Bromocriptine

Inhibition of lactation for medical reasons Prevention or suppression of post-partum physiological lactation only where medically indicated (such as in case of intrapartum loss, neonatal death, HIV infection of the mother). Bromocriptine 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 non-pharmacological intervention (such as firm breast support, ice application) and/or simple analgesics.

Hyperprolactinaemia The treatment of hyperprolactinaemia in men and women with hypogonadism and/or galactorrhoea. Menstrual cycle disorders and female infertility 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. Bromocriptine has been used successfully in the treatment of a number of infertile women with galactorrhoea who do not have demonstrable hyperprolactinaemia.

Prolactinomas To reduce tumour size, particularly in those at risk of optic nerve compression. Acromegaly Bromocriptine 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, Bromocriptine has been used both alone and in combination with Levodopa in the management of previously untreated patients and those disabled by 'on-off' phenomena.

Bromocriptine 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. 4 Special warnings and precautions for use).

BROMOCRIPTINE should always be taken with food. A number of disparate conditions are amenable to treatment with BROMOCRIPTINE 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 BROMOCRIPTINE.

5mg at bed time. 5mg twice daily is achieved. Further dosage increments, if necessary, should be added in a similar manner. 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 BROMOCRIPTINE is not necessary in this indication. 5mg twice daily for 14 days. Gradual introduction of BROMOCRIPTINE is not necessary in this indication. Hypogonadism/Galactorrhea syndromes/Infertility Introduce BROMOCRIPTINE gradually according to the suggested scheme.

5mg daily, in divided doses, but doses of up to 30mg daily have been used. 5mg twice daily. Prolactinomas Introduce BROMOCRIPTINE gradually according to the suggested scheme. 5mg six hourly, 5mg six hourly. Daily doses should not exceed 30 mg.

Acromegaly Introduce BROMOCRIPTINE gradually, according to the suggested scheme. 5mg six-hourly, 5mg six-hourly. 25mg at bed time. 5mg at bed time. 5mg twice daily. 5mg three times daily. 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 BROMOCRIPTINE is increased until the optimum balance is determined.

Use in Children and adolescents (aged 7-17) Prescribing of BROMOCRIPTINE 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 BROMOCRIPTINE 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.

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.

Nervous System Disorders Common:

Headache, Drowsiness, Uncommon: Dizziness, Dyskinesia Rare: Somnolence, Paraesthesia 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 Uncommon: Dry mouth Rare: Diarrhoea, Abdominal pain, Retroperitoneal fibrosis, Gastrointestinal ulcer, Gastrointestinal haemorrhage Vascular Disorders Uncommon: Hypotension including orthostatic hypotension (which may in very rare instances lead to collapse) Very Rare: Reversible pallor of fingers and toes induced by cold (especially in patients who have a history of Raynaud’s phenomenon) Cardiac Disorders Rare: Tachycardia, bradycardia, arrhthymia Very rare: Cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion).

Respiratory, thoracic and mediastinal disorders Common:

Nasal congestion Rare: Pleural effusion, pleural and pulmonary fibrosis, pleuritis, dyspneoa Musculoskeletal and connective tissue disorders Uncommon: Leg cramps Skin and subcutaneous tissue disorders Uncommon: Allergic skin reactions, Hair loss General disorders and administration site conditions Uncommon: Fatigue Rare: Peripheral oedema Very Rarely: A syndrome resembling Neuroleptic Malignant Syndrome has been reported on withdrawal of BROMOCRIPTINE.

Eye Disorders Rare:

Visual disturbances, vision blurred Ear and Labyrinth Disorders 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.

Post-partum women 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.

4 Special warnings and precautions for use). Impulse control disorders Pathological gambling, increased libido hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including BROMOCRIPTINE.

4 ‘Special warnings and precautions for use’). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

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Hypersensitivity to bromocriptine or to any of the excipients of Bromocriptine Tablets (see Section 2. 1 List of excipients) or other ergot alkaloids. Bromocriptine 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.

