Agalates (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Czech Industries, s.r.o. (Czech Republic)

Contact Information

TEVA (Israel)

ATC Code

G02CB03 (Cabergoline)

Active Substance

Cabergoline (Rec.INN registered by WHO)

Dosage Form

Agalates

Tablets 0.5 mg: 2 or 8 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, flat, oval, with a bevel and a score on one side, engraved with “0.5” on one side of the score and “CBG” on the other.

Excipients: lactose – 75.8 mg, L-leucine – 3.6 mg, magnesium stearate (E572) – 0.1 mg.

2 pcs. – dark glass bottles (1) – cardboard packs.
8 pcs. – dark glass bottles (1) – cardboard packs.

^x with a child-resistant closure system

Clinical-Pharmacological Group

Dopamine receptor agonist. Inhibitor of prolactin secretion

Pharmacotherapeutic Group

Prolactin inhibitors

Pharmacological Action

Dopamine receptor agonist. Cabergoline is a synthetic ergot alkaloid, an ergoline derivative, a long-acting dopamine agonist that inhibits prolactin secretion. The mechanism of action of cabergoline involves stimulation of central dopamine receptors in the hypothalamus. In doses higher than those required to suppress prolactin secretion, the drug causes a central dopaminergic effect due to stimulation of dopamine D₂ receptors. The drug’s action is dose-dependent. A decrease in blood prolactin levels is usually observed after 3 hours and persists for 2-3 weeks, which is why a single dose of the drug is usually sufficient to suppress milk secretion. In the treatment of hyperprolactinemia, blood prolactin levels normalize within 2-4 weeks of using the drug at an effective dose. Normal prolactin levels may persist for several months after discontinuation of the drug.

Cabergoline has a highly selective action and does not affect the basal secretion of other pituitary hormones and cortisol. The only pharmacodynamic effect not related to the therapeutic action is a decrease in blood pressure. The maximum hypotensive effect usually develops 6 hours after a single dose of the drug; the degree of blood pressure reduction and the frequency of the hypotensive effect are dose-dependent.

Pharmacokinetics

Absorption

After oral administration, Cabergoline is rapidly absorbed from the gastrointestinal tract. C_max in blood plasma is reached within 0.5-4 hours. Food does not affect the absorption or distribution of cabergoline.

Pharmacokinetics are linear up to a dose of 7 mg/day.

Distribution

The binding of cabergoline (at concentrations of 0.1-10 ng/ml) to plasma proteins is 41-42%.

Metabolism

The following metabolites of cabergoline have been found in urine: 6-allyl-8β-carboxy-ergoline in an amount of 4-6% of the administered dose, as well as three other metabolites with a total content of less than 3%.

All metabolites inhibit prolactin secretion to a much lesser extent compared to cabergoline.

Excretion

Cabergoline has a long T_1/2. T_1/2 in healthy volunteers is 63-68 hours, T_1/2 in female patients with hyperprolactinemia is 79-115 hours. With such a T_1/2, steady state is reached after 4 weeks.

18% and 72% of the administered dose were found in urine and feces, respectively. The content of unchanged cabergoline in urine is 2-3%.

Indications

• Suppression of physiological postpartum lactation (only for medical reasons);
• Suppression of established lactation (only for medical reasons);
• Disorders associated with hyperprolactinemia (including such functional disorders as amenorrhea, oligomenorrhea, anovulation, galactorrhea);
• Prolactin-secreting pituitary adenomas (micro- and macroprolactinomas);
• Idiopathic hyperprolactinemia.

ICD codes

Dosage Regimen

Cabergoline is taken orally preferably with meals.

For the treatment of disorders associated with hyperprolactinemia, the recommended initial dose is 500 mcg per week in 1 or 2 doses (for example, on Monday and Thursday). The dose is increased gradually, usually by 500 mcg per week at monthly intervals until the optimal therapeutic effect is achieved. The maximum daily dose is 3 g.

The maintenance dose is 1 mg/week (0.25-2 mg/week); in some cases in patients with hyperprolactinemia – up to 4.5 mg/week.

When using Agalates in doses greater than 1 mg/week, it is recommended to divide the weekly dose into 2 or more doses depending on tolerance.

For the suppression of physiological postpartum or established lactation the recommended dose is 1 mg as a single dose within the first 24 hours after childbirth.

Given the indications for use, experience with cabergoline in elderly patients over 65 years of age is limited. Available data indicate no specific risk.

Adverse Reactions

Definition of the frequency of adverse reactions (in accordance with WHO recommendations): very common (≥10%), common (≥1%, but < 10%), uncommon (≥ 0.1%, but <1%), rare (≥ 0.01%, but <0.1%), very rare (including isolated cases) – <0.01%.

