Parlodel® (bromocriptine mesylate) is an ergot derivative with potent dopamine receptor agonist activity. Each Parlodel® (bromocriptine mesylate) SnapTabs® tablet for oral administration contains 2½ mg and each capsule contains 5 mg bromocriptine (as the mesylate). Bromocriptine mesylate is chemically designated as Ergotaman-3′,6′,18-trione, 2-bromo-12′-hydroxy-2′- (1-methylethyl)-5′-(2-methylpropyl)-, (5′α)-monomethanesulfonate (salt).

The structural formula is:

2½ mg SnapTabs®

Active Ingredient: bromocriptine mesylate, USP

Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch, and another ingredient

5 mg Capsules

Active Ingredient: bromocriptine mesylate, USP

Inactive Ingredients: colloidal silicon dioxide, gelatin, lactose, magnesium stearate, red iron oxide, silicon dioxide, sodium lauryl sulfate, starch, titanium dioxide, yellow iron oxide, and another ingredient

Last updated on RxList: 5/9/2008

Hyperprolactinemia-Associated Dysfunctions

Parlodel® (bromocriptine mesylate) is indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Parlodel 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 Parlodel therapy may be used to reduce the tumor mass prior to surgery.

Acromegaly

Parlodel therapy is indicated in the treatment of acromegaly. Parlodel 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 Parlodel offers potential benefit before the effects of irradiation are manifested.

Parkinson's Disease

Parlodel SnapTabs® 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), Parlodel 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. Parlodel therapy may permit a reduction of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of adverse reactions associated with long-term levodopa therapy such as abnormal involuntary movements (e.g., dyskinesias) and the marked swings in motor function ("on-off'' phenomenon). Continued efficacy of Parlodel 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 Parlodel. Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in Parlodel-treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for Parlodel therapy.

General

It is recommended that Parlodel® (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 Parlodel SnapTabs® in adults is ½ to one 2½ mg scored tablet daily. An additional 2½ mg tablet may be added to the treatment regimen as tolerated every 2-7 days until an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily in adults studied clinically.

Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is ½ to one 2½ mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-secreting pituitary adenomas.

In order to reduce the likelihood of prolonged exposure to Parlodel should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with Parlodel 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, Parlodel therapy should be discontinued and a pregnancy test performed.

Acromegaly

Virtually all acromegalic patients receiving therapeutic benefit from Parlodel 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 Parlodel. If, after a brief trial with Parlodel 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 ½ to one 2½ mg Parlodel SnapTabs tablet on retiring (with food) for 3 days. An additional ½ to 1 SnapTabs tablet should be added to the treatment regimen as tolerated every 3-7 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 Parlodel 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 Parlodel therapy on a yearly basis to assess both the clinical effects of radiation on the disease process as well as the effects of Parlodel therapy. Usually a 4-8 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 Parlodel should be considered.

Parkinson's Disease

The basic principle of Parlodel 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 Parlodel is ½ of a 2½ mg SnapTabs 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 14-28 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 Parlodel, if increased, should be accomplished gradually in small (2½ mg) increments.

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

Parlodel® (bromocriptine mesylate) SnapTabs®
2½ mg

Round, off-white, bevelled-edge SnapTabs®, each containing 2½ mg bromocriptine (as the mesylate). Engraved "PARLODEL 2½'' on one side and scored on reverse side. Complies with USP dissolution test 1.

Packages of 30................................NDC 0078-0017-15
Packages of 100..............................NDC 0078-0017-05

Parlodel® (bromocriptine mesylate) Capsules
5 mg

Caramel and white capsules, each containing 5 mg bromocriptine (as the mesylate). Imprinted in red ink "PARLODEL 5 mg'' on one half and " A '' on other half.

Packages of 30................................NDC 0078-0102-15
Packages of 100..............................NDC 0078-0102-05

Store and Dispense

Below 25ºC (77ºF); tight, light-resistant container.

REV: MAY 2006. Manufactured by: Novartis Pharmaceuticals Corporation., Suffern, New York 10901. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. FDA rev date: 11/9/2005

Last updated on RxList: 5/9/2008

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 Parlodel® (bromocriptine mesylate) treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to ½ SnapTabs® tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving Parlodel 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 Parlodel 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 Parlodel 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 Parlodel 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

Pleural and pericardial effusions, pleural, and pulmonary fibrosis or retroperitoneal fibrosis and constrictive pericarditis have been reported rarely in patients treated with Parlodel.

Very rarely, a syndrome resembling Neuroleptic Malignant Syndrome has been reported on abrupt withdrawal of Parlodel.

Blurred vision, dyskinesia, and psychomotor agitation/excitation have also occurred in postmarketing experiences.

