Tablets from white to almost white, oval, biconcave, engraved "AA250".
abiraterone acetate 250 mg
Excipients: lactose monohydrate - 198.65 mg, microcrystalline cellulose - 141.22 mg, croscarmellose sodium 42.9 mg, povidone (K29 / K32) 35.75 mg, sodium lauryl sulfate 28.6 mg, silicon colloidal dioxide 7.15 mg, magnesium stearate 10.73 mg.
120 pcs. - bottles of high-density polyethylene (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
Zitiga В® reduces the concentration of testosterone and other androgens in the serum below those that can be obtained with the use of agonists lyuliberin or after an orchidectomy. This is due to the selective inhibition of the CYP17 enzyme, which is required for androgen biosynthesis. The concentration of PSA serves as a biomarker in patients with prostate cancer.
Mechanism of action
Abiraterone acetate in vivo is converted to abiraterone, which is an inhibitor of androgen biosynthesis. In particular, abiraterone selectively inhibits the activity of the enzyme 17? -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. CYP17 catalyzes the conversion of pregnenolone and progesterone by 17? -hydroxylation and breaking of the C17,20 bond in the testosterone precursors: dehydroepiandrosterone and androstenedione, respectively. The inhibition of CYP17 activity 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. Anti-androgen therapy, for example, the use of luliberin agonists or orchidectomy, weakens the synthesis of androgens in the testicles, but does not affect the synthesis of androgens in the adrenals and in the tumor. The use of Zitig В® together with lylyberyrin agonists (or orchidectomy) reduces serum testosterone concentration to a level below the detection threshold.
Use of spironolactone
Patients who participated in the main clinical trials of the Zytiga В® preparation were not given spironolactone, t. its molecules bind to androgen receptors and can increase the level of PSA.
The proportion of patients who had a palliative analgesic effect was significantly higher with Zitig В® , compared with the placebo group. In addition, compared with patients who received placebo, a smaller proportion of patients receiving Zitig В® received progression of the pain syndrome.
Risk of development of bone complications
In comparison with the placebo group, a smaller proportion of patients receiving Zitig В® received bone lesions, including pathological fracture, compression of the spinal cord, the need for palliative radiotherapy, and the need for surgical intervention.
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 is rapidly converted to abiraterone, which is an inhibitor of androgen biosynthesis.
When Zitiga В® is taken intravenously on an empty stomach, the time to reach C max of abiraterone in the blood plasma is approximately 2 hours. Taking ZitigВ® with food, as compared to fasting, leads to a 10-fold increase in AUC and a 17-fold increase in C max of abiraterone, depending on the fat content of the food. Taking into account the normal diversity in the content and composition of food, taking Zitig В® simultaneously with food has the ability to exert a variety of systemic effects.Therefore, the preparation Zitiga В® should not be taken with food.
The binding to plasma proteins of labeled 14 C-abiraterone is 99.8%. The apparent V d is approximately 5,630 liters, indicating that abiraterone is actively distributed in peripheral tissues.
With oral administration of 14 C-abirterone acetate in abirterone capsules, acetate is hydrolyzed to abiraterone, which in turn undergoes metabolism, including sulfation, hydroxylation and oxidation, mainly in the liver. Most of the circulating 14C-abiraterone (approximately 92%) is in the form of metabolites of abiraterone.Of the 15 detectable metabolites for each of the two main metabolites - abiraterone sulfate and N-oxide abiraterone sulfate - accounted for 43% of the total radioactivity.
