I N S T R U C T I O N for medical use of the medicinal product DOSTINEX (DOSTINEX®)

Composition:

active substance: cabergoline;

1 tablet contains 0.5 mg of cabergoline;

excipients: leucine, anhydrous lactose.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, flat, oval tablets with engraving “PU” separated by a score line on one side and engraving “700” with a small notch above and below the central “0” on the other side.

Pharmacotherapeutic group. Drugs used in gynecology. Prolactin inhibitors. ATC code G02C B03.

Pharmacological Properties

Pharmacodynamics

Cabergoline is an ergot derivative with potent and long-lasting prolactin-lowering activity. The drug directly stimulates D2 dopamine receptors on the surface of pituitary lactotroph cells, thereby inhibiting prolactin secretion. This compound reduces prolactin secretion in rats following oral administration at doses of 3–25 mcg/kg and in vitro at a concentration of 45 pg/mL. Additionally, cabergoline exerts central dopaminergic effects through stimulation of D2 receptors at oral doses exceeding those effective for reducing serum prolactin levels. The prolonged effect of Dostinex® on lowering prolactin levels is likely related to its long persistence at the target organ, as indicated by the slow elimination rate of total radioactivity from the pituitary after a single oral dose in rats (t½ is approximately 60 hours).

Pharmacodynamic effects were studied in healthy volunteers, postpartum women, and patients with hyperprolactinemia. After a single oral dose of 0.3–1.5 mg, a significant reduction in plasma prolactin levels was observed in each of the studied populations. This effect develops rapidly—within 3 hours after administration—and persists for 7–28 days in healthy individuals and patients with hyperprolactinemia, and for 14–21 days in postpartum women. The extent of prolactin reduction and its duration are dose-dependent.

Regarding endocrine effects of Dostinex® unrelated to its anti-prolactin action, available human study data confirm animal experimental findings and indicate that the compound has high selectivity and does not affect basal secretion of other pituitary hormones or cortisol. The pharmacodynamic action of Dostinex® did not correlate with therapeutic effect only regarding reduction in blood pressure. The maximum hypotensive effect of a single dose usually occurs within the first 6 hours after administration and is dose-dependent both for the magnitude of blood pressure reduction and the frequency of occurrence.

Pharmacokinetics

The pharmacokinetics and metabolic profiles of Dostinex® were investigated in healthy volunteers of both sexes and in female patients with hyperprolactinemia.

After oral administration of radiolabeled substance, it was rapidly absorbed from the gastrointestinal tract, with peak plasma radioactivity reached within 0.5–4 hours.

Ten days after administration, approximately 18% and 72% of the radioactive dose was excreted in urine and feces, respectively. The amount of unchanged drug in urine accounted for 2–3% of the administered dose.

The main metabolite identified in urine was 6-allyl-8β-carboxy-ergoline, representing 4–6% of the administered dose. Three additional metabolites were found in urine, collectively accounting for less than 3% of the dose. In vitro, the activity of metabolites in inhibiting prolactin secretion is significantly lower than that of cabergoline. Biotransformation of cabergoline was also studied in plasma from healthy male volunteers receiving [14C]-cabergoline, showing that cabergoline undergoes rapid and extensive biotransformation.

The low urinary excretion of unchanged cabergoline was also confirmed in studies using non-radiolabeled drug. The elimination half-life of cabergoline, determined based on urinary excretion rate, is prolonged: 63–68 hours in healthy volunteers (using radioimmunoassay) and 79–115 hours in patients with hyperprolactinemia (using HPLC method).

Considering these half-life values, steady-state levels should be achieved after 4 weeks, which was confirmed by mean peak plasma concentrations of cabergoline after a single dose (37 ± 8 pg/mL) and after 4 weeks of multiple dosing (101 ± 43 pg/mL).

In vitro studies showed that the drug binds to plasma proteins by 41–42% at concentrations of 0.1–10 ng/mL. Food does not affect the absorption or distribution of the drug.

Clinical characteristics.

Indications.

Inhibition/suppression of physiological lactation

Inhibition of physiological postpartum lactation immediately after childbirth or suppression of established lactation in the following cases:

after childbirth, if the mother decides not to breastfeed or when breastfeeding is contraindicated for medical reasons in either the mother or the infant;
after stillbirth or abortion.

Cabergoline inhibits/suppresses physiological lactation by inhibiting prolactin secretion. In controlled clinical studies, a single 1 mg dose of cabergoline administered on the first day postpartum was effective in inhibiting milk secretion, as well as breast engorgement and pain, in 70–90% of women. Less than 5% of women experienced recurrence of breast symptoms by the third postpartum week (which was usually mild in severity).

