Tasigna (nilotinib hydrochloride monohydrate)
Company: Novartis
Approval Status: Approved October 2007
Treatment for: chronic myelogenous leukemia
Areas: Oncology
| General Information | Clinical Results | Side Effects | Mechanism of Action | Literature References | Additional Information |
General Information
Tasigna (nilotinib hydrochloride monohydrate) is an orally available signal transduction inhibitor of the Bcr-Abl kinase, c-kit and Platelet Derived Growth Factor (PDGF), all of which play a role in cell proliferation, cell migration, and angiogenesis.
Tasigna is specifically indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.
Tasigna is supplied as a 400 mg tablet designed for oral administration. The recommended initial dose of the drug is 400 mg orally twice daily, at approximately 12 hour intervals. No food should be consumed at least two hours before and one hour after administration of Tasigna. Dose adjustments or modifications should be followed according to the label for subjects with ECGs with a QTc > 480 msec, for subjects with neutropenia and/or thrombocytopenia and for subjects with selected non-hematologic laboratory abnormalities. The concomitant use of strong CYP3A4 inhibitors and strong CYP3A4 inducers should be avoided.
Clinical Results
FDA Approval
FDA approval of Tasigna was based on the results of a clinical
trial. This open-label, multi-center trial enrolled subjects with
imatinib-resistant or -intolerant CML with separate cohorts for
chronic phase (CML-CP) and accelerated phase (CML-AP) disease.
Overall 280 CML-CP subjects with a minimum follow-up of 6 months
and 105 CML-AP subjects with a minimum follow-up of 4 months were
enrolled. The efficacy endpoint in the CML-CP arm was unconfirmed
major cytogenetic response (MCyR) which included complete and
partial cytogenetic responses. A major cytogenetic response was
observed in 40% of the subjects. Complete response was observed in
28% and partial response was observed in 12% of this group. The
efficacy endpoint in the CML-AP arm confirmed hematologic response
(HR), defined as either a complete hematologic response (CHR) or no
evidence of leukemia (NEL). A confirmed hematologic response was
observed in 26%, with 18% showing a complete hematologic response
and 8% showing no evidence of leukemia. Median duration of response
had not been reached at this time for either group. However, based
on current data, 59% of the CML-CP subjects with a major
cytogenetic response had a duration of response of at least 6
months and 63% of CML-AP subjects with a confirmed hematologic
response had a duration of response of at least 6 months.
Ongoing Study Commitments
- Novartis has agreed to submit the complete study report (with
at least 24 months follow-up of all patients) and data from study
2101, a phase 2 multicenter study of nilotinib in patients with
imatinib resistant or intolerant chronic myeloid leukemia in
chronic and accelerated phases respectively (arms 4 & 3,
respectively).
Protocol Submission: Study 2101 filed to IND 69,764 in April 2004
Study Start: May 2004
Final Report Submission: by August 2010 - Novartis has agreed to submit the completed study report and
datasets for the hepatic impairment study.
Protocol Submission: Study 2116 filed to IND 69,764 on 10/9/06
Study Start: October 2006
Final Report Submission: by June 2008 - Novartis has agreed to conduct a relative bioavailability study
(using a liquid formulation as the reference).
Protocol Submission: by August 2009
Study Start: by November 2009
Final Report Submission: by July 2010 - Novartis has agreed to Conduct a clinical study or studies to
evaluate whether multiple doses of nilotinib alter the metabolism
of a sensitive CYP2C9 substrate (for example, S-warfarin). If a
significant interaction is demonstrated, additional clinical
studies may be needed to evaluate whether multiple doses of
nilotinib alter the metabolism of a sensitive CYP2C8 substrate (for
example, repaglinide) and/or a sensitive CYP3A4 substrate (for
example, midazolam).
Protocol Submission: by July 2008
Study Start: by September 2008
Final Report Submission: by June 2009 - Novartis has agreed to conduct a clinical study to evaluate if
H2 blockers/proton pump inhibitors alter the pharmacokinetics of
nilotinib.
Protocol Submission: by July 2008
Study Start: by September 2008
Final Report Submission: by June 2009
Side Effects
Adverse events associated with the use of Tasigna in CML-CP patients may include, but are not limited to, the following:
- Rash
- Pruritis
- Nausea
- Fatigue
- Headache
- Constipation
- Diarrhea
- Vomiting
- Thrombocytopenia
- Neutropenia
Adverse events associated with the use of Tasigna in CML-AP patients may include, but are not limited to, the following:
- Rash
- Pruritus
- Constipation
- Thrombocytopenia
- Neutropenia
- Pneumonia
- Febrile neutropenia
- Leukopenia
- Intracranial hemorrhage
- Elevated lipase
- Pyrexia
Mechanism of Action
Tasigna (nilotinib hydrochloride monohydrate) is an orally available signal transduction inhibitor of the Bcr-Abl kinase, c-kit and Platelet Derived Growth Factor (PDGF). Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model.
Literature References
Breccia M, Cannella L, Nanni M, Stefanizzi C, Alimena G Nilotinib can override dasatinib resistance in chronic myeloid leukemia patients with secondary resistance to imatinib first-line therapy. Acta haematologica 2007;118(3):162-4. Epub 2007 Sep 20
Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007 Nov 15;110(10):3540-6. Epub 2007 Aug 22
Belloc F, Moreau-Gaudry F, Uhalde M, Cazalis L, Jeanneteau M, Lacombe F, Praloran V, Mahon FX. Imatinib and nilotinib induce apoptosis of chronic myeloid leukemia cells through a bim-dependant pathway modulated by cytokines Cancer biology & therapy 2007 Jun;6(6):912-9
Golemovic M, Verstovsek S, Giles F, Cortes J, Manshouri T, Manley PW, Mestan J, Dugan M, Alland L, Griffin JD, Arlinghaus RB, Sun T, Kantarjian H, Beran M AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 2005 Jul 1;11(13):4941-7
Additional Information
For addiitonal information regarding tasigna or chronic myelogenous leukemia, please visit the Tasigna web page.
The FDA drug information shown here is licensed from Thomson CenterWatch. The information provided here is for general educational purposes only and does not constitute medical or pharmaceutical advice which should be sought from qualified medical and pharmaceutical advisers.
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