Atuss-12 DX

Dextromethorphan Polistirex:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• How supplied/storage and handling
• Patient counseling information
• Atuss-12 DX (Dextromethorphan Polistirex) reviews

1 INDICATIONS AND USAGE

Atuss-12 DX (Dextromethorphan Polistirex) 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.

Atuss-12 DX (Dextromethorphan Polistirex) is a combination product containing Atuss-12 DX (Dextromethorphan Polistirex) 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.
  

• Maintenance dose: After 7 days, 1 capsule every 12 hours. (2.1)

2.1 Recommended Dose

The recommended starting dose of Atuss-12 DX (Dextromethorphan Polistirex) 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

Atuss-12 DX (Dextromethorphan Polistirex) capsules contain 20 mg Atuss-12 DX (Dextromethorphan Polistirex) hydrobromide and 10 mg quinidine sulfate in a brick red gelatin capsule with “DMQ 20-10” printed in white ink on the capsule.

Capsules: Atuss-12 DX (Dextromethorphan Polistirex) hydrobromide 20 mg/quinidine sulfate 10 mg. (3)

4 CONTRAINDICATIONS

• Concomitant use with quinidine, quinine, or mefloquine.
  

• Patients with a history of quinidine, quinine or mefloquine-induced thrombocytopenia, hepatitis, or other hypersensitivity reactions. (4.2)
  

• Patients with known hypersensitivity to Atuss-12 DX (Dextromethorphan Polistirex). (4.2)
  

• Use with an MAOI or within 14 days of stopping an MAOI. Allow 14 days after stopping Atuss-12 DX (Dextromethorphan Polistirex) 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

Atuss-12 DX (Dextromethorphan Polistirex) contains quinidine, and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine.

4.2 Hypersensitivity

Atuss-12 DX is contraindicated in patients with a history of Atuss-12 DX (Dextromethorphan Polistirex), quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome. Atuss-12 DX (Dextromethorphan Polistirex) is also contraindicated in patients with a known hypersensitivity to Atuss-12 DX (Dextromethorphan Polistirex) (e.g. rash, hives) [ see Warnings and Precautions ( 5.1 ) ].

4.3 MAOIs

Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) before starting an MAOI [ see Drug Interactions ( 7.1 ) ].

4.4 Cardiovascular

Atuss-12 DX (Dextromethorphan Polistirex) 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 ) ].

Atuss-12 DX (Dextromethorphan Polistirex) 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 ) ].

Atuss-12 DX (Dextromethorphan Polistirex) 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.
  

• 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: Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) 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, Atuss-12 DX (Dextromethorphan Polistirex) should not be restarted in sensitized patients, because more rapid and more severe thrombocytopenia than the original episode can occur. Atuss-12 DX (Dextromethorphan Polistirex) 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

Atuss-12 DX 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 Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex). 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 Atuss-12 DX (Dextromethorphan Polistirex), and should be monitored during treatment.

If patients taking Atuss-12 DX (Dextromethorphan Polistirex) experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., syncope or palpitations, Atuss-12 DX (Dextromethorphan Polistirex) should be discontinued and the patient further evaluated.

5.4 Concomitant use of CYP2D6 Substrates

The quinidine in Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) that are metabolized by CYP2D6 [ see Drug Interactions ( 7.5 ) ].

5.5 Dizziness

Atuss-12 DX 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 Atuss-12 DX (Dextromethorphan Polistirex), 10% of patients on Atuss-12 DX (Dextromethorphan Polistirex) 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), Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) is intended to inhibit CYP2D6 so that higher exposure to Atuss-12 DX (Dextromethorphan Polistirex) can be achieved compared to when Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) is not expected to contribute to the effectiveness of Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex).

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 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 Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) (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.

6.2 Long-Term Exposure with Atuss-12 DX

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 Atuss-12 DX (Dextromethorphan Polistirex), Atuss-12 DX (Dextromethorphan Polistirex) 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.

Atuss-12 DX (Dextromethorphan Polistirex)

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.

7 DRUG INTERACTIONS

• Desipramine: Exposure increases 8-fold. Reduce desipramine dose and adjust based on clinical response.
  

• 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 Atuss-12 DX (Dextromethorphan Polistirex) 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 [ see Contraindications ( 4.4 ) ].

7.3 Drugs that Prolong QT and Concomitant CYP3A4 Inhibitors

Recommend ECG in patients taking drugs with Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX 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 Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) concurrently. If Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) due to quinidine-mediated inhibition of CYP2D6. Consider use of alternative treatment with Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex); 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 Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex) (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 Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex). 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 Atuss-12 DX concomitantly, and the digoxin dose reduced, as necessary.

7.7 Alcohol

As with any other CNS drug, caution should be used when Atuss-12 DX (Dextromethorphan Polistirex) is taken in combination with other centrally acting drugs and alcohol.

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Based on animal data, may cause fetal harm.
  

