Xenazine 25

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Xenazine® 25

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25 mg tetrabenazine.

Excipient: Each tablet also contains 64 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet

Yellowish-buff, circular, bevel-edged tablets with ‘CL25’ on one face and a single scoreline on the other. The tablet can be divided into equal halves.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Movement disorders associated with organic central nervous system conditions, e.g., Huntington’s chorea, hemiballismus, and senile chorea.

Xenazine 25 is also indicated for the treatment of moderate to severe tardive dyskinesia, which is disabling and/or socially embarrassing. The condition should be persistent despite withdrawal of antipsychotic therapy, or in cases where withdrawal of antipsychotic medication is not a realistic option; also where the condition persists despite reduction in dosage of antipsychotic medication or switching to atypical antipsychotic medication.

4.2 Posology and method of administration

Adults

The tablets are for oral administration.

Organic Central Nervous System Movement Disorders

Dosing of tetrabenazine involves careful titration of therapy to determine an individualised dose for each patient. When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to allow the identification of a dose for chronic use that reduces chorea and is well tolerated.

Dosage and administration are variable and only a guide is given. Starting doses should be 12.5 mg to 25 mg per day and should be titrated up slowly every 4 to 7 days to allow identification of a dose that is efficacious and well tolerated. After titration is initiated, the total daily dose should be given in two to three divided doses. Titration can be up to 200 mg per day or dose-limiting adverse events, whichever happens first. If the adverse event does not resolve, after dose reduction, consideration should be given to withdrawing tetrabenazine treatment.

If there is no improvement at the maximum dose in seven days, it is unlikely that the compound will be of benefit to the patient, either by increasing the dose or by extending the duration of treatment.

Discontinuation of Treatment with Tetrabenazine

Discontinuation of tetrabenazine is associated with the return of chorea (without significant worsening compared to baseline). Other adverse reactions to sudden treatment withdrawal are possible but unlikely and generally mild.

Resumption of Treatment

Following treatment interruption of greater than 5 days or a treatment interruption occurring due to a change in the patient’s medical condition or concomitant medications, tetrabenazine therapy should be retitrated when resumed. The dose should be initiated at 12.5 mg twice a day, wait 7 days then titrate up by 12.5 mg per day.

If adverse events such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety, or intolerable sedation occur, titration should be stopped and the dose should be reduced.

Tardive Dyskinesia

Recommended starting dose of 12.5 mg a day subsequently titrated according to response. Medication should be discontinued if there is no clear benefit or if the side-effects cannot be tolerated.

For any indication, if adverse events such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety, or intolerable sedation occur, titration should be stopped and the dose should be reduced.

The Elderly

No specific studies have been performed in the elderly.

Paediatric Population

The safety and efficacy of tetrabenazine in children have not been established.

Other information Hepatic Insufficiency

A study in hepatically impaired subjects has shown that there is a markedly decreased metabolism of tetrabenazine to its metabolites with a higher mean Cmax in hepatically impaired subjects in comparison with healthy subjects.

The elimination half life of tetrabenazine and its metabolites in subjects with hepatic impairment was also prolonged.

Increased exposure to other circulating metabolites and the contribution of tetrabenazine or those metabolites to safety and efficacy are unknown.

Therefore, tetrabenazine is contraindicated in hepatic impairment, regardless of the severity of the impairment (see section 5.2).

Renal Insufficiency

The use of tetrabenazine in patients with renal insufficiency has not been studied.

4.3 Contraindications

Tetrabenazine is contraindicated in patients:

• With hypersensitivity to the active substance (tetrabenazine) or to any of the excipients listed in section 6.1

• Who are actively suicidal

• During breast-feeding

• With poorly controlled clinical depression

• Taking a monoamine oxidase inhibitor (MAOI) (see sections 4.4, 4.5 and 4.8).

• With impaired hepatic function

With parkinsonism and hypokinetic-rigid syndrome (parkinsonism).

4.4 Special warnings and precautions for use

In the treatment of chorea, the dose of tetrabenazine should be titrated to determine the most appropriate dose for each patient. 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.

Tardive Dyskinesia

Pre-synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine. Tetrabenazine is a central monoamine depleting agent which can cause extrapyramidal symptoms and theoretically cause tardive dyskinesia in humans.

There have been cases of tardive dyskinesia with tetrabenzine 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.

Depression / Suicidality

Tetrabenazine may cause depression or worsen pre-existing depression. Cases of suicidal ideation and behaviour have been reported in patients taking the product. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation.

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.

