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Tofacitinib (Xeljanz) - A Biological DMARD

Tofacitinib (Xeljanz) is an inhibitor of JAK (Janus kinases) that is involved in cell signaling and gene expression and regulates immune function and hematopoiesis.

Tofacitinib should not be used in combination with other potent immunosuppressants like azathioprine or cyclosporin and should not be used with other biological DMARDS. It is used to treat the following conditions:

For the treatment of psoriatic arthritis in adults who are intolerant or have not responded to methotrexate or other DMARDs.
For the treatment of moderate to severely active rheumatoid arthritis who have not responded to or are intolerant to methotrexate. It may be used either as monotherapy or in combination with methotrexate or other nonbiologic DMARDs.
Treatment of moderate to severely active ulcerative colitis.

Read: Is Tofacitinib a Steroid?

Tofacitinib Dose in Adults

Note:

It should not be used in combination with biological DMARDs or with strong immunosuppressants such as azathioprine, tacrolimus, or cyclosporine.
Treatment should not be initiated in patients with a hemoglobin of less than 9 gm/dl, ANC of less than 1000 cells/mm³, or absolute lymphocyte counts of less than 500 cells/mm³.

Dose in the treatment of Psoriatic arthritis in combination with nonbiologic DMARDs:

Immediate-release:
- 5 mg orally two times a day
Extended-release:
- 10 mg orally once a day.

Dose in Rheumatoid arthritis as monotherapy or in combination with nonbiologic DMARDs:

Immediate-release:
- 5 mg orally two times a day
Extended-release:
- 10 mg orally once a day.

Dose in the treatment of Ulcerative Colitis:

Immediate-release:
- 10 mg two times a day 8 weeks or more followed by 5 or 10 mg two times a day.
- Therapy may be discontinued if an adequate response is not achieved after four months of treatment with 10 mg twice daily dosing.

Dosage adjustment for concomitant therapy:

CYP3A4 inducers like rifampin:
- Not recommended.
Strong CYP3A4 inhibitors like ketoconazole:
- Immediate release:
  - Reduce the dose to 5 mg two times a day if taking 10 mg twice daily or 5 mg once a day if taking 5 mg two times a day.
- Extended-release:
  - Not recommended.
Concomitant moderate CYP3A4 inhibitors and potent CYP2C19 inhibitors like fluconazole:
- Immediate release:
  - Reduce the dose to 5 mg two times a day if taking 10 mg twice daily or 5 mg once a day if taking 5 mg two times a day.
- Extended-release:
  - Not recommended.

Tofacitinib Dose in Children

Not recommended for use in children. Small studies suggest tofacitinib to be effective and safe in pediatric patients.

Pregnancy Risk Factor: D

Although data is not available, most experts recommend that pregnant women avoid it.

Tofacitinib use during breastfeeding:

There are limited data and it is not possible to determine if the drug is excreted into breastmilk.
Most experts recommend that you avoid it while breastfeeding.

Tofacitinib Dose in Renal Disease:

Mild impairment:
- Adjustment in the dose is not necessary.
Moderate to severe impairment:
- Immediate release:
  - Reduce the dose to 5 mg two times a day in patients on 10 mg twice daily dose or 5 mg once a day in patients on 5 mg two times a day dose.
- Extended-release:
  - It is not recommended. Patients may be shifted to the immediate-release formulation.

ESRD requiring hemodialysis:
- Immediate release:
  - Reduce the dose to 5 mg two times a day in patients on 10 mg twice daily dose or 5 mg once a day in patients on 5 mg two times a day dose.
- Extended-release:
  - It is not recommended. Patients may be shifted to the immediate-release formulation.

Tofacitinib Dose in Liver Disease:

Mild hepatic impairment:
- Adjustment in the dose is not necessary.
Moderate impairment:
- Immediate release:
  - Reduce the dose to 5 mg two times a day in patients on 10 mg twice daily dose or 5 mg once a day in patients on 5 mg two times a day dose.
- Extended-release:
  - It is not recommended. Patients may be shifted to the immediate-release formulation.
Severe impairment:
- It is not recommended in severe hepatic impairment.

