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IN THE TREATMENT OF ADULTS WITH NEWLY DIAGNOSED Ph+ CML-CP 99% of TASIGNA® (nilotinib) patients did not progress to AP/BC at 5 years vs 95% with imatinib¹*

*Based on Kaplan-Meier estimates of time to progression to AP or BC on core treatment (full analysis set) without clonal evolutions. Estimated rates of no progression at 5 years: TASIGNA 99.3% (95% CI, 98.2%-100%) vs imatinib 95.2% (95% CI, 92.6%-97.9%).¹

AP, accelerated phase; BC, blast crisis.

2X THE RATE OF MMR WAS ACHIEVED AT 1 YEAR vs IMATINIB²

44%
TASIGNA® (nilotinib)
(n=282; 95% CI, 38%-50%; P<.0001) 22%
IMATINIB
(n=283; 95% CI, 18%-28%) VS ENESTnd study design: A randomized, controlled, open-label, multicenter Phase 3 trial of 846 patients with newly diagnosed Ph+ CML-CP. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for real-time quantitative polymerase chain reaction (RQ-PCR) testing. The primary end point was MMR at 12 months. MMR was defined as ≥3 logs below baseline (≤0.1% International Scale [IS]) as measured by RQ-PCR assay.^2,3

MORE TASIGNA PATIENTS ACHIEVED MMR AT 2 YEARS vs IMATINIB²

62%
TASIGNA® (nilotinib)
(n=282; 95% CI, 56%-67%) 38%
IMATINIB
(n=283; 95% CI, 32%-43%) VS ENESTnd study design: A randomized, controlled, open-label, multicenter Phase 3 trial of 846 patients with newly diagnosed Ph+ CML-CP. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for real-time quantitative polymerase chain reaction (RQ-PCR) testing. The primary end point was MMR at 12 months. MMR was defined as ≥3 logs below baseline (≤0.1% International Scale [IS]) as measured by RQ-PCR assay.^2,3

A HIGHER RATE OF MMR WAS ACHIEVED vs IMATINIB BY 5 YEARS^1,2

77%
TASIGNA® (nilotinib)
(n=282; 95% CI, 72%-82%) 60%
IMATINIB
(n=283; 95% CI, 55%-66%) VS

Median time on treatment was approximately 61 months in all treatment arms²
The cumulative incidence of MMR end point by 5 years includes patients who achieved MMR at any time up to the 60-month cutoff. Subsequent loss of MMR, patients who did not attain MMR, or those lost to follow-up are not included in this calculation¹

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase 3 trial of 846 patients with newly diagnosed Ph+ CML-CP. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for real-time quantitative polymerase chain reaction (RQ-PCR) testing. The primary end point was MMR at 12 months. MMR was defined as ≥3 logs below baseline (≤0.1% International Scale [IS]) as measured by RQ-PCR assay.^2,3

MMR, major molecular response.

ACHIEVE RESPONSES FOR PATIENTS CHANGING FROM IMATINIB

51% OF IMATINIB-RESISTANT OR -INTOLERANT Ph+ CML-CP
PATIENTS ACHIEVED MCyR (UNCONFIRMED) (n=321; 95% CI, 46%-57%)²

37% of Ph+ CML-CP patients achieved CCyR with TASIGNA® (nilotinib) (95% Cl, 32%-42%)²
15% of Ph+ CML-CP patients achieved PCyR with TASIGNA (95% CI, 11%-19%)²
321 Ph+ CML-CP patients with prior imatinib use were treated with TASIGNA 400 mg bid for a median duration of 18.4 months²
2.8 months median time to MCyR among responders (range 1-28 months)²

39% OF IMATINIB-RESISTANT OR -INTOLERANT Ph+ CML-AP
PATIENTS ACHIEVED HR (CONFIRMED) (n=137; 95% CI, 31%-48%)²

30% of Ph+ CML-AP patients reached CHR (95% CI, 22%-38%), while 9% (95% CI, 5%-16%) attained NEL²
1 month median time to first HR among responders (range 1-14 months)²

Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥20 metaphase cells in each bone marrow sample.² Second-line study design: A single-arm, open-label, multicenter study in 321 patients with imatinib-resistant or -intolerant Ph+ CML-CP and 137 patients with Ph+ CML-AP. Patients received TASIGNA 400 mg bid for a minimum follow-up of 24 months. The definition of imatinib resistance included failure to achieve CHR (by 3 months), cytogenetic response (by 6 months), or MCyR (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of MCyR at time of study entry. The efficacy end point in CML-CP was unconfirmed MCyR, which included complete and partial cytogenetic responses.The efficacy end point in CML-AP was confirmed HR, defined as either a CHR or NEL.²

MCyR, major cytogenetic response (MCyR = CCyR + PCyR); CCyR, complete cytogenetic response (0% Ph+ metaphases); PCyR, partial cytogenetic response (1%-35% Ph+ metaphases); HR, hematologic response; CHR, complete hematologic response; NEL, no evidence of leukemia.

IMPORTANT SAFETY INFORMATION FOR TASIGNA® (nilotinib) Capsules

WARNING: QT PROLONGATION AND SUDDEN DEATHS

TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and following any dose adjustments
Sudden deaths have been reported in patients receiving nilotinib. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome
Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors
Avoid food 2 hours before and 1 hour after taking dose

CONTRAINDICATIONS

Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

WARNINGS AND PRECAUTIONS

Myelosuppression
Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform complete blood counts every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or dose reduction.
QT Prolongation
TASIGNA prolongs the QT interval. ECGs should be performed at baseline, 7 days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.

Significant prolongation of the QT interval may occur when TASIGNA is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.
Sudden Deaths
Sudden deaths have been reported in patients with resistant or intolerant Ph+ CML receiving nilotinib. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
Cardiac and Arterial Vascular Occlusive Events
Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed Ph+ CML patients and observed in the post-marketing reports of patients receiving nilotinib therapy. Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events.

If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during TASIGNA therapy according to standard guidelines.
Pancreatitis and Elevated Serum Lipase
TASIGNA can cause increases in serum lipase. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.
Hepatotoxicity
TASIGNA may result in hepatotoxicity as measured by elevations in bilirubin, AST/ALT, and alkaline phosphatase. Monitor hepatic function tests monthly or as clinically indicated.
Electrolyte Abnormalities
The use of TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating TASIGNA and these electrolytes should be monitored periodically during therapy.
Drug Interactions
Avoid administration of TASIGNA with agents that may increase nilotinib exposure (eg, strong CYP3A4 inhibitors) or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide). Should treatment with any of these agents be required, interrupt therapy with TASIGNA. If interruption of treatment with TASIGNA is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval.

The concomitant use of QT-prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of TASIGNA.

Drugs that affect gastric pH
Nilotinib has pH-dependent solubility, with decreased solubility and reduced bioavailability at higher pH. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TASIGNA is not recommended.

When the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of TASIGNA. If necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of TASIGNA.
Food Effects
The bioavailability of nilotinib is increased with food, thus TASIGNA must not be taken with food. No food should be consumed for at least 2 hours before and for at least 1 hour after the dose is taken. Also avoid grapefruit products and other foods that are known to inhibit CYP3A4.
Hepatic Impairment
Nilotinib exposure is increased in patients with impaired hepatic function. Use a lower starting dose for patients with mild to severe hepatic impairment (at baseline) and monitor the QT interval frequently.
Tumor Lysis Syndrome
Tumor lysis syndrome cases have been reported in TASIGNA-treated patients with resistant or intolerant Ph+ CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA.
Hemorrhage
Grade 3/4 hemorrhage from various sites including GI were reported in patients with newly diagnosed Ph+ CML and observed in the postmarketing reports of patients receiving TASIGNA. Monitor patients for signs of hemorrhage and evaluate etiology during therapy with TASIGNA.
Total Gastrectomy
Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy.
Lactose
Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.
Monitoring Laboratory Tests
Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose should be checked prior to therapy and periodically. ECGs should be obtained at baseline, 7 days after initiation and periodically thereafter, as well as following dose adjustments.

