New five-year data support superiority of Novartis drug Tasigna® over Gleevec® in newly diagnosed Ph+ CML patients

EAST HANOVER, N.J., Dec. 8, 2013 /PRNewswire/ -- Findings from three large, randomized Phase III studies demonstrate the superiority of Tasigna^® (nilotinib) compared to Gleevec^® (imatinib mesylate) tablets* at achieving deeper molecular responses across various Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) patient populations, including newly diagnosed patients, patients with residual disease who switched to Tasigna after long-term treatment with Gleevec, and patients who failed to respond to frontline Gleevec (as defined by 2013 European LeukemiaNet [ELN] guidelines)^1,2,3,4.

These results, which were presented in oral sessions at the 55^th annual meeting of the American Society of Hematology (ASH) in New Orleans, add to the growing body of evidence confirming the superiority of Tasigna to Gleevec at achieving molecular response in Ph+ CML patients^1,2,3.

"These new and updated data reaffirm the superiority of Tasigna over Gleevec at achieving deeper molecular responses and provide even more evidence supporting Tasigna as an appropriate treatment of choice in newly diagnosed patients and in those who switch to Tasigna after long-term treatment with Gleevec," said Giuseppe Saglio, MD, ENEST studies investigator, Professor of Internal Medicine and Haematology and Director of the Department of Molecular Medicine and Targeted Therapy at San Luigi Hospital, University of Turin, Italy. "Now we are looking at how deeper molecular responses may help guide our approach towards how we treat CML in the future."

Presented at ASH were the five-year ENESTnd data, which continued to support the use of Tasigna in newly diagnosed Ph+ CML patients and demonstrated higher rates of early and deeper sustained molecular response, including MR4.5, and a reduced risk of progression compared to Gleevec¹. The difference in the rates of both MR4 and MR4.5 continued to be higher for both Tasigna 300 mg and 400 mg twice daily arms compared to Gleevec (MR4: 9-14% difference by one year, 21-24% difference by five years; MR4.5: 6-10% difference by one year, 21-23% difference by five years)¹. Data indicated a trend for higher overall survival (OS) and event-free survival (EFS) rates in patients treated with Tasigna compared to patients treated with Gleevec. Fifteen patients treated with Gleevec had CML-related deaths, compared to six and four patients on the Tasigna 300 mg and 400 mg twice daily arms, respectively. Few new adverse events (AEs) and laboratory abnormalities were observed between four and five years. Rates of patients with AEs leading to discontinuation were 11.1%, 17.7% and 13.2% in the Tasigna 300 mg twice daily, Tasigna 400 mg twice daily and Gleevec arms, respectively¹.

In a separate follow-up analysis, results from the 36-month ENESTcmr data continued to show that Ph+ CML patients with residual disease following long-term treatment with Gleevec achieved deeper molecular responses^** after switching to Tasigna². Among patients without documented MR4.5 at baseline, cumulative incidence of MR4.5 was higher in patients randomized to Tasigna versus Gleevec (46.9% vs. 33.3%; nominal p=0.0453). MR4.5 was achieved faster with median time to response of 24.0 months in the Tasigna arm and was not reached in the Gleevec arm (nominal p=0.0011). The safety profiles for Tasigna and Gleevec were consistent with prior studies². By 36 months, no patients in either arm progressed to accelerated phase/blast crisis (AP/BC)².

Also presented were results from the LASOR study, which demonstrated higher rates of molecular response in patients who failed to achieve a cytogenetic response (CCyR) with frontline Gleevec (patients who do not achieve CCyR by six months, have loss of response at any time or have intolerance) who switched to Tasigna, versus those who dose escalated on Gleevec (600 mg daily)³. While the primary endpoint of CCyR at six months after randomization, which was confounded by high rates of crossover to Tasigna from the Gleevec arm, did not achieve statistical significance (p=0.3844), the clinical benefit of Tasigna was best evaluated when considering cross-over patients as non-responders³. A sensitivity analysis conducted supported the efficacy of Tasigna over Gleevec. The safety profile for both drugs was consistent with prior reports of patients who switched therapy after inadequate responses to Gleevec³.

