Instructions for Alactin tablets 0.5 mg No. 2
Composition
active ingredient: cabergoline;
1 tablet contains 0.5 mg of cabergoline;
excipients: anhydrous lactose, leucine, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white oval, flat, beveled tablets containing 0.5 mg of cabergoline. Each tablet has a score line on one side and is embossed with “CBG” on one side of the score line and “0.5” on the other side of the score line.
Pharmacotherapeutic group
Drugs used in gynecology. Prolactin inhibitors. ATX code G02C B03.
Pharmacological properties
Pharmacodynamics
Cabergoline is a synthetic ergot alkaloid and ergoline derivative with a pronounced and long-lasting prolactin-lowering effect. The central dopaminergic effect is achieved by stimulating D2 receptors at doses higher than those that reduce plasma prolactin levels.
The prolactin-lowering effect is dose-dependent. A decrease in plasma prolactin levels is observed 3 hours after taking the drug and persists for 2-3 weeks. The long-acting effect means that a single dose is sufficient to stop the stimulation of milk secretion. In the treatment of hyperprolactinemia, plasma prolactin levels normalize within 2-4 weeks after reaching the optimal dose. Prolactin levels may still decrease significantly for several months after discontinuation of treatment.
Regarding the endocrine effects of cabergoline, not related to the antiprolactinemic effect, the available data involving humans confirm the experimental results obtained in animal studies and indicate that the test substance is characterized by a highly selective action without affecting the basal level of secretion of other pituitary hormones or cortisol.
The pharmacodynamic effect of cabergoline, which is not correlated with the therapeutic effect, concerns only the reduction of blood pressure. The maximum hypotensive effect of cabergoline when used in a single dose is usually achieved within the first 6 hours after taking the drug, and the maximum reduction in blood pressure and the frequency of this effect are dose-dependent.
Pharmacokinetics
Absorption: Cabergoline is rapidly absorbed from the gastrointestinal tract after oral administration, with peak plasma concentrations occurring within 0.5–4 hours.
Food intake does not affect the absorption and distribution of cabergoline.
Distribution: In vitro experiments have shown that cabergoline is 41–42% bound to plasma proteins at concentrations of 0.1–10 ng/mL.
Biotransformation. The main metabolite identified in urine is 6-allyl-8β-carboxy-ergoline, which accounts for 4-6% of the dose. Three additional metabolites have been identified in urine, accounting for a total of less than 3% of the dose. The in vitro activity of the metabolites in inhibiting prolactin secretion is significantly lower than that of cabergoline.
Elimination: The elimination half-life of cabergoline is long: 63–68 hours in healthy volunteers and 79–115 hours in patients with hyperprolactinemia.
Given the half-life, steady state should be reached after 4 weeks, which was confirmed by the mean peak plasma concentrations of cabergoline after a single dose (37±8 pg/ml) and after 4 weeks with multiple doses (101±43 pg/ml) of cabergoline at a dose of 0.5 mg.
10 days after administration, approximately 18% and 72% of the dose were recovered in urine and feces, respectively. 2-3% of the dose was recovered in urine as unchanged drug.
Indication
Inhibition/suppression of physiological lactation
Alactin is prescribed to inhibit physiological postpartum lactation immediately after childbirth or to suppress established lactation in the following cases:
after childbirth, if the mother has decided not to breastfeed the baby or when breastfeeding is contraindicated for the mother or the baby for medical reasons;
after the birth of a stillbirth or after an abortion.
Cabergoline inhibits/suppresses physiological lactation by inhibiting prolactin secretion. In controlled clinical trials, a single dose of 1 mg of cabergoline on the first day postpartum was effective in inhibiting milk secretion and in reducing breast engorgement and pain in 70–90% of women. Less than 5% of women experienced a recurrence of breast symptoms by the third week postpartum (which were usually mild in severity).
Suppression of milk secretion and relief of breast engorgement and breast pain have been observed in approximately 85% of lactating women when a total dose of 1 mg cabergoline given in four divided doses for two days has been administered. Recurrence of breast symptoms after 10 days is uncommon (approximately 2% of cases).
Treatment of hyperprolactinemic conditions
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 cycles resumed in 83% of women with amenorrhea. Restoration of ovulation was documented in 89% of women based on progesterone levels monitored during the luteal phase. Galactorrhea that occurred before treatment was resolved in 90% of cases. Tumor size decreased in 50–90% of women and men with micro- or macroprolactinoma.
