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brand nuedexta 20-10 mg capsule

In stock Manufacturer AVANIR PHARMACE 64597030160
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Uses

Pseudobulbar Affect

The fixed combination of dextromethorphan hydrobromide and quinidine sulfate (dextromethorphan/quinidine; commercially available as Nuedexta) is used in the treatment of pseudobulbar affect (PBA) in adults. PBA occurs secondary to various otherwise unrelated neurologic conditions (e.g., amyotrophic lateral sclerosis [ALS], multiple sclerosis [MS], dementia of the Alzheimer's type [ Alzheimer's disease] or other dementia, parkinsonian syndrome, stroke, traumatic brain injury) and is characterized by involuntary, sudden, uncontrollable, and frequent episodes of laughing and/or crying. These episodes typically occur out of proportion or incongruent to the underlying emotional state. PBA episodes often cause severe embarrassment and social dysfunction, which can lead to social isolation, impaired function, and reduced quality of life.

Efficacy and safety of the fixed-dose combination of dextromethorphan hydrobromide and quinidine sulfate (Nuedexta) were principally demonstrated in the Safety, Tolerability, and Efficacy Results Trial of AVP-923 in PBA (the STAR trial), which was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 326 adults with clinically important PBA and underlying ALS or MS. Patients in the STAR trial were randomized to receive dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg, dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg, or placebo for 12 weeks; medication was administered once daily for the first week, then twice daily during weeks 2 through 12. The primary outcome measure, the number of PBA (laughing and crying) episodes, was substantially lower in both dextromethorphan/quinidine treatment groups compared with the placebo group, with a mean reduction in daily PBA episode rate of 49% in patients receiving dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg. The secondary end point in this trial was the Center for Neurologic Studies Lability Scale (CNS-LS; a 7-item self-report questionnaire assessing crying [3 items] and laughter [4 items]) score difference between day 84 and baseline. This secondary end point also was substantially lower in both dextromethorphan/quinidine groups compared with the placebo group. No clinically important differences were observed between the 2 dextromethorphan/quinidine groups. In addition, the fixed combination of dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg was found to be generally well tolerated in this trial.

Two additional randomized, double-blind, controlled studies using higher dosages of dextromethorphan/quinidine (dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg twice daily) provide supportive evidence for use of the drug combination in the treatment of PBA. CNS-LS scores and number of laughing and crying episodes both were substantially decreased in patients receiving dextromethorphan/quinidine compared with patients receiving higher dosages of either dextromethorphan or quinidine alone in a 4-week study in patients with PBA and underlying ALS and in a 12-week study comparing dextromethorphan/quinidine with placebo in patients with PBA and underlying MS.

The clinical studies evaluating dextromethorphan and quinidine in the treatment of PBA have been conducted in patients with underlying ALS or MS. Although dextromethorphan/quinidine potentially may be effective in reducing PBA symptoms in other brain disease and injury states (since the pathophysiologic mechanisms causing PBA are likely to be similar), the manufacturer states that the efficacy and safety of dextromethorphan/quinidine have not been established in patients with other types of emotional lability that commonly occur, such as in patients with Alzheimer's disease and other dementias. Further clinical studies specifically evaluating the efficacy and safety of the fixed combination in the treatment of PBA in patients with various other neurologic disorders are therefore needed.

Dextromethorphan/quinidine is the first treatment approved by the US Food and Drug Administration (FDA) for the treatment of PBA. Other agents that have been used to treat PBA include tricyclic antidepressants and selective serotonin-reuptake inhibitors (SSRIs); however, clinical studies evaluating these agents in the treatment of PBA have had limitations, including small numbers of patients and methodologic problems in definitions of PBA improvement. Clinical studies comparing dextromethorphan/quinidine with other agents used off-label in the treatment of PBA have not been performed to date.

Dosage and Administration

Administration

The commercially available fixed combination of dextromethorphan hydrobromide and quinidine sulfate (dextromethorphan/quinidine; Nuedexta) is administered orally as capsules without regard to food.

Dosage

Dosages of dextromethorphan hydrobromide and quinidine sulfate in the commercially available fixed combination (Nuedexta) are expressed in terms of the salts.

For the treatment of pseudobulbar affect (PBA) in adults, the recommended initial dosage of the fixed combination of dextromethorphan/quinidine is dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg once daily for the first 7 days of therapy. On the eighth day of therapy and thereafter, dosage of the fixed combination should be increased to dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg twice daily (every 12 hours). The need for continued treatment should be reassessed periodically since spontaneous improvement of PBA occurs in some patients.

