Dostinex^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pfizer, Inc. (USA)

Manufactured By

Pfizer Italia, S.r.L. (Italy)

Contact Information

Pfizer Innovations LLC (Russia)

ATC Code

G02CB03 (Cabergoline)

Active Substance

Cabergoline (Rec.INN registered by WHO)

Dosage Form

Dostinex®

Tablets 0.5 mg: 2 or 8 pcs.

Dosage Form, Packaging, and Composition

Tablets white, flat, oblong, marked with “P” and “U” separated by a score on one side and “700” with short scores above and below the central number “0” on the other side.

Excipients: lactose – 75.9 mg, leucine – 3.6 mg.

2 pcs. – dark glass type I bottles (1) – cardboard packs with first opening control.
8 pcs. – dark glass type I bottles (1) – cardboard packs with first opening control.
2 pcs. – high-density polyethylene bottles (1) – cardboard packs with first opening control.
8 pcs. – high-density polyethylene bottles (1) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Dopamine receptor agonist. Inhibitor of prolactin secretion

Pharmacotherapeutic Group

Prolactin inhibitors

Pharmacological Action

Cabergoline is a dopaminergic ergoline derivative characterized by a pronounced and long-lasting prolactin-lowering effect due to direct stimulation of dopamine D₂ receptors on pituitary lactotroph cells.

Furthermore, when taken in doses exceeding those for reducing plasma prolactin concentration, Cabergoline exerts a central dopaminergic effect due to stimulation of dopamine D₂ receptors.

A decrease in plasma prolactin concentration is observed within 3 hours after drug administration and persists for 7-28 days in healthy volunteers and patients with hyperprolactinemia, and up to 14-21 days in postpartum women.

Cabergoline has a strictly selective action and does not affect the basal secretion of other pituitary hormones and cortisol. The prolactin-lowering effect of cabergoline is dose-dependent both in terms of severity and duration of action.

Among the pharmacological effects of cabergoline not related to the therapeutic effect is only a decrease in blood pressure. After a single dose of the drug, the maximum hypotensive effect is observed within the first 6 hours and is dose-dependent.

Pharmacokinetics

Absorption

Cabergoline is rapidly absorbed from the gastrointestinal tract. C_max in plasma after a single oral dose ranging from 0.5 mg to 1.5 mg is 30-70 pg/ml and is achieved within 2-3 hours. The absolute bioavailability of cabergoline is unknown. Food intake does not affect the absorption and distribution of cabergoline.

Distribution

Binding to plasma proteins is 41-42%.

Metabolism

The main identified metabolite of cabergoline in urine is 6-allyl-8β-carboxy-ergoline at a concentration of up to 4-6% of the administered dose; the concentration of 3 additional metabolites is less than 3% of the dose. Metabolites have a significantly lesser effect on suppressing prolactin secretion compared to cabergoline.

Excretion

T_1/2, estimated by the renal excretion rate, is 63-68 hours in healthy volunteers and 79-115 hours in patients with hyperprolactinemia. Due to the long T_1/2, the steady-state concentration of cabergoline is reached after 4 weeks. Ten days after cabergoline administration, approximately 18% and 72% of the administered dose is detected in urine and feces, respectively, with the proportion of unchanged cabergoline in urine being 2-3%.

Indications

• Prevention of physiological lactation after childbirth;
• Suppression of established postpartum lactation;
• Treatment of disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation, and galactorrhea;
• Prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinemia, empty sella syndrome in combination with hyperprolactinemia.

ICD codes

Dosage Regimen

Take orally, with meals.

Prevention of lactation: 1 mg (2 tablets of 0.5 mg) as a single dose on the first day after childbirth (preferably with the first meal after childbirth).

Suppression of established lactation 0.25 mg (1/2 tablet) twice daily every 12 hours for 2 days (total dose equals 1 mg). To reduce the risk of orthostatic arterial hypotension in women, a single dose of cabergoline should not exceed 0.25 mg.

Treatment of disorders associated with hyperprolactinemia the recommended initial dose is 0.5 mg per week in a single dose (1 tablet of 0.5 mg) or in two doses (1/2 tablet of 0.5 mg each, for example, on Monday and Thursday). The weekly dose should be increased gradually – by 0.5 mg at monthly intervals until the optimal therapeutic effect is achieved. The therapeutic dose is usually 1 mg per week but can range from 0.25 mg to 2 mg per week. The maximum dose for patients with hyperprolactinemia is 4.5 mg per week.