Monitor lipid profiles and glucose periodically during the first year of TASIGNA therapy and at least yearly during chronic therapy. Assess glucose levels before initiating treatment with TASIGNA and monitor during treatment as clinically indicated. If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.
Embryo-Fetal Toxicity
Advise patients that the use of TASIGNA during pregnancy may cause harm to the fetus and that TASIGNA should not be taken during pregnancy unless necessary. Sexually active female patients taking TASIGNA should use adequate contraception to avoid pregnancy.
Fluid Retention
Grade 3/4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported in patients with newly diagnosed Ph+ CML receiving TASIGNA and observed in the postmarketing reports of patients receiving TASIGNA. Monitor patients for signs of severe fluid retention (eg, unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (eg, shortness of breath); evaluate etiology and treat patients accordingly.
ADVERSE REACTIONS
The most commonly reported non-hematologic adverse reactions (≥20% in patients with newly diagnosed Ph+ CML-CP, resistant or intolerant Ph+ CML-CP, or resistant or intolerant Ph+ CML-AP) were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats.

Hematologic adverse drug reactions (all grades) include myelosuppression: thrombocytopenia, neutropenia, and anemia.
DOSE ADJUSTMENTS OR MODIFICATIONS
TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe non-hematologic toxicities, laboratory abnormalities (lipase, bilirubin, or hepatic transaminase elevations) or concomitant use of strong CYP3A4 inhibitors.

Please see full Prescribing Information, including Boxed WARNING.

TWO WAYS TO HELP PATIENTS SAVE

3 months free for all patients new to TASIGNA® (nilotinib)
(see voucher for full details)
Monthly co-pay assistance with the Universal Co-Pay Card*

*Limitations apply. See Program Terms and Conditions. This offer is not valid under Medicare, Medicaid, or any other federal or state program. Novartis reserves the right to rescind, revoke, or amend this program without notice.

TASIGNA® (nilotinib) is indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates
TASIGNA is indicated for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. The effectiveness of TASIGNA is based on hematologic and cytogenetic response rates

TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and following any dose adjustments
Sudden deaths have been reported in patients receiving nilotinib. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome
Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors
Avoid food 2 hours before and 1 hour after taking dose

Myelosuppression: Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter
Cardiac and Arterial Vascular Occlusive Events: Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported
Pancreatitis and Elevated Serum Lipase: TASIGNA can cause increases in serum lipase. Caution is recommended in patients with a history of pancreatitis
Hepatotoxicity: The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase
Electrolyte Abnormalities: TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia
Drug Interactions:
- The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs and other drugs that may prolong the QT interval should be avoided. Grapefruit products should also be avoided
- The concomitant use of strong CYP3A4 inducers should be avoided. The concomitant use of proton pump inhibitors with TASIGNA is not recommended
- When the concurrent use of a H2 blocker is necessary, administer approximately 10 hours before and approximately 2 hours after the TASIGNA dose. If necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the TASIGNA dose
Food Effects: TASIGNA must be taken on an empty stomach. No food should be consumed for at least 2 hours before the dose and for at least 1 hour after the dose is taken
Hepatic Impairment: TASIGNA exposure is increased in patients with impaired hepatic function
Tumor Lysis Syndrome: Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients who were resistant or intolerant to prior CML therapy. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA
Hemorrhage: Grade 3/4 hemorrhage from various sites including GI were reported in patients receiving TASIGNA
Total Gastrectomy: The exposure of TASIGNA is reduced in patients with total gastrectomy
Lactose: Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption
Monitoring Laboratory Tests: Chemistry panels, including electrolytes, calcium, magnesium, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically
Embryo-Fetal Toxicity: Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do
Fluid Retention: Grade 3/4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported in patients receiving TASIGNA
ADVERSE REACTIONS: The most commonly reported non-hematologic adverse reactions (≥20% in patients) were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia and anemia
DOSE ADJUSTMENTS OR MODIFICATIONS: TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe non-hematologic toxicities, laboratory abnormalities or concomitant use of strong CYP3A4 inhibitors

Please see full Prescribing Information, including Boxed WARNING.

References: 1. Data on file. Study no. CAMN107A2303. Novartis Pharmaceuticals Corp; 2014. 2. TASIGNA [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2016. 3. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26(10):2197-2203.