Contraindication
Hypersensitivity to cabergoline, other ergot alkaloids or to any component of the drug.
History of fibrotic disease of the lungs, pericardium, and retroperitoneal space.
Concomitant use of antipsychotic medications.
For long-term treatment: signs of heart valve disease determined by echocardiography before starting treatment (see section "Special instructions").
Postpartum hypertension or uncontrolled hypertension.
Preeclampsia, eclampsia.
History of psychosis or risk of developing postpartum psychosis.
The drug is contraindicated in patients with liver failure and pregnant women with gestosis.
Interaction with other medicinal products and other types of interactions
Concomitant use of cabergoline with other drugs, especially ergot alkaloids, in the early postpartum period was not associated with apparent interactions that would alter the efficacy and safety of this drug.
Given that there is no data on the interaction of Alactin with other ergot alkaloids, concomitant therapy with these drugs for a long time is not recommended.
Since Alactin exerts its effect by 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 with macrolide antibiotics (erythromycin) due to increased systemic bioavailability of cabergoline.
The interaction of Alactin with other drugs that lower blood pressure should be taken into account.
Application features
General Disclaimer
The safety and efficacy of Alactin have not yet been established in patients with kidney or liver disease. As with other ergot derivatives, Alactin should be administered with caution to patients with severe cardiovascular disease, Raynaud's syndrome, renal failure, peptic ulcer or gastrointestinal bleeding, and a history of serious, especially psychotic, mental disorders. Particular caution should be exercised if patients are taking a psychotropic drug at the same time.
There are no data on the effect of alcohol on the tolerability of cabergoline.
Symptomatic hypotension may develop with the use of cabergoline in any indication.
Liver failure
In patients with severe hepatic impairment receiving long-term cabergoline therapy, it is advisable to consider using reduced doses of the drug. In contrast to healthy volunteers and individuals with less severe hepatic impairment, patients with severe hepatic impairment (Child-Pugh Class C) showed an increase in AUC after a single dose of 1 mg.
Kidney failure
No differences in the pharmacokinetics of cabergoline were observed in patients with moderate to severe renal disease. The pharmacokinetics of cabergoline in patients with end-stage renal disease or in patients undergoing hemodialysis have not been studied, so the drug should be used with caution in such patients.
Postural hypotension
Postural hypotension has been observed during the use of Alactin. Therefore, it should be used with caution with drugs that can also lower blood pressure.
Fibrosis, cardiac valvulopathy and possible related clinical phenomena
Fibrous and serous inflammations such as pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy involving one or more valves (aortic, mitral and tricuspid), or retroperitoneal fibrosis occur after long-term use of ergoline derivatives with agonist activity at serotonin 5HT2B receptors, such as cabergoline. In some cases, the severity of the symptoms and clinical manifestations of cardiac valvulopathy is alleviated after discontinuation of cabergoline.
Valvulopathy has been observed with cumulative doses, therefore patients should be treated with the lowest effective dose. The benefit-risk balance for the patient should be reassessed at each visit to determine the appropriateness of continued treatment with cabergoline.
Before initiating long-term treatment, all patients should undergo cardiovascular evaluation, including echocardiography, to determine the presence of asymptomatic valvular disease. It is also advisable to perform baseline ESR or other markers of inflammation, pulmonary function (chest radiography), and renal function prior to initiating treatment.
It is not known whether treatment with cabergoline may worsen the course of the disease in patients with valvular regurgitation. It has been established that patients with fibrotic valve changes should not receive treatment with cabergoline.
During long-term treatment: As fibrotic disorders may have an insidious onset, regular monitoring for possible signs of fibrosis progression should be carried out. Therefore, during treatment, attention should be paid to the following symptoms:
pleuropulmonary disease, such as dyspnea, shortness of breath, persistent cough, or chest pain;
renal failure or ureteral/abdominal vascular obstruction, which may present with back/flank pain and lower extremity swelling, as well as any abdominal masses or tenderness that may indicate retroperitoneal fibrosis;
Heart failure: Cases of valvular or pericardial fibrosis often present as heart failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be ruled out when symptoms occur.
