FDA Approves Tasigna® for Newly Diagnosed Chronic Myeloid Leukemia Patients, Data Demonstrate Major Advance Over Gleevec®

EAST HANOVER, N.J., June 17 /PRNewswire/ -- Following a priority review, the US Food and Drug Administration (FDA) has approved Tasigna® (nilotinib) 150 mg capsules for the treatment of adult patients with newly diagnosed 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. The study is ongoing and further data will be required to determine long-term outcome. With this approval, Tasigna becomes the first new therapeutic option for newly diagnosed patients since the introduction of Gleevec® (imatinib mesylate) tablets*, providing a major advance for patients with this blood cancer.

To view the multimedia assets associated with this release, please click: http://multivu.prnewswire.com/mnr/novartis/44658/

The US approval was based on results of the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients) Phase III clinical trial, which were published today in The New England Journal of Medicine (NEJM).

"With the faster and deeper responses we are seeing with Tasigna, newly diagnosed CML patients will have a new and more effective treatment option," said Herve Hoppenot, President, Novartis Oncology.

Tasigna is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML(2,3). It is also active against a broad spectrum of Bcr-Abl mutations associated with resistance to Gleevec(4). The first clinical trials of Tasigna began only 21 months after its discovery, with the drug receiving its first regulatory approval as a second-line treatment in 2007.

In its pivotal head-to-head trial against Gleevec, Tasigna demonstrated improved treatment efficacy, as has been previously reported. Tasigna reduced Bcr-Abl faster than Gleevec, resulting in lower rates of cancer progression even as early as 12 months(1). Deep reduction of Bcr-Abl, known as a major molecular response, is considered to be a critical therapeutic milestone associated with good long-term outcomes for patients with Ph+ CML(5-7). Treatment with Tasigna led to higher rates of both major molecular response and complete cytogenetic response (reduction in the level of Philadelphia chromosome that is the hallmark of this cancer) compared with Gleevec(1).

The randomized, open-label, multicenter ENESTnd trial compared the efficacy and safety of Tasigna versus Gleevec in adult patients with newly diagnosed Ph+ CML in chronic phase(1). It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients in chronic phase.

Two patients on the nilotinib arm progressed to either accelerated phase or blast crisis while 17 patients on the imatinib arm progressed to either accelerated phase or blast crisis. In the study, Tasigna was well tolerated. Fewer patients discontinued due to adverse events from the Tasigna 300 mg twice daily arm of the study compared to the Gleevec 400 mg once daily arm. No patients in the study had a prolongation of the QT interval >500 milliseconds(1). In addition, no sudden deaths occurred with either treatment(4).

Regulatory submissions for Tasigna in the first-line indication are under way worldwide, with applications currently filed in the EU, Switzerland and Japan.

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

About Tasigna

Tasigna® (nilotinib) is indicated for the treatment of adult patients with newly diagnosed 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. The study is ongoing and further data will be required to determine long-term outcome.

Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Tasigna has been approved in more than 80 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including Gleevec. The effectiveness of Tasigna for this indication is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Tasigna important safety information

Tasigna can cause a possible life-threatening heart problem called QTc prolongation. QTc prolongation causes an irregular heartbeat, which may lead to sudden death.

Your doctor should check the electrical activity of your heart with a test called an electrocardiogram (ECG):

• Before starting Tasigna
• 7 days after starting Tasigna
• With any dose changes
• Regularly during Tasigna treatment

You may lower your chances for having QTc prolongation with Tasigna if you:

• Take Tasigna:
  1. On an empty stomach. Do not take Tasigna with food.
  2. At least 2 hours after eating any food, and
  3. Wait at least 1 hour before eating any food
• Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract while taking Tasigna.  Food and grapefruit products increase the amount of Tasigna in your body.
• Avoid taking other medicines or supplements with Tasigna that can also cause QTc prolongation.
• Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects.
• Do not take any other medicine while taking Tasigna unless your doctor tells you it is okay to do so.

