Cabergoline Drug Information

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

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.

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 4 Constipation 16 0 Abdominal pain 9 1 Dyspepsia 4 0 Vomiting 4 0 Central and Peripheral Nervous System Headache 43 5 Dizziness 25 1 Paresthesia 2 0 Vertigo 2 0 Body As a Whole Asthenia 15 2 Fatigue 12 0 Hot flashes 2 1 Psychiatric Somnolence 9 1 Depression 5 1 Nervousness 4 0 Autonomic Nervous System Postural hypotension 6 0 Reproductive – Female Breast pain 2 0 Dysmenorrhea 2 0 Vision Abnormal vision 2 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 63 100 Constipation 15 21 Abdominal pain 12 19 Dyspepsia 11 16 Vomiting 9 16 Dry mouth 5 2 Diarrhea 4 7 Flatulence 4 3 Throat irritation 2 0 Toothache 2 0 Central and Peripheral Nervous System Headache 58 62 Dizziness 38 42 Vertigo 9 10 Paresthesia 5 6 Body As a Whole Asthenia 13 15 Fatigue 10 18 Syncope 3 3 Influenza-like symptoms 2 0 Malaise 2 0 Periorbital edema 2 2 Peripheral edema 2 1 Psychiatric Depression 7 5 Somnolence 5 5 Anorexia 3 3 Anxiety 3 3 Insomnia 3 2 Impaired concentration 2 1 Nervousness 2 5 Cardiovascular Hot flashes 6 3 Hypotension 3 4 Dependent edema 2 1 Palpitation 2 5 Reproductive – Female Breast pain 5 8 Dysmenorrhea 2 1 Skin and Appendages Acne 3 0 Pruritus 2 1 Musculoskeletal Pain 4 6 Arthralgia 2 0 Respiratory Rhinitis 2 9 Vision Abnormal vision 2 2 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 Senses: abnormal vision Urogenital System: dysmenorrhea, increased libido The safety of cabergoline has been evaluated in approximately 1,200 patients with Parkinson’s disease in controlled and uncontrolled studies at dosages of up to 11.5 mg/day which greatly exceeds the maximum recommended dosage of cabergoline for hyperprolactinemic disorders.

In addition to the adverse events that occurred in the patients with hyperprolactinemic disorders, the most common adverse events in patients with Parkinson’s disease were dyskinesia, hallucinations, confusion, and peripheral edema. Heart failure, pleural effusion, pulmonary fibrosis, and gastric or duodenal ulcer occurred rarely. One case of constrictive pericarditis has been reported.

Post-marketing Surveillance data The following events have been reported in association with cabergoline: cardiac valvulopathy and extracardiac fibrotic reactions Other events have been reported in association with cabergoline: impulse control/compulsive behavior symptoms, including hypersexuality, increased libido and pathological gambling (See PRECAUTIONS, Psychiatric ). In addition, cases of alopecia, aggression, and psychotic disorder have been reported in patients taking cabergoline. Some of these reports have been in patients who have had prior adverse reactions to dopamine agonist products. To report SUSPECTED ADVERSE REACTIONS, contact SOLA Pharmaceuticals at 1-1-866-747-7365 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions: Cabergoline should not be administered concurrently with D 2 -antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide.

• Pregnancy: Teratogenic Effects: Category B. Reproduction studies have been performed with cabergoline in mice, rats, and rabbits administered by gavage. (Multiples of the maximum recommended human dose in this section are calculated on a body surface area basis using total mg/m 2 /week for animals and mg/m 2 /week for a 50 kg human.) There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis. A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum human dose). In rats, doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) from 6 days before parturition and throughout the lactation period inhibited growth and caused death of offspring due to decreased milk secretion. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pediatric Use: Safety and effectiveness of cabergoline in pediatric patients have not been established.

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