SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Bromocriptine 2.5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Bromocriptine Mesilate BP 2.87 mg (equivalent to Bromocriptine Base 2.5 mg) Excipient(s) with known effect: Lactose For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

4 CLINICAL PARTICULARS

4.1. Therapeutic indications

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).

Bromocriptine 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 nonpharmacological intervention (such as firm breast support, ice application) and/or simple analgesics.

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

The treatment of hyperprolactinaemic infertility.

Bromocriptine has been used successfully in the treatment of a number of infertile women who do not have demonstrable hyperprolactinaemia.

In a number of specialised units patients who have been shown to have prolactin secreting adenomas have been treated successfully with bromocriptine. In particular, bromocriptine can be considered as a first choice of treatment in patients with macroadenomas and as an alternative to the surgical procedure, transsphenoidal hypophysectomy, in patients with microadenomas.

The treatment of cyclical benign breast disease/cyclical pronounced mastalgia.

Cyclical menstrual disorders have also responded to bromocriptine, particularly breast symptomatology, but in the premenstrual syndrome, there is also some evidence that other symptoms such as headache, mood changes and bloatedness may be alleviated.

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.

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 unable to tolerate levodopa and those whose response to levodopa is declining.

4.2 Posology and method of administration

Posology

A total daily dose of 30mg should not be exceeded.

Use in Adults

Bromocriptine should always be taken during a meal.

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

In most indications, irrespective of the final dosage, the optimum response with the minimum of side-effects is best achieved by gradual introduction of bromocriptine.

The following scheme is suggested:

Initially 1 mg to 1.25 mg at bedtime, increasing after 2 to 3 days to 2 mg to 2.5 mg at bedtime. Dosage may then be increased by 1 mg to 2.5 mg at 2 to 3 day intervals, until a dosage of 2.5 mg twice daily is achieved. Further dosage increments, if necessary, should be added in a similar manner.

Prevention of lactation: 2.5 mg on the day of delivery, followed by 2.5 mg twice daily for 14 days. Gradual introduction of bromocriptine is not necessary in this indication.

Suppression of lactation: 2.5 mg on the first day, increasing after 2 to 3 days to 2.5 mg twice daily for 14 days. Gradual introduction of bromocriptine is not necessary in this indication.

Hypogonadism/galactorrhoea syndromes/infertility: introduce bromocriptine gradually according to the suggest scheme.

Most patients with hyperprolactinaemia have responded to 7.5 mg daily, in divided doses, but doses of up to 30 mg daily have been used. In infertile patients without demonstrably elevated serum prolactin levels, the usual dosage is 2.5 mg twice daily.

Prolactinomas: introduce bromocriptine gradually according to the suggested scheme. Dosage may then be increased by 2.5 mg daily at 2 to 3 day intervals as follows: 2.5 mg eight-hourly, 2.5 mg six-hourly. Patients have responded to doses of up to 30 mg daily. Daily doses should not exceed 30mg.

Cyclical benign breast disease/cyclical pronounced mastalgia/cyclical menstrual disorders: introduce bromocriptine gradually, according to the suggested scheme, until the recommended dosage of 2.5 mg twice daily is reached.

Acromegaly: Introduce bromocriptine gradually, according to the suggested scheme.

Dosage may then be increased by 2.5 mg daily at 2 to 3 day intervals as follows: 2.5 mg eight hourly, 2.5 mg six-hourly, 5 mg six-hourly.

Parkinson’s disease: Introduce bromocriptine gradually: week 1: 1 mg to 1.25 mg at bed time. Week 2: 2 mg to 2.5 mg at bed time. Week 3: 2.5 mg twice daily. Week 4: 2.5 mg three times daily. Thereafter take three times a day increasing by 2.5 mg every 3 to 14 days depending on the patient's response. Continue until the optimum dose is reached. This will usually be between 10 and 30 mg daily. In patients already receiving levodopa the dosage of this drug may be gradually decreased, while the dosage of bromocriptine is increased, until the optimum balance is determined.

Paediatric population

Administration of bromocriptine is not appropriate for children less than 15 years old.

Older people

There is no clinical evidence that bromocriptine poses a special risk to older people.

Route of Administration

Oral

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or other ergot alkaloids.

Toxaemia of pregnancy

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.

Bromocriptine 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 bromocriptine for the indication of macroadenomas 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

Bromocriptine 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 bromocriptine in the treatment of premenstrual symptoms and benign breast disease. The use of bromocriptine 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 post-partum women treated with bromocriptine for the 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). Blood pressure should be carefully monitored, especially during the first days of therapy. If hypertension, suggestive chest pain, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of central nervous system toxicity develop, the administration of bromocriptine should be discontinued and the patient should be evaluated promptly.

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

Bromocriptine should not be used in the postpartum or puerperium in women with high blood pressure, coronary artery disease or symptoms and/or a history of serious mental disorders. In postpartum women receiving bromocriptine 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. Although there is no conclusive evidence of an interaction between bromocriptine and other ergot alkaloids, a concomitant course of these medications during the puerperium is not recommended. If hypertension, unremitting headache, or any signs of CNS toxicity develop, treatment should be discontinued immediately.

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. Bromocriptine 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 bromocriptine. 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 bromocriptine, careful observation is mandatory. Prolactin secreting adenomas may expand during pregnancy. In these patients, treatment with bromocriptine 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 bromocriptine 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 bromocriptine, 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.

