imatinib mesylate 100 MG Oral Tablet

Details

Generic Name: IMATINIB MESYLATE

Brand Name: Imatinib Mesylate

Substance Name(s):
IMATINIB MESYLATE

DRUG INTERACTIONS

7 • CYP3A4 inducers may decrease imatinib mesylate C max and area under curve (AUC).

( 2.12 , 7.1, 12.3 ) • CYP3A4 inhibitors may increase imatinib mesylate C max and AUC.

( 7.2, 12.3 ) • Imatinib mesylate is an inhibitor of CYP3A4 and CYP2D6 which may increase the C max and AUC of other drugs.

( 7.3 , 7.4, 12.3 ) • Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin.

( 7.3 ) 7.1 Agents Inducing CYP3A Metabolism Concomitant administration of imatinib mesylate tablets 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 tablets 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 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 tablets 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 with CYP2D6 substrates that have a narrow therapeutic window.

OVERDOSAGE

10 Experience with doses greater than 800 mg is limited.

Isolated cases of imatinib mesylate 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 (imatinib as free base) 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 (imatinib as free base) without recurrence of adverse reactions.

Another patient developed severe muscle cramps after taking 1,600 mg of imatinib mesylate (imatinib as free base) 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 (imatinib as free base), took 800 mg of imatinib mesylate (imatinib as free base) on Day 1 and 1,200 mg (imatinib as free base) 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.

DESCRIPTION

11 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-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is: Imatinib mesylate is a white to off-white crystalline powder.

Its molecular formula is C 29 H 31 N 7 O • CH 4 SO 3 and its molecular weight is 589.7 g/mol.

Imatinib mesylate is freely soluble in water and freely to sparingly soluble in methanol.

Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); and magnesium stearate (NF).

Tablet coating: ferric oxide red (NF); ferric oxide yellow (NF); hypromellose (USP); hydroxypropyl cellulose, and polyethylene glycol (NF).

CLINICAL STUDIES

14 14.1 Chronic Myeloid Leukemia Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study (imatinib mesylate versus IFN+Ara-C) has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.

This study compared treatment with either single-agent imatinib mesylate or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C).

Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR.

Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC).

In the imatinib mesylate arm, patients were treated initially with 400 mg daily.

Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily.

In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m 2 /day subcutaneously in combination with subcutaneous Ara-C 20 mg/m 2 /day for 10 days/month.

A total of 1,106 patients were randomized from 177 centers in 16 countries, 553 to each arm.

Baseline characteristics were well balanced between the two arms.

Median age was 51 years (range 18 to 70 years), with 21.9% of patients greater than or equal to 60 years of age.

There were 59% males and 41% females; 89.9% Caucasian and 4.7% black patients.

At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the imatinib mesylate and IFN arm, respectively.

The median duration of second-line treatment with imatinib mesylate was 64 months.

Sixty percent of patients randomized to imatinib mesylate are still receiving first-line treatment.

In these patients, the average dose of imatinib mesylate was 403 mg ± 57 mg.

Overall, in patients receiving first line imatinib mesylate, the average daily dose delivered was 406 mg ± 76 mg.

Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment.

In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the imatinib mesylate arm was severe intolerance to treatment (26%) and progression (14%).

The primary efficacy endpoint of the study was progression-free survival (PFS).

Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management.

The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive imatinib mesylate were compared with patients randomized to receive IFN.

Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment.

The estimated rate of progression-free survival at 84 months in the ITT population was 81.2% [95% CI: 78, 85] in the imatinib mesylate arm and 60.6% [56, 65] in the IFN arm (p less than 0.0001, log-rank test), (Figure 1).

With 7 years follow up there were 93 (16.8%) progression events in the imatinib mesylate arm: 37 (6.7%) progression to AP/BC, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and 10 (1.8%) CML unrelated deaths.

In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C.

The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92.5% [90, 95] in the imatinib mesylate arm compared to the 85.1%, [82, 89] (p less than or equal to 0.001) in the IFN arm, (Figure 2).

The annual rates of any progression events have decreased with time on therapy.

The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in complete cytogenetic response but without a major molecular response and 70% in patients who were not in complete cytogenetic response at this time point (p less than 0.001).

Figure 1: Progression Free Survival (ITT Principle) Figure 2: Time to Progression to AP or BC (ITT Principle) A total of 71 (12.8%) and 85 (15.4%) patients died in the imatinib mesylate and IFN+Ara-C group, respectively.

At 84 months the estimated overall survival is 86.4% (83, 90) vs.

83.3% (80, 87) in the randomized imatinib mesylate and the IFN+Ara-C group, respectively (p = 0.073 log-rank test).

The hazard ratio is 0.750 with 95% CI 0.547 to 1.028.

This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to imatinib mesylate.

Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints.

Response data are shown in Table 18.

Complete hematologic response, major cytogenetic response and complete cytogenetic response were also statistically significantly higher in the imatinib mesylate arm compared to the IFN + Ara-C arm (no cross-over data considered for evaluation of responses).