"Today, we know from clinical studies that patients who achieve and maintain deep levels of response, known as MR4.5, do not progress to the advanced stages of CML," said Herve Hoppenot, President, Novartis Oncology. "These large studies continue to establish the benefits of Tasigna at achieving deeper molecular responses and we are committed to exploring the impact this may have on how we treat CML in the future."

Novartis Commitment to CML
Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition and today, the company continues its long-standing commitment to the global CML community. The Novartis treatment-free remission (TFR) clinical trial program includes eight studies that are now underway and actively enrolling Ph+ CML patients in more than 100 study centers across 40 countries⁵. In total, it is planned that more than 2,500 patients will be enrolled in these studies⁵.

Stopping treatment is not a clinical recommendation and should only be attempted in the context of a well-controlled clinical study⁶. A very important part of these TFR studies is the inclusion of regular molecular monitoring with International Scale Real-Time Quantitative Polymerase Chain Reaction (IS RT-Q-PCR) testing. Once treatment is stopped, molecular monitoring is used to identify if a patient's level of disease remains in deep molecular response or if the reintroduction of treatment is needed⁷.

ENESTnd study details¹
ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) is a Phase III, randomized, open-label, multicenter trial comparing the efficacy and safety of Tasigna versus Gleevec in adult patients with newly diagnosed Ph+ CML in chronic phase. It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients.

The study is being conducted at 217 global sites with 846 patients enrolled. Patients were randomized to receive Tasigna 300 mg twice daily (n=282), Tasigna 400 mg twice daily (n=281) or Gleevec 400 mg once daily (n=283). The primary endpoint was major molecular response (MMR) at 12 months; the key secondary endpoint was durable MMR at 24 months (patients having MMR when evaluated at both 12 and 24 months). MMR was defined in this study as 0.1% or less of BCR-ABL as measured by IS RT-Q-PCR. Patients on the Gleevec treatment arm who had suboptimal response or treatment failure were allowed to escalate dose and/or switch to Tasigna in a separate extension study. These data, presented at ASH, were the five-year (defined as 60 cycles of 28 days) follow-up.

The five-year ENESTnd update found that higher rates of MMR, MR4 and MR4.5 by five years were achieved in Tasigna versus Gleevec-treated patients. The difference in the rates of both MR4 and MR4.5 continued to be higher for both Tasigna 300 mg and 400 mg twice daily arms compared to Gleevec (MR4: 9-14% difference by one year, 21-24% difference by five years; MR4.5: 6-10% difference by one year, 21-23% difference by five years). Fewer patients progressed to AP/BC on Tasigna versus Gleevec. The estimated rates of patients whose disease did not progress to AP/BC at 60 months in the Gleevec, Tasigna 300 mg and Tasigna 400 mg twice daily arms were 95.2%, 99.3% and 98.7%, respectively. The estimated rates of patients without on-treatment event (no death, progression to AP/BC, loss of partial cytogenetic response [PCyR], loss of CCyR or loss of complete hematologic response [CHR]) at 60 months in the Gleevec, Tasigna 300 mg and Tasigna 400 mg twice daily arms were 92.6%, 95.0% and 97.4%, respectively. The estimated rates of patients who are alive (OS) at 60 months in the Gleevec, Tasigna 300 mg and Tasigna 400 mg twice daily arms were 91.6%, 93.6% and 96.0%, respectively. The estimated rates of patients who didn't die from a CML-related cause at 60 months in the Gleevec, Tasigna 300 mg and Tasigna 400 mg twice daily arms were 93.7%, 97.7% and 98.5%, respectively. The safety profiles for both drugs were consistent with previous ENESTnd reports.

ENESTcmr study details² 
ENESTcmr (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Complete Molecular Response) is an open-label, randomized, prospective, multi-center, Phase III study of Tasigna 400 mg twice daily versus Gleevec (400 mg or 600 mg once daily) comparing kinetics of molecular response for patients with Ph+ CML in chronic phase who had achieved CCyR but were still BCR-ABL positive (i.e., had evidence of residual leukemia) after at least two years of treatment with Gleevec. The study enrolled 207 patients. The patients were randomized into one of two treatment arms: Tasigna 400 mg twice daily versus continuing Gleevec 400 mg or 600 mg once daily (same dose as at study entry).

