Cabergoline (Page 3 of 4)

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/m2 /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 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.

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 1.0 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 A 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
Postural hypotension 6 (4) 0
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

* Reported at ≥ 1% for cabergoline

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 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.

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