Alactin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALACTIN (ALACTIN)

Composition:

Active substance: cabergoline;

1 tablet contains 0.5 mg of cabergoline;

Excipients: anhydrous lactose, leucine, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, oval, flat tablets with a bevel, containing 0.5 mg of cabergoline. Each tablet has a dividing line on one side and the imprint "CBG" on one side of the line and "0.5" on the other side of the dividing line.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Cabergoline is a synthetic ergot alkaloid and ergoline derivative with a pronounced and prolonged prolactin-lowering effect. The central dopaminergic effect is achieved by stimulation of D2 receptors when using doses higher than those required to reduce plasma prolactin levels.

The prolactin-lowering effect is dose-dependent. A decrease in plasma prolactin levels is observed within 3 hours after drug administration and persists for 2–3 weeks. The long-acting nature of the drug means that a single dose is sufficient to suppress milk secretion stimulation. In the treatment of hyperprolactinemia, plasma prolactin levels normalize within 2–4 weeks after reaching the optimal dose. Prolactin levels may continue to decrease significantly for several months after discontinuation of therapy.

Regarding endocrine effects of cabergoline unrelated to its anti-prolactinemic action, available human data confirm experimental findings from animal studies, indicating that the substance exhibits high selectivity without affecting basal secretion levels of other pituitary hormones or cortisol.

A pharmacodynamic effect of cabergoline not correlated with its therapeutic action is the reduction of blood pressure. The maximum hypotensive effect of cabergoline following a single dose typically occurs within the first 6 hours after administration, with the extent of blood pressure reduction and the frequency of this effect being dose-dependent.

Pharmacokinetics

Absorption. Cabergoline is rapidly absorbed in the gastrointestinal tract after oral administration, with maximum plasma concentration reached within 0.5–4 hours.

Food intake does not affect the absorption or distribution of cabergoline.

Distribution. In vitro experiments have shown that cabergoline, at concentrations of 0.1–10 ng/mL, binds to plasma proteins by 41–42%.

Biotransformation. The main metabolite identified in urine is 6-allyl-8β-carboxy-ergoline, accounting for 4–6% of the administered dose. Three additional metabolites have been identified in urine, collectively accounting for less than 3% of the dose. The activity of these metabolites in inhibiting prolactin secretion, as studied in vitro, is significantly lower than that of cabergoline.

Elimination. The elimination half-life of cabergoline is prolonged: 63–68 hours in healthy volunteers and 79–115 hours in patients with hyperprolactinemia.

Due to the long elimination half-life, steady-state levels are expected to be reached after 4 weeks. This has been 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) at a dose of 0.5 mg.

Approximately 10 days after administration, about 18% and 72% of the administered dose are recovered in urine and feces, respectively. About 2–3% of the dose is excreted unchanged in urine.

Clinical characteristics.

Indications.

Inhibition/suppression of physiological lactation

Alaktin is indicated for the inhibition of physiological postpartum lactation immediately after delivery or for the suppression of established lactation in the following cases:

• after delivery, when the mother has decided 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 after delivery was effective in inhibiting milk secretion, as well as in reducing 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 were generally mild in severity).

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

Treatment of hyperprolactinemic conditions

Alaktin is indicated for the treatment of disorders associated with hyperprolactinemia, including amenorrhea, oligomenorrhea, anovulation, and galactorrhea. The drug is indicated for the treatment of patients with prolactin-secreting pituitary adenomas (micro- and macroprolactinomas), idiopathic hyperprolactinemia, or empty sella syndrome associated with hyperprolactinemia, which are the main pathological conditions underlying 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 were restored in 83% of women with amenorrhea. Ovulation was confirmed in 89% of women based on progesterone levels monitored during the luteal phase. Galactorrhea present prior to treatment resolved in 90% of cases.
Tumor size reduction was observed in 50–90% of women and men with micro- or macroprolactinomas.