In women suffering from prolactin-related fertility disorders, treatment with bromocriptine results in ovulation. Patients who do not wish to conceive should be advised to practice a reliable method of contraception. Oral contraceptives have, however, been reported to increase serum prolactin levels.

When women of child-bearing age are treated with bromocriptine 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 bromocriptine for extensive periods. Six monthly assessment is suggested for post-menopausal women and annual assessment for women with regular menstruation.

In acromegalic patients, whilst bromocriptine may effectively lower growth hormone levels, treatment to limit expansion of the tumour is also indicated. Acromegalic patients should be carefully assessed for peptic ulceration prior to treatment with bromocriptine and advised to report gastro-intestinal side-effects promptly, as gastro-intestinal bleeding has been reported, though the connection with treatment is not proven. A few cases of gastrointestinal bleeding and gastric ulcer have been reported. If this occurs, bromocriptine 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.

There have been reports of psychiatric disturbances associated with the use of dopamine agonists. These reactions have occurred at low and high doses of drug and may include aggression, agitation, anxiety, confusion, depression, hallucinations and psychotic episodes.

Bromocriptine is an ergot derivative. Among patients on bromocriptine, particularly on longterm 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 bromocriptine therapy should be contemplated.

In a few patients on bromocriptine, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at 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.

Bromocriptine medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.

The factors predisposing patients to the risk of such disorders are not known, however, Parkinson’s disease patients with a history of such disorders should not be treated with Bromocriptine, or any other ergot derivative, unless the potential benefit clearly outweighs the risk.

Attention should be paid to the signs and symptoms of:

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

•    renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb oedema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis

•    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 Bromocriptine for manifestations of progressive fibrotic disorders. Bromocriptine 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.

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.

Older people

Clinical studies for bromocriptine did not include sufficient numbers of subjects ages 65 and above to determine whether older people 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 older people and younger patients.

Even though no variation in efficacy or adverse reaction profile in older patients taking bromocriptine has been observed, greater sensitivity in some older individuals cannot be categorically ruled out. In general, dose selection for an older 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.

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 bromocriptine. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

4.5 Interaction with other medicinal products and other forms of interaction

Tolerance to bromocriptine 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 bromocriptine 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 Fertility, pregnancy and lactation

Pregnancy

If pregnancy occurs it is generally advisable to withdraw bromocriptine 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 therapy with bromocriptine.

As a precautionary measure, patients should be monitored to detect signs of pituitary enlargement so that bromocriptine may be reintroduced if necessary. Based on the outcome of more than 2,000 pregnancies the use of bromocriptine 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 effect in humans, maintenance of bromocriptine treatment during pregnancy may be considered where there is a large tumour or evidence of expansion.

Breast-feeding

Since bromocriptine 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 bromocriptine. 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 informed to refrain from driving and engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes and somnolence have resolved (see also Section 4.4).

4.8 Undesirable effects

The occurrence of side-effects can be minimized 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, 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 bromocriptine.

Eye Disorders

Rare: Visual disturbances, vision blurred.

Ear and Labyrinth Disorders

Rare: Tinnitus.

Post-partum women

In extremely rare cases (in post partum women treated with bromocriptine for the prevention of lactation) serious adverse events including hypertension, myocardial infarction, seizures, stroke, or mental disorders, have been reported although the causal relationship is uncertain. In some patients the occurrence of seizures or stroke was preceded by severe headache and/or visual disturbances (see section 4.4 Special warnings and precautions for use).

Bromocriptine is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.

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 bromocriptine (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 professional 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 is likely to result in vomiting and other symptoms which could be due to over stimulation of dopaminergic receptors and might include confusion, hallucinations and hypotension. 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 bromocriptine. 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

Bromocriptine is an analogue of prolactin release inhibiting factor. It stimulates dopaminergic receptors in both normal individuals and those with hyperprolactinaemic states by inhibiting the secretion of prolactin by the pituitary. This is associated with lowering of elevated growth hormone levels as seen in acromegaly.

5.2 Pharmacokinetic properties

Between 30 to 40% of an oral dose of bromocriptine is absorbed from the gastro intestinal tract. Peak plasma levels following a single dose occur after about 100 minutes. There is a two phase plasma half-life of 6 and 50 hours.

Bromocriptine is highly bound to plasma proteins and has an apparent volume of distribution of 1 to 3.7 L/Kg.

Bromocriptine enters the brain rapidly, 8% being extracted across the blood brain barrier.

There is extensive first pass metabolism of bromocriptine by the liver. Excretion is mainly as metabolites in the bile.

5.3 Preclinical safety data

None available

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Ph.Eur.

Corn starch Ph.Eur.

Maleic acid BP Colloidal silicon dioxide USP Magnesium stearate Ph.Eur. Polyvinylpyrrolidone BP

Incompatibilities

None known.

6.3 Shelf life 3 years

6.4 Special precautions for storage

Store below 25°C and protect from light and moisture.

6.5 Nature and contents of container

PVdC/PVC laminated blister 250gm (PVdC coating: 60 gm-2 hard temper aluminium foil backing in pack sizes of 7, 14, 21, 28, 30, 50, 56, 60, 84, 90, 100, 112 or 120 tablets.

6.6 Special precautions for disposal

None

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex

BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1395

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

01 September 2009

10 DATE OF REVISION OF THE TEXT

11/05/2015