Zoleta

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Zoleta uses


Warnings and Precautions, Renal Toxicity (5.14) 9/2017

1 INDICATIONS AND USAGE

Zoleta is a kinase inhibitor indicated for the treatment of:

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, 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

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

1.4 Pediatric patients with Ph+ Acute Lymphoblastic Leukemia

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

1.5 Myelodysplastic/Myeloproliferative Diseases

Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements as determined with an FDA-approved test .

1.6 Aggressive Systemic Mastocytosis

Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA-approved test or with c-Kit mutational status unknown.

1.7 Hypereosinophilic Syndrome 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

Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

1.9 Kit+ Gastrointestinal Stromal Tumors

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.10 Adjuvant Treatment of GIST

Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

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2 DOSAGE AND ADMINISTRATION


All doses of Zoleta should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Zoleta can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400 mg tablet 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. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

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 and above, dosing should be accomplished using the 400 mg 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 Zoleta is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg 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 Zoleta for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg). Zoleta 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 Zoleta treatment in children under 1 year of age.

2.4 Adult Patients with Ph+ ALL

The recommended dose of Zoleta is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.

2.5 Pediatric Patients with Ph+ ALL

The recommended dose of Zoleta to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m2/day. Zoleta 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. Information on FDA-approved tests for the detection of PDGFRb rearrangements is available at http://www.fda.gov/companiondiagnostics.

The recommended dose of Zoleta is 400 mg/day for adult patients with MDS/MPD.

2.7 Adult Patients with ASM

Determine D816V c-Kit mutation status prior to initiating treatment. Information on FDA-approved test for the detection of D816V c-Kit mutation is available at http://www.fda.gov/companiondiagnostics.

The recommended dose of Zoleta is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Zoleta 400 mg/day 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 is recommended. Dose increase from 100 mg to 400 mg 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 Zoleta is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

2.9 Adult Patients with DFSP

The recommended dose of Zoleta is 800 mg/day for adult patients with DFSP.

2.10 Adult Patients with Metastatic and/or Unresectable GIST

The recommended dose of Zoleta is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

2.11 Adult Patients with Adjuvant GIST

The recommended dose of Zoleta is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of Zoleta and three years of Zoleta were studied. In the patient population defined in Study 2, three years of Zoleta is recommended . The optimal treatment duration with Zoleta is not known.

2.12 Dose Modification Guidelines

Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided. If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Zoleta should be increased by at least 50%, and clinical response should be carefully monitored .

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 .

Renal Impairment: Patients with moderate renal impairment (CrCL=20–39 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 are not recommended in patients with mild renal impairment (CrCL=40–59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended.

Zoleta 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 .

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, Zoleta 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 Zoleta 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). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day.

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Zoleta 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.

ASM associated with eosinophilia

(starting dose 100 mg)

ANC1 less than 1.0 x 109/L

and/or

platelets less than 50 x 109/L

  • Stop Zoleta until ANC greater than or equal to 1.5 x 109/L and platelets greater than or equal to 75 x 109/L

  • Resume treatment with Zoleta 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 109/L

and/or

platelets less than 50 x 109/L

  • Stop Zoleta until ANC greater than or equal to 1.5 x 109/L and platelets greater than or equal to 75 x 109/L

  • Resume treatment with Zoleta at previous dose (i.e., dose before severe adverse reaction)
Chronic Phase CML (starting dose 400 mg)

MDS/MPD, ASM and HES/CEL (starting dose 400 mg)

GIST (starting dose 400 mg)

ANC less than 1.0 x 109/L

and/or

platelets less than 50 x 109/L

  • Stop Zoleta until ANC greater than or equal to 1.5 x 109/L and platelets greater than or equal to 75 x 109/L

  • Resume treatment with Zoleta at the original starting dose of 400 mg

  • If recurrence of ANC less than 1.0 x 109/L and/or platelets less than 50 x 109/L, repeat step 1 and resume Zoleta at a reduced dose of 300 mg
Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg)

Ph+ ALL

(starting dose 600 mg)

ANC less than 0.5 x 109/L

and/or

platelets less than 10 x 109/L

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

  • If cytopenia is unrelated to leukemia, reduce dose of Zoleta to 400 mg

  • If cytopenia persists 2 weeks, reduce further to 300 mg

  • If cytopenia persists 4 weeks and is still unrelated to leukemia, stop Zoleta until ANC greater than or equal to1 x 109/L and platelets greater than or equal to 20 x 109/L and then resume treatment at 300 mg
DFSP

(starting dose 800 mg)

ANC less than 1.0 x 109/L

and/or

platelets less than 50 x 109/L

  • Stop Zoleta until ANC greater than or equal to 1.5 x 109/L and platelets greater than or equal to 75 x 109/L

  • Resume treatment with Zoleta at 600 mg

  • In the event of recurrence of ANC less than 1.0 x 109/L and/or platelets less than 50 x 109/L, repeat step 1 and resume Zoleta at reduced dose of 400 mg
Pediatric newly diagnosed chronic phase CML

(starting dose 340 mg/m2)

ANC less than 1.0 x 109/L

and/or

platelets less than 50 x 109/L

  • Stop Zoleta until ANC greater than or equal to 1.5 x 109/L and platelets greater than or equal to 75 x 109/L

  • Resume treatment with Zoleta at previous dose (i.e., dose before severe adverse reaction)

  • In the event of recurrence of ANC less than 1.0 x 109/L and/or platelets less than 50 x 109/L, repeat step 1 and resume Zoleta at reduced dose of 260 mg/m2
1ANC = absolute neutrophil count
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3 DOSAGE FORMS AND STRENGTHS

100 mg film coated tablets

Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side

400 mg film coated tablets

Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side with score on the other side, and “SL” on each side of the score

400 mg film coated tablets

Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “gleevec” on one side and score on the other side.

Tablets (scored): 100 mg and 400 mg (3)

4 CONTRAINDICATIONS

None.