MAOI antidepressants should not be used until at least two weeks have elapsed since the last tetrabenazine dose to avoid a potentially serious drug interaction (see section 4.3, 4.5 and 4.8).

Anger and Aggression

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.

Parkinsonism

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

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.

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine and other drugs that reduce dopaminergic transmission. 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 management of NMS should include (1) immediate discontinuation of tetrabenazine 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.

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.

QTc Prolongation

Tetrabenazine causes a small increase (up to 8 msec) in the corrected QT interval.

Tetrabenazine should be used with caution in combination with other drugs known to prolong QTc and in patients with congenital long QT syndromes and a history of cardiac arrythmias (see section4.5).

Cardiac Disease

Tetrabenazine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

Akathisia, Restlessness, and Agitation

Patients taking tetrabenazine should be monitored for the presence of akathisia. Patients taking tetrabenazine 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 dose should be reduced; however, some patients may require discontinuation of therapy.

Orthostatic Hypotension

Tetrabenazine can induce postural dizziness. Patients who are vulnerable to hypotension should be closely monitored in the initial stages of therapy.

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 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.

Drug-Disease Interactions

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malsorption should not take this medicine.

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 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.

Laboratory Tests

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.

Paediatric Population

The safety and efficacy of tetrabenazine in children have not been established. Use in the Elderly

The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.

4.5 Interaction with other medicinal products and other forms of interaction

In v/Yro-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

Levodopa

Tetrabenazine inhibits the action of levodopa and thereby attenuates its effect. Monoamine Oxidase Inhibitors

Tetrabenazine should not be administered in the presence of MAOIs because of the risk of possible serious interactions resulting in hypertensive crisis (see sections 4.3 Contraindications and 4.8 Undesirable Effects). At least 14 days should elapse between the discontinuation of a MAOI and initiation of treatment with tetrabenazine.

Concomitant Use of Neuroleptic Drugs

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.

Antihypertensive Drugs and Beta-Blockers

The concurrent use of tetrabenazine with anti-hypertensive drugs and beta-blockers may increase the risk of orthostatic hypotension.

Interaction with CNS Depressants

The possibility of additive sedative effects should be considered when tetrabenazine is used in conjunction with CNS depressants (including alcohol, neuroleptics, hypnotics, and opioids).

Patients Taking CYP2D6 Inhibitors

In vitro and in vivo studies indicate that the tetrabenazine metabolites a-HTBZ and P-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 C_max and an approximately 3-fold increase in AUC for a-HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine given alone. For P-HTBZ, 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 a-HTBZ and P-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.

Medicines known to Prolong QTc

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).

Digoxin

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.

Paediatric Population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

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Pregnancy

There are no adequate and well controlled studies for the use of tetrabenazine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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.

Lactation

It is unknown whether tetrabenazine or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Tetrabenazine is contraindicated during breast-feeding (see section 4.3).

Fertility

In animal studies with tetrabenazine there was no evidence of effect on pregnancy or in utero survival. Female cycle lengths were increased and a delay in fertility was seen (see section 5.3).

4.7 Effects on ability to drive and use machines

Tetrabenazine may cause drowsiness and; therefore, may have a minor to moderate influence on the ability to drive and use machines.

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.

4.8 Undesirable effects

System/organ categories	Reactions
	Very common	Common	Uncommon	Rare	Very rare	Unknown
	(>1/10)	(<1/10 but >1/100)	(<1/100 but (>1/1,000)	(<1/1,000 but (>1/10,000)	(<1/10,000)
Blood & lymphatic system disorders					Leukopaenia, Neutropenia
Immune system disorders					Hypersensitivity
Metabolism and nutrition disorders		Decreased appetite			Dehydration

Psychiatric disorders	Depression, Anxiety, Restlessness, Confusion	Irritability, Obsessive- compulsive disorder, Agitation;		Aggression, Anger, Suicidal ideation, Suicide attempt, Nervousness, Sleep disorder
Nervous system disorders	Sedation/ Somnolence/ Drowsiness, Extrapyramidal event, Insomnia, Akathisia	Parkinsonism (may include balancing problems), Gait imbalance/ balance difficulty, Bradykinesia, Dystonia, Lethargy, Dizziness, Dysarthria, Headache		Neuroleptic Malignant Syndrome, Ataxia, Tremor, Excess salivation	Memory loss
Eye disorders	Blepharospasm			Oculogyric crisis, Photophobia
Cardiac disorders				Palpitations
Vascular disorders				Hypertension	Postural hypotension, Hypertensive crisis.
Respiratory, thoracic and mediastinal disorders	Upper respiratory tract infection	Pneumonia, Dyspnoea, Bronchitis		Cough, Pneumonia aspiration
Gastro intestinal disorders	Nausea	Diarrhoea, Vomiting, Constipation	Dysphagia	Dry mouth
Heptaobiliary disorders					Increased ALT, Increased AST
Skin & subcutaneous tissue disorders				Hyperhidrosis, Rash, Pruritus, Urticaria
Renal and urinary disorders		Dysuria		Urinary tract infection
Reproductive system and				Irregular menstrual

