BROMOCRIPTIN TABLETS 1mg & 2.5mg TAJ PHARMA

1.Name of the medicinal product

Bromocriptin 1mg Tablets Taj Pharma

2.Qualitative and quantitative composition

Active substance: Ergotaman-3`, 6`, 18-trione, 2-bromo-12`-hydroxy-2`-(1-methylethyl-5`-(2-methylpropyl)-, (5`alpha)-mono-methanesulphonate.

Each tablet contains:

a) Bromocriptine tablets 1mg Taj Pharma
Bromocriptine                                      1mg
(equivalent to of

bromocriptine mesylate 1.14mg.)
Excipients                                             q.s.

b) Bromocriptine tablets 2.5mg Taj Pharma
Bromocriptine                                       2.5mg

(equivalent to of
bromocriptine mesylate 2.87mg.)
Excipients                                                q.s.

For a full list of excipients see section 6.1
3.Pharmaceutical form

Tablet.

4.Clinical particulars

4.1 Therapeutic 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).

Bromocriptin 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. Bromocriptin 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

Bromocriptin 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, Bromocriptin has been used both alone and in combination with Levodopa in the management of previously untreated patients and those disabled by ‘on-off’ phenomena. Bromocriptin 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 (see section 4.4 Special warnings and precautions for use).

4.2 Posology and method of administration

Bromocriptin should always be taken with food.

A number of disparate conditions are amenable to treatment with Bromocriptin 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 Bromocriptin. 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 Bromocriptin 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 Bromocriptin is not necessary in this indication.

Hypogonadism/Galactorrhea syndromes/Infertility

Introduce Bromocriptin 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 Bromocriptin 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 Bromocriptin 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 Bromocriptin 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 Bromocriptin is increased until the optimum balance is determined.

Use in Children and adolescents (aged 7-17)

Prescribing of Bromocriptin 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 Bromocriptin 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.

4.3 Contraindications

Hypersensitivity to bromocriptine or to any of the excipients of Bromocriptin (see Section 2 Qualitative and Quantitative composition and 6.1 List of excipients) 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.

Bromocriptin 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 Bromocriptin for the indication of macro-adenomas should only take it if the perceived benefits outweigh the potential risks (see Section 4.4 Special Warnings and Precautions).

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

4.4 Special warnings and precautions for use

Bromocriptin 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 (see Section 4.3 Contraindications).

Other

There is insufficient evidence of efficacy of Bromocriptin in the treatment of premenstrual symptoms and benign breast disease. The use of Bromocriptin in patients with these conditions is therefore not recommended.

In rare cases, serious adverse events, including hypertension, myocardial infarction, seizures, stroke or psychiatric disorders have been reported in postpartum women treated with Bromocriptin for inhibition of lactation. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances (see Section 4.8, Undesirable Effects).

Patients with severe cardiovascular disorders or psychiatric disorders taking Bromocriptin for the indication of macro-adenomas should only take it if the perceived benefits outweigh the potential risks (see Section 4.3 Contraindications).

Blood pressure should be carefully monitored, especially during the first days of therapy. Particular caution is required in patients who are on concomitant therapy with, or have recently been treated with drugs that can alter blood pressure. Concomitant use of bromocriptine with vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine during the puerperium is not recommended.

If hypertension, suggestive chest pain, severe progressive or unremitting headache, or any signs of CNS toxicity develop, treatment should be discontinued immediately and the patient should be evaluated promptly.

Hyperprolactinaemia may be idiopathic, drug-induced, or due to hypothalamic or pituitary disease. The possibility that hyperprolactinaemic patients may have a pituitary tumour should be recognised and complete investigation at specialised units to identify such patients is advisable. Bromocriptin will effectively lower prolactin levels in patients with pituitary tumours but does not obviate the necessity for radiotherapy or surgical intervention where appropriate in acromegaly.

Since patients with macro-adenomas of the pituitary might have accompanying hypopituitarism due to compression or destruction of pituitary tissue, one should make a complete evaluation of pituitary functions and institute appropriate substitution therapy prior to administration of Bromocriptin. In patients with secondary adrenal insufficiency, substitution with corticosteroids is essential.

The evolution of tumour size in patients with pituitary macro-adenomas should be carefully monitored and if evidence of tumour expansion develops, surgical procedures must be considered.

