Imatinib Mesylate (Page 4 of 10)

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of imatinib. 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.

Blood and Lymphatic System Disorders: thrombotic microangiopathy

Cardiac Disorders: pericarditis, cardiac tamponade¹

Eye Disorders: vitreous hemorrhage

Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation¹ [see Warnings and Precautions (5.6)] , diverticulitis, gastric antral vascular ectasia

Infections: hepatitis B virus reactivation¹

Musculoskeletal and Connective Tissue Disorders: osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon

treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain)

Nervous System Disorders: cerebral edema¹

Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure¹, interstitial lung disease

Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus

Vascular Disorders: thrombosis/embolism, anaphylactic shock

¹Including some fatalities.

7 DRUG INTERACTIONS

7.1 Agents Inducing CYP3A Metabolism

Concomitant administration of imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12.3)].

7.2 Agents Inhibiting CYP3A Metabolism

Concomitant administration of imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see Clinical Pharmacology (12.3)].

7.3 Interactions With Drugs Metabolized by CYP3A4

Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering imatinib with CYP3A4 substrates that have a narrow therapeutic window.

Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation [see Clinical Pharmacology (12.3)].

7.4 Interactions With Drugs Metabolized by CYP2D6

Use caution when administering imatinib with CYP2D6 substrates that have a narrow therapeutic window.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Imatinib can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of

800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.

In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications.

In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes.

In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

8.2 Lactation

Risk Summary

Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from imatinib, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose.

Human Data

Based on data from 3 breastfeeding women taking imatinib, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight.

8.3 Females and Males of Reproductive Potential

Human postmarketing reports and animal studies have shown imatinib to be harmful to the developing fetus. [see Use in Specific Populations (8.1)].

Pregnancy Testing

Test pregnancy status in females with reproductive potential prior to the initiation of treatment with imatinib.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1 % pregnancy rates) when using imatinib during treatment and for fourteen days after stopping treatment with imatinib [see Use in Specific Populations (8.1)].

Infertility

The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected [see Nonclinical Toxicology (13)].

8.4 Pediatric Use

The safety and effectiveness of imatinib have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14.2, 14.4)]. There are no data in children under 1 year of age.

8.5 Geriatric Use

In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5.1)]. The efficacy of imatinib was similar in older and younger patients.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference

was observed in the safety profile in patients older than 65 years as compared to younger

patients, with the exception of a higher frequency of edema. The efficacy of imatinib was

similar in patients older than 65 years and younger patients.

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