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PERRIGO CO.
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00574010601

bromocriptine 2.5 mg tablet (generic parlodel)

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Uses

Hyperprolactinemic Disorders

Bromocriptine is used in males and females for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea, with or without galactorrhea; hypogonadism; and infertility. The drug is used in patients with prolactin-secreting adenomas (e.g., prolactinoma), including macroadenomas; this tumor may be the basic underlying endocrinopathy contributing to dysfunctions associated with hyperprolactinemia. The drug has decreased tumor size in both males and females with macroadenomas and may be used to reduce tumor size prior to surgery in patients undergoing excision of the tumor (adenectomy).

Amenorrhea and Galactorrhea

Bromocriptine mesylate is used for the short-term treatment of amenorrhea and/or galactorrhea associated with hyperprolactinemia of various etiologies. Bromocriptine reduces serum prolactin concentrations in patients with prolactin-secreting adenomas; however, use of the drug in these patients does not obviate the need for radiotherapy or surgery when indicated. Although bromocriptine may be effective in restoring menses in some patients with prolactin-secreting tumors and may decrease tumor growth during pregnancy in patients who have had partial surgical tumor removal, the risks associated with the use of the drug in these patients should be considered. (See Cautions: Pregnancy and Lactation and also Carcinogenicity.) Bromocriptine is not effective in patients with ovarian failure or inadequate concentrations of gonadotropin. Bromocriptine is not indicated in patients with normal prolactin concentrations although it is effective in the treatment of amenorrhea and/or galactorrhea in some of these patients. Treatment with bromocriptine mesylate is not curative. Following discontinuance of bromocriptine therapy, the recurrence rate of amenorrhea and/or galactorrhea is 70-80%.

Male Hypogonadism and Galactorrhea

Bromocriptine has been used effectively in hyperprolactinemic males with prolactin-secreting adenomas (e.g., prolactinoma) and adequate concentrations of testosterone to treat hypogonadism and galactorrhea which persisted following radiation therapy or surgery. Recent studies indicate that bromocriptine therapy, in addition to relieving symptoms of the disease, also results in a reduction in the size of prolactin-secreting adenomas in most patients. Some clinicians suggest that bromocriptine may be the treatment of choice for hyperprolactinemic males with large tumors (macroadenomas).

Female Infertility

Bromocriptine is used to induce ovulation in appropriately selected anovulatory women desiring pregnancy. Although the manufacturer states that bromocriptine is indicated in the treatment of female infertility associated with hyperprolactinemia in the absence of a demonstrable pituitary tumor, some clinicians state that bromocriptine is the treatment of choice to restore fertility in selected patients with prolactin-secreting adenomas. Bromocriptine restores ovulation without ovarian hyperstimulation and the risk of multiple ovulations with resulting plural gestations. However, bromocriptine probably should be reserved for patients who are not responsive to clomiphene, menotropins with chorionic gonadotropin, or estrogens. In some anovulatory women requiring concomitant treatment with 100-150 mg of clomiphene citrate and chorionic gonadotropin to induce ovulation, bromocriptine and a lower dosage of clomiphene have been used effectively to induce ovulation.

Parkinsonian Syndrome

Bromocriptine is used for the treatment of idiopathic or postencephalitic parkinsonian syndrome.

Dopamine receptor agonists (bromocriptine mesylate, pramipexole dihydrochloride, pergolide mesylate, ropinirole hydrochloride) are used as adjuncts to levodopa for the symptomatic management of parkinsonian syndrome in patients with advanced disease. Dopamine receptor agonists also are used as monotherapy for the initial symptomatic management of parkinsonian syndrome. Levodopa currently is the most effective drug for relieving the symptoms of parkinsonian syndrome and traditionally has been considered the drug of choice for the initial symptomatic management of idiopathic parkinsonian syndrome. However, long-term administration of levodopa is associated with motor complications. One strategy to reduce the risk of motor complications and to improve long-term outcome is to initiate symptomatic therapy with a dopamine receptor agonist and to add levodopa as supplemental therapy when dopamine receptor agonist monotherapy no longer provides adequate symptom control. However, clinical studies evaluating this strategy are limited both in number and duration, and it remains to be determined whether initiating therapy with a dopamine receptor agonist rather than levodopa results in a more favorable long-term outcome. Factors to consider when choosing an agent for the initial symptomatic management of idiopathic parkinsonian syndrome include patient age, cognitive status, disease severity, and cost. Most clinicians would use levodopa for initial therapy in individuals older than 70 years of age since these individuals are less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction, in patients with cognitive impairment, and in those with severe disease. A dopamine receptor agonist may be preferred for initial therapy in patients 70 years of age or younger.

