PARLODEL Capsule Ref.[6641] Active ingredients: Bromocriptine

PARLODEL 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 Parlodel in the treatment of premenstrual symptoms and benign breast disease. The use of Parlodel in patients with these conditions is therefore not recommended.

In rare cases, serious adverse events, including hypertension, myocardial infarction, convulsions, stroke or psychiatric disorders have been reported in postpartum women treated with PARLODEL for inhibition of lactation. In some patients the development of convulsions 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 PARLODEL 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, 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 specialized units to identify such patients is advisable. PARLODEL 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 PARLODEL. 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 PARLODEL, careful observation is mandatory. Prolactin-secreting adenomas may expand during pregnancy. In these patients, treatment with PARLODEL 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 macro-prolactinoma. Effective treatment with Parlodel 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 macro-prolactinoma 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 Parlodel, 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 PARLODEL 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 PARLODEL 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, PARLODEL 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 Parlodel, 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 Parlodel therapy should be contemplated.

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

Tolerance to PARLODEL 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 PARLODEL 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.

Pregnancy

If pregnancy occurs it is generally advisable to withdraw PARLODEL 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 PARLODEL therapy. As a precautionary measure, patients should be monitored to detect signs of pituitary enlargement so that PARLODEL may be reintroduced if necessary. Based on the outcome of more than 2,000 pregnancies, the use of PARLODEL 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 PARLODEL treatment during pregnancy may be considered where there is a large tumour or evidence of expansion.

Lactation

Since PARLODEL 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 Parlodel. Women of childbearing age who do not wish to conceive should therefore be advised to practice a reliable method of contraception.

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).

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 PARLODEL 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 PARLODEL.

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

Nervous System Disorders

Common: Headache, drowsiness

Uncommon: Dizziness, dyskinesia

Rare: Somnolence, paresthesia

Very Rare: Excess daytime somnolence and sudden sleep onset

Psychiatric Disorders

Uncommon: Confusion, psychomotor agitation, hallucinations

Rare: Psychotic disorders, insomnia

Gastrointestinal Disorders

Common: Nausea, constipation

Uncommon: Vomiting, dry mouth

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

Vascular Disorders

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

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

Cardiac Disorders

Rare: Tachycardia, bradycardia, arrhythmia

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

Respiratory, thoracic and mediastinal disorders

Common: Nasal congestion

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

Musculoskeletal and connective tissue disorders

Uncommon: Leg cramps

Skin and subcutaneous tissue disorders

Uncommon: Allergic skin reactions, hair loss

General disorders and administration site conditions

Uncommon: Fatigue

Rare: Peripheral oedema

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

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

None.