Abiraterone

Name: Abiraterone

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Abiraterone dosing information

Usual Adult Dose for Prostate Cancer:

1,000 mg orally once a day on an empty stomach (in combination with prednisone 5 mg orally 2 times a day)

Comments: No food should be consumed for at least 2 hours before the dose and for at least 1 hour after the dose of this drug.

Use: Treatment of metastatic castration-resistant prostate cancer

What other drugs will affect abiraterone?

Other drugs may interact with abiraterone, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Commonly used brand name(s)

In the U.S.

  • Zytiga

Available Dosage Forms:

  • Tablet

Therapeutic Class: Antiandrogen

Precautions While Using abiraterone

It is very important that your doctor check you at regular visits to make sure that abiraterone is working properly. Blood tests will be needed to check for any unwanted effects that may be caused by abiraterone.

Women and children should not use abiraterone. Pregnant women or women who may become pregnant should not handle or touch the tablets without protection (eg, gloves). abiraterone may also cause birth defects if the father is using it when his sexual partner becomes pregnant. You must use a condom and another effective method of birth control during and for 1 week after the last dose of abiraterone. If a pregnancy occurs while you are using abiraterone, tell your doctor right away.

You will also need to have your blood pressure measured before starting abiraterone and while you are using it. If you notice any change to your recommended blood pressure, call your doctor right away. If you have questions about this, talk to your doctor.

Do not interrupt or stop using abiraterone together with prednisone without asking your doctor. This may increase your risk of having adrenal gland problems. Talk to your doctor if you have more than one of these symptoms while you are using abiraterone: darkening of the skin, diarrhea, dizziness, fainting, loss of appetite, mental depression, nausea, skin rash, unusual tiredness or weakness, or vomiting.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Uses of Abiraterone

Abiraterone is a prescription medication approved to treat men with advanced prostate cancer that has spread to other areas of the body. It is often used when other medical or surgical treatments have not worked. Abiraterone is used in combination with prednisone.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Side Effects of Abiraterone

Serious side effects have been reported with abiraterone. See "Precautions”.

Common side effects of abiraterone include the following:

  • joint swelling or pain
  • muscle aches
  • hot flushes
  • diarrhea
  • urinary tract infection
  • cough
  • irregular heartbeats
  • urinate more often than normal
  • need to get up at night to urinate
  • heartburn
  • cold like symptoms
  • bone fractures

This is not a complete list of abiraterone side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

  

Adverse Effects

>10%

Joint swelling/discomfort (30%)

Hypokalemia (28%; all grades)

Edema (27%)

Muscle discomfort (26%)

Hypophosphatemia (24%; all grades)

Hot flush (19%)

Diarrhea (18%)

Urinary tract infection (12%)

Cough (11%)

1-10%

Hypertension (9%)

Arrhythmia (7%)

Urinary frequency (7%)

Hypophosphatemia (7%; grade 3-4)

Nocturia (6%)

Dyspepsia (6%)

Fractures (5.9%)

Hypokalemia (5%; grade 3-4)

Upper respiratory tract infection (5%)

Chest pain/discomfort (4%)

Cardiac failure (2%)

Hepatotoxicity (2%)

Postmarketing Reports

Respiratory, thoracic and mediastinal disorders: Noninfectious pneumonitis

Rhabdomyolysis

Myopathy

Acute hepatic failure

Warnings

Contraindications

Hypersensitivity

Women who are or may become pregnant

Cautions

Not for use in patients with preexisting severe hepatic impairment (Child-Pugh class C)

Mineralocorticoid excess: caution in patients with a history of cardiovascular disease; safety in patients with LVEF <50% or NYHA Class III or IV heart failure is not established

Hypertension, hypokalemia, and fluid retention may result from increased mineralocorticoid due to CYP17 inhibition; control hypertension and correct hypokalemia before treatment; monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly

Monitor for symptoms and signs of adrenocortical insufficiency; increased corticosteroid dosage may be indicated before, during, and after stressful situations; concurrent infection or interruption of daily corticosteroids associated with adrenocortical insufficiency

Hepatotoxicity: Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation (typically within the first 3 months of threatment); monitor liver function and modify, interrupt, or discontinue dosing as recommended

Strong inhibitor of CYP1A2 and CYP2D6; moderate inhibitor of CYP2C9, CYP2C19, and CYP3A4

CYP3A4 substrate (in vitro); avoid or use caution with drugs that are strong inhibitors or inducers of CYP3A4

Clinical Studies

The efficacy and safety of Abiraterone acetate in patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized, placebo-controlled, multicenter Phase 3 clinical trials. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials. Concurrent use of spironolactone was not allowed during the study period.