Special Populations

Dextromethorphan/quinidine has not been studied in patients with severe renal impairment and the manufacturer does not provide specific dosage recommendations in such patients; however, increases in dextromethorphan and/or quinidine concentrations are thought to be likely. Dosage adjustment of dextromethorphan/quinidine is not necessary in patients with mild or moderate renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dextromethorphan/quinidine has not been studied in patients with severe hepatic impairment and the manufacturer does not provide specific dosage recommendations in such patients; however, increases in dextromethorphan and/or quinidine concentrations are thought to be likely. Dosage adjustment of dextromethorphan/quinidine is not necessary in patients with mild or moderate hepatic impairment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer makes no specific recommendations regarding the need for dosage adjustment in geriatric patients.

Cautions

Contraindications

Because Nuedexta contains quinidine, it should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine.

Dextromethorphan/quinidine is contraindicated in patients with a history of dextromethorphan/quinidine-, quinine-, mefloquine-, or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression, or systemic lupus erythematosus-like syndrome.(See Thrombocytopenia and Other Hypersensitivity Reactions under Cautions: Warnings/Precautions.) Dextromethorphan/quinidine also is contraindicated in patients with known hypersensitivity to dextromethorphan (e.g., rash, urticaria).

Dextromethorphan/quinidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors and in patients who have received MAO inhibitors within the preceding 14 days because of the risk of serious and possibly fatal drug interactions, including serotonin syndrome. At least 14 days should elapse between discontinuance of dextromethorphan/quinidine and initiation of MAO inhibitor therapy. (See Serotonin Syndrome under Cautions: Warnings/Precautions and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Dextromethorphan/quinidine is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure.

Dextromethorphan/quinidine is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers and in patients at high risk of complete AV block.

Dextromethorphan/quinidine is contraindicated in patients concomitantly receiving drugs that both prolong the QT interval and are metabolized by cytochrome P-450 (CYP) 2D6 (e.g., pimozide, thioridazine), since effects on the QT interval may be increased. (See Cardiac Effects under Cautions: Warnings/Precautions and also see Drug Interactions.)

Warnings/Precautions

Thrombocytopenia and Other Hypersensitivity Reactions

Quinidine can cause immune-mediated thrombocytopenia, which can be severe or fatal. Nonspecific symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, may precede or occur with thrombocytopenia. If thrombocytopenia occurs, unless it clearly is not drug related, dextromethorphan/quinidine should be immediately discontinued since continued use increases the risk of fatal hemorrhage. Thrombocytopenia associated with quinidine usually, but not always, resolves within a few days following discontinuance of the sensitizing drug. Dextromethorphan/quinidine should not be reinitiated in sensitized patients since reexposure can result in thrombocytopenia that is more rapid and more severe than the original episode. The fixed combination also should not be used if immune-mediated thrombocytopenia from structurally related drugs, including quinine and mefloquine, is suspected since cross-sensitivity may occur.(See Cautions: Contraindications.)

Quinidine also has been associated with a systemic lupus erythematosus-like syndrome involving polyarthritis; in some cases, antinuclear antibodies (ANA) are present in the blood. Other possible manifestations include rash, bronchospasm, lymphadenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, the sicca syndrome, myalgia, elevated serum concentrations of skeletal muscle enzymes, and pneumonitis.(See Cautions: Contraindications.)

Hepatotoxicity

Hepatitis, including granulomatous hepatitis, has been reported in patients receiving quinidine. Hepatitis generally occurs during the first few weeks of therapy. Fever may be a presenting symptom; thrombocytopenia or other signs of hypersensitivity also may occur. If hepatitis occurs, dextromethorphan/quinidine therapy should be discontinued. In most cases, hepatitis resolves following discontinuance of quinidine. (See Cautions: Contraindications and also see Thrombocytopenia and Other Hypersensitivity Reactions under Cautions: Warnings/Precautions.)

Cardiac Effects

Dextromethorphan/quinidine causes dose-dependent prolongation of the corrected QT (QTc) interval. QT-interval prolongation can cause torsades de pointes-type ventricular tachycardia, with the risk increasing as the degree of QT-interval prolongation increases.

