FDA Approves Boxed Warning About Increased Risk of Blood Clots and Death with Higher Dose of Tofacitinib (Xeljanz, Xeljanz XR)

In continuation of my update on tofacitinib 

The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. We approved these changes, including adding our most prominent Boxed Warning, after reviewing interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis (RA) that examined a lower and this higher dose of the medicine.

The 10 mg twice daily dose of tofacitinib is not approved for RA or psoriatic arthritis (PsA). This dose is only approved for ulcerative colitis for initial treatment and for long-term use in limited situations. While the increased risks of blood clots and of death were seen in patients taking this dose for RA, these risks may also apply to those taking tofacitinib for ulcerative colitis.

Tofacitinib works by decreasing the activity of the immune system; an overactive immune system contributes to RA, PsA, and ulcerative colitis. Tofacitinib was first approved in 2012 to treat adult patients with RA who did not respond well to the medicine methotrexate. In RA, the body attacks its own joints, causing pain, swelling, and loss of function. In 2017, we approved the medicine to treat patients with a second condition that causes joint pain and swelling, PsA, who did not respond well to methotrexate or other similar medicines. In 2018, we approved tofacitinib to treat ulcerative colitis, which is a chronic, inflammatory disease affecting the colon.

Patients should tell your health care professionals if you have a history of blood clots or heart problems, and talk to them about any questions or concerns. Stop taking tofacitinib and seek emergency medical attention right away if you experience any unusual symptoms, including those that may signal a blood clot such as:

• Sudden shortness of breath
• Chest pain that worsens with breathing
• Swelling of a leg or arm
• Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm

Do not stop taking tofacitinib without first talking to your health care professional, as doing so can worsen your condition.

Health care professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed (See Additional Information for Health Care Professionals for more recommendations).

When FDA first approved tofacitinib in 2012, we required a postmarketing clinical trial in patients with RA on background methotrexate, to evaluate the risk of heart-related events, cancer, and infections. The trial is studying two different doses of tofacitinib (5 mg twice daily, which is the currently approved dose for RA, and a higher, 10 mg twice daily dosage) in comparison to a TNF blocker. An interim analysis of the trial’s results found an increased occurrence of blood clots and of death in patients treated with tofacitinib 10 mg twice daily compared to patients treated with tofacitinib 5 mg twice daily or a TNF blocker. Based on these results, the 10 mg twice daily treatment was stopped and patients were allowed to continue treatment on 5 mg twice daily.

This safety trial is ongoing. Patients in the 5 mg twice daily group and the TNF blocker group continue to be followed. FDA will reassess these safety issues when the trial has completed and final, verified data are available. We will update the public when additional information is available.

The interim results of the trial, as of January 2019, have identified the following:

• 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF blockers
• 45 cases of death from all causes out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 25 cases out of 3,982 patient-years in patients who received TNF blockers

https://en.wikipedia.org/wiki/Tofacitinib

Pfizer Announces U.S. FDA Approves Xeljanz (tofacitinib) for the Treatment of Moderately to Severely Active Ulcerative Colitis

In continuation of my update on tofacitinib

Pfizer Inc. announced that the United States (U.S.) Food and Drug Administration (FDA) approved Xeljanz (tofacitinib) 10 mg twice-daily (BID) for at least eight weeks, followed by Xeljanz 5 mg BID or 10 mg BID, for the treatment of adult patients in the U.S. with moderately to severely active ulcerative colitis (UC).“Ulcerative colitis is a chronic inflammatory bowel disease that can significantly impact the lives of patients and has limited therapeutic options available,” said Michael Goettler, Global President, Inflammation and Immunology, Pfizer. “With the FDA approval of Xeljanz, adults living with moderately to severely active UC now have an oral option that may help achieve and maintain steroid-free remission.”

Xeljanz is indicated for the treatment of adult patients with moderately to severely active UC. Use of Xeljanz in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.1

This approval was based on data from three pivotal Phase 3 studies from the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis global clinical development program (OCTAVE Induction 1, OCTAVE Induction 2 and OCTAVE Sustain), and OCTAVE Open, an ongoing open label long-term extension study. Data from all three pivotal Phase 3 studies met their respective primary endpoints, showing a statistically significant, greater proportion of patients in remission at week 8 in the induction studies and in remission at week 52 in the maintenance study in patients with moderately to severely active UC treated with tofacitinib compared to placebo. Remission was defined as a Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and a rectal bleeding subscore of 0.i Full results from OCTAVE Induction 1, OCTAVE Induction 2 and OCTAVE Sustain were published in the New England Journal of Medicine in May 2017.

“The FDA approval of Xeljanz is positive news for the ulcerative colitis community, a patient population that can often encounter frequent and debilitating disruptions to their daily lives,” said William J. Sandborn, MD, Chief, Division of Gastroenterology, Professor of Medicine at the University of California San Diego School of Medicine and OCTAVE study investigator. “Xeljanz provides people living with ulcerative colitis and their prescribing physicians with a new oral treatment option.”

