Dostinex

/ Pfizer

General: Dostinex is to be administered by the oral route. Since the tolerability of this class of compounds is improved with food, it is recommended that Dostinex be preferably taken with meals for all the therapeutic indications. In patients known to be intolerant to dopaminergic drugs, the likelihood of adverse events may be lessened by starting therapy with DOSTINEX at reduced doses (e.g., 0.25 mg once a week) with subsequent gradual increase until the therapeutic dosage is reached. If persistent or severe adverse events occur, temporary reduction of dosage followed by a more gradual increase (e.g., increments of 0.25 mg per week every two weeks) may increase tolerability.
Inhibition/suppression of physiological lactation: For inhibition of lactation: Dostinex should be administered during the first day post-partum. The recommended therapeutic dosage is 1 mg (two 0.5 mg tablets) given as a single dose.
For suppression of established lactation: The recommended therapeutic dosage regimen is 0.25 mg (one half 0.5 mg tablet) every 12 hours for two days (1 mg total dose).
Treatment of hyperprolactinemic disorders: The recommended initial dosage of Dostinex is 0.5 mg per week given in one or two (onehalf of one 0.5 mg tablet) doses (e.g. on Monday and Thursday) per week. The weekly dose should be increased gradually, preferably by adding 0.5 mg per week at monthly intervals until an optimal therapeutic response is achieved. The therapeutic dosage is usually 1 mg per week and ranges from 0.25 mg to 2 mg per week. Doses of Dostinex up to 4.5 mg per week have been used in hyperprolactinemic patients. The weekly dose may be given as a single administration or divided into two or more doses per week according to patient tolerability. Division of the weekly dose into multiple administrations is advised when doses higher than 1 mg per week are to be given since the Dostinex, Israel 14 July 2010 tolerability of doses greater than 1 mg taken as a single weekly dose has been evaluated only in a few patients. Patients should be evaluated during dose escalation to determine the lowest dose that produces the therapeutic response. Monitoring of serum prolactin levels at monthly intervals is advised since, once the effective therapeutic dosage regimen has been reached, serum prolactin normalization is usually observed within two to four weeks. After Dostinex withdrawal, recurrence of hyperprolactinemia is usually observed. However, persistent suppression of prolactin levels has been observed for several months in some patients. In most women, ovulatory cycles persist for at least 6 months after Dostinex discontinuation.
Patients with Severe Hepatic Insufficiency: Lower doses of DOSTINEX should be considered in patients with severe hepatic insufficiency.
Children: Safety and efficacy of Dostinex has not been established in patients younger than 16 years.
Elderly: Dostinex has not been formally studied in elderly patients with hyperprolactinemic disorders.
For full details see prescribing information.

Treatment of hyperprolactinemic disorders.
Treatment of dysfunctions associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation and galactorrhea.
Indicated in patients with prolactin-secreting pituitary adenomas (micro-and macroprolactinomas), idiopathic hyperprolactinemia, or empty sella syndrome with associated hyperprolactinemia. Inhibition and suppression of lactation.

Hypersensitivity to cabergoline, any of the excipients or any ergot
alkaloid.
History of pulmonary, pericardial and retroperitoneal fibrotic disorders.
Cabergoline is contraindicated in patients with hepatic insufficiency and with toxaemia of pregnancy. Cabergoline should not be co-administered with anti-psychotic medications or administered to women with a history of puerperal psychosis.
For long-term treatment: Evidence of cardiac valvulopathy as determined by pre-treatment echocardiography.

