Bromocriptine Mesylate Tablets, USP 2.5 mg

Absorption

Following single dose administration of bromocriptine mesylate tablets, 2 x 2.5 mg to 5 healthy volunteers under fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr, respectively.¹ Linear relationship was found between single doses of bromocriptine mesylate and C_max and AUC in the dose range of 1 to 7.5 mg.² The pharmacokinetics of bromocriptine metabolites have not been reported.

Food did not significantly affect the systemic exposure of bromocriptine following administration of bromocriptine mesylate tablets, 2.5 mg.³ It is recommended that bromocriptine mesylate be taken with food because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting conditions.

Following bromocriptine mesylate, 5 mg administered twice daily for 14 days, the bromocriptine C_max and AUC at steady-state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively.⁴

Distribution

In vitro experiments showed that bromocriptine was 90%-96% bound to serum albumin.

Metabolism

Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces.

In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway.⁵ Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine and lead to increased levels (see PRECAUTIONS, Drug Interactions section). The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 on the metabolism of bromocriptine has not been evaluated. Bromocriptine is also an inhibitor of CYP3A4 with a calculated IC50 value of 1.69 μM.⁶ Given the low therapeutic concentrations of bromocriptine in patients (C_max=0.82 nM), a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected. The potential effect of bromocriptine and its metabolites to act as inducers of CYP enzymes has not been reported.

Excretion

About 82% and 5.6 % of the radioactive dose orally administered was recovered in feces and urine, respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the radioactivity in urine.⁵

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¹Nelson, M. et. al. (1990). Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine. Clin Pharmacol Ther; 47(6):694-7.

²Schran, H.F., Bhuta, S.I., Schwartz, et al. (1980). The pharmacokinetics of bromocriptine in man. In: Golstein, M. Calne, D.B.,et. Al (eds). Ergot compound and brain function: Neuroendocrine and neuropsychiatric aspects, pp. 125-139, New York, Rave Press.

³Kopitar, Z., Vrhovac, B., Povsic, L., Plavsic, F., Francetic, I., Urbancic, J. (1991). The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine. Eur J Drug Metab Pharmacokinet; 16(3):177-81

⁴Flogstad, A.K., Halse, J., Grass, P., Abisch, E., Djoseland, O., Kutz, K., Bodd, E., and Jervell, J., (1994). A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. Journal of Clinical Endocrinology & Metabolism; Vol 79, 461-465

⁵Peyronneau MA, Delaforge M, Riviere R et al. 1994. High affinity of ergopeptides for CYP P450 3A. Importance of their peptide moiety for P450 recognition and hydroxylation of bromocriptine. Eur J Biochem 223:947-56.

⁶Wynalda, M.A., Wienkers, L.C. (1997). Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos; 25:1211-14.

Specific Populations

Effect of Renal Impairment

The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated.

Since parent drug and metabolites are almost completely excreted via metabolism, and only 6% eliminated via the kidney, renal impairment may not have a significant impact on the PK of bromocriptine and its metabolites (see PRECAUTIONS, General).

Effect of Hepatic Impairment

The effect of liver impairment on the PK of bromocriptine and its metabolites has not been evaluated. Since bromocriptine is mainly eliminated by metabolism, liver impairment may increase the plasma levels of bromocriptine, therefore, caution may be necessary (see PRECAUTIONS, General).

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

In about 75% of cases of amenorrhea and galactorrhea, bromocriptine mesylate 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 to 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 to 12 weeks. Some patients may fail to respond even after 12 months of therapy.

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

Bromocriptine mesylate tablets, USP are indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Bromocriptine mesylate tablets, USP treatment is indicated in patients with prolactin-secreting adenomas, which may be the basic underlying endocrinopathy contributing to the above clinical presentations. Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of bromocriptine mesylate tablets, USP therapy may be used to reduce the tumor mass prior to surgery.

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

Since the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with bromocriptine mesylate tablets, USP offers potential benefit before the effects of irradiation are manifested.

