Dostinex 0.500 mg

Since DOSTINEX exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with drugs that have dopamine-antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide) since these might reduce the prolactin-lowering effect of DOSTINEX.

Food is not noted to affect the absorption of DOSTINEX (see Dosage and Administration, Dosing Considerations and Action and Clinical Pharmacology, Pharmacokinetics).

By analogy with ergot derivatives, DOSTINEX should not be used in association with macrolide antibiotics (e.g., erythromycin) since systemic bioavailability and also adverse effects could increase.

Although there is no conclusive evidence of an interaction between DOSTINEX (cabergoline) and other ergot alkaloids, the concomitant use of these medications during long-term treatment with DOSTINEX is not recommended.

The recommended initial dosage of DOSTINEX is 0.5 mg per week given in one or two (one-half 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.

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 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 dosage 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 normalisation is usually observed within 2 to 4 weeks.

After a normal serum prolactin level has been maintained for 6 months, DOSTINEX may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with DOSTINEX should be reinstituted.

Since the tolerability of this class of compounds is improved when administered with food, it is recommended, that DOSTINEX (cabergoline) be taken with meals, for all the therapeutic indications. Food is not noted to affect the absorption of DOSTINEX (see Drug Interactions, Drug-Food Interactions, Action and Clinical Pharmacology, Pharmacokinetics).

For inhibition of physiological lactation the recommended therapeutic dosage is 1 mg (two 0.5 mg tablets) given as a single dose. DOSTINEX should be administered during the first day post-partum.

DOSTINEX is to be administered by the oral route.

If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time (e.g. 1 day) before the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

The following events have been reported in patients who have received cabergoline: aggression, alopecia, blood creatinine phosphokinase increased, delusions, dyspnea, edema, congenital abnormalities, fibrosis, hepatic function abnormal, hypersensitivity reaction, hypersexuality, increased libido, liver function tests abnormal, pathological gambling, psychotic disorder, rash, respiratory disorder, respiratory failure, sudden sleep onset, valvulopathy. It should be noted that the uncontrolled nature of post-marketing surveillance makes it difficult to determine definitively if a reported event was actually caused by cabergoline, or to reliably assess causation in individual cases (see Warnings and Precautions).

The prevalence of asymptomatic valvular regurgitation is significantly greater than that of non-ergot dopamine agonists (see Contraindications and Warnings and Precautions).

dry mouth, flatulence, diarrhea, anorexia.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

abnormal vision.

acne, pruritus.

facial edema, influenza-like symptoms, malaise.

Most side effects were transient and mild to moderate in severity. In women treated for inhibition of physiologic lactation the most frequently occurring adverse events were asymptomatic decreases in blood pressure, dizziness/vertigo, headache, nausea, and abdominal pain. In addition, on rare occasions, palpitations, epigastric pain, somnolence, epistaxis, and transient hemianopia have been reported (see Warnings and Precautions).

hypotension, syncope, palpitations.

somnolence, nervousness, paresthesia, insomnia, anxiety.

dysmenorrhea, increased libido.

nasal stuffiness, epistaxis.

The safety of cabergoline has been evaluated in approximately 1200 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, peripheral edema and sudden onset sleep. Heart failure, pleural effusion, pulmonary fibrosis, and gastric or duodenal ulcer occurred rarely. One case of constrictive pericarditis has been reported.

weight loss, weight gain.

Very limited data concerning experience of treatment of hyperprolactinemia in the elderly are available. However, available data do not indicate a special risk for this population.

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

DOSTINEX should be given with caution to subjects with renal insufficiency.

DOSTINEX should be given with caution to subjects with peptic ulcer and gastrointestinal bleeding.

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

Reproduction studies have been performed with cabergoline in mice, rats, and rabbits administered by gavage. 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. Before DOSTINEX administration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month.

DOSTINEX should be given with caution to subjects with a history of mental disease. Particular care should be taken when patients are taking concomitant psychoactive medication (see Drug Interactions).

Pathological gambling, aggression, psychotic behavior, 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.

As with other ergot derivatives, pleural effusion/pulmonary fibrosis has been reported following long-term administration of cabergoline. Therefore, DOSTINEX should not be used in patients with a history of, or current signs and/or symptoms of respiratory or cardiac disorders linked to fibrotic tissue (see Contraindications). 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. Following diagnosis of pleural effusion/pulmonary fibrosis, the discontinuance of cabergoline has been reported to result in improvement of signs and symptoms.

Since cabergoline is extensively metabolised by the liver, caution should be used, and careful monitoring exercised, when administering DOSTINEX to patients with hepatic impairment.

Very limited data concerning experience of treatment of hyperprolactinemia in the elderly are available. However, available data do not indicate a special risk for this population.

Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia and eclampsia, unless the potential benefit is judged to outweigh the possible risk.

Initial doses higher than 1 mg may produce orthostatic hypotension. Care should be exercised when administering DOSTINEX (cabergoline) with other medications known to lower blood pressure.

The effects of alcohol on overall tolerability of DOSTINEX are currently unknown.

Before DOSTINEX administration, pregnancy should be excluded and after treatment pregnancy should be prevented for at least one month.

Cabergoline has been associated with somnolence. Sudden sleep onset episodes that can be associated with dopamine agonists usually occur in patients with Parkinson’s disease. A reduction of dosage or termination of therapy may be considered.

Patients being treated with cabergoline should be warned of the potential for experiencing somnolence. Patients should be cautioned about engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) in case somnolence does occur.

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.