• Pediatric Use: Safety and effectiveness have not been established. (8.4)

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of Atuss-12 DX (Dextromethorphan Polistirex) 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. Atuss-12 DX (Dextromethorphan Polistirex) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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/m² basis. Oral administration (0/0, 5/60, 15/60, and 30/60 mg/kg/day) to pregnant rabbits during organogenesis resulted in an increased incidence of fetal malformations at all but the lowest dose tested. The no-effect dose (5/60 mg/kg/day) is approximately 2/60 times the RHD on a mg/m² basis.

When dextromethorphan/quinidine was orally administered (0/0, 5/100, 15/100, and 30/100 mg/kg/day) to female rats during pregnancy and lactation, pup survival and pup weight were decreased at all doses and developmental delay was seen in offspring at the mid- and high-doses. The lowest dose tested (5/100 mg/kg/day) is approximately 1/50 times the RHD on a mg/m² basis.

8.2 Labor and Delivery

The effects of Atuss-12 DX on labor and delivery are unknown.

8.3 Nursing Mothers

It is not known whether Atuss-12 DX (Dextromethorphan Polistirex) and/or quinidine are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Atuss-12 DX (Dextromethorphan Polistirex) is administered to a nursing mother.

8.4 Pediatric Use

The safety and effectiveness of Atuss-12 DX 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 Atuss-12 DX (Dextromethorphan Polistirex), 14 percent were 65 years old and over, while 2 percent were 75 and over. Clinical study of Atuss-12 DX (Dextromethorphan Polistirex) did not include sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients.

8.6 Renal Impairment

Dose adjustment of Atuss-12 DX is not required in patients with mild to moderate renal impairment [ see Clinical Pharmacology ( 12.3 )]. The pharmacokinetics of Atuss-12 DX (Dextromethorphan Polistirex) have not been evaluated in patients with severe renal impairment; however, increases in dextromethorphan and/or quinidine levels are likely to be observed.

8.7 Hepatic Impairment

Dose adjustment of Atuss-12 DX (Dextromethorphan Polistirex) is not required in patients with mild to moderate hepatic impairment. The pharmacokinetics of Atuss-12 DX (Dextromethorphan Polistirex) have not been evaluated in patients with severe hepatic impairment; however, increases in Atuss-12 DX (Dextromethorphan Polistirex) and/or quinidine levels are likely to be observed.

9 DRUG ABUSE AND DEPENDENCE

Atuss-12 DX (Dextromethorphan Polistirex) is a low-affinity uncompetitive NMDA antagonist and sigma-1 receptor agonist that has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. However, Atuss-12 DX (Dextromethorphan Polistirex) is a combination product containing Atuss-12 DX (Dextromethorphan Polistirex) and quinidine, and cases of Atuss-12 DX (Dextromethorphan Polistirex) abuse have been reported, predominantly in adolescents.

While clinical trials did not reveal drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this experience the extent to which Atuss-12 DX (Dextromethorphan Polistirex) will be misused, diverted, and/or abused once marketed. Therefore, patients with a history of drug abuse should be observed closely for signs of Atuss-12 DX (Dextromethorphan Polistirex) misuse or abuse (e.g. development of tolerance, increases in dose, drug-seeking behavior).

10 OVERDOSAGE

Evaluation and treatment of Atuss-12 DX overdose is based on experience with the individual components, Atuss-12 DX (Dextromethorphan Polistirex) and quinidine. Metabolism of the Atuss-12 DX (Dextromethorphan Polistirex) component of Atuss-12 DX (Dextromethorphan Polistirex) is inhibited by the quinidine component, such that adverse effects of overdose due to Atuss-12 DX (Dextromethorphan Polistirex) might be more severe or more persistent compared to overdose of Atuss-12 DX (Dextromethorphan Polistirex) alone.

During development of Atuss-12 DX (Dextromethorphan Polistirex), dose combinations of dextromethorphan/quinidine containing up to 6-times higher Atuss-12 DX (Dextromethorphan Polistirex) 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 Atuss-12 DX (Dextromethorphan Polistirex), potentially fatal cardiac arrhythmia, including torsades de pointes, can occur at quinidine exposures that are possible from Atuss-12 DX (Dextromethorphan Polistirex) overdose.

Adverse effects of Atuss-12 DX (Dextromethorphan Polistirex) 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. Atuss-12 DX (Dextromethorphan Polistirex) 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 (30-150 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 showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half-life of quinidine in the serum was apparently shortened by repeated gastric lavage. Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2 to 6 hours as a slurry with 8 mL/kg of tap water. Although renal elimination of quinidine might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit. Quinidine is not usefully removed from the circulation by dialysis. Following quinidine overdose, drugs that delay elimination of quinidine (cimetidine, carbonic anhydrase inhibitors, thiazide diuretics) should be withdrawn unless absolutely required.

Atuss-12 DX (Dextromethorphan Polistirex):

Treatment of Atuss-12 DX (Dextromethorphan Polistirex) overdosage should be directed at symptomatic and supportive measures.