Contraindications.

Hypersensitivity to cabergoline, other ergot alkaloids, or to any component of the drug.

History of fibrotic lung, pericardial, or retroperitoneal disorders.

Concomitant use of antipsychotic medicinal products.

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

Postpartum arterial hypertension or uncontrolled arterial hypertension.

Pre-eclampsia, eclampsia.

History of psychosis or risk of postpartum psychosis.

The drug is contraindicated in patients with hepatic insufficiency and in pregnant women with gestosis.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of cabergoline with other medicinal products, particularly with ergot alkaloids, in the early postpartum period has not been associated with any evident interactions affecting the efficacy and safety of this drug.

Due to the lack of data on the interaction of Alaktin with other ergot alkaloids, concomitant therapy with these agents over a prolonged period is not recommended.

Since Alaktin exerts its effect through direct stimulation of dopamine receptors, concomitant administration of dopamine antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide) is not recommended, as these drugs may reduce the prolactin-lowering effect of cabergoline.

The drug should not be used concomitantly with macrolide antibiotics (erythromycin) due to increased systemic bioavailability of cabergoline.

Potential interaction of Alaktin with other antihypertensive agents should be taken into account.

Special precautions for use.

General warnings

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

There are no data on the influence of alcohol on the tolerability of cabergoline.

Symptomatic arterial hypotension may occur during treatment with cabergoline regardless of the indication.

Hepatic impairment

In patients with severe hepatic impairment undergoing long-term cabergoline therapy, consideration should be given to using reduced doses. Unlike healthy volunteers and patients with milder hepatic impairment, patients with severe hepatic dysfunction (Child-Pugh class C) showed increased AUC after a single 1 mg dose.

Renal impairment

No differences in cabergoline pharmacokinetics were observed in patients with moderate to severe renal disease. Pharmacokinetics of cabergoline in patients with end-stage renal disease or those on hemodialysis have not been studied; therefore, the drug should be used with caution in such patients.

Postural arterial hypotension

Postural arterial hypotension has been observed during Alactin treatment. Therefore, caution is required when co-administering with other medicinal products that may lower blood pressure.

Fibrosis, cardiac valvulopathy, and related clinical conditions

Fibrotic and serosal inflammatory conditions such as pleuritis, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy affecting one or more valves (aortic, mitral, tricuspid), or retroperitoneal fibrosis may occur after long-term use of ergot derivatives with agonistic activity at serotonin 5HT2B receptors, such as cabergoline. In some cases, the severity of symptoms and clinical manifestations of cardiac valvulopathy may improve after discontinuation of cabergoline.

Elevated erythrocyte sedimentation rate (ESR) has been observed in pleural effusion/fibrosis above normal levels. In cases of unexplained ESR elevation significantly deviating from normal, chest X-ray examination is recommended. Clinical improvement has been reported after discontinuation of cabergoline in cases diagnosed with pleuritis/pulmonary fibrosis or valvulopathy.

Valvulopathy has been observed with cumulative dosing; therefore, patients should be treated with the lowest effective doses. The benefit-risk ratio should be re-evaluated at each visit to determine the appropriateness of continuing cabergoline treatment.

Prior to initiating long-term treatment, all patients should undergo cardiovascular evaluation, including echocardiography, to detect asymptomatic valvular disease. Baseline assessment of ESR or other inflammatory markers, pulmonary function (chest X-ray), and renal function should also be considered before starting treatment.

It is unknown whether cabergoline treatment may worsen the course of disease in patients with valvular regurgitation. Patients with fibrotic valve changes should not receive cabergoline treatment.

During long-term treatment: since fibrotic disorders may have an insidious onset, regular monitoring for possible signs of fibrosis progression is required. Therefore, attention should be paid to symptoms of:

• pleuropulmonary disease, such as dyspnea, shortness of breath, persistent cough, or chest pain;
• renal insufficiency or obstruction of ureteral/abdominal vessels, which may present as flank/side pain and lower limb edema, or any 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 when such symptoms appear.