None. (4)

5 WARNINGS AND PRECAUTIONS

5.1 Fluid Retention and Edema

Zoleta is often associated with edema and occasionally serious fluid retention . 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 Zoleta 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 Zoleta, and in 2%-6% of other adult CML patients taking Zoleta. 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 Zoleta, and in 2%-6% of other adult CML patients taking Zoleta. Severe fluid retention was reported in 9% to 13.1% of patients taking Zoleta for GIST . In a randomized trial in patients with newly diagnosed Ph+CML in chronic phase comparing Zoleta and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving Zoleta 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 Zoleta 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 Zoleta 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. 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 Zoleta. 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 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Zoleta 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 Zoleta and nilotinib, cardiac failure was observed in 1.1% of patient in the Zoleta 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 Zoleta . Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Zoleta. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with Zoleta interruption and/or dose reduction [see Dosage and Administration (2. 13 )].When Zoleta 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 Zoleta versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Zoleta and nilotinib, GI hemorrhage occurred in 1.4% of patients in the Zoleta 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 Zoleta 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

Zoleta is sometimes associated with GI irritation. Zoleta 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 Zoleta therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Zoleta.

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 for one to two weeks concomitantly with Zoleta 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 Zoleta. 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 Zoleta therapy after resolution or improvement of the bullous reaction. In these instances, Zoleta 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 Zoleta. Monitor TSH levels in such patients.

5.10 Embryo-fetal Toxicity

Zoleta can cause fetal harm when administered to a pregnant woman. Zoleta 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 Zoleta 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 when using Zoleta and for 14 days after stopping Zoleta. 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 .

5.11 Growth Retardation in Children and Adolescents

Growth retardation has been reported in children and pre-adolescents receiving Zoleta. The long term effects of prolonged treatment with Zoleta on growth in children are unknown. Therefore, monitor growth in children under Zoleta treatment .

5.12 Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome, including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Zoleta. 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 Zoleta.

5.13 Impairments Related to Driving and Using Machinery

Motor vehicle accidents have been reported in patients receiving Zoleta. Advise patients that they may experience side effects such as dizziness, blurred vision or somnolence during treatment with Zoleta. Recommend caution when driving a car or operating machinery.

5.14 Renal Toxicity

A decline in renal function may occur in patients receiving Zoleta. Median estimated glomerular filtration rate (eGFR) values in patients on Zoleta 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 ml/min/1.73m2 (N=1190) to 75 ml/min/1.73m2 at 12 months (N=1082) and 69 ml/min/1.73m2 at 60 months (N=549). Evaluate renal function prior to initiating Zoleta and monitor during therapy, with attention to risk factors for renal dysfunction such as pre-existing renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

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6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:


The most frequently reported adverse reactions (greater than or equal to 30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain. (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Chronic Myeloid Leukemia

The majority of Gleevec-treated patients experienced adverse reactions at some time. Zoleta was discontinued due to drug-related adverse reactions in 2.4% of patients receiving Zoleta in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Zoleta versus IFN+Ara-C, and in 12.5% of patients receiving Zoleta in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Zoleta and nilotinib. Zoleta was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis.

The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Zoleta [see Dosage and Administration (2. 13 )]. The frequency of severe superficial edema was 1.5%–6%.

A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Zoleta treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Zoleta treated patients are shown in Tables 2, 3, and 4.

(1)All adverse reactions occurring in greater than or equal to10% of Zoleta treated patients are listed regardless of suspected relationship to treatment.

(2)Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

All Grades CTC Grades 3/4
Zoleta IFN+Ara−C Zoleta IFN+Ara−C
Preferred Term N=551 (%) N=533 (%) N=551 (%) N=533 (%)
Fluid Retention 61.7 11.1 2.5 0.9
− Superficial Edema 59.9 9.6 1.5 0.4
− Other Fluid Retention Reactions2 6.9 1.9 1.3 0.6
Nausea 49.5 61.5 1.3 5.1
Muscle Cramps 49.2 11.8 2.2 0.2
Musculoskeletal Pain 47.0 44.8 5.4 8.6
Diarrhea 45.4 43.3 3.3 3.2
Rash and Related Terms 40.1 26.1 2.9 2.4
Fatigue 38.8 67.0 1.8 25.1
Headache 37.0 43.3 0.5 3.8
Joint Pain 31.4 38.1 2.5 7.7
Abdominal Pain 36.5 25.9 4.2 3.9
Nasopharyngitis 30.5 8.8 0 0.4
Hemorrhage 28.9 21.2 1.8 1.7
- GI Hemorrhage 1.6 1.1 0.5 0.2
- CNS Hemorrhage 0.2 0.4 0 0.4
Myalgia 24.1 38.8 1.5 8.3
Vomiting 22.5 27.8 2.0 3.4
Dyspepsia 18.9 8.3 0 0.8
Cough 20.0 23.1 0.2 0.6
Pharyngolaryngeal Pain 18.1 11.4 0.2 0
Upper Respiratory Tract Infection 21.2 8.4 0.2 0.4
Dizziness 19.4 24.4 0.9 3.8
Pyrexia 17.8 42.6 0.9 3.0
Weight Increased 15.6 2.6 2.0 0.4
Insomnia 14.7 18.6 0 2.3
Depression 14.9 35.8 0.5 13.1
Influenza 13.8 6.2 0.2 0.2
Bone Pain 11.3 15.6 1.6 3.4
Constipation 11.4 14.4 0.7 0.2
Sinusitis 11.4 6.0 0.2 0.2
aExcluding laboratory abnormalities

bNCI Common Terminology Criteria for Adverse Events, Version 3.0

Patients with Newly Diagnosed Ph+ CML-CP
Zoleta

400 mg

once daily

nilotinib

300 mg

twice daily

Zoleta

400 mg

once daily

nilotinib

300 mg

twice daily

N=280 N=279 N=280 N=279
Body System and Preferred Term All Grades (%) CTC Grades b 3/4 (%)
Skin and subcutaneous tissue disorders

