Cabergoline: Package Insert and Label Information

CABERGOLINE- cabergoline tablet
Teva Pharmaceuticals USA, Inc.

DESCRIPTION

Cabergoline tablets USP contain cabergoline, USP, a dopamine receptor agonist. The chemical name for cabergoline, USP is 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea and has the following structural formula:

C₂₆ H₃₇ N₅ O₂ M.W. 451.6

Cabergoline, USP is a white powder soluble in ethyl alcohol, chloroform, and N, N-dimethylformamide (DMF); slightly soluble in 0.1N hydrochloric acid; very slightly soluble in n-hexane; and insoluble in water.

Each cabergoline tablet USP, for oral administration, contains 0.5 mg of cabergoline, USP and has the following inactive ingredients: anhydrous lactose and leucine.

CLINICAL PHARMACOLOGY

Mechanism of Action

The secretion of prolactin by the anterior pituitary is mainly under hypothalamic inhibitory control, likely exerted through release of dopamine by tuberoinfundibular neurons. Cabergoline is a long-acting 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.

Clinical Studies

The prolactin-lowering efficacy of cabergoline was demonstrated in hyperprolactinemic women in two randomized, double-blind, comparative studies, one with placebo and the other with bromocriptine. In the placebo-controlled study (placebo n = 20; cabergoline n = 168), cabergoline produced a dose-related decrease in serum prolactin levels with prolactin normalized after 4 weeks of treatment in 29%, 76%, 74% and 95% of the patients receiving 0.125, 0.5, 0.75, and 1 mg twice weekly respectively.

In the 8-week, double-blind period of the comparative trial with bromocriptine (cabergoline n = 223; bromocriptine n = 236 in the intent-to-treat analysis), prolactin was normalized in 77% of the patients treated with cabergoline at 0.5 mg twice weekly compared with 59% of those treated with bromocriptine at 2.5 mg twice daily. Restoration of menses occurred in 77% of the women treated with cabergoline, compared with 70% of those treated with bromocriptine. Among patients with galactorrhea, this symptom disappeared in 73% of those treated with cabergoline compared with 56% of those treated with bromocriptine.

Pharmacokinetics

Absorption

Following single oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult volunteers, mean peak plasma levels of 30 to 70 picograms (pg)/mL of cabergoline were observed within 2 to 3 hours. Over the 0.5 to 7 mg dose range, cabergoline plasma levels appeared to be dose-proportional in 12 healthy adult volunteers and nine adult parkinsonian patients. A repeat-dose study in 12 healthy volunteers suggests that steady-state levels following a once-weekly dosing schedule are expected to be two-fold to three-fold higher than after a single dose. The absolute bioavailability of cabergoline is unknown. A significant fraction of the administered dose undergoes a first-pass effect. The elimination half-life of cabergoline estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect of cabergoline may be related to its slow elimination and long half-life.

Distribution

In animals, based on total radioactivity, cabergoline (and/or its metabolites) has shown extensive tissue distribution. Radioactivity in the pituitary exceeded that in plasma by > 100-fold and was eliminated with a half-life of approximately 60 hours. This finding is consistent with the long-lasting prolactin-lowering effect of the drug. Whole body autoradiography studies in pregnant rats showed no fetal uptake but high levels in the uterine wall. Significant radioactivity (parent plus metabolites) detected in the milk of lactating rats suggests a potential for exposure to nursing infants. The drug is extensively distributed throughout the body. Cabergoline is moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. Concomitant dosing of highly protein-bound drugs is unlikely to affect its disposition.

Metabolism

In both animals and humans, cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. Cabergoline does not cause enzyme induction and/or inhibition in the rat. 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 five 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.

Special Populations

Renal Insufficiency

The pharmacokinetics of cabergoline were not altered in 12 patients with moderate-to-severe renal insufficiency as assessed by creatinine clearance.

Hepatic Insufficiency

In 12 patients with mild-to-moderate hepatic dysfunction (Child-Pugh score ≤ 10), no effect on mean cabergoline C_max or area under the plasma concentration curve (AUC) was observed. However, patients with severe insufficiency (Child-Pugh score > 10) show a substantial increase in the mean cabergoline C_max and AUC, and thus necessitate caution.

Elderly

Effect of age on the pharmacokinetics of cabergoline has not been studied.

Food-Drug Interaction

In 12 healthy adult volunteers, food did not alter cabergoline kinetics.

Pharmacodynamics

Dose response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been documented following single cabergoline doses to healthy volunteers (0.05 to 1.5 mg) and hyperprolactinemic patients (0.3 to 1 mg). In volunteers, prolactin inhibition was evident at doses > 0.2 mg, while doses ≥ 0.5 mg caused maximal suppression in most subjects. Higher doses produce prolactin suppression in a greater proportion of subjects and with an earlier onset and longer duration of action. In 12 healthy volunteers, 0.5, 1, and 1.5 mg doses resulted in complete prolactin inhibition, with a maximum effect within 3 hours in 92% to 100% of subjects after the 1 and 1.5 mg doses compared with 50% of subjects after the 0.5 mg dose.

In hyperprolactinemic patients (N = 51), the maximal prolactin decrease after a 0.6 mg single dose of cabergoline was comparable to 2.5 mg bromocriptine; however, the duration of effect was markedly longer (14 days vs. 24 hours). The time to maximal effect was shorter for bromocriptine than cabergoline (6 hours vs. 48 hours).

In 72 healthy volunteers, single or multiple doses (up to 2 mg) of cabergoline resulted in selective inhibition of prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH, and TSH) or cortisol.

INDICATIONS AND USAGE

Cabergoline tablets are indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.

CONTRAINDICATIONS

Cabergoline tablets are contraindicated in patients with:

• Uncontrolled hypertension or 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 (see WARNINGS).
• History of pulmonary, pericardial, or retroperitoneal fibrotic disorders (see WARNINGS).

WARNINGS

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.

Fibrotic Complications

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). Postmarketing cases of cardiac valvulopathy have been reported in patients receiving cabergoline. These cases have generally occurred during administration of high doses of cabergoline (> 2 mg/day) for the treatment of Parkinson’s disease. Cases of cardiac valvulopathy have also been reported in patients receiving lower doses of cabergoline 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 (95% CI: 5.2 to 19.4) for non-ergot DAs and 11.3 (95% CI: 7.2 to 17) 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.

Extracardiac Fibrotic Reactions

Postmarketing cases of pleural, pericardial, and retroperitoneal fibrosis have been reported 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 failure: Cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur.

Clinical and diagnostic monitoring such as erythrocyte sedimentation rate, chest x-ray, serum creatinine measurements, and other investigations should be considered at baseline and as necessary while patients are treated with cabergoline.

Following diagnosis of pleural effusion or pulmonary fibrosis, the discontinuance of cabergoline was reported to result in improvement of signs and symptoms.

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 tablets are 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 Postmarketing 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 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/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.

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/m² /week in rats and mg/m² /week for a 50 kg human.