breast disorders				cycle/amenorrhea /menstrual disorders
General disorders and administration site conditions	Fatigue	Ecchymosis		Malaise, Pyrexia, Drug interaction	Weakness
Investigations				Weight decreased
Injury, poisoning and procedural complications	Fall	Laceration, Inflicted injury	Drug administration error	Overdose

Reporting of suspected adverse reactions

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms associated with overdoses of tetrabenazine may include: acute dystonia, oculogyric crisis, nausea, vomiting, diarrhoea, sweating, hypotension, hypothermia, confusion, hallucinations, sedation, rubor, and tremor.

Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other nervous system drugs, ATC Code: NO7XX06

Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system.

The precise mechanism by which tetrabenazine exerts its effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.

Studies conducted in vitro and in vivo have shown that tetrabenazine is a selective inhibitor of monoamine transportation into pre-synaptic neuronal vesicles, by reversible inhibition of the VMAT2 (vesicular monamine transporter 2), which is principally located in the central nervous system. Studies have shown that a-dihydrotetrabenazine, one of the principal metabolite of tetrabenazine, has a similar affinity and more significant selectivity for VMAT2.

At a synaptic level tetrabenazine and a-dihydrotetrabenazine creates a reversible depletion of monamines in the presynaptic terminals. Within the CNS tetrabenazine and a-dihydrotetrabenazine causes preferential depletion of dopamine from nerve terminals. Neurotransmitter depletion by a single dose of tetrabenazine is reversible and lasts only a few hours.

5.2 Pharmacokinetic Properties

Absorption and Distribution

Tetrabenazine is quickly and mostly absorbed after oral administration. Its absorption is not affected by the taking of food.

Clinical testing has shown that a single oral dose of tetrabenazine undergoes extensive (>75%) absorption from the gastro-intestinal tract.

After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine to a-HTBZ and P-HTBZ. a-HTBZ and P-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (C_max) of a-HTBZ and P-HTBZ are reached within 1 to 1/ hours post-dosing. a-HTBZ and P-HTBZ are subsequently metabolized to another major circulating metabolite, O-dealkylated-HTBZ, for which C_max is reached approximately 2 hours post-dosing.

The in vitro protein binding of tetrabenazine, a-HTBZ, and P-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, a-HTBZ binding ranged from 60% to 68%, and P-HTBZ binding ranged from 59% to 63%.

Biotransformation

The metabolism of tetrabenazine is complex, initially proceeding via the formation of alpha and beta dihydrotetrabenazine. a-HTBZ and P-HTBZ, major circulating metabolites, have half-lives of 4-8 hours and 2-4 hours, respectively. The majority of the observed metabolites appear to be formed from these dihydrotetrabenazines as a result of O-dealkylation, hydroxylation and conjugation.

Elimination

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated.

No significant build-up has been observed after daily administration. The elimination half-life of dihydrotetrabenazine is approximately 5 hours.

Tetrabenazine is mostly eliminated in metabolised form in urine (less than 2% of tetrabenazine is excreted in unchanged form).

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Linearity

After administration of single doses from 12.5 to 50 mg of tetrabenazine, the maximum plasma concentration and the area under the curve increased in proportion to the dose, indicating a linear kinetic.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

In repeated dose toxicity studies orally administered tetrabenazine is generally well tolerated across all animal species tested. Most effects observed are related to the pharmacological parameters of the drug and reflect central monoamine depletion. These signs typically include hypoactivity, lethargy, squinted eyes, or eyes closed. They last up to several hours after dosing and in some species at high doses interfere with normal food intake with consequent decreased or suppressed body weight gain. Across all animal species tested dose dependent sedation is the dose limiting effect of tetrabenazine and the principal adverse effect following oral administration of tetrabenazine. Histopathological changes consistent with elevated prolactin in female rats included mammary gland hyperplasia and changes in reproductive tissues.