Rash


19


38


2


<1

Pruritus 7 21 0 <1
Alopecia 7 13 0 0
Dry skin 6 12 0 0
Gastrointestinal disorders Nausea 41 22 2 2
Constipation 8 20 0 <1
Diarrhea 46 19 4 1
Vomiting 27 15 <1 <1
Abdominal pain upper 14 18 <1 1
Abdominal pain 12 15 0 2
Dyspepsia 12 10 0 0
Nervous system disorders Headache 23 32 <1 3
Dizziness 11 12 <1 <1
General disorders and administration site conditions

Fatigue


20


23


1


1

Pyrexia 13 14 0 <1
Asthenia 12 14 0 <1
Peripheral edema 20 9 0 <1
Face edema 14 <1 <1 0
Musculoskeletal and connective tissue disorders

Myalgia


19


19


<1


<1

Arthralgia 17 22 <1 <1
Muscle spasms 34 12 1 0
Pain in extremity 16 15 <1 <1
Back pain 17 19 1 1
Respiratory, thoracic and mediastinal disorders

Cough


13


17


0


0

Oropharyngeal pain 6 12 0 0
Dyspnea 6 11 <1 2
Infections and infestations Nasopharyngitis 21 27 0 0
Upper respiratory tract infection

14


17


0


<1

Influenza 9 13 0 0
Gastroenteritis 10 7 <1 0
Eye disorders Eyelid edema 19 1 <1 0
Periorbital edema 15 <1 0 0
Psychiatric disorders Insomnia 9 11 0 0
Vascular disorder Hypertension 4 10 <1 1
(1)All adverse reactions occurring in greater than or equal to10% of patients are listed regardless of suspected relationship to treatment.

(2)Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

Myeloid Blast Crisis

(n=260)

Accelerated Phase

(n=235)

Chronic Phase, IFN Failure

(n=532)

% % %
Preferred Term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
Fluid Retention 72 11 76 6 69 4
-Superficial Edema 66 6 74 3 67 2
-Other Fluid Retention Reactions (2) 22 6 15 4 7 2
Nausea 71 5 73 5 63 3
Muscle Cramps 28 1 47 0.4 62 2
Vomiting 54 4 58 3 36 2
Diarrhea 43 4 57 5 48 3
Hemorrhage 53 19 49 11 30 2
- CNS Hemorrhage 9 7 3 3 2 1
- GI Hemorrhage 8 4 6 5 2 0.4
Musculoskeletal Pain 42 9 49 9 38 2
Fatigue 30 4 46 4 48 1
Skin Rash 36 5 47 5 47 3
Pyrexia 41 7 41 8 21 2
Arthralgia 25 5 34 6 40 1
Headache 27 5 32 2 36 0.6
Abdominal Pain 30 6 33 4 32 1
Weight Increased 5 1 17 5 32 7
Cough 14 0.8 27 0.9 20 0
Dyspepsia 12 0 22 0 27 0
Myalgia 9 0 24 2 27 0.2
Nasopharyngitis 10 0 17 0 22 0.2
Asthenia 18 5 21 5 15 0.2
Dyspnea 15 4 21 7 12 0.9
Upper Respiratory Tract Infection 3 0 12 0.4 19 0
Anorexia 14 2 17 2 7 0
Night Sweats 13 0.8 17 1 14 0.2
Constipation 16 2 16 0.9 9 0.4
Dizziness 12 0.4 13 0 16 0.2
Pharyngitis 10 0 12 0 15 0
Insomnia 10 0 14 0 14 0.2
Pruritus 8 1 14 0.9 14 0.8
Hypokalemia 13 4 9 2 6 0.8
Pneumonia 13 7 10 7 4 1
Anxiety 8 0.8 12 0 8 0.4
Liver Toxicity 10 5 12 6 6 3
Rigors 10 0 12 0.4 10 0
Chest Pain 7 2 10 0.4 11 0.8
Influenza 0.8 0.4 6 0 11 0.2
Sinusitis 4 0.4 11 0.4 9 0.4

Hematologic and Biochemistry Laboratory Abnormalities

Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients. The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase. The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Zoleta, but may require permanent discontinuation of treatment.

*p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups)
Zoleta

N=551

IFN+Ara−C

N=533

% %
CTC Grades Grade 3 Grade 4 Grade 3 Grade 4
Hematology Parameters*
− Neutropenia* 13.1 3.6 20.8 4.5
− Thrombocytopenia* 8.5 0.4 15.9 0.6
− Anemia 3.3 1.1 4.1 0.2
Biochemistry Parameters
− Elevated Creatinine 0 0 0.4 0
− Elevated Bilirubin 0.9 0.2 0.2 0
− Elevated Alkaline Phosphatase 0.2 0 0.8 0
− Elevated SGOT /SGPT 4.7 0.5 7.1 0.4
*NCI Common Terminology Criteria for Adverse Events, version 3.0
Zoleta 400 mg

once-daily

N=280

(%)

nilotinib 300 mg

twice-daily

N=279

(%)

Hematologic Parameters
Thrombocytopenia 9 10
Neutropenia 22 12
Anemia 6 4
Biochemistry Parameters
Elevated lipase 4 9
Hyperglycemia <1 7
Hypophosphatemia 10 8
Elevated bilirubin (total) <1 4
Elevated SGPT (ALT) 3 4
Hyperkalemia 1 2
Hyponatremia <1 1
Hypokalemia 2 <1
Elevated SGOT (AST) 1 1
Decreased albumin <1 0
Hypocalcemia <1 <1
Elevated alkaline phosphatase <1 0
Elevated creatinine <1 0
1CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (hemoglobin greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), elevated SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN)
Myeloid Blast Crisis

(n=260)

Accelerated Phase

(n=235)

Chronic Phase, IFN Failure

(n=532)

600 mg n=223

400 mg n=37

600 mg n=158

400 mg n=77

400 mg
% % %
CTC Grades 1 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
Hematology Parameters
− Neutropenia 16 48 23 36 27 9
− Thrombocytopenia 30 33 31 13 21 <1
− Anemia 42 11 34 7 6 1
Biochemistry Parameters
− Elevated Creatinine 1.5 0 1.3 0 0.2 0
− Elevated Bilirubin 3.8 0 2.1 0 0.6 0
− Elevated Alkaline Phosphatase 4.6 0 5.5 0.4 0.2 0
− Elevated SGOT (AST) 1.9 0 3.0 0 2.3 0
− Elevated SGPT (ALT) 2.3 0.4 4.3 0 2.1 0

Hepatotoxicity

Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

Adverse Reactions in Pediatric Population

Single agent therapy

The overall safety profile of pediatric patients treated with Zoleta in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression.

