Tasigna® receives US approval providing new hope to chronic myeloid leukemia patients with resistance or intolerance to existing therapies

  • Tasigna produced responses in 40% of patients with Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to prior treatment
  •  
  • Approval and availability in US means Novartis can offer physicians and patients a comprehensive treatment approach for this disease

East Hanover · October 29, 2007 /PRNewswire/ — Tasigna® (nilotinib) capsules have been approved in the US as a new therapy for certain patients with a life-threatening form of leukemia who are resistant or intolerant to prior treatment including Gleevec® (imatinib mesylate) tablets *, an established treatment standard and a leading Novartis medicine.

Novartis will make Tasigna available throughout the US within days following this approval by the Food and Drug Administration (FDA) to meet the treatment needs of these patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

CML is one of the four most common types of leukemia, a form of blood cancer, and affects around 4,500 people in the US each year1.

"Tasigna represents an important advance for the small number of patients who are resistant or intolerant to prior therapy," said David Epstein, President and CEO of Novartis Oncology. "This approval means we can offer physicians a comprehensive treatment approach with effective medicines to treat their Ph+ CML patients."

Taken twice daily, Tasigna works by inhibiting the proliferation of cells containing an abnormal chromosome. It does this by targeting the production of the Bcr-Abl protein, which is produced only by cells containing the abnormal Philadelphia chromosome. This protein is recognized as the key cause and driver of the overproduction of cancer-causing white blood cells in patients with Ph+ CML.

Tasigna was specifically designed to target the Bcr-Abl protein more preferentially than Gleevec without adding new targets. At six months follow-up, Tasigna reduced or eliminated cells carrying the abnormal Philadelphia chromosome in 40% of patients in chronic phase of the disease.

Applying experience gained from the development of Gleevec, which remains the most frequently prescribed treatment for patients with Ph+ CML, a team of Novartis scientists created Tasigna in August 2002, just a year after the launch of Gleevec. In preclinical studies, the medicine was able to overcome resistance resulting from Bcr-Abl kinase mutations in 32 of 33 cell lines commonly associated with Ph+ CML. Patients with a variety of these mutations also responded to treatment with Tasigna.

The first worldwide approval for Tasigna came in Switzerland in July 2007. European Union approval is expected by the end of this year after the Committee for Medicinal Products for Human Use (CHMP), which reviews medicines in Europe, issued a positive opinion in September. Tasigna was also submitted for approval in Japan in June.

Without treatment, CML typically progresses over three to five years from the initial (chronic) phase through a transition period (accelerated phase) to a rapidly fatal form (blast crisis)2. Recent landmark clinical trial results for Gleevec show that nearly 90% of newly diagnosed chronic-phase Ph+ CML adult patients treated with Gleevec were alive after five years3, but some develop resistance or cannot tolerate this therapy.

The FDA approved Tasigna for treatment of chronic-phase and accelerated-phase Ph+ CML in adult patients resistant or intolerant to prior treatment that included Gleevec. This approval is based on an open-label multicenter clinical trial evaluating the drug's safety and rates of cytogenetic response (i.e. reduction or elimination of the Philadelphia chromosome) and hematologic response (i.e. normalization of white blood cell counts) in Gleevec-resistant or -intolerant patients with Ph+ CML in chronic phase (n=280) and accelerated phase (n=105).

In clinical trials, the primary endpoint for patients in chronic phase was unconfirmed major cytogenetic response (MCyR). After a minimum follow-up of six months (median treatment duration 8.7 months), Tasigna produced MCyR in 40% of 232 chronic-phase patients evaluated for efficacy. The complete cytogenetic response in these patients was 28%.

For patients in accelerated phase, the primary endpoint was confirmed hematological response (HR). Complete HR was reported in 18% of patients in accelerated phase. (Accelerated-phase patients had a minimum follow-up of 4 months and a median treatment duration of 5.6 months).

The highest prior Gleevec dose was greater than or equal to 600 mg/day in 77% of patients with 44% of patients receiving doses of 800 mg/day or higher. In addition, 24 different mutations in Bcr-Abl were noted in 19% of chronic-phase and 25% of accelerated-phase CML patients who were evaluated for mutations.

Because taking Tasigna with food may increase the amount of drug in the blood, Tasigna should not be taken with food and patients should wait at least two hours after a meal before taking Tasigna. In addition, no food should be consumed for at least one hour after the dose is taken.