The primary endpoint was the rate of best confirmed complete molecular response by 12 months of study therapy with Tasigna or Gleevec. Secondary objectives included the kinetics of molecular response, duration of molecular response, progression-free survival (PFS) and OS in both arms and were previously presented. After 24 months on study, Gleevec patients who did not achieve undetectable BCR-ABL transcript levels had the option to cross over to the Tasigna arm. Overall, 45 Gleevec patients (44.6%) crossed over to Tasigna in the 36-month follow up. These data, presented at ASH, were the 36-month follow-up.

More patients treated with Tasigna continued to achieve deeper molecular responses versus Gleevec. Among patients without documented MR4.5 at baseline, cumulative incidence of MR4.5 was higher in patients randomized to Tasigna versus Gleevec (46.9% vs. 33.3%; nominal p=0.0453). Seven out of the 32 responders in the Gleevec arm achieved MR4.5 after crossing over to Tasigna. Patients randomized to Tasigna achieved MR4.5 faster than those who remained on Gleevec. Estimated median time to achieve MR4.5 was 24.0 months in the Tasigna arm. In this 36-month follow-up, the estimated median time has not been reached in the Gleevec arm (nominal p=0.0011). The safety profiles for Tasigna and Gleevec were consistent with prior studies. By 36 months, no patients in either arm progressed to AP/BC.

LASOR study details³
LASOR (Imatinib Dose Optimization versus Nilotinib in CML Patients with Suboptimal Response to Imatinib) is a global, randomized, Phase III study comparing the efficacy of Tasigna 400 mg twice daily to Gleevec 600 mg once daily in 191 patients with Ph+ CML in the chronic phase who have a failed cytogenetic response to Gleevec (400 mg once daily). Patients were randomized to receive Tasigna 400 mg twice daily (n=96) or to dose escalate to Gleevec 600 mg once daily (n=95). At the initiation of the study, these patients were considered to be suboptimal cytogenetic responders by ELN guidelines, however are now classified as treatment failures by updated recommendations⁴.

The primary endpoint of the study was CCyR at six months, with a secondary endpoint of MMR at 12 months. Crossover to alternate treatment was allowed before and after the primary endpoint in patients who failed to achieve CCyR by six months or had loss of response or had intolerance to Gleevec dose escalation at any time, consistent with standard of care.

Complete cytogenetic response at six months was observed in 47 (49%) and 40 (42.9%) patients in the Tasigna and Gleevec arms, respectively (p=0.3844). The primary endpoint did not achieve statistical significance likely because of the confounding effects of crossover occurring before primary endpoint analysis. The most frequent reasons for crossover from Gleevec to Tasigna were lack of efficacy (no CCyR after six months) in 28 (30%) patients, intolerance to Gleevec dose escalation in 17 (18%) patients, loss of response in 10 (11%) patients, and other in one (1%) patient. While none of the patients who crossed over from Tasigna to Gleevec achieved CCyR at six months, six Gleevec patients who crossed over to Tasigna did achieve this primary endpoint. The key secondary endpoint of MMR at 12 months was achieved in 35 (36.5%) and 24 (25.3%) patients in the Tasigna and Gleevec arms, respectively. Up until the data cut-off, 56 patients crossed over from Gleevec to Tasigna and 13 patients crossed over from Tasigna to Gleevec. Counting cross-over patients as non-responders, a greater number of patients on Tasigna achieved MMR at 12 months versus Gleevec (34 [35.4%; 95% confidence interval (CI) 32-52%] versus 15 [15.8%; 95% CI 12-28%], respectively). The safety profiles for both drugs were consistent with prior reports of patients who switched therapy after inadequate responses to Gleevec.

TASIGNA^® (nilotinib) Indication(s) 
TASIGNA is a prescription medicine used to treat adults with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The efficacy of TASIGNA is based on major molecular response and cytogenetic response rates. The study is on-going and more data will be needed to determine long-term outcomes.

TASIGNA is also used to treat chronic phase or accelerated phase Ph+ CML in adults who are no longer benefiting from previous other treatments, including imatinib (GLEEVEC^®), or have taken other treatments, including imatinib (GLEEVEC) but cannot tolerate them. The efficacy of TASIGNA is based on hematologic response and cytogenetic response rates.