In controlled, double-blind studies in patients receiving optimum treatment of parkinsonian syndrome which included levodopa therapy, addition of bromocriptine allowed a gradual reduction in levodopa (with or without carbidopa) dosage. When used in conjunction with levodopa (alone or with a peripheral decarboxylase inhibitor), bromocriptine may provide additional therapeutic benefits in patients who are currently maintained on optimal dosages of levodopa, patients who are beginning to develop tolerance to levodopa, and patients who are experiencing ''end-of-dose failure'' on levodopa therapy. In several controlled studies, bromocriptine was as effective as levodopa (with or without carbidopa) when bromocriptine was substituted for levodopa in patients who were well controlled on levodopa therapy. Patients unresponsive to levodopa are poor candidates for bromocriptine therapy. Data are insufficient to evaluate the potential benefits of bromocriptine in patients with newly diagnosed parkinsonian syndrome. A higher incidence of adverse effects (e.g., nausea, hallucinations, confusion, hypotension) have been reported in patients receiving bromocriptine than in patients receiving levodopa and carbidopa; however, bromocriptine has a longer duration of action and causes the ''on-off'' phenomenon less often than does levodopa. Bromocriptine may be useful in patients who are unable to tolerate levodopa's adverse effects or when levodopa is ineffective; however, continued efficacy of bromocriptine for more than 2 years has not been established and long-term or high-dose bromocriptine therapy has caused adverse effects such as erythromelalgia and psychosis. (See Cautions: Nervous System Effects.) Further study is required to determine the precise role of bromocriptine in the treatment of parkinsonian syndrome and to establish safety and efficacy of the drug during long-term administration.

Acromegaly

Bromocriptine is used in the treatment of acromegaly. Although bromocriptine is not effective in all patients with acromegaly, the drug has reduced growth hormone concentrations in some patients. Reduction in growth hormone concentrations in these patients is associated with abolition of excessive sweating, reduction in soft tissue thickening, improvement in facial features, improvement in glucose tolerance, and reduction in urinary hydroxyproline excretion. However, further studies are required to determine the long-term effectiveness of bromocriptine in the treatment of acromegaly and to determine which patients may respond to the drug.

Other Uses

Although bromocriptine had been used to prevent lactation after stillbirth or abortion or when breast-feeding was contraindicated or the mother elected not to breast-feed, such use has been controversial (e.g., because of the low incidence of substantial painful engorgement, cost considerations, efficacy of appropriate supportive therapy, and concerns about potentially fatal toxicity) despite efficacy of the drug in inhibiting lactogenesis and the subsequent development of secretion, congestion, and engorgement. In addition, such use of bromocriptine no longer is recommended because of the risks of serious adverse effects (e.g., hypertension, seizures, myocardial infarction, cerebrovascular accidents, which may be fatal) nor is it included in the current US labeling for the drug. In 1994, the US Food and Drug Administration (FDA) proposed formally to withdraw approval of this indication based on accumulating reports of potentially fatal, serious adverse effects. The manufacturer of the drug (Sandoz) subsequently agreed voluntarily to withdraw the mentioned use for lactation prevention from their labeling, and FDA's approval withdrawal was finalized in February 1995. Although the absolute incidence and relative risk of associated serious effects remain to be clearly defined, the decision of FDA to seek withdrawal was based, in part, on conclusions by FDAs Fertility and Maternal Health Drugs Advisory Committee that the possible risks of serious adverse effects outweigh the limited benefits associated with the use of bromocriptine in postpartum breast engorgement, a temporary condition, that can be managed by more conservative treatments (e.g., cold packs, compression bandages, analgesics).

Bromocriptine has been used to relieve premenstrual breast symptoms (e.g., swelling, discomfort, discharge), edema, weight gain, migraine headache, and changes in mood.