Immune system disorders: uncommon – hypersensitivity reaction, skin rash.

Blood and lymphatic system disorders: uncommon – erythromelalgia.

Nervous system disorders: common – hallucinations, sleep disorders, confusion, dizziness, dyskinesia, increased libido, headache, somnolence, depression; uncommon – hyperkinesia, psychotic disorder, delusion, paresthesia, transient hemianopia, syncope; very rare – sudden onset of sleep, pathological gambling.

Cardiac and vascular disorders: common – postural hypotension, angina pectoris, heart valve damage (including with regurgitation), pericarditis, pericardial effusion, flushing, palpitations, peripheral edema.

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

Respiratory, thoracic and mediastinal disorders: common – dyspnea, uncommon – pleural effusion, pulmonary fibrosis, epistaxis.

Other: common – asthenia, weakness, impaired liver function, breast pain, visual impairment; very rare – muscle cramps in the lower extremities, increased CPK activity.

Contraindications

• Postpartum or uncontrolled arterial hypertension;
• Severe liver dysfunction;
• Undesirable pulmonary phenomena such as pleurisy or fibrosis (including in the anamnesis) associated with the use of dopamine agonists;
• Psychoses (including in the anamnesis) or the risk of their development;
• Pregnancy and pre-eclampsia and eclampsia developed during pregnancy;
• Lactation period (breastfeeding);
• Children under 16 years of age;
• Heart valve damage due to long-term cabergoline therapy, confirmed by echocardiography;
• Lactose intolerance;
• Lactase deficiency, glucose-galactose malabsorption syndrome;
• Simultaneous use with macrolide antibiotics;
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other ergot alkaloids.

With caution the drug should be prescribed to patients with cardiovascular diseases, arterial hypotension, Raynaud’s syndrome, peptic ulcers or gastrointestinal bleeding, somnolence, sudden attacks of sleep, patients with end-stage renal failure or on hemodialysis, elderly patients over 65 years of age, for a long time.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Pregnancy should be excluded before starting the drug. It is recommended to avoid pregnancy for at least 1 month after discontinuation of treatment. There is limited data on the use of the drug during pregnancy, obtained during the first 8 weeks after conception. The use of cabergoline was not accompanied by an increased risk of abortion, premature birth, multiple pregnancy or congenital disorders. No other data are available to date.

In animal studies, no direct or indirect adverse effects of cabergoline on the course of pregnancy, embryonic/fetal development, childbirth or postnatal development were found.

Given the limited experience with cabergoline during pregnancy, the drug should be discontinued when planning pregnancy. If pregnancy occurs during treatment with Cabergoline, it should be discontinued immediately. Due to the possibility of expansion of a pre-existing tumor, signs of pituitary enlargement in pregnant women should be monitored.

Since Cabergoline suppresses lactation, the drug should not be prescribed to mothers who prefer to breastfeed their infants. Breastfeeding should be discontinued during treatment with cabergoline.

Use in Hepatic Impairment

Data on the efficacy and safety of cabergoline in patients with impaired liver function. Therefore, the drug should be used with caution in such patients.

Use in Renal Impairment

Data on the efficacy and safety of cabergoline in patients with impaired renal function are limited. The pharmacokinetics of cabergoline do not change significantly in moderate or severe renal failure. Not studied in patients with end-stage renal failure or on hemodialysis. Therefore, the drug should be used with caution in such patients.

Pediatric Use

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

Geriatric Use

With caution the drug should be prescribed to elderly patients.

Special Precautions

To open the bottle, first press down on the cap, then turn it as shown on the cap. Do not remove or ingest the silica gel capsule from the bottle.

Data on the efficacy and safety of cabergoline in patients with impaired liver or kidney function are limited. In patients with severe liver failure (Child-Pugh class C), if long-term therapy with Agalates is necessary, it should be used in lower doses.

The pharmacokinetics of cabergoline do not change significantly in moderate or severe renal failure, and have not been studied in patients with end-stage renal failure or on hemodialysis. Therefore, the drug should be used with caution in such patients.

The effect of alcohol on the overall tolerability of cabergoline has not been established.

The use of Agalates may cause symptomatic arterial hypotension, especially when taken concomitantly with drugs that lower blood pressure. It is recommended to measure blood pressure regularly during the first 3-4 days after starting treatment.

