Dextromethorphan Hydrobromide and Quinidine Sulphate

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 is 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 )

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 is 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.

3 DOSAGE FORMS AND STRENGTHS Dextromethorphan hydrobromide and quinidine sulfate capsules contain 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate in dark brown opaque cap/dark brown opaque body hard gelatin capsules imprinted with ‘ RJ86 ’ on cap in white ink. Capsules: Dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg. (3)

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 contains quinidine and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine. 4.2 Hypersensitivity Dextromethorphan hydrobromide and quinidine sulfate is 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 is 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 is 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 before starting an MAOI [see Drug Interactions (7.1) ] . 4.4 Cardiovascular Dextromethorphan hydrobromide and quinidine sulfate is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome or a history suggestive of torsades de pointes, and in patients with heart failure [see Warnings and Precautions (5.3) ] . Dextromethorphan hydrobromide and quinidine sulfate is contraindicated in patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine and pimozide), as effects on QT interval may be increased [see Drug Interactions (7.2) ] . Dextromethorphan hydrobromide and quinidine sulfate is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block.

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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 ≥ 2 times Placebo in Dextromethorphan Hydrobromide and Quinidine Sulfate-treated Patients by System-Organ Class and Preferred Term Dextromethorphan hydrobromide and quinidine sulfate Placebo N = 107 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, nervousn …

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 described below. No other drug interactions with CYP2D6 substrates have been systematically investigated, although concomitant use of such drugs was allowed in clinical trials with dextromethorphan hydrobromide and quinidine sulfate and in clinical trials with higher dose formulations of dextromethorphan/quinidine. Desipramine (CYP2D6 substrate): The tricyclic antidepressant desipramine is metabolized primarily by CYP2D6. A drug interaction study was conducted between a higher combination dose of dextromethorphan (dextromethorphan 30 mg/quinidine 30 mg) and desipramine 25 mg. The combination dose of dextromethorphan/quinidine increased steady state desipramine levels approximately 8-fold. If dextromethorphan hydrobromide and quinidine sulfate and desipramine are prescribed concomitantly, the initial dose of desipramine should be markedly reduced. The dose of desipramine can then be adjusted based on clinical response; however, a dose above 40 mg/day is not recommended. Paroxetine (CYP2D6 inhi …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 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 dextromethorphan/quinidine was orally administered (0/0, 5/50, 15/50, 25/50 mg/kg) to male and female rats on postnatal day (PND) 7, the highest dose resulted in neuronal death in brain (thalamus and medulla oblongata). PND 7 in rat corresponds to the third trimester of gestation through the first several months of life but may extend to approximately three years of age in humans. 8.2 Lactation Risk Summary Quinidine is excreted in human milk. It is not known whether dextromethorphan is excreted in human milk. There are no data on the effects of quinidine or dextromethorphan on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dextromethorphan hydrobromide and quinidine sulfate and any potential adverse effects on the breastfed infant from dextromethorphan hydrobromide and quinidine sulfate or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Of the total number of patients with PBA in clinical studies of dextromethorphan hydrobromide and quinidine sulfate, 14 percent were 65 years old and over, while 2 percent were 75 and over. Clinical studies of dextromethorphan hydrobromide and quinidine sulfate did not include sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment Dose adjustment of dextromethorphan hydrobromide and quinidine sulfate is not required in patients with mild to moderate renal impairment [se …

11 DESCRIPTION Dextromethorphan hydrobromide and quinidine sulfate capsules are an oral formulation of dextromethorphan hydrobromide and quinidine sulfate in a fixed dose combination. Dextromethorphan hydrobromide, USP is the pharmacologically active ingredient of dextromethorphan hydrobromide and quinidine sulfate capsules that acts on the central nervous system (CNS). The chemical name is dextromethorphan hydrobromide: morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. Dextromethorphan hydrobromide, USP is practically white crystals or crystalline powder having faint odor. It is freely soluble in alcohol and chloroform; sparingly soluble in water; and insoluble in ether. Dextromethorphan hydrobromide has the empirical formula C 18 H 25 NO•HBr•H 2 O with a molecular weight of 370.32. The structural formula is: Quinidine sulfate, USP is a specific inhibitor of CYP2D6-dependent oxidative metabolism used in dextromethorphan hydrobromide and quinidine sulfate capsules to increase the systemic bioavailability of dextromethorphan. The chemical name is quinidine sulfate: cinchonan-9-ol, 6’-methoxy-, (9S) sulfate (2:1), (salt), dihydrate. Quinidine sulfate, USP is fine, needle-like, white crystals, frequently cohering in masses, or fine, white powder. Its solutions are neutral or alkaline to litmus. It is soluble in alcohol; sparingly soluble in chloroform; slightly soluble in water; and insoluble in ether. Quinidine sulfate dihydrate has the empirical formula of (C 20 H 24 N 2 O 2 ) 2 •H 2 SO 4 •2H 2 O with a molecular weight of 783. The structural formula is: The combination product, dextromethorphan hydrobromide and quinidine sulfate, are white to off-white powder. Dextromethorphan hydrobromide and quinidine sulfate are available for oral use as dextromethorphan hydrobromide and quinidine sulfate capsules which contains 20 mg dextromethorphan hydrobromide, USP and 10 mg quinidine sulfate, USP. The active ingredients are dextromethorphan hydrobromide monohydrate, USP and quinidine sulfate dihydrate, USP. Inactive ingredients in the capsule are colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The capsule shell contains D&C Red #28, D&C Yellow #10, FD&C Blue #1, gelatin, and titanium dioxide. The imprinting ink contains povidone, propylene glycol, shellac, sodium hydroxide, and titanium dioxide. Dextro HBr structural formula Quinidine Sulfate Structural formula

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 Overdose While serum quinidine levels can be measured, electrocardiographic monitoring of the QTc interval is a better predictor of quinidine-induced arrhythmia. Treatment of hemodynamically unstable polymorphic ventricular tachycardia (including torsades de pointes) is either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QTc interval. Factors contributing to QTc prolongation (especially hypokalemia and hypomagnesemia) should be sought out and (if possible) aggressively corrected. Prevention of recurrent torsades de pointes may require sustained overdrive pacing or the cautious administration of isoproterenol (30 to 150 ng/kg/min). Because of the theoretical possibility of QT-prolonging effects that might be additive to those of quinidine, other antiarrhythmics with Class I (procainamide) or Class III activities should (if possible) be avoided. If the post-cardioversion QTc interval is prolonged, then the pre-cardioversion polymorphic ventricular tachyarrhythmia was (by definition) torsades de pointes. In this case, class Ib antiarrhythmics like lidocaine are unlikely to be of value, and other Class I and Class III antiarrhythmics are likely to exacerbate the situation. Quinidine-induced hypotension that is not due to an arrhythmia is likely to be a consequence of quinidine-related α-blockade and vasorelaxation. Treatment of hypotension should be directed at symptomatic and supportive measures. Repletion of central volume (Trendelenburg positioning, saline infusion) may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α-agonist catecholamines (norepinephrine). Quinidine : Adequate studies of orally administered activated charcoal in human overdoses of quinidine have not been reported, but there are animal data …

16 HOW SUPPLIED/STORAGE AND HANDLING Dextromethorphan hydrobromide and quinidine sulfate capsules are supplied as white to off-white powder filled in dark brown opaque cap/dark brown opaque body hard gelatin capsules imprinted with ‘ RJ86 ’ on cap in white ink. Dextromethorphan hydrobromide and quinidine sulfate capsules are supplied in the following package configuration: NDC 63304-650-60 Bottles of 60 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].