In combination with multi-agent chemotherapy

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 study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n=92) were assigned to receive Zoleta and treated in 5 successive cohorts. Zoleta exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.

The safety of Zoleta given in combination with intensive chemotherapy was evaluated by comparing the incidence of grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive Zoleta. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without Zoleta. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with Zoleta and 647 without Zoleta. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included Zoleta are presented in Table 8.

*Defined as the frequency of AEs per patient per treatment cycles that included Zoleta (includes patients with Ph+ ALL that received cycles with Zoleta)

**Defined as the frequency of AEs per patient per treatment cycles that did not include Zoleta (includes patients with Ph+ ALL that received cycles without Zoleta as well as all patients with Ph- ALL who did not receive Zoleta in any treatment cycle)

Adverse Event Per Patient

Incidence

Ph+ALL

With Zoleta

N=92

n (%)

Per Patient

Incidence

Ph- ALL

No Zoleta

N=65

n (%)

Per Patient

Per Cycle Incidence

With Gleevec*

N=778

n (%)

Per Patient

Per Cycle

Incidence

No Gleevec**

N=647

n (%)

Grade 3 and 4 Adverse Events
Nausea and/or Vomiting 15 (16) 6 (9) 28 (4) 8 (1)
Hypokalemia 31 (34) 16 (25) 72 (9) 32(5)
Pneumonitis 7 (8) 1 (1) 7(1) 1(<1)
Pleural effusion 6 (7) 0 6 (1) 0
Abdominal Pain 8 (9) 2 (3) 9 (1) 3(<1)
Anorexia 10 (11) 3 (5) 19 (2) 4 (1)
Hemorrhage 11 (12) 4 (6) 17 (2) 8 (1)
Hypoxia 8 (9) 2 (3) 12 (2) 2 (<1)
Myalgia 5 (5) 0 4 (1) 1 (<1)
Stomatitis 15 (16) 8 (12) 22 (3) 14 (2)
Diarrhea 8 (9) 3 (5) 12 (2) 3 (<1)
Rash / Skin Disorder 4 (4) 0 5 (1) 0
Infection 49 (53) 32 (49) 131 (17) 92 (14)
Hepatic (transaminase and/or bilirubin) 52 (57) 38 (58) 172 (22) 113 (17)
Hypotension 10 (11) 5 (8) 16 (2) 6 (1)
Myelosuppression
Neutropenia (< 750/mcL) 92 (100) 63 (97) 556 (71) 218 (34)
Thrombocytopenia (< 75,000/mcL) 90 (92) 63 (97) 431 (55) 329 (51)

Adverse Reactions in Other Subpopulations

In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

Acute Lymphoblastic Leukemia

The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Zoleta.

Myelodysplastic/Myeloproliferative Diseases

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Zoleta for MDS/MPD in the Phase 2 study, are shown in Table 9.

Preferred Term N=7

n (%)

Nausea 4 (57.1)
Diarrhea 3 (42.9)
Anemia 2 (28.6)
Fatigue 2 (28.6)
Muscle Cramp 3 (42.9)
Arthralgia 2 (28.6)
Periorbital Edema 2 (28.6)

Aggressive Systemic Mastocytosis

All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued Zoleta due to drug-related adverse reactions or abnormal laboratory values.

Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia

The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Zoleta observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.

Dermatofibrosarcoma Protuberans

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Zoleta for DFSP in the Phase 2 study are shown in Table 10.

Preferred term N=12

n (%)

Nausea 5 (41.7)
Diarrhea 3 (25.0)
Vomiting 3 (25.0)
Periorbital Edema 4 (33.3)
Face Edema 2 (16.7)
Rash 3 (25.0)
Fatigue 5 (41.7)
Edema Peripheral 4 (33.3)
Pyrexia 2 (16.7)
Eye Edema 4 (33.3)
Lacrimation Increased 3 (25.0)
Dyspnea Exertional 2 (16.7)
Anemia 3 (25.0)
Rhinitis 2 (16.7)
Anorexia 2 (16.7)

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Zoleta for DFSP in the Phase 2 study are presented in Table 11.

1CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN)
N=12
CTC Grades 1 Grade 3

%

Grade 4

%

Hematology Parameters
- Anemia 17 0
- Thrombocytopenia 17 0
- Neutropenia 0 8
Biochemistry Parameters
- Elevated Creatinine 0 8

Gastrointestinal Stromal Tumors

Unresectable and/or Malignant Metastatic GIST

In the Phase 3 trials, the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Zoleta [see Dosage and Administration (2. 13 )]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Zoleta are shown in Table 12.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Reported or Specified Term Zoleta 400 mg

