Cabergoline

INDICATIONS AND USAGE Cabergoline Tablets, USP are indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.

CLINICAL PHARMACOLOGY Mechanism of Action: The secretion of prolactin by the anterior pituitary is mainly under hypothalamic inhibitory control, likely exerted through release of dopamine by tuberoinfundibular neurons. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D 2 receptors. Results of in vitro studies demonstrate that cabergoline exerts a direct inhibitory effect on the secretion of prolactin by rat pituitary lactotrophs. Cabergoline decreased serum prolactin levels in reserpinized rats. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D 1 , a 1 - and a 2 -adrenergic, and 5-HT 1 - and 5-HT 2 -serotonin receptors. Clinical Studies: The prolactin-lowering efficacy of cabergoline was demonstrated in hyperprolactinemic women in two randomized, double-blind, comparative studies, one with placebo and the other with bromocriptine. In the placebo-controlled study (placebo n=20; cabergoline n=168), cabergoline produced a dose-related decrease in serum prolactin levels with prolactin normalized after 4 weeks of treatment in 29%, 76%, 74% and 95% of the patients receiving 0.125, 0.5, 0.75, and 1 mg twice weekly, respectively. In the 8-week, double-blind period of the comparative trial with bromocriptine (cabergoline n=223; bromocriptine n=236 in the intent-to-treat analysis), prolactin was normalized in 77% of the patients treated with cabergoline at 0.5 mg twice weekly compared with 59% of those treated with bromocriptine at 2.5 mg twice daily. Restoration of menses occurred in 77% of the women treated with cabergoline, compared with 70% of those treated with bromocriptine. Among patients with galactorrhea, this symptom disappeared in 73% of those treated with cabergoline compared with 56% of those treated with bromocriptine. Pharmacokinetics Absorption: Following single oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult volunteers, mean peak plasma levels of 30 to 70 picograms (pg)/mL of cabergoline were observed within 2 to 3 hours. Over the 0.5 to 7 mg dose range, cabergoline plasma levels appeared to be dose-proportional in 12 healthy adult volunteers and nine adult parkinsonian patients. A repeat-dose study in 12 healthy volunteers suggests that steady-state levels following a once-weekly dosing schedule are expected to be twofold to threefold higher than after a single dose. The absolute bioavailability of cabergoline is unknown. A significant fraction of the administered dose undergoes a first-pass effect. The elimination half-life of cabergoline estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect of cabergoline may be related to its slow elimination and long half-life. Distribution: In animals, based on total radioactivity, cabergoline (and/or its metabolites) has shown extensive tissue distribution. Radioactivity in the pituitary exceeded that in plasma by >100-fold and was eliminated with a half-life o

DOSAGE AND ADMINISTRATION The recommended dosage of Cabergoline Tablets, USP for initiation of therapy is 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient’s serum prolactin level. Before initiating treatment, cardiovascular evaluation should be performed and echocardiography should be considered to assess for valvular disease. Dosage increases should not occur more rapidly than every 4 weeks, so that the physician can assess the patient's response to each dosage level. If the patient does not respond adequately, and no additional benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and other therapeutic approaches considered. Patients receiving long term treatment with Cabergoline should undergo periodic assessment of their cardiac status and echocardiography should be considered. After a normal serum prolactin level has been maintained for 6 months, cabergoline may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with cabergoline should be reinstituted. The durability of efficacy beyond 24 months of therapy with cabergoline has not been established.

