Gynodel

Hyperprolactinaemia

The treatment of hyperprolactinaemia in men and women with hypogonadism and/or galactorrhoea.

Menstrual cycle disorders and female infertility

Amenorrhoea and oligomenorrhoea, with or without galactorrhoea.

Drug-induced hyperprolactinaemic disorders.

Polycystic ovary syndrome.

Some infertile women with oligomenorrhoea or amenorrhoea and galactorrhoea may be unduly sensitive to prolactin. Gynodel has been used successfully in the treatment of a number of infertile women with galactorrhoea who do not have demonstrable hyperprolactinaemia.

Prolactinomas

To reduce tumour size, particularly in those at risk of optic nerve compression.

Acromegaly

Gynodel has been used in a number of specialised units, as an adjunct to surgery and/or radiotherapy to reduce circulating growth hormone in the management of acromegalic patients.

Parkinson's Disease

In the treatment of idiopathic Parkinson's Disease, Gynodel has been used both alone and in combination with Levodopa in the management of previously untreated patients and those disabled by 'on-off' phenomena.).

Gynodel should always be taken with food.

A number of disparate conditions are amenable to treatment with Gynodel and for this reason, the recommended dosage regimens are variable.

In most indications, irrespective of the final dose, the optimum response with the minimum of side effects is best achieved by gradual introduction of Gynodel. The following scheme is suggested: Initially, 1mg to 1.25mg at bed time, increasing after 2 to 3 days to 2mg to 2.5mg at bed time. Dosage may then be increased by 1mg to 2.5mg at 2 to 3 day intervals, until a dosage of 2.5mg twice daily is achieved. Further dosage increments, if necessary, should be added in a similar manner.

Hypogonadism/Galactorrhea syndromes/Infertility

Introduce Gynodel gradually according to the suggested scheme. Most patients with hyperprolactinaemia have responded to 7.5mg daily, in divided doses, but doses of up to 30mg daily have been used. In infertile patients without demonstrably elevated serum prolactin levels, the usual dose is 2,5mg twice daily.

Prolactinomas

Introduce Gynodel gradually according to the suggested scheme. Dosage may then be increased by 2.5mg daily at 2 to 3 day intervals as follows: 2.5mg eight-hourly, 2.5mg six hourly, 5mg six-hourly. Daily doses should not exceed 30 mg.

Acromegaly

Introduce Gynodel gradually, according to the suggested scheme. Dosage may then be increased by 2.5mg daily at 2 to 3 day intervals as follows 2.5mg eight-hourly, 2.5mg six-hourly, 5mg six-hourly, 5mg six-hourly.

Parkinson's Disease

Introduce Gynodel gradually, as follows: Week 1: 1mg to 1.25mg at bed time. Week 2: 2mg to 2.5mg at bed time. Week 3: 2.5mg twice daily. Week 4: 2.5mg three times daily. Thereafter take three times a day increasing by 2.5mg every 3 to 14 days, depending on the patient's response. Continue until the optimum dose is reached. This will usually be between 10mg and 30mg daily. Daily doses should not exceed 30 mg. In patients already receiving Levodopa the dosage of this drug may gradually be decreased while the dosage daily of Gynodel is increased until the optimum balance is determined.

Use in Children and adolescents (aged 7-17)

Prescribing of Gynodel in children and adolescents (aged 7-17) should be limited to Paediatric Endocrinologists.

Prolactinomas: Paediatric population 7 years and older: 1 mg 2 or 3 times daily, gradually increasing to several tablets daily as required to keep plasma prolactin adequately suppressed. Maximum daily dose recommended in children aged 7 to 12 years is 5 mg. Maximum daily dose recommended in adolescent patients (13-17 years) is 20 mg.

Gigantism (acromegaly): Paediatric population 7 years and older: The starting dose should be titrated in response to Growth Hormone levels. Maximum daily dose recommended in children ages 7 to 12 years is 10 mg. Maximum daily dose recommended in adolescent patients (13-17 years) is 20 mg.

Use in Elderly

There is no clinical evidence that Gynodel poses a special risk to the elderly.

Use in Patients with Hepatic Impairment

In patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase, requiring dose adjustment.

For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.

Gynodel is contraindicated for use in the suppression of lactation or other non-life threatening indications in patients with severe coronary artery disease, or symptoms and/or a history of serious mental disorders.

Other

There is insufficient evidence of efficacy of Gynodel in the treatment of premenstrual symptoms and benign breast disease.). Furthermore, a reduction of dosage or termination of therapy may be considered.

When women of child-bearing age are treated with Gynodel for conditions not associated with hyperprolactinaemia the lowest effective dose should be used. This is in order to avoid suppression of prolactin to below normal levels, with consequent impairment of luteal function.

Gynaecological assessment, preferably including cervical and endometrial cytology, is recommended for women receiving Gynodel for extensive periods. Six monthly assessment is suggested for post-menopausal women and annual assessment for women with regular menstruation.