Adverse Events Observed in Other Conditions

Postpartum Patients

In postpartum studies with Parlodel, 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. The most frequently occurring adverse reactions were: headache (10%), dizziness (8%), nausea (7%), vomiting (3%), fatigue (1.0%), syncope (0.7%), diarrhea (0.4%) and cramps (0.4%). 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. In postmarketing experience in the U.S., 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 Parlodel administration has not been established.

The risk of using Parlodel in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of Parlodel. Parlodel may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of Parlodel: phenothiazines, haloperidol, metoclopramide, pimozide. Bromocriptine is both a substrate and an inhibitor of CYP3A4. Caution should therefore be used when coadministering drugs that are strong inhibitors and/or substrates of this enzyme (azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin 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. Concomitant use of Parlodel with other ergot alkaloids is not recommended.

Last updated on RxList: 5/9/2008

Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients with pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with Parlodel® (bromocriptine mesylate).

If pregnancy occurs during Parlodel administration, careful observation of these patients is mandatory. Prolactin-secreting adenomas may expand and compression of the optic or other cranial nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the compression resolves following delivery. Reinitiation of Parlodel treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy. The safety of Parlodel treatment during pregnancy to the mother and fetus has not been established.

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.

Symptomatic hypotension can occur in patients treated with Parlodel for any indication. In postpartum studies with Parlodel, decreases in supine systolic and diastolic pressures of greater than 20 mm and 10 mm Hg, respectively, have been observed in almost 30% of patients receiving Parlodel. On occasion, the drop in supine systolic pressure was as much as 50-59 mm of Hg.

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.

While hypotension during the start of therapy with Parlodel occurs in some patients, in postmarketing experience in the U.S. in postpartum patients 89 cases of hypertension have been reported, sometimes at the initiation of therapy, but often developing in the second week of therapy; seizures have been reported in 72 cases (including 4 cases of status epilepticus), both with and without the prior development of hypertension; 30 cases of stroke have been reported mostly in postpartum patients whose prenatal and obstetric courses had been uncomplicated. Many of these patients experiencing seizures and/or strokes reported developing a constant and often progressively severe headache hours to days prior to the acute event. Some cases of strokes and seizures were also preceded by visual disturbances (blurred vision, and transient cortical blindness). Nine cases of acute myocardial infarction have been reported.

Although a causal relationship between Parlodel administration and hypertension, seizures, strokes, and myocardial infarction in postpartum women has not been established, use of the drug for prevention of physiological lactation, or in patients with uncontrolled hypertension is not recommended. In patients being treated for hyperprolactinemia, Parlodel should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that Parlodel 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 Parlodel must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When Parlodel is being used to treat acromegaly 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 Parlodel is considered to be medically contraindicated. Because of the possibility of an interaction between Parlodel and other ergot alkaloids, the concomitant use of these medications is not recommended. Periodic monitoring of the blood pressure, particularly during the first weeks of therapy is prudent. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops, drug therapy should be discontinued and the patient should be evaluated promptly. Particular attention should be paid to patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure. Their concomitant use in the puerperium is not recommended.

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 considered. In those instances in which Parlodel treatment was terminated, the changes slowly reverted towards normal.

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.

General

Safety and efficacy of Parlodel® (bromocriptine mesylate) have not been established in patients with renal or hepatic disease. Care should be exercised when administering Parlodel therapy concomitantly with other medications known to lower blood pressure.

The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson's disease are being treated with Parlodel during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease.

Patients with rare hereditary problems of galactose intolerance, the severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hyperprolactinemic States

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 normalized prolactin levels and tumor 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 tumor 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.

The relative efficacy of Parlodel versus surgery in preserving visual fields is not known. Patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy.

Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive measures, other than oral contraceptives, during treatment with Parlodel. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with Parlodel SnapTabs® or capsules should be discontinued as soon as pregnancy has been established. Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of Parlodel treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases.

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 tumors.

Acromegaly

Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with Parlodel. The response, should it occur, can be reversed by reducing the dose of Parlodel and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal. Although there is no evidence that Parlodel increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with Parlodel.

Possible tumor expansion while receiving Parlodel therapy has been reported in a few patients. Since the natural history of growth hormone-secreting tumors is unknown, all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered.

Parkinson's Disease

Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been established.

As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal function is recommended. Symptomatic hypotension can occur and, therefore, caution should be exercised when treating patients receiving antihypertensive drugs.

High doses of Parlodel may be associated with confusion and mental disturbances. Since parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients.

Parlodel administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of Parlodel is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of Parlodel.

As with levodopa, caution should be exercised when administering Parlodel to patients with a history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia.

Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2-10 years) with Parlodel in doses ranging from 30-140 mg daily.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes.

Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice.

No mutagenic effects were obtained in any of these tests.

Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg).

Pregnancy

Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6-15 postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6-15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period.

Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced.

No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg.

Information concerning 1276 pregnancies in women taking Parlodel has been collected. In the majority of cases, Parlodel was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg).

Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11%-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin.

Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%.

The incidence of birth defects in the population at large ranges from 2%-4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%.

There is no suggestion that Parlodel contributed to the type or incidence of birth defects in this group of infants.

Nursing Mothers

Parlodel should not be used during lactation in postpartum women.

Pediatric Use

The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response.

The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation.

Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section.

Geriatric Use

Clinical studies for Parlodel did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking Parlodel has been observed, greater sensitivity of 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.

Last updated on RxList: 5/9/2008

The most commonly reported signs and symptoms associated with acute Parlodel® (bromocriptine mesylate) overdose are: nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established and the drug has a very wide margin of safety. However, one death occurred in a patient who committed suicide with an unknown quantity of Parlodel and chloroquine.

Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering I.V. fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered.

Hypersensitivity to bromocriptine or to any of the excipients of Parlodel® (bromocriptine mesylate), uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for hyperprolactinemia, Parlodel should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that Parlodel 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 Parlodel must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When Parlodel 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 Parlodel 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.

Last updated on RxList: 5/9/2008

Parlodel® (bromocriptine mesylate) is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, Parlodel significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces longlasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors.

Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients.

In about 75% of cases of amenorrhea and galactorrhea, Parlodel therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles.

Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6-8 weeks. However, some patients respond within a few days, and others may take up to 8 months.

Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8-12 weeks. Some patients may fail to respond even after 12 months of therapy.

In many acromegalic patients, Parlodel produces a prompt and sustained reduction in circulating levels of serum growth hormone.

Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson's disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population.

Pharmacokinetics

The pharmacokinetics and metabolism of bromocriptine in human subjects were studied with the help of radioactively labeled drug. Twenty-eight percent of an oral dose was absorbed from the gastrointestinal tract. The blood levels following a 2½mg dose were in the range of 2-3 ng equivalents/mL. Plasma levels were in the range of 4-6 ng equivalents/mL indicating that the red blood cells did not contain appreciable amounts of drug and/or metabolites. In vitro experiments showed that the drug was 90%-96% bound to serum albumin.

When tablets or standard capsules are administered to healthy volunteers, the absorption half-life is 0.2 to 0.5 hours, and the peak plasma levels of bromocriptine are reached within 1 to 3 hours. An oral dose of 5 mg of bromocriptine results in a Cmax 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.

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 µM. However, given the low therapeutic concentrations of free bromocriptine in patients, a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected.

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, and only 6% eliminated via the kidney.

In patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase requiring dose adjustment.

Last updated on RxList: 5/9/2008

During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of Parlodel therapy. In postmarketing reports, 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. All patients receiving Parlodel should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with Parlodel 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 (e.g., operating machines) until such recurrent episodes and somnolence have resolved.

Patients receiving Parlodel for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery, should be told to report any persistent watery nasal discharge to their physician. Patients receiving Parlodel for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms.

Last updated on RxList: 5/9/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

BROMOCRIPTINE - ORAL

(brom-oh-KRIP-teen)

COMMON BRAND NAME(S): Parlodel

USES: This medication is used alone or with other medications (e.g., levodopa) to treat Parkinson's disease. It can improve your ability to move and decrease shakiness (tremor), stiffness, slowed movement, and unsteadiness. It may also decrease the number of episodes of not being able to move ("on-off syndrome").

Bromocriptine is also used to treat hormonal problems caused by high levels of a certain chemical made by the body (prolactin). Such problems include unwanted breast milk, missed/stopped periods, difficulty becoming pregnant, decreased sperm production, and decreased sexual ability. Because of possible serious side effects (e.g., high blood pressure, seizure, heart attack, stroke), bromocriptine is not recommended for stopping unwanted breast milk after pregnancy, miscarriage, or abortion.

This medication is also used alone or with other treatments to lower high growth hormone levels (acromegaly). Bromocriptine is also used to treat prolactin-secreting tumors. It may be used to reduce the tumor size before surgery or to control symptoms until other treatments start working.

Bromocriptine is an ergot medication that works by helping to restore the balance of a certain natural substance (dopamine) in the brain. It also prevents the release of certain hormones (growth hormone, prolactin). Bromocriptine can lower these hormone levels, but it does not cure the causes of the increased levels.

HOW TO USE: Take this medication by mouth with food, usually 1-2 times a day or as directed by your doctor. Your doctor may start your treatment at a lower dose and gradually increase it to find the best dose for you. This medication often causes dizziness, especially just after the first dose. Lie down immediately after taking your first dose to reduce the risk of injury from falling.

The dosage is based on your medical condition, the condition being treated, and your response to therapy.

Take this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time(s) each day.

For Parkinson's disease, your doctor will adjust your dose based on your symptoms and side effects. Your doctor may direct you to lower your levodopa dose after you start this medication. Do not change or stop your medication without talking with your doctor first.

