Nitoman

Nitoman is indicated for hyperkinetic motor disorders with Huntington's chorea.

Posology

Adults

Huntington's chorea

Dosage and administration are individual in each patient and therefore only a guide is given.

An initial starting dose of 12.5 mg/day one to three times a day is recommended. This can be increased every three or four days by 12.5 mg until the optimal effect is observed or up to the occurrence of intolerance effects (sedation, Parkinsonism, depression).

The maximum daily dose is 200 mg a day.

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.

Elderly

No specific studies have been performed in the elderly, but Nitoman has been administered to elderly patients in standard dosage without apparent ill effect. Parkinson-like adverse reactions are quite common in these patients and could be dose-limiting.

Paediatric population

No adequate controlled studies have been performed in children. The treatment is not recommended in children.

Hepatic impairment

In patients with mild and moderate hepatic impairment half the initial dose and a slower up-titration of the dose is recommended.2).

Renal impairment

No studies have been performed in patients with renal impairment. Caution is advised in the treatment of these patients.

Method of administration

The tablets are for oral administration. The therapy should be supervised by a doctor experienced in treating hyperkinetic disorders.

Nitoman can block the action of reserpine. Thus these substances should not be taken concomitantly.

Use of monoamine oxidase inhibitors

Presence of a hypokinetic-rigid-syndrome (Parkinsonism)

Untreated or inadequately treated depression. Patients who are actively suicidal.

Breast feeding

Pheochromocytoma

Pro-lactin-dependent tumours, e.g. pituitary or breast cancer

The dose of Nitoman should be titrated to determine the most appropriate dose for each patient.

In vitro and in vivo studies indicate that the Nitoman metabolites α-HTBZ and β-HTBZ are substrates for CYP2D6. Therefore dosing requirements may be influenced by a patient's CYP2D6 metaboliser status and concomitant medications which are strong CYP2D6 inhibitors. When first prescribed, Nitoman 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 Nitoman.

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.

It is known that dose dependent adverse events such as sedation, depression and the occurrence of a hypokinetic-rigid-syndrome (Parkinsonism) are possible. In such a case, the dose should be reduced and discontinuation of Nitoman be considered if events do not resolve.

Nitoman should be used with caution in patients with hepatic impairment .

Depression

Nitoman 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.

If depression or suicidal ideation occurs it may be controlled by reducing the dose of Nitoman and/or initiating antidepressant therapy. If depression suicidal ideation is profound, or persists, discontinuation of Nitoman and initiation of antidepressant therapy should be considered.

MAOI antidepressants are contraindicated and should be stopped 14 days before the treatment with Nitoman starts, and should not be used until at least 14 days have elapsed after the treatment with Nitoman has ended, to avoid a potentially serious drug interaction (see 4.3, 4.5 and 4.8).

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a rare complication of Nitoman therapy.

Neuroleptic malignant syndrome most often occurs early in treatment or in response to changes in dose or after prolonged treatment, and has also been described after abrupt withdrawal.

The main symptoms of this condition are mental changes, rigidity, hyperthermia, autonomic dysfunction (sweating and fluctuations in blood pressure) and elevated creatinine phosphokinase levels.

If neuroleptic malignant syndrome is suspected Nitoman should be withdrawn immediately and appropriate treatment initiated.

QTc

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

Nitoman 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 arrhythmias.

Nitoman tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Patients should be advised that Nitoman 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.

The following undesirable effects are ranked according to system organ class and to their frequency:

Very common (>1/10)

Common (>1/100 and <1/10)

Uncommon (>1/1000 and <1/100)

Rare (>1/10,000 and <1/1000)

Very rare (<1/10,000)

Not known (it is not possible to estimate the incidence from available data).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Signs and symptoms of overdosage may include drowsiness, sweating, hypotension and hypothermia.

Treatment is symptomatic.

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

The central effects of Nitoman closely resemble those of reserpine, but it differs from the latter in having less peripheral activity and being much shorter acting.

Mechanism of action

Animal studies have shown that Nitoman disturbs the metabolism of biogenic amines, for instance that of serotonin and noradrenaline, and that this activity is limited to the brain. The supposition is that this effect of Nitoman on amines in the brain explains the clinical effects in the brain.

Nitoman inhibits the re-uptake of monoamines in the neuroterminal of the presynaptic neurons of the central nervous system. This results in a depletion of monoamines, including dopamine. Dopamine depletion results in hypokinesis leading to a reduction in chorea severity.

Nitoman inhibits the re-uptake of monoamines in synaptic nerve terminals by a reversible and short-term binding to the vesicular monoamine transporter (VMAT). VMAT2 transports monoamines especially in peripheral and central neurons, while VMAT1 regulates the transport in peripheral chromaffine tissues. Nitoman has a higher affinity for VMAT2 than for VMAT1. Thus, Nitoman has a short, hardly peripheral effect.

Nitoman has a low and erratic bioavailability. It appears to be extensively metabolised by firstpass metabolism. The major metabolite, hydroxyNitoman, is formed by reduction. Little unchanged Nitoman can be detected in the urine. Since hydroxyNitoman is reported to be as active as Nitoman in depleting brain amines, it is likely that this is the major therapeutic agent.

Special populations

Hepatic impairment

Mild and moderate hepatic impairment increases the exposure and prolongs the half-lives of Nitoman and hydroxyNitoman (4 patients with Child Pugh score 5-6 and 1 patient with Child Pugh score 9.) Severe hepatic impairment has not been studied.

Adverse reactions possible when combined with:

• Benzodiazepines

• CNS depressants

• Antidepressants

• MAO inhibitors

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.