

Accidental ingestion of even one dose of hydrocodone/pseudoephedrine, especially by children, can result in a fatal overdose of hydrocodone.

Risk of medication errors:

Ensure accuracy when prescribing, dispensing, and administering hydrocodone/pseudoephedrine. Dosing errors can result in accidental overdose and death. Always use an accurate milliliter measuring device when measuring and administering hydrocodone/pseudoephedrine oral solution.

Cytochrome P450 3A4 interaction:

The concomitant use of hydrocodone/pseudoephedrine with all CYP450 3A4 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 concomitantly used CYP450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Avoid use in patients taking a CYP3A4 inhibitor or inducer.

Risks from concomitant use with benzodiazepines or 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. Avoid concomitant use in patients taking benzodiazepines, other CNS depressants, or alcohol.

Interaction with alcohol:

Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking hydrocodone/pseudoephedrine. The co-ingestion of alcohol may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

Neonatal opioid withdrawal syndrome:

Hydrocodone/pseudoephedrine is not recommended for use in pregnant women. Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. If used 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.

Brand Names: US
  • Rezira [DSC]
Pharmacologic Category
  • Antitussive/Decongestant
Dosing: Adult
Cough/Nasal congestion

Cough/Nasal congestion: Oral: Hydrocodone 5 mg/pseudoephedrine 60 mg (5 mL) every 4 to 6 hours as needed (maximum: hydrocodone 20 mg/pseudoephedrine 240 mg per [20 mL] per 24 hours).

Discontinuation of therapy: For patients on long-term opioid therapy, reduce dose gradually by 25% to 50% every 2 to 4 days. 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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution in severe renal impairment.

Dosing: Liver Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution in severe hepatic impairment.

Dosing: Older Adult

Refer to adult dosing. Use with caution.

Adverse Reactions

See individual agents.

Contraindications

Hypersensitivity to hydrocodone, pseudoephedrine, or any component of the formulation; children <6 years of age; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected GI obstruction, including paralytic ileus; severe hypertension; severe coronary artery disease; narrow-angle glaucoma; urinary retention

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 which require mental alertness (eg, operating machinery or driving).

• Hypotension: May cause severe hypotension (including orthostasis and syncope); risk is increased in patients with reduced blood volume or taking concurrent CNS depressants (eg, phenothiazines, general anesthetics). 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 with hydrocodone. 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. Use with caution in patients with underlying intestinal motility disorders; may result in constipation or obstructive bowel disease. Use is contraindicated with known or suspected obstruction, including paralytic ileus.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi and increase biliary tract pressure.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease (including hypertension and ischemic heart disease); contraindicated with severe disease.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Diabetes: Use with caution in patients with diabetes mellitus.

• 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: Use with caution in patients with increased intraocular pressure.

• Obesity: Use opioids with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary obstruction: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with severe renal impairment.

• Respiratory disease: Use opioids 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. Avoid use in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease unable to clear secretions. Use is contraindicated in patients with acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment.

• 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:

• Alcohol: [US Boxed Warning]: Patients should not consume alcoholic beverages or use prescription or nonprescription products containing alcohol while taking hydrocodone/pseudoephedrine. The co-ingestion of alcohol may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

• 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 concomitant use in patients taking benzodiazepines, other CNS depressants, or alcohol.

• CYP 3A4 interactions: [US Boxed Warning]: Concomitant use of hydrocodone/pseudoephedrine with all CYP 3A4 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 concomitantly used CYP 3A4 inducer may result in an increase in hydrocodone plasma concentration. Avoid use in patients taking a CYP 3A4 inhibitor or inducer. If concomitant use is necessary, monitor for signs and symptoms of toxicity or withdrawal.

Special populations:

• 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.

• CYP2D6 poor or intermediate 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), CYP2D6 poor and intermediate metabolizers may have decreased hydromorphone formation. However, limited data exist to determine if clinically significant differences of analgesia and toxicity can be predicted based on CYP2D6 phenotype (CPIC [Crews 2021]).

• Older adult: Use with caution in the elderly; 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.

Dosage form specific issues:

• Oral solution: [US Boxed Warning]: Ensure accuracy when prescribing, dispensing, and administering hydrocodone/pseudoephedrine oral solution. Dosing errors can result in accidental overdose and death. Always use an accurate milliliter measuring device when measuring and administering. A household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions.