Call your doctor right away if you feel lightheaded, faint or have an irregular heartbeat while taking Tasigna. These can be symptoms of QTc prolongation.

What is Tasigna?

Tasigna is a prescription medicine used to treat a type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in adults who:

• Are newly diagnosed, or
• Are no longer benefiting from previous other treatments, including treatment with imatinib (Gleevec®), or
• Have taken other treatments, including imatinib (Gleevec®), and cannot tolerate them

It is not known if Tasigna is safe or effective in children.

Who should not take Tasigna?

Do not take if you have:

• Low levels of potassium or magnesium in your blood
• Long QTc syndrome

What should I tell my doctor before starting Tasigna?

Tasigna may not be right for you. Before taking Tasigna, tell your doctor about all of your medical conditions, including if you have:

• Heart problems
• Irregular heartbeat
• QTc prolongation or a family history of it
• Liver problems
• Had pancreatitis
• Low blood levels of potassium or magnesium in your blood
• A severe problem with lactose (milk sugar) or other sugars. The Tasigna capsules contain lactose. Most patients who have mild or moderate lactose intolerance can take Tasigna.
• Had a surgical procedure involving the removal of the entire stomach (total gastrectomy)
• Are pregnant or plan to become pregnant. Tasigna may harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment with Tasigna. Talk to your doctor about the best birth control methods to prevent pregnancy while you are taking Tasigna.
• Are breastfeeding or plan to breastfeed. It is not known if Tasigna passes into your breast milk. You and your doctor should decide if you will take Tasigna or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non prescription medicines, vitamins and herbal supplements.

Tasigna can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects. See "What is the most important information I should know about Tasigna?"

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take Tasigna?

• Take Tasigna exactly as your doctor tells you to take it. Do not change your dose or stop taking Tasigna unless your doctor tells you.
• Tasigna is a long-term treatment.
• Your doctor will tell you how many Tasigna capsules to take and when to take them.
• Do not take Tasigna with food. Take Tasigna at least 2 hours after you eat and at least 1 hour before you eat.
• Swallow Tasigna capsules whole with water. If you cannot swallow Tasigna capsules whole, tell your doctor.
• Do not drink grapefruit juice, eat grapefruit, or take supplements containing grapefruit extract at any time during treatment. See "What is the most important information I should know about Tasigna?"
• If you miss a dose, just take your next dose as scheduled. Do not make up for a missed dose.
• If you take too much Tasigna, call your doctor or poison control center right away. Symptoms may include vomiting and drowsiness. During treatment with Tasigna your doctor will do tests to check for side effects and to see how well Tasigna is working for you. The tests will check your:
  1. Heart
  2. Blood cells (white blood cells, red blood cells, and platelets). Your blood cells should be checked every two weeks for the first two months and then monthly.
  3. Electrolytes (potassium, magnesium)
  4. Pancreas and liver function
  5. Bone marrow samples
• Your doctor may change your dose. Your doctor may have you stop Tasigna for some time or lower your dose if you have side effects with it.

What are the possible side effects of Tasigna?

Tasigna may cause serious side effects including:

• See "What is the most important information I should know about Tasigna?"
• Low blood counts. Low blood counts are common with Tasigna. Your doctor will check your blood counts regularly during treatment with Tasigna. Symptoms of low blood counts include:
  1. Unexplained bleeding or bruising
  2. Blood in urine or stool
  3. Unexplained weakness
• Liver damage. Symptoms include yellow skin and eyes.
• Pancreas inflammation (pancreatitis). Symptoms include sudden stomach area pain with nausea and vomiting.
• Bleeding in the brain: Symptoms include sudden headache, changes in your eyesight, not being aware of what is going on around you and becoming unconscious.

