Instructions for Dostinex tablets 0.5 mg No. 2
Composition
active ingredient: cabergoline;
1 tablet contains 0.5 mg of cabergoline;
excipients: leucine, lactose anhydrous.
Dosage form
Pills.
Main physicochemical properties: white, flat, oblong tablets engraved with “PU” separated by a score on one side and engraved with “700” and a slight score above and below the central “0” on the other side.
Pharmacotherapeutic group
Drugs used in gynecology. Prolactin inhibitors. ATC code G02C B03.
Pharmacological properties
Pharmacodynamics
Cabergoline is a dopaminergic ergot derivative with potent and long-lasting prolactin-lowering activity. The drug directly stimulates D2 dopamine receptors on the surface of pituitary lactotropic cells, thereby inhibiting prolactin secretion. This substance reduces prolactin secretion in rats when administered orally at a dose of 3-25 μg/kg and in vitro at a concentration of 45 pg/ml. In addition, cabergoline exerts central dopaminergic effects through stimulation of D2 receptors at oral doses exceeding those effective in reducing serum prolactin levels. The long-term effect of Dostinex on reducing prolactin levels is likely due to its long-term persistence in the target organ, as indicated by the slow rate of elimination of total radioactivity from the pituitary gland after a single oral dose in rats (t½ is approximately 60 hours).
Pharmacodynamic effects have been studied in healthy volunteers, postpartum women, and patients with prolactinemia. After a single oral dose of 0.3-1.5 mg, a significant decrease in plasma prolactin levels is observed in each of the studied populations. This effect develops rapidly - within 3 hours after administration of the drug and persists for 7-28 days in healthy individuals and patients with hyperprolactinemia and for 14-21 days in postpartum women. The degree of decrease in prolactin levels and its duration depend on the dose.
Regarding the endocrine effects of Dostinex, not related to antiprolactinemic action, the available data from studies involving humans confirm the experimental results obtained in animal studies and indicate that the test substance is characterized by a highly selective effect and does not affect the basal level of secretion of other pituitary hormones and cortisol. The pharmacodynamic effect of the drug Dostinex did not correlate with the therapeutic effect only in terms of lowering blood pressure. The maximum hypotensive effect of the drug in a single dose is usually observed within the first 6 hours after administration and is dose-dependent for both the maximum reduction and the frequency of occurrence.
Pharmacokinetics
The pharmacokinetics and metabolic profiles of Dostinex were studied in healthy volunteers of both sexes and in female patients with hyperprolactinemia.
After oral administration of the radiolabeled substance, it was rapidly absorbed from the gastrointestinal tract, and peak radioactivity in plasma was reached after 0.5–4 hours.
Ten days after administration, approximately 18% and 72% of the radioactive dose were excreted in the urine and feces, respectively. The content of unchanged drug in the urine was 2–3% of the administered dose.
The main metabolite identified in urine was 6-allyl-8b-carboxy-ergoline, which accounted for 4-6% of the dose. Three additional metabolites were found in urine, which together accounted for less than 3% of the dose. The in vitro activity of the metabolites in inhibiting prolactin secretion is significantly lower than that of cabergoline. The biotransformation of cabergoline was also studied in the plasma of healthy male volunteers treated with [14C]-cabergoline: cabergoline was found to undergo rapid and extensive biotransformation.
The low urinary excretion of unchanged cabergoline was also confirmed in studies using a non-radioactive drug. The elimination half-life of cabergoline, as determined by the rate of urinary excretion, is long: 63–68 hours in healthy volunteers (using radioimmunoassay) and 79–115 hours in patients with hyperprolactinemia (using HPLC).
Taking into account 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).
The results of in vitro experiments showed that the drug at concentrations of 0.1‒10 ng/ml is 41‒42% bound to blood plasma proteins. Food does not affect the absorption and distribution of the drug.
Indication
Inhibition/suppression of physiological lactation
Inhibition of physiological postpartum lactation immediately after delivery or suppression of 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;
Cabergoline inhibits/suppresses physiological lactation by inhibiting prolactin secretion. In controlled clinical trials, a single dose of 1 mg 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 were observed in approximately 85% of lactating women when a total dose of 1 mg cabregoline was administered for two days in four divided doses. Recurrence of breast symptoms after 10 days was uncommon (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 main pathological conditions causing the above-mentioned 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 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, to any of the excipients of the medicinal product or to any ergot alkaloids.
History of fibrotic diseases of the lungs, pericardium, and retroperitoneal space.