Median time to CCyR in the 454 responders was 6 months (range 2 to 64 months, 25 th to 75 th percentiles = 3 to 11 months) with 10% of responses seen only after 22 months of therapy.

Table 18: Response in Newly Diagnosed CML Study (84-Month Data) (Best Response Rate) Imatinib mesylate n = 553 I FN+Ara-C n = 553 Hematologic Response 1 CHR Rate n (%) 534 (96.6%)* 313 (56.6%)* [95% CI] [94.7%, 97.9%] [52.4%, 60.8%] Cytogenetic Response 2 Major Cytogenetic Response n (%) 472 (85.4%)* 93 (16.8%)* [95% CI] [82.1%, 88.2%] [13.8%, 20.2%] Unconfirmed 3 88.6%* 23.3%* Complete Cytogenetic Response n (%) 413 (74.7%)* 36 (6.5%)* [95% CI] [70.8, 78.3] [4.6, 8.9] Unconfirmed 3 82.5%* 11.6%* *p less than 0.001, Fischer’s exact test.

1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): WBC less than 10 x 10 9 /L, platelet less than 450 x 10 9 /L, myelocyte + metamyelocyte less than 5% in blood, no blasts and promyelocytes in blood, no extramedullary involvement.

2 Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1% to 35%).

A major response (0% to 35%) combines both complete and partial responses.

3 Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.

Molecular response was defined as follows: in the peripheral blood, after 12 months of therapy, reduction of greater than or equal to 3 logarithms in the amount of BCR-ABL transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline.

Molecular response was only evaluated in a subset of patients who had a complete cytogenetic response by 12 months or later (N = 333).

The molecular response rate in patients who had a complete cytogenetic response in the imatinib mesylate arm was 59% at 12 months and 72% at 24 months.

Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy – Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase.

After one month of therapy to six months of therapy, there was a 13% to 21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity.

There was no apparent change from baseline in median index for patients treated with imatinib mesylate.

An open-label, multicenter, randomized trial (imatinib mesylate versus nilotinib) was conducted to determine the efficacy of imatinib mesylate versus nilotinib in adult patients with cytogenetically confirmed, newly diagnosed Ph+ CML-CP.

Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide.

Efficacy was based on a total of 846 patients: 283 patients in the imatinib mesylate 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice-daily group.

Median age was 46 years in the imatinib mesylate group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients greater than or equal to 65 years of age in imatinib mesylate 400 mg once-daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively.

There were slightly more male than female patients in all groups (56%, 56%, and 62% in imatinib mesylate 400 mg once-daily, nilotinib 300 mg twice-daily and nilotinib 400 mg twice daily treatment groups, respectively).

More than 60% of all patients were Caucasian, and 25% were Asian.

The primary data analysis was performed when all 846 patients completed 12 months of treatment or discontinued earlier.

Subsequent analyses were done when patients completed 24, 36, 48 and 60 months of treatment or discontinued earlier.

The median time on treatment was approximately 61 months in all three treatment groups.

The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication.

MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline.

Efficacy endpoints are summarized in Table 19.

Twelve patients in the imatinib mesylate arm progressed to either accelerated phase or blast crises (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months) while two patients on the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment).

Table 19: Efficacy (MMR and CCyR) of Imatinib Mesylate Compared to Nilotinib in Newly Diagnosed Ph+ CML-CP Imatinib mesylate 400 mg once daily Nilotinib 300 mg twice daily N = 283 N = 282 MMR at 12 months (95% CI) 22% (17.6, 27.6) 44% (38.4, 50.3) P-Value a <0.0001 CCyR b by 12 months (95% CI) 65% (59.2, 70.6) 80% (75.0, 84.6) MMR at 24 months (95% CI) 38% (31.8, 43.4) 62% (55.8, 67.4) CCyR b by 24 months (95% CI) 77% (71.7, 81.8) 87% (82.4, 90.6) a CMH test stratified by Sokal risk group.

b CCyR: 0% Ph+ metaphases.

Cytogenetic responses were based on the percentage of Ph-positive metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample.

By 60 months, MMR was achieved by 60% of patients on imatinib mesylate and 77% of patients on nilotinib.

Median overall survival was not reached in either arm.

At the time of the 60-month final analysis, the estimated survival rate was 91.7% for patients on imatinib mesylate and 93.7% for patients on nilotinib.

Late Chronic Phase CML and Advanced Stage CML : Three international, open-label, single-arm Phase 2 studies were conducted to determine the safety and efficacy of imatinib mesylate in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis.

About 45% of patients were women and 6% were black.

In clinical studies, 38% to 40% of patients were greater than or equal to 60 years of age and 10% to 12% of patients were greater than or equal to 70 years of age.

Chronic Phase, Prior Interferon-Alpha Treatment: 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed.

The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%).

Patients had received a median of 14 months of prior IFN therapy at doses greater than or equal to 25 x 10 6 IU/week and were all in late chronic phase, with a median time from diagnosis of 32 months.

Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or complete cytogenetic response (0% Ph+ metaphases).

Median duration of treatment was 29 months with 81% of patients treated for greater than or equal to 24 months (maximum = 31.5 months).

Efficacy results are reported in Table 20.

Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%).

Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients.

Accelerated Phase: 235 patients with accelerated phase disease were enrolled.

These patients met one or more of the following criteria: greater than or equal to 15% to less than 30% blasts in PB or BM; greater than or equal to 30% blasts + promyelocytes in PB or BM; greater than or equal to 20% basophils in PB; and less than 100 x 10 9 /L platelets.

The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg.

Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML.

Cytogenetic responses were also evaluated.

Median duration of treatment was 18 months with 45% of patients treated for greater than or equal to 24 months (maximum = 35 months).

Efficacy results are reported in Table 20.

Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs.

64%), confirmed and unconfirmed major cytogenetic response (31% vs.

19%).

Myeloid Blast Crisis: 260 patients with myeloid blast crisis were enrolled.

These patients had greater than or equal to 30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”).

The first 37 patients were started at 400 mg; the remaining 223 patients were started at 600 mg.

Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase.

Cytogenetic responses were also assessed.

Median duration of treatment was 4 months with 21% of patients treated for greater than or equal to 12 months and 10% for greater than or equal to 24 months (maximum = 35 months).

Efficacy results are reported in Table 20.

The hematologic response rate was higher in untreated patients than in treated patients (36% vs.

22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs.

16%).

The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600 mg dose group than for the 400 mg dose group (17% vs.

8%).

Table 20: Response in CML Studies Chronic Phase IFN Failure(n = 532) Accelerated Phase(n = 235) Myeloid Blast Crisis(n = 260) 400 mg 600 mg n = 158400 mg n = 77 600 mg n = 223400 mg n = 37 % of patients [CI 95% ] Hematologic Response 1 95% [92.3−96.3] 71% [64.8-76.8] 31% [25.2−36.8] Complete Hematologic Response (CHR) 95% 38% 7% No Evidence of Leukemia (NEL) Not applicable 13% 5% Return to Chronic Phase (RTC) Not applicable 20% 18% Major Cytogenetic Response 2 60% [55.3−63.8] 21% [16.2−27.1] 7% [4.5−11.2] (Unconfirmed 3 ) (65%) (27%) (15%) Complete 4 (Unconfirmed 3 ) 39% (47%) 16% (20%) 2% (7%) Abbreviations: BM, bone marrow; PB, peripheral blood.

1 Hematologic response criteria (all responses to be confirmed after greater than or equal to 4 weeks): CHR: Chronic phase study [WBC less than 10 x 10 9 /L, platelet less than 450 x 10 9 /L, myelocytes + metamyelocytes less than 5% in blood, no blasts and promyelocytes in blood, basophils less than 20%, no extramedullary involvement] and in the accelerated and blast crisis studies [ANC greater than or equal to 1.5 x 10 9 /L, platelets greater than or equal to 100 x 10 9 /L, no blood blasts, BM blasts less than 5% and no extramedullary disease].

NEL: Same criteria as for CHR but ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L (accelerated and blast crisis studies).

RTC: less than 15% blasts BM and PB, less than 30% blasts + promyelocytes in BM and PB, less than 20% basophils in PB, no extramedullary disease other than spleen and liver (accelerated and blast crisis studies).

2 Cytogenetic response criteria (confirmed after greater than or equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1% to 35%).

A major response (0% to 35%) combines both complete and partial responses.

4 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least 1 month after the initial bone marrow study.

The median time to hematologic response was 1 month.

In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response.

After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% [88.3, 93.2].

In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg).

An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response.

The median survival was 20.9 [13.1, 34.4] months for the 400 mg group and was not yet reached for the 600 mg group (p = 0.0097).

An estimated 46.2% [34.7, 57.7] vs.

65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in the 400 mg vs.

600 mg dose groups, respectively.

In blast crisis, the estimated median duration of hematologic response is 10 months.

An estimated 27.2% [16.8, 37.7] of hematologic responders maintained their response 2 years after achieving their initial response.

Median survival was 6.9 [5.8, 8.6] months, and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were alive 2 years after start of study.

Efficacy results were similar in men and women and in patients younger and older than age 65.

Responses were seen in black patients, but there were too few black patients to allow a quantitative comparison.

14.2 Pediatric CML A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single-arm Phase 2 trial.

Patients were treated with imatinib mesylate 340 mg/m 2 /day, with no interruptions in the absence of dose limiting toxicity.

Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy.

The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults.

Additionally, partial cytogenetic response (PCyR) was observed in 16%.

The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months.

Patients were allowed to be removed from protocol therapy to undergo alternative therapy, including hematopoietic stem cell transplantation.

Thirty-one children received stem cell transplantation.

Of the 31 children, 5 were transplanted after disease progression on study and 1 withdrew from study during first week treatment and received transplant approximately 4 months after withdrawal.

