Amaranth - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 198.65 mg, microcrystalline cellulose 141.22 mg, croscarmellose sodium 42.90 mg, povidone K30 35.75 mg, sodium lauryl sulfate 28.60 mg, silicon colloidal dioxide 7.15 mg, magnesium stearate 10.73 mg.

Description:TOrifle, biconvex tablets white or almost white.

Pharmacotherapeutic group:Other hormone antagonists and their analogues

ATX: & nbsp

L.02.B Hormone antagonists and their analogues

L.02.B.X.03 Abiraterone

Pharmacodynamics:

Mechanism of action:

Abiraterone acetate in vivo turns into abiraterone, which is an inhibitor of androgen biosynthesis. In particular, abiraterone selectively inhibits the activity of the enzyme 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is expressed and is necessary for the biosynthesis of androgens in the testes, adrenals and prostate cancer cells.SRS 17 catalyzes the conversion of pregnenolone and progesterone by 17α-hydroxylation and breaking of the C 17,20 bond into testosterone precursors: dehydroepiandrosterone and androstenedione, respectively. Deceleration of activity CYP17 is also accompanied by increased synthesis of mineralocorticoids in the adrenal glands.

Androgen-sensitive prostate cancer responds to treatment that reduces the concentration of androgens. Antiandrogen therapy, for example, the use of lu-liberin agonists or orchidectomy, weaken the synthesis of androgen in the testicles, but does not affect the synthesis of androgens in the adrenals and in the tumor. The use of Amaranth with lu-liberin agonists (or orchidectomy) lowers the serum testosterone concentration to below the detection threshold.

Pharmacodynamics:

Amaranth's drug reduces the concentration of testosterone and other androgens in the serum below those that can be obtained with the use of agonists, lu-liberin or after an orchidectomy. This is due to the selective inhibition of the enzyme CYP17, which is required for the biosynthesis of androgens.The concentration of prostate-specific antigen (PSA) serves as a biomarker in patients with prostate cancer.

Analgesic effect

The proportion of patients who had a palliative analgesic effect was significantly higher with Amaranth. compared with the placebo group. In addition, compared to patients who received placebo, a smaller proportion of patients receiving Amaranth received progression of pain syndrome.

Risk of development of bone complications

Compared to the placebo group, a smaller proportion of patients receiving Amaranth received bone lesions, including pathological fracture, spinal compression, palliative bone irradiation, and surgical bone treatment.

Pharmacokinetics:

The pharmacokinetics of abiraterone acetate and abiraterone have been studied in healthy volunteers, in patients with advanced metastatic prostate cancer and in non-oncological patients, with renal or hepatic insufficiency. Abiraterone acetate in vivo quickly turns into a abiraterone. which is an inhibitor of androgen biosynthesis.

Absorption:

When administered orally with Amaranth, the fasting time for the maximum concentration of abiraterone in the blood plasma is approximately 2 hours. Taking Amaranth with food, in comparison with taking the drug on an empty stomach, leads to a 10-fold increase in the area under the curve "concentration-time" (AUC) and a 17-fold increase in the maximum concentration of abiraterone (C_max), depending on the fat content of the food. Taking into account the normal diversity in the content and composition of food, taking Amaranth with food has the ability to exert a diverse systemic effect. Therefore, Amaranth should not be taken with food.

Distribution:

Binding to plasma proteins ¹⁴C-abiraterone is 99.8%. The apparent volume of distribution is approximately 5,630 liters, indicating that abiraterone is actively distributed in peripheral tissues.

Metabolism:

When administered orally ¹⁴C-abiraterone acetate capsules, abiraterone acetate hydrolyses to abiraterone, which in turn undergoes metabolism, including sulfation, hydroxylation and oxidation, mainly in the liver.Most of the circulating ¹⁴C-abiraterone (approximately 92%) was in the form of metabolites of abiraterone. Of the 15 detectable metabolites, for each of the two main metabolites - abiraterone sulfate and A-oxide abiraterone sulfate - accounted for 43% of the total radioactivity.

