Imatinib Mesylate: Package Insert and Label Information (Page 3 of 6)

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of Imatinib mesylate tablets. 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.

Infections: hepatitis B virus reactivation1

Nervous System Disorders: cerebral edema1

Eye Disorders: vitreous hemorrhage

Cardiac Disorders: pericarditis, cardiac tamponade1

Vascular Disorders: thrombosis/embolism, anaphylactic shock

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

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

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.

Musculoskeletal and Connective Tissue Disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain)

Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

Blood and Lymphatic System Disorder s: thrombotic microangiopathy

1 Including some fatalities

7 DRUG INTERACTIONS

7.1 Agents Inducing CYP3A Metabolism

Concomitant administration of imatinib mesylate tablet 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 mesylate tablet 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 mesylate tablet 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 mesylate tablet 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 mesylate tablet with CYP2D6 substrates that have a narrow therapeutic window.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Imatinib mesylate tablet 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 mesylate tablets in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate tablets 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 body surface area. Advise women to avoid pregnancy when taking imatinib mesylate tablets. 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 2-4% and of miscarriage is 15%-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 body surface area), 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 body surface area, 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 body surface area) included an increased numbers 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 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 mesylate tablets, 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 mesylate tablets, 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

Pregnancy Testing

Human post-marketing reports and animal studies have shown imatinib mesylate tablets to be harmful to the developing fetus. Test pregnancy status in females with reproductive potential prior to the initiation of treatment with imatinib mesylate tablets.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1 % pregnancy rates) when using imatinib mesylate tablets during treatment and for fourteen days after stopping treatment with imatinib mesylate tablets [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 mesylate tablets have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML [see Clinical Studies (14.2)]. 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 mesylate tablet was similar in older and younger patients.

8.6 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of both Imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at Imatinib doses ranging from 100 to 800 mg.

Mild and moderate hepatic impairment do not influence exposure to imatinib and CGP74588. In patients with severe hepatic impairment, the imatinib Cmax and area under curve (AUC) increased by 63% and 45% and the CGP74588 Cmax and AUC increased by 56% and 55%, relative to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Reduce the dose by 25% for patients with severe hepatic impairment [see Dosage and Administration (2.12)]

Table 16: Liver Function Classifications

Liver Function Test Normal Mild Moderate Severe
(n = 14) (n = 30) (n = 20) (n = 20)
Total Bilirubin less than or equal toULN greater than1.0-1.5 times the ULN greater than 1.5-3 times the ULN greater than 3 — 10 times the ULN
SGOT less than or equal to ULN greater than ULN (can be normal if Total Bilirubin is greater than ULN) Any Any
ULN = upper limit of normal for the institution

8.7 Renal Impairment

The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state Imatinib doses ranging from 100 to 800 mg/day. The mean exposure to Imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. There are not sufficient data in patients with severe renal impairment [See Clinical Pharmacology (12.3) ]. Dose reductions are necessary for patients with moderate and severe renal impairment [See Dosage and Administration (2.12) ].

Table 17: Renal Function Classification

Renal Dysfunction Renal Function Tests
Mild CrCL = 40 — 59 mL/min
Moderate CrCL = 20 — 39 mL/min
Severe CrCL = less than 20 mL/min
CrCL = Creatinine Clearance

10 OVERDOSAGE

Experience with doses greater than 800 mg is limited. Isolated cases of Imatinib mesylate tablets overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment.

Adult Overdose

1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain.

6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.

8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of imatinib mesylate tablet daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Imatinib mesylate tablets daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of imatinib mesylate tablet on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.

Pediatric Overdose

One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea.

11 DESCRIPTION

Imatinib is a small molecule kinase inhibitor. Imatinib mesylate film-coated tablets contain Imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl­1-piperazinyl) methy1]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate and its structural formula is

image description
(click image for full-size original)

Imatinib mesylate is a off white to pale yellow crystalline powder. Its molecular formula is C29 H31 N7 O · CH4 SO3 and its molecular weight is 589.7. Imatinib mesylate is soluble in water, slightly soluble in methanol and dimethyl sulphoxide.

Inactive Ingredients: Povidone (USP) and Magnesium Stearate (NF). Tablet coating: Hypromellose (USP), yellow iron oxide (NF), poly ethylene glycol (NF), talc (USP), titanium dioxide (USP), and red iron oxide (NF).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients.

In vivo , Imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis.

Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events.

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