N=818

Zoleta 800 mg

N=822

All Grades

%

Grades 3/4/5

%

All Grades

%

Grades 3/4/5

%

Edema 76.7 9.0 86.1 13.1
Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2
Nausea 58.1 9.0 64.5 7.8
Abdominal pain/cramping 57.2 13.8 55.2 11.8
Diarrhea 56.2 8.1 58.2 8.6
Rash/desquamation 38.1 7.6 49.8 8.9
Vomiting 37.4 9.2 40.6 7.5
Myalgia 32.2 5.6 30.2 3.8
Anemia 32.0 4.9 34.8 6.4
Anorexia 31.1 6.6 35.8 4.7
Other GI toxicity 25.2 8.1 28.1 6.6
Headache 22.0 5.7 19.7 3.6
Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0
Other dermatology/skin toxicity 17.6 5.9 20.1 5.7
Leukopenia 17.0 0.7 19.6 1.6
Other constitutional symptoms 16.7 6.4 15.2 4.4
Cough 16.1 4.5 14.5 3.2
Infection (without neutropenia) 15.5 6.6 16.5 5.6
Pruritus 15.4 5.4 18.9 4.3
Other neurological toxicity 15.0 6.4 15.2 4.9
Constipation 14.8 5.1 14.4 4.1
Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2
Arthralgia (joint pain) 13.6 4.8 12.3 3.0
Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6
Fever in absence of neutropenia (ANC< 1.0 x 109/L) 13.2 4.9 12.9 3.4
Sweating 12.7 4.6 8.5 2.8
Other hemorrhage 12.3 6.7 13.3 6.1
Weight gain 12.0 1.0 10.6 0.6
Alopecia 11.9 4.3 14.8 3.2
Dyspepsia/heartburn 11.5 0.6 10.9 0.5
Neutropenia/ granulocytopenia 11.5 3.1 16.1 4.1
Rigors/chills 11.0 4.6 10.2 3.0
Dizziness/lightheadedness 11.0 4.8 10.0 2.8
Creatinine increase 10.8 0.4 10.1 0.6
Flatulence 10.0 0.2 10.1 0.1
Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10.0 4.3
Lymphopenia 6.0 0.7 10.1 1.9

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13.

1CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), albumin (Grade 3 less than 20 g/L)
400 mg

(n=73)

600 mg

(n=74)

% %
CTC Grades 1 Grade 3 Grade 4 Grade 3 Grade 4
Hematology Parameters
− Anemia 3 0 8 1
− Thrombocytopenia 0 0 1 0
− Neutropenia 7 3 8 3
Biochemistry Parameters
− Elevated Creatinine 0 0 3 0
− Reduced Albumin 3 0 4 0
− Elevated Bilirubin 1 0 1 3
− Elevated Alkaline Phosphatase 0 0 3 0
− Elevated SGOT (AST) 4 0 3 3
− Elevated SGPT (ALT) 6 0 7 1

Adjuvant Treatment of GIST

In Study 1, the majority of both Zoleta and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Zoleta and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.

In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the Zoleta 12-month and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Zoleta are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to Zoleta treatment in either trial.

(1)All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment.

A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

All CTC Grades CTC Grade 3 and above
Zoleta

(n=337)

Placebo

(n=345)

Zoleta

(n=337)

Placebo

(n=345)

Preferred Term % % % %
Diarrhea 59.3 29.3 3.0 1.4
Fatigue 57.0 40.9 2.1 1.2
Nausea 53.1 27.8 2.4 1.2
Periorbital Edema 47.2 14.5 1.2 0
Hemoglobin Decreased 46.9 27.0 0.6 0
Peripheral Edema 26.7 14.8 0.3 0
Rash (Exfoliative) 26.1 12.8 2.7 0
Vomiting 25.5 13.9 2.4 0.6
Abdominal Pain 21.1 22.3 3.0 1.4
Headache 19.3 20.3 0.6 0
Dyspepsia 17.2 13.0 0.9 0
Anorexia 16.9 8.7 0.3 0
Weight Increased 16.9 11.6 0.3 0
Liver enzymes (ALT) Increased 16.6 13.0 2.7 0
Muscle spasms 16.3 3.3 0 0
Neutrophil Count Decreased 16.0 6.1 3.3 0.9
Arthralgia 15.1 14.5 0 0.3
White Blood Cell Count Decreased 14.5 4.3 0.6 0.3
Constipation 12.8 17.7 0 0.3
Dizziness 12.5 10.7 0 0.3
Liver Enzymes (AST) Increased 12.2 7.5 2.1 0
Myalgia 12.2 11.6 0 0.3
Blood Creatinine Increased 11.6 5.8 0 0.3
Cough 11.0 11.3 0 0
Pruritus 11.0 7.8 0.9 0
Weight Decreased 10.1 5.2 0 0
Hyperglycemia 9.8 11.3 0.6 1.7
Insomnia 9.8 7.2 0.9 0
Lacrimation Increased 9.8 3.8 0 0
Alopecia 9.5 6.7 0 0
Flatulence 8.9 9.6 0 0
Rash 8.9 5.2 0.9 0
Abdominal Distension 7.4 6.4 0.3 0.3
Back Pain 7.4 8.1 0.6 0
Pain in Extremity 7.4 7.2 0.3 0
Hypokalemia 7.1 2.0 0.9 0.6
Depression 6.8 6.4 0.9 0.6
Facial Edema 6.8 1.2 0.3 0
Blood Alkaline Phosphatase Increased 6.5 7.5 0 0
Dry skin 6.5 5.2 0 0
Dysgeusia 6.5 2.9 0 0
Abdominal Pain Upper 6.2 6.4 0.3 0
Neuropathy Peripheral 5.9 6.4 0 0
Hypocalcemia 5.6 1.7 0.3 0
Leukopenia 5.0 2.6 0.3 0
Platelet Count Decreased 5.0 3.5 0 0
Stomatitis 5.0 1.7 0.6 0
Upper Respiratory Tract Infection 5.0 3.5 0 0
Vision Blurred 5.0 2.3 0 0
(1)All adverse reactions occurring in greater than or equal to5% of patients are listed regardless of suspected relationship to treatment.

A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.