According to studies conducted with healthy volunteers, the mean T 1/2 of abiraterone in plasma is approximately 15 hours. When ingested with labeled 14 C-abirterone acetate at a dose of 1 g, approximately 88% of the radioactive dose was excreted through the intestine and approximately 5% was excreted by the kidneys .The main substances that were detected in the stool were unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Pharmacokinetics in specific patient groups
Patients with hepatic insufficiency
The pharmacokinetics of abiraterone was studied in patients with mild to moderate hepatic insufficiency (class A and B according to the Child-Pugh classification, respectively) and in healthy volunteers. Systemic exposure to abirterone after a single oral dose of 1 g increased by approximately 11% in patients with mild hepatic insufficiency and by 260% in patients with moderate hepatic insufficiency. The mean T 1/2 of abiterotone is increased to approximately 18 hours in patients with mild hepatic insufficiency and up to about 19 hours in patients with moderate hepatic impairment. For patients with mild hepatic insufficiency, dose adjustment is not required. Zytiga В® is not recommended for patients with moderate or severe hepatic insufficiency (Child-Pugh class B or C), since it is not possible to predict the necessary dose adjustment in this case. Therefore, Zytiga В® should be used with caution in patients with moderate liver function disorders and only if the benefits of treatment significantly exceed the possible risk. Zitig В® should not be given to patients with severe hepatic insufficiency. 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 prescribe ZitigaВ® to patients with prostate cancer who have severe renal dysfunction, since there are no clinical data on the use of ZytigaВ® in these patients.
Effect on the QT interval
It has been established that the Zitig В® preparation has no significant effect on the QT / QT interval c .
- for the treatment of metastatic castration-resistant prostate cancer (in combination with prednisolone).
The recommended daily dose of Zytiga В® is 1 g (4 tablets of 250 mg) 1 time / 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.
Zitig В® should not be taken with food. Within 1 hour after taking the drug, eating is not recommended.
The preparation Zitiga В® is prescribed concomitantly with prednisolone in low doses. The recommended dose of prednisolone is 10 mg / day.
Before starting treatment with ZitigВ®, every 2 weeks for the first 3 months of treatment, and then monthly, the activity of serum transaminases and the concentration of bilirubin should be measured. AD, potassium concentration in the blood and the degree of fluid retention in the body should be evaluated on a monthly basis.
If you miss a regular daily dose of Zitig В® and prednisolone the 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. Zitig В®should be used with caution in patients with moderate liver function disorders, and only if the benefits of treatment significantly exceed the possible risk. Zitig В® can not be administered to patients with severe liver dysfunction .
If during treatment with the drug the patients developed signs of hepatotoxicity (increased ALT or ACT activity 5 times higher than UGN or bilirubin concentration 3 times higher than ULN), therapy should be stopped immediately before the liver function is fully normalized.
Repeated therapy in patients after normalization of liver function indicators can begin with a reduced dose of 500 mg (2 tab.) 1 time / day. In this case, control of the activity of serum transaminases and bilirubin concentration should be carried out at least every 2 weeks for 3 months, and then monthly. If signs of hepatotoxicity occur when the drug is used at a dose of 500 mg, ZitigВ® therapy should be discontinued.
If a severe form of hepatotoxicity develops in patients at any period of therapy (ALT or AST activity exceeds HHV 20-fold), ZitigВ® should be discontinued, and re-administration of the drug in such patients is impossible.
Special patient groups
For patients who have a mild liver function disorder (class A according to Child-Pugh classification) prior to treatment, dose adjustment is not required. Zitig В®should be used with caution in patients with moderate liver function disorders , and only if the benefits of treatment significantly exceed the possible risk. Zitig В®should not be administered to patients with severe liver function disorder (Child-Pugh class B and C) .
For patients with impaired renal function, dose adjustment is not required. Nevertheless, caution should be given to ZitigВ® in patients with prostate cancer who have severe renal dysfunction , because there are no clinical data on the use of ZytigaВ® in these patients.
For children, the use of Zytiga В® is irrelevant, since prostate cancer does not occur in this age group.
The most common adverse events in ZitigВ® treatment are peripheral edema, hypokalemia, increased blood pressure, urinary tract infection, hematuria, increased ACT activity, increased ALT activity, dyspepsia, fractures.
Undesirable reactions are systematized relative to each of the organ systems using the following frequency classification: very often (? 1/10); often (? 1/100, <1/10);infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000), including isolated cases.
Infectious diseases: very often - urinary tract infections; often - sepsis.
From the endocrine system: infrequently - insufficiency of adrenal function.
From the side of laboratory studies: very often - hypokalemia; often hypertriglyceridemia, increased ALT activity, increased AST activity.