If in adenoma patients, pregnancy occurs after the administration of Bromocriptin, careful observation is mandatory. Prolactin-secreting adenomas may expand during pregnancy. In these patients, treatment with Bromocriptin often results in tumour shrinkage and rapid improvement of the visual fields defects. In severe cases, compression of the optic or other cranial nerves may necessitate emergency pituitary surgery.

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with Bromocriptin leads to a reduction in hyperprolactinaemia and often to resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalised prolactin levels and tumour shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumour re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage.

In some patients with prolactin-secreting adenomas treated with Bromocriptin, cerebrospinal fluid rhinorrhea has been observed. The data available suggest that this may result from shrinkage of invasive tumours.

Bromocriptine has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see Section 4.7 Effects on ability to drive and use machines). Furthermore, a reduction of dosage or termination of therapy may be considered.

When women of child-bearing age are treated with Bromocriptin 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 Bromocriptin 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,

Bromocriptin 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 Bromocriptin, 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 Bromocriptin therapy should be contemplated.

In a few patients on Bromocriptin, 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. Bromocriptin 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 Bromocriptin for manifestations of progressive fibrotic disorders. Bromocriptin 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 Bromocriptin. 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 Bromocriptin 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 Bromocriptin 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.

4.5 Interaction with other medicinal products and other forms of interaction

Tolerance to Bromocriptin may be reduced by alcohol.

Caution is required in patients who are on concomitant therapy with, or have recently been treated with drugs that can alter blood pressure.

Although there is no conclusive evidence of an interaction between Bromocriptin and other ergot alkaloids concomitant use of bromocriptine with these medications during the puerperium is not recommended (see also Section 4.4, Special Warnings and Precautions).

The concomitant use of erythromycin and other macrolide antibiotics may increase bromocriptine plasma levels.

Bromocriptine is both a substrate and an inhibitor of CYP3A4 (see Section 5.2 Pharmacokinetic properties). Caution should therefore be used when co-administering drugs which are strong inhibitors and/or substrates of this enzyme (azole antimycotics, HIV protease inhibitors). The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine.

Dopamine antagonists such as antipsychotics (phenothiazines, butyrophenones and thioxanthenes) may reduce the prolactin-lowering and antiparkinsonian effects of bromocriptine. Metoclopramide and domperidone may reduce the prolactin-lowering effect.

4.6 Pregnancy and lactation

Pregnancy

If pregnancy occurs it is generally advisable to withdraw Bromocriptin after the first missed menstrual period.

Rapid expansion of pituitary tumours sometimes occurs during pregnancy and this may also occur in patients who have been able to conceive as a result of Bromocriptin therapy.

As a precautionary measure, patients should be monitored to detect signs of pituitary enlargement so that Bromocriptin may be reintroduced if necessary. Based on the outcome of more than 2,000 pregnancies, the use of Bromocriptin to restore fertility has not been associated with an increased risk of abortion, premature delivery, multiple pregnancy or malformation in infants. Because this accumulated evidence suggests a lack of teratogenic or embryopathic effects in humans, maintenance of Bromocriptin treatment during pregnancy may be considered where there is a large tumour or evidence of expansion.

Lactation

Since Bromocriptin inhibits lactation, it should not be administered to mothers who elect to breast-feed.

Women of child-bearing potential

Fertility may be restored by treatment with Bromocriptin. Women of childbearing age who do not wish to conceive should therefore be advised to practice a reliable method of contraception.

4.7 Effects on ability to drive and use machines

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. Operating machines) until such recurrent episodes and somnolence have resolved (see also Section 4.4 Special Warnings and Precautions).

4.8 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 Bromocriptin 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 Bromocriptin.

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, 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 Bromocriptin.

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 Bromocriptin 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. In some patients the occurrence of convulsion or stroke was preceded by severe headache and/or transient visual disturbances (see Section 4.4 Special warnings and precautions for use).

Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Bromocriptin. (see section 4.4 ‘Special warnings and precautions for use’).

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

Signs and Symptoms

Overdosage with Bromocriptin 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 Bromocriptin. 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.

5.Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Dopamine agonist, prolactin inhibitor.

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

Endocrinological indications

Bromocriptin inhibits the secretion of the anterior pituitary hormone prolactin without affecting normal levels of other pituitary hormones. However, Bromocriptin 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, Bromocriptin 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), Bromocriptin 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 Bromocriptin. In addition, Bromocriptin does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism.