Clinical diagnostic monitoring for fibrotic disorders is mandatory. The first echocardiography should be performed within 3–6 months after starting treatment; thereafter, the frequency of echocardiographic examinations should be determined based on individual clinical signs. The above-mentioned symptoms require particular attention, but monitoring should be performed at least every 6–12 months.

Cabergoline treatment should be discontinued if new-onset or worsening valvular regurgitation, valvular restriction, or thickening of valve leaflets is detected on echocardiography (see section "Contraindications").

The need for additional clinical investigations (e.g., physical examination, cardiac auscultation, X-ray, CT scan) should be determined individually.

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

Impulse control disorders

Patients should be carefully monitored for the development of impulse control disorders. Patients and their caregivers should be informed about possible behavioral changes indicating impulse control disorders, such as pathological gambling, increased libido, hypersexuality, compulsive shopping, bulimia, or compulsive eating, which may occur during treatment with dopamine agonists, including cabergoline. In such cases, dose reduction or discontinuation of the drug should be considered.

Inhibition/suppression of physiological lactation

As with other ergot derivatives, Alactin should not be used in patients with pregnancy-induced hypertension, such as pre-eclampsia or postpartum hypertension, except when the expected benefit outweighs the potential risk.

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

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 (see section "Dosage and administration"). 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 approximately doubled when the drug was administered as a single 0.5 mg dose.

Treatment of hyperprolactinemic conditions

Complete pituitary evaluation is recommended before initiating cabergoline treatment, as hyperprolactinemia associated with amenorrhea/galactorrhea and infertility may be related to pituitary tumors.

The drug restores ovulation and fertility in women with hyperprolactinemic hypogonadism.

Pregnancy must be excluded before initiating treatment. Due to limited clinical experience with the drug and its long elimination half-life, as a precautionary measure, women planning pregnancy should discontinue cabergoline one month before expected conception.

Since pregnancy may occur before the resumption of menstrual cycles, pregnancy testing is recommended every 4 weeks during amenorrhea and each time after menstruation resumes if menstruation is delayed by more than 3 days. Women who do not wish to become pregnant should use mechanical contraception during treatment and after discontinuation of the drug until anovulation returns. If pregnancy occurs during treatment, cabergoline administration should be discontinued. As a precaution, women who become pregnant should be monitored for signs of pituitary enlargement, as existing pituitary tumors may increase in size during pregnancy.

For patients on long-term treatment, regular gynecological examinations, including cervical and endometrial cytology, are recommended.

Serious adverse reactions in postpartum women

Serious adverse reactions, including arterial hypertension, myocardial infarction, seizures, stroke, or psychiatric disorders, have been reported in women who used cabergoline to suppress lactation postpartum. In some patients, seizures or stroke were preceded by severe headache and/or transient visual disturbances. Blood pressure should be carefully monitored during treatment. If arterial hypertension, chest pain suggestive of an adverse reaction, severe, progressive, or persistent headache (with or without visual disturbances), or signs of central nervous system toxicity occur, cabergoline should be discontinued immediately and the patient's condition promptly evaluated.

Somnolence/sudden sleep onset

Cabergoline may cause somnolence. Dopamine agonists may cause 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. Patients should be informed of this risk and advised to exercise caution when driving or operating machinery during cabergoline treatment. Patients experiencing somnolence and/or episodes of sudden sleep should refrain from driving or operating machinery. Dose reduction or discontinuation of treatment should be considered for such patients (see section "Effect on ability to drive and use machines").

Other

This medicinal product contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding.