Clinical diagnostic monitoring for the development of fibrotic disorders is mandatory. The first echocardiography should be performed within 3–6 months after the start of treatment; the frequency of echocardiographic examinations should be determined by the relevant individual clinical signs. Particular attention should be paid to the symptoms listed above, but monitoring should be carried out at least every 6–12 months.
Cabergoline should be discontinued if echocardiogram reveals new or worsening valvular regurgitation, valve restriction, or valve leaflet thickening (see Contraindications).
The need for other clinical investigations (e.g., physical examination, cardiac auscultation, radiography, CT scan) should be determined on an individual basis.
Appropriate additional studies, such as determination of ESR and serum creatinine levels, should be performed if necessary to confirm the diagnosis of fibrotic disorders.
Impulse control disorders
Patients should be closely monitored for the development of impulse control disorders. Patients and their caregivers should be warned about possible changes in behavior that indicate impulse control disorders, such as pathological gambling, increased libido, hypersexuality, compulsive shopping, bulimia, compulsive eating when using dopamine agonists, including cabergoline. In such cases, the dose should be reduced or the drug should be discontinued.
Inhibition/suppression of physiological lactation
As with other ergot derivatives, Alactin should not be used in patients with pregnancy-induced hypertension, such as preeclampsia or postpartum hypertension, unless the expected benefit of treatment is considered to outweigh the potential risk.
In studies of cabergoline use in the postpartum period, the decrease in blood pressure was mostly asymptomatic and often occurred once 2–4 days after the start of treatment. Since a decrease in blood pressure is often observed in the postpartum period regardless of drug treatment, it is likely that a significant number of reported cases of a decrease in blood pressure after taking cabergoline were not due to the drug. However, periodic monitoring of blood pressure is recommended, especially during the first few days after taking cabergoline.
In order to avoid possible postural hypotension, a single dose of cabergoline should not exceed 0.25 mg for women who are breastfeeding and taking a drug to suppress established lactation (see section "Method of administration and dosage"). In a clinical study to evaluate the efficacy and tolerability of a single dose of cabergoline 0.5 mg for suppression of lactation, it was found that the risk of side effects in this indication increases approximately twice when the drug is used as a single dose of 0.5 mg.
Treatment of hyperprolactinemic conditions
A complete pituitary examination is indicated before starting treatment with cabergoline, since hyperprolactinemia accompanied by amenorrhea/galactorrhea and infertility may be associated with a pituitary tumor.
Pregnancy should be excluded before prescribing the drug. Given the limited clinical experience with the drug and its long half-life, as a precautionary measure, women planning a pregnancy are advised to discontinue cabergoline 1 month before the expected conception after achieving a regular ovulatory cycle.
Since pregnancy may occur before the return of menstruation, it is recommended to perform a pregnancy test every 4 weeks during the period of amenorrhea and each time after the return of menstruation if their delay is more than 3 days. Women who do not wish to become pregnant should use barrier methods of contraception during therapy and after drug withdrawal until anovulation returns. If pregnancy occurs during treatment, cabergoline should be discontinued. As a precautionary measure, women who become pregnant should be monitored for signs of pituitary enlargement, since there is a possibility of an increase in the volume of a pre-existing pituitary tumor during pregnancy.
For patients taking the drug for a long time, regular gynecological examinations, including cytological examinations of the cervix and endometrium, are recommended.
Serious adverse reactions in postpartum women
Serious adverse reactions, including hypertension, myocardial infarction, seizures, stroke, or psychiatric disorders, have been reported in women taking cabergoline for postpartum lactation suppression. In some patients, seizures or stroke have been preceded by severe headache and/or reversible visual disturbances. Blood pressure should be closely monitored during treatment. If 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 and the patient evaluated immediately.
Drowsiness/sudden falling asleep
Cabergoline may cause drowsiness. Dopamine agonists may cause sudden sleep onset in patients with Parkinson's disease. Uncommon cases of sudden sleep onset during daily activities have been reported, in some cases without awareness or warning signs. Patients should be informed of the above information and advised to exercise caution when driving or operating machinery during treatment with cabergoline. Patients who experience drowsiness and/or episodes of sudden sleep onset should refrain from driving or operating machinery. In such patients, a dose reduction or discontinuation of treatment should be considered (see section 4.4).
Other
This medicinal product contains lactose, therefore patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take it.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate and well-controlled studies of cabergoline in pregnant women. Animal studies have shown no teratogenic effects, but have reported reduced fertility and embryotoxicity related to pharmacodynamic activity.