Bromocriptine has been used to restore fertility in oligospermic men without hyperprolactinemia. Unlike traditional therapy with fluoxymesterone, testosterone, or chorionic gonadotropin, bromocriptine may increase sperm counts both during and after treatment. However, unless these patients are unresponsive to traditional drug therapy, bromocriptine should not be used since safety and efficacy of the drug for the management of this condition have not been established.

Bromocriptine has been used with some success in the treatment of neuroleptic malignant syndrome (NMS) associated with neuroleptic drug therapy (e.g., haloperidol, fluphenazine). In a limited number of patients, bromocriptine has relieved extrapyramidal reactions, hyperthermia, and hypertension associated with NMS.

In a limited number of patients, bromocriptine has been used effectively in the management of Cushing's disease or chronic hepatic encephalopathy.

Bromocriptine is not effective in the management of Huntington's chorea.

Dosage and Administration

Administration

Bromocriptine mesylate is administered orally with food.

Dosage

Dosage of bromocriptine mesylate is expressed in terms of bromocriptine. Dosage of bromocriptine should be individualized and carefully adjusted, using frequent evaluation during dosage adjustment and employing the lowest possible effective dosage. A temporary reduction in dosage or discontinuance of the drug may occasionally be necessary in patients who develop intolerable adverse effects.

When bromocriptine therapy is discontinued (e.g., during pregnancy) in patients receiving the drug for hyperprolactinemic disorders, the patient should be carefully monitored for signs and symptoms of tumor development or progression. (See Cautions: Carcinogenicity.) Patients receiving bromocriptine for the treatment of macroadenoma should be warned to not discontinue the drug unless otherwise directed by their physician, since such discontinuance could result in rapid regrowth of the tumor and recurrence of symptoms.

The safety of bromocriptine dosages exceeding 100 mg daily has not been established.

Hyperprolactinemic Disorders

The usual initial adult dosage of bromocriptine for the treatment of dysfunctions associated with hyperprolactinemia such as amenorrhea, galactorrhea, hypogonadism, and/or infertility in males and females is 1.25 or 2.5 mg daily. Dosage may be increased in increments of 2.5 mg daily at 3- to 7-day intervals as tolerated until the desired therapeutic response is achieved. The usual therapeutic dosage in these patients is 5-7.5 mg daily but ranges from 2.5-15 mg daily. Up to 30 mg daily has been required in some patients with amenorrhea and/or galactorrhea. For the treatment of hypogonadism in hyperprolactinemic males, dosages up to 40 mg daily have occasionally been used.

To reduce the possibility of prolonged exposure to bromocriptine in an unsuspected pregnancy during initial therapy with the drug in women in whom one of the goals of therapy is successful pregnancy, a mechanical contraceptive should be used in conjunction with bromocriptine therapy until normal ovulatory menstrual cycles have been restored. Contraception can then be discontinued. If menstruation does not occur within 3 days of the expected date, bromocriptine should be discontinued and a pregnancy test performed. Women not desiring pregnancy and women with large adenomas should use a mechanical contraceptive throughout bromocriptine therapy. (See Cautions: Carcinogenicity.)

Parkinsonian Syndrome

For the treatment of parkinsonian syndrome, bromocriptine therapy is initiated at a low dosage and increased slowly until the maximum therapeutic response is achieved. The usual initial adult dosage of bromocriptine for the treatment of parkinsonian syndrome is 1.25 mg twice daily. In patients receiving levodopa, therapy with the drug should be continued, if possible, during initiation of bromocriptine therapy. Assessments of the patient's therapeutic response are generally made at 2-week intervals to ensure that the lowest effective dosage is not exceeded. If necessary, dosage may be increased by 2.5 mg daily every 14-28 days. If levodopa dosage must be decreased because of adverse effects, daily dosage of bromocriptine may be increased gradually in 2. 5-mg increments. The manufacturer states that safety of bromocriptine in dosages greater than 100 mg daily has not been established.

Acromegaly

To reduce growth hormone concentrations in adults with acromegaly, the usual initial bromocriptine dosage is 1.25 or 2.5 mg daily at bedtime for 3 days. Dosage may be increased in increments of 1.25 or 2.5 mg daily at 3- to 7-day intervals until the desired therapeutic effect is achieved. The usual therapeutic dosage in these patients is 20-30 mg daily; the manufacturer states that dosage should not exceed 100 mg daily. Dosages of 20-60 mg of bromocriptine have been administered daily in divided doses.