Tetrabenazine was not mutagenic in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation but negative in the in vivo micronucleus test. a-HTBZ and P-HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. Tetrabenazine was negative in male mice and rats but equivocal in female rats in in vivo micronucleus tests.

In a fertility and early embryonic development study at systemic exposures below those observed clinically there was no evidence of effect on pregnancy or in utero survival in rats. Length of the estrous cycle was increased and a delay in fertility was seen in female rats. Reproduction was unaffected in male rats.

In embryo-fetal developmental toxicity studies there was no evidence of embryotoxicity or teratogenicity in either rats or rabbits. In a perinatal and postnatal study in rats, neonatal deaths and delayed pup maturation were observed at systemic exposures below those observed clinically. These effects could either be indirect effects due to inadequate maternal care or a direct effect of tetrabenazine on the pups.

Tetrabenazine did not cause an increase in any tumour type when administrated for 26 weeks in the transgenic p53 heterozygous mouse model at doses up to 30 mg/kg/day. In a limited study in male rats tetrabenazine was noncarcinogenic when administered for 94 weeks at doses up to 12 mg/kg/day.

Tetrabenazine and metabolites accumulate in melanin-containing tissues in partially pigmented rats. A single oral administration of ¹⁴C-tetrabenazine to Lister Hooded rats resulted in high levels of radioactivity that persisted in pigmented tissues (eye, uveal tract and pigmented fur) and were still

measurable 21 days after administration while all other tissues were BLQ (Below Limit of Quantification).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch

Lactose Monohydrate Talc

Magnesium Stearate Iron Oxide Yellow E172

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

Do not store above 30^oC.

6.5 Nature and contents of container

White HDPE bottle with a white HDPE cap. Pack size of 112 tablets.

6.6 Instructions for use, handling and disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Lundbeck UK LLP

Lundbeck House Caldecotte Lake Business Park Milton Keynes MK7 8LF England

8. MARKETING AUTHORISATION NUMBER

PL 39386/0001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

23 October 1995 / 23 October 2005

10. DATE OF REVISION OF THE TEXT

June 2014

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25mg Tetrabenazine.

Excipient: Each tablet also contains 64mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Yellowish-buff, circular, bevel-edged tablets with ‘CL25’ on one face and a single scoreline on the other. The tablet can be divided into equal halves.

4 CLINICAL PARTICULARS

Movement disorders associated with organic central nervous system conditions, e.g. Huntington’s chorea, hemiballismus and senile chorea.

Tetrabenazine is also indicated for the treatment of moderate to severe tardive dyskinesia, which is disabling and/or socially embarrassing. The condition should be persistent despite withdrawal of antipsychotic therapy, or in cases where withdrawal of antipsychotic medication is not a realistic option; also where the condition persists despite reduction in dosage of antipsychotic medication or switching to atypical antipsychotic medication.

4.2 Posology and method of administration

The tablets are for oral administration.

Organic Central Nervous System Movement Disorders.

Adults

Dosage and administration are variable and only a guide is given. An initial starting dose of 25mg three times a day is recommended. This can be increased by 25mg a day every three or four days until 200mg a day is being given or the limit of tolerance, as dictated by unwanted effects, is reached, whichever is the lower dose.

Tardive Dyskinesia

Recommended starting dose of 12.5mg a day, subsequently titrated according to response. Medication should be discontinued if there is no clear benefit or if the side-effects cannot be tolerated.

The elderly

No specific studies have been performed in the elderly, but Tetrabenazine has been administered to elderly patients in standard dosage without apparent ill effect.

Children

No specific dosage recommendations are made for the administration of Tetrabenazine to children, although it has been used without ill effect.

4.3 Contraindications

Tetrabenazine is contraindicated in patients:

• With hypersensitivity to the active substance (tetrabenazine) or to any of the excipients listed in section 6.1

• Who are actively suicidal

• During breast-feeding

• With poorly controlled clinical depression

• Taking a monoamine oxidase inhibitor (MAOI) (see sections 4.4, 4.5 and 4.8).

• With impaired hepatic function

• With parkinsonism and hypokinetic-rigid syndrome (parkinsonism).

4.4 Special warnings and precautions for use

Once a stable dose has been achieved, treatment should be reassessed periodically in the context of the patient’s underlying condition.

In vitro and in vivo studies indicate that the tetrabenazine metabolites a-HTBZ and B-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 45).

Treatment should be reassessed periodically in the context of the patient’s underlying condition and their concomitant medications (see section 4.5).

Tardive Dyskinesia

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.

