Caberyn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KABERLIN (CABERLIN)

Composition:

Active substance: cabergoline;

1 tablet contains 0.5 mg of cabergoline;

Excipients: microcrystalline cellulose, L-leucine.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat tablets with bevelled edges and a break line on both sides.

Pharmacotherapeutic group. Drugs used in gynecology. Prolactin inhibitors. ATC code G02CB03.

Pharmacological Properties

Pharmacodynamics

Cabergoline is a dopamine agonist derived from ergot alkaloids, characterized by 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 via stimulation of D2-receptors at oral doses exceeding those effective for reducing serum prolactin levels. The prolonged prolactin-lowering effect of cabergoline is likely related to its long persistence at the target organ, as indicated by the slow elimination rate of total radioactivity from the pituitary gland after a single oral dose in rats (t½ approximately 60 hours).

Pharmacodynamic effects were studied in healthy volunteers, postpartum women, and patients with hyperprolactinemia. After a single oral dose of cabergoline (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 volunteers and patients with hyperprolactinemia, and for 14–21 days in postpartum women. The extent of prolactin reduction and duration of effect are dose-dependent.

Regarding endocrine effects of cabergoline unrelated to its anti-prolactinemic action, available human study data confirm animal experimental findings, indicating that the compound has high selectivity and does not affect basal secretion levels of other pituitary hormones or cortisol. The only pharmacodynamic effect not correlated with therapeutic efficacy is the reduction in blood pressure. The maximal hypotensive effect of a single dose typically occurs within the first 6 hours after administration and is dose-dependent both in terms of the magnitude of blood pressure reduction and the frequency of occurrence.

Pharmacokinetics

The pharmacokinetics and metabolic profiles of cabergoline have been investigated in healthy volunteers of both sexes and in female patients with hyperprolactinemia.

Following oral administration of radiolabeled cabergoline, the substance 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 were 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 detected in urine, collectively accounting for less than 3% of the dose. The in vitro activity of these 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, confirming that cabergoline undergoes rapid and extensive biotransformation.

The low urinary excretion of unchanged cabergoline has also been 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, as measured by radioimmunoassay, and 79–115 hours in patients with hyperprolactinemia, as measured by HPLC).

Given the long elimination half-life, steady-state levels are expected to be reached 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 demonstrated that cabergoline, at concentrations of 0.1–10 ng/mL, binds to plasma proteins by 41–42%. 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 delivery, if the mother has decided not to breastfeed or when breastfeeding is contraindicated for medical reasons in either the mother or the infant;
• after the birth of a stillborn fetus or following 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 week postpartum (which was generally mild in severity).

Suppression of milk secretion and relief from breast engorgement and pain were observed in approximately 85% of women during established lactation when a total dose of 1 mg 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 was restored in 89% of women, as documented by 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 of the excipients of the medicinal product, or to any ergot alkaloids.

Uncontrolled hypertension.

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

For long-term treatment: evidence of valvular heart disease detected by echocardiography prior to initiation of therapy (see section "Special precautions").

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.

Interaction with other medicinal products and other forms of interaction.

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

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

Since the therapeutic effect of Cabergoline is mediated 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, Caberlin should not be used concomitantly with macrolide antibiotics (e.g., erythromycin) due to increased systemic bioavailability of cabergoline.

Special precautions for use.

General.

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

Symptomatic arterial hypotension may occur during treatment with Cabergoline regardless of the indication; therefore, Cabergoline should be used cautiously when administered concomitantly with other medicinal products that lower blood pressure.

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

Before initiating treatment with Cabergoline, pregnancy should be excluded. After completion of treatment, pregnancy should be avoided for at least one month.

Hepatic impairment

Lower doses of Cabergoline should be considered for patients with severe hepatic impairment who require long-term treatment. In patients with severe hepatic impairment (Child-Pugh class C) who received a single 1 mg dose of cabergoline, increased AUC values were observed compared to healthy volunteers and patients with less severe hepatic impairment.

Postural arterial hypotension

Postural arterial hypotension may occur after administration of Cabergoline; therefore, this medicinal product should be used cautiously in combination with other medicinal products that lower blood pressure.

Somnolence/sudden sleep onset

Cabergoline 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, sometimes without prior warning signs or awareness, have been reported. 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 episodes of falling asleep should refrain from driving or operating machinery. In such cases, dose reduction or discontinuation of treatment should also be considered (see section "Ability to influence reaction speed when driving or operating machinery").