Twenty-five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range, 4 to 24).

Of the 25 patients 13 (52%) had CCyR and 5 (20%) had PCyR at the end of protocol therapy.

One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy.

These patients had not previously received imatinib mesylate and ranged in age from 3 to 20 years old; 3 were 3 to 11 years old, 9 were 12 to 18 years old, and 2 were greater than 18 years old.

Patients were treated at doses of 260 mg/m 2 /day (n = 3), 340 mg/m 2 /day (n = 4), 440 mg/m 2 /day (n = 5) and 570 mg/m 2 /day (n = 2).

In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response.

In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m 2 /day.

14.3 Acute Lymphoblastic Leukemia A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended imatinib mesylate dose of 600 mg/day.

In addition, 2 patients with relapsed/refractory Ph+ ALL received imatinib mesylate 600 mg/day in a phase 1 study.

Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ALL Phase 2 study patients and for the 2 Phase 1 patients are shown in Table 21.

The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months.

Table 21: Effect of Imatinib Mesylate on Relapsed/Refractory Ph+ ALL Phase 2 Study (N = 43) n (%) Phase 1 Study (N = 2) n (%) CHR 8 (19) 2 (100) NEL 5 (12) RTC/PHR 11 (26) MCyR 15 (35) CCyR 9 (21) PCyR 6 (14) 14.4 Pediatric ALL Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5-year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol.

The safety and effectiveness of imatinib mesylate tablets (340 mg/m 2 /day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL.

The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor.

There were 92 eligible patients with Ph+ ALL enrolled.

The median age was 9.5 years (1 to 21 years: 2.2% between 1 and less than 2 years, 56.5% between 2 and less than 12 years, 34.8% between 12 and less than 18 years, and 6.5% between 18 and 21 years).

Sixty-four percent were male, 75% were white, 9% were Asian/Pacific Islander, and 5% were black.

In 5 successive cohorts of patients, imatinib mesylate tablets exposure was systematically increased by earlier introduction and prolonged duration.

Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of imatinib mesylate tablets exposure.

There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received imatinib mesylate tablets plus chemotherapy; 30 were treated exclusively with chemotherapy and imatinib mesylate tablets and 20 received chemotherapy plus imatinib mesylate tablets and then underwent hematopoietic stem cell transplant, followed by further imatinib mesylate tablets treatment.

Patients in cohort 5 treated with chemotherapy received continuous daily exposure to imatinib mesylate tablets beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy.

During maintenance cycles 5 through 12 imatinib mesylate tablets was administered 28 days out of the 56 day cycle.

Patients who underwent hematopoietic stem cell transplant received 42 days of imatinib mesylate tablets prior to HSCT, and 28 weeks (196 days) of imatinib mesylate tablets after the immediate post-transplant period.

The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81).

The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months.

14.5 Myelodysplastic/Myeloproliferative Diseases An open-label, multicenter, Phase 2 clinical trial was conducted testing imatinib mesylate in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 7 patients with MDS/MPD.

These patients were treated with imatinib mesylate 400 mg daily (imatinib as free base).

The ages of the enrolled patients ranged from 20 to 86 years.

A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study.

These patients also received imatinib mesylate at a dose of 400 mg (imatinib as free base) daily with the exception of three patients who received lower doses.

Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response).

Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement.

All of these patients responded hematologically (13 completely).

Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely).

Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response.

A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly.

Median duration of therapy was 12.9 months (0.8 to 26.7) in the 7 patients treated within the Phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature.

Results are provided in Table 22.

Response durations of Phase 2 study patients ranged from 141+ days to 457+ days.

Table 22: Response in MDS/MPD Number of patients N Complete Hematologic Response N (%) Major Cytogenetic Response N ( % ) Overall Population 31 14 (45) 12 (39) Chromosome 5 Translocation 14 11 (79) 11 (79) Chromosome 4 Translocation 2 2 (100) 1 (50) Others / no Translocation 14 1 (7) 0 Molecular Relapse 1 NE 1 NE 1 1 NE: Not Evaluable.

14.6 Aggressive Systemic Mastocytosis One open-label, multicenter, Phase 2 study was conducted testing imatinib mesylate in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 5 patients with ASM treated with 100 mg to 400 mg of imatinib mesylate (imatinib as free base) daily.

These 5 patients ranged from 49 to 74 years of age.

In addition to these 5 patients, 10 published case reports and case series describe the use of imatinib mesylate in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of imatinib mesylate (imatinib as free base) daily.

Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with imatinib mesylate from the published reports and in the Phase 2 study.

Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion).

Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease.

Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to imatinib mesylate), one with concomitant CML.

Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate).

Median duration of imatinib mesylate therapy for the 5 ASM patients in the Phase 2 study was 13 months (range 1.4 to 22.3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature.

A summary of the response rates to imatinib mesylate in ASM is provided in Table 23.

Response durations of literature patients ranged from 1+ to 30+ months.

