ctice 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 murmur, 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 failure: cases of valvular and pericardial fibrosis have ofter manifested as cardiac failure. therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur. clinical and diagnostic monitoring such as erythrocyte sedimentation rate, chest x-ray, serum creatinine measurements, and other investigations should be considered at baseline and as necessary while patients are treated with cabergoline. following diagnosis of pleural effusion or pulmonary fibrosis, the discontinuance of cabergoline was reported to result in improvement of signs and symptoms.

line 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 cabergoline tablets, usp are a white to off-white, oval shape, flat face, beveled edge tablet containing 0.5 mg cabergoline usp. each tablet is debossed "p" bisect line "p" on one side and "673" on the other side. cabergoline tablets, usp are available as follows: bottles of 8 tablets ndc 23155-823-73 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

che 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 2 (1) 0 dysmenorrhea 2 (1) 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, 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* 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 dizziness vertigo paresthesia 58 (26) 38 (17) 9 (4) 5 (2) 62 (27) 42 (18) 10 (4) 6 (3) body as a whole asthenia fatigue syncope influenza-like symptoms malaise periorbital edema peripheral edema 13 (6) 10 (5) 3 (1) 2 (1) 2 (1) 2 (1) 2 (1) 15 (6) 18 (8) 3 (1) 0 0 2 (1) 1 psychiatric depression somnolence anorexia anxiety insomnia impaired concentration nervousness 7 (3) 5 (2) 3 (1) 3 (1) 3 (1) 2 (1) 2 (1) 5 (2) 5 (2) 3 (1) 3 (1) 2 (1) 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 <1.0% 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 (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 avet pharmaceuticals inc. at 1-866-901-drug (3784) or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

e-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 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. pharmacodyanamics 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 to 1.5 mg) and hyperprolactinemic patients (0.3 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, 1 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 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.