Risks observed in the UC clinical program include serious infection, including herpes zoster and opportunistic infections, malignancies (including non-melanoma skin cancer [NMSC] and lymphoproliferative disorders), gastrointestinal perforation and laboratory abnormalities. There was no discernable difference in frequency of gastrointestinal perforation between the placebo and Xeljanz arms in clinical trials of patients with UC, and many of the trial participants were receiving background corticosteroids.

Dose-dependent adverse reactions seen in patients treated with 10 mg BID, in comparison to 5 mg BID, include the following: herpes zoster infections, serious infections, and NMSC.

“What works for one ulcerative colitis patient may not work for another and some struggle with ongoing symptoms. That is why it is so critical that our patients have different treatment options available to them,” said Michael Osso, President & CEO of the Crohn’s & Colitis Foundation. “We are thrilled to have this new treatment option available to ulcerative colitis patients. Every new treatment provides new hope to our community.”

Pfizer Announces U.S. FDA Approves Xeljanz (tofacitinib) for the Treatment of Moderately to Severely Active Ulcerative Colitis

FDA approves first oral medication for adults with moderately to severely active ulcerative colitis

In continuation of my update on Tofacitinib

The U.S. Food and Drug Administration  expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

"New treatments are needed for patients with moderately to severely active ulcerative colitis," said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research. "Today's approval provides an alternative therapy for a debilitating disease with limited treatment options."

Ulcerative colitis is a chronic, inflammatory bowel disease affecting the colon. Patients experience recurrent flares of abdominal pain and bloody diarrhea. Other symptoms include fatigue, weight loss and fever. More than 900,000 patients are affected in the U.S., many of them experiencing moderately to severely active ulcerative colitis, and there is currently no cure.

The efficacy of Xeljanz for the treatment of moderately to severely active ulcerative colitis was demonstrated in three controlled clinical trials. This included two 8-week placebo-controlled trials that demonstrated that 10 mg of Xeljanz given twice daily induces remission in 17 to 18 percent of patients by week eight. In a placebo-controlled trial among patients who achieved a clinical response by week eight, Xeljanz, at a 5 mg or 10 mg dose given twice daily, was effective in inducing remission by week 52 in 34 percent and 41 percent of patients, respectively. Among patients who achieved remission after 8 weeks of treatment, 35 percent and 47 percent achieved sustained corticosteroid-free remission when treated with 5 mg and 10 mg, respectively.

The most common adverse events associated with Xeljanz treatment for ulcerative colitis were diarrhea, elevated cholesterol levels, headache, herpes zoster (shingles), increased blood creatine phosphokinase, nasopharyngitis (common cold), rash and upper respiratory tract infection.

Less common serious adverse events included malignancy and serious infections such as opportunistic infections. Xeljanz has a boxed warning for serious infections and malignancy. Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Lymphoma and other malignancies have been observed in patients treated with Xeljanz.

Use of Xeljanz in combination with biological therapies for ulcerative colitis or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

Pfizer Announces FDA Approval of Xeljanz (tofacitinib) and Xeljanz XR for the Treatment of Active Psoriatic Arthritis

In continuation of my update on tofacitinib 

Pfizer Inc.  announced that the United States Food and Drug Administration (FDA) has approved Xeljanz 5 mg twice daily (BID) and Xeljanz XR (tofacitinib) extended release 11 mg once daily (QD) for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). Xeljanz/Xeljanz XR is the first and only Janus kinase (JAK) inhibitor approved by the FDA for both moderate to severe rheumatoid arthritis (RA) and active PsA.

“Psoriatic arthritis is a complex and progressive disease with an unpredictable course,” said Angela Hwang, Global President, Inflammation and Immunology, Pfizer. “The approval of Xeljanz is an important step forward for patients seeking new treatments and is a testament to Pfizer’s unwavering commitment to advancing patient care.”

The recommended dose of Xeljanz/Xeljanz XR is in combination with nonbiologic DMARDs, and use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

The FDA approval of Xeljanz for the treatment of adult patients with active PsA was based on data from the Phase 3 Oral Psoriatic Arthritis Trial (OPAL) clinical development program, which consisted of two pivotal studies, OPAL Broaden and OPAL Beyond, as well as available data from an ongoing long-term extension trial, OPAL Balance. The findings from OPAL Broaden and OPAL Beyond were published in October 2017 in the New England Journal of Medicine.

Both pivotal studies met their two primary efficacy endpoints, demonstrating statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI) score at three months in patients receiving Xeljanz 5 mg BID treatment in combination with a nonbiologic DMARD, compared to those treated with placebo. In OPAL Broaden, 50% of patients taking Xeljanz 5 mg BID achieved an ACR20 response, compared to 33% of patients taking placebo (p≤0.05), at three months. In OPAL Beyond, 50% of patients achieved an ACR20 response with Xeljanz 5 mg BID, compared to 24% of patients taking placebo (p≤0.05), at three months. In both studies, statistically significant improvements in ACR20 response was also seen with Xeljanz 5 mg BID compared to placebo at week 2, a secondary endpoint and the first post-baseline assessment (OPAL Broaden: 22% and 6% [p=0.0003], respectively; OPAL Beyond: 27% and 13% [p=0.0046], respectively).