Bromocriptine 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 Bromocriptine for the indication of macro-adenomas should only take it if the perceived benefits outweigh the potential risks (see Section

INDICATIONS & USAGE

Hyperprolactinemia-Associated Dysfunctions Bromocriptine mesylate is indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Bromocriptine mesylate treatment is indicated in patients with prolactin-secreting adenomas, which may be the basic underlying endocrinopathy contributing to the above clinical presentations.

Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of bromocriptine mesylate therapy may be used to reduce the tumor mass prior to surgery.

Acromegaly Bromocriptine mesylate therapy is indicated in the treatment of acromegaly. Bromocriptine mesylate therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels.

Since the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with bromocriptine mesylate offers potential benefit before the effects of irradiation are manifested. Parkinson’s Disease Bromocriptine mesylate tablets or capsules are indicated in the treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson’s disease.

As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor), bromocriptine mesylate therapy may provide additional therapeutic benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing “end of dose failure” on levodopa therapy.

, dyskinesias) and the marked swings in motor function (“on-off” phenomenon). Continued efficacy of bromocriptine mesylate therapy during treatment of more than 2 years has not been established. Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson’s disease with bromocriptine mesylate.

Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in bromocriptine mesylate-treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for bromocriptine mesylate therapy.

DOSAGE & ADMINISTRATION

General It is recommended that bromocriptine mesylate be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response. Hyperprolactinemic Indications The initial dosage of bromocriptine mesylate tablets in adults is one ½ to one 2½ mg scored tablet daily.

An additional 2½ mg tablet may be added to the treatment regimen as tolerated every 2 to 7 days until an optimal therapeutic response is achieved. 5-15 mg daily in adults studied clinically. Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is one ½ to one 2½ mg scored tablet daily.

Dosing may need to be increased as tolerated until a therapeutic response is achieved. 5-10 mg daily in children with prolactin-secreting pituitary adenomas. In order to reduce the likelihood of prolonged exposure to bromocriptine mesylate should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with bromocriptine mesylate therapy until normal ovulatory menstrual cycles have been restored.

Contraception may then be discontinued in patients desiring pregnancy. Thereafter, if menstruation does not occur within 3 days of the expected date, bromocriptine mesylate therapy should be discontinued and a pregnancy test performed.

Acromegaly Virtually all acromegalic patients receiving therapeutic benefit from bromocriptine mesylate also have reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic potential of bromocriptine mesylate.

If, after a brief trial with bromocriptine mesylate therapy, no significant reduction in growth hormone levels has taken place, careful assessment of the clinical features of the disease should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy should be considered.

The initial recommended dosage is one ½ to one 2½ mg bromocriptine mesylate tablet on retiring (with food) for 3 days. An additional one ½ to 1 bromocriptine mesylate tablet should be added to the treatment regimen as tolerated every 3 to 7 days until the patient obtains optimal therapeutic benefit.

Patients should be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical response. The usual optimal therapeutic dosage range of bromocriptine mesylate varies from 20-30 mg/day in most patients.

The maximal dosage should not exceed 100 mg/day. Patients treated with pituitary irradiation should be withdrawn from bromocriptine mesylate therapy on a yearly basis to assess both the clinical effects of radiation on the disease process as well as the effects of bromocriptine mesylate therapy.

Usually a 4 to 8 week withdrawal period is adequate for this purpose. Recurrence of the signs/symptoms or increases in growth hormone indicate the disease process is still active and further courses of bromocriptine mesylate should be considered.

Parkinson’s Disease The basic principle of bromocriptine mesylate therapy is to initiate treatment at a low dosage and, on an individual basis, increase the daily dosage slowly until a maximum therapeutic response is achieved. The dosage of levodopa during this introductory period should be maintained, if possible.

The initial dose of bromocriptine mesylate is one ½ of a 2½ mg bromocriptine mesylate tablet twice daily with meals. Assessments are advised at 2-week intervals during dosage titration to ensure that the lowest dosage producing an optimal therapeutic response is not exceeded.

If necessary, the dosage may be increased every 14 to 28 days by 2½ mg/day with meals. Should it be advisable to reduce the dosage of levodopa because of adverse reactions, the daily dosage of bromocriptine mesylate, if increased, should be accomplished gradually in small (2½ mg) increments.