It is recommended that before initiating treatment with cabergoline all patients undergo a cardiovascular evaluation, including an echocardiogram, to assess potential presence of an occult valvular disease. Subsequent regular clinical diagnostic monitoring for development of valvular disease or fibrosis, as appropriate, is recommended (eg, physical examination, x-ray, echocardiogram, CT scan) (see Contraindications).

There have been post-marketing reports of cardiac valvulopathy involving one or more valves in patients taking DOSTINEX. The incidence of treatment emergent cardiac valvulopathy has not yet been determined, although some studies have suggested that the risk is cumulative, and asymptomatic cases of valvulopathy have been identified using echocardiography.

Valvulopathy has been reported with substantially greater frequency during treatment with ergot derivatives with 5-HT2B agonist activity, including cabergoline, compared to non-ergot dopamine agonists.

DOSTINEX is contraindicated in patients with a history of cardiac valvulopathy (see Contraindications). Physicians should inform patients/caregivers of the risk of cardiac valvulopathy.

It is recommended that before initiating treatment, patients undergo a cardiovascular evaluation, including an echocardiogram, to assess for the presence of occult valvular disease. Periodic clinical echocardiogram monitoring for development of valvular disease is recommended during treatment for all patients, although the ideal interval for sequential monitoring has not been established. Subsequent regular clinical diagnostic monitoring for development of valvular disease or fibrosis, as appropriate, is recommended (eg, physical examination, x-ray, echocardiogram, CT scan).

Based on information from animal studies, excretion in human milk is very likely. 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.

Due to this interference with lactation, DOSTINEX should not be given to women postpartum who are breastfeeding or who are planning to breastfeed.

A patient should be instructed to notify her physician if she suspects she is pregnant, becomes pregnant, or intends 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 her physician.

DOSTINEX should be given with caution to subjects with cardiovascular disease and Raynaud’s syndrome. Symptomatic hypotension can occur with DOSTINEX administration. Care should be exercised when administering DOSTINEX concomitantly with other drugs known to lower blood pressure.

Hepatic insufficiency of severe degree (>10 Child Pugh score, maximum score 12) has been shown to be associated with an increase of AUC (about six-fold).

In vitro experiments showed that the drug at concentrations of 0.1 to 10 ng/mL is 41% to 42% bound to plasma proteins.

The pharmacokinetic and metabolic profiles of cabergoline have been studied in healthy volunteers of both sexes and in female hyperprolactinemic patients.

After oral administration of the labeled compound, radioactivity was rapidly absorbed from the gastrointestinal tract as the peak of radioactivity in plasma was between 0.5 and 4 hours. Ten days after administration, about 18% and 72% of the radioactive dose of ¹⁴C cabergoline was recovered in the urine and feces, respectively. Unchanged drug in urine accounted for 2% to 3% of the dose. Food does not appear to affect absorption and disposition of cabergoline.

Cabergoline, the active ingredient in DOSTINEX (cabergoline), is a dopaminergic ergoline derivative endowed with a potent and long-lasting prolactin-lowering activity. It acts by direct stimulation of the D₂-dopamine receptors on pituitary lactotrophs, thus inhibiting prolactin secretion. In rats the compound decreases prolactin secretion at oral doses of 3 to 25 µg/kg, and in vitro at a concentration of 45 pg/mL. In addition, cabergoline exerts a central dopaminergic effect via D₂ receptor stimulation at oral doses higher than those effective in lowering serum prolactin levels.

The low urinary excretion of unchanged cabergoline has been confirmed also in studies with non radioactive product. The elimination half-life of cabergoline, estimated from urinary excretion rates, is long (63 to 68 hours in healthy volunteers and 79 to 115 hours in hyperprolactinemic patients as assessed by radioimmunoassay).

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

In urine, the main metabolite identified was 6-allyl-8b-carboxy-ergoline, which accounted for 4% to 6% of the dose. Three additional metabolites were identified in urine, which accounted overall for less than 3% of the dose. The metabolites have been found to be much less potent than cabergoline in inhibiting prolactin secretion in vitro.

The pharmacokinetics of cabergoline were found to be dose independent in healthy volunteers at doses of 0.5 to 1.5 mg. On the basis of the elimination half-life, steady state conditions should be achieved after 4 weeks, as confirmed by the mean peak plasma levels of cabergoline obtained after a single dose (37±8 pg/mL) and after a 4-week multiple-dose regimen (101±43 pg/mL). While renal insufficiency has been shown not to modify cabergoline kinetics, hepatic insufficiency of severe degree (>10 Child Pugh score, maximum score 12) has been shown to be associated with an increase of AUC.

The long-lasting prolactin-lowering effect of cabergoline is probably due to its long persistence in the target organ as suggested by the slow elimination of total radioactivity from the pituitary after a single oral dose in rats (t_½ of approximately 60 hours).

The pharmacodynamic effects of cabergoline have been studied in healthy volunteers, puerperal women and hyperprolactinemic patients. After a single oral administration of cabergoline (0.3 to 1.5 mg), a significant decrease in serum prolactin levels was observed in each of the populations studied. The effect is prompt (within 3 hours from administration) and persistent (up to 7 to 28 days in healthy volunteers and hyperprolactinemic patients, and up to 14 to 21 days in puerperal women). The prolactin lowering effect is dose-related both in terms of degree of effect and duration of action.

With regard to the endocrine effects of cabergoline not related to the antiprolactinemic effect, available data from humans confirm the experimental findings in animals indicating that the test compound is endowed with a selective action with no effect on basal secretion of other pituitary hormones or cortisol. The pharmacodynamic actions of cabergoline not correlated with the therapeutic effect relate only to blood pressure decrease. The maximal hypotensive effect of a single dose usually occurs during the first 6 hours after drug intake and is dose-dependent both in terms of maximal decrease and frequency.