Depression / Suicidality

MAOI antidepressants should not be used until at least two weeks have elapsed since the last tetrabenazine dose to avoid a potentially serious drug interaction (see section 4.3, 4.5 and 4.8).

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.

Parkinsonism

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

Neuroleptic Malignant Syndrome

There is no general agreement about specific pharmacological treatment regimens for NMS.

QTc Prolongation

Tetrabenazine causes a small increase (up to 8 msec) in the corrected QT interval.

Tetrabenazine should be used with caution in combination with other drugs known to prolong QTc and in patients with congenital long QT syndromes and a history of cardiac arrythmias (see section4.5).

Cardiac Disease

Tetrabenazine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

Akathisia, Restlessness, and Agitation

Orthostatic Hypotension

Tetrabenazine can induce postural dizziness. Patients who are vulnerable to hypotension should be closely monitored in the initial stages of therapy.

Hyperprolactinemia

Drug-Disease Interactions

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malsorption should not take this medicine.

Binding to Melanin-Containing Tissues

Although there are no specific recommendations for periodic ophthalmic monitoring, prescribers should be aware of the possibility of ophthalmologic effects after long term exposure.

Laboratory Tests

Paediatric Population

The safety and efficacy of tetrabenazine in children have not been established.

Use in the Elderly

The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.

4.5 Interaction with other medicinal products and other forms of interaction

In wV/'o-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

Levodopa

Tetrabenazine inhibits the action of levodopa and thereby attenuates its effect. Monoamine Oxidase Inhibitors

Concomitant Use of Neuroleptic Drugs

Antihypertensive Drugs and Beta-Blockers

The concurrent use of tetrabenazine with anti-hypertensive drugs and beta-blockers may increase the risk of orthostatic hypotension.

Interaction with CNS Depressants

The possibility of additive sedative effects should be considered when tetrabenazine is used in conjunction with CNS depressants (including alcohol, neuroleptics, hypnotics, and opioids).

Patients Taking CYP2D6 Inhibitors

In vitro and in vivo studies indicate that the tetrabenazine metabolites a-HTBZ and B-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 C_max and an approximately 3-fold increase in AUC for a-HTBZ in subjects given paroxetine prior to tetrabenazine compared to tetrabenazine given alone. For B-HTBZ, 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 a-HTBZ and B-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.

Medicines known to Prolong QTc

Digoxin

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

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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.

Paediatric Population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well controlled studies for the use of tetrabenazine in pregnant women. Studies in animals have shown reproductive toxicity (see section5.3). 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.

Lactation

Fertility

In animal studies with tetrabenazine there was no evidence of effect on pregnancy or in utero survival. Female cycle lengths were increased and a delay in fertility was seen (see section 5.3).

4.7 Effects on ability to drive and use machines

Patients should be advised that Tetrabenazine may cause drowsiness and therefore may modify their performance at skilled tasks (driving ability, operation of machinery, etc.) to a varying degree, depending on dose and individual susceptibility.

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4.8 Undesirable effects

System/			Reactions
organ categor
ies
	Very	Comm	Unco	Rare	Very	Un
	com	on	mmo	(<1/1.0	rare	kno
	mon	(<1/10	n	00 but	(<1/10.	wn
	01/1	but	(<1/1	(>1/10.	000}
	0}	>1/100	00	000}
		}	but
			(>1/1
			.000}
Blood					Leukop
&					aenia.
lymph					Neutrop
atic					enia
system disorde
rs
Immune system					Hyperse
disorders					nsitivity
Metab		Decreas			Dehydra
olism		ed			tion
and		appetite
nutriti
on
disorde
rs
	Depre	Irritabili
	ssion.	ty,			Aggression.
Psychi	Anxie	Obsessi			Anger. Suicidal
Psychi	ty,	ve-			ideation. Suicide
atric	Restle	compuls			attempt.
disorde	ssness	ive			Nervousness.
rs		disorder			Sleep disorder
	Confu				Sleep disorder
	sion	Agitatio n;
Nervou	Sedati	Parkins			Neurole	Me
s	on/	onism			ptic	mor
system disorde	Somn	(may			Maligna	y
system disorde	olence	include			nt	loss
rs	/	balancin			Syndro
rs	Drows	g			me.
	mess.	problem			Ataxia.
	Extrap	sX			Tremor.
	yrami	Gait			Excess
	dal	imbalan			salivatio
	event.	ce/			n
	Insom	balance
	nia.	difficult
	Akath	y.
	isia	Bradyki
		nesia.
		Dystoni a, Letharg

