Active ingredients: Abiraterone (Abiraterone acetate)
ZYTIGA 250 mg tablets
Why is Zytiga used? What is it for?
ZYTIGA contains a medicine called abiraterone acetate. It is used to treat prostate cancer in adult men that has spread to other parts of the body. ZYTIGA stops the body from making testosterone, which can slow the growth of prostate cancer.
When you take this medicine, your doctor will also prescribe another medicine called prednisone or prednisolone. This medicine is used to reduce the possibility of having high blood pressure, too much water in the body (fluid retention), or low blood levels of a chemical known as potassium.
Contraindications When Zytiga should not be used
Do not take ZYTIGA
- if you are allergic to abiraterone acetate or any of the other ingredients of this medicine (listed in section 6).
- if you are a woman, especially if you are pregnant. The use of ZYTIGA is indicated for men only.
- if you have severe liver damage.
Do not take this medicine if any of these apply to you. If you are not sure, ask your doctor or pharmacist before taking this medicine.
Precautions for use What you need to know before taking Zytiga
Talk to your doctor or pharmacist before taking this medicine:
- if you have liver problems
- if you have been told that you have high blood pressure or heart failure or low level of potassium in your blood (a low level of potassium may increase the risk of heart rhythm problems)
- if you have ever had other problems with your heart or blood vessels
- if you have an irregular or rapid heartbeat
- if you are short of breath
- if you have gained weight rapidly
- if you have swelling of your feet, ankles or legs
- if you have taken a medicine called ketoconazole in the past for prostate cancer
- about the need to take this drug with prednisone or prednisolone
- about the possible effects on the bones
- if you have high blood sugar levels.
Tell your doctor if you have been told that you have any problems with your heart or blood vessels, including heart rhythm problems (arrhythmia) or if you are being treated with medicines for these conditions.
Tell your doctor if you have yellow skin or eyes, dark urine or severe nausea or vomiting, as these could be signs or symptoms of liver problems. Rarely, a problem with liver function (called acute liver failure) can occur, which can lead to death.
Decreased red blood cells, decreased sex drive (libido), muscle weakness and / or muscle pain may occur.
If you are not sure if any of the above points apply to you, talk to your doctor or pharmacist before taking this medicine.
Blood monitoring
ZYTIGA can affect the liver and may not have symptoms. When you take this medicine, your doctor will periodically test blood to check for any effects of ZYTIGA on the liver.
Children and adolescents
The drug is not indicated in children and adolescents. If ZYTIGA is accidentally ingested by a child or adolescent, go to the hospital immediately and take the package leaflet with you to show to the emergency room doctor.
Interactions Which drugs or foods can change the effect of Zytiga
Ask your doctor or pharmacist before taking any medicine.
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is important because ZYTIGA can increase the effects of some medicines including heart medicines, tranquilizers, herbal medicines (eg St. John's wort) and others. Your doctor may decide to change the dose of these medicines. Also, some medicines can increase or decrease the effects of ZYTIGA, which can lead to side effects or ZYTIGA may not work as well as it should.
Other medicines taken together with ZYTIGA
Androgen deprivation treatment can increase the risk of heart rhythm problems.
Tell your doctor if you are taking any medicines:
- used to treat heart rhythm problems (eg quinidine, procainamide, amiodarone and sotalol);
- known to increase the risk of heart rhythm problems [eg methadone (used to relieve pain and to treat drug addiction), moxifloxacin (an antibiotic), antipsychotics (used for severe mental illness)].
ZYTIGA with food
- This medicine must not be taken with food (see section "Taking this medicine").
- Taking ZYTIGA with food can cause side effects.
Warnings It is important to know that:
Pregnancy and breastfeeding
The use of ZYTIGA is not indicated in women.
- This medicine can cause fetal harm when taken by pregnant women.
- Pregnant women or those who may be pregnant should wear gloves if they need to touch or handle ZYTIGA.
- If you have sex with a woman of childbearing age, you should use a condom and another "effective contraceptive measure. If you have sex with a pregnant woman, use a condom to protect the fetus."
Driving and using machines
This medicine is unlikely to affect your ability to drive and use any tools or machines.
ZYTIGA contains lactose and sodium
- ZYTIGA contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
- This medicinal product contains approximately 27 mg of sodium in a daily dose of four tablets. This should be taken into consideration in patients on a reduced sodium diet.
Dose, Method and Time of Administration How to use Zytiga: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
How much to take
The recommended dose is 1,000 mg (four tablets) once a day.
Taking this medicine
- Take this medicine by mouth.
- Do not take ZYTIGA with food.
- Take ZYTIGA at least two hours after a meal and do not eat anything for at least one "hour after taking ZYTIGA (see section 2" ZYTIGA with food ").
- Swallow the tablets whole with some water.
- Do not break the tablets.
- ZYTIGA is taken with a medicine called prednisone or prednisolone. Take prednisone or prednisolone exactly following your doctor's instructions.
- You must take prednisone or prednisolone every day while taking ZYTIGA.
- The amount of prednisone or prednisolone may need to be changed in an emergency. Your doctor will advise you if you need to change the amount of prednisone or prednisolone you take. Don't stop taking prednisone or prednisolone, unless your doctor tells you to.
Your doctor may also prescribe other medicines while you are taking ZYTIGA and prednisone or prednisolone.
If you forget to take ZYTIGA
- If you forget to take ZYTIGA or prednisone or prednisolone, take your usual dose the next day.
- If you forget to take ZYTIGA or prednisone or prednisolone for more than a day, talk to your doctor without waiting too long.
If you stop taking ZYTIGA
Don't stop taking ZYTIGA or prednisone or prednisolone, unless your doctor tells you to.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Zytiga
If you take more ZYTIGA than you should, talk to your doctor or go to a hospital straight away.
Side Effects What are the side effects of Zytiga
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you notice any of the side effects listed in this leaflet, stop taking ZYTIGA and contact a doctor immediately:
- muscle weakness, muscle spasms or a pounding heartbeat sensation (palpitations). These can be signs of a low level of potassium in the blood.
Other side effects include:
Very common (may affect more than 1 in 10 patients)
Fluid in the legs or feet, low potassium levels in the blood, high blood pressure, urinary tract infection, diarrhea.
Common (may affect up to 1 in 10 patients)
High levels of fat in the blood, increased liver function tests, chest pain, heart rhythm disturbances, heart failure, fast heart rhythm, severe infection called sepsis, bone fractures, indigestion, blood in urine, rash.
Uncommon (may affect up to 1 in 100 patients)
Problems with your adrenal glands (related to salt and water problems), muscle weakness and / or muscle pain.
Rare (may affect up to 1 in 1,000 patients)
Lung irritation (also called allergic alveolitis). Problems with liver function (also called acute liver failure).
Not known (frequency cannot be estimated from the available data)
Heart attack, changes in ECG - electrocardiogram (QT interval prolongation).
Bone loss can occur in men treated for prostate cancer. ZYTIGA in combination with prednisone or prednisolone can increase bone loss.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the carton and bottle label. The expiry date refers to the last day of this month.
- Store below 30 ° C.
- Do not throw any medicines into water or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What ZYTIGA contains
- The active ingredient is abiraterone acetate. Each tablet contains 250 mg of abiraterone acetate.
- The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose monohydrate; magnesium stearate, povidone (K29 / K32), anhydrous colloidal silica and sodium lauryl sulfate (see section 2 "ZYTIGA contains lactose and sodium").
Description of what ZYTIGA looks like and contents of the pack
- ZYTIGA tablets are oval shaped, white to off-white in color, debossed with "AA250" on one side.
- The tablets are supplied in a plastic bottle with a plastic child resistant closure. Each bottle contains 120 tablets. Each box contains one bottle.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
ZYTIGA 250 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each tablet contains 250 mg of abiraterone acetate.
Excipients with known effects
Each tablet contains 189 mg of lactose and 6.8 mg of sodium.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Tablet
White to off-white, oval shaped tablets (15.9 mm long x 9.5 mm wide), debossed with AA250 on one side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
ZYTIGA is indicated together with prednisone or prednisolone for:
• the treatment of metastatic castration-resistant prostate cancer in asymptomatic or mildly symptomatic adult men after failure of androgen deprivation therapy and for whom chemotherapy is not yet clinically indicated (see section 5.1).
• the treatment of metastatic castration-resistant prostate cancer in adult men whose disease has progressed during or after a docetaxel-based chemotherapy regimen.
04.2 Posology and method of administration -
This medicine should be prescribed by a doctor experienced in the use of anticancer therapies.
Dosage
The recommended dose is 1,000 mg (four 250 mg tablets) to be taken on an empty stomach as a single daily dose (see "Method of administration" below). Taking the tablets with food results in an increase in systemic exposure to abiraterone (see sections 4.5 and 5.2).
ZYTIGA should be taken with a low dose of prednisone or prednisolone. The recommended dose of prednisone or prednisolone is 10 mg per day.
Medical castration with an analogue of the gonadotropin-releasing factor (luteinising hormone releasing hormone, LHRH) should be continued during treatment in patients not surgically castrated.
Before starting treatment, serum transaminase levels should be measured every two weeks for the first three months of treatment and every month thereafter. Monitor blood pressure, serum potassium and fluid retention monthly (see section 4.4). However, patients with a significant risk of congestive heart failure should be monitored every 2 weeks for the first three months of treatment and monthly thereafter (see section 4.4).
Consider maintaining potassium levels ≥ 4.0 mM in patients with pre-existing hypokalaemia or in those who develop hypokalaemia during treatment with ZYTIGA.
For patients who develop Grade ≥ 3 toxicities including hypertension, hypokalaemia, edema and other, non-mineralocorticoid toxicities, treatment should be discontinued and appropriate therapy instituted. Treatment with ZYTIGA should not be resumed until symptoms of toxicity have reduced to Grade 1 or baseline.
If a daily dose of ZYTIGA, prednisone or prednisolone is missed, treatment should be resumed the following day, with the usual daily dose.
Hepatotoxicity
In patients who develop hepatotoxicity during treatment (increase in alanine aminotransferase [ALT] or aspartate aminotransferase [AST] by more than 5 times the upper limit of normal [ULN]), treatment should be stopped immediately (see section 4.4) . Resumption of treatment, after the patient's liver function test values have returned to baseline, can be done with a reduced dose of 500 mg (two tablets) once daily. In patients undergoing re-treatment, serum transaminase levels should be monitored at least every two weeks for three months and, thereafter, every month. Should hepatotoxicity recur with the reduced dose of 500 mg per day, treatment must be stopped.
If patients develop severe hepatotoxicity at any time during therapy (ALT or AST 20 times ULN), treatment should be discontinued and patients should not be re-treated.
Hepatic impairment
In patients with pre-existing mild hepatic impairment, Child-Pugh Class A, no dose adjustment is required.
Moderate hepatic impairment (Child-Pugh Class B) results in an approximately four-fold increase in systemic exposure to abiraterone after single oral doses of abiraterone acetate 1,000 mg (see section 5.2). There are no clinical and safety data. efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Plugh Class B or C). No dose adjustment can be expected. The use of ZYTIGA should be considered with caution in patients with moderate hepatic impairment in whom the benefit must clearly outweigh the possible risk (see sections 4.2 and 5.2). ZYTIGA should not be used in patients with severe hepatic impairment (see sections 4.3 , 4.4 and 5.2).