Impulse control disorders

Patients should be routinely monitored for the development of impulse control disorders. Patients and caregivers should be informed that behavioral symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending and shopping, bulimia, and compulsive overeating, may occur in patients receiving dopamine agonists, including cabergoline. 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, Cabergoline should not be used in women with pregnancy-induced hypertension, such as pre-eclampsia or postpartum hypertension, except when the potential benefit is considered to outweigh the possible risk.

In postpartum studies using cabergoline, blood pressure reduction was predominantly asymptomatic and often occurred as a single event 2–4 days after initiation of treatment. Since blood pressure reduction frequently occurs postpartum independently of medication, many of the reported cases of hypotension following cabergoline administration may not be drug-related. However, periodic monitoring of blood pressure is recommended, particularly during the first few days after taking cabergoline.

To avoid possible postural arterial hypotension, a single dose of Cabergoline should not exceed 0.25 mg in breastfeeding women taking the drug to suppress established lactation. In a clinical study evaluating the efficacy and tolerability of a single 0.5 mg dose of cabergoline for lactation suppression, the risk of adverse effects with this indication approximately doubled when the medicinal product was administered as a single 0.5 mg dose.

Treatment of hyperprolactinemic conditions

Prior to initiating treatment with Cabergoline, a complete pituitary evaluation is recommended, as hyperprolactinemia associated with amenorrhea/galactorrhea and infertility may be caused by a pituitary tumor.

Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism.

Since pregnancy may occur before the resumption of the menstrual cycle, pregnancy testing should be performed at least every 4 weeks during amenorrhea, and after menstruation resumes, whenever a delay of more than 3 days occurs. Women who wish to avoid pregnancy should be advised to use mechanical contraception during treatment with Cabergoline and after discontinuation of the drug until anovulation recurs. As a precaution, women who become pregnant should be monitored for signs of pituitary enlargement, as there is a possibility of growth of an existing pituitary tumor during pregnancy.

Before initiating treatment with Cabergoline, pregnancy must be excluded. Women who wish to become pregnant should discontinue treatment with Cabergoline one month before planned conception as a precautionary measure, due to limited clinical experience with the drug and its long elimination half-life. If pregnancy occurs during treatment, cabergoline administration should be discontinued. Women who become pregnant should be monitored for signs of pituitary enlargement, as there is a possibility of growth of an existing pituitary tumor during pregnancy.

Regular gynecological examinations, including cytological studies of the cervix and endometrium, are recommended for patients receiving long-term Cabergoline therapy.

Fibrosis, valvular heart disease, and related clinical phenomena

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 long-term use of ergot derivatives with agonistic activity at the serotonin 5HT2B receptor, such as Cabergoline. In some cases, symptoms or manifestations of valvular heart disease may improve after discontinuation of cabergoline.

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

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

Prior to initiating long-term treatment, all patients should undergo cardiovascular evaluation, including echocardiography, to detect possible asymptomatic valvular heart disease. Prior to treatment initiation, baseline assessment of ESR or other inflammatory markers, pulmonary function/chest X-ray, and renal function is also advisable. It is unknown whether cabergoline treatment may worsen the course of disease in patients with valvular regurgitation. If a patient is diagnosed with fibrotic valvular disease, continued treatment with Cabergoline is not recommended (see section "Contraindications").

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

• Pulmonary and pleural disorders such as dyspnea, shortness of breath, persistent cough, or chest pain;
• Renal insufficiency or obstruction of ureteral/abdominal vessels, which may manifest 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 presents as heart failure; therefore, valvular fibrosis (and constrictive pericarditis) should be ruled out upon symptom onset.

Regular clinical monitoring for the development of fibrotic disorders is mandatory. The first echocardiogram should be performed within 3–6 months after treatment initiation. Subsequent echocardiographic examination frequency should be determined based on individual clinical assessment, with particular attention to the above-mentioned signs and symptoms, but at intervals of no less than every 6–12 months.

Cabergoline treatment should be discontinued if echocardiography reveals new valvular regurgitation, worsening of existing regurgitation, valvular restriction, or leaflet thickening (see section "Contraindications").

The need for additional clinical investigations (e.g., physical examination including cardiac auscultation, X-ray, or computed tomography) should be determined individually for each patient.

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.

Adequate and well-controlled studies of cabergoline use in pregnant women have not been conducted. Animal studies have shown no teratogenic effects, but reduced fertility and embryotoxicity related to pharmacodynamic activity have been reported.