		£ Dizzine ss, Dysarth ria, Headac he
Eye disorde rs	Blech arospa sm			Oculogy ric crisis, Photoph obia
Cardia c disorde rs				Palpitati ons
Vascul ar disorde rs				Hypertension	Post ural hyp oten sion Hyp erte nsiv e crisi s.
Respiratory, thoracic and mediastinal disorders	Upper respiratory tract infection	Pneumo nia, Dyspno ea, Bronchi tis		Cough, Pneumo nia aspiratio n
Gastro intestin al disorde rs	Nausea	Diarrhoea, Vomiting, Constipation	Dysphagia	Dry mouth
HeDtaobiliarv disorders					Increased ALT, Increased AST
Skin & subcut aneous tissue disorde rs				Hyperhi drosis, Rash, Pruritus, Urticari a
Renal and urinary disorders		Dysuria		Urinary tract infectio n
Repro ductive system				Irregula r menstru

and breast disorde rs				al cycle/a menorrh ea/mens trual disorder s
Genera 1 disorde rs and admini stratio n site conditi ons	Fatigu e	Ecchvmosis		Malaise, Pyrexia, Drug interaction	Wea knes s
Investigations				Weight decrease d
Injury, poisoning and procedural complications	Fall	Lacerati on, Inflicted injury	Drug administ ration error	Overdos e

Reporting of suspected adverse reactions

4.9 Overdose

Symptoms associated with overdoses of tetrabenazine may include: acute dystonia, oculogyric crisis, nausea, vomiting, diarrhoea, sweating, hypotension, hypothermia-confusion, hallucinations, sedation, rubor and tremor.

overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control centre on the treatment of any overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC Code: NO7XX06

Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system.

The precise mechanism by which tetrabenazine exerts its effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine. serotonin. norepinephrine. and histamine) from nerve terminals.

Studies conducted in vitro and in vivo have shown that tetrabenazine is a selective inhibitor of monoamine transportation into pre-synaptic neuronal vesicles. by reversible inhibition of the VMAT2 (vesicular monamine transporter 2). which is principally located in the central nervous system. Studies have shown that a-dihydrotetrabenazine. one of the principal metabolite of tetrabenazine. has a similar affinity and more significant selectivity for VMAT2.

5.2 Pharmacokinetic properties

Tetrabenazine is quickly and mostly absorbed after oral administration. Its absorption is not affected by the taking of food.

After administration of single doses from 12.5 to 50 mg of tetrabenazine. the maximum plasma concentration and the area under the curve increased in proportion to the dose. indicating a linear kinetic.

Clinical testing has shown that a single oral dose of tetrabenazine undergoes extensive (>75%) absorption from the gastro-intestinal tract. The metabolism of Tetrabenazine is complex, initially proceeding via the formation of alpha and beta dihydrotetrabenazine. The majority of the observed metabolites appear to be formed from these dihydrotetrabenazines as a result of O-dealkylation, hydroxylation and conjugation.

No significant build-up has been observed after daily administration. The elimination half-life of dihydrotetrabenazine is approximately five hours.

Tetrabenazine is mostly eliminated in metabolised form in urine (less than 2% of tetrabenazine is excreted in unchanged form).

5.3 Preclinical safety data

In repeated dose toxicity studies most effects observed are related to the phamacodynamic action of tetrabenazine and reflect central monoamine depletion. Dose dependent sedation was the principal dose limiting adverse effects of tetrabenazine. Common symptoms were hypoactivitv. lethargy, strabismus, tremor, and convulsions. Histopathological changes consistent with elevated prolactin in female rats included mammary gland hyperplasia and changes in reproductive tissues.

Tetrabenazine and its metabolites accumulate in melanin-containing tissues in partially pigmented rats. The clinical relevance of this finding is unknown.

Tetrabenazine and its metabolites a-HTBZ and B-HTBZ were not mutagenic in the in vitro bacterial reverse mutation assay but were clastogenic in the in vitro chromosome aberration assay. Tetrabenazine was not genotoxic in vivo in male mice and rats but produced equivocal results in female rats.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize Starch Lactose Monohydrate Talc

Magnesium Stearate Iron Oxide Yellow E172

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Do not store above 30^oC.

6.5 Nature and contents of container

White HDPE bottle with a white HDPE cap. Pack size of 112 tablets.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Lundbeck UK LLP Building K1 Timbold Drive Kents Hill Milton Keynes MK7 6BZ UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 39386/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23 October 1995

10 DATE OF REVISION OF THE TEXT

06/06/2014

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