Pregnancy

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

Available data from a 12-year observational study on pregnancy outcomes after cabergoline therapy include 256 pregnancies. In 17 of 256 pregnancies (6.6%), major congenital malformations or abortions were recorded. Among 258 newborns, 27 neonatal abnormalities (major and minor) were observed in 23 infants. The most common newborn anomalies were musculoskeletal malformations (10) and cardiopulmonary anomalies (5). There is no information on perinatal disorders or long-term infant development following in utero exposure to cabergoline. 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. An increased risk cannot be precisely determined, 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").

Pregnancy should be excluded before starting cabergoline and avoided for at least one month after stopping treatment. Due to the drug’s long elimination half-life and insufficient data on fetal exposure, women planning pregnancy should discontinue cabergoline one month before planned conception. This will prevent potential fetal exposure and will not interfere with conception, as ovulatory cycles may persist for up to 6 months after discontinuation. If conception occurs during treatment, therapy should be discontinued after pregnancy is confirmed to minimize fetal exposure.

Contraception should be used for at least 4 weeks after stopping cabergoline.

Lactation

Due to its ability to suppress lactation, cabergoline should not be used in women with hyperprolactinemic disorders who wish to breastfeed.

Cabergoline and/or its metabolites were excreted in milk in rat studies. There is no information on excretion in human breast milk; however, women should be advised not to breastfeed if lactation suppression with cabergoline is ineffective.

Fertility

Cabergoline restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy may occur before the resumption of menstrual cycles, pregnancy testing is recommended during the amenorrheic period and each time menstruation is delayed by more than three days after resumption. Women who do not wish to become pregnant are advised to use effective non-hormonal contraception during treatment and after stopping cabergoline.

Due to the long elimination half-life and limited safety data on fetal exposure, women planning pregnancy should wait at least one month after stopping cabergoline before attempting conception. Pregnant women should be monitored for signs of pituitary enlargement, as existing pituitary tumors may grow during pregnancy.

Effect on ability to drive and use machines.

Patients should exercise caution when performing tasks requiring rapid and precise reactions, especially at the beginning of treatment.

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

Patients treated with cabergoline who experience somnolence and/or sudden episodes of sleep should refrain from driving or engaging in other activities where reduced alertness may endanger themselves or others (e.g., operating automated systems). Driving and operating machinery may be resumed only after somnolence and impaired alertness have resolved (see section "Special precautions for use").

Dosage and Administration

Alaktin is intended for oral use. The tablet may be divided in half.

To reduce the risk of gastrointestinal adverse effects, it is recommended to take cabergoline with food for all therapeutic indications.

Inhibition/Suppression of Physiological Lactation

To inhibit postpartum lactation, Alaktin should be administered within the first 24 hours after delivery. The recommended therapeutic dose is a single dose of 1 mg (2 tablets of 0.5 mg) of cabergoline.

To suppress established lactation: 0.25 mg (1/2 tablet of 0.5 mg) every 12 hours for 2 days (total dose: 1 mg). This dosing regimen is better tolerated by women who decide to suppress lactation compared to a single dose regimen, and is associated with a lower incidence of adverse events, particularly symptoms of arterial hypotension.

Treatment of Hyperprolactinemic Conditions

The recommended initial dose of Alaktin is 0.5 mg once weekly or 1/2 of a 0.5 mg tablet twice weekly (e.g., on Monday and Thursday). If necessary, the dose may be gradually increased under medical supervision by 0.5 mg per week at monthly intervals until the optimal therapeutic effect is achieved. The usual therapeutic dose is 1 mg per week and may range from 0.25 mg to 2 mg per week. Cabergoline 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/day.

The weekly dose may be administered as a single dose or divided into two or more doses per week, depending on patient tolerance. Dividing the weekly dose into multiple administrations is recommended when the weekly dose exceeds 1 mg, as tolerability of doses exceeding 1 mg administered as a single weekly dose has been evaluated in only a few patients.

When titrating the dose, patients should be monitored to determine the minimum effective therapeutic dose. After an effective dosing regimen has been established, regular (monthly) measurement of plasma prolactin levels is recommended, as normalization of prolactin levels usually occurs within 2–4 weeks of treatment.