Suppression of milk secretion and relief from breast engorgement and pain occurred in approximately 85% of lactating women when a total dose of 1 mg of cabergoline was administered over two days, divided into four doses. Recurrence of breast symptoms after 10 days was infrequent (approximately 2% of cases).

Treatment of hyperprolactinemic conditions

Disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation, and galactorrhea. Treatment of patients with prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinemia, or empty sella syndrome with concomitant hyperprolactinemia, which are the primary pathological conditions causing the aforementioned clinical manifestations.

With long-term treatment at doses of 1 to 2 mg per week, cabergoline was effective in normalizing serum prolactin levels in approximately 84% of patients with hyperprolactinemia.
Regular menstrual cycles resumed in 83% of women with amenorrhea. Ovulation resumption was documented in 89% of women based on progesterone levels monitored during the luteal phase. Galactorrhea present prior to treatment disappeared in 90% of cases. Tumor size reduction was observed in 50–90% of women and men with micro- or macroprolactinomas.

Contraindications.

Hypersensitivity to cabergoline, to any excipients of the medicinal product, or to any ergot alkaloids.

History of fibrotic disorders of the lungs, pericardium, or retroperitoneal space.

Cabergoline is contraindicated in patients with hepatic insufficiency and in pregnant women with gestosis. Cabergoline should not be used concomitantly with antipsychotic medicinal products or in women with a history of postpartum psychosis.

Cabergoline is contraindicated for long-term treatment if there are signs of valvular heart disease detected by echocardiography prior to initiation of therapy (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Dostinex with other medicinal products, particularly with ergot alkaloids, in the early postpartum period has not been associated with evident interactions affecting the efficacy or safety of this product.

Due to the lack of data on interactions between cabergoline and other ergot alkaloids, concomitant administration of these agents during long-term treatment with Dostinex is not recommended.

Since Dostinex exerts its therapeutic effect through direct stimulation of dopamine receptors, its concomitant use with dopamine receptor antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, and metoclopramide) is not recommended, as these agents may reduce the prolactin-lowering effect of cabergoline.

Like other ergot derivatives, Dostinex should not be administered with macrolide antibiotics (e.g., erythromycin) due to increased systemic bioavailability of cabergoline.

Special precautions for use.

General warnings

The safety and efficacy of Dostinex have not been established in patients with renal or hepatic impairment. As with other ergot derivatives, Dostinex should be administered with caution to patients with severe cardiovascular disorders, Raynaud's syndrome, renal impairment, peptic ulcer disease, or gastrointestinal bleeding, as well as in patients with a history of serious psychiatric disorders, particularly psychosis. Particular caution should be exercised if patients are concurrently taking psychotropic medicinal products.

This medicinal product is contraindicated in patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Symptomatic arterial hypotension may occur during treatment with Dostinex regardless of the indication. Dostinex should be used with caution when administered concomitantly with other medicinal products that lower blood pressure.

The effect of alcohol on the overall tolerability of the drug is currently unknown.

Pregnancy should be excluded before initiating treatment with Dostinex, and pregnancy should be avoided for at least 1 month after discontinuation of therapy.

Hepatic impairment

Lower doses should be considered for patients with severe hepatic impairment receiving long-term Dostinex therapy. In patients with severe hepatic impairment (Child-Pugh class C), a single 1 mg dose resulted in increased AUC values compared to healthy volunteers and patients with less severe hepatic impairment.

Postural arterial hypotension

Postural arterial hypotension may occur after administration of Dostinex. This medicinal product should be used with caution when administered concomitantly with other medicinal products that lower blood pressure.

Somnolence/sudden sleep onset

Treatment with Dostinex has been associated with somnolence. Dopamine agonists may cause episodes of sudden sleep onset in patients with Parkinson’s disease. Rare cases of sudden sleep onset during daily activities have been reported, sometimes without awareness or warning signs. This information should be communicated to patients, and they should be advised to exercise caution when driving or operating machinery during treatment with cabergoline. Patients who experience somnolence and/or sudden sleep episodes should refrain from driving or operating machinery. Dose reduction or discontinuation of treatment may be considered in such cases (see section "Ability to affect reaction speed when driving or operating machinery").

Impulse control disorders

Patients should be routinely monitored for the development of impulse control disorders. During treatment with dopamine agonists, including cabergoline, behavioral symptoms of impulse control disorders may occur, such as pathological gambling, increased libido, hypersexuality, compulsive spending, bulimia, and compulsive overeating. Patients and caregivers should be informed about these potential effects. If such symptoms occur, dose reduction or gradual discontinuation of the medicinal product should be considered.

