2.1 Recommended Evaluation Before Initiating DOSTINEX

Before initiating DOSTINEX evaluate for valvular heart disease, including with an echocardiogram. If valvular disease is detected, do not administer DOSTINEX [see Contraindications (4) and Warnings and Precautions (5.1)].

2.2 Recommended Dosage

The recommended starting dosage of DOSTINEX is 0.25 mg orally twice weekly. Titrate DOSTINEX to achieve normal serum prolactin levels by increasing DOSTINEX by 0.25 mg orally twice weekly at intervals of no less than 4 weeks. The maximum recommended dosage is 1 mg orally, twice weekly [see Warnings and Precautions (5.2)]. Administer DOSTINEX with or without food [see Clinical Pharmacology (12.3)].

If DOSTINEX is discontinued, monitor the serum prolactin level periodically to determine whether DOSTINEX should be reinstituted.

5.1 Cardiac Valvulopathy and Pericardial Fibrosis

Before initiating DOSTINEX, perform a cardiovascular evaluation, including with an echocardiogram, to evaluate for valvular disease. DOSTINEX is contraindicated in the presence of valvular disease or pericardial fibrosis [see Contraindications (4)].

Cases of valvular and pericardial fibrosis have often manifested as heart failure. Following DOSTINEX 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 DOSTINEX 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 DOSTINEX treatment. Use DOSTINEX in patients treated with other drugs associated with valvulopathy only if the potential benefit of DOSTINEX outweighs the risk.

Discontinue DOSTINEX 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 DOSTINEX. These cases have generally occurred during administration of high doses of DOSTINEX (>2 mg/day) for the treatment of Parkinson’s disease (PD) (DOSTINEX is not approved for the treatment of PD). Cases of cardiac valvulopathy have also been reported in patients who received lower dosages of DOSTINEX for the treatment of hyperprolactinemic disorders. In a 12-year, multi-country retrospective cohort study, the use of DOSTINEX for PD was associated with an increased risk of cardiac valvular regurgitation (CVR). Compared to non-ergot-derived dopamine agonists and levodopa, CVR with DOSTINEX 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

DOSTINEX is contraindicated in patients with a history of pleural, pulmonary, or retroperitoneal fibrosis. During DOSTINEX 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 DOSTINEX treatment. If pleural, pericardial, retroperitoneal, or pulmonary fibrosis occur, discontinue DOSTINEX.

Postmarketing cases of pleural, pulmonary, and retroperitoneal fibrosis have been reported following DOSTINEX administration. Some reports were in patients previously treated with other ergotinic dopamine agonists. DOSTINEX-treated patients who developed a pleural effusion or pulmonary fibrosis and subsequently discontinued DOSTINEX had improvement of their pulmonary symptoms.

5.3 Orthostatic Hypotension

Check blood pressure at baseline and during treatment with DOSTINEX 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.

DOSTINEX can cause orthostatic hypotension [see Adverse Reactions (6.1)]. In a 4-week, placebo-controlled trial in patients with hyperprolactinemic disorders, the percentage of DOSTINEX-treated patients and placebo-treated patients who developed orthostatic hypotension was 4% and 0%, respectively [see Adverse Reactions (6.1)]. The risk of orthostatic hypotension is greater in DOSTINEX-treated patients when taking concomitant drugs that lower blood pressure.

5.4 Risks with Use of DOSTINEX for Postpartum Lactation Inhibition or Suppression

Avoid use of DOSTINEX 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 DOSTINEX. Consider dosage reduction or stopping DOSTINEX if a patient develops such urges while taking DOSTINEX.

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 DOSTINEX. In some cases, these urges were reported to have stopped when the dosage was reduced, or the drug was stopped.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DOSTINEX has been evaluated in more than 900 patients with hyperprolactinemic disorders.

In a 4-week, double-blind, placebo-controlled trial (DOSTINEX vs. placebo) [see Clinical Studies (14)], the incidence of the most common adverse reactions during the placebo-controlled trial in patients with hyperprolactinemic disorders is presented in Table 1.

In the 8-week, double-blind period of the comparative trial with bromocriptine, 2% (4/221) of DOSTINEX-treated patients (0.5 mg twice weekly) discontinued treatment because of an adverse event and 6% (14/231) of bromocriptine-treated patients (at a dose of 2.5 mg twice daily) discontinued treatment because of an adverse event. The most common reasons for DOSTINEX discontinuation were headache, nausea, and vomiting (3, 2, and 2 patients, respectively). The incidence of the most common adverse events during the double-blind period of the comparative trial with bromocriptine is presented in Table 2.

Events that were reported at an incidence of <1% in the 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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of DOSTINEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

•

Psychiatric: impulse control disorders and compulsive behaviors including, hypersexuality, increased libido, pathological gambling; psychotic disorder, aggression

•

Skin and subcutaneous: alopecia

8.1 Pregnancy

Risk Summary

If conception occurs during DOSTINEX therapy, discontinue DOSTINEX if the risks to the mother or fetus outweigh the benefits to the mother. There are risks to the mother associated with the use of DOSTINEX (see Clinical Considerations).