Depending on tolerance, the weekly dose can be taken as a single dose or divided into two or more doses per week. Dividing the weekly dose into several doses is recommended when prescribing the drug at a dose of more than 1 mg per week.

In patients with increased sensitivity to dopaminergic drugs, the likelihood of adverse reactions can be reduced by initiating cabergoline therapy at a lower dose (0.25 mg once a week), followed by a gradual increase to the therapeutic dose. To improve drug tolerance in case of severe adverse reactions, a temporary dose reduction followed by a gradual increase (e.g., by 0.25 mg per week every 2 weeks) is possible.

When increasing the dose, patients should undergo regular examination to establish the lowest effective dose of cabergoline. It is recommended to determine plasma prolactin concentration at least once a month, as its normalization usually occurs within 2-4 weeks after selecting an effective dose of cabergoline.

After discontinuation of cabergoline, a recurrence of hyperprolactinemia is usually observed. However, some patients experience a persistent decrease in plasma prolactin concentration for several months. In most women, ovulatory cycles persist for at least 6 months after cessation of therapy.

The efficacy and safety of cabergoline use in children and adolescents under 16 years of age have not been established.

Due to the indications for cabergoline use, experience with the drug in elderly patients is extremely limited. Available data do not indicate a special risk.

In patients with severe hepatic impairment, Cabergoline should be used at lower doses (see section “Special Precautions”).

Adverse Reactions

In clinical studies using cabergoline for prevention of physiological lactation (1 mg single dose) and for suppression of lactation (0.25 mg every 12 hours for 2 days), adverse reactions were observed in approximately 14% of women. When using cabergoline for 6 months at a dose of 1-2 mg per week, divided into two doses, for treatment of disorders associated with hyperprolactinemia, the frequency of adverse reactions was 68%. Adverse reactions occurred mainly within the first 2 weeks of therapy and in most cases disappeared with continued therapy or a few days after discontinuation of cabergoline. Adverse reactions were usually transient, mild or moderate in severity, and dose-dependent. At least once during therapy, severe adverse reactions were noted in 14% of patients; treatment was discontinued due to adverse reactions in approximately 3% of patients.

Possible adverse reactions with cabergoline use are distributed by system-organ class with an indication of their frequency of occurrence according to WHO recommendations: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Immune system disorders uncommon – hypersensitivity reactions.

Psychiatric disorders common – depression; uncommon – increased libido; frequency unknown – aggression, delusions, hypersexuality, gambling addiction/pathological gambling, psychotic disorders, hallucinations.

Nervous system disorders very common – headache, dizziness/vertigo; common – somnolence; uncommon – transient hemianopia, syncope (brief fainting with loss of consciousness), paresthesia; frequency unknown – sudden onset of sleep attacks, tremor.

Eye disorders frequency unknown – visual disturbances.

Cardiac and vascular disorders very common – heart valve damage (valvulopathy), including regurgitation, and related disorders (pericarditis and pericardial effusion); common – with long-term use Cabergoline usually has a hypotensive effect, in some cases orthostatic arterial hypotension, “hot flashes” may occur; uncommon – palpitations, vasospasm of upper and lower extremities, fainting; frequency unknown – angina pectoris.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, pleural effusion, fibrosis (pulmonary fibrosis), epistaxis; very rare – pleural fibrosis; frequency unknown – breathing disorders, respiratory failure, pleurisy and chest pain.

Gastrointestinal disorders very common – nausea, dyspepsia, gastritis, abdominal pain; common – constipation, vomiting; rare – epigastric pain.

Hepatobiliary disorders frequency unknown – impaired liver function.

Skin and subcutaneous tissue disorders uncommon – rash, alopecia.

Musculoskeletal and connective tissue disorders uncommon – leg cramps.

Reproductive system and breast disorders common – mastodynia.

General disorders and administration site conditions very common – asthenia, increased fatigue; uncommon – edema, peripheral edema.

Investigations common – asymptomatic decrease in blood pressure (systolic – by at least 20 mm Hg; diastolic – by at least 10 mm Hg); uncommon – possible decrease in hemoglobin content in women with amenorrhea in the first months after resumption of menstruation; rare – deviation from normal standard laboratory parameters during long-term therapy with cabergoline; frequency unknown – increased CPK activity, deviations from normal liver function tests.

