DOSTINEX 0,5 mg Tablet HDPE Bottle 8

White, flat, oblong tablet, bearing the mark "PU" separated by a breaking line on one side, and the mark "700" separated by a slight breaking line above and below the central "0" on the other side.

The tablet can be divided into equal doses.

For one tablet:

Cabergoline: 0,5 mg

Excipient with known effect: lactose.

DOSTINEX 0,5 mg, tablet contains 75,9 mg of lactose per tablet.

Excipients:

• Inhibition/suppression of lactation for medical reasons:
  • for inhibition of physiological lactation shortly after delivery,
  • for suppression of established lactation.
• Idiopathic hyperprolactinaemia.
• Hyperprolactinaemia related to the presence of a pituitary microadenoma or macroadenoma, and their clinical manifestations:
  • in women: galactorrhoea, oligo- or amenorrhoea, infertility;
  • in men: gynaecomastia, impotence.

Dosage

Inhibition/suppression of physiological lactation for medical reasons

For inhibition of lactation : the recommended dose is 1 mg (two tablets of 0,5 mg) administered as a single dose. DOSTINEX must be administered within the first 24 hours post-partum.

For suppression of established lactation : the recommended dosage is 0,25 mg (half a 0,5 mg tablet) every 12 hours for 2 days (total dose of 1 mg)

This dose must not be exceeded in breastfeeding women treated to stop established lactation, in order to avoid possible orthostatic hypotension (see section Warnings and precautions).

Treatment of hyperprolactinaemic disorders

The initial dosage is 0,5 mg per week as a single dose, i.e. 1 tablet per week.

This dosage of 0,5 mg per week will be maintained for 4 weeks, then adjusted according to prolactinaemia, which will be measured the day before taking a tablet. The dosage will either be maintained or increased in steps of 0,5 mg according to prolactinaemia measured at most every four weeks until an optimal response to treatment is obtained.

Once the dosage has been balanced, a quarterly measurement of prolactinaemia is sufficient. Most patients are controlled with a dose less than or equal to 1 mg/week. In this case, a single weekly dose is sufficient. The dosage may vary from 0,25 to 2 mg, or even up to 4,5 mg per week. When the dosage exceeds 1 mg, it is recommended to divide the weekly dose into two or more doses depending on the patient's tolerance.

To improve tolerance, the medicine should be administered in the middle of a meal, preferably in the evening, or at bedtime with a light snack.

This medicine MUST NEVER BE prescribed in the following cases:

• hypersensitivity to the active substance, to any ergot derivative or to any of the excipients listed in section Composition,
• history of pulmonary, pericardial and retroperitoneal fibroses,
• association with antiemetic neuroleptics and antipsychotic neuroleptics (except clozapine) (see section Interactions),
• for long-term treatment: sign of cardiac valvulopathy detected during echocardiography prior to treatment (see section Warnings and precautions - Fibrosis and cardiac valvulopathy and related clinical phenomena).

General

Like other ergot derivatives, cabergoline must be administered with caution to patients with severe cardiovascular disease, obliterative vascular disorders (including coronary insufficiency), Raynaud's syndrome, peptic ulcers or gastrointestinal bleeding, or with a history of severe mental disorders, particularly psychotic ones.

Hepatic impairment

The use of lower doses should be considered in patients with severe hepatic impairment receiving prolonged treatment with cabergoline. In patients with severe hepatic impairment (C in the Child-Pugh classification) receiving a single dose of 1 mg, a greater increase in AUC was observed compared with healthy volunteers or with less severe hepatic impairment.

Orthostatic hypotension

Blood pressure monitoring during the first days of treatment is necessary due to the risk of orthostatic hypotension. Particular monitoring should also be carried out when cabergoline is administered concomitantly with other treatments known to lower blood pressure.

Fibrosis and cardiac valvulopathy and related clinical phenomena

Fibrotic and serous inflammatory disorders, for example pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy affecting one or more valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis, have occurred after prolonged use of ergot derivatives with agonist activity on the 5HT receptor_2B of serotonin, such as cabergoline. In some cases, symptoms or manifestations of cardiac valvulopathy regressed after discontinuation of cabergoline.

An abnormal elevation of the erythrocyte sedimentation rate (ESR) has been observed in association with pleural effusion/fibrosis. It is recommended to perform a chest X-ray in case of unexplained elevations of ESR to abnormal values.