The estimated background risk of major birth defects and miscarriage in patients with hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Maternal Adverse Reactions: In general, avoid use of dopamine agonists, including DOSTINEX, during pregnancy and the postpartum period. The risks of DOSTINEX use increase in pregnant females with pregnancy-induced hypertension, preeclampsia, and eclampsia.

Data

Human Data: Published case reports have not reported a clear association with DOSTINEX and major birth defects, miscarriage, or adverse fetal outcomes when DOSTINEX was used during early pregnancy. However, these case reports cannot definitely establish the absence of DOSTINEX-associated risk.

Animal Data: Embryo-fetal development studies have been performed with cabergoline administered by oral gavage in mice, rats, and rabbits:

•

There were no teratogenic effects in the presence of maternal toxicity in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose based on body surface area) during the period of organogenesis.

•

A dose of 0.012 mg/kg/day (approximately 0.14 times the maximum recommended human dose) administered during the period of organogenesis in rats caused an increase in post-implantation loss. This finding is likely due to the role of prolactin in implantation in rats and is not thought to be relevant to humans.

•

At doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) administered during the period of organogenesis in rabbits, cabergoline caused maternal toxicity 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) administered 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 embryofetal toxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

8.2 Lactation

Risk Summary

DOSTINEX is not recommended in postpartum women who are breastfeeding or who are planning to breastfeed. Avoid use of DOSTINEX for the inhibition or suppression of physiologic lactation [see Indications and Usage (1) and Warnings and Precautions (5.4)].

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies of DOSTINEX did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Hepatic Impairment

The use of DOSTINEX in patients with severe hepatic impairment (HI) (Child-Pugh C) is not recommended. When using DOSTINEX in patients with moderate HI (Child-Pugh B) increase monitoring of DOSTINEX-associated adverse reactions. The recommendations for use of DOSTINEX in patients with mild HI (Child Pugh A) is the same as those with normal hepatic function.

Patients with moderate or severe HI had increased cabergoline exposure [see Clinical Pharmacology (12.3)], which may increase the risk of DOSTINEX-associated adverse reactions.

12.1 Mechanism of Action

Cabergoline is an ergot derivative and dopamine receptor agonist with a high affinity for D2 receptors. Results of in vitro studies demonstrate that cabergoline exerts a direct inhibitory effect on the secretion of prolactin by rat pituitary lactotrophs. Cabergoline decreased serum prolactin levels in reserpinized rats. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α1- and α2-adrenergic, and 5-HT1- and 5-HT2-serotonin receptors.

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of DOSTINEX have not been fully characterized.

12.3 Pharmacokinetics

Absorption

The time to reach maximum cabergoline plasma concentration was 2 to 3 hours after single oral doses of 0.5 mg to 1.5 mg (1.5 times the maximum recommended dose) of DOSTINEX in healthy subjects. Following dosing of DOSTINEX between 0.5 mg to 7 mg (7 times the maximum recommended dose), cabergoline plasma levels appeared to be dose-proportional. The absolute bioavailability of cabergoline is unknown. A significant fraction of the administered dose undergoes a first-pass effect.

Effect of Food: High-fat food did not alter the pharmacokinetics of cabergoline [see Dosage and Administration (2.2)].

Distribution

Protein binding of cabergoline was 40% to 42%.

Elimination

The elimination half-life of cabergoline estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours.

Metabolism: Cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. 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 5 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.

Specific Populations

Patients with Hepatic Impairment:

In a pharmacokinetic hepatic impairment (HI) study [see Use in Specific Populations (8.6)]:

•

In 4 DOSTINEX-treated patients with mild HI (Child-Pugh A), no effect on mean area under the cabergoline plasma concentration-time curve (AUC) was observed.

•

In 4 DOSTINEX-treated patients with moderate HI (Child-Pugh B) there was a 1.5-fold increase in mean cabergoline AUC.

•

In 4 DOSTINEX-treated patients with severe HI (Child-Pugh C) there was a 5.6-fold increase in the mean cabergoline AUC.

Male and Female Patients: Males aged 20 to 34 years were shown to have had higher Cmax than females aged 20 to 27 years) while males aged 66 to 75 years had lower Cmax compared to females aged 66 to 74 years. The clinical significance of the findings is unknown.

Patients with Renal Impairment: The pharmacokinetics of cabergoline were not altered in 12 patients with moderate-to-severe renal impairment as assessed by creatinine clearance.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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/m2/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.

Mutagenesis

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.

Impairment of Fertility

In female rats, a daily cabergoline dose of 0.003 mg/kg for 2 weeks prior to mating and throughout the mating period inhibited conception. This dose represents approximately 0.04 times the maximum recommended human dose calculated on a body surface area basis using total mg/m2/week in rats and mg/m2/week for a 50 kg human. This finding is likely due to the role of prolactin in implantation in rats and is not thought to be relevant to humans.