Table 23: Response in ASM Cytogenetic Abnormality Number of Patients N Complete Hematologic Response N (%) Partial Hematologic Response N (%) FIP1L1-PDGFRα Fusion Kinase (or CHIC2 Deletion) 7 7 (100) 0 Juxtamembrane Mutation 2 0 2 (100) Unknown or No Cytogenetic Abnormality Detected 15 0 7 (44) D816V Mutation 4 1* (25) 0 Total 28 8 (29) 9 (32) *Patient had concomitant CML and ASM.

Imatinib mesylate has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM).

Imatinib mesylate is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma.

Patients that harbor the D816V mutation of c-Kit are not sensitive to imatinib mesylate and should not receive imatinib mesylate.

14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia One open-label, multicenter, Phase 2 study was conducted testing imatinib mesylate in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL).

HES patients were treated with 100 mg to 1000 mg of imatinib mesylate daily.

The ages of these patients ranged from 16 to 64 years.

A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series.

These patients received imatinib mesylate at doses of 75 mg to 800 mg (imatinib as free base) daily.

Hematologic response rates are summarized in Table 24.

Response durations for literature patients ranged from 6+ weeks to 44 months.

Table 24: Response in HES/CEL Cytogenetic Abnormality Number o f Patients Complete Hematological Response N (%) Partial Hematological Response N (%) Positive FIP1L1-PDGFRα Fusion Kinase 61 61 (100) 0 Negative FIP1L1-PDGFRα Fusion Kinase 56 12 (21) 9 (16) Unknown Cytogenetic Abnormality 59 34 (58) 7 (12) Total 176 107 (61) 23 (13) 14.8 Dermatofibrosarcoma Protuberans Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma.

It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene.

An open-label, multicenter, Phase 2 study was conducted testing imatinib mesylate in a diverse population of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.

This study included 12 patients with DFSP who were treated with imatinib mesylate 800 mg daily (imatinib as free base) (age range 23 to 75 years).

DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry.

A further 6 DFSP patients treated with imatinib mesylate are reported in 5 published case reports, their ages ranging from 18 months to 49 years.

The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease.

The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib mesylate (imatinib as free base) daily.

A single pediatric patient received 400 mg/m 2 /daily, subsequently increased to 520 mg/m 2 /daily.

Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities.

Responses to treatment are described in Table 25.

Table 25: Response in DFSP Number of Patients ( n = 18) % Complete Response 7 39 Partial Response * 8 44 Total Responders 15 83 * 5 patients made disease free by surgery.

Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%.

A further 3 patients achieved a partial response, for an overall response rate of 83%.

Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%).

For the 10 study patients with the PDGF B gene rearrangement, there were 4 complete and 6 partial responses.

The median duration of response in the Phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months.

HOW SUPPLIED

16 /STORAGE AND HANDLING Each imatinib mesylate film-coated tablet contains 100 mg or 400 mg of imatinib free base.

100 mg Tablets Brownish orange, slightly biconvex, round film-coated tablets with functional scoring, engraved “IMA” over score “100” on one side, “APO” on the other side Bottles of 30 tablets……………………………………NDC 60505-2900-3 Bottles of 90 tablets……………………………………NDC 60505-2900-9 Bottles of 100 tablets………………………………….NDC 60505-2900-1 Bottles of 1,000 tablets…………………………………NDC 60505-2900-8 Blisters of 100 tablets (10 x 10)………………….…….NDC 60505-2900-0 400 mg Tablets Brownish orange, capsule shaped, biconvex film-coated tablets with functional scoring, engraved “IMA” score “400” on one side, “APO” on the other side Bottles of 30 tablets………………………………..…..NDC 60505-2901-3 Bottles of 90 tablets…………………………………….NDC 60505-2901-9 Bottles of 100 tablets…………………………………..NDC 60505-2901-1 Bottles of 500 tablets…………………………………..NDC 60505-2901-5 Blisters of 100 tablets (10 x 10)…………….…………..NDC 60505-2901-0 Storage and Handling Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15°C to 30ºC (59°F to 86ºF) [see USP Controlled Room Temperature].

Protect from moisture.

Dispense in a tight container, USP.

Do not crush imatinib mesylate tablets.

Avoid direct contact of crushed tablets with the skin or mucous membranes.

If such contact occurs, wash thoroughly as outlined in the references.

Avoid exposure to crushed tablets.

RECENT MAJOR CHANGES

Indications and Usage ( 1.5 , 1.6 ) 08/2020 Dosage and Administration ( 2.6 , 2.7 ) 08/2020

GERIATRIC USE

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 was similar in older and younger patients.

DOSAGE FORMS AND STRENGTHS

3 100 mg film coated tablets Brownish orange, slightly biconvex, round film-coated tablets with functional scoring, engraved “IMA” over score “100” on one side, “APO” on the other side 400 mg film coated tablets Brownish orange, capsule shaped, biconvex film-coated tablets with functional scoring, engraved “IMA” score “400” on one side, “APO” on the other side.