Cases of major congenital malformations or spontaneous abortion have been reported following cabergoline therapy in pregnant women. The most common neonatal abnormalities were musculoskeletal malformations and cardiopulmonary anomalies. 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 different populations. It is not possible to precisely determine whether there is an increased risk.

Before initiating treatment with Cabergoline, pregnancy should be excluded, and after completion of treatment, pregnancy should be avoided for at least one month.

Women who wish to become pregnant should discontinue cabergoline treatment one month before planned conception. This will prevent potential drug effects on the fetus and will not interfere with the possibility of conception, as ovulatory cycles may persist for up to 6 months after discontinuation of the drug. If conception occurs during treatment, the drug should be discontinued immediately upon confirmation of pregnancy to minimize fetal exposure (see section "Special precautions for use").

Breastfeeding is not recommended for mothers if Cabergoline has not suppressed/inhibited lactation. Since the drug inhibits lactation, Cabergoline should not be used in mothers with hyperprolactinemic conditions who wish to breastfeed.

Ability to influence reaction speed when driving or operating machinery.

During the first days of Cabergoline treatment, patients should be warned against engaging in activities requiring rapid and precise reactions, such as driving or operating machinery.

Patients taking Cabergoline who experience somnolence should be advised to refrain from driving or engaging in activities where reduced alertness could endanger themselves or others with risk of serious injury or death (e.g., operating machinery), except when patients are able to overcome feelings of somnolence (see section "Special precautions for use").

Method of Administration and Dosage.

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

Inhibition/suppression of physiological lactation

Kaberlin is administered on the first day after delivery. The recommended therapeutic dose is 1 mg (2 tablets of 0.5 mg) given 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 decide to suppress lactation compared to a single dose, and is associated with a lower incidence of adverse events, particularly symptoms of arterial hypotension.

Treatment of hyperprolactinemic conditions

The recommended initial dose of Kaberlin is 0.5 mg once weekly or 1/2 tablet of 0.5 mg twice weekly (e.g., on Monday and Thursday). Weekly dose increases should be gradual, preferably increasing by 0.5 mg per week each month until optimal therapeutic efficacy is achieved. The usual therapeutic dose is 1 mg per week and may range between 0.25 and 2 mg per week. Patients with hyperprolactinemia have been treated with Kaberlin at doses up to 4.5 mg per week.

The maximum dose of the medication 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 given as a single weekly dose has been evaluated in only a few patients.

When increasing the dose, patients should be monitored to determine the minimum dose that produces a therapeutic effect. After an effective 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 Kaberlin, recurrence of hyperprolactinemia is usually observed. However, in some patients, suppression of prolactin levels persisted for several months. In 23 out of 29 women in a follow-up study after stopping Kaberlin, ovulatory cycles lasted longer than 6 months.

Geriatric patients

Experience with the use of the medication in elderly patients is very limited due to the proposed indications for use of Kaberlin. Available data indicate no specific risk.

Children.

Safety and efficacy of Kaberlin in patients under 16 years of age have not been studied.

Overdose.

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

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

Adverse Reactions

Adverse events are generally dose-dependent. In patients with known intolerance to dopaminergic agents, the likelihood of adverse reactions may be reduced by initiating treatment with low doses of Caberlin, for example 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 drug tolerability.

The following adverse reactions have been observed during treatment with cabergoline, with the following frequencies: 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 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: dyspnea, 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 reaction.

Nervous system disorders:

Very common: headache*, dizziness/vertigo;

Common: somnolence;

Uncommon: transient hemianopsia, syncope, paresthesia;

Frequency not known: sudden sleep attacks, 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 on 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: edema, peripheral edema.

Hepatobiliary disorders:

Frequency not known: hepatic 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 amenorrhea, decreased hemoglobin levels were observed during the first few months after menstruation;

Frequency not known: elevated blood creatine phosphokinase levels, abnormal liver function tests.

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

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

***Very common – in female patients treated for hyperprolactinemic conditions; common – 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 dopamine agonist therapy, including cabergoline (see section "Special precautions").

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

2 or 4 tablets per blister or strip, 1 blister or strip per cardboard package.

Prescription status. Prescription only.

Manufacturer.

San Pharmaceuticals Industries Limited.

Manufacturer's address and location of business operations.

Village Ganguwala, Paonta Sahib, District Sirmaur, Himachal Pradesh 173025, India.