Study 1:

Patients with metastatic CRPC who had received prior docetaxel chemotherapy:

A total of 1195 patients were randomized 2:1 to receive either Abiraterone acetate orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal.

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39–95) and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0–1 and 45% had a Brief Pain Inventory-Short Form score of ≥4 (patient's reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens.

The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival (OS) in patients treated with Abiraterone acetate compared to patients in the placebo arm (Table 5 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 5).

Table 5: Overall Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in Study 1 (Intent-to-Treat Analysis)
Abiraterone Acetate
(N=797)
Placebo
(N=398)
* p-value is derived from a log-rank test stratified by ECOG performance status score (0–1 vs. 2), pain score (absent vs. present), number of prior chemotherapy regimens (1 vs. 2), and type of disease progression (PSA only vs. radiographic). † Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors Abiraterone acetate.
Primary Survival Analysis
Deaths (%) 333 (42%) 219 (55%)
Median survival (months)
(95% CI)
14.8 (14.1, 15.4) 10.9 (10.2, 12.0)
p-value* <0.0001
Hazard ratio (95% CI)† 0.646 (0.543, 0.768)
Updated Survival Analysis
Deaths (%) 501 (63%) 274 (69%)
Median survival (months)
(95% CI)
15.8 (14.8, 17.0) 11.2 (10.4, 13.1)
Hazard ratio (95% CI)† 0.740 (0.638, 0.859)

Figure 1: Kaplan-Meier Overall Survival Curves in Study 1 (Intent-to-Treat Analysis)

Study 2:

Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy

In Study 2, 1088 patients were randomized 1:1 to receive either Abiraterone acetate at a dose of 1,000 mg once daily (N=546) or Placebo once daily (N=542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.

Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with Abiraterone acetate was 95.4% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0–1 (asymptomatic) in 66% of patients and 2–3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).

Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.

The planned final analysis for OS, conducted after 741 deaths (median follow up of 49 months) demonstrated a statistically significant OS improvement in patients treated with Abiraterone acetate compared to those treated with placebo (Table 6 and Figure 2). Sixty-five percent of patients on the Abiraterone acetate arm and 78% of patients on the placebo arm used subsequent therapies that may prolong OS in metastatic CRPC. Abiraterone acetate was used as a subsequent therapy in 13% of patients on the Abiraterone acetate arm and 44% of patients on the placebo arm.

Table 6: Overall Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)
Overall Survival Abiraterone Acetate
(N=546)
Placebo
(N=542)
* p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1). † Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors Abiraterone acetate.
Deaths 354 (65%) 387 (71%)
Median survival (months)
(95% CI)
34.7 (32.7, 36.8) 30.3 (28.7, 33.3)
p-value* 0.0033
Hazard ratio† (95% CI) 0.81 (0.70, 0.93)

Figure 2: Kaplan Meier Overall Survival Curves in Study 2

At the pre-specified rPFS analysis, 150 (28%) patients treated with Abiraterone acetate and 251 (46%) patients treated with placebo had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 7 and Figure 3).

Table 7: Radiographic Progression-free Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)
Radiographic Progression-free Survival Abiraterone Acetate
(N=546)
Placebo
(N=542)
NR=Not reached.
* p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1). † Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors Abiraterone acetate.
Progression or death 150 (28%) 251 (46%)
Median rPFS (months)
(95% CI)
NR
(11.66, NR)
8.28
(8.12, 8.54)
p-value* <0.0001
Hazard ratio† (95% CI) 0.425 (0.347, 0.522)

Figure 3: Kaplan Meier Curves of Radiographic Progression-free Survival in Study 2 (Intent-to-Treat Analysis)

The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving Abiraterone acetate and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: [0.487, 0.691], p < 0.0001).

The median time to opiate use for prostate cancer pain was not reached for patients receiving Abiraterone acetate and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: [0.566, 0.833], p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the Abiraterone acetate arm.

(web3)