PARLODEL 5 MG CAPSULES - Summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Parlodel 5mg Capsules

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 capsule contains 11.47mg of bromocriptine mesilate Ph Eur equivalent to 10 mg of bromocriptine base.

Excipients with known effect:

Each tablet contains 0.5mg di-sodium edetate

Each tablet contains 116.38 mg Lactose monohydrate

For a full list of excipients see section 6.1

3 PHARMACEUTICAL FORM

Light blue and white opaque hard gelatin capsules imprinted with ‘5 mg’ on the capsule body.

4 CLINICAL PARTICULARS

4.1 Therapeutic indicationsHyperprolactinaemia

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

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

To reduce tumour size, particularly in those at risk of optic nerve compression.

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.

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.

(See section 4.4 Special warnings and precautions for use).

4.2 Posology and method of administration

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.

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. Daily doses should not exceed 30 mg.

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 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 Parlodel is increased until the optimum balance is determined.

Use in Children and adolescents (aged 7–17)

Prescribing of Parlodel 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 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.

4.3 Contraindications

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.

Parlodel is contraindicated in patients with uncontrolled hypertension, hypertensive disorders of pregnancy (including eclampsia, pre-eclampsia or pregnancy-induced hypertension), hypertension postpartum and in the puerperium.

Parlodel is contraindicated for use in the suppression of lactation or other nonlife 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).

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

4.4 Special Warnings and Precautions

When dose reduction or discontinuation of this drug is necessary, the dose should be gradually reduced. Rapid dose reduction or discontinuation may cause a neuroleptic malignant syndrome. In addition, rapid dose reduction or discontinuation of dopamine receptor agonists may cause drug withdrawal syndrome (characterized by apathy, anxiety, depression, fatigue, sweating, pain, etc.).

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction 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 coadministering 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 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.

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 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, <1/10); uncommon (>1/1,000,

<1/100); rare (>1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports.

Common: Headache,

Drowsiness, Uncommon:

Dizziness, Dyskinesia Rare:

Somnolence, Paraesthesia

Very Rare: Excess daytime somnolence and sudden sleep onset

Uncommon: Confusion, Psychomotor agitation, Hallucinations

Rare: Psychotic disorders,

Disorders Common: Nausea,

Constipation Uncommon:

Vomiting

Uncommon: Dry mouth

Rare: Diarrhoea, Abdominal pain, Retroperitoneal fibrosis, Gastrointestinal ulcer, Gastrointestinal haemorrhage

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)

Rare: Tachycardia, bradycardia, arrhthymia

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

Common: Nasal congestion

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

Musculoskeletal and connective tissue disorders

Uncommon: Leg cramps

Uncommon: Allergic skin reactions, Hair loss

Uncommon: Fatigue

Rare: Peripheral oedema

Very Rarely: A syndrome resembling Neuroleptic Malignant

Syndrome has been reported on withdrawal of BROMOCRIPTINE.

Rare: Visual disturbances, vision blurred

Rare: Tinnitus

Other Adverse Reactions

Drug withdrawal syndrome*

Apathy, anxiety, depression, fatigue, sweating, pain, etc

*When any abnormalities are observed, appropriate measures should be taken such as resuming administration or returning the dose to the level prior to reduction.

In extremely rare cases (in postpartum women treated with BROMOCRIPTINE 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).

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 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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.

There have been isolated reports of children who accidentally ingested PARLODEL. 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 (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.

5.2 Pharmacokinetic properties

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 Cmax of 0.465ng/ml. The prolactinlowering effect occurs 1–2 hours after ingestion, reaches its maximum within about 5 hours and lasts for 8–12 hours.

PARLODEL is extensively metabolised. In plasma the elimination half life is 3–4 hours for the parent drug and 50 hours for the inactive metabolites. The parent drug and its metabolites are also completely excreted via the liver with only 6% being eliminated via the kidney. PARLODEL is 96% bound to plasma proteins.

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.

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 |iM. 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 PARLODEL (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

Capsule Content:

Silica, colloidal anhydrous,

Magnesium stearate,

Maleic acid,

Maize starch,

Lactose monohydrate

Capsule Shell:

Indigo carmine (E132),

Titanium dioxide (E171),

Gelatin

Printing Ink:

Shellac (E904),

Iron Oxide Black (E172)

Propylene glycol.

6.2 Incompatibilities

None.

6.3 Shelf life

Opaque white PV/PVDC blister strip : 24 months

Amber glass bottle                    : 36 months

6.4 Special precautions for storage

Amber glass bottle:

Store below 30°C. Store in the original package in order to protect from light

Opaque white PV/PVDC blister strip:

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

6.5 Nature and contents of container

Opaque white PV/PVDC blister strip containing 30 PARLODEL 5 mg capsules.

Amber glass bottle with a tamper resistant closure containing 100 PARLODEL 5 mg capsules.

Not all pack sizes will be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Mylan Products Ltd.,

Station Close,

Potters Bar,

Herts,

EN6 1TL,

United Kingdom.

8 MARKETING AUTHORISATION NUMBER(S)

PL 46302/0138

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09 October 1981 / 27 October 1997