Source: Health Products Regulatory Authority (IE) Revision Year: 2019 Publisher: Bausch Health Ireland Limited, 3013 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Tetrabenazine is contraindicated in patients:
The dose of tetrabenazine should be titrated to determine the most appropriate dose for each patient. In vitro and in vivo studies indicate that the tetrabenazine metabolites α- HTBZ and β- HTBZ are substrates for CYP2D6 (see section 5.2).
Therefore dosing requirements may be influenced by a patient’s CYP2D6 metaboliser status and concomitant medications which are strong CYP2D6 inhibitors (see section 4.5).
When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is well tolerated. If the adverse effect does not resolve or decrease, consideration should be given to discontinuing tetrabenazine.
Once a stable dose has been achieved, treatment should be reassessed periodically in the context of the patient’s underlying condition and their concomitant medications (see section 4.5).
Tetrabenazine may cause depression or worsen pre- existing depression. Cases of suicidal ideation and behavior have been reported in patients taking this product. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation (see also section 4.3).
Patients should be closely monitored for the emergence of such adverse events and patients and their caregivers should be informed of the risks and instructed to report any concerns to their doctor immediately.
If depression or suicidal ideation occurs, it may be controlled by reducing the dose of tetrabenazine and/or initiating antidepressant therapy. If depression or suicidal ideation is profound, or persists, discontinuation of tetrabenazine and initiation of antidepressant therapy should be considered.
There is a potential risk of anger and aggressive behavior occurring or worsening in patients taking tetrabenazine with a history of depression or other psychiatric illnesses.
Tetrabenazine can induce parkinsonism and exacerbate pre- existing symptoms of Parkinson’s disease. The tetrabenazine dose should be adjusted as clinically indicated to minimise this side effect.
Dysphagia is a component of Huntington’s disease. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pheumonia. In clinical trials, some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.
Pre- synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine. Tetrabenazine is a central monoamine depleting agent which has can cause extrapyramidal symptoms and theoretically cause tardive dyskinesia in humans.
There have been cases of tardive dyskinesia with tetrabenazine reported in the literature and in post- marketing; therefore, physicians should be aware of the possible risk. If signs and symptoms of tardive dyskinesia appear in a patient treated with tetrabenazine, drug discontinuation should be considered.
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in patients treated with t etr abenazine and other drugs that reduce dopaminergic transmission. This may occur soon after initiation of therapy, following changes in dosage or after prolonged treatment. Clinical manifestations of NMS include 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. If NMS is suspected, tetrabenazine should be withdrawn immediately and appropriate supportive therapy instituted.
If the patient requires treatment with tetrabenazine after recovery from NMS, the potential reintroduction of therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Tetrabenazine causes a small increase (about 8 msec) in the corrected QT interval. Tetrabenazine should be used with caution with other drugs known to prolong QTc and in patients with congenital long QT syndromes and a history of cardiac arrhythmias (see section 4.5).
Tetrabenazine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease.
Patients taking tetrabenazine should be monitored for the presence of akathisia and also for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine dose should be reduced. Some patients may require discontinuation of therapy.
Sedation is the most common dose- limiting adverse effect of tetrabenazine. Patients should be cautioned about performing activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine and know how the drug affects them.
Tetrabenazine may induce postural hypotension at therapeutic doses, and symptoms may include postural dizziness and syncope. This should be considered in patients who may be vulnerable to hypotension or its effects. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.
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 is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia and impotence can be caused by elevated serum 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.
Since tetrabenazine or its metabolites bind to melanin – containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. The clinical relevance of tetrabenazine’s binding to melanin – containing tissues is unknown.
Although there are no specific recommendations for periodic ophthalmic monitoring, prescribers should be aware of the possibility of ophthalmologic effects after long term exposure.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose- galactose malsorption should not take this medicine.
No clinically significant changes in laboratory parameters were reported in clinical trials with tetrabenazine. In controlled clinical trials, tetrabenazine caused a small mean increase in ALT and AST laboratory values as compared to placebo.
The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.
The safety and efficacy of tetrabenazine in children have not been established.
No interaction studies have been performed in vivo. The metabolising enzymes of tetrabenazine are partly unknown.
In vitro-studies indicate that tetrabenazine may be an inhibitor of CYP2D6 and therefore may cause increased plasma concentrations of medicinal products metabolised via CYP2D6, e.g. metoprolol, amitriptyline, imipramine, haloperidol, and risperidone.
In vitro and in vivo studies indicate that the tetrabenazine metabolites 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 approximately 30% increase in Cmax 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, Cmax 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. Caution should be used when adding a strong CYP2D6 inhibitor (such as fluoxetine, paroxetine, or quinidine) to a patient already receiving a stable dose of tetrabenazine and a reduction in the dose of tetrabenazine should be considered. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline has not been evaluated.
Other Cytochrome P450 inhibitors: Based on in vitro studies, a clinically significant interaction between tetrabenazine and other P450 inhibitors (other than CYP2D6 inhibitors) is not likely.
