Dextromethorphan Hydrobromide And Quinidine Sulfate
FDA Drug Information • Also known as: Dextromethorphan Hydrobromide And Quinidine Sulfate, Nuedexta
- Brand Names
- Dextromethorphan Hydrobromide And Quinidine Sulfate, Nuedexta
- Dosage Form
- CAPSULE, GELATIN COATED
- Product Type
- DRUG FOR FURTHER PROCESSING
Description
11 DESCRIPTION Dextromethorphan hydrobromide and quinidine sulfate capsules are an oral formulation of dextromethorphan hydrobromide USP and quinidine sulfate USP in a fixed dose combination. Dextromethorphan hydrobromide is the pharmacologically active ingredient of dextromethorphan hydrobromide and quinidine sulfate capsules that acts on the central nervous system (CNS). The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. Dextromethorphan hydrobromide has the molecular formula C 18 H 25 NO
What Is Dextromethorphan Hydrobromide And Quinidine Sulfate Used For?
1 INDICATIONS AND USAGE Dextromethorphan hydrobromide and quinidine sulfate capsules are indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state. PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurological disease or injury. Dextromethorphan hydrobromide and quinidine sulfate capsules are a combination product containing dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 agonist) and quinidine sulfate (a CYP450 2D6 inhibitor) indicated for the treatment of pseudobulbar affect (PBA). ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Starting dose: one capsule daily by mouth for 7 days. ( 2.1 ) Maintenance dose: After 7 days, 1 capsule every 12 hours. ( 2.1 ) 2.1 Recommended Dose The recommended starting dose of dextromethorphan hydrobromide and quinidine sulfate capsules are one capsule daily by mouth for the initial seven days of therapy. On the eighth day of therapy and thereafter, the daily dose should be a total of two capsules a day, given as one capsule every 12 hours. The need for continued treatment should be reassessed periodically, as spontaneous improvement of PBA occurs in some patients.
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS A total of 946 patients participated in four Phase 3 controlled and uncontrolled PBA studies and received at least one dose of the combination product of dextromethorphan/quinidine in various strengths at the recommended or higher than the recommended dose. Of those patients, 393 patients were exposed for at least 180 days and 294 patients were exposed for at least one year. Median exposure was 168 days. Controlled trials enrolled only patients with either ALS or MS. Uncontrolled studies enrolled 136 patients with PBA secondary to a wide variety of underlying neurological conditions including stroke (45 patients) and traumatic brain injury (23 patients). Consequently, patients with other underlying neurologic diseases may experience other adverse reactions not described below. The most common adverse reactions (incidence of ≥ 3% and two-fold greater than placebo) in patients taking dextromethorphan hydrobromide and quinidine sulfate are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma-glutamyltransferase, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience A 12-week, placebo-controlled study evaluated dextromethorphan hydrobromide and quinidine sulfate (dextromethorphan 20 mg/quinidine 10 mg) (N=107) and a 30 mg dextromethorphan/10 mg quinidine combination (N=110) compared to placebo (N=109). Approximately 60% of patients had ALS and 40% had MS. Patients were 25 to 80 years of age, with a mean age of approximately 51 years. Three (3) ALS patients in each drug treatment arm and 1 ALS patient in the placebo arm died during the 12-week placebo-control period. All deaths were consistent with the natural progression of ALS. Adverse Reactions Leading to Discontinuation The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) that led to discontinuation with the 20 mg dextromethorphan/10 mg quinidine twice daily dose were muscle spasticity (3%), respiratory failure (1%), abdominal pain (2%), asthenia (2%), dizziness (2%), fall (1%), and muscle spasms (2%). Most Common Adverse Reactions Adverse drug reactions that occurred in ≥ 3% of patients receiving the 20 mg dextromethorphan/10 mg quinidine twice daily dose, and at an incidence of ≥ 2 times placebo in short-term clinical trials in ALS and MS are provided in Table 1. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Table 1: Adverse Drug Reactions with an Incidence of ≥3% of Patients and ≥ 2x Placebo in Dextromethorphan Hydrobromide and Quinidine Sulfate-treated Patients by System-Organ Class and Preferred Term Dextromethorphan Hydrobromide and Quinidine Sulfate N=107 % Placebo N=109 % Diarrhea 13 6 Dizziness 10 5 Cough 5 2 Vomiting 5 1 Asthenia 5 2 Peripheral edema 5 1 Urinary tract infection 4 1 Influenza 4 1 Increased gamma- glutamyltransferase 3 0 Flatulence 3 1 6.2 Long-Term Exposure with Dextromethorphan Hydrobromide and Quinidine Sulfate The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. 6.3 Safety Experience of Individual Components The following adverse reactions have been reported with the use of the individual components of dextromethorphan hydrobromide and quinidine sulfate, dextromethorphan and quinidine, from post-marketing experience. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dextromethorphan Drowsiness, dizziness, nervousness or restlessness, nausea,...