Data are available from a 12-year observational study of pregnancy outcomes following cabergoline therapy in 256 pregnancies. In the study, 17 of 256 pregnancies (6.6%) had major congenital malformations or abortions, and 27 neonatal abnormalities, both major and minor, were observed in 23 of 258 newborns. The most common neonatal anomalies (10) were musculoskeletal malformations and cardiopulmonary anomalies (5). There is no information on perinatal or long-term development of infants exposed to cabergoline in utero. According to the latest published scientific data, the prevalence of major congenital malformations in the general population is 6.9% or more. The incidence of congenital anomalies varies between populations. It is not possible to determine with certainty whether there is an increased risk because no control group was included in the study.
Cabergoline should be administered during pregnancy if clearly indicated and only after careful benefit/risk assessment (see section "Special warnings and precautions for use").
After stopping cabergoline, contraception should be used for at least 4 weeks.
Breastfeeding period
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 rats. There is no information on excretion in human milk, but 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. Because pregnancy may occur before the menstrual cycle returns, it is recommended to perform a pregnancy test during the amenorrhea period, after menstruation has returned, and whenever menstruation is delayed by more than three days. Women who do not wish to become pregnant are advised to use effective non-hormonal contraception during treatment and after discontinuation of cabergoline.
Due to the long half-life and limited experience with the safety of cabergoline on the fetus, it is recommended that women planning a pregnancy wait at least one month after stopping cabergoline before conceiving. After pregnancy, women should be monitored for signs of pituitary enlargement, as existing pituitary tumors may grow during pregnancy.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients should be cautious when performing activities that require quick and accurate reactions at the beginning of treatment.
During the first days of cabergoline use, patients should be cautioned against engaging in activities that require quick and accurate reactions, such as driving a car or working with other automated systems.
Patients treated with cabergoline and experiencing drowsiness and/or sudden sleep onset episodes should not drive or engage in other activities where impaired alertness may put themselves or others at risk of serious injury or death (operation with automated systems). Driving and operating machinery may be resumed after drowsiness and alertness have resolved (see section 4.4).
Method of administration and doses
Alactin is intended for oral use. The tablet can be divided in half.
To reduce the risk of gastrointestinal side effects, it is recommended to take cabergoline with food for all therapeutic indications.
Inhibition/suppression of physiological lactation
For inhibition of postpartum lactation, Alactin should be used within the first 24 hours after delivery. The recommended therapeutic dose is 1 mg (2 tablets of 0.5 mg) of cabergoline once.
To suppress existing lactation - 0.25 mg (1/2 tablet of 0.5 mg) every 12 hours for 2 days (total dose - 1 mg). This dosage regimen is better tolerated by women who decide to suppress lactation than taking a single dose, and it is accompanied by a lower incidence of adverse events, especially symptoms of arterial hypotension.
Treatment of hyperprolactinemic conditions
The recommended initial dose of Alactin is 0.5 mg once a week or ½ tablet of 0.5 mg twice a week (for example, on Monday and Thursday). If necessary, the dose can be gradually increased under the supervision of a physician - by 0.5 mg per week at monthly intervals until the optimal therapeutic effect is achieved. Usually, the therapeutic dose is 1 mg per week and can range from 0.25 mg to 2 mg per week. For the treatment of patients with hyperprolactinemia, cabergoline was used in doses up to 4.5 mg per week.
The maximum dose of the drug should not exceed 3 mg/day.
The weekly dose of the drug can be administered as a single dose or divided into 2 or more doses per week, depending on the patient's tolerability. Dividing the weekly dose into several doses is recommended if the weekly dose is more than 1 mg, since the tolerability of the drug in doses exceeding 1 mg when administered as a single weekly dose has been evaluated in only a few patients.
When selecting a dose, patients should be examined to determine the minimum effective therapeutic dose. Once an effective therapeutic dosage regimen has been selected, regular (monthly) determination of prolactin levels in the blood plasma is recommended, since normalization of prolactin levels is usually observed within 2-4 weeks of treatment.
After discontinuation of cabergoline, hyperprolactinemia usually recurs. However, in some patients, suppression of prolactin levels was observed for several months. In 23 of 29 women in the follow-up group after discontinuation of cabergoline, ovulatory cycles lasted longer than 6 months.
