Azacitidine (Page 3 of 5)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Azacitidine for Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Interstitial lung disease
Tumor lysis syndrome
Injection site necrosis
Sweet’s syndrome (acute febrile neutrophilic dermatosis)
Necrotizing fasciitis (including fatal cases)
Differentiation syndrome

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 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/m2 (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 to 12 mg/m2 (approximately 4% to 16% the recommended human daily dose on a mg/m2 basis).

In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4 to 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 to 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 to 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).

8.2 Lactation

Risk Summary

There is no information on the presence of azacitidine or its metabolites in human milk, the effects on a breast-fed child, or the effects 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 ( 13.1)] and the potential for serious adverse reactions in a nursing child from azacitidine, advise patients not to breastfeed during treatment with azacitidine and for 1 week after the final dose.

8.3 Females and Males of Reproductive Potential

Based on its mechanism of action and findings in animals, Azacitidine for Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Azacitidine for Injection.

Contraception

Females

Azacitidine for Injection can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 6 months after the final dose [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Azacitidine for Injection and for 3 months after the final dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal data, azacitidine could have an effect on male or female fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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 less than 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 (2.5) and Warnings and Precautions (5.3)].

10 OVERDOSAGE

One case of overdose with Azacitidine for Injection was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2 , almost 4 times the recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for Azacitidine for Injection overdosage.

11 DESCRIPTION

Azacitidine for Injection contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is as follows:

9dca4f01-figure-01
(click image for full-size original)

The molecular formula is C8 H12 N4 O5 . The molecular weight is 244. Azacitidine is a white to almost white powder. Azacitidine was found to be insoluble in acetone, ethanol, and methyl ethyl ketone; slightly soluble in ethanol/water (50/50), propylene glycol, and polyethylene glycol; sparingly soluble in water, water saturated octanol, 5% dextrose in water, N-methyl-2-pyrrolidone, normal saline and 5% Tween 80 in water; and soluble in dimethylsulfoxide (DMSO).

The finished product is supplied in a sterile form for reconstitution as a suspension for subcutaneous injection or reconstitution as a solution with further dilution for intravenous infusion. Each vial of Azacitidine for Injection contains 100 mg of azacitidine, 170 mg sucrose, monosodium phosphate monohydrate and disodium hydrogen phosphate, dihydrate as a sterile lyophilized powder.

12 CLINICAL PHARMACOLOGY

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