“As a practicing rheumatologist, I’ve seen the significant physical impact psoriatic arthritis has on people living with the disease, and many patients are looking for additional therapeutic options,” said Philip Mease, M.D., Swedish Medical Center, University of Washington and study investigator. “I’m pleased that Xeljanz is now available for use in the treatment of this chronic condition.”

The safety profile observed in patients with active psoriatic arthritis treated with Xeljanz was consistent with the safety profile observed in rheumatoid arthritis patients. The most common adverse events observed occurring in greater than 3% of patients on Xeljanz 5 mg BID were nasopharyngitis, upper respiratory tract infection, headache and diarrhea.

“Psoriatic arthritis is a serious and debilitating chronic illness that should be diagnosed and treated early,” said Randy Beranek, president and CEO, National Psoriasis Foundation. “As an organization that advocates for people living with psoriatic arthritis, we welcome the availability of new therapies for treating this disease.”

Pfizer Announces FDA Approval of Xeljanz (tofacitinib) and Xeljanz XR for the Treatment of Active Psoriatic Arthritis

Pfizer reports positive results from two tofacitinib Phase 3 trials for chronic plaque psoriasis

In continuation of my update on Tofacitinib

We know that, Tofacitinib (trade name Xeljanz, formerly tasocitinib, CP-690550) is a drug of the janus kinase (JAK) inhibitor class, discoveredand developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States and is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection. Tofacitinib was not approved by the European regulatory agencies because of concerns over efficacy and safety...

Pfizer reports positive results from two tofacitinib Phase 3 trials for chronic plaque psoriasis

FDA AAC recommends approval of Pfizer’s tofacitinib for RA

In continuation of my update on  Tofacitinib...

FDA AAC recommends approval of Pfizer’s tofacitinib for RA: Pfizer Inc. the Arthritis Advisory Committee to the U.S. Food and Drug Administration (FDA) voted 8-2 to recommend approval of the investigational agent tofacitinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). The Committee's recommendation will be considered by the FDA in its review of the New Drug Application (NDA) for tofacitinib. The FDA has provided an anticipated Prescription Drug User Fee Act (PDUFA) action date in August 2012. If approved by the FDA, tofacitinib would be the first new oral disease-modifying antirheumatic drug (or DMARD) for RA in more than 10 years and the first RA treatment in a new class of medicines known as Janus kinase (JAK) inhibitors..

Pfizer seeks FDA support for its new anti-rheumatoid arthritis pill

In continuation of my update on Tofacitinib

Pfizer seeks FDA support for its new anti-rheumatoid arthritis pill: Pfizer is waiting for the Food and Drug Administration to approve its new pill for rheumatoid arthritis (RA) - the first oral biologic for treating this ailment.

Pfizer RA Drug Meets Study Goals

We knew that,  Tofacitinib (see structure, formerly tasocitinib is a drug being investigated by Pfizer for the treatment of rheumatoid arthritis (RA), psoriasis,inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection. It is an inhibitor of the enzyme Janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway that transmits information outside the cell into the cell nucleus, influencing DNA transcription.

Now Pfizer now claims that the drug has   met its key goals of reducing signs and symptoms of the condition in separate studies on patients over a 12-month and six-month period. Rheumatoid arthritis is a chronic inflammatory disease typically affecting joints.

The company's Oral Standard study involved 717 patients over a 12-month period with moderate-to-severe rheumatoid arthritis who had an inadequate response to the drug methotrexate. Meanwhile, the Oral Step study involved 399 patients over a six-month period with moderate-to-severe rheumatoid arthritis who did not have an adequate response to TNF inhibitor drugs.  Pfizer said no new safety signals emerged in the Oral Standard and Oral Step studies. A more detailed analysis off the data will be submitted to a future scientific meeting. 

The most common side effects of treatment with tofacitinib have included bronchitis, headache, infections, and gastrointestinal symptoms like nausea, vomiting, and diarrhea. More serious side effects in a mid-stage trial included lower levels of a type of white blood cell called neutrophils, higher cholesterol levels and increased creatinine levels.

Tofacitinib is a key developing drug for Pfizer and is also being studied as a potential treatment for psoriasis, inflammatory bowel disease, and renal transplant. A topical version of the drug is being studied as a psoriasis treatment and a dry eye disease treatment....

Press Release...

Top-line results from Pfizer's tofacitinib Phase 3 studies in RA

In continuation of my update on drugs discovery on  rheumatoid arthritis, 

Top-line results from Pfizer's tofacitinib Phase 3 studies in RA..