Acromegaly:

As an add-on therapy; as an alternative to surgery or radiotherapy in special cases.

Hyperprolactinaemia in males:

Prolactin-induced hypogonadism (oligospermia, loss of libido, impotence).

Prolactinomas: Conservative treatment of pituitary micro- or macroprolactinomas; pre-surgical reduction of tumour size to facilitate resection; post-surgical inhibition of persistent hyperprolactinaemia.

Inhibition of lactation for medical reasons (e.g. intrapartum loss, stillbirth, HIV infection of the mother):

Prevention or suppression of puerperal lactation; prevention of lactation following abortion; treatment of incipient puerperal mastitis.

Parlodel is not recommended for the routine prevention or suppression of puerperal breast engorgement, which can be adequately treated with simple analgesics and breast support.

Disorders of the menstrual cycle and female infertility:

Prolactin-induced hyperprolactinaemic and apparently normoprolactinaemic conditions: Amenorrhoea (with or without galactorrhoea), oligomenorrhoea; luteal-phase deficiency; drug-induced hyperprolactinaemic disorders (e.g. due to certain psychotropic or antihypertensive agents).

Prolactin-independent female infertility: Polycystic ovary syndrome; anovulatory cycles (to supplement anti-oestrogens, e.g. clomifene).

Parkinsonism:

All stages of idiopathic and postencephalitic Parkinson’s disease, either as monotherapy or in combination with other antiparkinsonian drugs.

Parlodel should always be taken with food.

Acromegaly: 1.25 mg (½ tablet) two or three times daily, gradually increasing to 10-20 mg daily depending on clinical response and adverse effects.

Hyperprolactinaemia in males: 1.25 mg (½ tablet) two or three times daily, gradually increasing to 5-10 mg (2-4 tablets) daily.

Inhibition of lactation for medical reasons: 1.25 mg (½ tablet) with the morning meal and again with the evening meal on the first day of treatment, followed by 2.5 mg (one tablet) twice daily for 14 days. To prevent the onset of lactation, treatment should be instituted within a few hours after parturition or abortion, but not before vital signs have stabilised. Slight milk secretion occasionally occurs 2-3 days after treatment has been withdrawn. This can be stopped by resuming treatment at the same dosage for a further week.

Incipient puerperal mastitis: Same dosage as for inhibition of lactation (see above). An antibiotic may be added to the regimen as required.

Disorders of the menstrual cycle and female infertility: 1.25 mg (½ tablet) two or three times daily; if this proves inadequate, gradually increase to 2.5 mg (one tablet) two or three times daily. Treatment should be continued until the menstrual cycle is normalised and/or ovulation occurs and, if necessary, over several cycles to prevent relapse.

Prolactinomas: 1.25 mg (½ tablet) two or three times daily, gradually increasing to several tablets daily as required for control of plasma prolactin.

Parkinsonism: In order to ensure optimum tolerability, treatment should be started at a small dose of 1.25 mg (½ tablet) daily. During the first week, the dose should preferably be taken in the evening. The dosage should then be increased slowly until the lowest effective dose is established. The daily dose should be gradually increased in steps of 1.25 mg at weekly intervals; it should be given in two or three divided doses. If a satisfactory therapeutic response is not achieved within 6-8 weeks, further dose increases of 2.5 mg/day at weekly intervals may be attempted.

If adverse effects occur during the titration phase, the daily dose should be reduced temporarily for at least one week. It may be increased again once the adverse effects disappear.

In patients exhibiting levodopa-induced motor disturbances, the dosage of levodopa should be reduced before introducing Parlodel. Further gradual reduction of the levodopa dosage may be possible once a satisfactory response to Parlodel has been obtained, with the possibility of complete withdrawal of levodopa in some cases.

The total daily dose in monotherapy and combination therapy should not exceed 30 mg bromocriptine. The adverse pleuropulmonary effects mentioned under "Warnings and precautions" were reported in connection with long-term treatment in which high doses exceeding 20 mg daily were given for 6 months.

Special dosage recommendations

Children and adolescents

The following dosage recommendations apply for children aged 7 and over, and adolescents:

	Dosage/administration in children aged 7 and over	Maximum recommended daily dose
		7-12 years	13-18 years
Prolactinomas	1.25 mg (½ tablet) twice or three times daily; increase gradually to several tablets per day, as needed, to control plasma prolactin.	5 mg	10 mg
Acromegaly	Initially 1.25 mg (½ tablet) twice or three times daily; depending on clinical response and desired efficacy, increase gradually to several tablets per day.	10 mg	10 mg

In children and adolescents aged 7-18 years, the use of Parlodel is not recommended for menstrual cycle disorders, female infertility, hyperprolactinaemia in men, incipient puerperal mastitis, inhibition of lactation for medical reasons and Parkinson's disease, if the need arises.