• 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 ["Inactive" 1997]; Zar 2007).

Other warnings/precautions:

• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose of hydrocodone/pseudoephedrine, especially in children, can result in a fatal overdose of hydrocodone.

• Cough: Appropriate use: Underlying cause of cough should be determined prior to prescribing and re-evaluated within 5 days for an unresponsive cough. Reserve for use in adult patients for whom the benefits of cough suppression outweigh the risks and in whom an adequate assessment of cough etiology has been made.

• Substance use disorder, abuse, and misuse: [US Boxed Warning]: Hydrocodone/pseudoephedrine exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Reserve for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient's risk prior to prescribing and prescribe for the shortest duration consistent with individual patient treatment goals, monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists; do not abruptly discontinue in a physically-dependent patient. Other risk factors associated with increased risk include a personal or family history of substance use disorder or mental illness (eg, major depression).

Dosage Forms: US

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

Solution, oral:

Rezira: Hydrocodone bitartrate 5 mg and pseudoephedrine hydrochloride 60 mg per 5 mL (480 mL [DSC]) [contains propylene glycol; grape flavor]

Generic Equivalent Available: US

No

Pricing: US

Solution (Rezira Oral)

60-5 mg/5 mL (480 mL): $574.20

Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single manufacturer of the brand and/or generic product, respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for reimbursement or purchasing functions. Pricing data is updated monthly.

Controlled Substance

C-II

Administration: Adult

Oral: Use an accurate milliliter measuring device; a household teaspoon is not an accurate measuring device and could lead to possible overdosage.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Rezira: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022442s009lbl.pdf#page=13

Use: Labeled Indications

Cough/nasal congestion: Symptomatic relief of cough and nasal congestion associated with common cold in adults.

Limitations of use: Reserve for use in adult patients for whom the benefits of cough suppression outweigh the risks and in whom an adequate assessment of cough etiology has been made.

Medication Safety Issues
High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (opioids, all formulations and routes of administration) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Agents with Clinically Relevant Anticholinergic Effects: May increase adverse/toxic effects of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor

Alcohol (Ethyl): May increase CNS depressant effects of HYDROcodone. Alcohol (Ethyl) may increase serum concentration of HYDROcodone. Management: Patients using hydrocodone extended-release capsules 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. Risk X: Avoid

Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Alpha1-Blockers: May decrease therapeutic effects of Alpha-/Beta-Agonists. Risk C: Monitor

Alvimopan: Opioid Agonists may increase adverse/toxic effects 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. Risk D: Consider Therapy Modification

Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Amphetamines: May increase analgesic effects of Opioid Agonists. Risk C: Monitor

Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification

Atomoxetine: May increase hypertensive effects of Sympathomimetics. Atomoxetine may increase tachycardic effects of Sympathomimetics. Risk C: Monitor

Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Benzylpenicilloyl Polylysine: Coadministration of Alpha-/Beta-Agonists and Benzylpenicilloyl Polylysine may alter diagnostic results. Management: Consider use of a histamine skin test as a positive control to assess a patient's ability to mount a wheal and flare response. Risk D: Consider Therapy Modification

Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification

Bornaprine: Sympathomimetics may increase anticholinergic effects of Bornaprine. Risk C: Monitor

Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromocriptine: May increase hypertensive effects of Alpha-/Beta-Agonists. Management: Consider alternatives to this combination when possible. If combined, monitor for hypertension and tachycardia, and do not coadminister these agents for more than 10 days. Risk D: Consider Therapy Modification

Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification

Buprenorphine: May decrease therapeutic effects of Opioid Agonists. Management: Seek alternatives to buprenorphine in patients receiving pure opioid agonists. If combined in certain pain management situations (eg, surgery), monitor for symptoms of therapeutic failure/high dose requirements or opioid withdrawal symptoms. Risk D: Consider Therapy Modification

BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor

Cannabinoid-Containing Products: May increase tachycardic effects of Sympathomimetics. Risk C: Monitor

Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification

Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification

Chlormethiazole: May increase CNS depressant effects 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. Risk D: Consider Therapy Modification

Chloroprocaine (Systemic): May increase hypertensive effects of Alpha-/Beta-Agonists. Risk C: Monitor

Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

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

CNS Depressants: May increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider Therapy Modification

Cocaine (Topical): May increase hypertensive effects of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider Therapy Modification