General: The safety and efficacy of cabergoline have not yet been established in patients with renal and hepatic disease. As with other ergot derivatives, cabergoline should be given with caution to patients with severe cardiovascular disease, Raynaud’s syndrome, renal insufficiency, peptic ulcer or gastrointestinal bleeding, or with a history of serious, particularly psychotic, mental disorders. Particular care should be taken when patients are taking concomitant psychoactive
medication.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Symptomatic hypotension can occur with cabergoline administration for any indication. Care should be exercised when administering cabergoline concomitantly with other drugs known to lower blood pressure.
The effects of alcohol on overall tolerability of cabergoline are currently unknown.
Before cabergoline administration, pregnancy should be excluded and after treatment
pregnancy should be prevented for at least one month.
Hepatic Insufficiency: Lower doses should be considered in patients with severe hepatic insufficiency who receive prolonged treatment with cabergoline.
Postural Hypotension: Postural hypotension can occur following administration of cabergoline. Care should be exercised when administering cabergoline concomitantly with other drugs known to lower blood pressure.
Somnolence/Sudden Sleep Onset: Cabergoline has been associated with somnolence. Dopamine agonists can be associated with sudden sleep onset episodes in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with cabergoline. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction in dosage or termination of therapy may be considered.
Impulse control disorders: Patients should be regularly monitored for the development of impulse control disorders.
Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Inhibition/suppression of physiological lactation: As with other ergot derivatives, cabergoline should not be used in women with pregnancyinduced hypertension, for example, post-partum hypertension, unless the potential benefit is judged to outweigh the possible risk, except for toxaemia of pregnancy.
Serious adverse events including hypertension, myocardial infarction, seizures, stroke or psychiatric disorders have been reported in postpartum women treated with cabergoline for inhibition of lactation. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances. Blood pressure should be carefully monitored after the treatment. If hypertension, suggestive chest pain, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of central nervous system toxicity develop, cabergoline should be discontinued and the patient should be evaluated promptly.
In post-partum studies with cabergoline, blood pressure decreases were mostly asymptomatic and were frequently observed on a single occasion 2 to 4 days after treatment. Since decreases in blood pressure are frequently noted during the puerperium, independently of drug therapy, it is likely that many of the observed decreases in blood pressure after cabergoline administration were not drug-induced. However, periodic monitoring of blood pressure, particularly during the first few days after cabergoline administration, is advised.
A single dose of 0.25 mg of cabergoline should not be exceeded in nursing women treated for suppression of established lactation to avoid potential postural hypotension.
Treatment of hyperprolactinaemic disorders: Because hyperprolactinaemia accompanied with amenorrhoea/galactorrhoea and infertility may be associated with pituitary tumour, a complete evaluation of the pituitary is indicated before treatment with cabergoline is initiated.
Cabergoline restores ovulation and fertility in women with hyperprolactinaemic
hypogonadism.
Because pregnancy might occur prior to reinitiation of menses, a pregnancy test is
recommended at least every four weeks during the amenorrhoeic period and, once menses are reinitiated, every time a menstrual period is delayed by more than three days. Women who wish to avoid pregnancy should be advised to use mechanical contraception during treatment with cabergoline and after discontinuation of cabergoline until recurrence of anovulation. As a precautionary measure, women who become pregnant should be monitored to detect signs of pituitary enlargement since expansion of pre-existing pituitary tumours may occur during gestation.
Before administration of cabergoline, pregnancy should be excluded. Because clinical
experience is still limited and the product has a long half-life, as a precautionary measure it is recommended that once regular ovulatory cycles have been achieved women seeking pregnancy discontinue cabergoline one month before intended conception. Should pregnancy occur during treatment, cabergoline is to be discontinued.
Fibrosis and cardiac valvulopathy and possibly related clinical phenomena: Fibrotic and serosal inflammatory disorders such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis have occurred after prolonged usage of ergot derivatives with agonist activity at the serotonin 5HT2B receptor, such as cabergoline. In some cases, symptoms or manifestations of cardiac valvulopathy improved after discontinuation of cabergoline.
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.
Valvulopathy has been associated with cumulative doses, therefore, patients should be treated with the lowest effective dose.
Before initiating long-term treatment: All patients must undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of asymptomatic valvular disease. It is also appropriate to perform baseline investigations of erythrocyte sedimentation rate or other inflammatory markers, lung function/chest X-ray and renal function prior to initiation of therapy. In patients with valvular regurgitation, it is not known whether cabergoline treatment might worsen the underlying disease. If fibrotic valvular disease is detected, the patient should not be treated with cabergoline.
During long-term treatment: Fibrotic disorders can have an insidious onset and patients should be regularly monitored for possible manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of:
-Pleuro-pulmonary disease such as dyspnoea, 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 oedema 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 diagnostic monitoring for development of fibrotic disorders, as appropriate, is essential. Following treatment initiation, the first echocardiogram must occur within 3-6 months, thereafter, the frequency of echocardiographic monitoring should be determined by appropriate individual clinical assessment with particular emphasis on the above-mentioned signs and symptoms, but must occur at least every 6 to 12 months.
Cabergoline should be discontinued if an echocardiogram reveals new or worsened valvular regurgitation, valvular restriction or valve leaflet thickening.
The need for other clinical monitoring (e.g. physical examination including, cardiac
auscultation, X-ray, CT scan) should be determined on an individual basis.
Additional appropriate investigations such as erythrocyte sedimentation rate, and serum creatinine measurements should be performed if necessary to support a diagnosis of a fibrotic disorder.
See prescribing information for full details.

Very common: Valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion), headache, dizziness/vertigo, nausea, dyspepsia, gastritis, abdominal pain, asthenia, fatigue.
Common: Somnolence, depression, cabergoline generally exerts a hypotensive effect in patients on long-term treatment, postural hypotension, hot flushes, constipation, vomiting, breast pain, asymptomatic decreases in blood pressure. See prescribing information for full details.

Neuroleptics, dopamine antagonists, ergot alkaloids, macrolides, antihypertensives.

There are no adequate and well-controlled studies from the use of cabergoline in pregnant women. Animal studies have not demonstrated teratogenic effects, but reduced fertility and embryo-toxicity were observed in association with pharmacodynamic activity.
Cabergoline should only be used during pregnancy if clearly indicated and after an accurate benefit/risk evaluation.
Due to the long half-life of the drug and limited data on in utero exposure, women planning to become pregnant should discontinue cabergoline one month before intended conception. If conception occurs during therapy, treatment should be discontinued as soon as pregnancy is confirmed to limit foetal exposure to the drug.
See prescribing information for full details.

Symptoms of overdose would likely be those of over-stimulation of dopamine receptors e.g. nausea, vomiting, gastric complaints, postural hypotension, confusion/psychosis or hallucinations.
Supportive measures should be taken to remove any unabsorbed drug and maintain blood pressure, if necessary. In addition, the administration of dopamine antagonist drugs may be advisable.