Serum growth hormone concentrations should be determined monthly, and bromocriptine dosage should be adjusted based on the reduction in these concentrations and the patient's clinical response. If an adequate response is not apparent after a brief trial with the drug and/or dosage adjustment and clinical evaluation, discontinuance of bromocriptine should be considered. Bromocriptine therapy should be withdrawn annually in patients undergoing radiation therapy of the pituitary to determine if continued therapy with the drug and/or radiation is necessary. Usually, a 4- to 8-week period is adequate; if signs and/or symptoms of acromegaly recur or growth hormone concentrations increase during this period, the disease process is probably still active and additional bromocriptine therapy should be considered.

Other Uses

Premenstrual symptoms have been treated with 2.5-7.5 mg of bromocriptine twice daily from the tenth day of the menstrual cycle until onset of menstruation.

For the treatment of neuroleptic malignant syndrome (NMS) associated with neuroleptic drug therapy (e.g., haloperidol, fluphenazine), 2.5-5 mg of bromocriptine has been given 2-6 times daily.

For the treatment of Cushing's disease, 1.25-2.5 mg of bromocriptine has been given 2-4 times daily. For the treatment of chronic hepatic encephalopathy, the initial dosage of bromocriptine was 1.25 mg daily followed by increases of 1.25 mg daily every third day up to a total maintenance dosage of 15 mg daily.

Cautions

The incidence of adverse effects associated with bromocriptine mesylate therapy is quite high, especially at the beginning of treatment and with dosages greater than 20 mg daily. Adverse effects are usually mild to moderate and can be minimized by starting with small doses, increasing dosage gradually to effective levels, and administering the drug with food and in the evening. Generally, adverse effects are decreased when dosage is reduced and then increased more gradually, although treatment with bromocriptine may have to be discontinued in a few patients because of adverse effects. Healthy individuals seem to be the most sensitive to adverse effects, while patients with hyperprolactinemia and acromegaly are not as sensitive, and women immediately postpartum experience minimal adverse effects. About 70% of patients receiving the drug for hyperprolactinemic disorders experience adverse effects; discontinuance of the drug was necessary in 5% of such patients.

GI Effects

Nausea occurs frequently in patients receiving bromocriptine. Nausea has been reported in about 50 or 20% of patients receiving the drug for hyperprolactinemic disorders or acromegaly, respectively. Vomiting, anorexia, abdominal cramps or discomfort, epigastric pain, indigestion or dyspepsia, constipation during long-term use, or diarrhea occurs less frequently. These adverse GI effects may be relieved by temporary reduction of dosage or administration of the drug with food. Dysphagia has occurred occasionally in patients receiving the drug for parkinsonian syndrome. Some patients receiving bromocriptine have developed peptic ulcer, possibly as a result of increased gastric acid secretion; GI hemorrhage has also been reported.

Nervous System Effects

Adverse nervous system effects of bromocriptine include headache, migraine, dizziness, drowsiness, fatigue, insomnia, lightheadedness, faintness, fainting, and sedation. Headache or dizziness occurs in about 20 or less than 2% of patients receiving the drug for hyperprolactinemic disorders or acromegaly, respectively. Confusion, hallucinations, delusions (usually paranoid), nightmares, and erythromelalgia may occur, especially in patients with parkinsonian syndrome receiving long-term and/or high-dose (100 mg or greater daily) bromocriptine therapy; these adverse effects are usually reversible 2-3 weeks after the drug is discontinued and are generally more severe and persist longer than with levodopa. Patients with parkinsonian syndrome have also experienced abnormal involuntary movements, ''on-off'' phenomenon, asthenia, ataxia, mental depression, epileptiform seizure, anxiety, nervousness, and paresthesia. Mania also has been reported in several patients without parkinsonian syndrome receiving bromocriptine; after the drug was discontinued, mania was treated successfully with haloperidol. Patients receiving the drug for acromegaly have also experienced decreased sleep requirements, visual hallucinations, lassitude, sluggishness, paresthesia, vertigo, delusional psychosis, paranoia, heavy headedness, and tingling of the ears.

One patient receiving bromocriptine experienced a relapse of severe depression with suicidal thoughts and another developed anxiety and extreme agitation; these effects are similar to those seen with levodopa and are probably caused by dopamine receptor stimulation. Therefore, bromocriptine may be contraindicated in patients with preexisting psychiatric disorders.

