Cabergoline

1 INDICATIONS AND USAGE Cabergoline tablets are an ergot derivative indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas in adults. Limitations of Use Avoid use of cabergoline tablets for the inhibition or suppression of postpartum physiologic lactation because of the risk of serious adverse reactions [see Warnings and Precautions (5.4)]. Cabergoline tablets are an ergot derivative indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas in adults. ( 1 ) Limitations of Use Avoid use of cabergoline tablets for the inhibition or suppression of postpartum physiologic lactation because of the risk of serious adverse reactions. ( 5.4 )

2 DOSAGE AND ADMINISTRATION Before initiating cabergoline tablets evaluate for valvular heart disease, including with an echocardiogram. If valvular disease is detected, do not administer cabergoline tablets. ( 2.1 ) Recommended starting dosage of cabergoline tablets is 0.25 mg orally twice weekly. ( 2.2 ) Titrate cabergoline tablets to achieve normal serum prolactin levels by increasing cabergoline tablets by 0.25 mg orally twice weekly at intervals of no less than 4 weeks. ( 2.2 ) Maximum recommended dosage is 1 mg orally, twice weekly. ( 2.2 ) 2.1 Recommended Evaluation Before Initiating cabergoline tablets Before initiating cabergoline tablets evaluate for valvular heart disease, including with an echocardiogram. If valvular disease is detected, do not administer cabergoline tablets [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . 2.2 Recommended Dosage The recommended starting dosage of cabergoline tablets is 0.25 mg orally twice weekly. Titrate cabergoline tablets to achieve normal serum prolactin levels by increasing cabergoline tablets by 0.25 mg orally twice weekly at intervals of no less than 4 weeks. The maximum recommended dosage is 1 mg orally, twice weekly [see Warnings and Precautions ( 5.2 )] . Administer cabergoline tablets with or without food [see Clinical Pharmacology ( 12.3 )]. If cabergoline tablets are discontinued, monitor the serum prolactin level periodically to determine whether cabergoline tablets should be reinstituted.

5 WARNINGS AND PRECAUTIONS Cardiac Valvulopathy and Pericardial Fibrosis : Before initiating cabergoline tablets, perform a cardiovascular evaluation, including echocardiogram, to evaluate for valvular disease. During cabergoline tablets treatment, monitor for the development of valvulopathy with a cardiac echocardiogram at intervals of 6 to 12 months or as clinically indicated and monitor for chest pain and signs and symptoms of heart failure (if heart failure occurs, exclude valvular fibrosis and pericarditis). Consider additional clinical and diagnostic monitoring at baseline and as necessary during cabergoline tablets treatment. Use cabergoline tablets in patients treated with other drugs associated with valvulopathy only if the potential benefit of cabergoline tablets outweighs the risk. Discontinue cabergoline tablets if the patient has a new diagnosis of valvular regurgitation, valvular restriction, valve leaflet thickening, or pericarditis. ( 5.1 ) Pleural, Pulmonary and Retroperitoneal Fibrosis : During cabergoline tablets treatment monitor for signs and symptoms of progressive fibrosis, (e.g., pleuro-pulmonary disease, renal impairment, ureteral/abdominal vascular obstruction). Consider clinical and diagnostic monitoring for pleural, pulmonary, and retroperitoneal fibrosis at baseline and as necessary during cabergoline tablets treatment. If pleural, pericardial, retroperitoneal, or pulmonary fibrosis occur, discontinue cabergoline tablets. ( 5.2 ) Orthostatic Hypotension : Check blood pressure at baseline and during treatment with cabergoline tablets and monitor for orthostatic hypotension. ( 5.3 ) Risks with Use of cabergoline tablets for Postpartum Lactation Inhibition or Suppression : Avoid use of cabergoline tablets for the inhibition or suppression of physiologic lactation. Use of bromocriptine, another dopamine agonist for this unapproved use has been associated with cases of hypertension, stroke, myocardial infarction, seizures, and death. ( 5.4 ) Impulse Control Disorders and Compulsive Behaviors : Specifically ask patients about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with cabergoline tablets. Consider dosage reduction or stopping cabergoline tablets if a patient develops such urges while taking cabergoline tablets. ( 5.5 ) 5.1 Cardiac Valvulopathy and Pericardial Fibrosis Before initiating cabergoline tablets, perform a cardiovascular evaluation, including with an echocardiogram, to evaluate for valvular disease. cabergoline tablets are contraindicated in the presence of valvular disease or pericardial fibrosis [see Contraindications ( 4 )]. Cases of valvular and pericardial fibrosis have often manifested as heart failure. Following cabergoline tablets treatment initiation, monitor for the development of valvulopathy with a cardiac echocardiogram at intervals of 6 to 12 months or as clinically indicated with new onset edema, cardiac murmur, dyspnea, or heart failure. During cabergoline tablets treatment, monitor for chest pain and signs and symptoms of heart failure and if heart failure occurs, valvular fibrosis and pericarditis should be excluded. Consider clinical and diagnostic monitoring such as erythrocyte sedimentation rate, serum creatinine measurements, chest-x- ray, and other investigations and cardiac imaging at baseline and as necessary while patients are treated with during cabergoline tablets treatment. Use cabergoline tablets in patients treated with other drugs associated with valvulopathy only if the potential benefit of cabergoline tablets outweighs the risk. Discontinue cabergoline tablets if the patient has a new diagnosis of valvular regurgitation, valvular restriction, valve leaflet thickening, or pericarditis. Postmarketing cases of cardiac valvulopathy have been reported in patients who received cabergoline tablets. These cases have generally occurred during administration of high doses of cabergoline…

