Cabergoline

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

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 )

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.

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 , α 1 - and α 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 mg, 0.5 mg, 0.75 mg, 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 picograms (pg)/mL to 70 picograms (pg)/mL of cabergoline were observed within 2 hours to 3 hours. Over the 0.5 mg 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 hours 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 of approximately 60 hours. This finding is consistent with the long-lasting prolactin-lowering effect of the drug. Whole body autoradiography studies in pregnant rats showed no fetal uptake but high levels in the uterine wall. Significant radioactivity (parent plus metabolites) detected in the milk of lactating rats suggests a potential for exposure to nursing infants. The drug is extensively distributed throughout the body. Cabergoline is moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. Concomitant dosing of highly protein-bound drugs is unlikely to affect its disposition. Metabolism In both animals and humans, cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. Cabergoline does not cause enzyme induction and/or inhibition in the rat. Hydrolysis of the acylurea or urea moiety abolishes the prolactin-lowering effect of cabergoline, and major metabolites identified thus far do not contribute to the therapeutic effect. Excretion After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was excreted unchanged in the urine. Nonrenal and renal clearances for cabergoline are about 3.2 L/min and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic patients was similar. Special Populations Renal Insufficiency The pharmacokinetics of cabergoline were not altered in 12 patients with moderate-to-severe renal insufficiency as assessed by creatinine clearance. Hepatic Insufficiency In 12 patients with mild-to-moderate hepatic dysfunction (Child-Pugh score ≤ 10), no effect on mean cabergoline C max or area under the plasma concentration curve (AUC) was observed. However, patients with severe insufficiency (Child-Pugh score > 10) show a substantial increase in the mean cabergoline C max and AUC, and thus necessitate caution. Elderly Effect of age on the pharmacokinetics of cabergoline has not been studied. Food-Drug Interaction In 12 healthy adult volunteers, food did not alter cabergoline kinetics. Pharmacodynamics Dose response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been documented following single cabergoline doses to healthy volunteers (0.05 mg to 1.5 mg) and hyperprolactinemic patients (0.3 mg to 1 mg). In volunteers, prolactin inhibition was evident at doses > 0.2 mg, while doses ≥ 0.5 mg caused maximal suppression in most subjects. Higher doses produce prolactin suppression in a greater proportion of subjects and with an earlier onset and longer duration of action. In 12 healthy volunteers, 0.5 mg, 1 mg, and 1.5 mg doses resulted in complete prolactin inhibition, with a maximum effect within 3 hours in 92% to 100% of subjects after the 1 mg and 1.5 mg doses compared with 50% of subjects after the 0.5 mg dose. In hyperprolactinemic patients (N = 51), the maximal prolactin decrease after a 0.6 mg single dose of cabergoline was comparable to 2.5 mg bromocriptine; however, the duration of effect was markedly longer (14 days vs. 24 hours). The time to maximal effect was shorter for bromocriptine than cabergoline (6 hours vs. 48 hours). In 72 healthy volunteers, single or multiple doses (up to 2 mg) of cabergoline resulted in selective inhibition of prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH, and TSH) or cortisol.