CYP2D6 Inhibitors (Strong): May decrease active metabolite exposure of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Risk C: Monitor

CYP3A4 Inducers (Moderate): May decrease serum concentration of HYDROcodone. Risk C: Monitor

CYP3A4 Inducers (Strong): May decrease serum concentration of HYDROcodone. Risk C: Monitor

CYP3A4 Inhibitors (Moderate): May increase serum concentration of HYDROcodone. Risk C: Monitor

CYP3A4 Inhibitors (Strong): May increase serum concentration of HYDROcodone. Risk C: Monitor

Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification

Desmopressin: Opioid Agonists may increase hyponatremic effects of Desmopressin. Risk C: Monitor

DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification

Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor

Dihydralazine: Sympathomimetics may decrease therapeutic effects of Dihydralazine. Risk C: Monitor

Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Diuretics: Opioid Agonists may increase adverse/toxic effects of Diuretics. Opioid Agonists may decrease therapeutic effects of Diuretics. Risk C: Monitor

Doxofylline: Sympathomimetics may increase adverse/toxic effects of Doxofylline. Risk C: Monitor

DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification

Eluxadoline: Opioid Agonists may increase constipating effects of Eluxadoline. Risk X: Avoid

Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor

Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): May increase vasoconstricting effects of Alpha-/Beta-Agonists. Risk X: Avoid

Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid

Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification

Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor

Grapefruit Juice: May increase serum concentration of HYDROcodone. Risk C: Monitor

Guanethidine: May increase hypertensive effects of Sympathomimetics. Guanethidine may increase arrhythmogenic effects of Sympathomimetics. Risk C: Monitor

Hexoprenaline: May increase adverse/toxic effects of Alpha-/Beta-Agonists. Risk X: Avoid

HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification

Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): May decrease therapeutic effects of Opioid Agonists. Opioid Agonists may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor

Iobenguane Radiopharmaceutical Products: Alpha-/Beta-Agonists (Indirect-Acting) may decrease therapeutic effects of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid

Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Kratom: May increase adverse/toxic effects of Sympathomimetics. Risk X: Avoid

Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Landiolol: Sympathomimetics may decrease therapeutic effects of Landiolol. Risk C: Monitor

Lemborexant: May increase CNS depressant effects 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. Risk D: Consider Therapy Modification

Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Levothyroxine: May increase therapeutic effects of Sympathomimetics. Sympathomimetics may increase therapeutic effects of Levothyroxine. Levothyroxine may increase adverse/toxic effects of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Risk C: Monitor

Linezolid: May increase hypertensive effects of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider Therapy Modification

Lisuride: May increase hypertensive effects of Alpha-/Beta-Agonists. Risk X: Avoid

Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification

Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Metergoline: May increase adverse/toxic effects of Alpha-/Beta-Agonists (Indirect-Acting). Risk C: Monitor

Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification

Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor

Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Monoamine Oxidase Inhibitors: HYDROcodone may increase serotonergic effects of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Monoamine Oxidase Inhibitors may increase adverse/toxic effects of HYDROcodone. Management: Consider alternatives to this combination when possible. If coadministration is required, use test doses, titrate small doses frequently, and monitor patients closely for evidence of serotonergic and opioid toxicities. Risk D: Consider Therapy Modification

Monoamine Oxidase Inhibitors: May increase hypertensive effects of Alpha-/Beta-Agonists (Indirect-Acting). While linezolid is expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to linezolid specific monographs for details. Risk X: Avoid

Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Nalfurafine: Opioid Agonists may increase adverse/toxic effects of Nalfurafine. Opioid Agonists may decrease therapeutic effects of Nalfurafine. Risk C: Monitor

Nalmefene: May decrease therapeutic effects of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider Therapy Modification

Naltrexone: May decrease therapeutic effects of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid

Nefazodone: Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase serum concentration of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for increased opioid effects, including fatal respiratory depression, when these agents are combined and consider opioid dose reductions until stable drug effects are achieved. Additionally, monitor for serotonin syndrome/serotonin toxicity. Risk C: Monitor

Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid

Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Ombitasvir, Paritaprevir, and Ritonavir: May increase 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. Risk D: Consider Therapy Modification

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase 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. Risk D: Consider Therapy Modification

Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider Therapy Modification

Opioids (Mixed Agonist / Antagonist): May decrease analgesic effects 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. Risk X: Avoid

Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid

Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid

Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification

OxyCODONE: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification

Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid

Pegvisomant: Opioid Agonists may decrease therapeutic effects of Pegvisomant. Risk C: Monitor

Pergolide: May increase hypertensive effects of Alpha-/Beta-Agonists. Risk C: Monitor

PHENobarbital: May increase CNS depressant effects of HYDROcodone. PHENobarbital may decrease serum concentration of HYDROcodone. Management: Avoid use of hydrocodone and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased hydrocodone efficacy and withdrawal if combined. Risk D: Consider Therapy Modification

Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor

Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor

Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor

Primidone: May increase CNS depressant effects of HYDROcodone. Primidone may decrease 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. Risk D: Consider Therapy Modification

Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ramosetron: Opioid Agonists may increase constipating effects of Ramosetron. Risk C: Monitor

Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification

ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor

Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor

Samidorphan: May decrease therapeutic effects of Opioid Agonists. Risk X: Avoid

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may increase serotonergic effects of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may decrease therapeutic effects of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for decreased therapeutic response (eg, analgesia) and opioid withdrawal when coadministered with SSRIs that strongly inhibit CYP2D6. Additionally, monitor for serotonin syndrome/serotonin toxicity if these drugs are combined. Risk C: Monitor

Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may increase serotonergic effects 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. Risk C: Monitor

Serotonin/Norepinephrine Reuptake Inhibitor: May increase tachycardic effects of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitor may increase vasopressor effects of Alpha-/Beta-Agonists. Management: If possible, avoid coadministration of direct-acting alpha-/beta-agonists and serotonin/norepinephrine reuptake inhibitors. If coadministered, monitor for increased sympathomimetic effects (eg, increased blood pressure, chest pain, headache). Risk D: Consider Therapy Modification

Sincalide: Drugs that Affect Gallbladder Function may decrease therapeutic effects of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider Therapy Modification

Solriamfetol: Sympathomimetics may increase hypertensive effects of Solriamfetol. Sympathomimetics may increase tachycardic effects of Solriamfetol. Risk C: Monitor

Somatostatin Analogs: Opioid Agonists may decrease analgesic effects of Somatostatin Analogs. Opioid Agonists may increase analgesic effects of Somatostatin Analogs. Risk C: Monitor

Spironolactone: May decrease vasoconstricting effects of Alpha-/Beta-Agonists. Risk C: Monitor

Succinylcholine: May increase bradycardic effects of Opioid Agonists. Risk C: Monitor

Suvorexant: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification

Sympathomimetics: May increase adverse/toxic effects of Sympathomimetics. Risk C: Monitor

Tedizolid: May increase adverse/toxic effects of Sympathomimetics. Specifically, the risk for increased blood pressure and heart rate may be increased. Risk C: Monitor

Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid

Tilidine: May increase therapeutic effects of Opioid Agonists. Risk X: Avoid

Tranylcypromine: May increase hypertensive effects of Alpha-/Beta-Agonists (Indirect-Acting). Risk X: Avoid

Tricyclic Antidepressants: May increase vasopressor effects of Alpha-/Beta-Agonists. Management: Avoid, if possible, the use of alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist. Risk D: Consider Therapy Modification

Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor

Zolpidem: CNS Depressants may increase CNS depressant effects 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. Risk D: Consider Therapy Modification

Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction and infertility (Brennan 2013).

Pregnancy Considerations

[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.

Refer to individual monographs for additional information.

Breastfeeding Considerations

Hydrocodone and pseudoephedrine are present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer. See individual agents.

Monitoring Parameters

Relief of symptoms; signs/symptoms of substance use disorder, abuse or misuse; respiratory status and blood pressure (if clinically indicated)

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.

Pseudoephedrine: Directly stimulates alpha-adrenergic receptors of respiratory mucosa causing vasoconstriction; directly stimulates beta-adrenergic receptors causing bronchial relaxation, increased heart rate and contractility.

Pharmacokinetics (Adult Data Unless Noted)

See individual agents.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (PR) Puerto Rico: Detussin | H-t tussin dm 20/200 | Histinex d | Rezira
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  9. Rezira (hydrocodone bitartrate and pseudoephedrine hydrochloride) [prescribing information]. Morristown, NJ: Hawthorn Pharmaceuticals Inc; June 2018.
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