The safety of bromocriptine mesylate has not been demonstrated in dosages exceeding 100 mg/day.

ADVERSE REACTIONS

Adverse Reactions from Clinical Trials Hyperprolactinemic Indications The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in degree. Therapy was discontinued in approximately 5% of patients because of adverse effects.

These in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%) and drowsiness (3%).

A slight hypotensive effect may accompany bromocriptine mesylate treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to ½ bromocriptine mesylate tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving bromocriptine mesylate for treatment of large prolactinomas.

This has occurred rarely, usually only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who were receiving bromocriptine mesylate for tumor recurrence. It may also occur in previously untreated patients whose tumor extends into the sphenoid sinus.

Acromegaly The most frequent adverse reactions encountered in acromegalic patients treated with bromocriptine mesylate were: nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%).

Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation of Raynaud’s syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation, faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial pallor and muscle cramps have been reported.

Parkinson’s Disease In clinical trials in which bromocriptine mesylate was administered with concomitant reduction in the dose of levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo.

Less common adverse reactions which may be encountered include: anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome.

Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance. Adverse Reactions from Postmarketing Experience The following adverse reactions have been reported during postapproval use of bromocriptine mesylate (All Indications Combined).

Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Psychiatric disorders:

Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality, and impulse control/compulsive behaviors (including gambling, spending, and other intense urges).

Nervous system disorders:

Headache, drowsiness, dizziness, dyskinaesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep.

Eye disorders:

Visual disturbance, vision blurred.

Ear and labyrinth disorders:

Tinnitus.

Cardiac disorders:

Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis.

Vascular disorders:

Hypotension, orthostatic hypotension (very rarely leading to syncope), reversible pallor of fingers and toes induced by cold (especially in patients with history of Raynaud's phenomenon).

Respiratory, thoracic and mediastinal disorders:

Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea.

Gastrointestinal disorders:

Nausea, constipation, vomiting, dry mouth, diarrhea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal hemorrhage.

Skin and subcutaneous tissue disorders:

Allergic skin reactions, hair loss.

Musculoskeletal and connective tissue disorders:

Leg cramps.

General disorders and administration site conditions:

Fatigue, peripheral oedema, a syndrome resembling Neuroleptic Malignant Syndrome on abrupt withdrawal of bromocriptine mesylate, withdrawal symptoms (including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain) with taper or after discontinuation (see Precautions) .

Adverse Events Observed in Other Conditions Postpartum Patients (see above Warnings) In postpartum studies with bromocriptine mesylate, 23 percent of postpartum patients treated had at least 1 side effect, but they were generally mild to moderate in degree.

Therapy was discontinued in approximately 3% of patients. 4%). Decreases in blood pressure (≥ 20 mm Hg systolic and ≥ 10 mm Hg diastolic) occurred in 28% of patients at least once during the first 3 postpartum days; these were usually of a transient nature.

Reports of fainting in the puerperium may possibly be related to this effect. , serious adverse reactions reported include 72 cases of seizures (including 4 cases of status epilepticus), 30 cases of stroke, and 9 cases of myocardial infarction among postpartum patients.

Seizure cases were not necessarily accompanied by the development of hypertension. An unremitting and often progressively severe headache, sometimes accompanied by visual disturbance, often preceded by hours to days many cases of seizure and/or stroke.

Most patients had shown no evidence of any of the hypertensive disorders of pregnancy including eclampsia, preeclampsia or pregnancy-induced hypertension. One stroke case was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis.

One case of myocardial infarction was associated with unexplained disseminated intravascular coagulation and a second occurred in conjunction with use of another ergot alkaloid. The relationship of these adverse reactions to bromocriptine mesylate administration has not been established.

In rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, or psychic disorders have been reported in postpartum women treated with bromocriptine mesylate. 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 bromocriptine mesylate. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of CNS toxicity develop, the administration of bromocriptine mesylate should be discontinued and the patient should be evaluated promptly.

, vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine and their concomitant use in the puerperium is not recommended. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc.

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CONTRAINDICATIONS

Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate, uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for hyperprolactinemia, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States) .