Renal impairment
No dose adjustment is required in patients with renal impairment (see section 5.2). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients (see section 4.4).
Pediatric population
There is no indication for a specific use of ZYTIGA in the pediatric population.
Method of administration
ZYTIGA is for oral use.
The tablets should be taken at least two hours after a meal and no food can be consumed for at least one hour after taking the tablets. The tablets should be swallowed whole with some water.
04.3 Contraindications -
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Women who are pregnant or of childbearing potential (see section 4.6).
• Severe hepatic impairment [Child-Plugh class C scale (see sections 4.2, 4.4 and 5.2)].
04.4 Special warnings and appropriate precautions for use -
Hypertension, hypokalaemia, fluid retention and heart failure caused by an excess of mineralocorticoids
ZYTIGA may cause hypertension, hypokalaemia and fluid retention (see section 4.8), as a consequence of the increased mineralocorticoid levels caused by CYP17 inhibition (see section 5.1). Co-administration of a corticosteroid inhibits the activity of adrenocorticotropic hormone (ACTH), resulting in a reduction in the incidence and severity of these adverse reactions. Caution is recommended when treating patients with underlying clinical conditions that may be compromised by an increase in blood pressure, from hypokalaemia (e.g. those treated with cardiac glycosides), or fluid retention (e.g. those with heart failure), with severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia, and those with renal impairment strict.
ZYTIGA should be used with caution in patients with a history of cardiovascular disease. Phase 3 clinical trials excluded patients with uncontrolled hypertension, clinically significant heart disease evidenced by myocardial infarction, or atherothrombotic events within the past 6 months, severe or unstable angina, or heart failure class III or IV of the New York Heart Association (NYHA) (study 301) or class II - IV heart failure (study 302) or measurement of cardiac ejection fraction atrial fibrillation or other cardiac arrhythmias requiring medical therapy. Safety in patients with left ventricular ejection fraction (LVEF)
Before treating patients with a significant risk of congestive heart failure (eg, history of heart failure, uncontrolled hypertension, or cardiac events such as ischemic heart disease) consider obtaining an assessment of cardiac function (eg, echocardiogram). Before treatment with ZYTIGA should be treated for heart failure and optimized cardiac function. Hypertension, hypokalaemia and fluid retention should be corrected and controlled. During treatment, blood pressure, serum potassium and fluid retention (weight gain , peripheral edema) and any other signs and symptoms of congestive heart failure should be monitored every 2 weeks for 3 months and then monthly and corrected for abnormalities. QT interval prolongation has been observed in patients with hypokalaemia in association with ZYTIGA treatment. Evaluate cardiac function as clinically indicated, institute appropriate management and consider discontinuing this treatment in case of significant decrease in cardiac function ( see section 4.2).
Hepatotoxicity and hepatic impairment
Marked elevations in liver enzymes, leading to treatment interruption or dose modification, have been observed in controlled clinical trials (see section 4.8). Serum transaminase levels should be measured every two weeks before starting treatment. for the first three months of treatment and every month thereafter. If clinical signs and symptoms suggestive of hepatotoxicity develop, serum transaminases should be measured immediately. If, at any time, ALT or AST were to increase 5-fold l "ULN, treatment should be stopped immediately and liver function should be carefully monitored. Treatment can be resumed at a reduced dose only after the patient's liver function test values have returned to baseline (see section 4.2).
If patients develop severe hepatotoxicity (ALT or AST increase of 20 times ULN) at any time during therapy, treatment should be discontinued and such patients should not be re-treated.
Patients with active or symptomatic viral hepatitis were excluded from clinical studies; therefore, there are no data to support the use of ZYTIGA in this population.
There are no data on the clinical safety and efficacy of multiple doses of abiraterone acetate when administered to patients with moderate or severe hepatic impairment (Child-Plugh Class B or C). The use of ZYTIGA should be evaluated with caution in patients. patients with moderate hepatic impairment in whom the benefit must clearly outweigh the possible risk (see sections 4.2 and 5.2). ZYTIGA must not be used in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).
There have been rare post-marketing reports of acute hepatic failure and fulminant hepatitis, some with fatal outcome (see section 4.8).
Discontinuation of corticosteroid administration and treatment of stressful situations
Caution and monitoring for adrenocortical insufficiency is recommended if patients discontinue prednisone or prednisolone treatment. If ZYTIGA continues after discontinuation of corticosteroids, patients should be monitored for symptoms of mineralocorticoid excess (see information above).
In patients on prednisone or prednisolone who are subject to unusual stress, an increase in the dose of corticosteroids may be advised before, during and after the stressful situation.
Bone density
A decrease in bone density may occur in men with metastatic advanced prostate cancer (castration-resistant prostate cancer). The use of ZYTIGA in combination with a glucocorticoid may enhance this effect.
Previous use of ketoconazole
Prostate cancer patients previously treated with ketoconazole may have lower response rates.
Hyperglycemia
The use of glucocorticoids can increase hyperglycemia, therefore blood glucose should be measured frequently in patients with diabetes.
Use in chemotherapy
The safety and efficacy of ZYTIGA used concomitantly with cytotoxic chemotherapy have not been established (see section 5.1).
Intolerance to excipients
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. In addition, this medicine contains more than 1 mmol (or 27.2 mg) sodium in a four tablet dose. This should be considered for patients on a reduced sodium diet.
Potential Risks
Anemia and sexual dysfunction may occur in men with metastatic castration-resistant prostate cancer including those being treated with ZYTIGA.