A few cases of gastrointestinal bleeding and gastric ulcer have been reported. If this occurs, Gynodel should be withdrawn. Patients with a history of evidence of peptic ulceration should be closely monitored when receiving the treatment.

Since, especially during the first few days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery.

Among patients on Gynodel, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis have occasionally been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of Gynodel therapy should be contemplated.

In a few patients on Gynodel, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage it is recommended that its manifestations (e.g. back pain, oedema of the lower limbs, impaired kidney function) should be watched in this category of patients. Gynodel medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.

Attention should be paid to the signs and symptoms of

pleuro-pulmonary disease such as dyspnoea, shortness of breath, persistent cough or chest pain

cardiac failure as cases of pericardial fibrosis have often manifested as cardiac failure. Constrictive pericarditis should be excluded if such symptoms appear.

Appropriate investigations such as erythrocyte sedimentation rate, chest X-ray and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder. It is also appropriate to perform baseline investigations of erythrocyte sedimentation rate or other inflammatory markers, lung function/chest X-ray and renal function prior to initiation of therapy.

These disorders can have an insidious onset and patients should be regularly and carefully monitored while taking Gynodel for manifestations of progressive fibrotic disorders. Gynodel should be withdrawn if fibrotic or serosal inflammatory changes are diagnosed or suspected.

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

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists, including Gynodel.. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

Children and Adolescents (aged 7-17)

Bromocriptine has been used to treat prolactinomas and gigantism (acromegaly) indications in patients aged 7 or above and case series have been documented in the literature. Only isolated data are available for bromocriptine use in paediatric patients under the age of 7 years. Data on safety are limited, particularly in the long term. Prescribing is restricted to Paediatric Endocrinologists.

Elderly

Clinical studies for Gynodel did not include sufficient numbers of subjects ages 65 and above to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including post-marketing reporting of adverse events have identified no differenced in response or tolerability between elderly and younger patients.

Even though no variation in efficacy or adverse reaction profile in elderly patients taking Gynodel has been observed, greater sensitivity in some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population.

Hypotensive reactions may be disturbing in some patients during the first few days of treatment and particular care should be exercised when driving vehicles or operating machinery.

Patients being treated with bromocriptine and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (eg.).

The occurrence of side-effects can be minimised by gradual introduction of the dose or a dose reduction followed by a more gradual titration. If necessary, initial nausea and/or vomiting may be reduced by taking Gynodel during a meal and by the intake of a peripheral dopamine antagonist, such as domperidone, for a few days, at least one hour prior to the administration of Gynodel.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.

Nervous System Disorders

Common: Headache, drowsiness

Uncommon: Dizziness, dyskinesia

Rare: Somnolence, paresthesia

Very Rare: Excess daytime somnolence and sudden sleep onset

Psychiatric Disorders

Uncommon: Confusion, psychomotor agitation, hallucinations

Rare: Psychotic disorders, insomnia

Gastrointestinal Disorders

Common: Nausea, constipation

Uncommon: Vomiting, dry mouth

Rare: Diarrhoea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal haemorrhage

Vascular Disorders

Uncommon: Hypotension including orthostatic hypotension (which may in very rare instances lead to collapse)

Very Rare: Reversible pallor of fingers and toes induced by cold (especially in patients who have a history of Raynaud's phenomenon)

Cardiac Disorders

Rare: Tachycardia, bradycardia, arrhythmia

Very rare: Cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion).

Respiratory, thoracic and mediastinal disorders

Common: Nasal congestion

Rare: Pleural effusion, pleural and pulmonary fibrosis, pleuritis, dyspneoa

Musculoskeletal and connective tissue disorders

Uncommon: Leg cramps

Skin and subcutaneous tissue disorders

Uncommon: Allergic skin reactions, hair loss

General disorders and administration site conditions

Uncommon: Fatigue

Rare: Peripheral oedema

Very Rarely: A syndrome resembling Neuroleptic Malignant Syndrome has been reported on withdrawal of Gynodel.

Eye Disorders

Rare: Visual disturbances, vision blurred

Ear and Labyrinth Disorders

Rare: Tinnitus

Post-partum women

In extremely rare cases (in postpartum women treated with Gynodel for the prevention of lactation) serious adverse events including hypertension, myocardial infarction, convulsion, stroke or mental disorders have been reported, although the causal relationship is uncertain.).

Impulse control disorders

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 f the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Signs and Symptoms

Overdosage with Gynodel is likely to result in vomiting and other symptoms which could be due to over stimulation of dopaminergic receptors and might include nausea, dizziness, hypotension, postural hypotension, tachycardia, drowsiness, somnolence, lethargy, confusion and hallucinations. General supportive measures should be undertaken to remove any unabsorbed material and maintain blood pressure if necessary.

There have been isolated reports of children who accidentally ingested Gynodel. Vomiting, somnolence and fever were reported as adverse events. Patients recovered either spontaneously within a few hours or after symptomatic treatment.