ADVERSE REACTIONS The safety of Cabergoline Tablets has been evaluated in more than 900 patients with hyperprolactinemic disorders. Most adverse events were mild or moderate in severity. In a 4-week, double-blind, placebo-controlled study, treatment consisted of placebo or cabergoline at fixed doses of 0.125, 0.5, 0.75, or 1 mg twice weekly. Doses were halved during the first week. Since a possible dose-related effect was observed for nausea only, the four cabergoline treatment groups have been combined. The incidence of the most common adverse events during the placebo-controlled study is presented in the following table. Incidence of Reported Adverse Events During the 4-Week, Double-Blind, Placebo-Controlled Trial Adverse Event Reported at ≥1% for cabergoline Cabergoline (n=168) 0.125 to 1 mg two times a week Placebo (n=20) Number (percent) Gastrointestinal Nausea 45 (27) 4 (20) Constipation 16 (10) 0 Abdominal pain 9 (5) 1 (5) Dyspepsia 4 (2) 0 Vomiting 4 (2) 0 Central and Peripheral Nervous System Headache 43 (26) 5 (25) Dizziness 25 (15) 1 (5) Paresthesia 2 (1) 0 Vertigo 2 (1) 0 Body As a Whole Asthenia 15 (9) 2 (10) Fatigue 12 (7) 0 Hot flashes 2 (1) 1 (5) Psychiatric Somnolence 9 (5) 1 (5) Depression 5 (3) 1 (5) Nervousness 4 (2) 0 Autonomic Nervous System Postural hypotension 6 (4) 0 Reproductive – Female Breast pain 2 (1) 0 Dysmenorrhea 2 (1) 0 Vision Abnormal vision 2 (1) 0 In the 8-week, double-blind period of the comparative trial with bromocriptine, cabergoline (at a dose of 0.5 mg twice weekly) was discontinued because of an adverse event in 4 of 221 patients (2%) while bromocriptine (at a dose of 2.5 mg two times a day) was discontinued in 14 of 231 patients (6%). The most common reasons for discontinuation from cabergoline were headache, nausea and vomiting (3, 2, and 2 patients, respectively); the most common reasons for discontinuation from bromocriptine were nausea, vomiting, headache, and dizziness or vertigo (10, 3, 3, and 3 patients, respectively). The incidence of the most common adverse events during the double-blind portion of the comparative trial with bromocriptine is presented in the following table. Incidence of Reported Adverse Events During the 8-Week, Double-Blind Period of the Comparative Trial With Bromocriptine Adverse Event Reported at ≥1% for cabergoline Cabergoline (n=221) Bromocriptine (n=231) Number (percent) Gastrointestinal Nausea 63 (29) 100 (43) Constipation 15 (7) 21 (9) Abdominal pain 12 (5) 19 (8) Dyspepsia 11 (5) 16 (7) Vomiting 9 (4) 16 (7) Dry mouth 5 (2) 2 (1) Diarrhea 4 (2) 7 (3) Flatulence 4 (2) 3 (1) Throat irritation 2 (1) 0 Toothache 2 (1) 0 Central and Peripheral Nervous System Headache 58 (26) 62 (27) Dizziness 38 (17) 42 (18) Vertigo 9 (4) 10 (4) Paresthesia 5 (2) 6 (3) Body As a Whole Asthenia 13 (6) 15 (6) Fatigue 10 (5) 18 (8) Syncope 3 (1) 3 (1) Influenza-like symptoms 2 (1) 0 Malaise 2 (1) 0 Periorbital edema 2 (1) 2 (1) Peripheral edema 2 (1) 1 Psychiatric Depression 7 (3) 5 (2) Somnolence 5 (2) 5 (2) Anorexia 3 (1) 3 (1) Anxiety 3 (1) 3 (1) Insomnia 3 (1) 2 (1) Impaired concentration 2 (1) 1 Nervousness 2 (1) 5 (2) Cardiovascular Hot flashes 6 (3) 3 (1) Hypotension 3 (1) 4 (2) Dependent edema 2 (1) 1 Palpitation 2 (1) 5 (2) Reproductive – Female Breast pain 5 (2) 8 (3) Dysmenorrhea 2 (1) 1 Skin and Appendages Acne 3 (1) 0 Pruritus 2 (1) 1 Musculoskeletal Pain 4 (2) 6 (3) Arthralgia 2 (1) 0 Respiratory Rhinitis 2 (1) 9 (4) Vision Abnormal vision 2 (1) 2 (1) Other adverse events that were reported at an incidence of <1.0% in the overall clinical studies follow. Body As a Whole: facial edema, influenza-like symptoms, malaise Cardiovascular System: hypotension, syncope, palpitations Digestive System: dry mouth, flatulence, diarrhea, anorexia Metabolic and Nutritional System: weight loss, weight gain Nervous System: somnolence, nervousness, paresthesia, insomnia, anxiety Respiratory System: nasal stuffiness, epistaxis Skin and Appendages: acne, pruritus Special Sense