4 CONTRAINDICATIONS Cabergoline tablets are contraindicated in patients with: Uncontrolled hypertension. 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, or history of pericardial fibrosis [see Warnings and Precautions ( 5.1 )]. History of pleural, pulmonary, or retroperitoneal fibrotic disorders [see Warnings and Precautions ( 5.2 )]. Uncontrolled hypertension ( 4 ) Known hypersensitivity to ergot derivatives ( 4 ) History of cardiac valvular disorders, or pericardial fibrosis. ( 5.1 ) History of pleural, pulmonary, or retroperitoneal fibrotic disorders. ( 5.2 )

7 DRUG INTERACTIONS Cabergoline tablets, a dopamine receptor agonist, is not recommended for concomitant use with D2-antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide. Cabergoline tablets, a dopamine receptor agonist, is not recommended for concomitant use with D2-antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide. ( 7 )

8.1 Pregnancy Risk Summary If conception occurs during cabergoline tablets therapy, discontinue cabergoline tablets if the risks to the mother or fetus outweigh the benefits to the mother. There are risks to the mother associated with the use of cabergoline tablets ( see Clinical Considerations ). The estimated background risk of major birth defects and miscarriage in patients with hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal Adverse Reactions: In general, avoid use of dopamine agonists, including cabergoline tablets, during pregnancy and the postpartum period. The risks of cabergoline tablets use increase in pregnant females with pregnancy-induced hypertension, preeclampsia, and eclampsia. Data Human Data: Published case reports have not reported a clear association with cabergoline tablets and major birth defects, miscarriage, or adverse fetal outcomes when cabergoline tablets was used during early pregnancy. However, these case reports cannot definitely establish the absence of cabergoline tablets-associated risk. Animal Data: Embryo-fetal development studies have been performed with cabergoline administered by oral gavage in mice, rats, and rabbits: There were no teratogenic effects in the presence of maternal toxicity in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose based on body surface area) during the period of organogenesis. A dose of 0.012 mg/kg/day (approximately 0.14 times the maximum recommended human dose) administered during the period of organogenesis in rats caused an increase in post-implantation loss. This finding is likely due to the role of prolactin in implantation in rats and is not thought to be relevant to humans. At doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) administered during the period of organogenesis in rabbits, cabergoline caused maternal toxicity 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) administered 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 embryofetal toxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiac Valvulopathy and Pericardial Fibrosis [see Warnings and Precautions ( 5.1 )] . Pleural, Retroperitoneal, and Pulmonary Fibrosis [see Warnings and Precautions ( 5.2 )] . Orthostatic Hypotension [see Warnings and Precautions ( 5.3 )] . Impulse Control Disorders