Drug Interactions
7 DRUG INTERACTIONS Desipramine: Exposure increases 8-fold. Reduce desipramine dose and adjust based on clinical response. ( 7.5 , 12.4 ) Paroxetine: Exposure increases 2-fold. Reduce paroxetine dose and adjust based on clinical response. ( 7.5 , 12.4 ) Digoxin: Increased digoxin substrate plasma concentration may occur. ( 7.6 ) 7.1 MAOIs Do not use dextromethorphan hydrobromide and quinidine sulfate with monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days [see Contraindications ( 4.3 )] . 7.2 Drugs that Prolong QT and are Metabolized by CYP2D6 Do not use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide) [see Contraindications ( 4.4 )] . 7.3 Drugs that Prolong QT and Concomitant CYP3A4 Inhibitors Recommend ECG in patients taking drugs with dextromethorphan hydrobromide and quinidine sulfate that prolong the QT interval and in patients taking concomitant moderate or strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.3 )] . 7.4 SSRIs and Tricyclic Antidepressants Use of dextromethorphan hydrobromide and quinidine sulfate with SSRIs or tricyclic antidepressants increases the risk of ‘serotonin syndrome’ [see Warnings and Precautions ( 5.6 )] . 7.5 CYP2D6 Substrate The co-administration of dextromethorphan hydrobromide and quinidine sulfate with drugs that undergo extensive CYP2D6 metabolism may result in altered drug effects, due to accumulation of parent drug and/or failure of metabolite formation [see Warnings and Precautions ( 5.4 )]. Therapy with medications that are primarily metabolized by CYP2D6 and that have a relatively narrow therapeutic index should be initiated at a low dose if a patient is receiving dextromethorphan hydrobromide and quinidine sulfate concurrently. If dextromethorphan hydrobromide and quinidine sulfate is added to the treatment regimen of a patient already receiving a drug primarily metabolized by CYP2D6, the need for a dose modification of the original medication should be considered. The extent to which CYP2D6 interactions may pose clinical problems will depend on the pharmacokinetics of the substrate involved. In cases of prodrugs whose actions are mediated by the CYP2D6-produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in the presence of dextromethorphan hydrobromide and quinidine sulfate due to quinidine-mediated inhibition of CYP2D6. Consider use of alternative treatment with dextromethorphan hydrobromide and quinidine sulfate when clinically indicated. Drug interactions with desipramine and paroxetine have been studied in controlled clinical trials with a higher dose combination of dextromethorphan/quinidine (dextromethorphan 30 mg/quinidine 30 mg) than dextromethorphan hydrobromide and quinidine sulfate; study results are...
Contraindications
4 CONTRAINDICATIONS Concomitant use with quinidine, quinine, or mefloquine. ( 4.1 ) Patients with a history of quinidine, quinine or mefloquine-induced thrombocytopenia, hepatitis, or other hypersensitivity reactions. ( 4.2 ) Patients with known hypersensitivity to dextromethorphan. ( 4.2 ) Use with an MAOI or within 14 days of stopping an MAOI. Allow 14 days after stopping dextromethorphan hydrobromide and quinidine sulfate before starting an MAOI. ( 4.3 ) Prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure. ( 4.4 ) Complete atrioventricular (AV) block without implanted pacemaker, or patients at high risk of complete AV block. ( 4.4 ) Concomitant use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide). ( 4.4 ) 4.1 Quinidine and Related Drugs Dextromethorphan hydrobromide and quinidine sulfate capsules contain quinidine and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine. 4.2 Hypersensitivity Dextromethorphan hydrobromide and quinidine sulfate capsules are contraindicated in patients with a history of dextromethorphan hydrobromide and quinidine sulfate, quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome. Dextromethorphan hydrobromide and quinidine sulfate capsules are also contraindicated in patients with a known hypersensitivity to dextromethorphan (e.g. rash, hives) [see Warnings and Precautions ( 5.1 )] . 4.3 MAOIs Dextromethorphan hydrobromide and quinidine sulfate capsules are contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. Allow at least 14 days after stopping dextromethorphan hydrobromide and quinidine sulfate capsules before starting an MAOI [see Drug...
