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Nuedexta

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Nuedexta Capsules

Nuedexta Capsules

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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 Most cases remit when quinidine is withdrawn.

Cardiac Effects

NUEDEXTA causes dose-dependent QTc prolongation [see CLINICAL PHARMACOLOGY]. 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.

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 CYP2D6 Poor Metabolizers, Pharmacokinetics, Pharmacogenomics]. 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].

Dizziness

NUEDEXTA may cause dizziness [see ADVERSE REACTIONS]. 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.

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, OVERDOSAGE].

Anticholinergic effects of quinidine

Monitor for worsening clinical condition in myasthenia gravis and other conditions that may be adversely affected by anticholinergic effects.

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 Concomitant use of CYP2D6 substrates, Pharmacokinetics, Pharmacogenomics]. 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 26-week carcinogenicity study in the Tg.rasH2 transgenic mouse, dextromethorphan and quinidine, alone and in combination, at oral doses up to 100/100 mg/kg/day did not show any evidence of carcinogenic potential.

In a two-year carcinogenicity study in rats, dextromethorphan/quinidine were administered at oral doses of 0/0, 5/100,20/100, 50/100, 50/0, 0/100 mg/kg/day. No biologically significant tumor findings were observed. The highest dose tested (50/100 mg/kg/day) is approximately 12/50 times the recommended human dose (RHD) of 40/20 mg/day on a mg/m2 basis.

Mutagenesis

Dextromethorphan/quinidine was negative in an in vitro chromosomal aberration assay in human lymphocytes.

Dextromethorphan was negative in in vitro (bacterial reverse mutation, chromosomal aberration in human lymphocytes) and in vivo (mouse micronucleus) assays.

Quinidine was negative in an in vitro bacterial reverse mutation assay and in an in vivo mouse micronucleus assay. Quinidine induced chromosomal aberrations in an in vitro chromosomal aberration assay in the presence of metabolic activation.

Impairment of fertility

When dextromethorphan/quinidine was administered orally (0/0, 5/100,15/100, and 50/100 mg/kg/day) to male and female rats prior to and during mating, and continuing to Day 7 of gestation in females, no effect on fertility was observed up to the highest dose tested, which is approximately 12/50 times the RHD on a mg/m2 basis.

Use In Specific Populations

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies 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. NUEDEXTA 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.

Labor and Delivery

The effects of NUEDEXTA on labor and delivery are unknown.

Nursing Mothers

It is not known whether dextromethorphan or quinidine are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NUEDEXTA is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of NUEDEXTA in pediatric patients below the age of 18 have not been established.

Geriatric Use

Of the total number of patients with PBA in clinical studies of NUEDEXTA, 14 percent were 65 years old and over, while 2 percent were 75 and over. Clinical study of NUEDEXTA did not include sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients.

Renal Impairment

Dose adjustment of NUEDEXTA is not required in patients with mild to moderate renal impairment [see CLINICAL PHARMACOLOGY]. The pharmacokinetics of NUEDEXTA have not been evaluated in patients with severe renal impairment; however, increases in dextromethorphan and/or quinidine levels are likely to be observed.

Hepatic Impairment

Dose adjustment of NUEDEXTA is not required in patients with mild to moderate hepatic impairment. The pharmacokinetics of NUEDEXTA have not been evaluated in patients with severe hepatic impairment; however, increases in dextromethorphan and/or quinidine levels are likely to be observed

Last reviewed on RxList: 12/10/2010
This monograph has been modified to include the generic and brand name in many instances.

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