Excretion:

According to studies conducted with healthy volunteers, the average half-life of abiraterone in plasma is approximately 15 hours. When administered orally to a labeled ¹⁴C-abiraterone acetate at a dose of 1 g of approximately 88% of the radioactive dose was excreted through the intestine and approximately 5% was excreted by the kidneys. The main substances found in feces were unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

Pharmacokinetics in special clinical cases

Patients with hepatic insufficiency

The pharmacokinetics of abiraterone was studied in patients with mild to moderate hepatic insufficiency (Child-Pugh class A and B, respectively) and in healthy volunteers. The systemic effect of abiraterone after a single oral administration at a dose of 1 g increasedapproximately 11% of patients with mild liver failure and 260% in patients with moderate hepatic impairment. The average half-life of abiraterone increases to approximately 18 hours in patients with mild liver failure and up to about 19 hours in patients with moderate hepatic impairment. For patients with mild hepatic insufficiency, dose adjustment is not required. Amaranth is not recommended for patients with moderate or severe hepatic insufficiency (Child-Pugh class B or C), since it is impossible to predict the necessary dose adjustment in this case. Therefore, Amaranth should be used with caution in patients with moderate liver function impairment only if the benefit of treatment clearly outweighs the possible risk. Amaranth preparation can not be administered to patients with severe liver failure. Patients who developed hepatotoxicity during the treatment with the drug may need to temporarily stop the drug and adjust the dose.

Patients with renal insufficiency

The pharmacokinetics of abiraterone were compared in patients with terminal renal failure receiving a standard hemodialysis regimen and in patients with normal renal function. Systemic exposure of abirterone acetate after oral administration at a dose of 1 g in patients with terminal stage of renal failure receiving hemodialysis did not increase. Caution should be used to administer Amaranth to patients with prostate cancer with impaired renal function of a serious degree, as there is no clinical data on the use of Amaranth in these patients.

Influence on the interval QT

It was found that Amaranth does not significantly affect the interval QT/QTc.

Indications:

The drug Amirant in combination with prednisolone is intended for the treatment of metastatic castration-resistant prostate cancer.

Contraindications:

- Hypersensitivity to the active component or any auxiliary substance of the drug;

- children's age till 18 years;

- severe liver dysfunction.

Carefully:

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption;

- caution should be used to administer Amaranth to patients with prostate cancer with impaired renal function of a serious degree, as there is no clinical data on the use of Amaranth in these patients;

- caution should be exercised in the treatment of patients whose condition may worsen with increased blood pressure or hypokalemia, for example, patients with heart failure, with recent myocardial infarction or ventricular arrhythmia: a fraction of left ventricular ejection of less than 50%, heart failure III-IV functional class by classification NYHA.

Pregnancy and lactation:

There are no data on the use of Amaranth in pregnant women. Amaranth is not used in women and is contraindicated in pregnant women and able to become pregnant with women. It is not known whether abiraterone acetate or its metabolites with milk is excreted.

Dosing and Administration:

Doses

The recommended daily dose of Amaranth is 1 g (4 tablets of 250 mg) 1 time per day for 1 hour before meals or 2 hours after meals. Tablets should be swallowed whole, not liquid, squeezed with a small amount of water. Amaranth is used together with low doses of prednisone or prednisolone.The recommended dose of prednisone or prednisolone is 10 mg / day.

The drug Amaranth can not be used with food.

Within 1 hour after taking the drug, eating is not recommended.

Before starting treatment with Amaranth. every 2 weeks for the first three months of treatment, and then monthly, the activity of serum transaminases and the concentration of bilirubin should be measured.

Arterial pressure, potassium concentration in the blood and the degree of fluid retention in the body should be assessed on a monthly basis.

If you miss a regular daily dose of Amaranth, prednisolone next day, you should take the usual dose of the missed drug.

Correction of dose in patients with impaired liver function

Correction of the dose in patients with impaired liver function of mild degree is not required.

There is no data on the efficacy and safety of abiraterone acetate in repeated use in patients with moderate or severe liver dysfunction (Child-Pugh class B or C), so it is impossible to predict the necessary dose adjustment.

Amaranth should be used with caution in patients with moderate liver function impairment, and only if the benefits of treatment clearly exceed the possible risk.

Amaranth preparation can not be administered to patients with severe hepatic dysfunction.

If during treatment with the drug in patients developed signs of hepatotoxicity (increased activity of alanine aminotransferase or aspartate aminotransferase 5 times higher than the upper limit of the norm or the concentration of bilirubin 3 times higher than the upper limit of the norm), therapy should be immediately stopped until the liver functions are fully normalized.

Repeated therapy in patients with normalized liver function can begin with a reduced dose of 500 mg (two tablets) once a day. In this case, the control of the activity of serum transaminases and bilirubin concentration should be carried out at least every two weeks for three months, and then monthly. If signs of hepatotoxicity occur when taking a dose of 500 mg, therapy with Amaranth should be discontinued.