Tablets (with functional scoring): 100 mg and 400 mg ( 3 )

MECHANISM OF ACTION

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.

INDICATIONS AND USAGE

1 Imatinib mesylate is a kinase inhibitor indicated for the treatment of: • Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase ( 1.1 ) • Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy ( 1.2 ) • Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) ( 1.3 ) • Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy ( 1.4 ) • Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements ( 1.5 ) • Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown ( 1.6 ) • Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown ( 1.7 ) • Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) ( 1.8 ) 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

1.3 Adult patients with Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

1.4 Pediatric patients with Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements.

1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

PEDIATRIC USE

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 and Ph+ ALL [see Clinical Studies ( 14.2, 14.4 )] .

There are no data in children under 1 year of age.

PREGNANCY

8.1 Pregnancy Risk Summary Imatinib mesylate tablets 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% 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 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 F 1 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.

F 1 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 F 1 generation was 15 mg/kg/day.

NUSRING MOTHERS

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, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose.

Human Data Based on data from three 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Edema and severe fluid retention have occurred.

Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics.

( 5.1 , 6.1 ) • Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred.

Manage with dose reduction, dose interruption, or discontinuation of treatment.

Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter.

( 5.2 ) • Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors.

Monitor and treat patients with cardiac disease or risk factors for cardiac failure.

( 5.3 ) • Severe hepatotoxicity including fatalities may occur.

Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated.

Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction.

( 5.4 ) • Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML.

( 5.5 ) • Gastrointestinal perforations, some fatal, have been reported.

( 5.6 ) • Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of imatinib mesylate in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD and ASM).

( 5.7 ) • Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of imatinib mesylate.

( 5.8 ) • Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement.

Closely monitor TSH levels in such patients.

( 5.9 ) • Fetal harm can occur when administered to a pregnant woman.

Apprise women of the potential harm to the fetus, and to avoid pregnancy when taking imatinib mesylate tablets.

( 5.10 , 8.1 ) • Growth retardation occurring in children and pre-adolescents receiving imatinib mesylate has been reported.

Close monitoring of growth in children under imatinib mesylate treatment is recommended.

( 5.11 , 6.2 ) • Tumor Lysis Syndrome.

Close monitoring is recommended.

( 5.12 ) • Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate.

Caution patients about driving a car or operating machinery.

( 5.13 ) • Renal Toxicity.

A decline in renal function may occur in patients receiving imatinib mesylate tablets.

Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction.

( 5.14 ) 5.1 Fluid Retention and Edema Imatinib mesylate is often associated with edema and occasionally serious fluid retention [ see Adverse Reactions ( 6.1 ) ].

Weigh and monitor patients regularly for signs and symptoms of fluid retention.

Investigate unexpected rapid weight gain carefully and provide appropriate treatment.

The probability of edema was increased with higher imatinib mesylate dose and age greater than 65 years in the CML studies.

Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate.

In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate.

In a randomized trial in patients with newly diagnosed Ph+CML in chronic phase comparing imatinib mesylate and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate and in 3.9% of patients receiving nilotinib 300 mg twice daily.

Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the imatinib mesylate arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm.

5.2 Hematologic Toxicity Treatment with imatinib mesylate tablets is associated with anemia, neutropenia, and thrombocytopenia.

Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 3 months).

In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML.

In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia and anemia.

These generally occur within the first several months of therapy [ see Dosage and Administration ( 2.14 ) ].

5.3 Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib mesylate.

Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease.

In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib mesylate compared to 0.9% of patients taking IFN + Ara-C.

In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib mesylate and nilotinib, cardiac failure was observed in 1.1% of patient in the imatinib mesylate arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group.

Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure.

Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with imatinib mesylate [ see Adverse Reactions ( 6.1 ) ] .

Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib mesylate.

Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated.

Manage laboratory abnormalities with imatinib mesylate interruption and/or dose reduction [ see Dosage and Administration ( 2.13 ) ] .

When imatinib mesylate is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed.

Additionally, there have been reports of acute liver failure.

Monitoring of hepatic function is recommended.

5.5 Hemorrhage In a trial of imatinib mesylate versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage.

In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm.

None of these events were Grade 3 or 4 in the imatinib mesylate arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm.

In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

5.6 Gastrointestinal Disorders Imatinib mesylate is sometimes associated with GI irritation.

Imatinib mesylate tablets should be taken with food and a large glass of water to minimize this problem.

There have been rare reports, including fatalities, of gastrointestinal perforation.

5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate therapy.

The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate.

Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels.

Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels.

If either is abnormal, consider prophylactic use of systemic steroids (1 to 2 mg/kg) for one to two weeks concomitantly with imatinib mesylate at the initiation of therapy.

5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib mesylate.

In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge.

Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib mesylate therapy after resolution or improvement of the bullous reaction.

In these instances, imatinib mesylate was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate tablets.

Monitor TSH levels in such patients.

5.10 Embryo-fetal Toxicity Imatinib mesylate can cause fetal harm when administered to a pregnant woman.

Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area.

Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area.

Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate tablets and for 14 days after stopping 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 a fetus [ see Use in Specific Populations ( 8.1 ) ] .

5.11 Growth Retardation in Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate tablets.

The long-term effects of prolonged treatment with imatinib mesylate on growth in children are unknown.

Therefore, monitor growth in children under imatinib mesylate treatment [ see Adverse Reactions ( 6.1 ) ] .

5.12 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, ALL, and eosinophilic leukemia receiving imatinib mesylate tablets.

The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment.

Monitor these patients closely and take appropriate precautions.

Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib mesylate.

5.13 Impairments Related to Driving and Using Machinery Motor vehicle accidents have been reported in patients receiving imatinib mesylate tablets.

Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate.

Recommend caution when driving a car or operating machinery.

5.14 Renal Toxicity A decline in renal function may occur in patients receiving imatinib mesylate tablets.

Median estimated glomerular filtration rate (eGFR) values in patients on imatinib mesylate tablets 400 mg daily for newly-diagnosed CML (four randomized trials) and another indication declined from a baseline value of 85 mL/min/1.73m 2 (N = 1190) to 75 mL/min/1.73m 2 at 12 months (N = 1082) and 69 mL/min/1.73m 2 at 60 months (N = 549).

Evaluate renal function prior to initiating imatinib mesylate tablets and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Dosing and Administration Advise patients to take imatinib mesylate tablets exactly as prescribed, not to change their dose or to stop taking imatinib mesylate unless they are told to do so by their doctor.

If the patient missed a dose of imatinib mesylate tablets, the patient should take the next scheduled dose at its regular time.

The patient should not take two doses at the same time.

Advise patients to take imatinib mesylate tablets with a meal and a large glass of water [ see Dosage and Administration ( 2.1 ) ] .

Fluid Retention and Edema Inform patients of the possibility of developing edema and fluid retention.

Advise patients to contact their health care provider if unexpected rapid weight gain occurs [see Warnings and Precautions ( 5.1 )] .

Hepatotoxicity Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity.

Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding, or bruising [see Warnings and Precautions ( 5.4 )] .

Pregnancy and Breastfeeding Advise patients to inform their doctor if they are or think they may be pregnant.

Advise women of reproductive potential to avoid becoming pregnant while taking imatinib mesylate tablets.

Female patients of reproductive potential taking imatinib mesylate tablets should use highly effective contraception during treatment and for fourteen days after stopping treatment with imatinib mesylate tablets [see Use in Specific Populations ( 8.3 )] .

Avoid breastfeeding during treatment and for 1 month after the last dose [see Use in Specific Populations ( 8.2 )] .

Drug Interactions Imatinib mesylate tablets and certain other medicines, such as warfarin, erythromycin, and phenytoin, including over-the-counter medications, such as herbal products, can interact with each other.

Advise patients to tell their doctor if they are taking or plan to take iron supplements.

Avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking imatinib mesylate tablets [ see Drug Interactions ( 7 ) ].

Pediatric Advise patients that growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate.

The long-term effects of prolonged treatment with imatinib mesylate on growth in children are unknown.

Therefore, closely monitor growth in children under imatinib mesylate treatment [ see Warnings and Precautions ( 5.11 ) ].

Driving and Using Machines Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate.

Therefore, caution patients about driving a car or operating machinery [ see Warnings and Precautions ( 5.13 ) ].

APOTEX INC.

Imatinib Mesylate Tablets 100 mg and 400 mg Manufactured by Manufactured for Apotex Inc.

Apotex Corp.

Toronto, Ontario Canada M9L 1T9 Weston Florida USA 33326 Revised: August 2020 Revision: 21

DOSAGE AND ADMINISTRATION

2 • Adults with Ph+ CML CP ( 2.2 ): 400 mg/day • Adults with Ph+ CML AP or BC ( 2.2 ): 600 mg/day • Pediatrics with Ph+ CML CP ( 2.3 ): 340 mg/m 2 /day • Adults with Ph+ ALL ( 2.4 ): 600 mg/day • Pediatrics with Ph+ ALL ( 2.5 ): 340 mg/m 2 /day • Adults with MDS/MPD ( 2.6 ): 400 mg/day • Adults with ASM ( 2.7 ): 100 mg/day or 400 mg/day • Adults with HES/CEL ( 2.8 ): 100 mg/day or 400 mg/day • Adults with DFSP ( 2.9 ): 800 mg/day • Patients with mild to moderate hepatic impairment ( 2.12 ): 400 mg/day • Patients with severe hepatic impairment ( 2.12 ): 300 mg/day All doses of imatinib mesylate tablets should be taken with a meal and a large glass of water.

Doses of 400 mg or 600 mg (imatinib as free base) should be administered once daily, whereas a dose of 800 mg (imatinib as free base) should be administered as 400 mg (imatinib as free base) twice a day.

Imatinib mesylate tablets can be dissolved in water or apple juice for patients having difficulty swallowing.

