ONUREG Film-coated tablet Ref.[28040] Active ingredients: Azacitidine

Absorption

Exposure was generally linear with dose-proportional increases in systemic exposure; high intersubject variability was observed. The geometric mean (coefficient of variation [%CV]) C_max and AUC values after oral administration of a 300 mg single dose were 145.1 ng/mL (63.7) and 241.6 ng h/mL (64.5), respectively. Multiple dosing at the recommended dose regimen did not result in drug accumulation.

Absorption of azacitidine was rapid, with a median Tmax of 1 hour post dose. Mean oral bioavailability relative to subcutaneous (SC) administration was approximately 11%.

Effect of food

The impact of food on the exposure of Onureg was minimal. Therefore, Onureg can be administered with or without food.

Distribution

After oral administration, the geometric mean apparent volume of distribution was 12.6 L/kg for a 70 kg person. The plasma protein binding of azacitidine was 6 to 12%.

Biotransformation

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs). Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase.

Elimination

The geometric mean apparent clearance was 1242 L/hour and the geometric mean half-life was approximately 0.5 hours. Following intravenous administration of ¹⁴C azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Faecal excretion accounted for <1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following subcutaneous administration of ¹⁴C-azacitidine was 50%. The amount of unchanged azacitidine recovered in urine relative to dose was <2% following either subcutaneous (SC) or oral administration. Faecal excretion has not been measured following oral administration.

Pharmacodynamic effects

The epigenetic regulatory effect of azacitidine on DNA global methylation reduction in the blood was sustained with prolonged exposure of 300 mg daily administered for 14 or 21 days of a 28-day cycle in myeloid cancers including AML patients from a Phase ½ study. A positive correlation was observed between azacitidine plasma exposure and the pharmacodynamic effect of reduction in global DNA methylation in blood.

Special populations

Elderly

In a population pharmacokinetics (PK) analysis from 286 AML patients, age (46 to 93 years) did not have clinically meaningful effects on the PK of Onureg. Therefore, dose modification for Onureg is not required, regardless of patient age.

Hepatic impairment

No formal studies have been conducted in patients with hepatic impairment. Hepatic impairment is unlikely to affect the PK to a clinically relevant extent since azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. A population PK analysis determined that AST (8 to 155 U/L), ALT (5 to 185 U/L) and mild hepatic impairment (BIL ≤ ULN and AST > ULN, or BIL 1 to 1.5 × ULN and any AST) did not have clinically meaningful effects on the PK of azacitidine. The effects of moderate to severe hepatic impairment (BIL >1.5 × ULN and any AST) on the PK of azacitidine is unknown.

Renal impairment

In patients with cancer, the PK of azacitidine in 6 patients with normal renal function (CLcr >80 mL/min) and 6 patients with severe renal impairment (CLcr <30 mL/min) were compared following daily subcutaneous dosing (Days 1 through 5) at 75 mg/m²/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events.

A population PK analysis following a 300 mg dose of Onureg determined that patients with mild (CLcr: ≥60 to <90 mL/min), moderate (CLcr: ≥30 to <60 mL/min), and severe (CLcr: <30 mL/min) renal impairment had 19%, 25%, and 38% increases in azacitidine plasma AUC, respectively. The effect of severe renal impairment on Onureg was similar to the above referenced clinical renal impairment study with injectable azacitidine (~40% increase in AUC). The exposure of azacitidine (AUC) is approximately 75% lower after oral administration relative to the exposure achieved following SC administration; therefore, an increase in exposure of approximately 40% following oral administration is still considered safe and tolerable. Thus, no dose adjustment of Onureg is recommended in patients with mild, moderate, or severe renal impairment.

Race / ethnicity

The effects of race/ethnicity on the PK of Onureg is unknown.

In a 14-day oral toxicity study in dogs, mortality occurred at doses of 8 and 16 mg/m²/day. The maximum tolerated dose (MTD) was 4 mg/m²/day. At 1 or all doses, pancytopenia correlated with bone marrow hypoplasia, lymphoid depletion, gland/lumen dilation and single cell necrosis in mucosal crypts of small and large intestines and/or centrilobular hepatocellular vacuolation were observed. At the MTD, these findings were partially or completely resolved after 3 weeks. Following parenteral azacitidine administrations at comparable dose ranges, mortality and similar target organ toxicities were observed in rodents, dogs and monkeys. Non-clinical data from repeat-dose toxicity studies with azacitidine revealed no special hazard for humans.

Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammalian cell systems in vitro. The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumours of the haematopoietic system in female mice, when administered intraperitoneally 3 times per week for 52 weeks. An increased incidence of tumours in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine administered intraperitoneally for 50 weeks. A tumorigenicity study in rats revealed an increased incidence of testicular tumours.

Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single intraperitoneal injection of azacitidine during organogenesis. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before closure of the hard palate. In rats, azacitidine caused no adverse reactions when given pre-implantation, but it was clearly embryotoxic when given during organogenesis.

Foetal abnormalities during organogenesis in rats included: Central nervous system (CNS) anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly) and others (microphthalmia, micrognathia, gastroschisis, oedema, and rib abnormalities).

Administration of azacitidine to male mice 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 resulted in decreased weight of the testes and epididymides, decreased sperm counts, decreased pregnancy rates, an increase in abnormal embryos and increased loss of embryos in mated females (see section 4.6).