CSF rhinorrhea has occurred in a few patients receiving bromocriptine for the treatment of large prolactinomas. CSF rhinorrhea occurs rarely, mainly in patients who previously underwent transsphenoidal surgery and/or radiation therapy and who were receiving the drug for tumor recurrence. CSF rhinorrhea may also occur in patients with previously untreated prolactinoma that extends into the sphenoid sinus.

Seizures and stroke have been associated rarely with bromocriptine therapy for suppression of postpartum lactation (see Cautions: Cardiovascular Effects); however, the drug no longer is labeled for such use in the US. (See Uses: Other Uses)

Cardiovascular Effects

A persistent hypotensive effect commonly accompanies bromocriptine mesylate treatment, and the drug may produce postural hypotension, syncope, and severe prolonged hypotension or shock. Exacerbation of angina may occur. Other adverse cardiovascular effects reported include palpitation, arrhythmia, ventricular tachycardia, bradycardia, and erythematous and edematous ankles and feet. Cold-induced vasospasm with pallor of fingers and toes has been reported in patients receiving 20-60 mg of bromocriptine daily; when the drug was discontinued, vasospasm was reversed and pain did not occur during recovery. Exacerbation of Raynaud's syndrome and decreased tolerance to cold have also occurred. The drug's vasodilating action on renal arteries may produce diuresis in some patients. Very high dosages of bromocriptine (100 mg daily) may cause cardiac dysrhythmia. One patient receiving 35 mg of bromocriptine daily for 8 weeks developed paroxysmal breathlessness and acute left ventricular failure associated with atrial flutter-fibrillation; sinus rhythm returned within 24 hours following discontinuance of the drug.

Decreases in blood pressure (20 mm Hg or greater systolic and 10 mm Hg or greater diastolic) have occurred at least once during the first 3 days postpartum in about 30% of women receiving bromocriptine for suppression of postpartum lactation (no longer included as a labeled use in the US); the hypotensive effect is usually transient. Occasionally, supine systolic blood pressure has decreased by as much as 50-60 mm Hg in these women. Since decreases in blood pressure are common during the puerperium independent of drug therapy, many but not all of these decreases may have not been drug related. Fainting during the puerperium also has occurred rarely and may have been related to the drug.

Hypertension (sometimes developing with initiation of therapy but often during the second week); seizures (mean onset about 7 days postpartum but up to 2 weeks in some patients), with or without hypertension, occasionally presenting as status epilepticus; potentially fatal cerebrovascular accident (stroke) (mean onset about 13 days postpartum), principally in postpartum women whose prenatal and obstetric courses were uncomplicated; and acute myocardial infarction have occurred rarely in women receiving the drug for postpartum lactation. Some of these women had toxemia of pregnancy (including postpartum eclampsia) and some (including at least one fatality) received concomitant therapy with other ergot alkaloids or other drugs that can increase blood pressure. Accumulating reports of such adverse effects when the drug was used for postpartum lactation prevention include 31 cases of stoke, 9 of which were fatal, and 63 cases of seizures; no other potential cause for stroke or seizures could be identified in 40% of these cases. While the absolute incidence and relative risk (the ratio of the incidence of these bromocriptine-associated effects to the background of such effects occurring in the postpartum period in women not receiving the drug) remain to be clearly defined, FDA's Fertility and Maternal Health Drugs Advisory Committee concluded that the possibility of serious adverse effects associated with use of bromocriptine for postpartum lactation prevention outweighs the limited benefits of such therapy.

Many postpartum patients who developed stroke and/or seizures in associated with bromocriptine therapy complained of constant and often progressively severe headaches hours to days prior to the acute event. Some such patients also developed prodromal visual disturbances (blurred vision and transient cortical blindness). At least one case of stroke was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis. At least one case of acute myocardial infarction was associated with unexplained disseminated intravascular thrombosis, and another was associated with concomitant use of another ergot alkaloid. Most of the women who developed hypertension became normotensive only after discontinuance of therapy with the drug; in 2 patients who were rechallenged, hypertension recurred in one and remained elevated during the entire week of rechallenge. Seizures also resolved following discontinuance of bromocriptine. Although spontaneous, late-onset postpartum hypertension or eclampsia has been reported in women not receiving bromocriptine, it is unlikely that all cases associated with bromocriptine therapy were due to chance alone. In addition, postpartum hypertension or eclampsia as an adverse effect with other ergot alkaloids has been well documented.