From the osteomuscular system: often - fractures (with the exception of pathological fractures); infrequently - rhabdomyolysis, myopathy.
From the urinary system: often - hematuria.
From the cardiovascular system : very often - increased blood pressure; often - heart failure, incl. acute heart failure, left ventricular failure, reduction of the left ventricular ejection fraction; stenocardia, arrhythmia, atrial fibrillation, tachycardia.
From the respiratory system: rarely - allergic alveolitis.
From the digestive tract: very often - diarrhea; often - indigestion.
From the liver and bile ducts: rarely - fulminant hepatitis, acute liver failure.
From the skin and subcutaneous tissues: often - skin rash.
Common disorders: very often - peripheral edema.
- children and adolescence under 18;
severe liver dysfunction;
- hypersensitivity to abiraterone acetate or any auxiliary substance of the drug.
- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
- Patients with prostate cancer with impaired renal function of a serious degree, as there is no clinical data on the use of Zytiga В® in such patients;
- in the treatment of patients whose condition may worsen with increased blood pressure or the development of hypokalemia, for example, patients with heart failure, with a recent myocardial infarction or ventricular arrhythmia; left ventricular ejection fraction less than 50%, heart failure of III-IV functional class according to NYHA classification.
PREGNANCY AND LACTATION
Zitiga В® is not used in women. There are no data on the use of Zitig В® in pregnant women. Zitiga В® 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.
Women of childbearing age
Zitiga В® is not intended for use in women. It is assumed that taking CYP17 inhibitors by 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 abiraterone or its metabolites are present in the sperm. It is necessary to use a condom if a sexual intercourse with a pregnant woman is planned. If a sexual intercourse 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 effects of abiraterone acetate on the reproductive system have not been conducted, there is no evidence of the effect of the drug on fertility.
APPLICATION FOR FUNCTIONS OF THE LIVER
Caution should be used to administer ZitigВ® to patients with prostate cancer who have severe renal dysfunction, since there are no clinical data on the use of Zyttig in these patients.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
For patients who have a liver function disorder of a mild degree (class A according to Child-Pugh classification) prior to treatment, no dose adjustment is required.
Zitiga В® should not be used in patients with moderate or severe hepatic impairment, Child-Pugh class B and C.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
For children and adolescents, the use of Zitiga is not relevant, since prostate cancer does not occur in this age group.
Taking Zitig В® concomitantly with food significantly increases absorption of abiraterone. The effectiveness and safety of Zitig В® , taken with food, is not established.Zitig В® should not be taken concomitantly with food.
Increased blood pressure, hypokalemia and fluid retention due to excess mineralocorticoids
Zitiga В® can cause an increase in blood pressure, hypokalemia and fluid retention due to an increase in the concentration of mineralocorticoids due to inhibition of the CYP17 enzyme. The intake of corticosteroids weakens the stimulating effect of ACTH, which leads to a decrease in the frequency and severity of these adverse reactions. Caution should be exercised in the treatment of 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).
Zitig В® should be given with caution to patients with a history of cardiovascular disease. Safety of the drug in patients with a left ventricular ejection fraction <50% or with heart failure III-IV functional class according to the NYHA classification is not established.
Before starting the Zitig drug, hypokalemia and increased blood pressure should be adjusted.
AD, the concentration of potassium in the blood plasma and the degree of fluid retention should be monitored at least 1 time per month.
Hepatotoxicity and impaired liver function
In clinical studies reported marked increase in liver enzymes that required cancellation or correction of the dose. The activity of serum transaminase and bilirubin should be measured prior to application of the drug Zitiga В® , every 2 weeks during the first 3 months of treatment and then monthly. With the development of clinical symptoms and signs, to suggest the liver, immediately measure the activity of serum transaminase.
By increasing the activity of ALT or AST 5 times above ULN or bilirubin concentration in 3 times above ULN, the preparation Zitiga В® should be stopped immediately, it is necessary to carefully monitor liver function. Preparation Zitiga В®can be used again only after the return of liver function to reference values, and only when the drug administration in lower doses.