Effects on skeletal muscles
Cases of myopathy have been reported in patients treated with ZYTIGA. Some patients had rhabdomyolysis with renal impairment. Most cases developed within the first month of treatment and resolved after discontinuation of ZYTIGA. Caution is advised in patients concomitantly treated with medicinal products known to be associated with myopathy / rhabdomyolysis.
Interactions with other medicines
Potent inducers of CYP3A4 should be avoided during treatment, unless there is no therapeutic alternative, due to the risk of reduced exposure to abiraterone (see section 4.5).
04.5 Interactions with other medicinal products and other forms of interaction -
Effect of food on abiraterone acetate
Administration with food significantly increases the absorption of abiraterone acetate. Efficacy and safety when given with food have not yet been established, therefore this medicinal product should not be taken with food (see sections 4.2 and 5.2).
Interaction with other medicinal products
Potential for other medicinal products to affect abiraterone exposure
In a clinical pharmacokinetic interaction study in healthy subjects pretreated with a potent CYP3A4 inducer, rifampicin 600 mg daily for 6 days, followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC of abiraterone was decreased by 55. %.
Potent inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John's wort [Hypericum perforatum]) are to be avoided during treatment, unless there is no therapeutic alternative.
In another clinical pharmacokinetic interaction study in healthy subjects, co-administration of ketoconazole, a potent CYP3A4 inhibitor, had no clinically significant effect on abiraterone pharmacokinetics.
Potential to influence exposure of other medicinal products
Abiraterone is an inhibitor of the hepatic enzymes CYP2D6 and CYP2C8.
In a study to determine the effects of abiraterone acetate (plus prednisone), with a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately 2.9-fold. The AUC24 per dextrorphan, the active metabolite of dextromethorphan, was increased by approximately 33%.
Caution is advised when administering medicinal products activated or metabolised by CYP2D6, particularly medicinal products with a low therapeutic index. A dose reduction of medicinal products with a low therapeutic index metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecanide, codeine, oxycodone and tramadol (the latter three drugs require CYP2D6 activity for the formation of their active analgesic metabolites).
In a clinical drug-drug interaction study of CYP2C8 in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUC for M-III and M-IV, the active metabolites of pioglitazone, were decreased by 10% when pioglitazone was administered together with a single 1,000 mg dose of abiraterone acetate. Although these results indicate that clinically significant increases in exposure are not expected when ZYTIGA is combined with medicinal products that are primarily cleared by CYP2C8, patients should be carefully monitored for signs of toxicities related to CYP2C8 substrates with a narrow therapeutic index when used concomitantly.
In vitro, the major metabolites abiraterone sulfate and N-oxide abiraterone sulfate have been shown to inhibit the transporter ofuptake hepatic OATP1B1 and, as a consequence, this may increase the concentrations of medicinal products eliminated by OATP1B1. No clinical data are available to confirm the interaction with the transporter.
Use with medicinal products known to prolong the QT interval
Since androgen deprivation therapy can prolong the QT interval, caution should be exercised when administering ZYTIGA together with medicinal products known to prolong the QT interval or medicinal products capable of inducing torsade de pointes such as class IA antiarrhythmics (eg. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics, etc.
Use with spironolactone
Spironolactone binds the androgen receptor and can increase prostate specific antigen (PSA) levels. Use with ZYTIGA is not recommended (see section 5.1).
04.6 Pregnancy and breastfeeding -
Women of childbearing potential
There are no data on the use of ZYTIGA in pregnant women and the use of this medicine is contraindicated in women of childbearing potential.
Contraception in men and women
It is unknown whether abiraterone or its metabolites are excreted in semen. If the patient has sexual intercourse with a woman during pregnancy, it is recommended to use a condom. If the patient has sexual intercourse with a woman of childbearing potential, it is recommended that a condom be used in conjunction with another effective contraceptive measure. Animal studies have shown reproductive toxicity (see section 5.3).
Pregnancy
ZYTIGA is not indicated in women and is contraindicated during pregnancy or in women of childbearing potential (see sections 4.3 and 5.3).
Feeding time
The use of ZYTIGA is contraindicated in women.
Fertility
Abiraterone affects fertility in male and female rats but these effects are fully reversible (see section 5.3).
04.7 Effects on ability to drive and use machines -
ZYTIGA has no or negligible influence on the ability to drive and use machines.
04.8 Undesirable effects -
Summary of the safety profile
The most commonly observed adverse reactions are peripheral edema, hypokalaemia, hypertension and urinary tract infections.
Other important adverse reactions include heart disease, hepatotoxicity, fractures and allergic alveolitis.
ZYTIGA can cause hypertension, hypokalaemia and fluid retention as a pharmacodynamic consequence of the mechanism of action. In clinical studies, expected adverse reactions of mineralocorticoids were observed more commonly in patients treated with abiraterone acetate than in patients treated with placebo: hypokalaemia, respectively. 21% vs 11%, hypertension 16% vs 11% and fluid retention (peripheral edema) 26% vs 20%. In patients treated with abiraterone acetate, Grade 3 and 4 hypokalaemia and Grade 3 and 4 hypertension (Common Terminology Criteria for Adverse Events, CTCAE, version 3.0) were observed in 4% and 2% of patients, respectively. The reactions of mineralocorticoids were managed pharmacologically with positive results. Concomitant use of corticosteroids reduces the incidence and severity of these adverse reactions (see section 4.4).
Table of adverse reactions
Studies conducted in patients with advanced metastatic prostate cancer, on LHRH analog therapy, or previously undergoing orchiectomy, involved the administration of a dose of ZYTIGA of 1,000 mg per day, in combination with a low dose of prednisone or prednisolone. (10 mg per day).