Impulse control disorders pathological gambling, increased libido, hypersexuality, compulsive spending or compulsive buying, binge eating and bulimia may occur in patients receiving therapy with dopamine receptor agonists, including Cabergoline.

Contraindications

• Hypersensitivity to cabergoline and/or any excipient in the drug, as well as to any ergot alkaloids;
• History of fibrotic changes in the lungs, pericardium, or retroperitoneal space;
• For long-term therapy: anatomical signs of cardiac valve pathology (such as valve leaflet thickening, valve restriction, mixed pathology – restriction and stenosis), confirmed by echocardiography performed before initiation of therapy;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Childhood and adolescence under 16 years (safety and efficacy of use have not been established);
• Pregnancy (due to lack of clinical data on the efficacy and safety of cabergoline use);
• Breastfeeding period (due to lack of clinical data on the efficacy and safety of cabergoline use).

With caution

Like other ergot derivatives, Cabergoline should be prescribed with caution in the following conditions and/or diseases

• Arterial hypertension developed during pregnancy, e.g., preeclampsia or postpartum arterial hypertension (Cabergoline is prescribed only in cases where the potential benefit of using the drug significantly outweighs the possible risk);
• Severe cardiovascular diseases, Raynaud’s syndrome;
• Peptic ulcer, gastrointestinal bleeding;
• Severe hepatic impairment (use of lower doses is recommended);
• Severe psychotic or cognitive disorders (including history);
• Concomitant use with drugs that have a hypotensive effect (due to the risk of orthostatic hypotension).

Use in Pregnancy and Lactation

Pregnancy

Adequate controlled clinical studies on the use of cabergoline in pregnant women have not been conducted. Animal studies have not demonstrated a teratogenic effect of cabergoline, but reduced fertility and embryotoxicity were identified. Results of a 12-year observational study on the effect of cabergoline on pregnancy outcomes showed that 6.6% (17 pregnancies out of 256) resulted in serious congenital malformations or premature termination of pregnancy (the most frequent were malformations of the musculoskeletal system, heart, and lungs). There is no information regarding perinatal disorders or long-term follow-up of the development of newborns whose mothers took Cabergoline during pregnancy. In this regard, cabergoline therapy during pregnancy is possible only in cases of extreme necessity, taking into account a careful assessment of the “benefit-risk” ratio for the woman and the fetus.

Considering the long T_1/2 of cabergoline and limited data on the effect of cabergoline on the fetus, patients planning pregnancy should discontinue its use one month before the planned date of pregnancy. If pregnancy occurs during cabergoline therapy, the drug should be discontinued after pregnancy is confirmed.

Breastfeeding period

Cabergoline penetrates into the milk of lactating rats; there is no information on the penetration of cabergoline into human breast milk. Nevertheless, in the absence of sufficient effect of cabergoline for preventing or suppressing lactation, breastfeeding should be avoided.

Since Cabergoline prevents lactation, the use of the drug in patients with hyperprolactinemia planning to breastfeed is contraindicated.

Use in Hepatic Impairment

The drug should be prescribed with caution in severe hepatic impairment.

Use in Renal Impairment

The use of cabergoline in patients with impaired renal function is not recommended due to the lack of clinical data on the efficacy and safety of cabergoline in this patient population.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 16 years of age.

Geriatric Use

Due to the indications for cabergoline use, experience with the drug in elderly patients is extremely limited.

Special Precautions

Before prescribing cabergoline therapy for the treatment of disorders associated with hyperprolactinemia, a complete investigation of pituitary function must be performed.

Before initiating long-term therapy with cabergoline, all patients should undergo a cardiovascular system examination, including echocardiography (to exclude asymptomatic heart defects). In addition, it is advisable to determine CRP or other markers of inflammation, chest X-ray, lung function tests, and kidney function tests.

As with the use of other ergot derivatives, pleural effusion/pleural fibrosis and valvulopathy have been observed in patients after long-term use of cabergoline. In some cases, patients received prior therapy with ergot-derived dopamine agonists. Therefore, Cabergoline should not be used in patients with existing signs and/or clinical symptoms of impaired cardiac or respiratory function associated with fibrotic changes or with a history of such conditions. The drug should be discontinued if signs of the appearance or worsening of blood regurgitation, valve restriction, or valve leaflet thickening are detected.

ESR has been found to increase with the development of pleural effusion or fibrosis. If an unexplained increase in ESR is detected, a chest X-ray examination is recommended. Measurement of plasma creatinine concentration and assessment of renal function may also aid in diagnosis. After discontinuation of cabergoline, improvement in symptoms was noted in patients with pleural effusion/pleural fibrosis or valvulopathy.

