April 27, 2017
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Vidaza

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Vidaza




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Anemia, Neutropenia And Thrombocytopenia

VIDAZA causes anemia, neutropenia and thrombocytopenia. Monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, adjust dosage for subsequent cycles based on nadir counts and hematologic response [see DOSAGE AND ADMINISTRATION].

Hepatotoxicity In Patients With Severe Pre-existing Hepatic Impairment

Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin < 30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumors [see CONTRAINDICATIONS]. Monitor liver chemistries prior to initiation of therapy and with each cycle.

Safety and effectiveness of VIDAZA in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials.

Renal Toxicity

Renal toxicity ranging from elevated serum creatinine to renal failure and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to < 20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium < 3 mEq/L) developed in 5 patients with CML treated with azacitidine and etoposide. Monitor serum creatinine and electrolytes prior to initiation of therapy and with each cycle. If unexplained reductions in serum bicarbonate < 20 mEq/L or elevations of BUN or serum creatinine occur, reduce or hold the dose [see DOSAGE AND ADMINISTRATION].

Patients with renal impairment may be at increased risk for renal toxicity. Also, azacitidine and its metabolites are primarily excreted by the kidney. Therefore, monitor these patients closely for toxicity [see DOSAGE AND ADMINISTRATION]. Patients with MDS and renal impairment were excluded from the clinical studies.

Tumor Lysis Syndrome

VIDAZA may cause fatal or serious tumor lysis syndrome, including in patients with MDS. Tumor lysis syndrome may occur despite concomitant use of allopurinol. Assess baseline risk and monitor and treat as appropriate.

Embryo-Fetal Risk

Based on the mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to a pregnant woman. Azacitidine administered to pregnant rats via a single intraperitoneal (IP) dose approximating 8% of the recommended human daily dose caused fetal death and anomalies [see Use in Specific Populations].

Advise females with reproductive potential to avoid pregnancy during treatment with VIDAZA [see Use in Specific Populations]. Men should be advised to not father a child while receiving treatment with VIDAZA.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m², approximately 8% the recommended human daily dose on a mg/m² basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m², approximately 8% the recommended human daily dose on a mg/m² basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m (approximately 20%-80% the recommended human daily dose on a mg/m² basis) revealed an increased incidence of testicular tumors compared with controls.

The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.

Administration of azacitidine to male mice at 9.9 mg/m² (approximately 9% the recommended human daily dose on a mg/m² basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m (approximately 20%-40%, the recommended human daily dose on a mg/m² basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m² resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. There are no data on the use of azacitidine in pregnant women. Azacitidine was teratogenic and caused embryo-fetal lethality in animals at doses lower than the recommended human daily dose [see Data]. Advise pregnant women of the potential risk to the fetus.

The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data

Animal Data

Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m (approximately 8% of the recommended human daily dose on a mg/m² basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m² (approximately 4%-16% the recommended human daily dose on a mg/m² basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m² (approximately 8% of the recommended human daily dose on a mg/m² basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m² (approximately 8% the recommended human daily dose on a mg/m² basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m² on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

Lactation

Risk Summary

There is no information regarding the presence of azacitidine in human milk, the effects of VIDAZA on the breastfed infant, or the effects of VIDAZA on milk production. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for azacitidine in animal studies [see Nonclinical Toxicology] and the potential for serious adverse reactions in nursing infants from VIDAZA, advise patients not to breastfeed during treatment with VIDAZA.

Females And Males Of Reproductive Potential

Based on its mechanism of action and findings in animals, VIDAZA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating VIDAZA.

Contraception

Females

Advise females of reproductive potential to avoid pregnancy during treatment with VIDAZA.

Males

Males with female sexual partners of reproductive potential should not father a child and should use effective contraception during treatment with VIDAZA.

Infertility

Based on animal data, azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients.

Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older.

Elderly patients are more likely to have decreased renal function. Monitor renal function in these patients [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Renal Impairment

Severe renal impairment (creatinine clearance [CLcr] < 30 mL/min) has no major effect on the exposure of azacitidine after multiple SC administrations. Therefore, azacitidine can be administered to patients with renal impairment without Cycle 1 dose adjustment [see CLINICAL PHARMACOLOGY].

Gender

There were no clinically relevant differences in safety and efficacy based on gender.

Race

Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-Caucasians were possible.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/3/2017

Warnings
Precautions

Vidaza - User Reviews

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