Bromocriptin 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 – Bromocriptin has a beneficial effect on clinical symptoms and on glucose tolerance.

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

Neurological Indications

Because of its dopaminergic activity, Bromocriptin, 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 Bromocriptin can in this condition restore the neurochemical balance within the striatum.

Clinically, Bromocriptin 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). Bromocriptin 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. Bromocriptin 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.

Bromocriptin 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.

5.2 Pharmacokinetic properties

Following oral administration, Bromocriptin (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 Bromocriptin 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.

5.3 Preclinical safety data

Pre-clinical data for Bromocriptin (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.

6.Pharmaceutical particulars

6.1 List of excipients

Silica, colloidal anhydrous, Disodium edetate, Magnesium stearate, Maleic acid, Maize starch, Lactose monohydrate

6.2 Incompatibilities

None.

6.3 Shelf life

Opaque white PVC/PVDC blister strip:24 months
Amber glass bottles:36 months

6.4 Special precautions for storage

Store below 25°C. Store in the original package in order to protect from light.

6.5 Nature and contents of container

Opaque white PVC/PVDC blister strip containing 30 Bromocriptin 1mg and 2.5 mg tablets.

Amber glass bottles with a tamper resistant closure containing 100 and 500 Bromocriptin 1mg and 2.5 mg tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

7.Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

              BROMOCRIPTINE 1mg & 2.5mg TABLETS TAJ PHARMA

(Bromocriptine mesylate)

Read all of this leaflet carefully before you start taking this medicine.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
  • In this leaflet, Bromocriptine 1 mg & 2.5 mg Tablets will be called Bromocriptine.

In this leaflet:

  1. What Bromocriptine is for
  2. Before you take Bromocriptine
  3. How to take Bromocriptine
  4. Possible side effects
  5. How to store Bromocriptine
  6. Further information

1.What Bromocriptine is for

Bromocriptine belongs to a group of medicines called dopamine agonists and prolactin inhibitors.

It works by increasing the release of dopamine in the brain, which treats diseases where you need more of this substance. It also works by decreasing the release of prolactin and growth hormone in the body, which treats diseases where you need less of these substances.

Bromocriptine may be used for:

  • Stopping breast milk production for medical reasons only, and when you and your doctor have decided that it is necessary. Bromocriptine should not routinely be used to stop breast milk production. It should

also not be used to relieve symptoms of painful breast engorgement after giving birth if these can be adequately treated with non-medical means (such as firm breast support, ice application) and/or a painkiller.

  • Treating fertility and period problems usually caused by not having the right amount of prolactin. This includes polycystic ovary syndrome (reduces prolactin levels)
  • Treating non-cancerous tumours in the brain called prolactinomas (reduces prolactin levels)
  • Treating diseases where too much growth hormone is made, which causes people to be very tall or to have large hands and feet. This is called acromegaly (reduces growth hormone levels)

Treating Parkinson’s Disease (increases dopamine levels).

2.Before You Take Bromocriptine

Do not take Bromocriptine if:

  • You are allergic to bromocriptine mesilate or other ergot alkaloids such as ergotamine
  • You are allergic to any of the other ingredients in Bromocriptine (see Section 6)
  • You have high blood pressure
  • You have ever had blood pressure problems during pregnancy or after giving birth, such as eclampsia, pre-eclampsia, pregnancy-induced high blood pressure, high blood pressure after giving birth
  • You have, or have ever had, heart disease, or other severe blood vessel disease
  • You have, or have ever had, fibrotic reactions (scar tissue) affecting your heart
  • You have, or have ever had, serious mental health problems
  • You are breast-feeding.

If any of the above applies to you, talk to your doctor or pharmacist.

Warnings and precautions

Talk to your doctor before taking Bromocriptine if

  • You have just given birth as you may be more at risk of certain conditions. These are very rare but may include high blood pressure, heart attack, convulsions, stroke or mental problems. Therefore your doctor will need to check your blood pressure regularly during the first days of treatment. Speak immediately to your doctor if you experience high blood pressure, chest pain or unusually severe or persistent headache, with or without vision problems.
  • You have, or have ever had stomach ulcers and bleeding
  • You have liver disease
  • You have, or have ever had a condition called fibrosis. Fibrosis causes thickening and stiffening of the heart, lungs and abdomen which can stop them working properly. Before you are given Bromocriptine your doctor will check that your heart, lungs and kidneys are in good condition. The doctor may also do an ultrasound (an echocardiogram) of your heart for check for scar tissue You are pregnant or planning to become pregnant. If so, tell your doctor immediately
  • You have recently given birth, had a miscarriage or an abortion
  • You have premenstrual problems or non-cancerous breast disease
  • You have a non-cancerous tumour. You may need a full medical check-up first.