Children under 7 years of age

The use and safety of Parlodel have not yet been investigated.

There are insufficient data regarding the safety and efficacy of Parlodel in children under 7 years of age. Use in this age group is therefore not recommended.

 

 

 

Elderly patients

In general, dose selection for elderly patients should be cautious, starting at the lowest dose in the dose range in question, in view of the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapies.

Renal impairment

Parlodel has not been studied in renally impaired patients. As bromocriptine and its metabolites are almost exclusively excreted via the liver, it is unlikely that a dose adjustment is necessary in renally impaired patients.

Hepatic impairment

Parlodel has not been studied in hepatically impaired patients. As the elimination of bromocriptine may be delayed in patients with hepatic impairment, dose adjustment may be necessary. Parlodel is contraindicated in severe hepatic impairment (Child Pugh C).

• Existing or previous serious psychiatric disorders. • Inadequately controlled arterial hypertension, hypertensive disorders during pregnancy (such as eclampsia, preeclampsia or pregnancy-induced hypertension). Postpartum and puerperal hypertension. • Coronary artery disease and other severe cardiovascular conditions. • History of cerebrovascular events. • Arterial occlusive disease. • Raynaud’s phenomenon. • Giant-cell arteritis. • temporal arteritis • Stomach ulcers, duodenal ulcers, gastrointestinal bleeding. • Severe hepatic dysfunction. • Sepsis. • Treatment with methylergometrine or other ergot alkaloids. • Concomitant treatment with strong or moderate cytochrome P450 inhibitors (such as itraconazole, voriconazole and clarithromycin; see "Interactions"). • Nicotine abuse. • Hypersensitivity to bromocriptine, to any of the excipients (see "Composition") or to other ergot alkaloids.

Blood pressure should be carefully monitored, especially at the start of treatment, and regularly thereafter on Parlodel treatment.

In the event of hypertension, vasospastic or thrombotic symptoms, severe, increasing or persistent headache (with or without visual disturbances) or other signs of CNS toxicity, treatment should be discontinued immediately and the patient monitored accordingly.

There have been reports of gastrointestinal bleeding and gastric ulcers. In such cases, Parlodel should be withdrawn. Patients presenting with an active ulcer or with a history of ulcer should be carefully monitored during treatment with Parlodel.

Impulse control disorders such as pathological gambling, compulsive spending or buying, increased libido, hypersexuality, binge eating and compulsive eating have been reported during treatment with dopamine agonists such as Parlodel. Patients and carers should be made aware of the possible occurrence of such symptoms. Dose reduction or tapered discontinuation of therapy should be considered in patients who develop such symptoms.

Hypotensive reactions due to a fall in blood pressure occasionally occur during the first few days of treatment and may cause decreased mental alertness.

 

Postpartum and puerperal use

In rare cases, serious adverse effects such as hypertension, myocardial infarction, seizures, stroke and psychiatric disorders have been reported in postpartum women treated with Parlodel for the inhibition of lactation. In some patients, seizure or stroke was preceded by severe headache and/or transient visual disturbances. Although a causal relationship of these events to Parlodel has not been proven, blood pressure must be monitored regularly.

Particular caution is required in patients either recently treated with or concurrently using drugs that can alter blood pressure, e.g. vasoconstrictors such as sympathomimetics or ergot alkaloids (including ergometrine or methylergometrine). Concomitant use of such drugs in the puerperium is not recommended.

In some cases, pleural effusions, pleural, pulmonary and retroperitoneal fibrosis and constrictive pericarditis have been reported in parkinsonian patients receiving long-term treatment with high doses of Parlodel. Fibrotic changes also cannot be ruled out when Parlodel is used in indications other than Parkinson’s disease. Parkinsonian patients with a history of such conditions should not be treated with Parlodel.

Unexplained pleuropulmonary changes should therefore be investigated, and consideration given to discontinuing Parlodel. It is advisable to pay attention to relevant manifestations of retroperitoneal fibrosis (e.g. back pain, oedema of the lower limbs, impaired kidney function) in such patients in order to ensure detection of this condition at its early, reversible stage. Parlodel should be withdrawn if retroperitoneal fibrotic changes are diagnosed or suspected. The pleuropulmonary fibrotic changes observed may be associated with fibrotic thickening of the heart valves, as has been the case in patients treated with other ergot alkaloid derivatives.