Tetrabenazine inhibits the action of levodopa and thereby attenuates its effect.
Tetrabenazine should not be administered in the presence of MAOIs because of the risk of possible serious interactions resulting in hypertensive crisis (see section 4.3). At least 14 days should elapse between the discontinuation of MAOI and initiation of treatment with tetrabenazine.
Adverse reactions associated with tetrabenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists. There is a potential for significant dopamine depletion when administering tetrabenazine concomitantly with neuroleptic agents (e.g. haloperidol, chlorpromazine, metoclopramide, etc.) and patients should be monitored clinically for the development of parkinsonism.
The concurrent use of tetrabenazine with antihypertensive drugs and beta-blockers may increase the risk of orthostatic hypotension.
The possibility of additive sedative effects should be considered when tetrabenazine is used in conjunction with CNS depressants (including alcohol, neuroleptics, hypnotics, and opioids).
Tetrabenazine should be used with caution with drugs known to prolong QTc including antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g,. gatifloxacin, moxifloxacin) and Class IA and III antiarrythmic medications (e.g., quinidine, procainamide, amiodarone, sotalol).
Concomitant use of tetrabenazine and reserpine is contraindicated (see section 4.3). Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Caution should therefore be used when switching a patient from reserpine to tetrabenazine. The physician should wait for chorea to re-emerge before administering tetrabenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. Since the effects of reserpine can be prolonged, clinical judgment and caution should be used regarding time to discontinuation before starting tetrabenazine.
Digoxin is a substrate for P-glycoprotein. A study in healthy volunteers showed that tetrabenazine (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors.
Interaction studies have only been performed in adults.
There are no adequate and well controlled studies for the use of tetrabenazine in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Tetrabenazine is not recommended during pregnancy and in women of childbearing potential not using contraception.
The effect of tetrabenazine on labour and delivery in humans is unknown.
It is unknown whether tetrabenazine or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Tetrabenazine is contra-indicated during breast-feeding (see section 4.3).
In animal studies with tetrabenazinethere was no evidence of effect on pregnancy or in utero survival. Female cycle lengths were increased and a delay in fertility was seen.
Tetrabenazine may cause drowsiness and therefore may impair the ability to drive and use machines.
Very rare (≤1/10,000): Leukopaenia, Neutropenia
Very rare (≤1/10,000): Hypersensitivity
Common (≥1/100 to <1/10): Decreased appetite
Very rare (≤1/10,000): Dehydration
Not known (cannot be estimated from the available data): Increased appetite
Very common (≥1/10): Depression, Anxiety, Restlessness, Confusion
Common (≥1/100 to <1/10): Irritability, Obsessive-compulsive disorder, Agitation
Very rare (≤1/10,000): Aggression, Anger, Suicidal ideation, Suicide attempt, Nervousness, Sleep disorder
Very common (≥1/10): Sedation/Somnolence/Drowsiness, Extrapyramidal event, Insomnia, Akathisia
Common (≥1/100 to <1/10): Parkinsonism (may include balancing problems), Gait imbalance/balance difficulty, Bradykinesia, Dystonia, Lethargy, Dizziness, Dysarthria, Headache
Very rare (≤1/10,000): Neuroleptic malignant syndrome, Ataxia, Tremor, Excess salivation
Not known (cannot be estimated from the available data): Memory loss
Very common (≥1/10): Blepharospasm
Very rare (≤1/10,000): Oculogyric crisis, Photophobia
Very rare (≤1/10,000): Palpitations
Very rare (≤1/10,000): Hypertension
Not known (cannot be estimated from the available data): Postural hypotension, Hypertensive crisis
Very common (≥1/10): Upper respiratory tract infection
Common (≥1/100 to <1/10): Pneumonia, Dyspnoea, Bronchitis
Very rare (≤1/10,000): Cough, Pneumonia aspiration
Very common (≥1/10): Nausea
Common (≥1/100 to <1/10): Diarrhoea, Vomiting, Constipation
Rare (≥1/10,000 to ≤1/1,000): Dysphagia
Very rare (≤1/10,000): Dry mouth
Not known (cannot be estimated from the available data): Increased ALT, Increased AST
Very rare (≤1/10,000): Hyperhidrosis, Rash, Pruritus, Urticaria
Common (≥1/100 to <1/10): Dysuria
Very rare (≤1/10,000): Urinary tract infection
Very rare (≤1/10,000): Irregular menstrual cycle/amenorrhea/menstrual disorders
Very common (≥1/10): Fatigue
Common (≥1/100 to <1/10): Ecchymosis
Very rare (≤1/10,000): Malaise, Pyrexia, Drug interaction
Not known (cannot be estimated from the available data): Weakness
Very rare (≤1/10,000): Weight decreased
Not known (cannot be estimated from the available data): Weight increased
Very common (≥1/10): Fall
Common (≥1/100 to <1/10): Laceration, Inflicted injury
Rare (≥1/10,000 to ≤1/1,000): Drug administration error
Very rare (≤1/10,000): Overdose
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax; +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
Not applicable.
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