Adverse drug reactions observed during clinical trials and post-marketing experience are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100,
Within each frequency category, undesirable effects are reported in order of decreasing severity. Table 1: Adverse reactions identified in clinical and post-marketing studies
* Heart failure also includes congestive heart failure, left ventricular failure and decreased ejection fraction.
** Fractures includes all fractures except pathological fracture
a Spontaneous reports from post-marketing experience
In patients treated with abiraterone acetate, the following Grade 3 adverse reactions (CTCAE version 3.0) occurred: hypokalaemia 3%; urinary tract infection, alanine aminostransferase increased, hypertension, aspartate aminotransferase increased, fractures 2%; peripheral edema, heart failure and atrial fibrillation 1% each. Grade 3 hypertriglyceridaemia and angina pectoris (CTCAE version 3.0) occurred in
Description of selected adverse reactions
Cardiovascular reactions
Both Phase 3 clinical trials excluded patients with uncontrolled hypertension, clinically significant heart disease, evidenced by myocardial infarction, or atherothrombotic events within the past 6 months, severe or unstable angina, or NYHA class III or IV heart failure (study 301 ) o heart failure class II - IV (study 302) o measurement of cardiac ejection fraction apoplexy and sudden cardiac death. In phase 3 clinical studies, the incidences of vascular-type adverse reactions in patients taking abiraterone acetate versus patients taking placebo were: hypertension 14.5% versus 10.5%, atrial fibrillation 3.4% versus 3.4%, tachycardia 2.8% versus 1.7%, angina pectoris 1.9% versus 0.9%, heart failure 1.9% versus 0.6%, and arrhythmia 1.1% versus 0,4%.
Hepatotoxicity
Hepatotoxicity with elevation of ALT, AST and total bilirubin has been reported in patients treated with abiraterone acetate.In all clinical studies, elevations in liver function tests (elevations in ALT or AST> 5 x ULN [upper limit of normal] or bilirubin> 1.5 x ULN) were reported in approximately 4% of patients. who received abiraterone acetate, usually during the first 3 months of starting treatment. In clinical study 301, patients with elevated baseline ALT or AST were more likely to have elevated liver function tests than patients who began with normal values. When elevated ALT or AST> 5 x ULN, or bilirubin elevations> 3 x ULN were observed, abiraterone acetate was discontinued or discontinued. In two cases there were marked elevations in liver function tests (See section 4.4) Two patients with normal liver function at baseline had elevations in ALT or AST from 15 to 40 x ULN and in bilirubin from 2 to 6 x ULN. liver function tests in both patients returned to normal and one patient underwent re-treatment, without recurring increases in values. In study 302, grade 3 or 4 elevations in ALT or AST were observed in 35 patients (6.5%) treated with abiraterone acetate. Aminotransferase elevations resolved in all but 3 patients (2 with new multiple liver metastases and 1 with AST elevation approximately 3 weeks after the last dose of abiraterone acetate). Treatment interruptions due to ALT elevations and AST was reported in 1.7% and 1.3% of patients treated with abiraterone acetate and 0.2% and 0% of patients treated with placebo, respectively; no deaths were reported due to hepatotoxic events.
In clinical studies, the risk of hepatotoxicity was mitigated by the exclusion of patients with baseline hepatitis or with significant liver function test abnormalities. In clinical trial 301, patients with baseline ALT and AST ≥ 2.5 x ULN, in absence of liver metastases and> 5 x ULN, liver metastases were excluded. In clinical study 302 patients with liver metastases were ineligible and patients with baseline ALT and AST ≥ 2.5 x ULN were excluded. Abnormalities of liver function tests, observed in patients who took part in clinical trials, were managed dynamically by resorting to the interruption of therapy and allowing a repeat of the treatment only after the values in the liver function tests had returned to the patient's baseline levels (see section 4.2). Patients with ALT or AST elevations> 20 x ULN did not undergo re-treatment. The safety of repeat treatment in such patients is not known. The mechanism of ZYTIGA associated hepatotoxicity is unknown.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
Human experience of overdose with ZYTIGA is limited.
There is no specific antidote. In the event of an overdose, dosing should be discontinued and general supportive measures undertaken, including monitoring for arrhythmias, hypokalaemia and signs and symptoms of fluid retention. An assessment of liver function should also be performed.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related agents.
ATC code: L02BX03.
Mechanism of action
Abiraterone acetate (ZYTIGA) is converted in vivo in abiraterone, an inhibitor of androgen biosynthesis. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is normally expressed and is required for the biosynthesis of androgen hormones in testicular, adrenal and neoplastic prostatic tissues. CYP17 catalyzes conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. Inhibition of CYP17 also causes an increase in mineralocorticoid production by the adrenal glands (see section 4.4) .
Androgen-sensitive prostate cancer responds to treatment by reducing androgen levels. Androgen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, reduce the production of androgens in the testes, without affecting the production of androgens by the adrenal glands or in the tumor. Treatment with ZYTIGA reduces serum testosterone to undetectable levels (using commercial tests) when administered with LHRH analogues (or after orchiectomy).
Pharmacodynamic effects
ZYTIGA reduces serum testosterone and other androgenic hormones to levels lower than those achieved with the use of LHRH analogues or orchiectomy alone. This effect is the consequence of the selective inhibition of the CYP17 enzyme required for the biosynthesis of androgens . PSA acts as a biomarker in patients with prostate cancer. In a Phase 3 clinical study, conducted in patients progressing after previous taxane chemotherapy, 38% of patients treated with abiraterone acetate showed a reduction of at least 50% of PSA levels from baseline, versus 10% of patients who received placebo.
