Parlodel

One scored tablet contains bromocriptine mesilate 2.87 mg (corresponding to 2.5 mg bromocriptine base).
Active moiety: Bromocriptine.
Excipients/Inactive Ingredients: One tablet contains as excipients silica colloidal anhydrous, disodium edetate, magnesium stearate, maleic acid, maize starch, maize starch pre-gelatinized and lactose.

Pharmacotherapeutic Group/ATC Code: Dopamine agonists (ATC code N04B C01), prolactin inhibitors (ATC code G02C B01).
Pharmacology: Pharmacodynamics: Mechanism of Action: Parlodel inhibits the 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.
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 (galactorrhea) 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 amenorrhea and/or anovulation (with or without galactorrhea), Parlodel can be used to restore menstrual cycles and ovulation.
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 in addition to 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.
Because of its dopaminergic activity, Parlodel, at 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. 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 at all stages of the disease. Usually the therapeutic effectiveness lasts over years (so far, good results have been reported in patients treated for up to 8 years). Parlodel can be given either alone or at both early and advanced stages combined with other antiparkinsonian drugs. Combination with levodopa treatment results in enhanced antiparkinsonian effects, often making possible a reduction of the levodopa dosage. Parlodel offers particular benefit to patients on levodopa treatment exhibiting a deteriorating therapeutic response or complications such as abnormal involuntary movements (choreo-athetoid dyskinesia and/or painful dystonia), end-of-dose failure, and 'on-off' phenomenon.
Parlodel improves the depressive symptomatology often observed in parkinsonians. This is due to its inherent antidepressant properties as substantiated by controlled studies in non-parkinsonian patients with endogenous or psychogenic depression.
Clinical Studies: Parlodel is an established product. No recent clinical studies have been conducted.
Pharmacokinetics: Absorption: Parlodel is well absorbed after oral administration. When tablets or standard capsules are administered to healthy volunteers, the absorption half-life is 0.2 to 0.5 hours, and peak plasma levels of bromocriptine are reached within 1 to 3 hours. An oral dose of 5 mg of bromocriptine results in a C_max of 0.465 ng/mL. The prolactin-lowering effect begins within 1 to 2 hours of ingestion, reaches its maximum, i.e. a reduction of prolactin in the plasma by more than 80%, within 5 to 10 hours and remains close to maximum for 8 to 12 hours.
With Parlodel SRO capsules, a form designed for once-a-day administration, peak plasma levels are reached within 7 to 10 hours, and the maximal inhibitory effect on prolactin secretion, similar in magnitude to that achieved with tablets or standard capsules, occurs within 10 to 17 hours after the ingestion. As the period of time during which plasma concentrations higher than 50% of the maximal level are maintained for about 14.5 hours (compared with 3.5 hours with standard capsules), the duration of the prolactin-lowering effect is prolonged.
With single-dose administration the bioavailability of SRO capsules relative to the standard capsules is more than 90%. Under steady-state conditions, a slight reduction in bioavailability (to about 80%) is observed, but there is no loss of therapeutic effectiveness.
Food effect: The rate of absorption (C_max) of standard bromocriptine tablets/capsules may be reduced by food to an extent of 10-40%. However, the bioavailability (AUC) of standard tablets/capsules is not significantly influenced. Food has no impact on rate and extent of absorption for modified release bromocriptine. Overall, there is no clinically significant effect of food on Parlodel and Parlodel SRO formulations.
Distribution: Plasma protein binding is 96%.
Biotransformation/Metabolism: 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 feces. 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 microM. 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.
Elimination: The elimination of the parent drug from plasma is biphasic, with a terminal half-life of about 15 hours (range 8 to 20 hours). Parent drug and metabolites are almost completely excreted via the liver, only 6% being eliminated via the kidney.
Special Populations: Geriatric patients (65 years of age or above): The effect of age on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated.
Hepatic Impairment: In patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase.
Renal Impairment: The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated. The parent drug and metabolites are almost completely excreted via liver, and only approx. 6% eliminated via the kidney. Therefore, impact on patients with renal impairment is less likely.
Toxicology: Non-Clinical Safety Data: Pre-clinical data for Parlodel (bromocriptine) reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, mutagenicity, carcinogenic potential, or toxicity to reproduction.
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.
Uterine 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.