When initiating dextromethorphan/quinidine in patients at risk for QT-interval prolongation and torsades de pointes, electrocardiographic (ECG) evaluation of the QT interval should be performed at baseline and 3-4 hours after the first dose. Such patients include those concomitantly receiving other drugs that prolong the QT interval or drugs that are potent or moderate inhibitors of CYP3A4 (see CYP3A4 Inhibitors under Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes and Drug Interactions: Drugs that Prolong the QT Interval) and patients with left ventricular hypertrophy or left ventricular dysfunction. Left ventricular hypertrophy and left ventricular dysfunction, which can be diagnosed using echocardiography or other cardiac imaging modalities, are more likely to be present in patients with chronic hypertension, known coronary artery disease, or a history of stroke.

If risk factors for cardiac arrhythmia change during the course of dextromethorphan/quinidine therapy, the ECG should be reevaluated. Risk factors for arrhythmia include concomitant use of drugs associated with QT-interval prolongation, electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), bradycardia, and family history of QT-interval abnormalities. Hypokalemia and hypomagnesemia should be corrected before initiation of dextromethorphan/quinidine therapy and potassium and magnesium concentrations should be monitored during treatment.

If patients experience symptoms indicating a possible cardiac arrhythmia (e.g., syncope, palpitations) during therapy, dextromethorphan/quinidine should be discontinued and the patient should be further evaluated.

Concomitant Use of CYP2D6 Substrates

The quinidine component of Nuedexta inhibits CYP2D6 in patients in whom the isoenzyme is not genetically absent or its activity otherwise pharmacologically inhibited. Because of this inhibitory effect on CYP2D6, accumulation of parent drug and/or failure of active metabolite formation may decrease the safety and/or efficacy of concomitantly used drugs that are metabolized by CYP2D6. (See Contraindications and also see Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Dizziness

Dextromethorphan/quinidine may cause dizziness. In a controlled study, dizziness was reported in 10% of patients receiving dextromethorphan/quinidine compared with 5% of patients receiving placebo. Precautions to reduce the risk of falls should be taken during therapy, particularly in patients with motor impairment affecting gait or with a history of falls.

Serotonin Syndrome

Concomitant use of dextromethorphan/quinidine with selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants (e.g., clomipramine, imipramine), or MAO inhibitors may result in serotonin syndrome. Manifestations of serotonin syndrome may include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor. (See Contraindications and also see Drug Interactions.)

For detailed information on serotonin syndrome, including its management,

Anticholinergic Effects of Quinidine

Because quinidine may cause anticholinergic effects, patients with myasthenia gravis or other conditions that may be adversely affected by anticholinergic effects should be monitored for possible worsening of their clinical condition.

Poor Metabolizers of CYP2D6

The quinidine component of Nuedexta is used to inhibit CYP2D6 so that higher exposure of dextromethorphan can be achieved compared with dextromethorphan administered alone. Poor metabolizers of CYP2D6, constituting approximately 7-10% of white patients and 3-8% of black patients, lack the capacity to metabolize CYP2D6 substrates. In poor metabolizers of CYP2D6, the quinidine component of Nuedexta is not expected to contribute to the therapeutic effects of the fixed-drug combination, but adverse effects caused by quinidine are still possible. In patients who may be at substantial risk for quinidine toxicity, genotyping to determine whether they are poor metabolizers should be considered prior to deciding whether to use dextromethorphan/quinidine.

Specific Populations

Pregnancy

Category C.

The effect of dextromethorphan/quinidine on labor and delivery is unknown.

Lactation

The manufacturer states that it is not known whether dextromethorphan and/or quinidine is distributed into human milk. Because many drugs are distributed into human milk, dextromethorphan/quinidine should be used with caution in nursing women.

Pediatric Use

Safety and efficacy of dextromethorphan/quinidine have not been established in pediatric patients younger than 18 years of age. In addition, the pharmacokinetics of dextromethorphan/quinidine have not been studied in pediatric patients.

Geriatric Use

In clinical trials with dextromethorphan/quinidine, 14% of patients were 65 years of age or older and 2% were 75 years of age or older. Clinical study of the fixed-dose combination did not include a sufficient number of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.

The pharmacokinetics of dextromethorphan/quinidine have not been systematically evaluated in geriatric individuals older than 65 years of age, although such individuals were included in the clinical trial program. In a population pharmacokinetic analysis of patients receiving dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg, similar pharmacokinetics were observed in individuals younger than 65 years of age and those 65 years of age or older.

