Dextromethorphan Hydrobromide and Quinidine Sulphate

5 WARNINGS AND PRECAUTIONS Thrombocytopenia or other hypersensitivity reactions: Discontinue if occurs. ( 5.1 ) Hepatitis: Discontinue if occurs. ( 5.2 ) QT Prolongation: Monitor ECG if concomitant use of drugs that prolong QT interval cannot be avoided or if concomitant CYP3A4 inhibitors used. ( 5.3 ) Left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD): Monitor ECG in patients with LVH or LVD. ( 5.3 ) CYP2D6 substrate:Dextromethorphan hydrobromide and quinidine sulfate inhibits CYP2D6. Accumulation of parent drug and/or failure of metabolite formation may decrease safety and/or efficacy of concomitant CYP2D6 metabolized drugs. Adjust dose of CYP2D6 substrate or use alternative treatment when clinically indicated. ( 5.4 , 12.4 ) Dizziness: Take precautions to reduce falls. ( 5.5 ) Serotonin syndrome: Use of dextromethorphan hydrobromide and quinidine sulfate with selective serotonin reuptake inhibitor (SSRIs) or tricyclic antidepressants increases the risk. Discontinue if occurs. ( 5.6 , 7.4 ) Anticholinergic effects of quinidine: Monitor for worsening in myasthenia gravis and other sensitive conditions. ( 5.7 ) 5.1 Thrombocytopenia and Other Hypersensitivity Reactions Quinidine can cause immune-mediated thrombocytopenia that can be severe or fatal. Non-specific symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, can precede or occur with thrombocytopenia. Dextromethorphan hydrobromide and quinidine sulfate should be discontinued immediately if thrombocytopenia occurs, unless the thrombocytopenia is clearly not drug-related, as continued use increases the risk for fatal hemorrhage. Likewise, dextromethorphan hydrobromide and quinidine sulfate should not be restarted in sensitized patients, because more rapid and more severe thrombocytopenia than the original episode can occur. Dextromethorphan hydrobromide and quinidine sulfate should not be used if immune-mediated thrombocytopenia from structurally related drugs, including quinine and mefloquine is suspected, as cross-sensitivity can occur. Quinidine-associated thrombocytopenia usually, but not always, resolves within a few days of discontinuation of the sensitizing drug. Quinidine has also been associated with a lupus-like syndrome involving polyarthritis, sometimes with a positive antinuclear antibody test. Other associations include rash, bronchospasm, lymphadenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, the sicca syndrome, myalgia, elevation in serum levels of skeletal-muscle enzymes, and pneumonitis. 5.2 Hepatotoxicity Hepatitis, including granulomatous hepatitis, has been reported in patients receiving quinidine, generally during the first few weeks of therapy. Fever may be a presenting symptom, and thrombocytopenia or other signs of hypersensitivity may also occur. Most cases remit when quinidine is withdrawn. 5.3 Cardiac Effects Dextromethorphan hydrobromide and quinidine sulfate causes dose-dependent QTc prolongation [see Clinical Pharmacology (12.2) ] . QT prolongation can cause torsades de pointes-type ventricular tachycardia, with the risk increasing as the degree of prolongation increases. When initiating dextromethorphan hydrobromide and quinidine sulfate in patients at risk of QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of QT interval should be conducted at baseline and 3 to 4 hours after the first dose. This includes patients concomitantly taking/initiating drugs that prolong the QT interval or that are strong or moderate CYP3A4 inhibitors, and patients with left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD). LVH and LVD are more likely to be present in patients with chronic hypertension, known coronary artery disease, or history of stroke. LVH and LVD can be diagnosed utilizing echocardiography or another suitable cardiac imaging modality. Strong and moderate CYP3A inhibitors include, but are not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil. Reevaluate ECG if risk factors for arrhythmia change during the course of treatment with dextromethorphan hydrobromide and quinidine sulfate. Risk factors include concomitant use of drugs associated with QT prolongation, electrolyte abnormality (hypokalemia, hypomagnesemia), bradycardia, and family history of QT abnormality. Hypokalemia and hypomagnesemia should be corrected prior to initiation of therapy with dextromethorphan hydrobromide and quinidine sulfate, and should be monitored during treatment. If patients taking dextromethorphan hydrobromide and quinidine sulfate experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., syncope or palpitations, dextromethorphan hydrobromide and quinidine sulfate should be discontinued and the patient further evaluated. 5.4 Concomitant use of CYP2D6 Substrates The quinidine in dextromethorphan hydrobromide and quinidine sulfate inhibits CYP2D6 in patients in whom CYP2D6 is not otherwise genetically absent or its activity otherwise pharmacologically inhibited [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) , (12.5) ] . Because of this effect on CYP2D6, accumulation of parent drug and/or failure of active metabolite formation may decrease the safety and/or the efficacy of drugs used concomitantly with dextromethorphan hydrobromide and quinidine sulfate that are metabolized by CYP2D6 [see Drug Interactions (7.5) ] . 5.5 Dizziness Dextromethorphan hydrobromide and quinidine sulfate may cause dizziness [see Adverse Reactions (6.1) ] . Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls. In a controlled trial of dextromethorphan hydrobromide and quinidine sulfate, 10% of patients on dextromethorphan hydrobromide and quinidine sulfate and 5% on placebo experienced dizziness. 5.6 Serotonin Syndrome When used with SSRIs (such as fluoxetine) or tricyclic antidepressants (such as clomipramine and imipramine), dextromethorphan hydrobromide and quinidine sulfate may cause “serotonin syndrome”, with changes including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor [see Drug Interactions (7.4) , Overdosage (10) ] . 5.7 Anticholinergic Effects of Quinidine Monitor for worsening clinical condition in myasthenia gravis and other conditions that may be adversely affected by anticholinergic effects. 5.8 CYP2D6 Poor Metabolizers The quinidine component of dextromethorphan hydrobromide and quinidine sulfate is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) , (12.5) ] . Approximately 7 to 10% of Caucasians and 3 to 8% of African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs). The quinidine component of dextromethorphan hydrobromide and quinidine sulfate is not expected to contribute to the effectiveness of dextromethorphan hydrobromide and quinidine sulfate in PMs, but adverse events of the quinidine are still possible. In those patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered prior to making the decision to treat with dextromethorphan hydrobromide and quinidine sulfate.

