Cabergoline (Page 2 of 3)

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 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.

A patient 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 D2 -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/m2 /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 P1 and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D4 , 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/m2 /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/m2 /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 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.

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, 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

*Reported at ≥1% for cabergoline

Adverse Event* Cabergoline (n = 168) 0.125 to 1 mg two times a week Placebo (n = 20)
Number (percent)
Gastrointestinal
Nausea 45 (27) 4 (20)
Constipation 16 (10) 0
Abdominal pain 9 (5) 1 (5)
Dyspepsia 4 (2) 0
Vomiting 4 (2) 0
Central and Peripheral Nervous System
Headache 43 (26) 5 (25)
Dizziness 25 (15) 1 (5)
Paresthesia 2 (1) 0
Vertigo 2 (1) 0
Body As Hyperlink Whole
Asthenia 15 (9) 2 (10)
Fatigue 12 (7) 0
Hot flashes 2 (1) 1 (5)
Psychiatric
Somnolence 9 (5) 1 (5)
Depression 5 (3) 1 (5)
Nervousness 4 (2) 0
Autonomic Nervous System 6 (4) 0
Postural hypotension
Reproductive — Female
Breast pain 2 (1) 0
Dysmenorrhea 2 (1) 0
Vision Abnormal vision 2 (1) 0

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 Title Here

*Reported at ≥1% for cabergoline

Cabergoline Bromocriptine
Adverse Event* (n = 221) (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 Hyperlink 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 6 (3) 3 (1)
Hypotension 3 (1) 4 (2)
Dependent edema 2 (1) 1
Palpitation 2 (1) 5 (2)
Reproductive — Female
Breast pain 5 (2) 8 (3)
Dysmenorrhea 2 (1) 1
Skin and Appendages
Acne 3 (1) 0
Pruritus 2 (1) 1
Musculoskeletal
Pain 4 (2) 6 (3)
Arthralgia 2 (1) 0
Respiratory Rhinitis 2 (1) 9 (4)
Vision Abnormal vision 2 (1) 2 (1)

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.

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