If at any time during patient treatment has severe liver toxicity (ALT or AST greater than 20 times ULN), drug Zitiga В® should be canceled, re-use of the drug in these patients impossible.
Dose adjustment in patients with impaired hepatic function a mild degree is not required. No data on the efficacy and safety of repeated application of abiraterone acetate in patients with impaired liver moderate or severe function (class B or C on the Child-Pugh), and therefore impossible to predict the need for dose adjustment. Preparation Zitiga В®should be used with caution in patients with impaired liver function moderate and only if the benefits of treatment far exceeds the potential risk. Preparation Zitiga В® should not be administered to patients with impaired liver function severe.
Cancel GCS and relief of stress
In case of cancellation of prednisolone should be cautious and monitor signs of insufficiency of adrenocortical function. If the application of the drug Zitiga В® is continued after withdrawal of GCS, it should control the appearance of symptoms mineralocorticoid excess. In patients receiving prednisolone, with the development of stressful situations may require a higher dose of corticosteroids before, during and after the stressful situation.
Simultaneous administration of drug Zitiga В® and chemotherapy
safety and efficacy of the drug simultaneously Zitiga В® and cytotoxic chemotherapy have not been established.
Information about some of the excipients included with the drug Zitiga В®
preparation contains 1 mmol (27.2 mg) of sodium in each dose (Table 4.), That must be taken into account when treating patients receiving a diet with a controlled sodium.
Impact on the ability to drive vehicles and manage mechanisms
Preparation Zitiga В® does not or has negligible effect on the ability to drive and moving mechanisms.
Data on drug overdose Zitiga В® limited.
Treatment: there is no specific antidote. In the case of drug overdose reception Zitiga В® should be stopped; should be general supportive measures, including monitoring of arrhythmia. You should also monitor liver function.
The potential impact of other drugs on the impact of abiraterone
In a study involving healthy volunteers, pharmacokinetic interactions of a strong inducer of CYP3A4 isoenzyme - rifampicin at a dose of 600 mg / day for 6 days, and then a single dose of abiraterone acetate 1,000 mg, the mean plasma the AUC ? abiraterone reduced by 55%.
Avoid joint use drug Zitiga В® and strong inducers isoenzyme CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital). The purpose of this group of drugs is possible only after careful evaluation of clinical effectiveness.
The potential influence of the preparation Zitiga В® on the effect of other drugs
Abiraterone inhibits hepatic isozymes involved in the metabolism of drugs - CYP2D6 and CYP2C8.
In a clinical study in determining the effectiveness of abiraterone acetate (plus prednisone) per dose CYP2D6 substrate dextromethorphan systemic effect of dextromethorphan was increased by about 200%. AUC 24 for dextrorphan, active metabolite dektrometorfana increased by approximately 33%.
Recommended with caution drug Zitiga В®patients receiving drugs that are metabolized isoenzyme CYP2D6, especially for drugs with a narrow therapeutic index. In such cases it is necessary to consider reducing the dose of drugs with a narrow therapeutic index metabolized isoenzyme CYP2D6, including drugs such as metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.
In the same study, the determination of the effectiveness of abiraterone acetate (plus prednisone) per dose theophylline CYP1A2 substrate was not observed systemic exposure substrate theophylline.
In a study of CYP2C8 drug-drug interactions in healthy volunteers AUC of pioglitazone has been increased by 46% and AUC sM-III and M-IV, each of the active metabolites of pioglitazone, decreased by 10% when administered pioglitazone together with a single dose of 1000 mg of abiraterone acetate. Although these results show that not expected clinically significant increase in exposure when Zitiga preparation В® is used in combination with other drugs that are eliminated primarily CYP2C8, patients should be monitored for any signs of toxicity associated with the substrate CYP2C8 with a narrow therapeutic index, while the use of drug Zitiga В®.
The combined use with spironolactone
spironolactone binds to the androgen receptor and can enhance the PSA concentration. The use of spironolactone is not recommended in patients taking the drug ZitigaВ® .
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The preparation should be stored in their original packaging in reach of children at a temperature not higher than 30 В° C. Shelf life - 2 years.
The information is provided for your information, do not self-medicate, it is dangerous for your health.