Cabergoline .5 mg Tablet, 8-count — NDC 50090-6596-0 (Billing 50090-6596-00)

WARNINGS 1. Pregnancy : Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia, eclampsia, and postpartum hypertension, unless the potential benefit is judged to outweigh the possible risk. 2.

Fibrotic Complications: a. Cardiac Valvulopathy: All patients should undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of valvular disease. If valvular disease is detected, the patient should not be treated with Cabergoline (See CONTRAINDICATIONS ).

Post-marketing cases of cardiac valvulopathy have been reported in patients receiving Cabergoline. These cases have generally occurred during administration of high doses of Cabergoline (>2mg/day) used for the treatment of Parkinson's disease. Cases of cardiac valvulopathy have also been reported in patients receiving lower doses for the treatment of hyperprolactinemic disorders.

A multi-country, retrospective cohort study using general practice 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 failur… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The safety of Cabergoline Tablets, USP 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, 0.5, 0.75, 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 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, pruri… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General: Initial doses higher than 1.0 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 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. Patients should be alerted 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 ). Drug Interactions: Cabergoline should not be administered concurrently with D 2 -antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide. Carcinogenesis, Mutagenesis, 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 i… [Excerpted — this section continues on DailyMed.]