Inhibition/suppression of physiological lactation

As with other ergot derivatives, Dostinex should not be used in women with hypertension arising during pregnancy, such as pre-eclampsia or postpartum hypertension, except when potential benefit outweighs the possible risk.

Serious adverse reactions, including hypertension, myocardial infarction, convulsions, stroke, or mental disorders, have been reported in postpartum women receiving cabergoline to suppress lactation.

In some patients, the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances.

Blood pressure should be closely monitored after treatment.

If arterial hypertension, suggestive chest pain, severe, progressive, or persistent headache (with or without visual disturbances), or signs of central nervous system toxicity develop, cabergoline should be discontinued immediately and the patient should be evaluated urgently.

In postpartum studies with Dostinex, blood pressure reduction was mostly asymptomatic and often occurred once between 2 and 4 days after initiation of treatment. Since blood pressure reduction commonly occurs in the postpartum period regardless of medication, many of the reported cases of hypotension after Dostinex administration may not be drug-related. However, periodic monitoring of blood pressure is recommended, especially during the first few days after taking cabergoline.

To avoid possible postural arterial hypotension, a single dose of Dostinex should not exceed 0.25 mg in breastfeeding women receiving the drug to suppress established lactation (see section "Dosage and administration"). In a clinical study evaluating the efficacy and tolerability of a single 0.5 mg dose of Dostinex for lactation suppression, the risk of adverse effects approximately doubled when the drug was administered as a single 0.5 mg dose.

Treatment of hyperprolactinemic conditions

A complete pituitary evaluation is recommended before initiating Dostinex therapy, as hyperprolactinemia associated with amenorrhea/galactorrhea and infertility may be caused by a pituitary tumor.

Dostinex restores ovulation and fertility in women with hyperprolactinemic hypogonadism.

Since pregnancy may occur before the resumption of menstruation, pregnancy testing is recommended at least every four weeks during amenorrhea and after any delay of more than three days following resumption of menses. Women who wish to avoid pregnancy should be advised to use mechanical contraception during treatment with Dostinex and after discontinuation of the drug until anovulation recurs. Women who become pregnant should be monitored for signs of pituitary enlargement, as there is a risk of growth of an existing pituitary tumor during pregnancy.

Pregnancy must be excluded before initiating Dostinex. Women who wish to become pregnant are advised to discontinue Dostinex one month before planned conception due to limited clinical experience and the drug’s long elimination half-life. If pregnancy occurs during treatment, cabergoline should be discontinued immediately.

Regular gynecological examinations, including cervical and endometrial cytology, are recommended for patients receiving long-term Dostinex therapy.

Fibrosis, cardiac valve involvement, and related clinical conditions

Fibrotic and serosal inflammatory disorders, such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, involvement of one or more cardiac valves (aortic, mitral, or tricuspid), or retroperitoneal fibrosis, have been observed after prolonged use of ergot derivatives with agonistic activity on the serotonin 5HT2B receptor, such as Dostinex. In some cases, symptoms or manifestations of valve involvement may improve after discontinuation of Dostinex.

Elevated erythrocyte sedimentation rate (ESR) has been observed in association with pleural effusion/fibrosis. In cases of unexplained ESR elevation significantly deviating from normal, chest radiography is recommended.

Valvular lesions are associated with drug accumulation; therefore, patients should be treated with the lowest effective doses. The safety profile of Dostinex treatment should be re-evaluated at each visit to determine the need for continued therapy.

Before initiating long-term therapy, all patients should undergo cardiovascular evaluation, including echocardiography, to detect possible asymptomatic valvular heart disease. Baseline assessment of ESR or other inflammatory markers, pulmonary function/chest radiography, and renal function may also be advisable. It is unknown whether cabergoline treatment may worsen the course of disease in patients with valvular regurgitation. Dostinex therapy should not be continued in patients diagnosed with fibrotic valvular heart disease (see section "Contraindications").

Fibrotic disorders may develop asymptomatically during long-term treatment; therefore, patients should be monitored for possible signs of fibrosis progression. During treatment, attention should be paid to the following signs and symptoms:

Pulmonary and pleural disorders, such as dyspnea, shortness of breath, persistent cough, or chest pain;
Renal impairment or obstruction of ureteral/abdominal vessels, which may present as flank/side pain and lower limb edema, as well as any possible abdominal masses or tenderness suggesting retroperitoneal fibrosis;
Heart failure: valvular or pericardial fibrosis often manifests as heart failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be ruled out if such symptoms occur.