Bromocriptine mesylate tablets, USP are indicated in the treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson's disease. As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor), bromocriptine mesylate tablets, USP 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. Bromocriptine mesylate tablets, USP 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 bromocriptine mesylate tablets, USP therapy during treatment of more than two years has not been established.

Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson's disease with bromocriptine mesylate tablets, USP. Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in bromocriptine mesylate tablets, USP-treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for bromocriptine mesylate tablets, USP therapy.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine mesylate, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with bromocriptine mesylate for Parkinson’s disease or hyperprolactinemia-associated dysfunctions. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking bromocriptine mesylate.

Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine mesylate 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 bromocriptine mesylate 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, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate 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 bromocriptine mesylate 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 bromocriptine mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every four weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets 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 bromocriptine mesylate treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases.

Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting adenomas treated with bromocriptine mesylate.

Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine mesylate. The response, should it occur, can be reversed by reducing the dose of bromocriptine mesylate 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 bromocriptine mesylate 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 bromocriptine mesylate.

Possible tumor expansion while receiving bromocriptine mesylate 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.

Safety during long-term use for more than two 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 bromocriptine mesylate 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.

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

As with levodopa, caution should be exercised when administering bromocriptine mesylate 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 to 10 years) with bromocriptine mesylate in doses ranging from 30 to 140 mg daily.

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using bromocriptine mesylate for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Discontinuation of bromocriptine mesylate should be undertaken gradually whenever possible, even if the patient is to remain on levodopa. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including bromocriptine mesylate. These symptoms generally do not respond to levodopa. Prior to discontinuation of bromocriptine mesylate, patients should be informed about potential withdrawal symptoms, and closely monitored during and after discontinuation of bromocriptine mesylate. In case of severe withdrawal symptoms, re-administration of a dopamine agonist at the lowest effective dose may be considered.

During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy. In postmarketing reports, bromocriptine mesylate 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 bromocriptine mesylate 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 bromocriptine mesylate 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).

Patients receiving bromocriptine mesylate 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 bromocriptine mesylate 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.

Patients and their caregivers should be alerted to the possibility that patients may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking bromocriptine mesylate. Advise patients and their caregivers to inform their healthcare provider if they develop new or increased uncontrolled spending, gambling urges, sexual urges, or other urges while being treated with bromocriptine mesylate (see PRECAUTIONS).

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.

Advise patients to contact their healthcare provider if they wish to discontinue bromocriptine mesylate or decrease the dose of bromocriptine mesylate. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as fever, muscular rigidity, altered consciousness, apathy, anxiety, depression, fatigue, insomnia, sweating, or pain (see PRECAUTIONS).

The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine mesylate. Bromocriptine mesylate may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine mesylate: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when coadministering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine (mean AUC and C_max values increased 3.7-fold and 4.6-fold, respectively).¹ The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%).⁴ Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where high doses of bromocriptine are being used (such as Parkinson’s disease indication).

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).

Administration of 10 to 30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 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 to 15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8 to 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 bromocriptine mesylate has been collected. In the majority of cases, bromocriptine mesylate 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 to 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% to 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% to 4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%.

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

Bromocriptine mesylate should not be used during lactation in postpartum women.

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 USAGEsection.

Clinical studies for bromocriptine mesylate 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 bromocriptine mesylate 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.

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%), light-headedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%), and drowsiness (3%).

A slight hypotensive effect may accompany bromocriptine mesylate treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to 1.25 mg two or three times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving bromocriptine mesylate for treatment of large prolactinomas. This has occurred rarely, usually only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who were receiving bromocriptine mesylate for tumor recurrence. It may also occur in previously untreated patients whose tumor extends into the sphenoid sinus.

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

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

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

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

Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance.

The following adverse reactions have been reported during postapproval use of bromocriptine mesylate (All Indications Combined). Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

Nervous System Disorders: Headache, drowsiness, dizziness, dyskinaesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep.

Eye Disorders: Visual disturbance, vision blurred.

Ear and Labyrinth Disorders: Tinnitus.