Cabergoline is contraindicated in patients with hepatic insufficiency and pregnant women with gestosis. Cabergoline should not be used concomitantly with antipsychotic drugs or in women with a history of postpartum psychosis.
Cabergoline is contraindicated for long-term treatment if there are signs of valvular heart disease, determined by echocardiography before starting treatment (see section "Special warnings and precautions for use").
Interaction with other medicinal products and other types of interactions
Concomitant use of Dostinex with other drugs, especially ergot alkaloids, in the early postpartum period was not associated with obvious interactions that would alter the efficacy and safety of this drug.
Given that there is no data on the interaction of cabergoline with other ergot alkaloids, the simultaneous use of these drugs during long-term treatment with Dostinex is not recommended.
Since Dostinex exerts its therapeutic effect by direct stimulation of dopamine receptors, its simultaneous use with dopamine receptor antagonists (e.g. phenothiazines, butyrophenones, thioxanthenes and metoclopramide) is not recommended, as these drugs may reduce the prolactin-lowering effect of cabergoline.
Like other ergot derivatives, Dostinex should not be used with macrolide antibiotics (e.g. erythromycin) due to increased systemic bioavailability of cabergoline.
Application features
General Disclaimer
The safety and efficacy of Dostinex have not been established in patients with renal or hepatic disease. As with other ergot derivatives, Dostinex should be administered with caution to patients with severe cardiovascular disease, Raynaud's phenomenon, renal failure, peptic ulcer or gastrointestinal bleeding, and a history of serious psychiatric disorders, especially psychotic disorders. Particular caution should be exercised if patients are taking a psychotropic drug at the same time.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Symptomatic hypotension may occur with Dostinex for any indication. Dostinex should be used with caution in combination with other drugs that lower blood pressure.
The effect of alcohol on the overall tolerability of the drug is currently unknown.
Pregnancy should be excluded before using Dostinex, and pregnancy should be prevented for at least 1 month after treatment.
Liver failure
Lower doses should be considered for patients with severe hepatic impairment receiving long-term treatment with Dostinex. In patients with severe hepatic impairment (Child-Pugh C) who received a single dose of the drug (1 mg), increased AUC values were observed compared to healthy volunteers and patients with less severe hepatic impairment.
Postural hypotension may occur after use of Dostinex. Caution should be exercised when using this drug with other drugs that lower blood pressure.
Drowsiness/sudden falling asleep
Dostinex has been associated with somnolence. Dopamine agonists may cause sudden sleep onset episodes 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 somnolence and/or sudden sleep onset episodes should refrain from driving or operating machinery. In such cases, it may be appropriate to reduce the dose of the drug or discontinue treatment (see section "Ability to affect the speed of reactions when driving or operating machinery").
Impulse control disorder
Patients should be monitored regularly for the development of impulse control disorders. Behavioural symptoms of impulse control disorders, including pathological gambling, increased libido, hypersexuality, compulsive spending and buying, bulimia and compulsive overeating, may occur during treatment with dopamine agonists, including cabergoline, and patients and their caregivers should be informed. If such symptoms occur, dose reduction/discontinuation should be considered.
Inhibition/suppression of physiological lactation
As with other ergot derivatives, Dostinex should not be used in women with pregnancy-induced hypertension, such as preeclampsia or postpartum hypertension, unless the potential benefit outweighs the potential risk.
Serious adverse reactions, including hypertension, myocardial infarction, seizures, stroke, or psychiatric disorders, have been reported in postpartum women receiving cabergoline for lactation suppression.
In some patients, the development of seizures or stroke was preceded by severe headache and/or transient visual impairment.
Blood pressure should be carefully monitored after treatment.
If hypertension, suggestive chest pain, severe, progressive or persistent headache (with or without visual disturbances), or signs of central nervous system toxicity develop, cabergoline should be discontinued and the patient should be evaluated immediately.
In studies of Dostinex 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 Dostinex 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 Dostinex 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 Dostinex 0.5 mg for suppression of lactation, it was found that the risk of side effects in this indication increases approximately twice if the drug is used as a single dose of 0.5 mg.
Treatment of hyperprolactinemic conditions
Before starting treatment with Dostinex, a complete examination of the pituitary gland is indicated, since hyperprolactinemia accompanied by amenorrhea/galactorrhea and infertility may be caused by a pituitary tumor.
Dostinex restores ovulation and fertility in women with hyperprolactinemic hypogonadism.
