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

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