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, nervousness or restlessness, nausea, vomiting, and stomach pain. Quinidine Cinchonism is most often a sign of chronic quinidine toxicity, but it may appear in sensitive patients after a single moderate dose of several hundred milligrams. Cinchonism is characterized by nausea, vomiting, diarrhea, headache tinnitus, hearing loss, vertigo, blurred vision, diplopia, photophobia, confusion, and delirium. Convulsions, apprehension, and ataxia have been reported with quinidine therapy, but it is not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion in patients being treated for cardiovascular indications. Acute psychotic reactions have been reported to follow the first dose of quinidine, but these reactions appear to be extremely rare. Other adverse reactions occasionally reported with quinidine therapy include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, keratopathy, and abnormalities of skin pigmentation.

<table width="100%" cellspacing="0" cellpadding="0" border="1"><tbody><tr><td/><td><paragraph><content styleCode="bold">Dextromethorphan hydrobromide and quinidine sulfate</content></paragraph></td><td><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td/><td><paragraph><content styleCode="bold">N = 107</content></paragraph></td><td><paragraph><content styleCode="bold">N = 109</content></paragraph></td></tr><tr><td/><td><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td><paragraph>13</paragraph></td><td><paragraph>6</paragraph></td></tr><tr><td><paragraph>Dizziness</paragraph></td><td><paragraph>10</paragraph></td><td><paragraph>5</paragraph></td></tr><tr><td><paragraph>Cough</paragraph></td><td><paragraph>5</paragraph></td><td><paragraph>2</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>5</paragraph></td><td><paragraph>1</paragraph></td></tr><tr><td><paragraph>Asthenia</paragraph></td><td><paragraph>5</paragraph></td><td><paragraph>2</paragraph></td></tr><tr><td><paragraph>Peripheral edema</paragraph></td><td><paragraph>5</paragraph></td><td><paragraph>1</paragraph></td></tr><tr><td><paragraph>Urinary tract infection</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>1</paragraph></td></tr><tr><td><paragraph>Influenza</paragraph></td><td><paragraph>4</paragraph></td><td><paragraph>1</paragraph></td></tr><tr><td><paragraph>Increased gamma-glutamyltransferase</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Flatulence</paragraph></td><td><paragraph>3</paragraph></td><td><paragraph>1</paragraph></td></tr></tbody></table>