Before starting the use of Dostinex, pregnancy must be excluded. Women who wish to become pregnant are advised to discontinue treatment with Dostinex 1 month before planned conception when a regular ovulatory cycle appears, as clinical experience with the drug is still quite limited and the drug is characterized by a long half-life. If pregnancy occurs during treatment, cabergoline should be discontinued.
It is recommended to perform regular gynecological examinations, including cytological examinations of the cervix and endometrium, in patients taking Dostinex for a long period.
Fibrosis, heart valve damage, and possible related clinical phenomena
Fibrous and serous inflammatory disorders such as pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion, involvement of one or more heart valves (aortic, mitral and tricuspid) or retroperitoneal fibrosis have been observed after long-term use of ergot derivatives with serotonin 5HT2B receptor agonist activity, such as Dostinex. In some cases, the symptoms or manifestations of valvular heart disease may improve after discontinuation of Dostinex.
An excessive increase in erythrocyte sedimentation rate (ESR) has been observed in association with pleural effusion/fibrosis. In the case of an ESR of unknown etiology that is significantly abnormal, a chest X-ray is recommended.
Valvular lesions are associated with drug accumulation, so patients should be treated with the lowest effective dose. The safety profile of patients treated with Dostinex should be reassessed at each visit to determine the appropriateness of continued treatment.
Before initiating long-term treatment, all patients should undergo cardiovascular evaluation, including echocardiography, to determine the possible presence of asymptomatic valvular heart disease. It is also advisable to determine baseline ESR or other markers of inflammation, pulmonary function/chest radiography, and renal function before initiating treatment. It is not known whether treatment with cabergoline may worsen the course of the disease in patients with valvular regurgitation. If a patient is diagnosed with fibrotic valvular heart disease, continued treatment with Dostinex is not recommended (see section 4.3).
During long-term treatment, fibrotic diseases may develop asymptomatically, so the patient should be monitored for possible manifestations of fibrosis progression. Therefore, during treatment, attention should be paid to the following signs and symptoms:
lung and pleural diseases such as dyspnea, shortness of breath, persistent cough, or chest pain;
renal failure or ureteral/abdominal vascular obstruction, which may present as back/flank pain and lower extremity swelling, as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis;
Heart failure: valvular or pericardial fibrosis often manifests as heart failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded when these symptoms occur.
Clinical diagnostic monitoring of the development of fibrotic diseases is mandatory in accordance with the established procedure. The first echocardiography should be performed within 3-6 months after the start of treatment, after which the frequency of echocardiographic examinations should be determined by appropriate individual clinical examination with special attention to the above symptoms, but at least every 6-12 months.
Dostinex 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 including cardiac auscultation, radiography and computed tomography) should be determined on an individual patient basis.
Appropriate additional studies, including determination of ESR and serum creatinine, should be performed as necessary to confirm the diagnosis of fibrotic disease.
Use during pregnancy or breastfeeding
There are currently no adequate and well-controlled studies of cabergoline in pregnant women. Data are available from a 12-year observational study of pregnancy outcomes following cabergoline therapy in 256 pregnancies. In 17 of 256 pregnancies (6.6%), major congenital malformations or abortions were reported, and 27 neonatal abnormalities, both major and minor, were reported 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 greater. The incidence of congenital anomalies varies in different 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").
Due to the long half-life of the drug and limited data on intrauterine exposure, women wishing to become pregnant should discontinue treatment with cabergoline 1 month before planned conception.
If fertilization occurs during treatment, the drug should be discontinued as soon as pregnancy is confirmed to limit the effect of the drug on the fetus.
There is no information available on the excretion of cabergoline into breast milk, but mothers are advised not to breastfeed unless the use of Dostinex has resulted in inhibition/suppression of lactation. Since the drug suppresses lactation, Dostinex should not be used in mothers with hyperprolactinemic conditions who wish to breastfeed.
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 using Dostinex, patients should refrain from activities that require quick and accurate reactions, such as driving a car or working with other automated systems.
Patients taking Dostinex and experiencing drowsiness 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 "Special warnings and precautions for use").
Method of administration and doses
Dostinex is for oral use. Since Dostinex was administered predominantly with food in clinical studies and since the tolerability of this class of drugs is improved when taken with food, it is recommended that the drug be taken with food for all therapeutic indications.
Inhibition/suppression of physiological lactation
Dostinex should be used within the first day after delivery. The recommended therapeutic dose of the drug is 1 mg (2 tablets of 0.5 mg), taken once.