WARNINGS 1. Pregnancy: Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia, eclampsia, and postpartum hypertension, unless the potential benefit is judged to outweigh the possible risk. 2. Fibrotic Complications: a. Cardiac Valvulopathy: All patients should undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of valvular disease. If valvular disease is detected, the patient should not be treated with Cabergoline (See CONTRAINDICATIONS ) . Post-marketing cases of cardiac valvulopathy have been reported in patients receiving Cabergoline. These cases have generally occurred during administration of high doses of Cabergoline (>2mg/day) used for the treatment of Parkinson’s disease. Cases of cardiac valvulopathy have also been reported in patients receiving lower doses for the treatment of hyperprolactinemic disorders. A multi-country, retrospective cohort study using general practice records and record linkage systems in the UK, Italy and the Netherlands was conducted to assess the association between new use of dopamine agonists including cabergoline (n=27,812) for Parkinson’s disease and hyperprolactinemia and cardiac valvular regurgitation (CVR), other fibroses, and other cardiopulmonary events over a maximum of 12 years of follow up. In this study, the use of cabergoline among persons with Parkinson’s disease was associated with an increased risk of CVR when compared to non-ergot-derived dopamine agonists (Das) and levodopa [Incidence Rate (IR) per 10,000 person years of 68.1 (95% confidence interval (CI): 37.2 to 115.3) for cabergoline vs. 10.0 (95% CI: 5.2 to 19.4) for non-ergot Das and 11.3 (95% CI: 7.2 to 17.0) for levodopa]. In the study analysis confined to persons with dopamine agonist-treated hyperprolactinemia (n=8,386), when compared to non-use (n=15,147), persons exposed to cabergoline did not have an elevated risk of CVR. The findings with respect to the risk of CVR associated with cabergoline treatment for persons with Parkinson’s disease (increased risk) and those with hyperprolactinemia (no increased risk) are consistent with the findings in other published studies. Physicians should use the lowest effective dose of Cabergoline for the treatment of hyperprolactinemic disorders and should periodically reassess the need for continuing therapy with Cabergoline. Following treatment initiation, clinical and diagnostic monitoring (for example, chest x-ray, CT scan and cardiac echocardiogram) should be conducted to assess the risk of cardiac valvulopathy. The recommended frequency of routine echocardiographic monitoring is every 6 to 12 months or as clinically indicated with the presence of signs and symptoms such as edema, new cardiac murmer, dyspnea or congestive heart failure. Cabergoline should be discontinued if an echocardiogram reveals new valvular regurgitation, valvular restriction or valve leaflet thickening. Cabergoline should be used with caution in patients exposed to other medications associated with valvulopathy. b. Extracardiac Fibrotic Reactions: Post-marketing cases of pleural, pericardial and retroperitoneal fibrosis have been following administration of Cabergoline. Some reports were in patients previously treated with other ergotinic dopamine agonists. Cabergoline should not be used in patients with a history of cardiac or extracardiac fibrotic disorders. Fibrotic disorders can have an insidious onset and patients should be monitored for manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of: Pleuro-pulmonary disease such as dyspnea, shortness of breath, persistent cough or chest pain. Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb edema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis. Cardiac failu

CONTRAINDICATIONS Cabergoline Tablets, USP are contraindicated in patients with Uncontrolled hypertension or known hypersensitivity to ergot derivatives. History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis (See WARNINGS ). History of pulmonary, pericardial, or retroperitoneal fibrotic disorders (See WARNINGS ).

OVERDOSAGE Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to support blood pressure should be taken if necessary.