Hepatic Impairment

In a study of combined use of dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg given twice daily in individuals with mild or moderate hepatic impairment compared with healthy individuals, individuals with moderate hepatic impairment showed similar area under the concentration-time curve (AUC), peak plasma concentrations, and clearance of dextromethorphan compared with healthy individuals. Mild to moderate hepatic impairment had little effect on quinidine pharmacokinetics. Therefore, dosage adjustment of dextromethorphan/quinidine is not necessary in patients with mild or moderate hepatic impairment. However, adverse effects have been reported more frequently in patients with moderate hepatic impairment; therefore, additional monitoring for adverse reactions should be considered in such patients.

The clearance of quinidine is not affected by hepatic cirrhosis; however, the volume of distribution is increased, which leads to an increase in the elimination half-life of the drug.

Neither dextromethorphan alone nor dextromethorphan/quinidine has been studied in patients with severe hepatic impairment. However, increases in dextromethorphan and/or quinidine concentrations are likely to occur in such patients.

Renal Impairment

In a study of combined use of dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg given twice daily in individuals with mild or moderate renal impairment, little difference in the pharmacokinetics of quinidine or dextromethorphan in the renally impaired individuals was observed compared with healthy individuals. Therefore, no dosage adjustment is necessary in patients with mild or moderate renal impairment.

Dextromethorphan/quinidine has not been studied in patients with severe renal impairment. However, increases in dextromethorphan and/or quinidine concentrations are likely to occur in such patients.

Common Adverse Effects

Adverse effects occurring in at least 3% of patients receiving dextromethorphan/quinidine and with an incidence of at least twice that reported with placebo in short-term clinical studies in patients with amyotrophic lateral sclerosis or multiple sclerosis include diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased serum γ-glutamyltransferase (γ-glutamyltranspeptidase, GT, GGTP) concentrations, and flatulence. The most common adverse effects leading to discontinuance of dextromethorphan/quinidine include muscle spasticity, respiratory failure, abdominal pain, asthenia, dizziness, falls, and muscle spasms.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Dextromethorphan does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro. Quinidine does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4 in vitro. Neither dextromethorphan nor quinidine induces CYP1A2, CYP2B6, or CYP3A4 in vitro.

Substrates of CYP2D6

The quinidine component of Nuedexta inhibits CYP2D6 in patients in whom CYP2D6 is not genetically absent or its activity otherwise pharmacologically inhibited. Concomitant use of dextromethorphan/quinidine and drugs that are extensively metabolized by CYP2D6 may result in altered drug effects because of accumulation of the parent drug and/or failure of metabolite formation. Therapy with drugs that are principally metabolized by CYP2D6 and that have a relatively narrow therapeutic index should be initiated at a low dosage in patients concurrently receiving dextromethorphan/quinidine.

If dextromethorphan/quinidine is initiated in a patient already receiving a drug metabolized principally by CYP2D6, the need for dosage adjustment of the original drug metabolized by CYP2D6 should be considered. The extent to which CYP2D6-mediated drug interactions may pose clinical problems depends on the pharmacokinetics of the substrate that is involved. For prodrugs dependent on CYP2D6 for activation (e.g., codeine, hydrocodone), it may not be possible to achieve the desired clinical benefits in the presence of dextromethorphan/quinidine. Therefore, the use of alternative drugs should be considered in patients receiving dextromethorphan/quinidine when clinically indicated.

Drugs that Prolong QT Interval and are Substrates of CYP2D6

Dextromethorphan/quinidine should not be used concurrently with drugs that both prolong the QT interval and are metabolized by CYP2D6 (e.g., pimozide, thioridazine). (See Contraindications and also see Drug Interactions: Drugs that Prolong the QT Interval.)

CYP3A4 Inhibitors

Because of the increased risk of QT-interval prolongation and torsades de pointes in patients concurrently receiving dextromethorphan/quinidine and CYP3A4 inhibitors, the manufacturer states that electrocardiographic (ECG) evaluation of the QT interval should be performed at baseline and 3-4 hours after the first dose of dextromethorphan/quinidine in patients concurrently receiving moderate or potent CYP3A4 inhibitors (e.g., aprepitant, atazanavir, clarithromycin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit or grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, verapamil).(See Cardiac Effects under Cautions: Warnings/Precautions.)