Clinical efficacy and safety
Efficacy was established in two phase 3 multicentre, randomized, placebo-controlled clinical trials (studies 301 and 302) in patients with metastatic castration-resistant prostate cancer. Study 302 enrolled patients naïve to treatment with docetaxel. and study 301 enrolled patients who had previously received docetaxel. Patients were taking an LHRH analogue or had previously undergone orchiectomy. In the active substance treatment arm, ZYTIGA was administered at a dose of 1,000 mg per day, in combination with a low dose of prednisone or prednisolone of 5 mg twice daily. Patients in the control group received placebo and a low dose of prednisone or prednisolone of 5 mg twice daily.
Variations found in serum PSA concentration separately are not always predictive of clinical benefit. Therefore, in both clinical trials it was recommended that patients be maintained on the treatment regimen with the assigned study treatments until the discontinuation criteria as outlined below were met for each clinical study.
In both studies, the use of spironolactone was not allowed as it binds the androgen receptor and can increase PSA levels.
Study 302 (chemotherapy naïve patients)
This study enrolled chemotherapy naïve patients who were asymptomatic or mildly symptomatic and for whom chemotherapy was not yet clinically indicated. A more intense pain episode in the last 24 h with a score of 0-1 was considered asymptomatic second Brief Pain Inventory-Short Form (BPI-SF) and a score of 2-3 was considered mildly symptomatic.
In study 302, (n = 1088) the median age of enrolled patients was 71 years for patients treated with ZYTIGA plus prednisone or prednisolone and 70 years for patients treated with placebo plus prednisone or prednisolone. The number of patients treated. with ZYTIGA by racial group was 520 Caucasian (95.4%), 15 Black (2.8%), 4 Asian (0.7%) and 6 other (1.1%).Eastern Cooperative Oncology Group (ECOG) was 0 for 76% of patients and 1 for 24% of patients in both arms. Fifty percent of patients had only bone metastases, a further 31% of patients had bone and soft tissue or lymph node metastases, and 19% of patients had only soft tissue or lymph node metastases. Patients with visceral metastases were excluded. The endpoint primary efficacy results were overall survival and radiological progression-free survival (rPFS). In addition to the size of the endpoint benefit was also assessed using opioid use time for cancer pain, time to initiation of cytotoxic chemotherapy, time to regression of ≥ 1 point ECOG score, and time to PSA progression based on the criteria of Prostate Cancer Working Group-2 (PCWG2). Study treatments were discontinued at the time of unambiguous clinical progression. Treatments could also be discontinued, at the investigator's discretion, at the time of confirmed radiological progression.
Radiological progression-free survival (rPFS) was assessed with the use of imaging sequential as defined by the PCWG2 criteria (for bone lesions) and the modified criteria of Response Evaluation Criteria In Solid Tumors (RECIST) (for soft tissue injuries). The rPFS analyzes used centrally reviewed radiological assessment of progression.
At the "planned analysis of rPFS c" there were 401 events, 150 (28%) of the patients treated with ZYTIGA and 251 (46%) of the patients treated with placebo had radiological evidence of progression or had died. A significant difference in rPFS was observed between treatment groups (see Table 2).
NE = Not estimated
* P-value based on log-rank test adjusted for ECOG stratification factors (0 or 1)
** Hazard ratio
However, the collection of patient data continued until the date of the second analysis ad interim overall survival (overall survival - OS). The investigator's radiological examination of rPFS is presented in Tables 3.
Six hundred and seven patients had radiological progression or died: 271 (50%) in the abiraterone acetate group and 336 (62%) in the placebo group. Treatment with abiraterone acetate reduced the risk of radiological progression or death by 47% compared to placebo (HR = 0.530; 95% CI: [0.451; 0.623], p
* P-value based on log-rank test adjusted for ECOG stratification factors (0 or 1)
** Hazard ratio
A planned interim analysis (IA) for OS was conducted after observation of 333 deaths. Based on the observed significant clinical benefit the study was opened and treatment with ZYTIGA was offered to patients in the placebo group. Survival overall was longer for ZYTIGA than placebo with a 25% reduction in the risk of death (HR = 0.752; 95% CI: [0.606; 0.934], p = 0.0097), but OS was not mature and the results ad interim did not meet target stopping limits for statistical significance (see Table 4). Survival continued after this AI.
The final planned OS analysis was conducted after the observation of 741 deaths (median follow up of 49 months). Sixty-five percent of patients (354 of 546) treated with ZYTIGA, compared with 71% (387 of 542). ) of patients treated with placebo, had died. A statistically significant advantage in OS in the ZYTIGA group was demonstrated with a 19.4% reduction in the risk of death (HR = 0.806; 95% CI: [0.697; 0.931] , p = 0.0033) and a median OS improvement of 4.4 months (ZYTIGA 34.7 months, placebo 30.3 months) (see Table 4). This improvement was demonstrated despite 44% of patients in the placebo received ZYTIGA as subsequent therapy.
NE = Not estimated
* P-value based on log-rank test adjusted for ECOG stratification factors (0 or 1)
** Hazard ratio
In addition to the observed improvements in overall survival and rPFS, the benefit was demonstrated for treatment with ZYTIGA versus placebo in all endpoint secondary as follows:
Time to PSA progression based on PCWG2 criteria: Median time to PSA progression was 11.1 months for patients who received ZYTIGA and 5.6 months for patients who received placebo (HR = 0.488; 95% CI : [0.420; 0.568], p
Time to opioid use for cancer pain: The median time to opioid use for pain caused by prostate cancer at the time of final analysis was 33.4 months for patients receiving ZYTIGA and was 23, 4 months for patients receiving placebo (HR = 0.721; 95% CI: [0.614, 0.846], p
Time to cytotoxic chemotherapy: Median time to cytotoxic chemotherapy was 25.2 months for patients receiving ZYTIGA and 16.8 months for patients receiving placebo (HR = 0.580; 95% CI: [0.487; 0.691], p
Time to worsening of ECOG score ≥ 1 point: Median time to worsening of ECOG score ≥ 1 point was 12.3 months for patients receiving ZYTIGA and 10.9 months for patients receiving placebo (HR = 0.821; 95% CI: [0.714, 0.943], p = 0.0053).