Preferred Term All CTC Grades CTC Grades 3 and above
Zoleta

12 Months

(N=194)

%

Zoleta

36 Months

(N=198)

%

Zoleta

12 Months

(N=194)

%

Zoleta

36 Months

(N=198)

%

Patients with at least one AE 99.0 100.0 20.1 32.8
Hemoglobin decreased 72.2 80.3 0.5 0.5
Periorbital edema 59.3 74.2 0.5 1.0
Blood lactate dehydrogenase increased 43.3 60.1 0 0
Diarrhea 43.8 54.0 0.5 2.0
Nausea 44.8 51.0 1.5 0.5
Muscle spasms 30.9 49.0 0.5 1.0
Fatigue 48.5 48.5 1.0 0.5
White blood cell count decreased 34.5 47.0 2.1 3.0
Pain 25.8 45.5 1.0 3.0
Blood creatinine increased 30.4 44.4 0 0
Edema peripheral 33.0 40.9 0.5 1.0
Dermatitis 29.4 38.9 2.1 1.5
Aspartate aminotransferase increased 30.9 37.9 1.5 3.0
Alanine aminotransferase increased 28.9 34.3 2.1 3.0
Neutrophil count decreased 24.2 33.3 4.6 5.1
Hypoproteinemia 23.7 31.8 0 0
Infection 13.9 27.8 1.5 2.5
Weight increased 13.4 26.8 0 0.5
Pruritus 12.9 25.8 0 0
Flatulence 19.1 24.7 1.0 0.5
Vomiting 10.8 22.2 0.5 1.0
Dyspepsia 17.5 21.7 0.5 1.0
Hypoalbuminemia 11.9 21.2 0 0
Edema 10.8 19.7 0 0.5
Abdominal distension 11.9 19.2 0.5 0
Headache 8.2 18.2 0 0
Lacrimation increased 18.0 17.7 0 0
Arthralgia 8.8 17.2 0 1.0
Blood alkaline phosphatase increased 10.8 16.7 0 0.5
Dyspnea 6.2 16.2 0.5 1.5
Myalgia 9.3 15.2 0 1.0
Platelet count decreased 11.3 14.1 0 0
Blood bilirubin increased 11.3 13.1 0 0
Dysgeusia 9.3 12.6 0 0
Paresthesia 5.2 12.1 0 0.5
Vision blurred 10.8 11.1 1.0 0.5
Alopecia 11.3 10.6 0 0
Decreased appetite 9.8 10.1 0 0
Constipation 8.8 9.6 0 0
Pyrexia 6.2 9.6 0 0
Depression 3.1 8.1 0 0
Abdominal pain 2.6 7.6 0 0
Conjunctivitis 5.2 7.6 0 0
Photosensitivity reaction 3.6 7.1 0 0
Dizziness 4.6 6.6 0.5 0
Hemorrhage 3.1 6.6 0 0
Dry skin 6.7 6.1 0.5 0
Nasopharyngitis 1.0 6.1 0 0.5
Palpitations 5.2 5.1 0 0

Adverse Reactions from Multiple Clinical Trials

Cardiac Disorders:

Estimated 1%–10%: palpitations, pericardial effusion

Estimated 0.1%–1%: congestive cardiac failure, tachycardia, pulmonary edema

Estimated 0.01%–0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris

Vascular Disorders:

Estimated 1%–10%: flushing, hemorrhage

Estimated 0.1%–1%: hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma

Investigations:

Estimated 1%–10%: blood CPK increased, blood amylase increased

Estimated 0.1%–1%: blood LDH increased

Skin and Subcutaneous Tissue Disorders:

Estimated 1%–10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura

Estimated 0.1%–1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme

Estimated 0.01%–0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis

Gastrointestinal Disorders:

Estimated 1%–10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis

Estimated 0.1%–1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis

Estimated 0.01%–0.1%: colitis, ileus, inflammatory bowel disease

General Disorders and Administration Site Conditions:

Estimated 1%–10%: weakness, anasarca, chills

Estimated 0.1%–1%: malaise

Blood and Lymphatic System Disorders:

Estimated 1%–10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia

Estimated 0.1%–1%: thrombocythemia, bone marrow depression, lymphadenopathy

Estimated 0.01%–0.1%: hemolytic anemia, aplastic anemia

Hepatobiliary Disorders:

Estimated 0.1%–1%: hepatitis, jaundice

Estimated 0.01%–0.1%: hepatic failure and hepatic necrosis1

Immune System Disorders:

Estimated 0.01%–0.1%: angioedema

Infections and Infestations:

Estimated 0.1%–1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis

Estimated 0.01%–0.1%: fungal infection

Metabolism and Nutrition Disorders:

Estimated 1%–10%: weight decreased, decreased appetite

Estimated 0.1%–1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia

Musculoskeletal and Connective Tissue Disorders:

Estimated 1%–10%: joint swelling

Estimated 0.1%–1%: joint and muscle stiffness, muscular weakness, arthritis

Nervous System/Psychiatric Disorders:

Estimated 1%–10%: paresthesia, hypesthesia

Estimated 0.1%–1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor

Estimated 0.01%–0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis

Renal and Urinary Disorders:

Estimated 0.1%–1%: renal failure acute, urinary frequency increased, hematuria, renal pain

Reproductive System and Breast Disorders:

Estimated 0.1%–1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema

Respiratory, Thoracic and Mediastinal Disorders:

Estimated 1%–10%: epistaxis

Estimated 0.1%–1%: pleural effusion

Estimated 0.01%–0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage

Eye, Ear and Labyrinth Disorders:

Estimated 1%–10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye

Estimated 0.1%–1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract

Estimated 0.01%–0.1%: papilledema1, glaucoma

1Including some fatalities

6.2 Postmarketing Experience

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

1Including some fatalities

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7 DRUG INTERACTIONS

7.1 Agents Inducing CYP3A Metabolism

Concomitant administration of Zoleta and strong CYP3A4 inducers may reduce total exposure of Zoleta; consider alternative agents .

7.2 Agents Inhibiting CYP3A Metabolism

Concomitant administration of Zoleta and strong CYP3A4 inhibitors may result in a significant Zoleta exposure increase. Grapefruit juice may also increase plasma concentrations of Zoleta; avoid grapefruit juice .

7.3 Interactions with Drugs Metabolized by CYP3A4

Zoleta 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 Zoleta 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 .

7.4 Interactions with Drugs Metabolized by CYP2D6

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Zoleta can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of Zoleta in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to Zoleta during pregnancy. Reproductive studies in rats have demonstrated that Zoleta mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to Zoleta 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 Zoleta. 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 Zoleta mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.