Parlodel has been associated with drowsiness and sudden sleep attacks, particularly in patients with Parkinson’s disease. There have been very rare reports of sudden sleep attacks during daily activities, without warning signs. Patients must be informed of this. A reduction in dosage, or withdrawal of therapy, must be considered in patients experiencing drowsiness or sudden sleep onset.

Special warnings for the use of Parlodel in patients with pituitary macroadenoma or microadenoma

Since patients with pituitary macroadenoma resulting from compression or destruction of pituitary tissue may also suffer from hypopituitarism, a thorough examination of pituitary function and appropriate substitution therapy should be carried out before using Parlodel. In patients with secondary adrenocortical insufficiency, corticosteroid substitution is essential.

Tumour growth must be closely monitored in patients with pituitary macroadenoma. Surgery should be considered if there is evidence of tumour expansion.

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with Parlodel leads to a reduction in hyperprolactinaemia and often to improvement of the visual field. In some patients, however, secondary visual field impairment may develop despite normalised prolactin levels and tumour shrinkage. This is due to mechanical stress exerted on the optic chiasm, which is pulled down into the now partially empty sella when the tumour shrinks. In such cases, the visual field defect may improve on reduction of the dose of Parlodel due to a rise in prolactin levels and some renewed tumour growth. Regular monitoring of visual fields is therefore indicated in patients with macroprolactinoma in order to allow early detection of secondary visual field impairment and adaptation of the dose of Parlodel, if necessary.

Close monitoring is necessary in adenoma patients who become pregnant during Parlodel therapy. Prolactin-secreting adenomas may expand during pregnancy. In patients with symptoms of considerable prolactinoma expansion, e.g. headache or visual field impairment, Parlodel treatment may be recommenced. In this case, Parlodel therapy often results in tumour shrinkage and rapid improvement of visual field impairment. In severe cases, compression of the optic nerve or other cerebral nerves may necessitate emergency pituitary surgery.

Cerebrospinal fluid rhinorrhoea has been observed in some patients with prolactin-secreting adenomas treated with Parlodel. The available data suggest that this may result from shrinkage of invasive tumours.

If women of child-bearing age with conditions not associated with hyperprolactinaemia are treated with Parlodel, the drug should be given in the lowest effective dose necessary to relieve the symptoms. This should prevent prolactin from falling below normal levels, with a consequent impairment of luteal function.

There is insufficient evidence of efficacy of bromocriptine in the treatment of premenstrual symptoms or benign breast disease. Parlodel is not recommended for treatment of patients with such illnesses.

Caution is required when using Parlodel in patients with severe renal impairment.

Infertility may be reversed by treatment with Parlodel. Women of child-bearing age who do not wish to conceive should therefore be advised to use a reliable method of contraception.

Parlodel tablets contain lactose. Patients with rare hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take Parlodel.

Pharmacokinetic interactions

Bromocriptine is both a substrate and an inhibitor of cytochrome P450 (CYP3A).

Influence of other medicinal products on bromocriptine pharmacokinetics

Co-administration of potent or moderate CYP3A4 inhibitors (e.g. itraconazole, voriconazole, fluconazole, clarithromycin, erythromycin, indinavir, nelfinavir, ritonavir or grapefruit juice) can lead to an increase in bromocriptine plasma levels (see "Contraindications"). There are no data on co-administration with weak CYP3A4 inhibitors.

Concomitant use of bromocriptine and octreotide in acromegalic patients resulted in elevated plasma levels of bromocriptine, and an increased incidence of adverse effects is likely.

 

Influence of bromocriptine on the pharmacokinetics of other medicinal products

Bromocriptine may increase plasma levels of concomitantly administered medicinal products metabolised by CYP3A4. Caution is therefore required when co-administering substances with a narrow therapeutic window, particularly medicinal products that may prolong the QT interval (e.g. amiodarone, imipramine, terbinafine).

 

Pharmacodynamic interactions

Ergot alkaloids: Co-administration of methylergometrine or other ergot alkaloids may increase the stimulant effect on dopamine receptors and lead to dopaminergic side effects such as headache, nausea and vomiting (see "Contraindications").

Sympathomimetic drugs: Co-administration of sympathomimetics and bromocriptine may lead to hypertension and severe headache (see "Warnings and precautions").

Sumatriptan: Co-administration of sumatriptan may increase the risk of vasospastic reactions due to additive pharmacological effects.