Adults and Pediatrics (aged 7-17 years): The safety and effectiveness of bromocriptine in pediatric patients has only been established for the Prolactinomas and Acromegaly indications, in pediatrics aged 7-17 years (see Precautions).
Prolactinomas: Conservative treatment of prolactin-secreting pituitary micro- or macro-adenomas; Prior to surgery in order to reduce tumour size and to facilitate removal; After surgery if prolactin level is still elevated.
Acromegaly: As an adjunct, or in special cases as an alternative, to surgery or radiotherapy.
Adults: Parkinson's disease: All stages of idiopathic and postencephalitic Parkinson's disease, either as monotherapy or in combination with other antiparkinsonian drugs. Hyperprolactinemia in men: Prolactin-related hypogonadism (oligospermia, loss of libido, impotence).
Menstrual cycle disorders, female infertility: Prolactin-dependent hyperprolactinemic or apparently normoprolactinemic conditions: Amenorrhea (with or without galactorrhea), oligomenorrhea; luteal phase deficiency; drug-induced hyperprolactinemic disorders (e.g. induced by certain psychotropic or antihypertensive agents).
Prolactin-independent female infertility: Polycystic ovary syndrome; anovulatory cycles (supplementary to anti-estrogens, e.g. clomiphene).
Inhibition of lactation for medical reasons: Prevention or suppression of puerperal lactation; Prevention of lactation after abortion; 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.
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.

Tablets or capsules (standard forms): Parlodel should always be taken with food.
General target population: Adults: Parkinson's disease: In order to ensure optimal tolerability, treatment should be started with a low dose of 1.25 mg (½ tablet) per day, given preferably in the evening, for the first week. Parlodel should be titrated slowly in order to arrive at the minimal effective dose for each patient. The daily dosage should be increased gradually by 1.25 mg/day each week, and given as 2 to 3 divided doses. An adequate therapeutic response may be reached within 6 to 8 weeks; if it is not, the daily dose may be further increased by 2.5 mg/day each week.
The usual therapeutic range for monotherapy or combined therapy is 10-40 mg bromocriptine per day, but higher doses may be required in some patients.
Should undesirable reactions occur during the titration phase, the daily dose should be reduced and maintained at the lower level for at least a week. If the adverse reactions disappear, the dose can be increased again.
For patients exhibiting motor disorders on levodopa therapy, it is suggested that the levodopa dosage should be reduced before Parlodel treatment is initiated. When a satisfactory response to Parlodel has been obtained, a further stepwise reduction in levodopa dosage can be made. In certain patients, levodopa may be withdrawn completely.
Prolactinomas: 1.25 mg (½ tablet) 2 or 3 times daily, gradually increasing to several tablets or capsules daily as required to keep plasma prolactin adequately suppressed.
Acromegaly: Initially 1.25 mg (½ tablet) 2 or 3 times daily, gradually increasing to 10 to 20 mg daily, depending on clinical response and side effects.
Hyperprolactinemia in men: 1.25 mg (½ tablet) 2 or 3 times daily, gradually increasing to 5 to 10 mg per day.
Menstrual cycle disorders, female infertility: 1.25 mg (½ tablet) 2 or 3 times daily; if this proves inadequate, gradually increase to 2.5 mg 2 or 3 times daily. Continue treatment until the menstrual cycle has returned to normal and/or ovulation is restored. If required, treatment may be continued over several cycles to prevent relapse.
Inhibition of lactation for medical reasons: On the first day, 1.25 mg (½ tablet) with food in the morning and evening, followed by 2.5 mg (1 tablet) twice a day for 14 days. To prevent the onset of lactation, treatment should be instituted within a few hours of parturition or abortion, but not before vital signs have stabilised. Slight milk secretion occasionally occurs 2 or 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. An antibiotic should be added to the regimen, as required.
Pediatric patients (aged 7-17 years): Prolactinomas: Pediatric population older than 7 years: 1.25 mg (½ tablet) 2 or 3 times daily, gradually increasing to several tablets or capsules 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.
Acromegaly: Pediatric population older than 7 years: Initially 1.25 mg (½ tablet) 2 or 3 times daily, gradually increasing to several tablets or capsules daily, depending on clinical response and side effects. Maximum daily dose recommended in children aged 7 to 12 years is 10 mg. Maximum daily dose recommended in adolescent patients (13-17 years) is 20 mg.
Special populations: Geriatric patients (aged 65 years of age or above): 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 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.
Renal impairment: No studies have been performed in renally impaired patients.
Hepatic impairment: No studies have been performed in hepatically impaired patients.

Signs and symptoms: The observed symptoms of overdosage were nausea, vomiting, dizziness, hypotension, postural hypotension, tachycardia, drowsiness, somnolence, lethargy and hallucinations.
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 appropriate management.
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.

Hypersensitivity to bromocriptine or to any of the excipients of Parlodel/Parlodel SRO (see Description) or to other ergot alkaloids; Uncontrolled hypertension, hypertensive disorders of pregnancy (including eclampsia, pre-eclampsia or pregnancy-induced hypertension), hypertension post partum and in the puerperium; Coronary artery disease and other severe cardiovascular conditions; Symptoms and/or a history of serious psychic disorders.