Regular clinical monitoring for fibrotic disorders is mandatory. The first echocardiogram should be performed within 3–6 months after initiation of treatment, with subsequent echocardiographic evaluations scheduled based on individual clinical assessment and attention to the above-mentioned symptoms, but at least every 6–12 months.

Dostinex should be discontinued if echocardiography reveals new-onset or worsening valvular regurgitation, valve restriction, or leaflet thickening (see section "Contraindications").

The need for additional clinical evaluations (e.g., physical examination including cardiac auscultation, radiography, or computed tomography) should be determined on an individual basis.

Appropriate additional tests, including ESR and serum creatinine, should be performed as needed to confirm the diagnosis of fibrotic disease.

Use during pregnancy or breastfeeding

There are no adequate and well-controlled studies on the use of cabergoline in pregnant women. Available data from a 12-year observational study on 256 pregnancies following cabergoline therapy show that 17 out of 256 pregnancies (6.6%) were associated with major congenital malformations or miscarriages, and 27 neonatal abnormalities (major and minor) were observed in 23 out of 258 newborns. The most common neonatal anomalies were musculoskeletal malformations (10) and cardiopulmonary anomalies (5). There is no information on perinatal disorders or long-term development of infants exposed to cabergoline in utero. According to recent published scientific data, the prevalence of major congenital malformations in the general population is 6.9% or higher. The frequency of congenital anomalies varies across populations. It is not possible to precisely determine whether there is an increased risk, as no control group was included in the study.

Cabergoline should be prescribed during pregnancy only if clearly indicated and after careful benefit-risk assessment (see section "Special precautions for use").

Due to the long elimination half-life of the drug and limited data on fetal exposure, women planning pregnancy should discontinue cabergoline one month before planned conception.

If conception occurs during treatment, the drug should be discontinued immediately upon confirmation of pregnancy to minimize fetal exposure.

There is no available information on the excretion of cabergoline into breast milk. However, breastfeeding is not recommended in mothers receiving Dostinex unless the drug has been used specifically to inhibit or suppress lactation. Since Dostinex suppresses lactation, it should not be used in mothers with hyperprolactinemic conditions who wish to breastfeed.

Ability to affect reaction speed when driving or operating machinery

Patients should exercise caution when performing tasks requiring rapid and accurate responses at the beginning of treatment.

During the first days of Dostinex administration, patients should refrain from activities requiring rapid and precise reactions, such as driving or operating automated systems.

Patients taking Dostinex who experience somnolence should not drive or engage in other activities where reduced alertness may endanger themselves or others (e.g., operating machinery). Driving and operating machinery may be resumed only after somnolence and impaired alertness have resolved (see section "Special precautions for use").

Method of Administration and Dosage

Dostinex is intended for oral administration. Since in clinical studies Dostinex was predominantly administered with food and because the tolerability of this class of medicinal products is improved when taken with food, the drug is recommended to be taken during meals for all therapeutic indications.

Inhibition/Suppression of Physiological Lactation

Dostinex should be administered on the first day after delivery. The recommended therapeutic dose is 1 mg (2 tablets of 0.5 mg) taken as a single dose.

For suppression of established lactation, the recommended therapeutic dosage regimen is 0.25 mg (1/2 tablet of 0.5 mg) every 12 hours for 2 days (total dose – 1 mg). This regimen is better tolerated by women who have decided to suppress lactation than a single-dose administration, and it is associated with a lower incidence of adverse events, particularly symptoms of arterial hypotension.

Treatment of Hyperprolactinemic Conditions

The recommended initial dose of Dostinex is 0.5 mg once weekly or 1/2 tablet of 0.5 mg twice weekly (e.g., on Monday and Thursday). The weekly dose should be increased gradually, preferably by 0.5 mg per week every month, until optimal therapeutic efficacy is achieved. The usual therapeutic dose is 1 mg per week and may range between 0.25 mg and 2 mg per week. Dostinex has been used in doses up to 4.5 mg per week for the treatment of patients with hyperprolactinemia.

The maximum dose of the drug should not exceed 3 mg per day.

The weekly dose may be taken as a single dose or divided into two or more doses per week, depending on patient tolerability. If prescribed doses exceed 1 mg per week, it is recommended to divide the weekly dose into several administrations, as tolerability of doses exceeding 1 mg taken as a single weekly dose has been evaluated in only a few patients.