Common Side Effects of Tofacitinib Include:

Infection:
- Infection
Respiratory:
- Nasopharyngitis

Less Common Side Effects Of Tofacitinib Include:

Cardiovascular:
- Hypertension
Central Nervous System:
- Headache
Dermatologic:
- Skin Rash
- Acne Vulgaris
Endocrine & Metabolic:
- Increased Serum Cholesterol
Gastrointestinal:
- Diarrhea
- Gastroenteritis
- Nausea
Genitourinary:
- Urinary Tract Infection
Hematologic & Oncologic:
- Anemia
Infection:
- Herpes Zoster Infection
Neuromuscular & Skeletal:
- Increased Creatine Phosphokinase
Renal:
- Increased Serum Creatinine
Respiratory:
- Upper Respiratory Tract Infection
Miscellaneous:
- Fever

Frequency Not Defined:

Cardiovascular:
- Peripheral Edema
Central Nervous System:
- Fatigue
- Insomnia
- Paresthesia
Dermatologic:
- Erythema
- Pruritus
Endocrine & Metabolic:
- Dehydration
Gastrointestinal:
- Abdominal Pain
- Diverticulitis of the Gastrointestinal Tract
- Dyspepsia
- Gastritis
- Vomiting
Hematologic & Oncologic:
- Malignant Lymphoma
- Skin Carcinoma
Hepatic:
- Increased Liver Enzymes
- Liver Steatosis
Infection:
- Bacterial Infection
- Fungal Infection
- Opportunistic Infection
- Serious Infection
- Viral Infection
Neuromuscular & Skeletal:
- Arthralgia
- Joint Swelling
- Musculoskeletal Pain
- Tendonitis
Respiratory:
- Cough
- Dyspnea
- Interstitial Pulmonary Disease
- Paranasal Sinus Congestion

Contraindications to Tofacitinib Include:

Allergy reactions to tofacitinib and any component of the formulation
Hepatic impairment severe
Pregnancy
Breastfeeding

Warnings and Precautions

Suppression of bone marrow

Tofacitinib treatment has been linked to anemia, neutropenia, and lymphocytopenia.

A lower lymphocyte count of 500 cells/mm3 is associated with a higher risk of serious infections. Patients with a lymphocyte count of less than 500 should avoid Tofacitinib.

Patients with ANC below 1000 cells/mm3 should be treated immediately.

Patients with hemoglobin below 9 gms/dl should not be treated. If hemoglobin falls below 9 gms/dl or by 2 gms/dl during treatment, it should be stopped.

Monitoring of lymphocyte counts at baseline and every three to six months should be done.

At baseline, hemoglobin, platelet counts, and ANC should all be checked after 4-8 weeks of therapy and every three months after that.

Cardiovascular effects

It has been associated with Bradycardia and QT interval lengthening.

Patients with a lower heart rate than 60 beats per hour, conduction abnormalities, syncope and arrhythmias, heart failure, and patients taking drugs that prolong the PR/QT interval should be advised to discontinue use.

Gastrointestinal perforations:

Tofacitinib can increase the risk of gastrointestinal perforation, especially for patients who have had diverticulitis in the past.

Patients suffering from new abdominal symptoms must be seen immediately.

Hepatotoxicity:

Drug-induced liver injury can occur. At baseline, patients should have liver function testing done. Then, they should be tested periodically thereafter.

If drug-induced liver damage is suspected, treatment should be stopped immediately

Hypersensitivity

It is possible to experience allergic reactions, including angioedema and urticaria.

If severe allergic reactions, such as angioedema, occur, it is best to stop treatment immediately.

Infections [US Boxed Warning]

It can lead to serious, sometimes life-threatening, infections in patients.

These are the most commonly reported infections:

pneumonia
cellulitis
Urinary tract infections
Diverticulitis
appendicitis
herpes zoster infection

Some other serious infections that are not uncommon include:

Extrapulmonary or pulmonary tuberculosis
Invasive fungal infections (cryptococcosis, pneumocystosis).
Other opportunistic diseases include esophageal candidiasis, multi-dermatomal herpes, cytomegalovirus infections and BK virus infections.

Screening for viral hepatitis should be done on all patients

If the patient is at high risk for infection, including localized ones, treatment should be stopped immediately.

Interstitial lung disease (ILD):

ILD has been reported, particularly when combined with methotrexate.

Patients who have a history of ILD or chronic lung disease should not use it.

Lipid abnormalities

After tofacitinib is initiated, it is important to monitor your lipid levels for 4-8 weeks.

Dose-dependent tofacitinib can cause dyslipidemia.

Malignancy [US Boxed Warning]

It is associated with an increased risk of malignancies.

There have been several cases of malignancies linked to its use:

Lung cancer, breast cancer, gastric, colorectal, and renal cell carcinoma.
Epstein Barr Virus-associated Lymphoproliferative Disorder in Patients with Renal Transplant has also been reported.
High doses of radiation can increase the risk of non-melanoma.
Tuberculosis [US Boxed Warning]

Every patient should be tested for active and latent tuberculosis.

Before starting therapy with tofacitinib, a Tuberculin skin test should be performed.