TASIGNA^® (NILOTINIB) CAPSULES IMPORTANT SAFETY INFORMATION

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 CML treated with TASIGNA in clinical studies (n=5661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of TASIGNA suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

Elevated Serum Lipase 
Caution is recommended in patients with a history of pancreatitis. 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 
Serum bilirubin and hepatic transaminases 
The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.

Electrolyte Abnormalities
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 
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.

Concomitant strong CYP3A4 inhibitors 
The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted. 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. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. If the strong inhibitor is discontinued, a washout period should be allowed before TASIGNA is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.

Concomitant strong CYP3A4 inducers 
The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital). Patients should also refrain from taking St. John's wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of TASIGNA when co-administered with such agents is unlikely to compensate for the loss of exposure. TASIGNA is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9 and decrease the concentrations of drugs that are eliminated by these enzymes. Single-dose administration of TASIGNA to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of TASIGNA to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering TASIGNA with substrates for these enzymes that have a narrow therapeutic index. TASIGNA inhibits human P-glycoprotein (Pgp). If TASIGNA is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.

Drugs that affect gastric 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 
Food increases blood levels of TASIGNA. Patients should avoid food for at least 2 hours before and for at least 1 hour after the dose is taken.

Hepatic Impairment 
Nilotinib exposure is increased in patients with impaired hepatic function.

Tumor Lysis Syndrome 
Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell counts, and/or dehydration were present in most of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA.

Total Gastrectomy 
The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered 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.

Use in Pregnancy  
No adequate and well-controlled studies of TASIGNA in pregnant women exist. However, TASIGNA may cause fetal harm when administered to a pregnant woman. 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.

ADVERSE REACTIONS 
In patients with newly diagnosed Ph+ CML-CP 
The most common (>10%) nonhematologic adverse drug reactions (ADRs) were rash, pruritus, headache, nausea, fatigue, and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, pain in extremity, dyspepsia and asthenia were observed less commonly (<= 10% and >5%) and have been mild to moderate in severity, manageable, and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% and <1% of patients, respectively. Gastrointestinal hemorrhage was reported in 2.5% of patients.

The most common hematologic ADR (all grades) was myelosuppression, including thrombocytopenia (18%), neutropenia (15%), and anemia (7%).

In patients with resistant or intolerant Ph+ CML-CP and CML-AP 
In chronic phase patients, the most commonly reported nonhematologic ADRs (>=10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia. The common serious ADRs (>=1% and <10%) were thrombocytopenia, neutropenia, and anemia.

In accelerated phase patients, the most commonly reported nonhematologic ADRs (>=10%) were rash, pruritus, and fatigue. The common serious ADRs (>=1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia.

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 nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors.

For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily.

Hepatic Impairment 
If possible, consider alternative therapies. If TASIGNA must be administered to patients with hepatic impairment, a lower starting dose is recommended and QT interval should be monitored. The following dose reductions should be considered:

Newly diagnosed Ph+ CML-CP 
For patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe hepatic impairment (Child-Pugh Class C), an initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability should be considered. 

Resistant or intolerant Ph+ CML-CP and CML-AP 
For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability should be considered.

OTHER PATIENTS IN WHOM TASIGNA SHOULD BE USED WITH CAUTION

TASIGNA should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast-feed while taking TASIGNA. The safety and effectiveness of TASIGNA in pediatric patients have not been established.

Please see accompanying full Prescribing Information including Boxed WARNING.

About Gleevec 
Gleevec^® (imatinib mesylate) tablets are indicated for newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP). Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha therapy.

GLEEVEC Important Safety Information 
GLEEVEC can cause fetal harm when administered to a pregnant woman.  Women should not become pregnant, and should be advised of the potential risk to the unborn child.

GLEEVEC is often associated with edema (swelling) and serious fluid retention. Studies have shown that edema (swelling) tended to occur more often among patients who are 65 and older or those taking higher doses of GLEEVEC.

Cytopenias (reduction or lack of certain cell elements in blood circulation), such as anemia, have occurred. If the cytopenia is severe, your doctor may reduce your dose or temporarily stop your treatment with GLEEVEC.

Severe congestive heart failure and left ventricle dysfunction have been reported, particularly in patients with other health issues and risk factors. Patients with heart disease or risk factors or history of renal failure will be monitored and treated for the condition.

Severe liver problems (hepatotoxicity) may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC.

Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. GI tumor sites may be the cause of this bleeding; therefore, GI symptoms should be monitored at the start of treatment.

In patients with hypereosinophilic syndrome (a condition with increased eosinophils, which are a type of white blood cell) and heart involvement, cases of heart disease (cardiogenic shock/left ventricular dysfunction) have been associated with the initiation of GLEEVEC therapy.

Skin reactions, such as fluid-filled blisters, have been reported with the use of GLEEVEC.
Clinical cases of hypothyroidism (reduction in thyroid hormones) have been reported in patients taking levothyroxine replacement with GLEEVEC.

Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use.

GI perforation (small holes or tears in the walls of the stomach or intestine), in some cases fatal, has been reported.

Growth retardation has been reported in children taking GLEEVEC. The long-term effects of extended treatment with GLEEVEC on growth in children are unknown.

Cases of tumor lysis syndrome (TLS), which refers to a metabolic and electrolyte disturbance caused by the breakdown of tumor cells, have been reported and can be life-threatening in some cases. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC.

Reports of motor vehicle accidents have been received in patients receiving GLEEVEC. Caution patients about driving a car or operating machinery.

Almost all patients treated with GLEEVEC experience side effects at some time. Some common side effects you may experience are fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash.

GLEEVEC is sometimes associated with stomach or intestinal irritation. GLEEVEC should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including deaths, of stomach or intestinal perforation (a small hole or tear).

If you are experiencing any of the mentioned side effects, please be sure to speak with your doctor immediately.

Do not take any other medications without talking to your doctor or pharmacist first, including Tylenol^® (acetaminophen); herbal products (St. John's wort, Hypericum perforatum); Coumadin^® (warfarin sodium); rifampin; erythromycin; metoprolol; ketoconazole; and Dilantin^® (phenytoin). Taking these with GLEEVEC may affect how they work, or affect how GLEEVEC works. 

You should also tell your doctor if you are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods that may affect how GLEEVEC works.

Please see full Prescribing Information.

Disclaimer 
The foregoing release contains forward-looking statements that can be identified by words such as "trend," "committed," "continues," "commitment," "underway," "planned," "will," or similar terms, or by express or implied discussions regarding potential new indications orlabeling for Tasigna or Gleevec, or regarding potential future revenues from Tasigna and Gleevec. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Tasigna or Gleevec will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that Tasigna and Gleevec will be commercially successful in the future. In particular, management's expectations regarding Tasigna and Gleevec could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; unexpected manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis 
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets innovative prescription drugs used to treat a number of diseases and conditions, including cardiovascular, dermatological, central nervous system, bone disease, cancer, organ transplantation, psychiatry, infectious disease and respiratory. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2012, the Group achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 133,000 full-time equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis at http://twitter.com/novartis.

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* Known as Glivec^® (imatinib) outside the US, Canada and Israel.

^** In ENESTcmr, molecular response (reduction of BCR-ABL transcripts in the blood of patients) is measured at four levels, based on an international standard:

• MMR (<= 0.1% BCR-ABL)
• MR4 (<= 0.01% BCR-ABL)
• MR4.5 (<= 0.0032% BCR-ABL)
• Undetectable BCR-ABL (no detectable BCR-ABL transcript level with sample sensitivity of at least 4.5 log)

References

1. Saglio G, et al. ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes. Abstract #92. 2013 American Society of Hematology Annual Meeting, New Orleans, LA.
2. Leber B, et al. Achievement and Maintenance Of Deeper Molecular Response By Switching To Nilotinib In Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) With Residual Disease On Long-Term Imatinib:  ENESTcmr 36-Month Follow-Up. Abstract #94. 2013 American Society of Hematology Annual Meeting, New Orleans, LA.
3. Cortes J, et al. Switching To Nilotinib In Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) With Suboptimal Cytogenetic Response (CyR) On Imatinib: First Results Of The LASOR Trial. Abstract #95. 2013 American Society of Hematology Annual Meeting, New Orleans, LA.
4. Baccarani M, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. Pre-published online June 26, 2013.
5. Novartis data on file.
6. National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, V4.2013.  Available at: http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf.
7. Kim, D. Recent advances in the path toward the cure for chronic myeloid leukemia. The Korean Journal of Hematology. 2011; 46(3), 169-174.

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