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Logo DOSTINEX™ (Tablet)
SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DOSTINEX™ (Tablet)

COMPOSITION:
Each DOSTINEX tablet contains 0,5 mg cabergoline.

PHARMACOLOGICAL CLASSIFICATION:
A 21.12 Hormone inhibitors

PHARMACOLOGICAL ACTION:
DOSTINEX is a dopaminergic ergoline derivative with prolactin-lowering activity. It acts by direct stimulation of the D2-dopamine receptors on pituitary lactotrophs, thus selectively inhibiting prolactin secretion.
In addition, DOSTINEX exerts a central dopaminergic effect via D2-receptor stimulation at oral doses higher than those effective in lowering serum prolactin levels.
The prolactin-lowering effect of DOSTINEX is probably due to its persistence in the target organ as suggested by the slow elimination of total radioactivity from the pituitary after a single oral dose in rats (t½ of approximately 60 hours).
The pharmacodynamic effects of DOSTINEX have been studied in healthy volunteers, puerperal women and hyperprolactinemic patients. After a single oral administration of DOSTINEX (0,3-1,5 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 7-28 days in healthy volunteers and hyperprolactinemic patients and up to 14-21 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 DOSTINEX not related to the antiprolactinemic effect, available data from humans confirm the experimental findings in animals, indicating that the test compound has a selective action with no effect on basal secretion of other pituitary hormones or cortisol. The pharmacodynamic actions of DOSTINEX, not correlated with the therapeutic effect, only relate to blood pressure decrease. The maximal hypotensive effect of DOSTINEX as a single dose usually occurs during the first 6 hours after intake and is dose-dependent both in terms of maximal decrease and frequency.
Pharmacokinetics:
The elimination half-life of DOSTINEX, estimated from urinary excretion rates, is long (63-68 hours in healthy volunteers, 79-115 hours in hyperprolactinemic patients).
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 DOSTINEX obtained after a single dose (37 + 8 pg/mL) and after a 4 week multiple regimen (101 + 43 pg/mL).
In vitro experiments showed that the drug at concentrations of 0,1-10 ng/mL is 41-42% bound to plasma proteins.
Food does not appear to affect absorption and disposition of DOSTINEX.
Biliary excretion is the main route of elimination.
In rats DOSTINEX and/or its metabolites are excreted in milk; no information on its excretion in maternal milk in humans is available.

INDICATIONS:
Inhibition of lactation before the commencement of breastfeeding as well as inhibition of established lactation for medical reasons.
Not recommended for the routine suppression of lactation or for the relief of symptoms of postpartum pain and engorgement, which can be adequately treated with simple analgesics and breast support.
Treatment of hyperprolactinemic disorders.

CONTRA-INDICATIONS:
Pregnancy:
DOSTINEX is contra-indicated in confirmed or suspected pregnancy.
Before DOSTINEX is administered, pregnancy must be excluded and after treatment pregnancy must be prevented for at least a month. Pregnancy could occur in women treated for hyperprolactinemic hypogonadism before restoration of the menstrual cycle; it is advisable to carry out a pregnancy test at least every four weeks during the period of amenorrhea and afterwards every time the menstrual period is delayed by more than three days. The use of DOSTINEX does not appear to be linked to an increase in the number of abortions, premature delivery, multiple pregnancy or congenital abnormalities. However, since the clinical experience is still limited, as a precautionary measure women who wish to conceive are advised to stop taking DOSTINEX at least a month beforehand.
Women who do not wish to become pregnant should use a mechanical contraceptive during the treatment and after discontinuation until the ovulatory cycles cease.
When pregnancy is confirmed during the treatment, the use of DOSTINEX should be suspended, and as a precautionary measure, pituitary size should be monitored since expansion of pre-existent tumours could occur during pregnancy.
Breast-feeding:
Puerperal women should not breast-feed in case of failed lactation inhibition/suppression by DOSTINEX.
Hypersensitivity to any ergot alkaloid.
By analogy with other ergot derivatives, DOSTINEX should not be used in women with preeclampsia or post-partum hypertension.