The following endpoints demonstrated a statistically significant advantage in favor of ZYTIGA treatment:
Objective Response: Objective response was defined as the percentage of patients with measurable disease achieving complete or partial response according to RECIST criteria (baseline lymph node size ≥ 2 cm was required to be considered a target lesion). The percentage of patients with measurable disease at baseline with an objective response was 36% in the ZYTIGA group and 16% in the placebo group (p
Pain: Treatment with ZYTIGA significantly reduced the risk of progression of mean pain intensity by 18% compared to the placebo group (p = 0.0490). Median time to progression was 26.7 months in the ZYTIGA group and 18 , 4 months in the placebo group.
Time to worsening of FACT-P (total score): Treatment with ZYTIGA reduced the risk of worsening of FACT-P (total score) by 22% compared to placebo (p = 0.0028). Median time to worsening of FACT-P (total score) was 12.7 months in the ZYTIGA group and 8.3 months in the placebo group.
Study 301 (patients who previously received chemotherapy)
Study 301 enrolled patients who had previously received docetaxel. Patients were not required to progress during docetaxel, as toxicity to this chemotherapy may have led to its discontinuation. Patients continued study treatments until PSA progression (confirmed 25% increase from patient baseline / lower levels), along with protocol-defined radiological progression and symptomatic or clinical progression. Patients with prior ketoconazole treatment for prostate cancer were excluded from this study. L"endpoint primary efficacy was overall survival.
The mean age of enrolled patients was 69 years (range 39-95). The number of patients treated with ZYTIGA by racial group was 737 Caucasian (93.2%), 28 Black (3.5%), 11 Asian ( 1.4%) and 14 other (1.8%). 11% of enrolled patients had a score of performance score according to the ECOG scale of 2; 70% presented radiographic evidence of disease progression with or without PSA progression; 70% had undergone previous cytotoxic chemotherapy and 30% had two. Liver metastases were present in 11% of patients treated with ZYTIGA.
In a planned analysis, conducted after 552 deaths, 42% (333 out of 797) of patients treated with ZYTIGA had died, compared with 55% (219 out of 398) of patients treated with placebo. A statistically significant improvement in placebo was observed. median overall survival of patients treated with ZYTIGA (see Table 5).
a p-value based on log-rank test adjusted for ECOG stratification factors (0-1 vs 2), pain score (absent vs present), number of previous chemotherapy regimens (1 vs 2), and type of progression of disease (only PSA versus radiological).
b Hazard ratio based on risk models adjusted for stratification factors. Risk ratio
At all stages of assessment, after the initial few months of treatment, a higher proportion of patients treated with ZYTIGA remained alive than the proportion of patients who received placebo.
Survival subgroup analyzes showed a significant survival benefit for treatment with ZYTIGA.
In addition to the observed improvement in overall survival, all endpoint Secondaries of the study were in favor of ZYTIGA, as well as being statistically significant after adjusting for multiple trials, based on the following:
Patients treated with ZYTIGA had a significantly higher total PSA response rate (defined as a ≥ 50% reduction from baseline) compared to patients who received placebo, 38% vs 10%, p
The mean time to PSA progression was 10.2 months for patients treated with ZYTIGA and 6.6 months for patients treated with placebo (HR = 0.580; 95% CI: [0.462; 0.728], p
The mean progression-free survival, as determined by radiological examination, was 5.6 months for patients treated with ZYTIGA and 3.6 months for patients treated with placebo (HR = 0.673; 95% CI: [0.585; 0.776 ], p
Ache
The percentage of patients reporting pain relief was statistically significantly greater in the ZYTIGA group than in the placebo group (44% vs 27%, p = 0.0002). responder for pain relief was defined as a patient who experienced a reduction of at least 30% from baseline in the worst pain intensity score according to the BPI SF, over the past 24 hours, with no increase in analgesic use score, observed in two consecutive evaluations four weeks apart. Only patients with a score of ≥ 4 and at least one post-baseline pain score were analyzed (N = 512) for pain relief.
A smaller percentage of patients treated with ZYTIGA had pain progression than patients who took placebo at 6 (22% vs 28%), 12 (30% vs 38%) and 18 months (35% vs 46%). Pain progression was defined as a ≥ 30% increase from baseline in BPI SF worst pain intensity score over the previous 24 hours, with no decrease in analgesic use score observed in two consecutive visits, or a ≥ 30% increase in analgesic use score observed on two consecutive visits. The time to pain progression to the 25th percentile was 7.4 months in the ZYTIGA group, compared to 4.7 months of the placebo group.
Events affecting the skeletal system
A lower percentage of patients in the ZYTIGA group experienced skeletal system events compared to patients in the placebo group at 6 months (18% vs 28%), 12 months (30% vs 40%) and 18 months ( 35% vs 40%). In the ZYTIGA treatment group, the time to the first skeletal event at the 25th percentile was twice that of the control group at 9.9 months versus 4.9 months. A skeletal system event was defined as a pathological fracture, spinal cord compression, palliative radiation to the bone, or surgery to the bone.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with ZYTIGA in all subsets of the pediatric population in advanced prostate cancer. See section 4.2 for information on pediatric use.
