PARLODEL

Bromocriptine mesylate is a semisynthetic ergot alkaloid derivative with potent dopaminergic activity.

It inhibits prolactin secretion and may be used to treat dysfunctions associated with hyperprolactinemia.

Bromocriptine is also indicated for the management of signs and symptoms of Parkinsonian Syndrome, as well as the treatment of acromegaly.

Bromocriptine has been associated with pulmonary fibrosis, and can also cause sustained suppression of somatotropin (growth hormone) secretion in some patients with acromegaly.

In 1995, the FDA withdrew the approval of bromocriptine mesylate for the prevention of physiological lactation after finding that bromocriptine was not shown to be safe for use. 8, 9 It continues to be used for the indications mentioned above.

For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications.

Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome.

Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects.

Five dopamine receptor types from two dopaminergic subfamilies have been identified.

The dopaminergic

D1 receptor subfamily consists of D and D 5 subreceptors, which are associated with dyskinesias.

D2 receptor subfamily consists of D 2, D and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders.

Thus, agonist activity specific for D2 subfamily receptors, primarily D and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents.

It is thought that postsynaptic

D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects.

This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors.

It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D and 5-HT 7 receptors.

Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost.

As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs.

High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain.

The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism.

The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland.

In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin.

Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin.

Pulmonary fibrosis may be associated bromocriptine's agonist activity at 5-HT 1B and 5-HT 2B receptors.

Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged.

Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours.

Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours.

Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours.

Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic.

Bromocriptine is metabolized by cytochrome

P450 3A4 and excreted primarily in the feces via biliary secretion.

Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney.

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Symptoms of overdosage include nausea, vomiting, and severe hypotension.

The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension.

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 bromocriptine mesylate.

If pregnancy occurs during bromocriptine mesylate 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 bromocriptine mesylate treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy.

The safety of bromocriptine mesylate treatment during pregnancy to the mother and fetus has not been established.

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.

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 bromocriptine mesylate for any indication.

In postpartum studies with bromocriptine mesylate, 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 bromocriptine mesylate.

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 bromocriptine mesylate occurs in some patients, in rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, have been reported in postpartum women treated with bromocriptine mesylate for the inhibition of lactation.

Hypertension has been reported, sometimes at the initiation of therapy, but often developing in the second week of therapy; seizures have also been reported both with and without the prior development of hypertension; stroke has been reported mostly in postpartum patients whose prenatal and obstetric courses had been uncomplicated.

Many of these patients experiencing seizures (including cases of status epilepticus) 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).

Cases of acute myocardial infarction have also been reported.

Although a causal relationship between bromocriptine mesylate 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, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed.

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

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

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

Because of the possibility of an interaction between bromocriptine mesylate 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 bromocriptine mesylate, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have been reported.

Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of bromocriptine mesylate therapy should be considered.

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

In a few patients on bromocriptine mesylate, 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.

Bromocriptine mesylate medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.

Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate tablets, uncontrolled hypertension and sensitivity to any ergot alkaloids.

In patients being treated for hyperprolactinemia, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed.

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

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

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

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

If the drug is used in the postpartum period, the patient should be observed with caution.

It is recommended that bromocriptine mesylate be taken with food.

Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response.

The initial dosage of bromocriptine mesylate tablets in adults is 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 to 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 to 15, See Pediatric Use the initial dose is 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 2.5-10 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 tablets therapy until normal ovulatory menstrual cycles have been restored.

Contraception may then be discontinued in patients desiring pregnancy.

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

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 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 half to one 2.5 mg bromocriptine mesylate tablet on retiring (with food) for 3 days.

An additional half to 1 tablet should be added to the treatment regimen as tolerated every 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 20-30 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 tablets 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 tablets therapy.

Usually a 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.

Parkinson's Disease The basic principle of bromocriptine mesylate tablets therapy is to initiate treatment at a low dosage and, on an individual basis, increase the daily dosage slowly until a maximum therapeutic response is achieved.

The dosage of levodopa during this introductory period should be maintained, if possible.

The initial dose of bromocriptine mesylate is half of a 2.5 mg 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 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, if increased, should be accomplished gradually in small (2.5 mg) increments.

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

Tablets, USP are available in bottles containing and 100 tablets of 2.5 mg, each bottle contains a desiccant.

Tablets, USP are available containing 2.5 mg of bromocriptine (as the mesylate).

The 2.5 mg tablets are white to off-white, round, bevel edged snap tablets, debossed with "PAD" over "0106" on one side and scored on the other side.

Bottles of 30.NDC 0574.

• 0106 -03 Bottles of 100.NDC 0574.

• 0106 -01 Store at 20° to 25°C (68° to 77°F) Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 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 to 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 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.

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 to day 18 p.c.

In 2 studies with the Yellow-silver strain, cleft palate was found in and 2 fetuses at maternally toxic doses of 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 1-40 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 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 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 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 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 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.

Clinical studies for bromocriptine mesylate did not include sufficient numbers of subjects aged 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.