When increasing the dose, the patient should be monitored to determine the minimum dose that produces a therapeutic effect. After an effective therapeutic dosage regimen has been established, regular (monthly) measurement of serum prolactin levels is recommended, as normalization of these levels usually occurs within two to four weeks.

After discontinuation of Dostinex, hyperprolactinemia usually recurs. However, in some patients, suppression of prolactin levels has persisted for several months. In 23 out of 29 women in a follow-up observation group, ovulatory cycles continued for longer than 6 months after stopping Dostinex.

Geriatric Patients

Experience with administration to elderly patients is very limited due to the indications for use of Dostinex. Available data indicate no special risk.

Children

The safety and efficacy of Dostinex in patients under 16 years of age have not been studied.

Overdose

Symptoms of overdose may be similar to those arising from excessive stimulation of dopamine receptors (e.g., nausea, vomiting, gastrointestinal discomfort, postural arterial hypotension, confusion/psychosis, or hallucinations).

If necessary, supportive measures should be applied to remove any remaining unabsorbed drug and to maintain blood pressure. In addition, administration of dopamine antagonist agents may be appropriate.

Side effects.

Adverse reactions are generally dose-dependent. The likelihood of adverse reactions in patients with known intolerance to dopaminergic agents can be reduced by initiating treatment with Cabergoline at a reduced dose, e.g. 0.25 mg once weekly, with subsequent gradual dose escalation to reach the therapeutic dose. If persistent or severe adverse reactions occur, temporary dose reduction followed by slower dose escalation (e.g. by 0.25 mg/week every 2 weeks) may improve tolerability.

The following adverse reactions have been observed during treatment with Cabergoline at the following frequencies: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10000 and < 1/1000; very rare: < 1/10000; frequency not known (cannot be estimated from available data).

Cardiac disorders:

very common: valvular disorders (including regurgitation) and related disorders (pericarditis and pericardial effusion);

uncommon: palpitations;

frequency not known: angina pectoris.

Respiratory, thoracic and mediastinal disorders:

uncommon: dyspnoea, pleural effusion, fibrosis (including pulmonary fibrosis), epistaxis;

very rare: pleural fibrosis;

frequency not known: respiratory disorders, respiratory failure, pleuritis, chest pain.

Immune system disorders:

uncommon: hypersensitivity reactions.

Nervous system disorders:

very common: headache*, dizziness/vertigo;

common: somnolence;

uncommon: transient hemianopia, syncope, paraesthesia;

frequency not known: sudden sleep onset, tremor.

Eye disorders:

frequency not known: visual disturbances.

Psychiatric disorders:

common: depression;

uncommon: increased libido;

frequency not known: aggression, delusions, hypersexuality, pathological gambling, psychiatric disorders, hallucinations.

Vascular disorders:

common: hypotensive effect in patients receiving long-term treatment; postural hypotension, flushing**;

uncommon: peripheral vasospasm, 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***, increased fatigue;

uncommon: oedema, peripheral oedema.

Hepatobiliary disorders:

frequency not known: liver function abnormalities.

Skin and subcutaneous tissue disorders:

uncommon: rash, alopecia.

Musculoskeletal and connective tissue disorders:

uncommon: leg cramps.

Reproductive system and breast disorders:

common: breast pain.

Investigations:

common: asymptomatic decrease in blood pressure (≥ 20 mmHg systolic and ≥ 10 mmHg diastolic);

uncommon: in women with amenorrhoea, a decrease in haemoglobin levels was observed during the first few months after menstruation;

frequency not known: increased blood creatine phosphokinase levels, abnormal liver function tests.

*Very common – in female patients treated for hyperprolactinaemia; common – in female patients treated for inhibition/suppression of lactation.

**Common – in female patients treated for hyperprolactinaemia; uncommon – in female patients treated for inhibition/suppression of lactation.

***Very common – in female patients treated for hyperprolactinaemia; uncommon – in female patients treated for inhibition/suppression of lactation.

Impulse control disorders.

Pathological gambling, increased libido, hypersexuality, compulsive spending and shopping, loss of appetite, and compulsive overeating may occur in patients receiving treatment with dopamine agonists, including cabergoline.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 2 years.

Storage conditions. Store out of reach and sight of children, at temperatures below 25°C.

Packaging. 2 or 8 tablets in a glass bottle made of amber glass with an aluminium screw cap and tamper-evident seal, or in a high-density polyethylene bottle with a polypropylene cap and child-resistant closure. One bottle per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Pfizer Italia S.r.l.

Manufacturer's address.

Località Marino del Tronto – 63100 Ascoli Piceno (AP), Italy.