05.2 "Pharmacokinetic properties -
Following administration of abiraterone acetate, the pharmacokinetic profile of abiraterone and abiraterone acetate was studied in healthy subjects, in patients with advanced metastatic carcinoma of the prostate and in non-cancer subjects with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo in abiraterone, an inhibitor of androgen biosynthesis (see section 5.1).
Absorption
After oral administration of abiraterone acetate in the fasted state, the time taken to reach the maximum plasma concentration of abiraterone is approximately 2 hours.
Administration of abiraterone acetate with food, compared to administration in the fasted state, results in an increase in mean systemic exposure to abiraterone up to 10 times [AUC] and up to 17 times [Cmax] higher, based on the fat contained in the meal. Given the normal variation in the content and composition of meals, taking ZYTIGA with meals can result in highly variable exposures. Therefore, ZYTIGA should not be taken with food. It should be taken at least one hour before or at least two hours after a meal. The tablets should be swallowed whole with some water (see section 4.2).
Distribution
The binding of 14C-labeled abiraterone to plasma proteins is 99.8%. The apparent volume of distribution is approximately 5,630 l, indicative of an extensive distribution of abiraterone in peripheral tissues.
Biotransformation
Following administration of 14C radioactive isotope-labeled abiraterone acetate in capsules, abiraterone acetate is hydrolyzed to abiraterone, which is then subjected to metabolism, including sulfation, hydroxylation and oxidation, primarily in the liver. Most of the radioactivity present in the circulation (approximately 92%) was found in the form of metabolites of abiraterone. Two major metabolites of the 15 detectable, abiraterone sulfate and N-oxide abiraterone sulfate, each account for approximately 43% of the total radioactivity.
Elimination
The mean half-life of abiraterone in plasma is approximately 15 hours, based on data from healthy subjects. Following oral administration of a 1,000 mg dose of 14C radioactive isotope-labeled abiraterone acetate, approximately 88% of the dose radioactive was recovered in faeces and 5% circanell "urine. The main compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Hepatic impairment
The pharmacokinetics of abiraterone acetate were examined in subjects with pre-existing mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone following a single 1,000 mg oral dose increased by approximately 11% and 260%, respectively, in subjects with pre-existing mild and moderate hepatic impairment. The mean half-life of abiraterone was prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in those with moderate hepatic impairment.
In another clinical study, abiraterone pharmacokinetics were examined in subjects with pre-existing severe hepatic impairment (n = 8) (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The abiraterone AUC was increased by approximately 600% and the free fraction of the drug by 80% in subjects with severe hepatic impairment compared to subjects with normal hepatic function.
No dose adjustment is required for patients with pre-existing mild hepatic impairment.
The use of abiraterone acetate should be considered with caution in patients with moderate hepatic impairment in whom the benefit must clearly outweigh the possible risk (see sections 4.2 and 4.4). Abiraterone acetate should not be used in patients with severe hepatic impairment (see sections 4.2, 4.3 and 4.4).
For patients who develop hepatotoxicity during treatment, treatment interruption and dose adjustment may be necessary (see sections 4.2 and 4.4)..
Renal impairment
The pharmacokinetics of abiraterone acetate were compared in patients with end-stage renal disease undergoing a stable schedule of hemodialysis versus matched control subjects with normal renal function. Systemic exposure to abiraterone following a single 1000 mg oral dose was not increased in patients with end-stage renal disease undergoing dialysis. Administration to patients with renal impairment, including severe, requires no dose reduction (see section 4.2 However, there is no clinical experience in patients with prostate cancer and severe renal impairment.Caution is recommended in these patients.
05.3 Preclinical safety data -
In all animal toxicity studies, a significant reduction in circulating testosterone levels was observed. As a result, a reduction in organ weight and morphological and / or histopathological changes in the reproductive organs and the adrenal, pituitary and mammary glands were found. All changes showed complete or partial reversibility. The changes in the reproductive organs and those sensitive to androgen hormones are compatible with the pharmacology of abiraterone. All drug-related hormone changes reversed or resolved after a 4-week recovery period.
In fertility studies in both male and female rats, abiraterone acetate reduced fertility, an effect which is fully reversible 4 to 16 weeks after discontinuation of abiraterone acetate.
In a developmental toxicity study in the rat, abiraterone acetate affected pregnancy including decreased fetal weight and survival. Effects on the external genitalia were observed although abiraterone acetate was not teratogenic.
In these rat fertility and developmental toxicity studies, all effects correlated with the pharmacological activity of abiraterone acetate.
Apart from the variations found in the reproductive organs in all toxicological studies conducted in animals, the non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Abiraterone acetate was not carcinogenic in a 6-month study in transgenic mice (Tg.rasH2). In a 24-month carcinogenicity study in rats, abiraterone acetate increased the incidence of interstitial cell neoplasms in the testes. This finding is believed to be related to the pharmacological action of abiraterone and is rat-specific. Abiraterone acetate was not carcinogenic in female rats.
The active substance abiraterone poses a risk to the aquatic environment, especially to fish.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Povidone (K29 / K32)
Anhydrous colloidal silica
Sodium lauryl sulfate
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
2 years.
06.4 Special precautions for storage -
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package -
Round white high density polyethylene bottles with child resistant polypropylene closure containing 120 tablets. Each pack contains one bottle.
06.6 Instructions for use and handling -
Due to the mechanism of action, this medicine may harm the developing fetus; therefore, women who are pregnant or of childbearing age should not handle it without using protection, such as gloves.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations. This medicinal product may pose a risk to the aquatic environment (see section 5.3).
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/11/714/001
041427016
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 05 September 2011
Last renewal date: May 26, 2016
10.0 DATE OF REVISION OF THE TEXT -
11/2016