Before starting tofacitinib therapy, anyone with a positive tuberculin test skin test should be treated.

Patients with a negative TST must be closely monitored throughout treatment.

Patients living in endemic areas need to be warned about the dangers of the drug.

Diabetes:

Diabetic patients are more at risk for infection. These patients should use it with caution.

Hepatic impairment

It should be avoided by patients with severe hepatic impairment. Patients with moderate hepatic impairment will need to adjust the dosage.

Lung disease:

Patients with interstitial or chronic lung disease should be cautious.

Renal impairment

Patients with severe or moderate renal impairment may require adjustments in their dose.

Tofacitinib: Drug Interaction

Risk Factor C (Monitor therapy)
Aprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Bradycardia-Causing Agents	Tofacitinib may enhance the bradycardic effect of BradycardiaCausing Agents.
Ceritinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Exceptions are discussed separately.
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Speciﬁcally, the risk for neutropenia may be increased.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Speciﬁcally, the risk for serious infections may be increased.
Fosaprepitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Methotrexate	May enhance the immunosuppressive effect of Tofacitinib. Management: Avoid the use of tofacinib in combination with potent immunosuppressive methotrexate-containing regimens.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Simeprevir	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
CYP3A4 Inhibitors (Strong)	May increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of ﬁngolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Fluconazole	May increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with ﬂuconazole. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details.
Immunosuppressants	May enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Leﬂunomide	Immunosuppressants may enhance the adverse/toxic effect of Leﬂunomide. Speciﬁcally, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leﬂunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leﬂunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
MiFEPRIStone	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Pitolisant	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
Roﬂumilast	May enhance the immunosuppressive effect of Immunosuppressants.
St John's Wort	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be speciﬁcally contraindicated. Consult appropriate manufacturer labeling.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine eﬃcacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Risk Factor X (Avoid combination)
Baricitinib	May enhance the adverse/toxic effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs).
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Biologic Disease-Modifying Antirheumatic Drugs (DMARDs)	May enhance the adverse/toxic effect of Tofacitinib.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Tofacitinib.
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Speciﬁcally, the risk for agranulocytosis and pancytopenia may be increased
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Speciﬁcally, the risk of concurrent infection may be increased.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.

Monitor:

Absolute lymphocyte count at baseline and every three months thereafter.
Neutrophils and platelet count at baseline, after 4 - 8 weeks, and every three months thereafter.
Hemoglobin at baseline, after 4 - 8 weeks, and every three months thereafter
Lipids 4 - 8 weeks after treatment initiation and periodically thereafter.
Liver Function Tests.
Viral hepatitis before the start of therapy
Monitor for the clinical features of tuberculosis during and after therapy.
Monitor for abdominal symptoms
Skin examinations should be done periodically in patients at increased risk for skin cancer
Monitor heart rate and blood pressure before the initiation of treatment and periodically thereafter.

How to administer Tofacitinib?

It may be taken with or without food.
The extended-release tablets should be swallowed whole. It should not be crushed, split or chewed.

Mechanism of action of Tofacitinib:

Tofacitinib, also known as Xeljanz, inhibits Janus kinase. JAK activates signal transcription and transcription (STAT), which regulates gene expression in response to extracellular cytokines and growth factor signaling.
JAK is an intracellular enzyme that plays a role in immune cell function, hematopoiesis and signaling pathways. JAK inhibition prevents gene expression and intracellular immunity.
JAK inhibition causes a decrease in circulating CD16/CD56 positive natural killer cells, serum IgG/IgM and C-reactive proteins levels, and an increase in B cells.

Tablets for immediate release exhibit rapid absorption, with reduced absorption when taken with high-fat meals. Approximately 40% of the drug binds to plasma proteins.

Tofacitinib is predominantly metabolized in the liver by enzymes CYP3A4 and CYP2C19, leading to the formation of inactive metabolites.

The instant-release formulation of tofacitinib has a half-life of around 3 hours, whereas the extended-release formulation has a half-life of approximately 6 hours.

The time it takes to achieve maximum plasma concentration following the administration of the immediate-release medication is measured between 0.5 and 1 hour, and then again at 4 hours. The primary route of excretion for this drug is through the urine.

Read: Tofacitinib for Polymyositis

International brands of Tofacitinib:

Jakvinus
Kselyanz
Xeljanz
Xeljanz XR

Tofacitinib Brands in Pakistan:

Tofacitinib is now available in Pakistan as 5 mg tablets. Here are some of the brands that are easily available:

Tofacit (Kaizen Pharma)
Tofacnet (Macter International)
Tofajak