Testosteron-Depot GALEN

Testosteron-Depot GALEN 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 Testosteron-Depot GALEN 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.

Testosteron-Depot GALEN 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 Testosteron-Depot GALEN should be titrated to determine the most appropriate dose for each patient.

In vitro and in vivo studies indicate that the Testosteron-Depot GALEN 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, Testosteron-Depot GALEN 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 Testosteron-Depot GALEN.

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 Testosteron-Depot GALEN be considered if events do not resolve.

Testosteron-Depot GALEN should be used with caution in patients with hepatic impairment .

Depression

Testosteron-Depot GALEN 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 Testosteron-Depot GALEN and/or initiating antidepressant therapy. If depression suicidal ideation is profound, or persists, discontinuation of Testosteron-Depot GALEN and initiation of antidepressant therapy should be considered.

MAOI antidepressants are contraindicated and should be stopped 14 days before the treatment with Testosteron-Depot GALEN starts, and should not be used until at least 14 days have elapsed after the treatment with Testosteron-Depot GALEN 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 Testosteron-Depot GALEN 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 Testosteron-Depot GALEN should be withdrawn immediately and appropriate treatment initiated.

QTc

Testosteron-Depot GALEN causes a small increase (up to 8msec) in the corrected QT interval.

Testosteron-Depot GALEN 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.

Testosteron-Depot GALEN 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 Testosteron-Depot GALEN 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 Testosteron-Depot GALEN 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 Testosteron-Depot GALEN 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 Testosteron-Depot GALEN on amines in the brain explains the clinical effects in the brain.

Testosteron-Depot GALEN 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.

Testosteron-Depot GALEN 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. Testosteron-Depot GALEN has a higher affinity for VMAT2 than for VMAT1. Thus, Testosteron-Depot GALEN has a short, hardly peripheral effect.

Testosteron-Depot GALEN has a low and erratic bioavailability. It appears to be extensively metabolised by firstpass metabolism. The major metabolite, hydroxyTestosteron-Depot GALEN, is formed by reduction. Little unchanged Testosteron-Depot GALEN can be detected in the urine. Since hydroxyTestosteron-Depot GALEN is reported to be as active as Testosteron-Depot GALEN 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 Testosteron-Depot GALEN and hydroxyTestosteron-Depot GALEN (4 patients with Child Pugh score 5-6 and 1 patient with Child Pugh score 9.) Severe hepatic impairment has not been studied.

In repeated dose toxicity studies, the effects observed with orally administered Testosteron-Depot GALEN were related to depletion of central stores of monoamines. Common symptoms were hypoactivity, lethargy, strabismus, or closed eyes. Primarily pharmacological effects such as sedation were observed and considered dose limiting.

The genotoxic potential of Testosteron-Depot GALEN has been studied using a series of conventional tests. In vitro, Testosteron-Depot GALEN was negative for point mutations and positive for chromosomal aberrations in Chinese hamster ovary cells, at cytotoxic concentrations only. Testosteron-Depot GALEN was not genotoxic in an in vivo chromosomal aberration test.

Testosteron-Depot GALEN did not reveal any carcinogenic potential when administered for 26 weeks in the transgenic p53 heterozygous mouse model at doses up to 30 mg/kg/day and in a limited study in male rats Testosteron-Depot GALEN was noncarcinogenic when administered for 94 weeks at doses up to 12 mg/kg/day.

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 Testosteron-Depot GALEN on the pups.

Not applicable

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