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 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 Dostinex is 0.5 mg once a week or 1/2 tablet of 0.5 mg twice a week (e.g. on Monday and Thursday). The weekly dose should be increased gradually, preferably 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 from 0.25 mg to 2 mg per week. Dostinex has been used in doses up to 4.5 mg per week for the treatment of patients with hyperprolactinemia.
The maximum dose of the drug should not exceed 3 mg per day.
When increasing the dose, the patient should be examined to determine the minimum dose of the drug that causes a therapeutic effect. Once an effective therapeutic dosage regimen has been selected, regular (monthly) determination of serum prolactin levels is recommended, since normalization of these levels is usually observed within two to four weeks.
After discontinuation of Dostinex, recurrence of hyperprolactinemia is usually observed. 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 Dostinex, ovulatory cycles lasted longer than 6 months.
Elderly patients
Experience in elderly patients is very limited due to the indications for the use of Dostinex. Available data indicate no special risk.
Children
The safety and efficacy of Dostinex in patients under 16 years of age have not been studied.
Overdose
Symptoms of overdose may be similar to those resulting from excessive stimulation of dopamine receptors (e.g. nausea, vomiting, complaints of stomach discomfort, postural hypotension, confusion/psychosis or hallucinations).
If necessary, supportive measures should be used to remove any unabsorbed drug and maintain blood pressure. In addition, the administration of dopamine antagonists may be appropriate.
Adverse reactions
In general, adverse events are dose-related. The likelihood of adverse events in patients with known intolerance to dopaminergic drugs may be reduced by initiating Dostinex treatment at a low dose, e.g. 0.25 mg once weekly, followed by gradual increases to the therapeutic dose. In the event of persistent or severe adverse events, a temporary dose reduction followed by a more gradual dose increase, e.g. by 0.25 mg/week every 2 weeks, may improve tolerability.
The following adverse reactions have been observed during treatment with Dostinex with the following frequencies: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10000 and < 1/1000; very rare: < 1/10000; frequency unknown (cannot be estimated from the available data).
Heart disorders:
very common: valvular lesions (including regurgitation) and related disorders (pericarditis and pericardial effusion);
uncommon: palpitations;
frequency unknown: angina pectoris.
Respiratory, thoracic and mediastinal disorders:
uncommon: dyspnea, 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;
frequency unknown: sudden sleep onset, tremor.
Disorders of the organs of vision:
frequency unknown: visual impairment.
Mental disorders:
common: depression;
uncommon: increased libido;
frequency unknown: aggression, delusions, hypersexuality, pathological gambling, mental disorders, hallucinations.
Vascular disorders:
common: hypotensive effect in patients receiving long-term treatment; postural hypotension, hot flashes**;
uncommon: peripheral vasospasm, loss of consciousness.
Digestive system disorders:
very common: nausea*, dyspepsia, gastritis, abdominal pain*;
common: constipation, vomiting**;
Rare: epigastric pain.
General disorders and administration site conditions:
very common: asthenia***, fatigue;
uncommon: edema, peripheral edema.
From the hepatobiliary system:
frequency unknown: liver dysfunction.
Skin and subcutaneous tissue disorders:
uncommon: rash, alopecia.
Musculoskeletal and connective tissue disorders:
uncommon: leg cramps.
From the reproductive system and mammary glands:
Common: breast pain.
Research:
common: asymptomatic decrease in blood pressure (≥ 20 mmHg systolic and ≥ 10 mmHg diastolic);
uncommon: in women with amenorrhea, a decrease in hemoglobin levels has been observed during the first few months after menstruation;
frequency unknown: increased blood creatine phosphokinase, abnormal liver function tests.
*Very common in patients treated for hyperprolactinemic conditions; common in patients with inhibited/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.
Pathological gambling, increased libido, hypersexuality, compulsive spending and buying, food refusal and compulsive overeating may occur in patients treated with 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 out of the reach of children at a temperature below 25 ºС.
Packaging
2 or 8 tablets in a dark glass bottle with an aluminum screw cap and tamper-evident seal or in a high-density polyethylene bottle with a polypropylene cap and child-resistant system. 1 bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Pfizer Italia Srl / Pfizer Italia Srl
Location of the manufacturer and its business address.
The location of Marino del Tronto is 63100 Ascoli Piceno (AP), Italy.
Localita Marino del Tronto – 63100 Ascoli Piceno (AP), Italy.
