CABERGOLINE: 2,099 Adverse Event Reports & Safety Profile

DESCRIPTION Cabergoline tablets, USP contain cabergoline, USP a dopamine receptor agonist. The chemical name for cabergoline is 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea. Its molecular formula is C 26 H 37 N 5 O 2 , and its molecular weight is 451.62 g/mol. The structural formula is as follows: Cabergoline, USP is a white or almost white crystalline powder practically insoluble in water and hexane, very soluble in ethanol, chloroform, acetone, dichloromethane, soluble in 0.1M HCl and freely soluble in toluene. Cabergoline tablets, USP for oral administration, contain 0.5 mg of cabergoline, USP. Inactive ingredients consist of citric acid anhydrous powder, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. chemical structure

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

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

CABERGOLINE is 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 )

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.

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. 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 (&gt;2 mg/day) for the treatment of Parkinson’s disease (PD) (cabergoline tablets is 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 urges, and the inability to control these urges while taking one or more drugs that increase central dopaminergic tone, including cabergoline tablets. In some cases, these urges were reported to have stopped when the dosage was reduced, or the drug was stopped.

PRECAUTIONS General Precautions General: Initial doses higher than 1 mg may produce orthostatic hypotension. Care should be exercised when administering cabergoline with other medications known to lower blood pressure.

Postpartum Lactation

Inhibition or Suppression: Cabergoline is not indicated for the inhibition or suppression of physiologic lactation. Use of bromocriptine, another dopamine agonist for this purpose, has been associated with cases of hypertension, stroke, and seizures.

Hepatic

Impairment: Since cabergoline is extensively metabolized by the liver, caution should be used, and careful monitoring exercised, when administering cabergoline to patients with hepatic impairment. Psychiatric: Impulse control/compulsive behaviors, including pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including cabergoline. This has been generally reversible upon reduction of the dose or treatment discontinuation (see Post-marketing Surveillance data ). Prescribers should consider dose reduction or stopping the medication if a patient develops such urges while taking cabergoline. Information for patients Patients should be altered to the possibility that patients may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking cabergoline. Advise patients to inform their healthcare provider if they develop new or increased uncontrolled spending, gambling urges, sexual urges, or other urges while being treated with cabergoline [See PRECAUTIONS ]. Patients should be instructed to notify their physician if they suspect they are pregnant, become pregnant, or intend to become pregnant during therapy. A pregnancy test should be done if there is any suspicion of pregnancy and continuation of treatment should be discussed with their physician. Patients should notify their physician if they develop shortness of breath, persistent cough, difficulty with breathing when lying down, or swelling in their extremities.

Drug Interactions

Cabergoline should not be administered concurrently with D 2 -antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide. Carcinogenesis and Mutagenesis and Impairment of Fertility Carcinogenicity studies were conducted in mice and rats with cabergoline given by gavage at doses up to 0.98 mg/kg/day and 0.32 mg/kg/day, respectively. These doses are 7 times and 4 times the maximum recommended human dose calculated on a body surface area basis using total mg/m 2 /week in rodents and mg/m 2 /week for a 50 kg human. There was a slight increase in the incidence of cervical and uterine leiomyomas and uterine leiomyosarcomas in mice. In rats, there was a slight increase in malignant tumors of the cervix and uterus and interstitial cell adenomas. The occurrence of tumors in female rodents may be related to the prolonged suppression of prolactin secretion because prolactin is needed in rodents for the maintenance of the corpus luteum. In the absence of prolactin, the estrogen/progesterone ratio is increased, thereby increasing the risk for uterine tumors. In male rodents, the decrease in serum prolactin levels was associated with an increase in serum luteinizing hormone, which is thought to be a compensatory effect to maintain testicular steroid synthesis. Since these hormonal mechanisms are thought to be species-specific, the relevance of these tumors to humans is not known. The mutagenic potential of cabergoline was evaluated and found to be negative in a battery of in vitro tests. These tests included the bacterial mutation (Ames) test with Salmonella typhimurium , the gene mutation assay with Schizosaccharomyces pombe P 1 and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D 4 , and chromosomal aberrations in human lymphocytes. Cabergoline was also negative in the bone marrow micronucleus test in the mouse. In female rats, a daily dose of 0.003 mg/kg for 2 weeks prior to mating and throughout the mating period inhibited conception. This dose represents approximately 1/28 the maximum recommended human dose calculated on a body surface area basis using total mg/m 2 /week in rats and mg/m 2 /week for a 50 kg human. 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 recommended 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.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cabergoline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Use of cabergoline for the inhibition or suppression of physiologic lactation is not recommended (see PRECAUTIONS section). The prolactin-lowering action of cabergoline suggests that it will interfere with lactation. Due to this interference with lactation, cabergoline should not be given to women postpartum who are breastfeeding or who are planning to breastfeed.

Pediatric Use

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

Geriatric Use

Clinical studies of cabergoline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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 )