In the event that bromocriptine mesylate is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine mesylate must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy.

When bromocriptine mesylate is being used to treat acromegaly, prolactinoma, or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn.

If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine mesylate is considered to be medically contraindicated.

The drug should not be used during the postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions unless withdrawal is considered medically contraindicated. If the drug is used in the postpartum period, the patient should be observed with caution.

BROMOCRIPTINE (Bromocriptine Mesylate) is indicated for:  Galactorrhea with or without amenorrhea due to hyperprolactinemia. g. secondary amenorrhea, ovulatory insufficiency and short luteal phase.  Prolactin-secreting adenomas: as a treatment for inoperable macroadenomas or prior to surgery in order to facilitate removal, and as an alternative to surgery in patients with microadenomas.

 Prolactin-dependent male hypogonadism.  Acromegaly: the first-line treatment of this condition is by surgery or radiotherapy. BROMOCRIPTINE (bromocriptine mesylate) may be a useful adjunct to such treatment, and can be used as monotherapy in special cases.

 Parkinson’s Disease: BROMOCRIPTINE is effective when used as adjunct therapy to levodopa in the symptomatic management of Parkinson’s Disease. Used concomitantly with levodopa, bromocriptine facilitates the use of lower doses of levodopa in early disease and attenuates the rate of increase in the levodopa dosages on long-term usage.

In this way the risk of long– term complications such as prominent dyskinesias and/or end-of-dose failure can be reduced. 1 Pediatrics Pediatrics: Based on the data submitted and reviewed by Health Canada, the safety and efficacy of BROMOCRIPTINE in pediatric patients has not been established.

Therefore, Health Canada has not authorized an indication for pediatric use. See 5 OVERDOSAGE. 2 Geriatrics Geriatrics (> 65 years of age): The therapeutic experience in this population is limited. Therefore, BROMOCRIPTINE should be used with caution in geriatric patients.

1 Dosing Considerations BROMOCRIPTINE (bromocriptine mesylate) should always be taken with food. 5 mg (1/2 - 1 tablet), depending on the indication should be given at bedtime with food. Please consult the detailed dosage recommendations for each indication.

5 mg (1 tablet) twice daily with meals. 5 mg three times daily. Continue treatment until milk secretion has ceased completely or, in the case of menstrual dysfunction, until the menstrual cycle has returned to normal. 5 mg (1/2 to 1 tablet) at bedtime with food to establish tolerance.

Gradually increase after 2-3 days to one tablet twice daily with meals. 5 mg three times daily. 5 mg daily). If necessary to keep plasma prolactin adequately suppressed, dosage may be increased gradually over a period of several weeks to 10 - 20 mg (4 to 8 tablets or 2 to 4 capsules) daily with meals.

5 mg (1/2 to 1 tablet) at bedtime to establish tolerance. 5 mg three times per day with meals. 5 mg (1/2 to 1 tablet) at bedtime with food to establish tolerance, increasing gradually over a period of 2 to 4 weeks to 10 -20 mg (4 to 8 tablets or 2 to 4 capsules) daily with meals, depending on clinical response.

Daily requirements of 20 mg should be taken in four equally divided doses. For convenience and after initial titration, some patients may use the 5 mg capsules for maintenance therapy. 5 mg tablets or four 5 mg capsules). 25 mg (1/2 tablet) and increased again gradually to the recommended dose.

If reactions such as nausea, vomiting, vertigo or headaches continue to be severe, BROMOCRIPTINE should be discontinued.

Parkinson’s Disease:

BROMOCRIPTINE should be added to levodopa therapy. It is desirable to combine a slow increase of bromocriptine with a concomitant, limited and gradual reduction of levodopa. BROMOCRIPTINE dosage should be individualized. 25 mg (1/2 tablet) at bedtime to establish tolerance.

5 mg daily in two divided doses, with meals. 5 mg per day, once every 2 to 4 weeks, taken in 2 or 3 divided doses with meals. The maximum recommended daily dosage is 40 mg. Clinical assessments are recommended during dosage titration to ensure that the lowest effective dose is employed.

Where dose levels permit, use of the 5 mg capsule may be found more convenient by many patients.

