Cabergoline for Pituitary Disorders

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 )

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. HOW SUPPLIED Product: 50090-6596 NDC: 50090-6596-0 8 TABLET in a BOTTLE STORAGE Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP]. Dispense in original container. Distributed by: Avet Pharmaceuticals Inc. East Brunswick, NJ 08816 1.866.901.DRUG (3784) Revised: 05/2022 OS673A-01-1-01 logo

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 tablets (>2 mg/day) for the treatment of Parkinson's disease (PD) (cabergoline tablets are not approved for the treatment of PD). Cases of cardiac valvulopathy have also been reported in patients who received lower dosages of cabergoline tablets for the treatment of hyperprolactinemic disorders. In a 12-year, multi-country retrospective cohort study, the use of cabergoline tablets for PD was associated with an increased risk of cardiac valvular regurgitation (CVR). Compared to non-ergot-derived dopamine agonists and levodopa, CVR with cabergoline tablets use had an incidence rate per 10,000 person years of 68 (95% CI: 37, 115) versus 10 (95% CI: 5, 19) for non-ergot dopamine agonists and 11 (95% CI: 7, 17) for levodopa. 5.2 Pleural, Pulmonary and Retroperitoneal Fibrosis Cabergoline tablets are contraindicated in patients with a history of pleural, pulmonary, or retroperitoneal fibrosis. During cabergoline tablets treatment monitor for signs and symptoms of progressive fibrosis, including: Pleuro-pulmonary disease (e.g., dyspnea, shortness of breath, persistent cough, chest pain). Renal impairment or ureteral/abdominal vascular obstruction (e.g., pain in the loin/flank, lower limb edema, abdominal masses or tenderness that may indicate retroperitoneal fibrosis). Consider clinical and diagnostic monitoring for pleural, pulmonary, and retroperitoneal fibrosis such as with erythrocyte sedimentation rate, serum creatinine measurements, chest-x-ray, and other investigations at baseline and as necessary during cabergoline tablets treatment. If pleural, pericardial, retroperitoneal, or pulmonary fibrosis occur, discontinue cabergoline tablets. Postmarketing cases of pleural, pulmonary, and retroperitoneal fibrosis have been reported following cabergoline tablets administration. Some reports were in patients previously treated with other ergotinic dopamine agonists. Cabergoline tablets-treated patients who developed a pleural effusion or pulmonary fibrosis and subsequently discontinued cabergoline tablets had improvement of their pulmonary symptoms. 5.3 Orthostatic Hypotension Check blood pressure at baseline and during treatment with cabergoline tablets and monitor for orthostatic hypotension. Warn patients about the risk of orthostatic hypotension and precautions to take when rising from a supine or sitting position. Instruct patients to report dizziness or lightheadedness with changes in position to their healthcare provider. Cabergoline tablets can cause orthostatic hypotension [see Adverse Reactions (6.1) ]. In a 4-week, placebo-controlled trial in patients with hyperprolactinemic disorders, the percentage of cabergoline tablets-treated patients and placebo-treated patients who developed orthostatic hypotension was 4% and 0%, respectively [see Adverse Reactions (6.1) ] . The risk of orthostatic hypotension is greater in cabergoline tablets-treated patients when taking concomitant drugs that lower blood pressure. 5.4 Risks with Use of Cabergoline Tablets for Postpartum Lactation Inhibition or Suppression Avoid use of cabergoline tablets for the inhibition or suppression of postpartum physiologic lactation because of the risk of serious adverse reactions. Use of bromocriptine, another dopamine agonist for this unapproved use has been associated with cases of hypertension, stroke, myocardial infarction seizures, and death. 5.5 Impulse Control Disorders and Compulsive Behaviors Because patients may not recognize impulse control and compulsive behaviors as abnormal, it is important for health care providers to 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. Patients can experience intense urges to gamble or to spend money, increased sexual urges, binge eating, and/or other intense u

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, are not recommended for concomitant use with D2-antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide. ( 7 )

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 mg, 0.5 mg, 0.75 mg, 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 * Cabergoline (n = 168) 0.125 to 1 mg two times a week Placebo (n = 20) Number (percent) Gastrointestinal Nausea Constipation Abdominal pain Dyspepsia Vomiting 45 (27) 16 (10) 9 (5) 4 (2) 4 (2) 4 (20) 0 1 (5) 0 0 Central and Peripheral Nervous System Headache Dizziness Paresthesia Vertigo 43 (26) 25 (15) 2 (1) 2 (1) 5 (25) 1 (5) 0 0 Body As a Whole Asthenia Fatigue Hot flashes 15 (9) 12 (7) 2 (1) 2 (10) 0 1 (5) Psychiatric Somnolence Depression Nervousness 9 (5) 5 (3) 4 (2) 1 (5) 1 (5) 0 Autonomic Nervous System Postural hypotension 6 (4) 0 Reproductive – Female Breast pain Dysmenorrhea 2 (1) 2 (1) 0 0 Vision Abnormal vision 2 (1) 0 * Reported at ≥ 1% for cabergoline 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 patients, 2 patients and 2 patients respectively); the most common reasons for discontinuation from bromocriptine were nausea, vomiting, headache, and dizziness or vertigo (10 patients, 3 patients, 3 patients, 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* 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 Hypotension Dependent edema Palpitation 6 (3) 3 (1) 2 (1) 2 (1) 3 (1) 4 (2) 1 5 (2) Reproductive – Female Breast pain Dysmenorrhea 5 (2) 2 (1) 8 (3) 1 Skin and Appendages Acne Pruritus 3 (1) 2 (1) 0 1 Musculoskeletal Pain Arthralgia 4 (2) 2 (1) 6 (3) 0 Respiratory Rhinitis 2 (1) 9 (4) Vision Abnormal vision 2 (1) 2 (1) * Reported at ≥ 1% for cabergoline Other adverse events that were reported at an incidence of < 1% 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. Postmarketing Surveillance Data The following events have been reported in association with cabergoline: cardiac valvulopathy and extracardiac fibrotic reactions, (See WARNINGS, 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 Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.