Cases of valvulopathy have been associated with the administration of cumulative doses; patients should therefore be treated at the minimum effective dose. At each visit, the benefit/risk balance of cabergoline treatment for the patient should be re-evaluated to determine whether it is appropriate to continue cabergoline treatment.

Before starting long-term treatment

All patients must undergo a cardiovascular assessment including performance of an echocardiogram to evaluate the potential presence of asymptomatic valvular pathology. It is also appropriate to determine the erythrocyte sedimentation rate or measure other inflammation markers and to examine lung function, perform a chest X-ray and assess renal function before starting treatment.

It is not known whether treatment with cabergoline is likely to worsen an underlying valvular regurgitation. In cases of fibrotic valvular pathology, do not treat the patient with cabergoline (see section Contraindications).

During long-term treatment

Fibrotic disorders may have an insidious onset; patients should therefore be regularly checked for possible manifestations of progressive fibrosis.

Therefore, during treatment, signs and symptoms should be monitored for:

• pleuropulmonary disease: dyspnoea, shortness of breath, persistent cough or chest pain;
• renal insufficiency or ureteral/abdominal vascular obstruction which may be accompanied by pain in the kidneys/flanks and oedema of the lower limbs, as well as masses or tender points in the abdomen which may indicate retroperitoneal fibrosis;
• heart failure; cases of valvular and pericardial fibrosis observed have often presented as heart failure. If this type of symptom appears, valvular fibrosis (and constrictive pericarditis) should be ruled out.

Clinical diagnostic monitoring for the onset of fibrotic disorders is essential. Once treatment has started, the first echocardiogram should be performed after 3 to 6 months; thereafter, the frequency of echocardiographic follow-up should be determined based on individual clinical assessment, paying particular attention to the signs and symptoms mentioned above, but in all cases an echocardiogram should be performed at least every 6 to 12 months.

Administration of cabergoline should be stopped if the echocardiogram reveals the onset or worsening of valvular regurgitation, valvular restriction or thickening of a valve leaflet (see section Contraindications).

The need for further clinical follow-up examinations (for example clinical examination including cardiac auscultation, radiography, CT scan) should be determined on a case-by-case basis.

Appropriate additional investigations, for example erythrocyte sedimentation rate and serum creatinine measurements, should be performed if necessary to confirm the diagnosis of fibrotic disorder.

Somnolence/Sudden onset of sleep

Somnolence and episodes of sudden onset sleep have been reported during treatment with dopamine agonists including cabergoline, particularly in patients with Parkinson's disease.

Sudden falling asleep during daily activities, in some cases without warning, has been reported in a few uncommon cases. Patients must be informed of the possibility of these effects and advised to exercise caution when driving or using machines during treatment with cabergoline. Patients who have experienced somnolence or episodes of sudden onset sleep must not drive vehicles or use machines. A reduction in dose or discontinuation of treatment may be considered (see section Driving and using machines).

Inhibition/suppression of physiological lactation for medical reasons

As with other ergot derivatives, cabergoline should not be used in women with pregnancy-induced hypertension, for example, pre-eclampsia or postpartum hypertension, unless the potential benefit is judged to outweigh the possible risk.

A single dose of 0,25 mg of cabergoline should not be exceeded in breastfeeding women treated for suppression of established lactation, in order to avoid possible orthostatic hypotension (see section Dosage and administration "Inhibition/suppression of physiological lactation" and the above subsection "Orthostatic hypotension").

Treatment of hyperprolactinaemic disorders

Hyperprolactinaemia accompanied by amenorrhoea/galactorrhoea and infertility, which may be associated with a pituitary tumour, a complete evaluation of the pituitary is recommended before cabergoline treatment is initiated.

In case of signs of tumour expansion (visual field impairment or headaches), management in a specialised setting is necessary and appropriate treatment must be undertaken.

Before administering cabergoline, a possible pregnancy must be excluded. As cabergoline may restore ovulation and fertility, an adequate method of contraception must be adopted in women who do not wish to become pregnant during and after treatment.

In the absence of contraception, as pregnancy may occur before menses return, it is recommended to perform a pregnancy test at least every 4 weeks during the period of amenorrhoea and, once menses have resumed, each time there is a menstrual delay of more than 3 days.