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

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

Respiratory, Thoracic and Mediastinal Disorders: Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea.

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

Skin and Subcutaneous Tissue Disorders: Allergic skin reactions, hair loss.

Musculoskeletal and Connective Tissue Disorders: Leg cramps.

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

Postpartum Patients (see above WARNINGS)

In postpartum studies with bromocriptine mesylate, 23 percent of postpartum patients treated had at least 1 side effect, but they were generally mild to moderate in degree. Therapy was discontinued in approximately 3% of patients. 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 bromocriptine mesylate administration has not been established.

In rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, or psychic disorders have been reported in postpartum women treated with bromocriptine mesylate. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances. Although the causal relationship of these events to the drug is uncertain, periodic monitoring of blood pressure is advisable in postpartum women receiving bromocriptine mesylate. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of CNS toxicity develop, the administration of bromocriptine mesylate should be discontinued and the patient should be evaluated promptly.

Particular caution is required in patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure, e.g., vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine and their concomitant use in the puerperium is not recommended.

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

It is recommended that bromocriptine mesylate tablets be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response.

The initial dosage of bromocriptine mesylate tablets in adults is one-half to one 2.5 mg scored tablet daily. An additional 2.5 mg tablet may be added to the treatment regimen as tolerated every 2 to 7 days until an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5 to 15 mg daily in adults studied clinically.

Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is one-half to one 2.5 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 to 10 mg daily in children with prolactin-secreting pituitary adenomas.

In order to reduce the likelihood of prolonged exposure to bromocriptine mesylate tablets should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with bromocriptine mesylate tablet therapy until normal ovulatory menstrual cycles have been restored. Contraception may then be discontinued in patients desiring pregnancy.

Thereafter, if menstruation does not occur within 3 days of the expected date, bromocriptine mesylate tablet therapy should be discontinued and a pregnancy test performed.

Virtually all acromegalic patients receiving therapeutic benefit from bromocriptine mesylate tablets also have reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic potential of bromocriptine mesylate tablets. If, after a brief trial with bromocriptine mesylate tablet therapy, no significant reduction in growth hormone levels has taken place, careful assessment of the clinical features of the disease should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy should be considered.

The initial recommended dosage is one-half to one 2.5 mg bromocriptine mesylate tablet on retiring (with food) for 3 days. An additional one-half to 1 tablet should be added to the treatment regimen as tolerated every 3 to 7 days until the patient obtains optimal therapeutic benefit. Patients should be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical response. The usual optimal therapeutic dosage range of bromocriptine mesylate tablets varies from 20 to 30 mg/day in most patients. The maximal dosage should not exceed 100 mg/day.

Patients treated with pituitary irradiation should be withdrawn from bromocriptine mesylate tablet therapy on a yearly basis to assess both the clinical effects of radiation on the disease process as well as the effects of bromocriptine mesylate tablet therapy. Usually a 4 to 8 week withdrawal period is adequate for this purpose. Recurrence of the signs/ symptoms or increases in growth hormone indicate the disease process is still active and further courses of bromocriptine mesylate tablets should be considered.

The basic principle of bromocriptine mesylate tablet therapy is to initiate treatment at a low dosage and, on an individual basis, increase the daily dosage slowly until a maximum therapeutic response is achieved. The dosage of levodopa during this introductory period should be maintained, if possible. The initial dose of bromocriptine mesylate tablets is one-half of a 2.5 mg tablet twice daily with meals. Assessments are advised at two week intervals during dosage titration to ensure that the lowest dosage producing an optimal therapeutic response is not exceeded. If necessary, the dosage may be increased every 14 to 28 days by 2.5 mg/day with meals. Should it be advisable to reduce the dosage of levodopa because of adverse reactions, the daily dosage of bromocriptine mesylate tablets, if increased, should be accomplished gradually in small (2.5 mg) increments.

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

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container.

Manufactured in Slovenia

by Novartis d.o.o.

for Sandoz Inc., Princeton, NJ 08540

Rev. June 2024