Daily dosing of 800 mg (imatinib as free base) and above should be accomplished using the 400 mg tablet (imatinib as free base) to reduce exposure to iron.

2.1 Drug Administration The prescribed dose should be administered orally, with a meal and a large glass of water.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice.

The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon.

The suspension should be administered immediately after complete disintegration of the tablet(s).

For daily dosing of 800 mg (imatinib as free base) and above, dosing should be accomplished using the 400 mg (imatinib as free base) tablet to reduce exposure to iron.

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

2.2 Adult Patients with Ph+ CML CP, AP, or BC The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients in chronic phase CML and 600 mg/day (imatinib as free base) for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg (imatinib as free base) in adult patients with chronic phase disease, or from 600 mg to 800 mg (imatinib as free base) (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

2.3 Pediatric Patients with Ph+ CML CP The recommended dose of imatinib mesylate tablets for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (imatinib as free base) (not to exceed 600 mg).

Imatinib mesylate tablets treatment can be given as a once daily dose or the daily dose may be split into two – one portion dosed in the morning and one portion in the evening.

There is no experience with imatinib mesylate treatment in children under 1 year of age.

2.4 Adult Patients with Ph+ ALL The recommended dose of imatinib mesylate tablets is 600 mg/day (imatinib as free base) for adult patients with relapsed/refractory Ph+ ALL.

2.5 Pediatric Patients with Ph+ ALL The recommended dose of imatinib mesylate tablets to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg).

Imatinib mesylate tablets treatment can be given as a once daily dose.

2.6 Adult Patients with MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment.

The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with MDS/MPD.

2.7 Adult Patients with ASM Determine D816V c-Kit mutation status prior to initiating treatment.

The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with ASM without the D816V c-Kit mutation.

If c-Kit mutational status is not known or unavailable, treatment with imatinib mesylate tablets 400 mg/day (imatinib as free base) may be considered for patients with ASM not responding satisfactorily to other therapies.

For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day (imatinib as free base) is recommended.

Dose increase from 100 mg to 400 mg (imatinib as free base) for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

2.8 Adult Patients with HES/CEL The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with HES/CEL.

For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day (imatinib as free base) is recommended.

2.9 Adult Patients with DFSP The recommended dose of imatinib mesylate tablets is 800 mg/day (imatinib as free base) for adult patients with DFSP.

2.12 Dose Modification Guidelines Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital).

If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of imatinib mesylate tablets should be increased by at least 50%, and clinical response should be carefully monitored [ see Drug Interactions ( 7.1 ) ].

Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose.

A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment [ see Use in Specific Populations ( 8.6 ) ].

Renal Impairment: Patients with moderate renal impairment (CrCL = 20 to 39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated.

Doses greater than 600 mg (imatinib as free base) are not recommended in patients with mild renal impairment (CrCL = 40 to 59 mL/min).

For patients with moderate renal impairment doses greater than 400 mg (imatinib as free base) are not recommended.

Imatinib should be used with caution in patients with severe renal impairment.

A dose of 100 mg/day was tolerated in two patients with severe renal impairment [ see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.7 ) ].

2.13 Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, imatinib mesylate tablets should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN.

In adults, treatment with imatinib mesylate tablets may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg (imatinib as free base).

In children, daily doses can be reduced under the same circumstances from 340 mg/m 2 /day to 260 mg/m 2 /day (imatinib as free base).

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), imatinib mesylate tablets should be withheld until the event has resolved.

Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

2.14 Dose Adjustment for Hematologic Adverse Reactions Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.

Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia ASM associated with eosinophilia (starting dose 100 mg) ANC 1 less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

Stop imatinib mesylate until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L 2.

Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

Stop imatinib mesylate until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L 2.

Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction) Chronic Phase CML (starting dose 400 mg) ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

Stop imatinib mesylate until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L MDS/MPD, ASM and HES/CEL (starting dose 400 mg) 2.

Resume treatment with imatinib mesylate at the original starting dose of 400 mg 3.

If recurrence of ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate at a reduced dose of 300 mg Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg) ANC less than 0.5 x 10 9 /L and/or platelets less than 10 x 10 9 /L 1.

Check if cytopenia is related to leukemia (marrow aspirate or biopsy) 2.

If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate to 400 mg Ph+ ALL (starting dose 600 mg) 3.

If cytopenia persists 2 weeks, reduce further to 300 mg 4.

If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib mesylate until ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L and then resume treatment at 300 mg DFSP (starting dose 800 mg) ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

Stop imatinib mesylate until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L.

Resume treatment with imatinib mesylate at 600 mg 3.

In the event of recurrence of ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate at reduced dose of 400 mg.

Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m 2 ) ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

Stop imatinib mesylate until ANC greater than or equal to 1.5 x10 9 /L and platelets greater than or equal to 75 x 10 9 /L.

Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction) 3.

In the event of recurrence of ANC less than 1.0 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate at reduced dose of 260 mg/m 2 1 ANC = absolute neutrophil count.