Overdose management

In the case of overdose, administration of activated charcoal is recommended and in the case of very recent oral intake, gastric lavage may be considered.

The management of acute intoxication is symptomatic; Metoclopramide may be indicated for the treatment of emesis or hallucinations.

Pharmacotherapeutic group: Dopamine agonist (ATC code N04B C01), prolactin inhibitor (ATC code G02C B01)

Gynodel, active ingredient bromocriptine, is an inhibitor of prolactin secretion and a stimulator of dopamine receptors. The areas of application of Gynodel are divided into endocrinological and neurological indications. The pharmacological particulars will be discussed under each indication.

Endocrinological indications

Gynodel inhibits the secretion of the anterior pituitary hormone prolactin without affecting normal levels of other pituitary hormones. However, Gynodel is capable of reducing elevated levels of growth hormone (GH) in patients with acromegaly. These effects are due to stimulation of dopamine receptors.

In the puerperium prolactin is necessary for the initiation and maintenance of puerperal lactation. At other times increased prolactin secretion gives rise to pathological lactation (galactorrhoea) and/or disorders of ovulation and menstruation.

As a specific inhibitor of prolactin secretion, Gynodel can be used to prevent or suppress physiological lactation as well as to treat prolactin-induced pathological states. In amenorrhoea and/or anovulation (with or without galactorrhoea), Gynodel can be used to restore menstrual cycles and ovulation.

The customary measures taken during lactation suppression, such as the restriction of fluid intake are not necessary with Gynodel. In addition, Gynodel does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism.

Gynodel has been shown to arrest the growth or to reduce the size of prolactin-secreting pituitary adenomas (prolactinomas).

In acromegalic patients - apart from lowering the plasma levels of growth hormone and prolactin - Gynodel has a beneficial effect on clinical symptoms and on glucose tolerance.

Gynodel improves the clinical symptoms of the polycystic ovary syndrome by restoring a normal pattern of LH secretion.

Neurological Indications

Because of its dopaminergic activity, Gynodel, in doses usually higher than those for endocrinological indications, is effective in the treatment of Parkinson's Disease, which is characterised by a specific nigrostriatal dopamine deficiency. The stimulation of dopamine receptors by Gynodel can in this condition restore the neurochemical balance within the striatum.

Clinically, Gynodel improves tremor, rigidity, bradykinesia and other Parkinsonian symptoms at all stages of the disease. Usually the therapeutic effect lasts over years (so far, good results have been reported in patients treated up to eight years). Gynodel can be given either alone or - at early as well as advanced stages - combined with other anti-Parkinsonian drugs. Combination with Levodopa treatment results in enhanced anti-Parkinsonian effects, often making possible a reduction of the Levodopa dose. Gynodel offers particular benefit to patients on Levodopa treatment exhibiting a deteriorating therapeutic response or complications such as abnormal involuntary movements (choreoatoid dykinesia and/or painful dystonia), end-of-dose failure, and 'on-off' phenomenon.

Gynodel improves the depressive symptomatology often observed in parkinsonian patients. This is due to its inherent antidepressant properties as substantiated by controlled studies in non-Parkinsonian patients with endogenous or psychogenic depression.

Following oral administration, Gynodel (bromocriptine) is rapidly and well absorbed. Peak plasma levels are reached within 1-3 hours. An oral dose of 5mg of bromocriptine results in a C_max of 0.465ng/ml. The prolactin-lowering effect occurs 1-2 hours after ingestion, reaches its maximum within about 5 hours and lasts for 8-12 hours.

Gynodel is extensively metabolised. In plasma the elimination half life is 3-4 hours for the parent drug and 50 hours for the inactive metabolites. The parent drug and its metabolites are also completely excreted via the liver with only 6% being eliminated via the kidney. Gynodel is 96% bound to plasma proteins.

There is no evidence that the pharmacokinetic properties and tolerability of Gynodel are directly affected by advanced age. However, in patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase, requiring dose adjustment.

Biotransformation

Bromocriptine undergoes extensive first-pass biotransformation in the liver, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and faeces. It shows a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constitute a main metabolic pathway. Inhibitors and/or potent substrates for CYP3A4 might therefore be expected to inhibit the clearance of bromocriptine and lead to increased levels. Bromocriptine is also a potent inhibitor of CYP3A4 with a calculated IC50 value of 1.69 µM. However, given the low therapeutic concentrations of free bromocriptine in patients, a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected.

Pre-clinical data for Gynodel (bromocriptine) reveal no special hazard for humans based on conventional studies of single and repeat dose toxicity, genotoxicity, mutagenicity, carcinogenic potential or toxicity to reproduction.

Endometrial carcinomas were observed in pre-clinical rat studies at high dosages only. They are considered to be due to the species-specific sensitivity of the test animals to the pharmacological activity of bromocriptine.

Other effects in pre-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

None

No special requirements.