If a severe form of hepatotoxicity develops in patients at any period of therapy (the activity of alanine aminotransferase or aspartate aminotransferase exceeds the upper limit of the norm by a factor of 20), Amaranth should be withdrawn, and the re-administration of the drug in such patients is impossible.

Side effects:

The most frequent adverse events in the treatment with Amaranth are peripheral edema, hypokalemia, increased blood pressure, urinary tract infections, hematuria, increased activity of aspartate aminotransferase, increased activity of alanine aminotransferase, dyspepsia, fractures.

Frequency of side effects: very often (≥1 / 10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1/1000 ), very rarely (<1/10000), the frequency is not established (there is currently no data on the prevalence of adverse reactions).

Infectious diseases: very often urinary tract infections; often - sepsis.

From the endocrine system: infrequent adrenal insufficiency.

Influence on the results of laboratory studies: very often - hypokalemia; often - hypertriglyceridemia, increased activity of alanine aminotransferase and aspartate aminotransferase.

From the musculoskeletal system: often fractures (except for pathological fractures); rarely - myopathy. rhabdomyolysis.

From the side of the kidneys and urinary tract: often - hematuria.

From the cardiovascular system: very often - increased blood pressure; often - heart failure, including acute heart failure, left ventricular failure, a decrease in the fraction of the ejection of the left ventricle; angina pectoris, arrhythmia, atrial fibrillation, tachycardia; frequency not established - myocardial infarction.

From the gastrointestinal tract: very often diarrhea; often - indigestion.

From the liver and bile ducts: rarely - fulminant hepatitis, acute liver failure.

From the respiratory system, chest and mediastinum: very rarely - allergic alveolitis.

From the skin and subcutaneous tissues: often - a rash.

Common violations: very often peripheral edema.

Overdose:

Data on overdose with Amaranth is limited. There is no specific antidote. AT In case of an overdose, the intake of Amaranth should be discontinued and general supportive measures, including arrhythmia control, should be carried out. Liver function should also be monitored.

Interaction:

In studies in vitro it was shown that abiraterone inhibits hepatic isoenzymes involved in the metabolism of drugs - CYP1A2, CYP2D6 and CYP2C8.

In a study evaluating the effect of abiraterone acetate, taken together with prednisone, on a single dose of dextromethorphan (an isoenzyme substrate CYP2D6) AUC (area under the concentration-time curve) dextromethorphan increased by approximately 200%. AUC₂₄ (the area under the concentration-time curve) of dextrophane, the active metabolite of dextromethorphan, increased by approximately 33%.

It is recommended to prescribe with caution the drug Amirant to patients receiving drugs that are metabolized by isoenzyme CYP2D6, especially for drugs with a narrow therapeutic index. In such cases, one should consider the possibility of reducing the dose of drugs with a narrow therapeutic index metabolized by isoenzyme CYP2D6, including such drugs as metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.

There are no clinical data on the use of Amaranth with preparations that are substrates of isoenzyme CYP2C8 (for example, with paclitaxel and repaglinin).

Based on the data in vitro Abiraterone is a substrate for isoenzyme CYP3A4. Caution should be exercised while taking with strong inhibitors of the isoenzyme CYP3A4 (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inductors (phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital).

When studying the pharmacokinetic interaction of a strong isoenzyme inducer CYP3A4 on healthy volunteers - rifampicin, 600 mg per day for 6 days and then a single dose of abiraterone acetate 1000 mg, medium plasma AUC_∞ abiraterone decreased by 55%.

It should avoid the combined use of Amaranth and strong isoenzyme inducers CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital). The purpose of this group of drugs is possible only after a thorough evaluation of clinical efficacy.

In clinical pharmacokinetic studies in healthy volunteers, simultaneous administration of ketoconazole, a potent inhibitor CYP3A4, had no clinically significant effect on the pharmacokinetics of abiraterone.

Special instructions:

Taking Amaranth simultaneously with food significantly increases the absorption of abiraterone. The effectiveness and safety of the Amaranth drug taken with food is not established. Amaranth should not be taken with food.

Increased blood pressure, hypokalemia and fluid retention due to excess mineralocorticoids

Amaranth may cause an increase in blood pressure, hypokalemia and fluid retention due to an increase in the concentration of mineralocorticoids due to inhibition of the enzyme CYP17. The intake of mineralocorticoids weakens the stimulating effect of adrenocorticotropic hormone (ACTH), which leads to a decrease in the frequency and severity of these adverse reactions. Caution should be exercised in treating patients whose clinical condition may worsen with increased blood pressure, development of hypokalemia, or fluid retention in the body (eg, in patients with heart failure, recent myocardial infarction, or ventricular arrhythmia).