Although there currently is no conclusive evidence of an interaction between bromocriptine and other ergot alkaloids, concomitant use of the drugs is not recommended. Particular caution is indicated in patients who recently have received other drugs that can alter blood pressure, and bromocriptine should not be used in patients with uncontrolled hypertension or toxemia of pregnancy. Because the risks of serious adverse effects (e.g., hypertensive crisis, seizures, stroke) outweigh the limited benefits of bromocriptine therapy for the prevention of postpartum lactation, such use no longer is recommended.(See Uses: Other Uses.) However, if bromocriptine were used for the prevention of lactation, therapy with the drug should not be initiated until postpartum vital signs have stabilized and no sooner than 4 hours after parturition. Periodic monitoring of blood pressure, especially during the first weeks of bromocriptine therapy and particularly during the postpartum period, is prudent. Bromocriptine therapy should be discontinued immediately and the patient evaluated promptly if hypertension; severe, progressive, or unremitting headache (with or without visual disturbances); or evidence of CNS toxicity develops; in addition, patients should be advised to discontinue the drug and seek prompt medical attention if any of these manifestations occurs. FDA states that similar hypertensive crises have not been reported with other drugs used to suppress lactation to date; however, reporting bias may contribute to this difference. Acute myocardial infarction also has occurred in at least one patient not receiving the drug for the prevention of lactation.

Other Adverse Effects

Other reported adverse effects of bromocriptine include leg cramps, dry mouth, metallic taste, anorexia, burning discomfort of the eyes, blepharospasm, diplopia or other visual disturbances, nasal congestion, rash, mottling of the skin, facial pallor, and urticaria. Hair loss, vasovagal attack, muscle cramps, and potentiation of the effects of alcohol have also occurred rarely in patients with acromegaly.

Pulmonary infiltrates, pleural effusion, and thickening of the pleura have been reported in a few patients receiving bromocriptine in dosages ranging from 20-100 mg daily for 6-36 months. In most reported cases in which bromocriptine therapy was discontinued, these pulmonary changes slowly reverted towards normal. Shortness of breath has been reported rarely. Retroperitoneal fibrosis also has been reported in a few patients receiving bromocriptine in dosages ranging from 30-140 mg daily for 2-10 years.

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 have been reported rarely in patients receiving bromocriptine for the treatment of parkinsonian syndrome. Urinary frequency, urinary incontinence, and urinary retention have also been reported rarely in these patients.

Bromocriptine therapy has caused transient increases in serum concentrations of AST (SGOT), ALT (SGPT), γ-glutamyl transferase (γ-glutamyltranspeptidase, GGT, GGTP), creatine kinase (CK, creatine phosphokinase, CPK), alkaline phosphatase, uric acid, and BUN.

Precautions and Contraindications

Blood pressure should be monitored periodically in all patients receiving bromocriptine, especially during the first few days of therapy with the drug. Particular care should be exercised in patients receiving other hypotensive drugs concomitantly. Decreases in blood pressure frequently have been reported during the puerperium independent of drug therapy, and some women have developed bromocriptine-induced hypotension or, rarely, hypertension, including hypertensive crisis. (See Cautions: Cardiovascular Effects.) Because of the risk of this and other potentially serious adverse effects, which may be fatal, use of bromocriptine for the prevention of postpartum lactation no longer is recommended.

Patients should be warned that bromocriptine may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Hepatic, hematopoietic, cardiovascular, and renal function should be evaluated periodically in patients receiving prolonged therapy with bromocriptine, as in the treatment of parkinsonian syndrome. The safety of long-term bromocriptine therapy for periods longer than 2 years at dosages used in the treatment of parkinsonian syndrome has not been established. Since high dosages of bromocriptine may be associated with confusion and mental disturbances, the drug should be used with caution in patients with parkinsonian syndrome who manifest mild degrees of dementia. Bromocriptine therapy, alone or combined with levodopa, has been associated with visual or auditory hallucinations in patients receiving the drug(s) for parkinsonian syndrome; hallucinations usually resolve following dosage reduction, but discontinuance of bromocriptine may occasionally be necessary. Rarely, after high dosages, hallucinations may persist for several weeks following discontinuance of the drug.