WARNINGS:
The safety and efficacy of DOSTINEX have not been established in patients with renal and hepatic disease or in patients younger than 16 years.
Since available data indicate that biliary excretion represents the main route of elimination of the drug, it is advisable not to administer the drug to subjects with severe liver insufficiency.
Since hyperprolactinemia with amenorrhea/galactorrhea and infertility may be associated with pituitary tumours, a complete evaluation of the pituitary is indicated before treatment with DOSTINEX is initiated.

DOSAGE AND DIRECTIONS FOR USE:
DOSTINEX is to be administered by the oral route, preferably taken with meals.
Adults:
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). DOSTINEX should not be administered as a single dose greater than 0,25 mg in this indication since this reduces tolerability.
For treatment of hyperprolactinemic disorders the recommended initial dosage is 0,5 mg given in one or two doses 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 up to 4,5 mg per week have been used.
The dosage should preferably be adjusted according to prolactin blood levels.
Division of the weekly dose into multiple administrations is advised when doses higher than 1 mg per week are to be given.
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.
Once the effective therapeutic dosage regimen has been reached, serum prolactin normalisation is usually observed within two to four weeks.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-Effects:
In women treated for inhibition/suppression of physiological lactation the most frequently occurring adverse events are asymptomatic decreases in blood pressure, dizziness/vertigo, headache, nausea, somnolence and abdominal pain. In addition, rarely palpitations, epigastric pain, epistaxis, transient hemianopsia, vomiting, syncope, asthenia and hot flushes have been reported.
In patients treated for hyperprolactinemia the side-effects in decreasing rank of frequency were nausea, headache, dizziness/vertigo, abdominal pain, dyspepsia/gastritis, asthenia/fatigue, constipation, vomiting, breast pain, hot flushes, depression and paresthesia. Symptomatic hypotension or fainting were occasionally reported.
DOSTINEX generally exerts a hypotensive effect in patients. Symptoms mainly appear during the first two weeks of therapy and disappear despite continued therapy.
Being an ergot derivative, DOSTINEX may also act in some patients as a vasoconstrictor: digital vasospasm and leg cramps have been occasionally reported.

Precautions:
DOSTINEX should be given with caution to subjects with cardiovascular disease, Raynaud's syndrome, liver disease, renal insufficiency, peptic ulcer or history of psychotic disorders or gastro-intestinal bleeding.
Symptomatic hypotension can occur with DOSTINEX administration for any indication; monitoring of blood pressure is advised and care should be exercised when administering DOSTINEX concomitantly with other agents known to lower blood pressure.
During the first days of DOSTINEX administration, patients should be cautioned about re-engaging in activities requiring rapid and precise responses such as driving an automobile or operating machinery.

Interactions:
The concomitant use of other agents during early puerperium, particularly of methylergonovine maleate, has not been associated with detectable interactions modifying the efficacy and safety of DOSTINEX.
Although there is no conclusive evidence of an interaction between DOSTINEX and other ergot alkaloids, the concomitant use of these medications during therapy with DOSTINEX is not recommended.
Since DOSTINEX exerts its therapeutic effect by direct stimulation of dopamine receptors, it should not be concurrently administered with agents which have dopamine antagonist activity (such as phenothiazines, butyrophenones, thioxanthenes, metoclopramide), since these might reduce the prolactin-lowering effect of DOSTINEX.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
There is no experience in humans of overdosage with DOSTINEX used in the proposed indications. Overdosage is likely to lead to symptoms due to over-stimulation of dopamine receptors. These might include nausea, vomiting, gastric complaints, hypotension or thought/perception disturbances.
General supportive measures should be undertaken to remove any unabsorbed drug and maintain blood pressure if necessary. In addition, the administration of dopamine antagonist drugs may be advisable.

IDENTIFICATION:
Capsule-shaped, flat, white tablets. On the one surface the letter “P”appears on a side of the score and the letter “U”on the other. On the other surface the number “700”appears with a short score in the middle of the upper and lower extremity of the tablet surface.

PRESENTATION:
Amber glass bottles containing 2 or 4 tablets.

STORAGE INSTRUCTIONS:
Store at room temperature below 25°C and protect from light.
Keep out of reach of children.

REGISTRATION NUMBER:
28/21.12/0244

NAME AND ADDRESS OF APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George St
MIDRAND 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
1 September 1995

New addition to this site: February 2005
Source: Pharmaceutical Industry

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