Elderly patients
Experience with the use of cabergoline in the elderly is very limited due to the proposed indications for the use of cabergoline. Available data suggest no special risk.
Dose reduction or discontinuation of treatment should be considered in patients with:
drowsiness or sudden falling asleep;
liver dysfunction.
Children
The safety and efficacy of the drug 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, gastric upset, hypotension, confusion/psychosis or hallucinations). In such cases, immediate medical attention is required.
In the event of overdose, general measures should be taken to remove any unabsorbed drug and, if necessary, to maintain blood pressure. In addition, the administration of dopamine antagonists may be appropriate.
Side effects
Side effects are dose-dependent and may decrease with gradual dose reduction.
In patients with known intolerance to dopaminergic drugs, the likelihood of adverse events may be reduced by initiating treatment with cabergoline at a low dose, e.g. 0.25 mg once weekly, followed by gradual increases to a therapeutic dose. In the event of persistent or severe adverse events, a temporary reduction in dose followed by a more gradual increase, e.g. by 0.25 mg/week every 2 weeks, may improve tolerability.
The frequency of adverse reactions observed and reported during treatment with cabergoline is defined according to the following convention: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), unknown frequency (cannot be estimated from the available data).
Cardiac disorders: very common: cardiac valvulopathy (including regurgitation) and related disorders (pericarditis and pericardial effusion); uncommon: palpitations; unknown frequency: angina pectoris.
Respiratory, thoracic and mediastinal disorders: uncommon: dyspnoea, pleural effusion, fibrosis (including pulmonary fibrosis), epistaxis; very rare: pleural fibrosis; frequency unknown: respiratory distress, respiratory failure, pleurisy, chest pain.
Immune system disorders: uncommon – hypersensitivity reactions.
Nervous system disorders: very common - headache*, dizziness/vertigo*; common - drowsiness; uncommon - transient hemianopsia, syncope, paresthesia; unknown frequency - sudden sleep onset, tremor.
On the part of the organs of vision: unknown frequency - visual impairment.
On the part of the psyche: often - depression; infrequently - increased libido; unknown frequency - aggression, delusions, hypersexuality, pathological gambling, psychotic disorders, hallucinations.
Vascular disorders: common: hypotension with prolonged use, postural hypotension, hot flashes**; uncommon: peripheral vasospasm, fainting.
From the digestive tract: very often - nausea*, dyspepsia, gastritis, abdominal pain*; often - constipation, vomiting**; rarely - epigastric pain.
General disorders: very common - asthenia***, fatigue; uncommon - edema, peripheral edema.
Hepatobiliary system: frequency unknown - liver dysfunction.
Skin and subcutaneous tissue disorders: common: facial flushing; uncommon: skin reactions, such as alopecia, itching, rash; rare: allergic skin reactions.
From the musculoskeletal system: infrequently - leg cramps; rarely - finger cramps, muscle weakness.
Reproductive system and breast disorders: often – breast pain.
Laboratory tests: often - asymptomatic decrease in blood pressure (≥20 mm Hg - systolic and ≥10 mm Hg - diastolic); infrequently - decrease in hemoglobin level in women with amenorrhea during the first few months after menstruation; unknown frequency - increase in blood creatine phosphokinase level, abnormal liver function tests.
*Very common in patients receiving treatment for hyperprolactinemic conditions; common in patients receiving treatment for inhibition/suppressed lactation.
**Common – in patients treated for hyperprolactinemic conditions; uncommon – in patients with inhibition/suppressed lactation.
***Very common – in patients treated for hyperprolactinemic conditions; uncommon – in patients with inhibited/suppressed lactation.
Description of selected adverse reactions
Impulse control disorders: pathological gambling, increased libido, hypersexuality, compulsive shopping, bulimia, and compulsive overeating may occur in patients taking dopamine agonists, including cabergoline.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after the registration of a medicinal product is important. This allows monitoring of the risk/benefit balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 30 ° C in the original packaging to protect from moisture and out of the reach of children. Do not remove the mini-packet with silica gel to adsorb moisture from the bottle.
Packaging
2 or 8 tablets per bottle; 1 bottle per box. The bottle contains a mini-packet of silica gel to absorb moisture.
Vacation category
According to the recipe.
Producer
Teva Czech Industries s.r.o.
Address
Ostravska Street 305/29, Komarov, 747 70 Opava, Czech Republic.