Due to limited clinical experience and the prolonged half-life of the product, as a precaution it is recommended that women wishing to become pregnant stop taking cabergoline one month before the planned conception date once regular ovulatory cycles have been restored (see section Fertility, pregnancy and breastfeeding) and after treatment a period of one month should be observed before pregnancy.

In case of a pituitary adenoma in a pregnant woman, and in particular if treatment has been interrupted, careful monitoring of the adenoma throughout pregnancy is essential.

Impulse control disorders

Patients should be regularly monitored for the occurrence of impulse control disorders. Patients and caregivers should be informed that impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, excessive food consumption (binge eating) and compulsive eating may occur in patients treated with dopamine agonists, including cabergoline. A dose reduction or gradual discontinuation should be considered if these symptoms occur.

Serious adverse events in postpartum women

Serious adverse events, including hypertension, myocardial infarction, convulsions, stroke or psychiatric disorders, have been reported in postpartum women treated with cabergoline for inhibition of lactation. In some patients, the occurrence of convulsions or stroke was preceded by severe headaches and/or transient visual disturbances. Blood pressure should be carefully monitored during treatment. In case of hypertension, suggestive chest pain, severe, progressive or persistent headaches (with or without visual disturbances) or signs of central nervous system toxicity, cabergoline intake must be discontinued and the patient must be promptly evaluated.

Excipients

Patients with galactose intolerance, total lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

Contraindicated combinations

+ Antipsychotic neuroleptics (except clozapine)

Reciprocal antagonism between the dopamine agonist and neuroleptics.

In case of neuroleptic-induced extrapyramidal syndrome, do not treat with a dopamine agonist but use an anticholinergic.

+ Antiemetic neuroleptics

Reciprocal antagonism between the dopaminergic agent and the neuroleptic.

Use an antiemetic free of extrapyramidal effects.

Combinations not recommended

+ Vasoconstrictor ergot alkaloids of rye

Risk of vasoconstriction and/or hypertensive surges.

+ Macrolides (except spiramycin)

Increase in plasma concentrations of cabergoline with possible increase in its activity or appearance of signs of overdose.

+ Alpha-sympathomimetics (oral and/or nasal route)

Risk of vasoconstriction and/or hypertensive surges.

+ Indirect sympathomimetics

Risk of vasoconstriction and/or hypertensive surges.

+ Tetrabenazine

Reciprocal antagonism between dopaminergic agents and tetrabenazine.

+ Alcohol consumption

Alcohol increases the sedative effect of these substances. Impaired alertness may make driving vehicles and using machines dangerous.

Avoid taking alcoholic beverages and medicines containing alcohol.

Associations requiring precautions for use

+ Anticholinergic antiparkinsonian agents

Risk of worsening neuropsychiatric disorders. Regular clinical and biological monitoring, particularly at the start of the combination.

Associations to be taken into account

+ Other sedative medicines

Increased central depression. Impaired alertness may make driving vehicles and using machines dangerous.

Pregnancy

No adequate and well-controlled studies have been conducted on the use of cabergoline in pregnant women. Animal studies have not shown a teratogenic effect, but reduced fertility and embryotoxicity have been observed in relation to the pharmacodynamic activity (see section Preclinical safety).

Information is available on 256 pregnancies from an observational study conducted over twelve years on pregnancy outcomes after treatment with cabergoline. Seventeen of these 256 pregnancies (6,6%) resulted in major congenital malformations or abortion. Information is available for 23 newborns out of 258, with 27 neonatal abnormalities in total, both major and minor. Musculoskeletal malformations were the most frequent neonatal abnormality (10), followed by cardiopulmonary abnormalities (5). There is no information on perinatal disorders or the long-term development of exposed newborns in utero to cabergoline. Recent publications in the literature report a prevalence of at least 6,9 % of major congenital malformations in the general population. Rates of congenital abnormalities vary between populations. It is not possible to determine precisely whether there is an increased risk of congenital malformations, as no control group was included.

Cabergoline should be used during pregnancy only if it is truly indicated and after careful assessment of the benefit/risk ratio (see section Warnings and precautions - Treatment of hyperprolactinaemic disorders).