Do not give Bromocriptine to children under 7 years old.

Take special care with Bromocriptine

Tell your doctor if you or your family/carer notices that you are developing urges or cravings to behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry out certain activities that could harm yourself or others. These are called impulse control disorders and can include behaviours such as addictive gambling, excessive eating or spending, and abnormally high sex drive or an increase in sexual thoughts or feelings. Your doctor may need to adjust or stop your dose.

Tell your doctor if you are taking any of the following medicines:

  • Any medicine used to change your blood pressure, such as diuretics (‘water tablets’), beta-blockers, calcium channel blockers or ACE inhibitors
  • Ergot alkaloids such as ergometrine (used to stop blood loss after giving birth) and ergotamine tartrate (used to treat migraines). This is especially important if you have just given birth or had an abortion
  • Erythromycin or any other macrolide antibiotics (used to treat infections)
  • Azole anti-fungals (used to treat fungal infections)
  • Protease inhibitors (used to treat HIV)
  • Octreotide (used to treat growth disorders)
  • Antipsychotics such as phenothiazines, butyrophenones, thioxanthenes (used to treat mental disorders)
  • Metoclopramide and domperidone (used to stop you feeling and being sick)
  • Any other medicine, including medicines obtained without a prescription.

Taking Bromocriptine with food and drink

You must take this medicine with a meal.

Avoid drinking alcohol as it may make the side effects of this medicine worse.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant or are planning to become pregnant.

You must not breast-feed. This medicine stops or slows down your breasts making milk.

Remember: Taking this medicine may increase or bring back your chances of getting pregnant. If you do not wish to get pregnant, ask your doctor for advice.

Driving and using machines

You must not drive or operate machines if you feel dizzy or faint. This may mean you have

low blood pressure. This is most likely to happen in the first few days. You may also feel very tired or suddenly fall asleep during the day whilst taking this medicine, if this happens you should not drive.

Warnings about the ingredients in Bromocriptine This medicine contains lactose which is a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3.How To Take Bromocriptine

Always take Bromocriptine exactly as your doctor has told you.

Important:

Your doctor will choose the dose that is right for you. The dose will be shown clearly on the label that your pharmacist puts on the medicine. If it does not, or you are not sure, ask your doctor or pharmacist.

Remember: Always take this medicine with a meal.

Adults and Children between 7 and 17 years old: For most diseases, your doctor will start you or your child on a low dose of Bromocriptine, and then gradually increase the dose as necessary. This will help the body adjust to the new medicine and stop you or your child from getting so many side effects. You should always follow the advice of your doctor about increasing the dose of the medicine.

As the dose changes, the tablets may need to be taken together to get to the right dose. You may also need to break the tablets in half along the line down the middle. Your doctor or pharmacist will tell you how to do this.

The maximum dose for children aged 7-12 years is 5 to 10 mg, depending on the condition they are being treated for. The maximum dose for children aged 13- 17 years is 20 mg.

If you are a woman, your doctor will advise you when in your menstrual cycle you should start to take this medicine.

The elderly:

If you are elderly, your doctor may suggest you take a slightly lower dose than the usual adult dose. This is because you are more likely to have kidney, liver and heart problems or be taking other medicines, which will change how well Bromocriptine works.

Patients with liver problems:

Your doctor will tell you how much to take.

Medical check-ups

When you are taking this medicine, your doctor may ask you to come for check-ups which may include:

  • An ultrasound of your heart (an echocardiogram). This is to ensure that your heart is working properly and to check for fibrotic reactions. If fibrotic reactions occur, your doctor may stop your treatment with Bromocriptine
  • Blood pressure checks. This is important when you first start to take this medicine
  • If you are a woman and you have been taking Bromocriptine for a long time you may have six monthly gynaecological exams and cervical smear tests
  • Eye sight checks
  • If you are taking Bromocriptine for a disease involving a tumour, the size, shape and type of tumour may be checked regularly.