and Compulsive Behaviors [see Warnings and Precautions ( 5.5 )] . The most common adverse reactions (incidence >10%) are nausea, headache, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of cabergoline tablets has been evaluated in more than 900 patients with hyperprolactinemic disorders. In a 4-week, double-blind, placebo-controlled trial (cabergoline tablets vs. placebo) [see Clinical Studies ( 14 )], the incidence of the most common adverse reactions during the placebo-controlled trial in patients with hyperprolactinemic disorders is presented in Table 1. Table 1. Adverse Reactions (n (%)* During the 4-Week, Double-Blind, Placebo-Controlled Trial in Hyperprolactinemic Females Cabergoline Tablets (n=168) Placebo (n=20) Nausea 45 (27%) 4 (20%) Headache 43 (26%) 5 (25%) Dizziness 25 (15%) 1 (5%) Constipation 16 (10%) 0% Fatigue 12 (7%) 0% Postural hypotension 6 (4%) 0% Dyspepsia 4 (2%) 0% Vomiting 4 (2%) 0% Nervousness 4 (2%) 0% Vertigo 2 (1%) 0% Paresthesia 2 (1%) 0% Breast pain 2 (1%) 0% Dysmenorrhea 2 (1%) 0% Abnormal vision 2 (1%) 0% * Adverse reactions that occurred ≥1% in the cabergoline tablets group and frequency more than that reported in the placebo group. In the 8-week, double-blind period of the comparative trial with bromocriptine, 2% (4/221) of cabergoline tablets-treated patients (0.5 mg twice weekly) discontinued treatment because of an adverse event and 6% (14/231) of bromocriptine-treated patients (at a dose of 2.5 mg twice daily) discontinued treatment because of an adverse event. The most common reasons for cabergoline tablets discontinuation were headache, nausea, and vomiting (3, 2, and 2 patients, respectively). The incidence of the most common adverse events during the double-blind period of the comparative trial with bromocriptine is presented in Table 2. Table 2. Adverse Events* During the 8-Week, Double-Blind Period of the Comparative Trial in Hyperprolactinemic Females Cabergoline Tablets (n=221) Bromocriptine (n=231) Nausea 63 (29%) 100 (43%) Headache 58 (26%) 62 (27%) Dizziness 38 (17%) 42 (18%) Constipation 15 (7%) 21 (9%) Asthenia 13 (6%) 15 (6%) Abdominal pain 12 (5%) 19 (8%) Dyspepsia 11 (5%) 16 (7%) Fatigue 10 (5%) 18 (8%) Vertigo 9 (4%) 10 (4%) Vomiting 9 (4%) 16 (7%) Depression 7 (3%) 5 (2%) Hot flashes 6 (3%) 3 (1%) Breast pain 5 (2%) 8 (3%) Dry mouth 5 (2%) 2 (1%) Paresthesia 5 (2%) 6 (3%) Somnolence 5 (2%) 5 (2%) Diarrhea 4 (2%) 7 (3%) Flatulence 4 (2%) 3 (1%) Pain 4 (2%) 6 (3%) Acne 3 (1%) 0% Anorexia 3 (1%) 3 (1%) Anxiety 3 (1%) 3 (1%) Hypotension 3 (1%) 4 (2%) Insomnia 3 (1%) 2 (1%) Syncope 3 (1%) 3 (1%) Abnormal vision 2 (1%) 2 (1%) Arthralgia 2 (1%) 0% Dependent edema 2 (1%) 1 (<1%) Dysmenorrhea 2 (1%) 1 (<1%) Impaired concentration 2 (1%) 1 (<1%) Influenza-like symptoms 2 (1%) 0% Malaise 2 (1%) 0% Nervousness 2 (1%) 5 (2%) Palpitation 2 (1%) 5 (2%) Periorbital edema 2 (1%) 2 (1%) Peripheral edema 2 (1%) 1 (<1%) Pruritus 2 (1%) 1 (<1%) Rhinitis 2 (1%) 9 (4%) Throat irritation 2 (1%) 0% Toothache 2 (1%) 0% * Adverse events reported ≥1% in the cabergoline tablets group. Abbreviation: n=number of patients. Events that were reported at an incidence of <1% in the clinical studies follow: Body As a Whole: facial edema, i…