Given the long half-life of this medicinal product and the limited data on in utero exposure, women planning a pregnancy are recommended to stop cabergoline treatment one month before the planned time of conception. If the patient becomes pregnant during treatment, treatment should be discontinued as soon as pregnancy is confirmed in order to limit the foetus's exposure to the medicinal product.

Breast-feeding

In rats, cabergoline and/or its metabolites are excreted in milk.

There are no data on the excretion of cabergoline in human breast milk; however, if cabergoline does not inhibit lactation, breastfeeding is not recommended.

Cabergoline should not be administered to women with hyperprolactinaemic disorders who wish to breastfeed, as it inhibits lactation.

During the initiation phase of treatment, patients should be cautious when performing tasks that require rapid and precise reactions.

Particularly at the start of treatment, drivers of vehicles and users of machinery should be made aware of the risk of hypotension and dizziness associated with the use of this medicinal product.

Patients treated with cabergoline who experience somnolence and/or episodes of sudden onset sleep should be informed that they must not drive vehicles or engage in activities where impaired alertness could expose themselves or others to a risk of serious accident or death (for example operating machinery), until these episodes and this somnolence have resolved (see section Warnings and precautions - Somnolence/sudden onset of sleep).

The following undesirable effects have been observed and reported during treatment with cabergoline at the following frequencies: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1 000 to < 1/100), rare (> 1/10 000 to < 1/1 000), very rare (< 1/10 000), frequency not known (cannot be estimated from the available data).

System Organ Class MedDRA	Frequency	Adverse effects
Cardiac disorders	Very common	Valvular heart disease (including regurgitation) and associated disorders (pericarditis and pericardial effusion)
	Uncommon	Palpitations
	Unknown	Angina pectoris
Respiratory, thoracic and mediastinal disorders	Uncommon	Dyspnea, pleural effusion, fibrosis (notably pulmonary fibrosis), epistaxis
	Very rare	Pleural fibrosis
	Unknown	Respiratory disorders, respiratory insufficiency, pleuritic chest pain
Immune system disorders	Uncommon	Hypersensitivity reaction
Nervous system disorders	Very common	Headache*, dizziness/vertigo*
	Common	Somnolence
	Uncommon	Transient hemianopia, syncope, paresthesias
	Unknown	Sudden onset of sleep, tremor
Eye disorders	Unknown	Abnormal vision
Psychiatric disorders	Common	Depression
	Uncommon	Increased libido
	Unknown	Aggressiveness, delirium, hypersexuality, pathological gambling, psychotic disorders, hallucinations
Vascular disorders	Common	Generally, DOSTINEX exerts a hypotensive effect in patients treated long-term, orthostatic hypotension, hot flushes**
	Uncommon	Raynaud's syndrome, loss of consciousness
Gastrointestinal disorders	Very common	Nausea*, dyspepsia, gastritis, abdominal pain*
	Common	Constipation, vomiting**
	Rare	Epigastric pain
General disorders and administration site conditions	Very common	Asthenia***, fatigue
	Uncommon	Oedema, peripheral oedema
Hepato-biliary disorders	Unknown	Abnormal liver function
Skin and subcutaneous tissue disorders	Uncommon	Rash, alopecia
Musculoskeletal and systemic disorders	Uncommon	Leg cramps
Disorders of the reproductive organs and breast	Common	Breast pain
Investigations	Common	Asymptomatic decreases in blood pressure (≥ 20 mmHg for systolic pressure and ≥ 10 mmHg for diastolic pressure)
	Uncommon	A decrease in haemoglobin levels has been observed in amenorrhoeic women in the first months following the return of menstruation
	Unknown	Increased creatine phosphokinase in the blood, abnormal liver function tests

* Very common in patients treated for hyperprolactinaemic disorders, common in female patients treated for inhibition or cessation of lactation.

** Common in patients treated for hyperprolactinaemic disorders, uncommon in female patients treated for inhibition or cessation of lactation.

*** Very common in patients treated for hyperprolactinaemic disorders, uncommon in female patients treated for inhibition or cessation of lactation.

Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, excessive food consumption (binge eating) and compulsive eating, are disorders that may occur in patients treated with dopamine agonists, including cabergoline (see section Warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: www.signalement-sante.gouv.fr.

No experience of acute overdose has been reported. An overdose would probably cause symptoms related to hyperstimulation of dopaminergic receptors: nausea and vomiting, gastric disorders, headache and dizziness, orthostatic hypotension, confusion/psychosis or hallucinations.