The most common side effects of Tasigna include:

1. Low blood count
2. Rash
3. Nausea
4. Fever
5. Headache
6. Itching
7. Tiredness
8. Stomach (abdominal) pain
9. Diarrhea
10. Constipation
11. Muscle and joint pain
12. Back pain
13. Muscle spasms
14. Weakness
15. Hair loss
16. Runny or stuffy nose, sneezing, sore throat
17. Cough

About Gleevec(8)

Gleevec® (imatinib mesylate) tablets are indicated for the treatment of 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 is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening.

Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).

Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions.

In Ph+ CML trials,* severe (NCI Grades 3/4) lab abnormalities -- including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%) -- and severe adverse reactions (NCI Grades 3/4), including hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5%-11%) and superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%) were reported among patients receiving Gleevec. Severe fluid retention appears to be dose-related, was more common in the advanced phase studies (where the dosage was 600 mg/day), and is more common in the elderly.

Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.

Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic 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/day 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/day are not recommended. Gleevec should be used with caution in patients with severe renal impairment.

In the newly diagnosed CML trial, 2% of patients had (NCI Grades 3/4) hemorrhage.

There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and gastrointestinal (GI) perforation.

Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.

Consider potential toxicities -- specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.

Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus.

Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)

For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Common side effects of Gleevec tablets

The majority of adult patients with Ph+ CML who received Gleevec in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%).*+

Supportive care may help management of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with Gleevec may be necessary.

Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.

Patients should be informed to take Gleevec exactly as prescribed, not to change their dose or stop taking Gleevec unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose.

*Numbers indicate the range of percentages in 4 studies among adult patients with newly diagnosed Ph+ CML and patients in BC, AP, and CP after failure of interferon-alpha therapy.

+For more detailed study information, please see full Prescribing Information.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such "will," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Tasigna in additional markets, or regarding potential future revenues from Tasigna or Gleevec. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Tasigna or Gleevec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Tasigna will be approved for any additional indications or labeling in any additional markets. Nor can there be any guarantee that Tasigna or Gleevec will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Tasigna and Gleevec could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; competition in general; government, industry and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. 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

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2009, the Group's continuing operations achieved net sales of USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.

References

1. Giuseppe Saglio, M.D., Dong-Wook Kim, M.D., Ph.D., Surapol Issaragrisil, M.D., F.R.C.P., F.A.C.P., F.R.C.P.A., F.R.C.Path., Philipp le Coutre, M.D., Gabriel Etienne, M.D., Clarisse Lobo, M.D., Ricardo Pasquini, M.D., Richard E. Clark, M.A., M.D., F.R.C.P., F.R.C.Path., Andreas Hochhaus, M.D., Timothy P. Hughes, M.D., M.B.B.S., Neil Gallagher, M.D., Ph.D., Albert Hoenekopp, M.D., Mei Dong, M.D., M.S, Ariful Haque, M.S., Richard A. Larson, M.D., and Hagop M. Kantarjian, M.D.4 on behalf of the ENESTnd investigators - ENESTnd: A Randomized Comparison of Nilotinib and Imatinib for Newly Diagnosed Chronic Myeloid Leukemia – The New England Journal of Medicine. 2010 June 17;362(24):2251-2259.
2. Tasigna (nilotinib) Prescribing Information. East Hanover, New Jersey, USA: Novartis Pharma. http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf.
3. Novartis data on file.
4. Swords R, Mahalingam D, Padmanabhan S, et al. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib. Drug Des Devel Ther. 2009 Sep 21;3:89-101.
5. Hochhaus A, O'Brien SG, Guilhot F,et al. IRIS Investigators. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009 Jun;23(6):1054-61.
6. Muller MC, Hanfstein B, Erben P, et al.  Molecular response to first line imatinib therapy is predictive for long term event free survival in patients with chronic phase chronic myelogenous leukemia – an interim analysis of the randomized German CML Study IV. Blood (ASH Annual Meeting Abstracts) 2008., 112: Abstract 333.
7. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-51.
8. Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2008. http://www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf

SOURCE Novartis