General: If women with conditions not associated with hyperprolactinemia are treated with Parlodel, the drug should be given in the lowest effective dose necessary to relieve the symptoms; this is in order to avoid the possibility of suppressing plasma prolactin below normal levels, with a consequent impairment of luteal function.
Gastrointestinal: A few cases of gastrointestinal bleeding and gastric ulcer have been reported. If this occurs, Parlodel should be withdrawn. Patients with a history or evidence of peptic ulceration should be closely monitored when receiving the treatment.
Fibrotic conditions: 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, edema 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.
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.
Use in postpartum women: In rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, or psychic disorders have been reported in postpartum women treated with Parlodel for the inhibition of lactation. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances. Although the causal relationship of these events to the drug is uncertain, periodic monitoring of blood pressure is advisable in postpartum women receiving Parlodel for the inhibition of lactation, as well as in patients treated for any other condition. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of CNS toxicity develop, the administration of Parlodel should be discontinued and the patient should be evaluated promptly.
Particular caution is required in patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure, e.g. vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine and their concomitant use in the puerperium is not recommended.
Use in prolactin-secreting adenoma patients: 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 field 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 hyperprolactinemia and often to a 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.
Driving and using machines: Since, especially during the first 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 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 not to drive or operate machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must not drive or operate machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Use in Children: Pediatric patients (aged 7 to 17 years): The safety and effectiveness of bromocriptine in pediatric patients has only been established for the Prolactinomas and Acromegaly indications, in patients aged 7 or above. Only isolated data are available for bromocriptine use in pediatric patients under the age of 7 years. However, other reported clinical experiences, including post-marketing reporting of adverse events, have not identified differences in tolerability between adults and adolescents or children. Even though no variation in adverse reaction profile in pediatric patients taking Parlodel has been observed, greater sensitivity in some younger individuals cannot be ruled out, and it is recommended that dose titration in pediatric patients should be cautious.
Use in the Elderly: Geriatric patients (aged 65 years or above): Clinical studies for Parlodel did not include sufficient numbers of subjects aged 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 differences 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 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.

Females and males of reproductive potential: Infertility: Fertility may be restored by treatment with Parlodel. Women of child-bearing age who do not wish to conceive should therefore be advised to practise a reliable method of contraception.
Pregnancy: Risk Summary: In patients wishing to conceive, Parlodel should be discontinued when pregnancy is confirmed, unless there is a medical reason for continuing therapy. No increased incidence of abortion has been observed following withdrawal of Parlodel at this point. Clinical experience indicates that Parlodel, administered during pregnancy, does not adversely affect its course or outcome.
If pregnancy occurs in the presence of a pituitary adenoma and Parlodel treatment has been stopped, close supervision throughout pregnancy is essential. In patients who show symptoms of a pronounced enlargement of a prolactinoma, e.g. headache or visual field deterioration, Parlodel treatment may be re-instituted or surgery may be appropriate.
Breast-feeding: Since Parlodel inhibits lactation, it should not be administered to mothers who elect to breast-feed.

The following adverse drug reactions with Parlodel have been derived from multiple sources including clinical trial and post-marketing experience via spontaneous case reports and literature cases (table) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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) and not known (cannot be estimated from the available data). (See table.)

Click on icon to see table/diagram/image

Pathological gambling, increased libido and hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Parlodel (see Precautions).
The use of Parlodel for the inhibition of physiological lactation post partum has been associated with the rare occurrence of hypertension, myocardial infarction, seizures, stroke or psychic disorders (see Precautions).

Observed interactions to be considered: CYP3A4 substrates/inhibitors: Bromocriptine is both a substrate and an inhibitor of CYP3A4 (see Pharmacology under Actions). 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 use of macrolide antibiotics such as erythromycin or josamycin, was shown to increase the plasma levels of bromocriptine. The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine.
Sympathomimetic drugs: Co-administration of sympathomimetics such as phenylpropanolamine and bromocriptine may lead to hypertension and severe headache (see Precautions).
Sumatriptan: Co-administration of sumatriptan may potentiate the risk of vasospastic reactions due to additive pharmacological effects.
Ergot alkaloids: Co-administration may increase the dopamine stimulant activity and lead to dopaminergic side effects such as headache, nausea, vomiting (see Precautions).
Dopamine receptor antagonists: Since Parlodel exerts its therapeutic effect by stimulating central dopamine receptors, dopamine antagonists such as antipsychotics (phenothiazines, butyrophenones and thioxanthenes), but also metoclopramide and domperidone may reduce its activity.
Alcohol: The tolerability to Parlodel may be reduced by alcohol.

Incompatibilities: Not applicable.

Special precautions for storage: Tablets: Store at temperatures not exceeding 30°C.

Antiparkinsonian Drugs / Trophic Hormones & Related Synthetic Drugs

G02CB01 - bromocriptine ; Belongs to the class of prolactine inhibitors. Used to suppress lactation.

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