Drugs Associated with Serotonin Syndrome

Concomitant use of dextromethorphan/quinidine with selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants (e.g., clomipramine, imipramine), or monoamine oxidase (MAO) inhibitors may result in serotonin syndrome. Manifestations of serotonin syndrome may include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor. (See Contraindications and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Alcohol and other CNS Depressants

Alcohol and other CNS depressants (e.g., sedatives, anxiolytics, antidepressants, antipsychotics, opiate analgesics) may increase the risk of additive CNS effects and should therefore be used concomitantly with caution in patients receiving dextromethorphan/quinidine.

Drugs that Prolong the QT Interval

Because dextromethorphan/quinidine causes dose-dependent QTc-interval prolongation, the manufacturer states that the ECG should be monitored at baseline and 3-4 hours after the first dose of dextromethorphan/quinidine in patients concomitantly receiving other drugs that can prolong the QT interval.

In addition, dextromethorphan/quinidine is contraindicated in patients receiving drugs that both prolong the QT interval and are metabolized by CYP2D6 (e.g., pimozide, thioridazine), since effects on the QT interval may be increased in such patients.

Quinine, Quinidine, and Mefloquine

Because Nuedexta contains quinidine, it should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine; combined use may result in potentially serious ECG abnormalities, including QTc-interval prolongation.(See Contraindications.)

Monoamine Oxidase Inhibitors

Because of the risk of serious and possibly fatal drug interactions, including serotonin syndrome, dextromethorphan/quinidine is contraindicated in patients who have received MAO inhibitors within the preceding 14 days. MAO inhibitors also should be avoided for at least 14 days following discontinuance of dextromethorphan/quinidine.

Desipramine

Desipramine, a tricyclic antidepressant, is metabolized mainly by CYP2D6. In a drug interaction study, an approximately eightfold increase in steady-state desipramine exposure was reported in healthy individuals receiving desipramine 25 mg once daily concomitantly with dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg compared with desipramine given alone. The initial dosage of desipramine should therefore be markedly reduced in patients concurrently receiving dextromethorphan/quinidine. The dosage of desipramine can subsequently be adjusted based on clinical response; however, desipramine dosages exceeding 40 mg daily are not recommended.

Digoxin

Quinidine is an inhibitor of P-glycoprotein (P-gp). Concomitant administration of quinidine with digoxin, a P-gp substrate, results in increased plasma digoxin concentrations by as much as twofold. Plasma concentrations of digoxin should therefore be monitored closely in patients receiving dextromethorphan/quinidine, and the digoxin dosage should be reduced if necessary.

Memantine

Additive antagonistic effects at N-methyl-d-aspartate (NMDA) receptors are theoretically possible when memantine is used concomitantly with dextromethorphan/quinidine. In a drug interaction study, addition of memantine (10 mg twice daily) in healthy individuals receiving dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg at steady state resulted in a small (20-30%) increase in quinidine plasma concentrations; plasma concentrations of dextromethorphan and dextrorphan were not substantially altered. In addition, no clinically important effect on the pharmacodynamics and tolerability of the drugs was observed during concurrent administration. Although these results suggest that memantine may be used concurrently with dextromethorphan/quinidine without initial dosage adjustment, patients should be monitored for possible increased adverse effects as a precaution.

Paroxetine

Concomitant use of paroxetine with dextromethorphan and quinidine results in increased paroxetine concentrations and may result in increased dextromethorphan and quinidine concentrations. Increases in dextromethorphan area under the plasma concentration-time curve (AUC) and peak plasma concentrations of 1.5- and 1.4-fold, respectively, in quinidine AUC and peak plasma concentrations of 1.4- and 1.3-fold, respectively, and in paroxetine AUC and peak plasma concentrations of 2.3- and 2-fold, respectively, were observed with the addition of paroxetine 20 mg once daily for 12 days in healthy individuals who had been receiving dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg twice daily for 8 days. Increases in paroxetine AUC and peak plasma concentrations of 1.7- and 1.5-fold, respectively, were observed with the addition of dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg twice daily for 8 days in patients who had been receiving paroxetine 20 mg once daily for 12 days; exposure to dextromethorphan and quinidine was not altered substantially.

A reduced initial dosage of paroxetine should be considered in patients concurrently receiving dextromethorphan/quinidine. The dosage of paroxetine can subsequently be adjusted based on clinical response; however, paroxetine dosages exceeding 35 mg daily are not recommended.

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