After discontinuation of cabergoline, 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 observation group, ovulatory cycles continued for more than 6 months after stopping cabergoline.

Elderly Patients

Experience with cabergoline in elderly patients is very limited due to the approved indications for cabergoline. Available data indicate no specific risk.

Dose Reduction or Discontinuation

Consideration should be given to dose reduction or discontinuation of treatment in patients with:

• Somnolence or episodes of sudden sleep;
• Impaired liver function.

Children

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

Overdose

Symptoms of overdose may resemble those caused by excessive stimulation of dopamine receptors (e.g., nausea, vomiting, gastrointestinal disturbances, arterial hypotension, disturbances of consciousness/psychosis, or hallucinations). In such cases, immediate medical attention is required.

In case of overdose, general measures to remove the unabsorbed drug should be taken, and if necessary, measures to support arterial blood pressure. Additionally, administration of dopamine antagonist agents may be appropriate.

Adverse Reactions

Adverse effects are dose-dependent and may be reduced by gradual dose reduction.

In patients with known intolerance to dopaminergic agents, the likelihood of adverse events may be minimized by initiating cabergoline therapy at reduced doses, e.g., 0.25 mg once weekly, with subsequent gradual dose escalation to reach the therapeutic dose. If persistent or severe adverse events occur, temporary dose reduction followed by slower dose escalation (e.g., by 0.25 mg/week every 2 weeks) may improve drug tolerability.

The frequency of adverse events observed and reported during cabergoline treatment is defined according to the following criteria: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Cardiac disorders: very common – cardiac valvulopathy (including regurgitation) and associated 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 disturbances, respiratory failure, pleuritis, chest pain.

Immune system disorders: uncommon – hypersensitivity reactions.

Nervous system disorders: very common – headache*, dizziness/vertigo*; common – somnolence; uncommon – transient hemianopsia, 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, delusional ideas, hypersexuality, pathological gambling, psychotic disorders, hallucinations.

Vascular disorders: common – arterial hypotension during long-term use, postural arterial hypotension, flushing**; uncommon – peripheral vasospasm, fainting.

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

General disorders: very common – asthenia***, fatigue; uncommon – edema, peripheral swelling.

Hepatobiliary disorders: frequency not known – liver function abnormalities.

Skin and subcutaneous tissue disorders: common – facial flushing; uncommon – skin reactions, e.g., alopecia, pruritus, rash; rare – allergic skin reactions.

Musculoskeletal and connective tissue disorders: uncommon – leg cramps; rare – finger cramps, muscle weakness.

Reproductive system and breast disorders: common – breast pain.

Investigations: common – asymptomatic decrease in blood pressure (≥20 mm Hg systolic and/or ≥10 mm Hg diastolic); uncommon – decreased hemoglobin levels in women with amenorrhea during the first few months after menstruation; frequency not known – increased blood creatine phosphokinase levels, liver function test abnormalities.

*Very common – in patients treated for hyperprolactinemia; common – in patients with inhibition/suppression of lactation.

**Common – in patients treated for hyperprolactinemia; uncommon – in patients with inhibition/suppression of lactation.

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

Description of selected adverse reactions

Impulse control disorders: pathological gambling, increased libido, hypersexuality, compulsive shopping, bulimia, and compulsive overeating may occur in patients receiving dopamine agonists, including cabergoline.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture, and keep out of reach of children. The mini-packet of silica gel for moisture adsorption must not be removed from the bottle.

Packaging. 2 or 8 tablets in a bottle; 1 bottle per carton. Each bottle contains a mini-packet of silica gel for moisture adsorption.

Prescription status. Prescription only.

Manufacturer.

Teva Czech Industries s.r.o.

Manufacturer's address and location of operations.

Ostravska 305/29, Komarov, 747 70 Opava, Czech Republic.