About Tasigna

Tasigna® (nilotinib) capsules are indicated for the treatment of chronic-phase and accelerated-phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included Gleevec® (imatinib mesylate) tablets. 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 important safety information

Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving Tasigna. Tasigna should not be used in patients with hypokalemia (low potassium levels), hypomagnesemia (low magnesium levels), or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food two hours before and one hour after taking dose. Use with caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

Warnings and precautions

Myelosuppression: Associated with neutropenia, thrombocytopenia and anemia. CBC should be done every 2 weeks for the first 2 months, then monthly. Reversible by withholding dose. Dose reduction may be required.

QT Prolongation: Tasigna prolongs the QT interval. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Use caution in patients with hepatic impairment. Obtain ECGs at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

Sudden deaths: There were sudden deaths reported in the safety population and the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence.

Elevated serum lipase: Caution is recommended in patients with history of pancreatitis. Check serum lipase periodically.

Liver function abnormality: Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Check hepatic function tests periodically.

Electrolyte abnormalities: Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy.

Hepatic impairment: Tasigna has not been investigated in patients with hepatic impairment. Caution is recommended in these patients and QT interval should be monitored closely.

Drug interactions: Avoid concomitant use of strong inhibitors or inducers of CYP3A4. If patients must be co-administered a strong CYP3A4 inhibitor, dose reduction should be considered and the QT interval should be monitored closely.

Food Effects: Food increases blood levels of Tasigna. Avoid food 2 hours before and 1 hour after a dose.

Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or of glucose-galactose malabsorption.

Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking Tasigna.

Adverse reactions

In chronic-phase CML patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritis, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In accelerated-phase CML patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus and constipation. The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Tasigna may need to be withheld and/or dose reduced for QT interval prolongation, myelosuppression, and certain non-hematologic laboratory abnormalities (e.g., Grade ≥ 3 elevated serum lipase or amylase, bilirubin and hepatic transaminases) as well as for other non-hematologic toxicities. Therapy with Tasigna was discontinued for drug-related adverse reactions in 11% and 8% of chronic-phase and accelerated-phase CML patients, respectively.

About Gleevec

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. Follow-up is limited to 5 years. Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferon-alpha therapy.

Gleevec important safety information4

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.

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 experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (1.3%-11%), hemorrhage (1.8%-19%), 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.

Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions. Therapy with Gleevec was discontinued for drug-related adverse reactions in 2.4% to 5% of patients.

A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.

Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, papilledema, 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.

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

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 Ph+ CML patients 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%), muscle cramps (28%-62%), vomiting (23%-58%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), and rash and related terms (36%-47%). ** †

Supportive care may help management of some mild-to-moderate adverse reactions so that the prescribed dose can be maintained whenever possible. 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.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "will," "should," "can," "expected," "may" or similar expressions, or by express or implied discussions regarding potential regulatory approvals, new indications or labeling for, or potential future sales of, Gleevec or Tasigna. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Gleevec or Tasigna 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 in the EU, Japan or any additional market; that Gleevec or Tasigna will be approved for any additional indications or labelling in any market; or that Gleevec or Tasigna will reach any particular level of sales. In particular, management's expectations regarding Gleevec or Tasigna 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; Novartis' ability to obtain or maintain patent or other proprietary intellectual property protection; unexpected delays due to manufacturing; competition in general; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the U.S. 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

Novartis AG (NYSE: NVS) is a world leader in offering medicines to protect health, cure disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. Novartis is the only company with leadership positions in these areas. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

References:

  1. American Cancer Society. Overview: Leukemia – Chronic Myeloid (CML).
    http://www.cancer.org/docroot/CRI/content/CRI_2_2_1x_How_Many_People_Get
    _Chronic_Myeloid_Leukemia.asp?rnav=cri
    Last accessed October, 2007.
  2. Faderl S; Talpaz M; Estrov Z; O'Brien S; Kurzrock R; Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 341:164-72, 1999.
  3. Druker, B. et al. Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. N Engl J Med 2006;355:2408-17.
  4. Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Sep 2007.

* Known as Glivec® (imatinib) outside the US, Canada and Israel.
** Numbers indicate the range of percentages in 4 studies among adult patients with Ph+ CML in blast crisis, accelerated phase, and chronic phase.
† For more detailed study information please see full Prescribing Information.

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