Dopamine receptor antagonists: Since Parlodel exerts its therapeutic effect by stimulating central dopamine receptors, dopamine antagonists such as antipsychotics (phenothiazines, butyrophenones or thioxanthenes), but also metoclopramide and domperidone, may reduce its activity.

Alcohol: The tolerability of Parlodel may be reduced by alcohol.

Pregnancy:

No data are available from clinical studies. Clinical experience in pregnant women exposed to bromocriptine have shown no adverse effects of bromocriptine on pregnancy or on the health of the fetus or neonate.

Animal studies have not shown any direct or indirect toxicity affecting pregnancy, embryonic development, fetal development and/or postnatal development (see "Preclinical data").

Parlodel must be withdrawn as soon as pregnancy is confirmed, except in cases in which continuation of therapy is medically indicated. No increased incidence of abortion has been observed following withdrawal of Parlodel.

Women with a pituitary adenoma who become pregnant and withdraw Parlodel must be closely monitored throughout the pregnancy (see "Warnings and precautions").

Breast-feeding:

Bromocriptine inhibits lactation. Parlodel should therefore not be administered to breastfeeding women outside of its specific postpartum indications (inhibition of lactation for medical reasons; see "Indications/Potential uses").

No relevant studies have been carried out. Hypotensive reactions due to a fall in blood pressure may occasionally occur during the first few days of treatment, causing reduced alertness, and particular caution is therefore necessary when driving a vehicle or operating machinery.

Patients being treated with Parlodel who have experienced drowsiness and/or sudden sleep attacks must be advised not to drive or operate machines, since they may endanger themselves or others. Patients should be informed of this problem and should avoid such activities until the extent to which they are affected by the symptoms is sufficiently clear.

Adverse effects observed in clinical trials with Parlodel and/or during post-marketing are listed below according to MedDRA system organ classes and frequency. The corresponding frequency category for each adverse effect is based on the following convention (CIOMS III): 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 (primarily based on spontaneous post-marketing reports; precise frequency cannot be estimated).

Psychiatric disorders

Uncommon: Depressive mood, confusion, psychomotor agitation, hallucinations.

Rare: Psychotic disorders.

Unknown: Impulse control disorders such as compulsive gambling (see "Warnings and precautions").

Nervous system disorders

Common: Headache, dizziness, drowsiness.

Uncommon: Dyskinesia.

Rare: Sleep disorders, paraesthesia.

Very rare: Excessive daytime somnolence, sudden sleep attacks (see "Warnings and precautions").

Eye disorders

Rare: Visual impairment, blurred vision.

Ear and labyrinth disorders

Rare: Tinnitus.

Cardiac disorders

Rare: Tachycardia, bradycardia, arrhythmia, pericardial effusion, constrictive pericarditis.

Very rare: Cardiac valve fibrosis.

Unknown: Aggravation of angina pectoris.

Vascular disorders

Uncommon: Hypotension, orthostatic hypotension (very rarely leading to syncope).

Very rare: Pallor of fingers and toes induced by cold (especially in patients with history of Raynaud’s phenomenon).

Respiratory disorders

Common: nasal congestion.

Rare: Dyspnoea, pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis.

Gastrointestinal disorders

Common: Nausea, vomiting, constipation.

Uncommon: Dry mouth.

Rare: Abdominal pain, diarrhoea, gastrointestinal ulcer, gastrointestinal haemorrhage, retroperitoneal fibrosis.

Skin and subcutaneous tissue disorders

Uncommon: Allergic dermatitis, alopecia.

Musculoskeletal disorders

Uncommon: Muscle spasms.

Renal and urinary disorders

Uncommon: Urinary incontinence.

General disorders

Rare: Peripheral oedema.

Very rare: A syndrome resembling neuroleptic malignant syndrome on abrupt withdrawal of Parlodel.

 

In rare cases (in postpartum use of Parlodel to inhibit lactation), hypertension, myocardial infarction, seizures, stroke or psychiatric disorders have been reported (see "Warnings and precautions").

 

--To reports any side effect(s):

·    Saudi Arabia:

·         Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966112057662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

o Toll free phone: 8002490000

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

 

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

O Toll Free Number: 8001240078

O Phone: +966112658100
O Fax: +966112658107
O Email: adverse.events@novartis.com

·    Other GCC States:

-- Please contact the relevant competent authority.

The following may be symptoms of overdose: nausea, vomiting, dizziness, hypotension, postural hypotension, tachycardia, drowsiness, somnolence, lethargy and hallucinations.

