PARLODEL 2.5mg Tablets

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

Bromocriptine mesilate Ph. Eur 2.87mg, equivalent to 2.5mg of bromocriptine base.

For a full list of excipients see section 6.1

Tablet: Each tablet is round, white, bevelled edged with a break line on one side, marked with “PARLODEL 2.5” circumferentially on the reverse.

Inhibition of lactation for medical reasons

The inhibition or suppression of puerperal lactation.

PARLODEL 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 simple analgesics and breast support.

Hyperprolactinaemia

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

Infertility

The treatment of hyperprolactinaemic infertility.

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

Prolactinomas

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

Acromegaly

PARLODEL 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, PARLODEL has been used both alone and in combination with Levodopa in the management of previously untreated patients and those disabled by 'on-off' phenomena. PARLODEL 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).

PARLODEL should always be taken with food.

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

Hypogonadism/Galactorrhea syndromes/Infertility

Introduce PARLODEL 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 PARLODEL 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. Patients have responded to doses of up to 30mg daily.

Acromegaly

Introduce PARLODEL 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 PARLODEL 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 40mg daily. In patients already receiving Levodopa the dosage of this drug may gradually be decreased, while the dosage of PARLODEL is increased until the optimum balance is determined.

Use in Children

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

Use in Elderly

There is no clinical evidence that PARLODEL 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.

Hypersensitivity to bromocriptine or to any of the excipients of PARLODEL (see Section 2 Qualitative and quantitative composition and 6.1 List of excipients) or other ergot alkaloids.

Uncontrolled hypertension, hypertensive disorders of pregnancy (including eclampsia, pre-eclampsia or pregnancy-induced hypertension), hypertension post partum and in the puerperium.

PARLODEL 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 PARLODEL 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).

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, seizures, stroke or psychiatric disorders have been reported in postpartum women treated with PARLODEL 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 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 specialised 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 macroprolactinoma. 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 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 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.

PARLODEL 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 PARLODEL, 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 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.

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

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: Pericardial effusion, Constrictive pericarditis, tachycardia, bradycardia, arrhthymia

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, 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 Special warnings and precautions for use).

Class effects

Patients treated with dopamine agonists for treatment with Parkinson's disease, including PARLODEL, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation.

Signs and Symptoms

Overdosage with PARLODEL 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.

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.

Pharmacotherapeutic group: Dopamine agonist (ATC code N04B C01), prolactin inhibitor (ATC code G02C B01)

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

Endocrinological indications

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

PARLODEL 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 - PARLODEL has a beneficial effect on clinical symptoms and on glucose tolerance.

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

Neurological Indications

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

Clinically, PARLODEL 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). PARLODEL 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. PARLODEL 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.

PARLODEL 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.

Following oral administration, PARLODEL (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 C_max 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 PARLODEL 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.

There are no other clinically relevant preclinical safety data in addition to those mentioned in other sections of the SmPC.

Aerosil 200 (Standard) Ph. Eur., Disodium edetate BP, Magnesium stearate Ph. Eur., Maleic acid Ph.Eur., Maize starch Ph. Eur., Lactose Ph. Eur.

None.

Opaque white PVC/PVDC blister strip: 36 months

Amber glass bottles: 60 months

Protect from direct light.

Opaque white PVC/PVDC blister strip containing 30 PARLODEL 2.5mg tablets.

Amber glass bottles with a CRC closure containing 100 and 500 PARLODEL 2.5mg tablets.

No special requirements.

Meda Pharmaceuticals Ltd

Trading as: Meda Pharmaceuticals

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

19166/0053

14 January 1976 / 21 April 1998

21st November 2007