In rats, Zoleta mesylate was teratogenic at 100 mg/kg/day, 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 Zoleta 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

Zoleta and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from Zoleta, 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 Zoleta, the milk:plasma ratio is about 0.5 for Zoleta and about 0.9 for the active metabolite. Considering the combined concentration of Zoleta 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 postmarketing reports and animal studies have shown Zoleta to be harmful to the developing fetus. Test pregnancy status in females with reproductive potential prior to the initiation of treatment with Zoleta.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception when using Zoleta during treatment and for fourteen days after stopping treatment with Zoleta .

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 .

8.4 Pediatric Use

The safety and effectiveness of Zoleta have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL . 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 . The efficacy of Zoleta 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 Zoleta was similar in patients older than 65 years and younger patients.

8.6 Hepatic Impairment

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

Mild and moderate hepatic impairment do not influence exposure to Zoleta and CGP74588. In patients with severe hepatic impairment, the Zoleta 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 )].

Liver Function Test Normal

(n=14)

Mild

(n=30)

Moderate

(n=20)

Severe

(n=20)

Total Bilirubin less than or equal to ULN greater than 1.0–1.5 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 Zoleta was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state Zoleta doses ranging from 100 to 800 mg/day. The mean exposure to Zoleta (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 . Dose reductions are necessary for patients with moderate and severe renal impairment [see Dosage and Administration (2. 12 )].

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 Zoleta 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 Zoleta 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 Zoleta 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 Zoleta 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

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

A total of 71 (12.8%) and 85 (15.4%) patients died in the Zoleta 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 Zoleta and the IFN+Ara-C group, respectively (p=0.073 log-rank test). The hazard ratio is 0.750 with 95% CI 0.547-1.028. This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to Zoleta. 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 Zoleta 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, 25th to 75th percentiles=3 to 11 months) with 10% of responses seen only after 22 months of therapy.

(Best Response Rate) Zoleta

n=553

IFN+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%]
Unconfirmed3 88.6%* 23.3%*
Complete Cytogenetic Response n (%) 413 (74.7%)* 36 (6.5%)*
[95% CI] [70.8, 78.3] [4.6, 8.9]
Unconfirmed3 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 109/L, platelet less than 450 x 109/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%–35%). A major response (0%–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 Zoleta 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 6 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 Zoleta.

An open-label, multicenter, randomized trial (Gleevec versus nilotinib) was conducted to determine the efficacy of Zoleta 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 Zoleta 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 Zoleta 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 Zoleta 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 Zoleta 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 to3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 19.

Twelve patients in the Zoleta 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).

Zoleta

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-Valuea <0.0001
CCyRb 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)
CCyRb 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 to20 metaphase cells in each bone marrow sample.

By the 60 months, MMR was achieved by 60% of patients on Zoleta 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 Zoleta 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 Zoleta 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 106 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% - 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 109/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%).

Chronic Phase IFN Failure

(n=532)

Accelerated Phase

(n=235)

Myeloid Blast Crisis

(n=260)

600 mg n=158 600 mg n=223
400 mg 400 mg n=77 400 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]
(Unconfirmed3) (65%) (27%) (15%)
Complete4 (Unconfirmed3) 39% (47%) 16% (20%) 2% (7%)
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 109/L, platelet less than 450 x 109/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 109/L, platelets greater than or equal to 100 x 109/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 109/L and platelets greater than or equal to 20 x 109/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).

BM=bone marrow, PB=peripheral blood

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

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 Zoleta 340 mg/m2/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 Zoleta 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/m2/day (n=3), 340 mg/m2/day (n=4), 440 mg/m2/day (n=5) and 570 mg/m2/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/m2/day.

14.3 Acute Lymphoblastic Leukemia

A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia patients with relapsed/refractory disease were studied, 43 of whom received the recommended Zoleta dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received Zoleta 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.

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 Zoleta (340 mg/m2/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, Zoleta exposure was systematically increased by earlier introduction and prolonged duration. Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of Zoleta exposure.

There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received Zoleta plus chemotherapy; 30 were treated exclusively with chemotherapy and Zoleta and 20 received chemotherapy plus Zoleta and then underwent hematopoietic stem cell transplant, followed by further Zoleta treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to Zoleta beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy. During maintenance cycles 5 through 12 Zoleta was administered 28 days out of the 56 day cycle. Patients who underwent hematopoietic stem cell transplant received 42 days of Zoleta prior to HSCT, and 28 weeks (196 days) of Zoleta 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 Zoleta 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 Zoleta 400 mg daily. 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 Zoleta at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 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.

Number of patients Complete Hematologic Response Major Cytogenetic Response
N n (%) 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 NE1 NE1
1 NE: Not Evaluable

14.6 Aggressive Systemic Mastocytosis

One open-label, multicenter, Phase 2 study was conducted testing Zoleta 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 Zoleta 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 Zoleta in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of Zoleta daily.

Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with Zoleta 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 Zoleta), 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 Zoleta 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 Zoleta in ASM is provided in Table 23. Response durations of literature patients ranged from 1+ to 30+ months.


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

Zoleta has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Zoleta 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 Zoleta and should not receive Zoleta.

14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia

One open-label, multicenter, Phase 2 study was conducted testing Zoleta 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 patients were treated with 100 mg to 1000 mg of Zoleta 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 Zoleta at doses of 75 mg to 800 mg daily. Hematologic response rates are summarized in Table 24. Response durations for literature patients ranged from 6+ weeks to 44 months.


Cytogenetic Abnormality


Number of 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 Zoleta 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 Zoleta 800 mg daily (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 Zoleta 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) Zoleta daily. A single pediatric patient received 400 mg/m2/daily, subsequently increased to 520 mg/m2/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.

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.

14.9 Gastrointestinal Stromal Tumors

Unresectable and/or Malignant Metastatic GIST

Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST.

The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 26.