If you take more Bromocriptine than you should Do not take more Bromocriptine than you should. If you accidentally take too much of your medicine,

immediately tell your doctor or go to the nearest hospital casualty department. Taking too much Bromocriptine may make you feel or be sick, have a fever or become abnormally tired.

If you forget to take Bromocriptine

Do not take a double dose to make up for a forgotten dose. Simply take the next dose as planned.

If you stop taking Bromocriptine

It is important to talk to your doctor if you want to stop taking your medicine. If you stop suddenly, you may get withdrawal symptoms including confusion, a reduced attention span and stiffness.

If you have any further questions about taking this medicine, ask your doctor or pharmacist.

4.Possible Side Effects

Like all medicines, Bromocriptine can cause side effects, although not everybody gets them.

Seek immediate medical help if you have any of the following symptoms:

  • You have a headache which does not go away, or is severe
  • You get any problems with your eyesight after giving birth
  • You feel faint, dizzy or have blurred vision
  • You have blood in your stools. They may look black and tarry
  • You vomit blood or dark particles that look like coffee granules
  • You have severe pains in your stomach
  • You have difficulty breathing, shortness of breath, swollen legs, chest or back pain.

Common side effects

(affect less than 1 in 10 people):

  • Headache
  • Dizziness
  • Drowsiness
  • Feeling and being sick
  • Constipation
  • Blocked nose.

Uncommon side effects

(affect less than 1 in 100 people):

  • Restlessness
  • Confusion or hallucinations
  • Dry mouth
  • Dizziness or light-headedness upon standing which may cause you to collapse (you may have low blood pressure)
  • Leg cramps
  • Itchy, red or swollen skin
  • Hair loss

Rare side effects

(affect less than 1 in 1000 people):

  • Extreme drowsiness
  • Insomnia (trouble sleeping)
  • Pins and needles
  • Mental health problems
  • Diarrhoea
  • Inability to pass water and back pain
  • Irregular heart beat including an abnormally slow or fast beating of the heart
  • Lung problems that may cause difficulty breathing, a shortness of breath, pain when you breath in, or a cough that doesn’t go away

Very rare side effects

  • (affect less than 1 in 10,000 people):
  • Heart valve disorders such as inflammation or leaking of fluid in the heart – these may cause difficulty breathing, chest pains, weakness and swelling of the legs and ankles
  • Extreme drowsiness during the day or falling asleep unexpectedly
  • Pale or white fingers and toes, caused by cold temperatures.
  • You may experience the following side effects: Inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include:
  • strong impulse to gamble excessively despite serious personal or family consequences
  • altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive
  • uncontrollable excessive shopping or spending
  • binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger)
  • Tell your doctor if you experience any of these behaviours; they will discuss ways of managing or reducing the symptoms.
  • If you have just given birth you may be more at risk of certain conditions. These are very rare, but may include high blood pressure, heart attack, convulsion, stroke or mental problems.

5. Reporting of side effects

  • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly.5.How To Store Bromocriptine
  • Keep out of the reach and sight of children.
  • Do not use Bromocriptine after the expiry date stated on the label or carton. The expiry date refers to the last day of that month.
  • Store the tablets below 25°C in the original package in order to protect from light.
  • Medicines should not be thrown away in waste water or in household waste. Return any medicine you no longer need to your pharmacist.

    6.
    Further Information
    What Bromocriptine contains
    The active substance in Bromocriptine is bromocriptine mesylate. Bromocriptine Tablets come in two strengths: 1 mg and 2.5 mg:
  • Each 1 mg tablet contains 1 mg bromocriptine mesilate. Each 2.5 mg tablet contains 2.5 mg bromocriptine mesilate.
  • The tablets also contain lactose, maize starch, disodium edetate, maleic acid, colloidal anhydrous silica, and magnesium stearate.

What Bromocriptine looks like

  • Bromocriptine 1 mg Tablets are round, white and marked with a break line on one side. The tablets come in an amber glass bottle containing 30 or 100 tablets.
  • Bromocriptine 2.5 mg Tablets are round, white and marked with a groove on one side. The tablets come in a blister strip containing 30 tablets or in an amber glass bottle containing 100 or 500 tablets.
  • Not all pack-sizes are marketed.

7.Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com