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of dextromethorphan hydrobromide and quinidine sulfate in pregnant women. In oral studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including teratogenicity (rabbits) and embryolethality, when given to pregnant animals (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When dextromethorphan/quinidine was administered orally (0/0, 5/100, 15/100, and 50/100 mg/kg/day) to pregnant rats during the period of organogenesis, embryo-fetal deaths were observed at the highest dose tested and reduced skeletal ossification was observed at all doses. The lowest dose tested (5/100 mg/kg/day) is approximately 1/50 times the recommended human dose (RHD) of 40/20 mg/day on a mg/m 2 basis. Oral administration to pregnant rabbits during organogenesis in two separate studies (0/0, 5/60, 15/60, and 30/60 mg/kg/day; 0/0, 5/100, 15/100, and 50/100 mg/kg/day) resulted in an increased incidence of fetal malformations at all but the lowest dose tested. The no-effect dose (5/100 mg/kg/day) is approximately 2/100 times the RHD on a mg/m 2 basis. When dextromethorphan/quinidine was orally administered to female rats during pregnancy and lactation in two separate studies (0/0, 5/100, 15/100, and 30/100 mg/kg/day; 0/0, 5/100, 15/100, and 50/100 mg/kg/day), pup survival and pup weight were decreased at all doses, and developmental delay was observed in offspring at the mid and high doses. A no-effect dose for adverse developmental effects was not identified. The lowest dose tested (5/100 mg/kg/day) is approximately 1/50 times the RHD on a mg/m 2 basis. When...
Overdosage
10 OVERDOSAGE Evaluation and treatment of dextromethorphan hydrobromide and quinidine sulfate overdose is based on experience with the individual components, dextromethorphan and quinidine. Metabolism of the dextromethorphan component of dextromethorphan hydrobromide and quinidine sulfate is inhibited by the quinidine component, such that adverse effects of overdose due to dextromethorphan hydrobromide and quinidine sulfate might be more severe or more persistent compared to overdose of dextromethorphan alone. During development of dextromethorphan hydrobromide and quinidine sulfate, dose combinations of dextromethorphan/quinidine containing up to 6-times higher dextromethorphan dose and 12-times higher quinidine dose were studied. The most common adverse events were mild to moderate nausea, dizziness, and headache. The most important adverse effects of acute quinidine overdose are ventricular arrhythmias and hypotension. Other signs and symptoms of overdose may include vomiting, diarrhea, tinnitus, high-frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium. While therapeutic doses of quinidine for treatment of cardiac arrhythmia or malaria are generally 10-fold, or more, higher than the dose of quinidine in dextromethorphan hydrobromide and quinidine sulfate, potentially fatal cardiac arrhythmia, including torsades de pointes, can occur at quinidine exposures that are possible from dextromethorphan hydrobromide and quinidine sulfate overdose. Adverse effects of dextromethorphan overdose include nausea, vomiting, stupor, coma, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis. Other adverse effects include ataxia, nystagmus, dystonia, blurred vision, and changes in muscle reflexes. Dextromethorphan may cause serotonin syndrome, and this risk is increased by overdose, particularly if taken with other serotonergic agents, SSRIs or tricyclic antidepressants. 10.1 Treatment of...
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Dextromethorphan hydrobromide and quinidine sulfate capsules are supplied as white to off-white colored opaque hard gelatin capsule imprinted with 'H' on cap with black ink and 'D22' on body with black ink filled with white to off-white powder. Dextromethorphan hydrobromide and quinidine sulfate capsules are supplied in the following package configuration: Package Configuration Capsule Strength (mg) NDC Code Bottles of 60 (30 day supply) dextromethorphan 20 mg/ quinidine 10 mg 31722-693-60 Storage Store dextromethorphan hydrobromide and quinidine sulfate capsules at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.