Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1806
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Cabergoline (Tablet)
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The recommended dosage of cabergoline tablets for initiation of therapy is 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient's serum prolactin level. Before initiating treatment, cardiovascular evaluation should be performed and echocardiography should be considered to assess for valvular disease. Dosage increases should not occur more rapidly than every 4 weeks, so that the physician can assess the patient's response to each dosage level. If the patient does not respond adequately, and no additional benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and other therapeutic approaches considered. Patients receiving long- term treatment with cabergoline should undergo periodic assessment of their cardiac status and echocardiography should be considered. After a normal serum prolactin level has been maintained for 6 months, cabergoline may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with cabergoline should be reinstituted. The durability of efficacy beyond 24 months of therapy with cabergoline has not been established.
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Cabergoline is a dopamine receptor agonist. The chemical name for cabergoline is 1-[(6-allylergolin-8��-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea and has the following structural formula: CHNOM. W. 451.62 Cabergoline 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, for oral administration, contains 0.5 mg of cabergoline and has the following inactive ingredients: anhydrous lactose and leucine.
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Mechanism of Action: The secretion of prolactin by the anterior pituitary is mainly under hypothalmic inhibitory control, likely exerted through release of dopamine by tuberoinfundibular neurons. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for Dreceptors. 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 D,��- and��- adrenergic, and 5-HT- and 5-HT-serotonin receptors.<br/>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.<br/>Pharmacokinetics:<br/>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.<br/>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.<br/>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.<br/>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.<br/>Special Populations:<br/>Renal Insufficiency: The pharmacokinetics of cabergoline were not altered in 12 patients with moderate-to-severe renal insufficiency as assessed by creatinine clearance.<br/>Hepatic Insufficiency: In 12 patients with mild-to-moderate hepatic dysfunction (Child-Pugh score���10), no effect on mean cabergoline Cor 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 Cand AUC, and thus necessitate caution.<br/>Elderly: Effect of age on the pharmacokinetics of cabergoline has not been studied.<br/>Food-Drug Interaction: In 12 healthy adult volunteers, food did not alter cabergoline kinetics.<br/>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.
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Cabergoline tablets are contraindicated in patients with
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Cabergoline Tablets are available as white, oval-shaped, scored tablets, debossed ,���0.5���with a score on one side and���5420���on the other side containing 0.5 mg cabergoline, packaged in bottles of 8 tablets. PHARMACIST: Dispense in a tight container as defined in the USP. Use child-resistant closure (as required). Store at 20��to 25��C (68��to 77��F) [See USP Controlled Room Temperature]. Made In Czech Republic By: IVAX PHARMACEUTICALS s.r.o. Opava-Komarov, Czech Republic Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 0093 12/07 B3 CABERGOLINE TABLETS
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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.<br/>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.<br/>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.<br/>Fibrosis: As with other ergot derivatives, pleural effusion or pulmonary fibrosis have been reported following long-term administration of cabergoline. Some reports were in patients previously treated with ergotinic dopamine agonists. Cabergoline should not be used in patients with a history of, or current signs and or clinical symptoms of, respiratory or cardiac disorders linked to fibrotic tissue. Following diagnosis of pleural effusion or pulmonary fibrosis, the discontinuance of cabergoline has been reported to result in improvement of signs and symptoms. Erythrocyte sedimentation rate (ESR) has been found to be abnormally increased in association with pleural effusion/fibrosis. Chest x-ray examination is recommended in cases of unexplained ESR increases to abnormal values. Serum creatinine measurements can also be used to help in the diagnosis of fibrotic disorder.<br/>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.<br/>Drug Interactions: Cabergoline should not be administered concurrently with D-antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide.<br/>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/week in rodents and mg/m/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 Pand V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D, 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/week in rats and mg/m/week for a 50 kg human.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>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.<br/>Pediatric Use: Safety and effectiveness of cabergoline in pediatric patients have not been established.<br/>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.
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Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to support blood pressure should be taken if necessary.
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Cabergoline
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Cabergoline (Tablet)
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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. 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. Other adverse events that were reported at an incidence of<1% 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.<br/>Postmarketing Surveillance Data: The following events have been reported in association with cabergoline: valvulopathy and fibrosis (see WARNINGS, Valvulopathy and PRECAUTIONS, Fibrosis). Other events have been reported in association with cabergoline: hypersexuality, increased libido, pathological gambling (see PRECAUTIONS, Psychiatric). In addition, during postmarketing surveillance, 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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Valvulopathy: Postmarketing cases of cardiac valvulopathy have been reported in patients receiving cabergoline. These cases have generally occurred during long-term administration of high doses of cabergoline (>2mg/day) used for the treatment of Parkinson's disease. Rare cases have been reported associated with short-term treatment (<6 months) or in patients receiving lower doses for the treatment of hyperprolactinemia. Physicians should use the lowest effective dose of cabergoline for the treatment of hyperprolactinemia and should periodically reassess the need for continuing therapy with cabergoline. In addition, patients receiving long-term treatment with cabergoline should undergo periodic reassessment of their cardiac status, and echocardiography should be considered. Any patient who develops signs or symptoms of cardiac disease, including dyspnea, edema, congestive heartfailure, or a new cardiac murmur, while being treated with cabergoline should be evaluated for possible valvulopathy. Cabergoline should be used with caution in patients who have hemodynamically significant valvular disease or have been exposed to other medications associated with valvulopathy.<br/>Pregnancy: Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia, eclampsia, and post partum hypertension, unless the potential benefit is judged to outweigh the possible risk.
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Cabergoline tablets are indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.
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Cabergoline
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