With long-term use of Agalates and other ergot derivatives that are active against serotonin 5-HT_2B receptors, the risk of developing fibrotic and serous-inflammatory diseases, such as exudative pleurisy, pleural fibrosis, pulmonary fibrosis, pericarditis, damage to one or more heart valves (aortic, mitral, tricuspid), retroperitoneal fibrosis, increases. Discontinuation of Agalates in case of development of the listed diseases led to an improvement in the condition of patients.

Before starting long-term therapy with Agalates, all patients should undergo a complete examination to identify heart valve damage, determine the functional state of the lungs and kidneys to prevent worsening of concomitant diseases.

If new clinical symptoms from the respiratory system appear, lung fluoroscopy is recommended. In patients with pleural effusions/fibrosis, an increase in ESR was noted, therefore, with an increased ESR without obvious clinical signs, an X-ray examination should also be performed, and the plasma creatinine concentration should be determined.

During long-term therapy with Agalates, fibrotic disorders may develop gradually, so during treatment it is necessary to monitor for the appearance of such symptoms as shortness of breath, dyspnea, cough, chest pain, back pain, swelling of the lower extremities, signs of retroperitoneal fibrosis (back pain, malaise), heart failure.

After starting therapy with Agalates, to prevent fibrotic disorders, the condition of the heart valves should be monitored and an echocardiographic examination should be performed within 3-6 months after the start of therapy. Further, the frequency of echocardiographic monitoring is established by the doctor individually for each patient, but not less than once every 6-12 months. If valve regurgitation appears or worsens, or if valve narrowing or thickening occurs, therapy with Agalates should be discontinued.

The need for other types of clinical examination of the patient is established by the doctor on an individual basis.

When using Agalates, drowsiness and episodes of sudden falling asleep may occur, especially in patients with Parkinson’s disease.

When using Agalates, increased libido, hypersexuality, and pathological gambling have been observed. These symptoms were reversible and disappeared when the dose was reduced or Agalates was discontinued.

Hyperprolactinemia in combination with amenorrhea and infertility may be associated with pituitary tumors, so before starting therapy with Agalates, it is necessary to examine pituitary function.

It is recommended to check serum prolactin levels every month, because after achieving an effective therapeutic regimen, normal prolactin concentration is maintained for 2-4 weeks.

After discontinuation of Agalates, hyperprolactinemia usually recurs. However, some patients experience a persistent decrease in prolactin concentration for several months.

The use of Agalates restores ovulation and fertility in women with hyperprolactinemic hypogonadism. Since pregnancy can occur before menstruation resumes, pregnancy tests are recommended during amenorrhea, and after restoration of the menstrual cycle – in all cases of delay of more than 3 days. Women not planning pregnancy are advised to use effective non-hormonal contraceptives during treatment with Agalates and after its completion. Women planning pregnancy are advised to conceive no earlier than 1 month after discontinuation of Agalates.

Effect on the ability to drive vehicles and operate machinery

Patients should be informed about the need to exercise caution when driving a car or operating machinery.

Patients who have already experienced drowsiness and/or episodes of sudden falling asleep during treatment with Agalates should refrain from driving a car or other activities that require increased concentration and speed of psychomotor reactions.

Preclinical safety data

As shown in preclinical studies, Cabergoline is safe over a wide dose range and has no teratogenic, mutagenic or carcinogenic effects.

Overdose

There is no information on drug overdose. Based on the results of experiments on animals, the appearance of symptoms due to hyperstimulation of dopamine receptors can be expected: nausea, vomiting, decreased blood pressure, impaired consciousness/psychosis or hallucinations.

Treatment: if indicated, measures should be taken to restore blood pressure. In addition, in case of severe symptoms from the central nervous system (hallucinations), the use of dopamine antagonists may be required.

Drug Interactions

The effect of macrolide antibiotics on the plasma concentration of cabergoline when used together has not been studied. Given the possibility of an increase in cabergoline levels, the drug is not recommended to be used in combination with macrolides.

The mechanism of action of cabergoline is associated with direct stimulation of dopamine receptors, so it should not be used in combination with dopamine receptor antagonists (phenothiazines, butyrophenones, thioxanthenes, metoclopramide).

There is no information on the interaction of cabergoline with other ergot alkaloids, nevertheless, long-term use of such a combination is not recommended.

Given the pharmacodynamics of cabergoline (hypotensive effect), interaction with drugs that lower blood pressure should be taken into account.

In clinical studies in patients with Parkinson’s disease, no pharmacokinetic interaction with levodopa or selegiline was found.

Pharmacokinetic interaction with other drugs cannot be predicted based on available information on the metabolism of cabergoline.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place, in a tightly closed original bottle at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

AGA-RU-00002-DOK-PHARM

Important Safety Information

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