Bromocriptine should be used with caution in patients with impaired liver or renal function, since safety and efficacy of the drug in these patients have not been definitely established. Dosage of bromocriptine may have to be reduced in patients with impaired liver function.

Bromocriptine should also be used with caution in patients, particularly those with parkinsonian syndrome, who have a history of myocardial infarction and a residual atrial, nodal, or ventricular arrhythmia.

The relative efficacy of bromocriptine therapy versus surgery in preserving the visual fields in patients with hyperprolactinemic disorders is not known. Patients with rapidly progressing visual field loss should be evaluated by a neurosurgeon.

Patients receiving bromocriptine for hyperprolactinemic disorders associated with macroadenomas and those who have undergone transsphenoidal surgery should be advised to report to their physician any persistent, watery nasal discharge that occurs during therapy with the drug, since this may be a sign of CSF rhinorrhea. (See Cautions: Nervous System Effects.)

Patients receiving long-term (e.g., 6-36 months), high-dose (e.g., 20-100 mg daily) bromocriptine therapy should be observed for pulmonary changes such as infiltrates, effusion, and thickening of the pleura since these effects have occasionally occurred.

Patients with acromegaly should be monitored for cold-induced digital vasospasm during bromocriptine therapy. Vasospasm usually resolves following a reduction in dosage and may be prevented by keeping the fingers warm. Patients with acromegaly should also be monitored for signs and symptoms of peptic ulcer during bromocriptine therapy; such signs and symptoms should be thoroughly evaluated and appropriate therapy instituted if necessary. GI bleeding from peptic ulcers, sometimes fatal, has occurred during therapy with the drug in patients with acromegaly, but bromocriptine has not been shown to increase the incidence of peptic ulcer in these patients.

Patients with hyperprolactinemic amenorrhea-galactorrhea and infertility should undergo complete evaluation of the pituitary, including radiographs and posterior-anterior and lateral tomography, to rule out the possibility of a pituitary tumor before treatment with bromocriptine is initiated.

Since bromocriptine may restore fertility and pregnancy may subsequently occur, women receiving the drug who do not desire pregnancy should use mechanical contraceptive measures; estrogen-progestin contraceptives are contraindicated since they may cause amenorrhea-galactorrhea. The manufacturer recommends that a pregnancy test be performed every 4 weeks in amenorrheic women and, once menses are reinstated, whenever a menstrual period is missed. If pregnancy occurs during bromocriptine therapy, the drug should be discontinued immediately. (See Cautions: Pregnancy and Lactation.)

Bromocriptine is contraindicated in patients with uncontrolled hypertension or toxemia of pregnancy and in those who are sensitive to any ergot alkaloid.

Pediatric Precautions

Safety and efficacy of bromocriptine mesylate have not been established in children younger than 15 years of age.

Carcinogenicity

Because the natural history of growth hormone-secreting tumors is not known, patients with acromegaly should be carefully monitored for tumor expansion during bromocriptine therapy; if evidence of tumor expansion occurs, the drug should be discontinued and alternative therapies considered. Possible tumor expansion has occurred during bromocriptine therapy in these patients.

Women with hyperprolactinemic disorders who become pregnant and subsequently discontinue bromocriptine therapy during pregnancy may develop enlargement of a previously undetected or existing prolactin-secreting tumor when therapy with the drug is suspended. These women should be monitored closely throughout pregnancy for signs and symptoms of tumor progression. Women not seeking pregnancy or those with large adenomas should be advised to use contraceptive measures, other than estrogen-progestin contraceptives, during bromocriptine therapy. Careful evaluation of the pituitary to detect the presence of a prolactin-secreting tumor is essential prior to initiating bromocriptine therapy in hyperprolactinemic women with amenorrhea-galactorrhea and hypogonadism (infertility), since one of the goals of bromocriptine therapy in these women often is successful pregnancy.

Rapid tumor regrowth occurs in most patients with known macroadenoma following discontinuance of bromocriptine therapy.

