TETRABENAZINE Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Strong CYP2D6 Inhibitors In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in tetrabenazine tablets dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of tetrabenazine tablets. The daily dose of tetrabenazine tablets should not exceed 50 mg per day and the maximum single dose of tetrabenazine tablets should not exceed 25 mg in patients taking strong CYP2D6 inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Warnings and Precautions (5.3) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]</span> .

7.2 Reserpine Reserpine binds irreversibly to VMAT2, and the duration of its effect is several days. Prescribers should wait for chorea to re-emerge before administering tetrabenazine tablets to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting tetrabenazine tablets. Tetrabenazine tablets and reserpine should not be used concomitantly <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

7.3 Monoamine Oxidase Inhibitors (MAOIs) Tetrabenazine tablets are contraindicated in patients taking MAOIs. Tetrabenazine tablets should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

7.4 Alcohol or Other Sedating Drugs Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

7.5 Drugs That Cause QTc Prolongation Tetrabenazine tablets cause a small prolongation of QTc (about 8 msec), concomitant use with other drugs that are known to cause QTc prolongation should be avoided, these including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. Tetrabenazine tablets should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain conditions may increase the risk for torsade de pointes or sudden death such as (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval <span class="opacity-50 text-xs">[see Warnings and Precautions (5.8) , Clinical Pharmacology (12.2) ]</span> .

7.6 Neuroleptic Drugs The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of tetrabenazine tablets and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4 , 5.5 , 5.6) ]</span> .

7.7 Concomitant Deutetrabenazine or Valbenazine Tetrabenazine tablets are contraindicated in patients currently taking deutetrabenazine or valbenazine.

Drug

Interactions CYP2D6 Inhibitors In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of tetrabenazine and its metabolites was studied in 25 healthy subjects following a single 50 mg dose of tetrabenazine given after 10 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. There was an approximately 30% increase in C max and an approximately 3-fold increase in AUC for α-HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine given alone. For β-HTBZ, the C max and AUC were increased 2.4- and 9-fold, respectively, in subjects given paroxetine prior to tetrabenazine given alone. The elimination half-life of α-HTBZ and β-HTBZ was approximately 14 hours when tetrabenazine was given with paroxetine. Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure to tetrabenazine tablets and its metabolites has not been evaluated [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) , Drug Interactions (7.1) , Use in Specific Populations (8.7) ] .

Digoxin

Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that tetrabenazine tablets (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine tablets does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine tablets or its metabolites are P-glycoprotein inhibitors.

Tetrabenazine tablets are contraindicated in patients:

• Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.1) ] .
• With hepatic impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .
• Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablets should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3) ] .
• Taking reserpine. At least 20 days should elapse after stopping reserpine before starting tetrabenazine tablets [see Drug Interactions (7.2) ] .
• Taking deutetrabenazine or valbenazine [see Drug Interactions (7.7) ] .
• Actively suicidal, or who have depression which is untreated or undertreated ( 4 , 5.1 )
• Hepatic impairment ( 4 , 8.6, 12.3 )
• Taking monoamine oxidase inhibitors (MAOIs) or reserpine ( 4 , 7.2 , 7.3 )
• Taking deutetrabenazine or valbenazine ( 4 , 7.7 )

AND PRECAUTIONS

• Periodically reevaluate the benefit and potential for adverse effects such as worsening mood, cognition, rigidity, and functional capacity (5.2)
• Do not exceed 50 mg/day and the maximum single dose should not exceed 25 mg if administered in conjunction with a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine). (5.3 , 7.1)
• Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs. (5.4 , 7.6)
• Restlessness, agitation, akathisia and parkinsonism: Reduce dose or discontinue if occurs (5.5 , 5.6)
• Sedation/Somnolence: May impair patient’s ability to drive or operate complex machinery (5.7)
• QTc prolongation: Not recommended in combination with other drugs that prolong QTc (5.8)

5.1 Depression and Suicidality Patients with Huntington’s disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Tetrabenazine tablets increases the risk for suicidality in patients with HD. All patients treated with tetrabenazine tablets should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine tablets. In a 12-week, double-blind placebo-controlled study in patients with chorea associated with Huntington’s disease, 10 of 54 patients (19%) treated with tetrabenazine tablets were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received tetrabenazine tablets for up to 48 weeks; in the second study, 75 patients received tetrabenazine tablets for up to 80 weeks), the rate of depression/worsening depression was 35%. In all of the HD chorea studies of tetrabenazine tablets (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation. When considering the use of tetrabenazine tablets, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with tetrabenazine tablets should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine tablets. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with tetrabenazine tablets, and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately.