The drug Amaranth should be used with caution in patients with cardiovascular disease in history.Safety of the drug in patients with a left ventricular ejection fraction <50% or with heart failure III-IV functional class by classification NYHA not installed.

Before beginning the use of the drug Amirant should correct hypokalemia and increase blood pressure.

Arterial pressure, potassium concentration in the blood plasma and the degree of fluid retention should be monitored at least once a month.

Hepatotoxicity and liver dysfunction

In clinical studies, a marked increase in the activity of liver enzymes, requiring the elimination or correction of the dose of the drug. The activity of serum transaminases and bilirubin should be measured before starting the Amaranth drug, every two weeks during the first months of treatment, and then monthly. With the development of clinical symptoms and signs suggesting a violation of liver function, it should immediately measure the activity of serum transaminases.

When the activity of alanine aminotransferase or aspartate aminotransferase is increased 5 times higher than the upper limit of the norm or the concentration of bilirubin is 3 times higher than the upper limit of the norm,The use of Amaranth should be stopped immediately, and liver function should be carefully monitored. The drug Amirant can be used again only after the return of liver function to the original values, and only if lower doses are prescribed.

Correction of the dose in patients with impaired liver function of mild degree is not required. There is no data on the efficacy and safety of repeated use of abiraterone acetate in patients with moderate or severe liver dysfunction (Child-Pugh class B or C), so the need for dose adjustment can not be predicted. Amaranth should be used with caution in patients with moderate liver function disorders, only if the benefits of treatment clearly exceed the possible risk.Amaranth preparation can not be administered to patients with severe hepatic dysfunction.

Women of childbearing age

Amaranth is not intended for use in women. It is assumed that the administration of inhibitors CYP17 pregnant women will change the concentration of hormones, which can affect the development of the fetus. To prevent accidental exposure, pregnant or pregnant women should not work with the drug without gloves.

Contraception in men and women

It is not known whether there is abiraterone or its metabolites in semen. It is necessary to use a condom if a sexual intercourse with a pregnant woman is planned. If the sexual act is planned with a woman of childbearing age, it is necessary to use a condom along with other effective methods of contraception.

Ability to conceive

Studies of the toxic effect of abiraterone acetate on the reproductive system have not been conducted, there is no evidence of the effect of the drug on fertility.

Pregnancy and lactemia

Amaranth does not apply the women. Data on the use of the drug abiraterone Pregnant women do not.The drug Amaranth is contraindicated in pregnancy and able to become pregnant women.

Abolition of glucocorticosteroids and relief of stressful situations With the withdrawal of prednisone or prednisolone, caution should be exercised and signs of insufficiency of adrenal cortex function should be monitored. If the use of Amaranth continues after the abolition of glucocorticosteroids, then the symptoms of excess mineralocorticoids should be monitored. In patients receiving prednisone or prednisolone when developing stressful situations, you may need an increased dose of glucocorticosteroids before, during, and after a stressful situation.

Simultaneous administration of Amaranth and chemotherapy

The safety and efficacy of simultaneous administration of Amaranth and cytotoxic chemotherapy have not been established.

Information on some of the excipients that make up Amaranth

This medication contains 1 mmol (27.2 mg) of sodium in each dose (four tablets) that must be taken into account when treating patients receiving a diet with a controlled sodium.

Effect on the ability to drive transp. cf. and fur:

The Amaranth drug does not affect or has a negligible influence on the ability to drive and move vehicles.

Form release / dosage:

Tablets, 250 mg.

Packaging:

For 120 tablets in a bottle of high density polyethylene, sealed with a polypropylene lid, equipped with a system for protecting children from opening the bottle.

1 bottle per pack of cardboard along with instructions for medical use.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003630

Date of registration:16.05.2016

Expiration Date:16.05.2021

The owner of the registration certificate:Laboratory Tutor SAASIFAALaboratory Tutor SAASIFAA Argentina

Manufacturer: & nbsp

Laboratorio TUTEUR S.A.C.I.F.I.A. Argentina

Representation: & nbspGENPHA LTD.GENPHA LTD.Russia

Information update date: & nbsp12.08.2017

Illustrated instructions

Instructions

Amaranth (Amaranth)