Date: 2017-12-22

Type of information: Granting of a Market Authorisation in the EU

Product name: Tasigna®

Compound: nilotinib

Therapeutic area: Cancer - Oncology

Action mechanism:

  • tyrosine kinase inhibitor. Tasigna® (nilotinib) 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.

Company: Novartis (Switzerland)

Disease: Philadelphia-chromosome-positive chronic myelogenous leukaemia (CML)

Latest news:

  • • On December 22, 2017, the FDA updated the product label for Tasigna® (nilotonib) to include information for providers about how to discontinue the drug in certain patients. With these updated dosing recommendations, patients with early phase CML who have been taking Tasigna® for three years or more, and whose leukemia has responded to treatment according to specific criteria as detected by a test that has received FDA marketing authorization, may be eligible to stop taking Tasigna®.
  • This action adds information to the product label for patients and health care providers regarding the conditions under which patients may be eligible to discontinue treatment and notes that if treatment is stopped patients must be regularly monitored for disease recurrence.
  • The information about discontinuing Tasigna® was based on two single-arm trials of patients with Ph+ chronic phase CML. The trials measured how long patients were able to stop taking Tasigna® without the leukemia returning (treatment-free remission, or TFR). In both trials, patients had to meet rigorous criteria showing how their cancer had responded to treatment before stopping Tasigna. An important part of both trials was regular and frequent monitoring of specific genetic (RNA) information that specifies the BCR-ABL protein level in the blood with a diagnostic test that has received FDA marketing authorization. Monitoring with a test able to detect reductions of specific RNA information with high accuracy and precision is critical to the safe discontinuation of Tasigna, as this monitoring provides the first signs of relapse. Common side effects in patients who discontinued Tasigna® include musculoskeletal symptoms such as body aches, bone pain and pain in extremities. Some patients experienced prolonged musculoskeletal symptoms.
  • • On September 14, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Tasigna® (nilotinib). The CHMP adopted an extension to the existing indication as follows: “Tasigna is indicated for the treatment of:
  • - adult and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia  in the chronic phase, - adult patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia with resistance or intolerance to prior therapy including imatinib. Efficacy data in patients with chronic myelogenous leukaemia in blast crisis are not available, - paediatric patients with chronic phase Philadelphia chromosome positive chronic myelogenous leukaemia with resistance or intolerance to prior therapy including imatinib
  • • On June 6, 2017, Novartis announced that the European Commission (EC) has approved the inclusion of Treatment-free Remission (TFR) data in the Tasigna® (nilotinib) Summary of Product Characteristics (SmPC). TFR is the ability to maintain molecular response (MR) after stopping tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients in chronic phase. Tasigna® is now the first and only TKI to include information on TFR in the European Union label. The approval  was based on efficacy and safety findings from the 48-week analyses of two open label trials, ENESTfreedom and ENESTop, which showed that more than 50% of Ph+ CML-CP patients who met the rigorous predefined response criteria of the trials were able to maintain TFR after stopping Tasigna® in both in the first-line setting and after switching from Glivec® (imatinib). No new major safety findings were observed in these studies at the 48-week analyses in patients treated with Tasigna® beyond those in the known safety profile of Tasigna®.
  • An important part of the ENESTfreedom and ENESTop trials was regular and frequent molecular monitoring of BCR-ABL levels with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5 (BCR-ABL1 International Scale [IS] <= 0.0032%). Frequent patient monitoring after discontinuation of Tasigna allows timely determination of loss of MR4.0 (BCR-ABL1 IS <= 0.01%) and major molecular response (MMR; BCR-ABL1 IS <= 0.1%) and need for treatment re-initiation.
  • • On June 27, 2014, the Committee for Medicinal Products for Human Use (CHMP) announced that, on 21 May 2014, Novartis officially notified the Committee that it wishes to withdraw its application for a new indication for Tasigna® to treat patients with Philadelphia-chromosome-positive chronic myelogenous leukaemia (CML) in whom treatment with another cancer medicine, imatinib, has not led to a ‘complete molecular response’. Tasigna® has been authorised in the EU since 19 November 2007. It is used to treat CML in patients who have the Philadelphia chromosome (Ph+ CML). It is used to treat the ‘chronic’ and ‘accelerated’ phases of CML in patients who have not responded to other treatments including imatinib or when they cannot tolerate these treatments. It is also used to treat newly diagnosed patients with CML in the chronic phase.Tasigna® was also expected to be used to treat adults with Ph+ CML in the chronic phase in whom treatment with imatinib did not lead to a ‘complete molecular response’. A complete molecular response is achieved when Bcr-Abl can no longer be detected in the patient’s blood. This would have meant that patients who had only partially responded to treatment with imatinib could have been switched to Tasigna®. In the new indication, Tasigna® was expected to work in the same way as it does in its existing indications by blocking Bcr-Abl kinase, an abnormal enzyme which is produced by leukaemia cells and causes them to multiply uncontrollably. Novartis presented the results from one main study with Tasigna® involving 207 patients with Ph+ CML in the chronic phase and who did not have a complete molecular response following imatinib treatment for at least two years. Patients in the study either received Tasigna® or had further treatment with imatinib. The main measure of effectiveness was based on the percentage of patients who had a complete molecular response during the first 12 months of the study. The application was withdrawn after the CHMP had evaluated the documentation provided by the company and formulated lists of questions. Based on the review of the data and the company’s response to the CHMP lists of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Tasigna® could not have been approved for the treatment of patients with Ph+ CML who did not have a complete molecular response following imatinib treatment. This was because the study failed to demonstrate that treatment with Tasigna® significantly increased the percentage of patients who had a complete molecular response by 12 months. In addition, it was unclear how a complete molecular response would translate into an improvement of patient’s outcome. The CHMP was also concerned that the dose of imatinib that was used in the study may have been too low. Regarding safety, more side effects were reported with Tasigna than with imatinib. Therefore, at the time of the withdrawal, the CHMP was of the opinion that the benefits of Tasigna® in this new indication did not outweigh its risks. In its letter notifying the Agency of the withdrawal of application, the company stated that the withdrawal was due to the fact that data gathered so far are insufficient for the CHMP to recommend approval of the new indication.


Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE: 2014-05-21

US authorization: 2007-10-29

UE authorization: 2007-11-19

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes