NUEDEXTA

1 INDICATIONS AND USAGE NUEDEXTA is 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. NUEDEXTA 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 NUEDEXTA 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.

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 NUEDEXTA 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 D rugs NUEDEXTA contains quinidine, and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine. 4.2 Hypersensitivity NUEDEXTA is contraindicated in patients with a history of NUEDEXTA, quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome. NUEDEXTA is also contraindicated in patients with a known hypersensitivity to dextromethorphan (e.g. rash, hives) [ see Warnings and Precautions ( 5.1 ) ] . 4.3 MAOIs NUEDEXTA 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 NUEDEXTA before starting an MAOI [ see Drug Interactions ( 7.1 ) ] . 4.4 Cardiovascular NUEDEXTA 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 ) ] . NUEDEXTA 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 ) ] . NUEDEXTA is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block.

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: Nuedexta 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 NUEDEXTA 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. NUEDEXTA 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, NUEDEXTA should not be restarted in sensitized patients, because more rapid and more severe thrombocytopenia than the original episode can occur. NUEDEXTA 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 NUEDEXTA 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 NUEDEXTA in patients at risk of QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of QT interval should be conducted at baseline and 3-4 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 NUEDEXTA. 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 NUEDEXTA, and should be monitored during treatment. If patients taking NUEDEXTA experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., syncope or palpitations, NUEDEXTA should be discontinued and the patient further evaluated. 5.4 Concomitant use of CYP2D6 Substrates The quinidine in NUEDEXTA 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 NUEDEXTA that are metabolized by CYP2D6 [ see Drug Interactions ( 7.5 ) ] . 5.5 Dizziness NUEDEXTA 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 NUEDEXTA, 10% of patients on NUEDEXTA 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), NUEDEXTA 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 Q uinidine 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 NUEDEXTA 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 7-10% of Caucasians and 3-8% of African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs). The quinidine component of NUEDEXTA is not expected to contribute to the effectiveness of NUEDEXTA 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 NUEDEXTA.

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 NUEDEXTA 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 NUEDEXTA 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 NUEDEXTA 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 NUEDEXTA 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 NUEDEXTA concurrently. If NUEDEXTA 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 NUEDEXTA due to quinidine-mediated inhibition of CYP2D6. Consider use of alternative treatment with NUEDEXTA 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 NUEDEXTA; 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 NUEDEXTA 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 NUEDEXTA 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 inhibitor and substrate) : When the combination dose of dextromethorphan 30 mg/quinidine 30 mg was added to paroxetine at steady state, paroxetine exposure (AUC 0-24 ) increased by 1.7 fold and C max increased by 1.5 fold. Consideration should be given to initiating treatment with a lower dose of paroxetine if given with NUEDEXTA. The dose of paroxetine can then be adjusted based on clinical response; however, dosage above 35 mg/day is not recommended. 7.6 Digoxin Quinidine is an inhibitor of P-glycoprotein. Concomitant administration of quinidine with digoxin, a P-glycoprotein substrate, results in serum digoxin levels that may be as much as doubled. Plasma digoxin concentrations should be closely monitored in patients taking NUEDEXTA concomitantly, and the digoxin dose reduced, as necessary. 7.7 Alcohol As with any other CNS drug, caution should be used when NUEDEXTA is taken in combination with other centrally acting drugs and alcohol.

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 NUEDEXTA 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 Avanir Pharmaceuticals, Inc. at 1-855-4NUEDEX (468-3339) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience A 12-week, placebo-controlled study evaluated NUEDEXTA (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 NUEDEXTA-treated Patients by System-Organ Class and Preferred Term NUEDEXTA 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 NUEDEXTA 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 NUEDEXTA, 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.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of NUEDEXTA 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 2-4% and 15-20%, 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 the gestation through the first several months of life but may extend to approximately three years of age in humans.