It is unknown whether Cabergoline can worsen the condition of patients with signs of blood regurgitation. Cabergoline should not be used if fibrotic lesions of the heart valves are detected.

Fibrotic disorders can develop asymptomatically. In this regard, the condition of patients receiving long-term cabergoline therapy should be regularly monitored, with particular attention paid to the following symptoms

• pleuro-pulmonary disorders: such as dyspnea, difficulty breathing, persistent cough, or chest pain;
• renal failure or obstruction of the ureteral vessels or abdominal organs, which may be accompanied by flank pain or pain in the lumbar region and edema of the lower extremities, any swelling or tenderness on palpation in the abdominal area, which may indicate the development of retroperitoneal fibrosis;
• pericardial fibrosis and fibrosis of the heart valves often manifest as heart failure. In this regard, it is necessary to exclude fibrosis of the heart valves (and constrictive pericarditis) when symptoms of heart failure appear.

Regular monitoring of the patient’s condition for the development of fibrotic disorders should be carried out. The first echocardiogram should be performed 3-6 months after the start of therapy. Then this examination should be performed depending on the clinical assessment of the patient’s condition, paying special attention to the symptoms described above, at least every 6-12 months of therapy.

The need for other monitoring methods (for example, physical examination, including cardiac auscultation, radiography, computed tomography) is assessed individually for each patient.

Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Pregnancy should be excluded before starting the use of cabergoline. Since pregnancy can occur before the restoration of menstruation, it is recommended to perform pregnancy tests at least once every 4 weeks during the period of amenorrhea, and after the restoration of menstruation – every time a delay in menstruation of more than 3 days is noted. Women wishing to avoid pregnancy should use barrier methods of contraception during treatment with cabergoline, as well as after discontinuation of the drug until anovulation recurs. Women who become pregnant should be under medical supervision for the timely detection of symptoms of pituitary enlargement, since pre-existing pituitary tumors may increase in size during pregnancy.

In patients with severe hepatic insufficiency, Cabergoline should be used in low doses for long-term therapy. In patients with severe hepatic insufficiency (Child-Pugh class C) after a single dose of cabergoline 1 mg, the AUC value was higher than in healthy volunteers or patients with less severe hepatic insufficiency.

The use of cabergoline causes drowsiness. In patients with Parkinson’s disease, the use of dopamine receptor agonists may cause sudden sleep onset. In such cases, it is recommended to reduce the dose of cabergoline or discontinue therapy.

The use of cabergoline in patients with impaired renal function is not recommended due to the lack of clinical data on the efficacy and safety of cabergoline in this patient population.

To identify signs of impulse control disorders during long-term therapy with cabergoline, patients should be under regular supervision, patients and/or their caregivers should be informed about possible behavioral disorders during therapy. Impulse control disorders, such as pathological gambling, increased libido, and hypersexuality, have been reported in patients receiving therapy with dopamine receptor agonists, including Cabergoline. These phenomena were usually reversible after dose reduction or drug discontinuation.

Effect on the ability to drive vehicles and mechanisms

Patients taking Cabergoline should refrain from driving vehicles and mechanisms and other potentially hazardous activities requiring concentration and speed of psychomotor reactions.

Overdose

Symptoms (most likely symptoms of dopamine receptor hyperstimulation): nausea, vomiting, dyspeptic symptoms, orthostatic arterial hypotension, confusion, psychosis, hallucinations.

Treatment supportive measures should be carried out aimed at removing the unabsorbed drug (gastric lavage) and, if necessary, maintaining blood pressure. The appointment of dopamine antagonists is recommended.

Drug Interactions

Information on the interaction of cabergoline and other ergot alkaloids is not available, so the simultaneous use of these drugs during long-term therapy with cabergoline is not recommended.

Since Cabergoline exerts its therapeutic effect by direct stimulation of dopamine receptors, the drug should not be prescribed simultaneously with drugs that act as dopamine antagonists (including phenothiazines, butyrophenones, thioxanthenes, metoclopramide, domperidone, alizapride), as they may weaken the effect of cabergoline aimed at reducing prolactin concentration.

Like other ergot derivatives, Cabergoline should not be used simultaneously with macrolide antibiotics (for example, with erythromycin, josamycin, troleandomycin), as this may lead to an increase in the systemic bioavailability of cabergoline.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.