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 )
5.1Thrombocytopenia 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.
5.2Hepatotoxicity
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.
5.3Cardiac 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 ) ] .
5.5Dizziness
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.
5.6Serotonin 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.
5.8CYP2D6 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.