Zoleta 400 mg

N=818

Zoleta 800 mg

N=822

Progression-Free Survival (months)

Median

18.9 23.2
95% CI 17.4–21.2 20.8–24.9
Overall Survival (months) 49.0 48.7
95% CI 45.3–60.0 45.3–51.6
Best Overall Tumor Response

Complete Response (CR)

Partial Response (PR)

43 (5.3%)

377 (46.1%)

41 (5.0%)

402 (48.9%)


Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups (p=0.98). Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n=347) had a 3.4 month median and a 7.7 month mean exposure to Zoleta following crossover.

One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally every day for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group. The median time to response was 12 weeks (range was 3 to 98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached).

Adjuvant Treatment of GIST

In the adjuvant setting, Zoleta was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to Zoleta at 400 mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size greater than or equal to 3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration.

Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month Zoleta arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p less than 0.0001. After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month Zoleta arm. Seventy-two of these 79 patients subsequently crossed over to Zoleta therapy. In an updated analysis, the median follow-up for patients without a RFS event was 50 months. There were 74 (21%) RFS events in the 12-month Zoleta arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3). The median follow-up for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%) deaths in the 12-month Zoleta and placebo arms, respectively with a hazard ratio of 0.816 (95% CI: 0.488-1.365).

A second randomized, multicenter, open-label, Phase 3 trial in the adjuvant setting (Study 2) compared 12 months of Zoleta treatment to 36 months of Zoleta treatment at 400 mg/day in adult patients with KIT (CD117) positive GIST after surgical resection with one of the following: tumor diameter greater than 5 cm and mitotic count greater than 5/50 high power fields (HPF), or tumor diameter greater than 10 cm and any mitotic count, or tumor of any size with mitotic count greater than 10/50 HPF, or tumors ruptured into the peritoneal cavity. There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range 22 to 84 years).

RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of Zoleta treatment significantly prolonged RFS compared to 12 months of Zoleta treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p less than 0.0001 (Figure 4).

The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of Zoleta treatment significantly prolonged OS compared to 12 months of Zoleta treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p=0.0187 (Figure 5).

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

Each film-coated tablet contains 100 mg or 400 mg of Zoleta free base.

100 mg Tablets

Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side.

Bottles of 90 tablets………………………………….NDC 0078-0401-34

400 mg Tablets

Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side with score on the other side, and “SL” on each side of the score.

Bottles of 30 tablets…………………………………NDC 0078-0438-15

400 mg Tablets

Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “gleevec” on one side and score on the other side.

Unit Dose (blister pack of 30) ………………………NDC 0078-0649-30

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Dispense in a tight container, USP.

Do not crush Zoleta 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.

17 PATIENT COUNSELING INFORMATION

Dosing and Administration

Advise patients to take Zoleta exactly as prescribed, not to change their dose or to stop taking Zoleta unless they are told to do so by their doctor. If the patient missed a dose of Zoleta, 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 Zoleta with a meal and a large glass of water .

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 .

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 .

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 Zoleta. Female patients of reproductive potential taking Zoleta should use highly effective contraception during treatment and for fourteen days after stopping treatment with Zoleta . Avoid breastfeeding during treatment and for 1 month after the last dose .

Drug Interactions

Zoleta 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 Zoleta .

Pediatric

Advise patients that growth retardation has been reported in children and pre-adolescents receiving Zoleta. The long term effects of prolonged treatment with Zoleta on growth in children are unknown. Therefore, closely monitor growth in children under Zoleta treatment .

Driving and Using Machines

Advise patients that they may experience side effects such as dizziness, blurred vision or somnolence during treatment with Zoleta. Therefore, caution patients about driving a car or operating machinery .

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

© Novartis

T2017-101

Zoleta pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Zoleta available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Zoleta destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Zoleta Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Zoleta pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."GLEEVEC (IMATINIB MESYLATE) TABLET [NOVARTIS PHARMACEUTICALS CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Imatinib". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "Imatinib". http://www.drugbank.ca/drugs/DB0061... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Zoleta?

Depending on the reaction of the Zoleta after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Zoleta not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Zoleta addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Zoleta, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Zoleta consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

One visitor reported useful

How is the drug Zoleta useful in reducing or relieving the symptoms? How useful is it?
According to the survey conducted by the website sdrugs.com, there are variable results and below are the percentages of the users that say the medicine is useful to them and that say it is not helping them much. It is not ideal to continue taking the medication if you feel it is not helping you much. Contact your healthcare provider to check if there is a need to change the medicine or if there is a need to re-evaluate your condition. The usefulness of the medicine may vary from patient to patient, depending on the other diseases he is suffering from and slightly depends on the brand name.
Visitors%
Useful1
100.0%

Visitor reported side effects

No survey data has been collected yet

One visitor reported price estimates

What is your opinion about drug cost? Did you feel the cost is apt, or did you feel it is expensive?
The report given by the sdrugs.com website users shows the following figures about several people who felt the medicine Zoleta is expensive, and the medicine is not expensive. The results are mixed. The perception of the cost of the medicine to be expensive or not depends on the brand name of the medicine, country, and place where it is sold, and the affordability of the patient. You can choose a generic drug in the place of the branded drug to save the cost. The efficiency of the medicine will not vary if it is generic or a branded one.
Visitors%
Not expensive1
100.0%

Two visitors reported frequency of use

How often in a day do you take the medicine?
Are you taking the Zoleta drug as prescribed by the doctor?

Few medications can be taken Twice in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Zoleta is mentioned below.
Visitors%
Twice in a day1
50.0%
Once in a day1
50.0%

Two visitors reported doses

What is the dose of Zoleta drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
50.0%
11-50mg1
50.0%

Three visitors reported time for results

What is the time duration Zoleta drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 1 month to notice the result from using Zoleta drug. The time needed to show improvement in health condition after using the medicine Zoleta need not be same for all the users. It varies based on other factors.
Visitors%
1 month1
33.3%
5 days1
33.3%
2 weeks1
33.3%

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
30-451
100.0%

Visitor reviews


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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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