5.2 Clinical Worsening and Adverse Effects Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In a 12-week controlled trial, tetrabenazine tablets were also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown. Prescribers should periodically re-evaluate the need for tetrabenazine tablets in their patients by assessing the effect on chorea and possible adverse effects, including depression and suicidality, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness, and disability. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician distinguish between the two possibilities. In some patients, underlying chorea itself may improve over time, decreasing the need for tetrabenazine tablets. 5.3Laboratory Tests Before prescribing a daily dose of tetrabenazine tablets that is greater than 50 mg per day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of tetrabenazine tablets. Patients who are PMs of tetrabenazine tablets will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient’s CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg. <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2), Use in Specific Populations ( 8.7), Clinical Pharmacology ( 12.3)]</span>. 5.4Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine tablets and other drugs that reduce dopaminergic transmission <span class="opacity-50 text-xs">[see Drug Interactions (7.6)]</span>. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection), and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include (1) immediate discontinuation of tetrabenazine tablets and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. Recurrence of NMS has been reported with resumption of drug therapy. If treatment with tetrabenazine tablets is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5.5Akathisia, Restlessness, and Agitation Tetrabenazine may increase the risk of akathisia, restlessness, and agitation. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of tetrabenazine-treated patients and 0% of placebo-treated patients. In an 80-week, open-label study, akathisia was observed in 20% of tetrabenazine-treated patients. Patients receiving tetrabenazine tablets should be monitored for the presence of akathisia. Patients receiving tetrabenazine tablets should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine tablets dose should be reduced; however, some patients may require discontinuation of therapy. 5.6Parkinsonism Tetrabenazine can cause parkinsonism. In a 12-week double-blind, placebo-controlled study in patients with chorea associated with HD, symptoms suggestive of parkinsonism (i.e., bradykinesia, hypertonia and rigidity) were observed in 15% of tetrabenazine-treated patients compared to 0% of placebo-treated patients.

In

48-week and 80-week, open-label studies, symptoms suggestive of parkinsonism were observed in 10% and 3% of tetrabenazine-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between this drug-induced adverse reaction and progression of the underlying disease process. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease. If a patient develops parkinsonism during treatment with tetrabenazine tablets, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.

5.7 Sedation and Somnolence Sedation is the most common dose-limiting adverse reaction of tetrabenazine tablets. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence occurred in 17/54 (31%) of tetrabenazine-treated patients and in 1 (3%) of placebo-treated patient. Sedation was the reason upward titration of tetrabenazine tablets was stopped and/or the dose of tetrabenazine tablets was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of tetrabenazine tablets resulted in decreased sedation.

In

48-week and 80-week, open-label studies, sedation/somnolence occurred in 17% and 57% of tetrabenazine treated patients, respectively. In some patients, sedation occurred at doses that were lower than recommended doses. Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine tablets and know how the drug affects them.

5.8 QTc Prolongation Tetrabenazine causes a small increase (about 8 msec) in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2)]</span>. The use of tetrabenazine tablets should be avoided in combination with other drugs that are known to prolong QTc, including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval <span class="opacity-50 text-xs">[see Drug Interactions (7.5)]</span>. Tetrabenazine tablets should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2)]</span> .

5.9 Hypotension and Orthostatic Hypotension Tetrabenazine tablets induced postural dizziness in healthy volunteers receiving single doses of 25 or 50 mg. One subject had syncope, and one subject with postural dizziness had documented orthostasis. Dizziness occurred in 4% of tetrabenazine-treated patients (vs. none on placebo) in the 12-week, controlled trial; however, blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.

5.10 Hyperprolactinemia Tetrabenazine elevates serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro , a factor of potential importance if tetrabenazine tablets are being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia, and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the tetrabenazine development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of tetrabenazine tablets.

5.11 Binding to Melanin-Containing Tissues Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine tablets may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species, such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure. The clinical relevance of tetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2)]</span>.