11 DESCRIPTION

Atuss-12 DX (Dextromethorphan Polistirex) is an oral formulation of Atuss-12 DX (Dextromethorphan Polistirex) hydrobromide USP and quinidine sulfate USP in a fixed dose combination.

Atuss-12 DX (Dextromethorphan Polistirex) hydrobromide is the pharmacologically active ingredient of Atuss-12 DX (Dextromethorphan Polistirex) that acts on the central nervous system (CNS). The chemical name is Atuss-12 DX (Dextromethorphan Polistirex) hydrobromide: morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula C₁₈H₂₅NO-HBr-H₂O with a molecular weight of 370.33. The structural formula is:

Two additional studies conducted using a higher dose combination of dextromethorphan/quinidine (dextromethorphan 30 mg/quinidine 30 mg) provided supportive evidence of Atuss-12 DX (Dextromethorphan Polistirex) efficacy. The first was a 4 week study in PBA patients with underlying ALS, and the second was a 12 week study in patients with underlying MS. In both studies, the primary outcome measure, CNS-LS, and the secondary outcome measure, laughing and crying episodes, were statistically significantly decreased by the dextromethorphan/quinidine combination.

Figure 1: Mean PBA Episode Rates by Visit Figure 2: Least Square Mean CNS-LS Scores by Visit

16 HOW SUPPLIED/STORAGE AND HANDLING

Atuss-12 DX (Dextromethorphan Polistirex) is supplied as brick red gelatin capsules imprinted with “DMQ 20-10”. Atuss-12 DX (Dextromethorphan Polistirex) is supplied in the following package configuration:

Storage

Store Atuss-12 DX (Dextromethorphan Polistirex) capsules at controlled room temperature, 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F) .

17 PATIENT COUNSELING INFORMATION

Hypersensitivity

Patients should be advised a hypersensitivity reaction to Atuss-12 DX (Dextromethorphan Polistirex) could occur. Patients should be instructed to seek medical attention immediately if they experience symptoms indicative of hypersensitivity after taking Atuss-12 DX (Dextromethorphan Polistirex) [ see Contraindications ( 4.2 ), Warnings and Precautions ( 5.1 ) ].

Cardiac effects

Patients should be advised to consult their healthcare provider immediately if they feel faint or lose consciousness. Patients should be counseled to inform their healthcare provider if they have any personal or family history of QTc prolongation [ see Contraindications ( 4.4 ), Warnings and Precautions ( 5.3 ) Drug Interactions ( 7 ) ].

Dizziness

Patients should be advised that Atuss-12 DX (Dextromethorphan Polistirex) may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls [ see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 ) ].

Drug Interactions

Inform patients that Atuss-12 DX (Dextromethorphan Polistirex) increases the risk of adverse drug interactions. Instruct patients to inform their healthcare provider about all the medications that they are taking before taking Atuss-12 DX (Dextromethorphan Polistirex). Before taking any new medications, patients should tell their healthcare provider that they are taking Atuss-12 DX (Dextromethorphan Polistirex) [ s ee Drug Interactions ( 7 ) ].

Dosing Instructions

Instruct patients to take Atuss-12 DX (Dextromethorphan Polistirex) exactly as prescribed. Instruct patients not to take more than 2 capsules in a 24-hour period and to make sure that there is an approximate 12-hour interval between doses, and not to take a double dose after they miss a dose [see Dosage and Administration ( 2.1 )].

General

Patients should not share or give Atuss-12 DX (Dextromethorphan Polistirex) to others, even if they have the same symptoms, because it may harm them.

Advise patients to contact their healthcare provider if their PBA symptoms persist or worsen.

Advise patients to keep this and all medications out of reach of children and pets.

Marketed by:

Avanir Pharmaceuticals, Inc.

Aliso Viejo, CA 92656

1-949-389-6700

Revised January 2016

Part No. 2000007715

AVANIR and Atuss-12 DX (Dextromethorphan Polistirex) are trademarks or registered trademarks of

Avanir Pharmaceuticals, Inc. in the United States and other countries.

U.S. Patent Nos.: 8,227,484 and 7,659,282

©2010-2016 Avanir Pharmaceuticals, Inc. All rights reserved.

Guaifenesin:

• Atuss-12 DX (Guaifenesin) reviews

Indication: Used to assist the expectoration of phlegm from the airways in acute respiratory tract infections.

Atuss-12 DX (Guaifenesin) is an expectorant which increases the output of phlegm (sputum) and bronchial secretions by reducing adhesiveness and surface tension. The increased flow of less viscous secretions promotes ciliary action and changes a dry, unproductive cough to one that is more productive and less frequent. By reducing the viscosity and adhesiveness of secretions, Atuss-12 DX (Guaifenesin) increases the efficacy of the mucociliary mechanism in removing accumulated secretions from the upper and lower airway.