Xeljanz

Refused

This medicine has been refused authorisation

tofacitinib

Overview

On 25 April 2013, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for the medicinal product Xeljanz, intended for the treatment of rheumatoid arthritis. The company that applied for authorisation is Pfizer Limited.

The applicant requested a re-examination of the opinion. After considering the grounds for this request, the CHMP re-examined the initial opinion, and confirmed the refusal of the marketing authorisation on 25 July 2013.

What is Xeljanz?

Xeljanz is a medicine that contains the active substance tofacitinib. It was to be available as tablets (5 mg).

What was Xeljanz expected to be used for?

Xeljanz was expected to be used in the treatment of moderate to severe active rheumatoid arthritis (an immune system disease causing damage and inflammation in the joints). It was to be used in patients in whom treatment with at least one other medicine known as a biological disease-modifying antirheumatic drug (biological DMARD¹), had been unsuccessful either because patients were unable to tolerate treatment due to side effects, or because they did not respond adequately.

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¹Biological DMARDs are medicines that target specific proteins in the immune system. They are produced by a method known as ‘recombinant DNA technology’: they are made by cells that have received a gene (DNA) that makes them able to produce the medicine.

How is Xeljanz expected to work?

The active substance in Xeljanz, tofacitinib, is an immunosuppressant (a medicine that reduces the activity of the immune system) that works by blocking the action of enzymes known as Janus kinases. These enzymes play an important role in the process of inflammation and damage of the joints that occurs in rheumatoid arthritis. By blocking the enzymes, tofacitinib is expected to reduce the inflammation and other symptoms of the disease.

What did the company present to support its application?

The effects of Xeljanz were first tested in experimental models before being studied in humans.

The company initially presented the results of five main studies of safety and effectiveness involving over 3,300 patients with rheumatoid arthritis. These studies compared Xeljanz (in a dose of 5 or 10 mg twice daily) with placebo (a dummy treatment), either alone or as an addition to other background medicines (DMARDs). The main measures of effectiveness were changes in patient scores for signs and symptoms of disease, physical function of the patient, structural damage to joints and disease activity; these were measured after 3 or 6 months, depending on the study.

What were the CHMP’s main concerns that led to the refusal?

The CHMP had major concerns about the overall safety profile of Xeljanz. There were significant and unresolved concerns about the risk and type of serious infections seen with tofacitinib, which are related to the immunosuppressant action of the medicine.

These safety concerns also included a risk of other severe side effects including certain cancers, gastro-intestinal perforations (holes in the wall of the gut), liver damage and problems with increased lipid (fat) levels in the blood. It was not clear that these risks could be managed successfully in medical practice.
In April 2013, the Committee considered that, taken together, the data from the five main studies showed that treatment with Xeljanz resulted in an improvement in the signs and symptoms of rheumatoid arthritis and the physical function of patients. However, the studies were not sufficient to show a consistent reduction in disease activity and structural damage to joints, particularly at the lower 5-mg dose of Xeljanz and in the target population of patients in whom treatment with at least two other DMARDs has been unsuccessful. At re-examination in July 2013 the company proposed to remove claims of an effect on structural damage from the indication. However, the lack of robust evidence on prevention of structural damage with Xeljanz in the proposed dose and population still contributed to the Committee’s view that the benefits of treatment did not outweigh significant and unresolved concerns about safety.

Therefore, in April 2013 the CHMP was of the opinion that the benefits of Xeljanz did not outweigh its risks and recommended that it be refused marketing authorisation. The CHMP refusal was confirmed after re-examination.

What consequences does this refusal have for patients in clinical trials or compassionate use programmes?

The company informed the CHMP that patients receiving tofacitinib in clinical trials will continue to receive it as planned. The company will consider future requests for compassionate use on an individual basis in accordance with local regulations.

If you are in a clinical trial or compassionate use programme and need more information about your treatment, contact the doctor who is giving it to you.

Questions and answers on refusal of the marketing authorisation for Xeljanz - Outcome of re-examination

AdoptedReference Number: EMA/460814/2013

Product details

• Name of medicine:
  Xeljanz
• Active substance:
  Tofacitinib
• International non-proprietary name (INN) or common name:
  tofacitinib
• Therapeutic area (MeSH):
  Arthritis, Rheumatoid

Pharmacotherapeutic group

Immunosuppressants

Application details

• EMA product number:
  EMEA/H/C/002542
• Marketing authorisation applicant:
  Pfizer Limited
• Opinion adopted:
  25/07/2013

Assessment history

Xeljanz : EPAR - Public assessment report

AdoptedReference Number: EMA/CHMP/425279/2013