In case of overdose, administration of activated charcoal is recommended. Gastric lavage may be considered if only a very short time has elapsed since oral ingestion. Management of acute intoxication is symptomatic

Dopamine agonist ATC code: N04BC01

Prolactin inhibitor: ATC code: G02CB01

Mechanism of action

Effect on the adenohypophysis

Following childbirth, prolactin is necessary for the initiation and maintenance of lactation. At other times, however, increased prolactin secretion gives rise to pathological lactation (galactorrhoea) and/or disorders of ovulation and menstruation.

Parlodel inhibits secretion of the anterior pituitary hormone prolactin without affecting normal levels of other pituitary hormones. It can, however, reduce elevated levels of growth hormone (GH) in patients with acromegaly. These effects are due to stimulation of dopamine receptors.

The prolactin-lowering action begins to take effect 1-2 hours after ingestion, peaks (i.e. brings about a reduction of > 80% in plasma prolactin) after 5-10 hours and is maintained for 8-12 hours.

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.

Customary measures taken during weaning, such as the restriction of fluid intake, are not necessary with Parlodel. In addition, Parlodel does not impair puerperal involution of the uterus or increase the risk of thromboembolism.

Parlodel improves the clinical symptoms of polycystic ovary syndrome by restoring a normal pattern of luteinising hormone secretion.

Parlodel has also been shown to arrest the growth or reduce the size of prolactin-secreting pituitary adenomas (prolactinomas).

In acromegalic patients, Parlodel has a beneficial effect on clinical symptoms and glucose tolerance, in addition to lowering the plasma levels of growth hormone and prolactin.

Dopaminergic effects

Because of its dopaminergic activity, Parlodel, at doses usually higher than those for its endocrinological indications, is effective in the treatment of Parkinson's disease, which is characterised by a specific nigrostriatal dopamine deficiency. In this condition, the stimulation of dopamine receptors by Parlodel can restore the neurochemical balance within the striatum.

Clinically, Parlodel improves tremor, rigidity, bradykinesia and other parkinsonian symptoms (e.g. depressive symptoms) at all stages of the disease. The therapeutic effect is normally maintained for years (good results have been reported in patients treated for up to 8 years). Parlodel can be given alone in both early and advanced-stage disease, or in combination with other antiparkinsonian drugs. Combination with levodopa results in an enhanced antiparkinsonian effect and frequently enables the levodopa dose to be reduced. Parlodel offers particular benefit to patients exhibiting a deteriorating therapeutic response to levodopa treatment or with complications such as abnormal involuntary movements (choreoathetoid dyskinesia and/or painful dystonia), end-of-dose failure, and "on-off" phenomenon.

Absorption

Bromocriptine is rapidly and readily absorbed following oral administration. Peak plasma levels are reached within 1-3 hours. The absorption half-life in healthy volunteers is 0.2-0.5 hours. An oral dose of 5 mg bromocriptine results in a C_max of 0.465 ng/ml.

Concomitant food intake has no relevant effect on bromocriptine exposure. However, it is recommended to always take Parlodel together with food to improve gastrointestinal tolerability.

Distribution

Plasma protein binding is 96%.

Metabolism

Bromocriptine is almost completely metabolised in the liver to inactive metabolites. The metabolite profile is complex. Bromocriptine shows a high affinity for CYP3A4, and hydroxylation at the proline ring constitutes a major metabolic pathway.

Elimination

Bromocriptine is eliminated in the form of parent drug and metabolites in bile; only 6% of the drug is eliminated via the kidneys. The elimination half-life is 3-4 hours for the parent substance and 50 hours for the metabolites.

Pharmacokinetics in special populations

Children and adolescents

The pharmacokinetics of bromocriptine have only been investigated in adults.

Elderly patients

The effect of age on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated.

 

Hepatic impairment

The pharmacokinetics of bromocriptine have not been evaluated in patients with hepatic impairment. In patients with hepatic impairment, bromocriptine elimination may be delayed and plasma levels may be increased (see "Dosage/Administration").

Renal impairment

The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated (see "Dosage/Administration").

Preclinical data for Parlodel (bromocriptine) reveal no evidence of any special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, mutagenicity, carcinogenic potential and reproductive toxicity.

Effects in preclinical studies were observed only at doses x times higher than the maximum doses recommended in humans, indicating little relevance to clinical use.

Uterine carcinomas were observed in preclinical 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.

Silica Colloidal Anhydrous

Disodium edetate

Magnesium stearate

Maleic acid

Maize starch pregelatinized

Maize starch

Lactose monohydrate

Not applicable.

3 years.

Protect Parlodel tablets from light and store below 25°C.

Keep out of the reach of children

Glass bottle.

None.