For high prolactin levels, it may take 6-8 weeks for the effects of high prolactin to decrease. It may take up to 12 months before you get the full benefit of this medication.

For acromegaly, your doctor will monitor your growth hormone levels and adjust the dose.

Do not stop taking this medication without your doctor's approval. If you suddenly stop taking this drug, withdrawal reactions may occur. Such reactions can include fever, muscle stiffness, and confusion. Report any such reactions to your doctor immediately. When stopping extended, regular treatment with this drug, gradually reducing the dosage as directed will help prevent withdrawal reactions. Consult your doctor or pharmacist for more details.

Tell your doctor if your symptoms do not improve or if they worsen.

SIDE EFFECTS: Nausea, constipation, dizziness, drowsiness, loss of appetite, vomiting, diarrhea, and headache may occur. If any of these effects persist or worsen, tell your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Some people taking bromocriptine have reported falling asleep suddenly during their usual daily activities (e.g., talking on the phone, driving). In some cases, sleep occurred without any feelings of drowsiness beforehand. Therefore, you should not drive or take part in other possibly dangerous activities until you are certain that this medication will not cause drowsiness or sudden sleep. If you experience increased sleepiness or fall asleep during the day, do not drive or take part in other possibly dangerous activities until you have discussed this effect with your doctor. Your risk is increased with use of alcohol or other medications that can make you drowsy.

You may also develop a sudden drop in blood pressure. This effect can cause dizziness, nausea, and fainting. A drop in blood pressure is more likely when you are first starting the medication, when your dose is increased, or when you get up suddenly. To lower your risk, get up slowly from a sitting or lying position.

Tell your doctor immediately if any of these unlikely but serious side effects occur: back pain, cold/slightly blue fingers/toes, mental/mood changes (e.g., depression, confusion, hallucinations, restlessness), trouble sleeping, constant watery discharge from the nose, stomach pain, swelling of the legs/ankles/feet, change in the amount of urine, tingling/numbness of hands/feet.

Seek immediate medical attention if any of these rare but very serious side effects occur: difficult/painful breathing, bloody/black/tarry stools, chest pain, fast/irregular/pounding heartbeat, severe or persistent headache, seizure, slurred speech, weakness on one side of the body, vision problems (e.g., decreased/blurred vision), vomit that looks like coffee grounds.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking bromocriptine, tell your doctor or pharmacist if you are allergic to it; or to other ergot medications (e.g., ergonovine, pergolide); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: certain genetic enzyme problems (galactose intolerance, lactase deficiency, glucose-galactose malabsorption), uncontrolled high blood pressure.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood flow problems (e.g., peripheral vascular disease, Raynaud's disease), low blood pressure, breathing problems (e.g., pulmonary fibrosis), gastrointestinal bleeding (e.g., peptic ulcer), heart problems (e.g., coronary artery disease, angina, heart attack, irregular heartbeat), kidney disease, liver disease, mental/mood disorders (e.g., depression, psychosis, schizophrenia, dementia), recent pregnancy (especially with high blood pressure).

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness. Avoid alcoholic beverages.

Bromocriptine can decrease blood circulation in the fingers and toes, especially during exposure to cold, increasing the risk of damage (e.g., frostbite). Keep hands and feet warm during cold weather.

During pregnancy, this medication should be used only when clearly needed. This medication can cause a dangerous increase in blood pressure during pregnancy. Discuss the risks and benefits with your doctor. If you are using this medication to make your periods regular and you are sexually active, a pregnancy test is recommended at least once every 4 weeks. Once your period has restarted, pregnancy tests are recommended every time you miss a period. Discuss non-hormonal birth control methods (e.g., condom, diaphragm) with your doctor. If you become pregnant or think you may be pregnant, tell your doctor immediately.

This drug may affect breast milk production. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: ergot alkaloids (e.g., ergonovine), "triptans" (e.g., sumatriptan, frovatriptan).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting bromocriptine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: medications for high blood pressure (e.g., methyldopa, reserpine, beta blockers such as metoprolol/propranolol), antipsychotic medication (e.g., haloperidol, pimozide), metoclopramide, nitrates (e.g., nitroglycerin), octreotide, drugs affecting liver enzymes that remove bromocriptine from your body (such as cimetidine, delavirdine, efavirenz, telithromycin, azole antifungals including ketoconazole, macrolide antibiotics including erythromycin, HIV protease inhibitors such as ritonavir, rifamycins including rifabutin, St. John's wort, certain anti-seizure medicines including carbamazepine).

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., phenytoin), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, nortriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood pressure, complete blood count, eye exams, kidney/liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the US product below 77 degrees F (25 degrees C) away from moisture and sunlight. Do not store in the bathroom.

Store the Canadian product between 59-86 degrees F (15-30 degrees C) away from moisture and sunlight. Do not store in the bathroom.

Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.