TRADE NAME: Dopagon Tablet GENERIC NAME: Bromocriptine mesylate COMPOSITION: Each tablet contains: Active ingredient: Bromocriptine mesylate 2.87mg (eq. to Bromocriptine 2.5 mg) Excipients: Microcrystalline cellulose, cross carmellose sodium, magnesium stearate. PHARMACEUTICAL FORM: Tablet. PHARMACOLOGICAL ACTION: PHARMACODYNAMICS: Pharmacotherapeutic group: Dopamine agonist, prolactin inhibitor. DOPAGON, active ingredient bromocriptine, is an inhibitor of prolactin secretion and a stimulator of dopamine receptors. The areas of application of DOPAGON are divided into endocrinological and neurological indications. The pharmacological particulars will be discussed under each indication. Endocrinological indications DOPAGON inhibits the secretion of the anterior pituitary hormone prolactin without affecting normal levels of other pituitary hormones. However, DOPAGON 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, DOPAGON 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), DOPAGON 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 DOPAGON. In addition, DOPAGON does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism. DOPAGON 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 - DOPAGON has a beneficial effect on clinical symptoms and on glucose tolerance. DOPAGON improves the clinical symptoms of the polycystic ovary syndrome by restoring a normal pattern of LH secretion. Neurological Indications Because of its dopaminergic activity, DOPAGON, 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 DOPAGON can in this condition restore the neurochemical balance within the striatum. Clinically, bromocriptine 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). DOPAGON 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. DOPAGON 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. DOPAGON 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. PHARMACOKINETICS: Following oral administration, DOPAGON (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 Cmax 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. The substance is extensively metabolised in the liver. The elimination of parent drug from plasma occurs biphasically, with a terminal half-life of about 15 hours. Parent drug and metabolites are almost completely excreted via the liver, with only 6% being eliminated via the kidney. Plasma protein-binding amounts to 96%. There is no evidence that the pharmacokinetic properties and tolerability of DOPAGON 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. INDICATIONS: Inhibition of lactation for medical reasons* Prevention or suppression of post-partum physiological lactation only where medically indicated (such as in case of intrapartum loss, neonatal death, HIV infection of the mother). DOPAGON is not recommended for the routine suppression of lactation or for the relief of symptoms of post-partum pain and engorgement which can be adequately treated with non-pharmacological intervention (such as firm breast support, ice application) and/or simple analgesics. *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. Bromocriptine 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 Bromocriptine 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, bromocriptine has been used both alone and in combination with Levodopa in the management of previously untreated patients and those disabled by 'on-off' phenomena. Bromocriptine has been used with occasional benefit in patients who do not respond to or are unable to tolerate Levodopa and those whose response to Levodopa is declining. *Premenstrual symptoms and benign breast disease. DOSAGE AND ADMINISTRATION: DOPAGON should always be taken with food. A number of disparate conditions are amenable to treatment with DOPAGON 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 DOPAGON. 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 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. Prevention of Lactation 2.5mg on the day of delivery, followed by 2.5mg twice daily for 14 days. Treatment should be instituted within a few hours of parturition once vital signs have been stabilised. Gradual introduction of DOPAGON is not necessary in this indication. Suppression of Lactation for Medical Reasons 2.5mg on first day, increasing after 2 to 3 days to 2.5mg twice daily for 14 days. Gradual introduction of is not necessary in this indication. Hypogonadism/Galactorrhea syndromes/Infertility Introduce DOPAGON 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 DOPAGON 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 DOPAGON gradually, according to the suggested scheme. Dosage may then be increased by 2.5mg at 2 to 3 day intervals as follows: - 2.5mg eight-hourly, 2.5mg six-hourly, 5mg six-hourly. Parkinson's Disease Introduce DOPAGON 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 of DOPAGON is increased until the optimum balance is determined. Use in Children and adolescents (aged 7-17) Prescribing of DOPAGON 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 DOPAGON 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. CONTRAINDICATIONS: Hypersensitivity to bromocriptine or to any of the excipients of DOPAGON or other ergot alkaloids. Bromocriptine is contraindicated in patients with uncontrolled hypertension, hypertensive disorders of pregnancy (including eclampsia, pre-eclampsia or pregnancy-induced hypertension), hypertension post partum and in the puerperium. DOPAGON is contraindicated for use in the suppression of lactation or other non-life threatening indications in patients with a history of coronary artery disease, or other severe cardiovascular conditions, or symptoms / history of severe psychiatric disorders. Patients with these underlying conditions taking DOPAGON for the indication of macro-adenomas should only take it if the perceived benefits outweigh the potential risks. For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiograph. UNDESIRABLE EFFECTS: 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 Bromocriptine 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 bromocriptine. Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <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, arrhthymia 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