Symptomatic treatment should be instituted to eliminate the unabsorbed medicinal product and to maintain blood pressure if necessary. Administration of a dopaminergic antagonist treatment may be considered.

Pharmacotherapeutic class: PROLACTIN INHIBITOR, ATC code: G02CB03

Cabergoline is a D₂ dopamine agonist derived from ergot of rye with a potent and prolonged prolactin secretion-inhibiting activity. It acts by direct stimulation of D₂-dopaminergic receptors on the lactotroph cells of the pituitary gland, inhibiting prolactin secretion.

The prolactin-inhibiting effect is dose-dependent, appears within three hours of administration and persists for two to three weeks. Due to the long duration of action, a single dose is generally sufficient to inhibit lactation. In the treatment of hyperprolactinaemia, serum prolactin concentrations are generally normalised two to four weeks after the optimal dose is reached. Prolactinaemia may still be significantly decreased several months after treatment is stopped.

With regard to the endocrine effects of cabergoline not related to its anti-prolactinaemic effect, available data in humans confirm the experimental observations in animals, which indicate that the compound tested has a highly selective activity with no effect on the basal secretion of other pituitary hormones or of cortisol.

The pharmacodynamic actions of cabergoline not correlated with the therapeutic effect are only linked to a decrease in blood pressure. The maximum hypotensive effect of cabergoline after a single dose generally occurs within six hours of administration of the active substance and is dose-dependent both in terms of frequency and maximum decrease in blood pressure.

Absorption

After oral administration, cabergoline is rapidly absorbed from the gastrointestinal tract and the peak plasma concentration is reached after 0,5 to 4 hours.

Food does not appear to have any effect on the absorption of cabergoline.

Distribution

Studies in vitro Plasma protein binding of cabergoline was shown to be 41 to 42% at concentrations ranging from 0,1 to 10 ng/mL.

Biotransformation

In urine, the main metabolite detected is 6-allyl-8β-carboxy-ergoline, which represents 4 to 6% of the dose. Three other metabolites have been identified in urine; together they represent less than 3% of the administered dose.

In vitro, the prolactin secretion-inhibiting activity of the metabolites is much weaker than that of cabergoline.

Elimination

The elimination half-life of cabergoline is long (63 to 68 hours in healthy volunteers and 79 to 115 hours in hyperprolactinaemic patients).

Based on the elimination half-life, steady state should be reached after 4 weeks, as confirmed by the mean maximum plasma concentrations observed after administration of a single dose of 0,5 mg of cabergoline (37 ± 8 pg/ml) and after repeated-dose treatment for 4 weeks (101 ± 43 pg/ml).

Ten days after administration, approximately 18% and 72% of the dose are eliminated in urine and faeces, respectively. In urine, unchanged cabergoline represents 2 to 3% of the dose.

Renal impairment/Hepatic impairment

In patients with renal impairment, the changes in excretion appear to be minor. In patients with severe hepatic impairment, a decrease in the metabolism of the molecule is observed, resulting in increased plasma concentrations of cabergoline and its derivatives (see section Warnings and precautions).

Maternotoxic effects, but no teratogenic effect, were observed in mice that received doses of cabergoline up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during organogenesis.

A dose of 0,012 mg/kg/day (approximately 1/7 times the maximum recommended human dose) administered to rats during organogenesis caused an increase in embryo-fetal losses after implantation. These losses could be attributable to the inhibition of prolactin secretion by cabergoline in rats. In rabbits, doses of 0,5 mg/kg/day of cabergoline (approximately 19 times the maximum recommended human dose) administered during organogenesis caused maternotoxicity characterised by loss of body weight and decreased food consumption. Also in rabbits, doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) administered during organogenesis caused an increase in the number of various malformations. However, in another study in rabbits, no treatment-related malformations or embryo-fetal toxicity were observed after administration of doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).

2 years.

Store at a temperature not exceeding 25 °C.

The tablets must be stored in their original container.

List I

Marketing authorisation (AMM)

CIP 3400930224311 (HDPE bottle/2). CIP 3400930224342 (HDPE bottle/8).

Price:

6,03 euros (HDPE bottle/2). 23,92 euros (HDPE bottle/8).