Pediatrics:

Health Canada has not authorized an indication for pediatric use. 5 Missed Dose If the patient misses a dose, instruct the patient to take the dose as soon as they remember. If it is almost time for the next dose, inform the patient to skip the missed dose and continue the regular dosing schedule.

1 Adverse Reaction Overview The most frequently observed adverse reactions are nausea, vomiting, headache and gastrointestinal side effects such as abdominal pain, diarrhea and constipation. All these effects may be minimized or even prevented by giving small initial doses of bromocriptine and by taking it with food.

Postural hypotension can, on rare occasions, lead to fainting, and shock-like syndromes have been reported in sensitive patients. This is most likely to occur during the first few days of BROMOCRIPTINE (bromocriptine mesylate) treatment.

25 mg two or three times daily. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

In clinical studies to date, the following adverse reactions were noted:

In postpartum women treated with bromocriptine mesylate, some rare serious adverse events (about 1 in 100,000) have been reported. These include hypertension, visual disturbances, myocardial infarction, seizures and strokes, or psychic disorders.

In some patients, the occurrence of seizures or strokes was preceded by severe headache and/or visual disturbances. Causal relationship of these events to the drug is uncertain.

Amenorrhea/Galactorrhea/Female Infertility/Acromegaly:

The incidence of side effects in these indications is higher (68%), reflecting the larger doses required, but they are generally mild to moderate in degree. Therapy was discontinued in approximately 6% of patients because of adverse effects.

BROMOCRIPTINE (Bromocriptine Mesylate) Page 11 of 29 Table 2 - Adverse reactions reported in patients who received BROMOCRIPTINE for Amenorrhea/Galactorrhea/Female Infertility/Acromegaly BROMOCRIPTINE (%) Gastrointestinal disorders nausea abdominal cramps vomiting constipation diarrhea 51% 7% 5% 3% 3% General disorders and administration site conditions fatigue 8% Nervous system disorders headache dizziness lightheadedness 18% 16% 6% Respiratory, thoracic and mediastinal disorders nasal congestion 5% USE IN COMBINATION WITH OTHER DRUGS: Parkinson’s Disease: When bromocriptine is added to levodopa therapy, the incidence of adverse reactions may increase.

The most common newly appearing adverse reactions in combination therapy with levodopa are: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off” phenomenon, dizziness, drowsiness, faintness, fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation and vertigo.

3 Less Common Clinical Trial Adverse Reactions General: Less common adverse reactions include, anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizures, fatigue, headache, lethargia, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, changes in urinary frequency, urinary incontinence, urinary retention and rarely signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome.

4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings Abnormalities in laboratory tests may include elevation of blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance.

5 Post-Market Adverse Reactions The following adverse reactions have been reported during post approval use of BROMOCRIPTINE (All Indications Combined). Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders:

Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis.

Eye disorders:

Visual disturbance, vision blurred.

Ear and labyrinth disorders:

Tinnitus.

Gastrointestinal disorders:

Nausea, constipation, vomiting, dry mouth, diarrhoea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal haemorrhage.

General disorders and administration site conditions:

Fatigue, peripheral edema, a syndrome resembling Neuroleptic Malignant Syndrome on abrupt withdrawal of BROMOCRIPTINE.

Musculoskeletal and connective tissue disorders:

Leg cramps.

Nervous system disorders:

Headache, drowsiness, dizziness, dyskinaesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep.

Psychiatric disorders:

Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality.

Respiratory, thoracic and mediastinal disorders:

Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea.

Skin and subcutaneous tissue disorders:

Allergic skin reactions, hair loss.

Vascular disorders:

Hypotension, orthostatic hypotension (very rarely leading to syncope), reversible pallor of fingers and toes induced by cold (especially in patients with history of Raynaud's phenomenon).

BROMOCRIPTINE is contraindicated in:  Patients with sensitivity to ergot alkaloids or to any ingredient in the formulation, including any non- medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

 Patients with uncontrolled hypertension of pregnancy.  Patients who had a history of toxemia of pregnancy. BROMOCRIPTINE (Bromocriptine Mesylate) Page 5 of 29