Pregnancy and Lactation

Pregnancy

Recent studies indicate that the incidence of spontaneous abortions and adverse effects in infants born to mothers who were receiving bromocriptine therapy at conception does not appear to exceed that generally reported for such occurrences in the population at large. Most of these women received the drug during the first 2-3 weeks of pregnancy, although some received the drug for up to 3 months and several throughout pregnancy. Use of bromocriptine to reduce serum prolactin concentrations and prevent possible pituitary tumor expansion has been reported in some women during the last week of pregnancy. Nevertheless, bromocriptine should be discontinued immediately if pregnancy occurs during therapy and the patient should be carefully observed throughout the pregnancy, including regular checks of the visual field. In pregnant women with underlying prolactin-secreting pituitary tumors, sudden enlargement of the tumors as a result of an increase in pituitary size which normally occurs during pregnancy may cause optic nerve compression, visual impairment, and even blindness, which usually disappear after delivery; diabetes insipidus and possible pituitary apoplexy also may occur.

In pregnant women receiving bromocriptine, fetal prolactin (but not growth hormone) concentrations are suppressed; concentrations of prolactin in amniotic fluid are not affected. Prolactin concentrations return to normal in these infants after birth. Cervical incompetence and premature delivery have been reported after bromocriptine therapy in pregnant women, but a direct correlation with the drug's use has not been established.

Lactation

Since bromocriptine interferes with lactation, the drug should not be administered to women who elect to breast-feed.

Drug Interactions

Effectiveness of bromocriptine mesylate in reducing serum prolactin concentrations is inhibited by drugs which increase prolactin concentrations, including amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine; therefore, the dosage of bromocriptine may have to be increased in patients receiving these drugs.

Administration of bromocriptine mesylate especially in high dosage, may result in decreased alcohol tolerance, and patients should be cautioned to limit alcohol intake while receiving bromocriptine.

There may be an additive neurologic effect of bromocriptine and levodopa in patients with parkinsonian syndrome which may be used to therapeutic advantage, enabling a reduction of levodopa dosage.

Additive hypotensive effects may occur in patients receiving bromocriptine mesylate and antihypertensive agents. Careful adjustment of antihypertensive dosage may be necessary when these drugs are used concomitantly. Although there currently is no conclusive evidence of an interaction between bromocriptine and other ergot alkaloids, concomitant use of the drugs is not recommended since potentially severe adverse effects (e.g., hypertension, myocardial infarction) have occurred when the drugs were used together. (See Cautions: Cardiovascular Effects.)

Pharmacokinetics

Absorption

Studies with radiolabeled bromocriptine mesylate have shown that approximately 28% of an oral dose of the drug is absorbed from the GI tract following oral administration; however, because of a substantial first-pass effect, only 6% of the dose reaches systemic circulation unchanged. Following oral administration of 3 mg of tritium-labeled bromocriptine in one study, the drug and its metabolites appeared in plasma in 10 minutes and maximum mean plasma concentrations were attained in about 1-1.5 hours. With fixed dosage, there are large interindividual variations in plasma concentrations. Plasma concentrations required for prolactin-lowering and antiparkinsonian effects are not known. Following oral administration of 2.5 mg of radiolabeled bromocriptine, peak plasma concentrations of unchanged drug and its metabolites range from 4-6 ng/mL.

Following oral administration of a single 1.25- to 5-mg dose of bromocriptine, serum prolactin decreases within 2 hours, is maximally decreased at 8 hours, and is still decreased at 24 hours. Maximum obtainable reduction of serum prolactin in hyperprolactinemic patients usually occurs within the first 4 weeks of bromocriptine therapy. A single oral dose of 2.5 mg of bromocriptine substantially reduces plasma growth hormone concentrations in patients with acromegaly within 1-2 hours and decreased concentrations persist for at least 4-5 hours.

Distribution

Bromocriptine and/or its metabolites do not distribute appreciably into erythrocytes. In vitro studies have found that bromocriptine is 90-96% bound to serum albumin.

Elimination

In one study, the elimination half-life of bromocriptine following a 3-mg oral dose of the drug was 4-4.5 hours for the initial phase and 45-50 hours for the terminal phase.

Bromocriptine mesylate is completely metabolized in the liver, principally by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment. The metabolites apparently are not pharmacologically active or toxic. Bromocriptine and its metabolites are excreted principally in feces via biliary elimination; approximately 2.5-5.5% of a single dose is excreted in urine. Within 5 days, about 85% of a dose is excreted in feces.

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