PIRODAL Tablet Ref.[28112] Active ingredients: Bromocriptine

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

Other

There is insufficient evidence of efficacy of Pirodal in the treatment of premenstrual symptoms and benign breast disease. The use of Pirodal 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 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).

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 Pirodal for the indication of macro-adenomas should only take it if the perceived benefits outweigh the potential risks (see section 4.3).

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.

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. Pirodal 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 Pirodal. 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 Pirodal, careful observation is mandatory. Prolactin-secreting adenomas may expand during pregnancy. In these patients, treatment with Pirodal 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 Pirodal 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 Pirodal, 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). Furthermore, a reduction of dosage or termination of therapy may be considered.

When women of child-bearing age are treated with Pirodal 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 Pirodal 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, Pirodal 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.

Bromocriptine is an ergot derivative. Fibrotic and serosal inflammatory disorders such as pleuritis, pleural and pericardial effusion, pleural and pulmonary fibrosis, constrictive pericarditis, and retroperitoneal fibrosis have occurred after prolonged usage of ergot derivatives. 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 Pirodal, 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 Pirodal for manifestations of progressive fibrotic disorders. Pirodal should be withdrawn if fibrotic or serosal inflammatory changes are diagnosed or suspected.

Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson’s disease, including bromocriptine.

Among patients on bromocriptine, 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 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.

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

Alcohol may reduce tolerance to bromocriptine.

Concomitant administration of erythromycin other macrolide antibiotics or octreotide may increase bromocriptine plasma levels.

There is no conclusive evidence of interaction between bromocriptine and other ergot alkaloids, but concurrent administration is not recommended.

Dopamine antagonists such as antipsychotics, butyrophenones, thioxanthenes and phenothiazines may impair prolactin suppression and antiparkinsonian effects by bromocriptine, concurrent administration should be avoided.

Metoclopramide and domperidone may reduce the prolactin lowering effect.

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

No data suggests that therapeutic levels of bromocriptine inhibit CYP3A4 to a clinically significant level. However, bromocriptine has been shown to be an inhibitor of CYP3A4 in vitro and caution should be used when coadministering drug substances of this enzyme.

Pregnancy

Bromocriptine should be withdrawn after the first missed menstrual period in pregnancy.

Rapid expansion of pituitary tumours can sometimes occur in pregnancy, and this may also occur in patients successfully treated for infertility with bromocriptine. Patients should be monitored, as a precautionary measure, for signs of pituitary enlargement so that bromocriptine can be reintroduced if necessary. Experience with bromocriptine to restore fertility has not shown an increase in risk of abortion, premature delivery, multiple pregnancy or malformation in infants. This suggests a lack of teratogenic or embryopathic effect in human pregnancy, allowing consideration for maintenance of bromocriptine therapy in pregnancy where there is evidence of a large tumour or tumour expansion.

Breast-feeding

Pirodal should not be administered to mothers who elect to breast feed for it inhibits lactation.

Fertility

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

Bromocriptine may cause dizziness or drowsiness and/or sudden sleep episodes. Hypotensive reactions may be disturbing in some patients during the first few days of treatment. If affected patients should not drive or operate machinery.

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 Pirodal 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 Pirodal.

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), not known (cannot be estimated from the available data).

Psychiatric disorders

Uncommon: Confusion, psychomotor agitation, hallucinations

Rare: Psychotic disorders, insomnia

Nervous system disorders

Common: Headache, drowsiness

Uncommon: Dizziness, dyskinesia

Rare: Somnolence, paresthesia

Very Rare: Excess daytime somnolence and sudden sleep onset

Eye disorders

Rare: Visual disturbances, vision blurred

Ear and labyrinth disorders

Rare: Tinnitus

Cardiac disorders

Rare: Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhthymia

Very Rare: cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion)

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)

Respiratory, thoracic and mediastinal disorders

Common: Nasal congestion

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

Gastrointestinal disorders

Common: Nausea, constipation

Uncommon: Vomiting, dry mouth

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

Skin and subcutaneous tissue disorders

Uncommon: Allergic skin reactions, hair loss

Musculoskeletal and connective tissue disorders

Uncommon: Leg cramps

General disorders and administration site conditions

Uncommon: Fatigue

Rare: Peripheral oedema

Very Rare: A syndrome resembling Neuroleptic Malignant Syndrome has been reported on withdrawal of bromocriptine.

Post-partum women

In extremely rare cases (in postpartum women treated with Pirodal 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 transient visual disturbances (see section 4.4).

Class effects

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 Pirodal (see section 4.4).

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

None known.