tofacitinib

Actions and spectrum: 

tofacitinib is a medication that belongs to Janus kinase (JAK) inhibitors. It works by inhibiting the activity of JAK enzymes, which play a role in the immune response. 

tofacitinib is primarily used to treat autoimmune diseases such as psoriatic arthritis,rheumatoid arthritis, and ulcerative colitis.  

The medication has a broad spectrum of action and can target multiple types of immune cells, like B cells, T cells, and NK cells. By suppressing the immune system, tofacitinib can reduce inflammation, pain, and joint damage in arthritis patients, as well as alleviate the symptoms of ulcerative colitis. 

However, as with all immunosuppressive medications, tofacitinib also carries the risk of increasing the patient’s susceptibility to infections and other adverse effects. Therefore, it is important to use the medication under the guidance of a healthcare provider and to monitor for any potential side effects. 

DRUG INTERACTION

Frequency defined 

>10% 

Ulcerative Colitis 

• Nasopharyngitis (10-14%) 

1-10% 

Rheumatoid Arthritis 

• Hypertension (2%) 
• Diarrhea (3-4%) 
• Nasopharyngitis (3-4%) 
• Headache (3-4%) 
• Upper respiratory tract infection (4%) 

Ulcerative Colitis 

• Nausea (1-4%) 
• Anemia (2-4%) 
• Gastroenteritis (3-4%) 
• Headache (3-9%) 
• Herpes zoster (1-5%) 
• Diarrhea (2-5%) 
• Rash (3-6%) 
• blood creatine phosphokinase (3-7%) 
• URTI (6-7%) 
• Elevated cholesterol levels (5-9%)

Frequency not defined 

• Psychiatric disorders: Insomnia 
• Infections and infestations: Diverticulitis 
• Respiratory, mediastinal and thoracic disorders: Dyspnea, sinus congestion, cough, interstitial lung disease  
• Hepatobiliary disorders: Hepatic steatosis 
• Musculoskeletal, bone disorders and connective tissue: arthralgia, Musculoskeletal pain, tendonitis, joint swelling 
• General disorders: Pyrexia, peripheral edema, fatigue 
• lymphatic system and blood disorders: Anemia 
• Nutrition and metabolism disorders: Dehydration 
• Disorders of Nervous system: Paresthesia 
• Gastrointestinal disorders: dyspepsia, Abdominal pain, vomiting, nausea, gastritis 
• Subcutaneous and skin tissue disorders:  erythema, Rash, pruritus 
• Neoplasms benign, unspecified and malignant: non-melanoma cancers 

Black Box Warning: 

tofacitinib has a black box warning of Serious infections, including tuberculosis (TB) and other opportunistic infections, have been reported in patients taking tofacitinib. Patients should be screened for TB before starting tofacitinib and monitored for signs and symptoms of infection during treatment. 

tofacitinib has also been associated with an increased risk of malignancies, including lymphoma and other cancers. Patients with a history of malignancy or who are at high risk for malignancy should be carefully evaluated before starting tofacitinib. Finally, tofacitinib has been associated with an increased risk of thrombosis, which can lead to serious complications such as stroke or heart attack. 

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: tofacitinib should not be used in patients with a known hypersensitivity to the medication or any of its components. 
• Active Infections: tofacitinib should not be used in patients with active infections, including tuberculosis (TB), due to the increased risk of serious infections associated with the medication. 
• Lymphoma: tofacitinib is contraindicated in patients with active, serious, or life-threatening malignancies, including lymphoma. 
• Pregnancy: tofacitinib is contraindicated in pregnant women as it may cause harm to the fetus.  
• Breastfeeding: tofacitinib is excreted into breast milk and may harm the nursing infant. Breastfeeding should be avoided while taking tofacitinib. 
• Severe hepatic impairment: tofacitinib is contraindicated in patients with severe hepatic impairment. 
• Severe renal impairment: tofacitinib should be used with caution in patients with severe renal impairment as the medication has not been extensively studied in this population.

Caution: 

• Infections: tofacitinib can increase the risk of serious infections, including opportunistic infections, viral, bacterial, and fungal infections.  
• Malignancies: tofacitinib has been associated with an increased risk of malignancies, including lymphoma and other cancers. Patients should be evaluated for any signs of malignancy before starting treatment with tofacitinib and monitored for any new or worsening symptoms during treatment. 
• Thrombosis: tofacitinib can increase the risk of blood clots, which can lead to serious complications such as stroke or heart attack.  
• Gastrointestinal perforation: tofacitinib can increase the risk of gastrointestinal perforation, a serious and potentially life-threatening condition.  
• Hepatic impairment: tofacitinib should be used with caution in patients with mild to moderate hepatic impairment.  
• Renal impairment: tofacitinib should be used with caution in patients with renal impairment. 
• Immunizations: Live vaccines should be avoided while taking tofacitinib due to the risk of infection.

Comorbidities: 

• Infections: Patients with a history of infections, or who are at risk of developing infections, may be at increased risk of serious infections when taking tofacitinib. Careful monitoring is required in these patients. 
• Malignancies: tofacitinib has been associated with an increased risk of malignancies, including lymphoma and other cancers. Patients with a history of malignancies or who are at high risk of developing malignancies may require close monitoring during treatment with tofacitinib. 
• Cardiovascular disease: tofacitinib may increase the risk of heart attack and stroke, particularly in patients with pre-existing cardiovascular disease. 
• Hepatic impairment: tofacitinib is metabolized in the liver and may be contraindicated or require dose adjustments in patients with hepatic impairment. 
• Renal impairment: tofacitinib is excreted by the kidneys and may be contraindicated or require dose adjustments in patients with renal impairment. 
• Chronic obstructive pulmonary disease (COPD): tofacitinib may increase the risk of serious lung infections in patients with COPD. 
• Diabetes: tofacitinib may increase blood glucose levels and require close monitoring in patients with diabetes. 
• Autoimmune diseases: tofacitinib is approved for the treatment of several autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Patients with these conditions may have other comorbidities that require careful monitoring during treatment with tofacitinib. 

Pregnancy consideration: pregnancy category: not assigned 

Lactation: It is unknown whether tofacitinib is excreted in human breast milk.  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology: 

tofacitinib is a medication that belongs to Janus kinase (JAK) inhibitors. It acts by inhibiting certain enzymes, called JAKs, which are involved in the signaling pathways of various cytokines and growth factors. By blocking the action of JAKs, tofacitinib reduces the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-alpha). This leads to a reduction in inflammation and helps to alleviate the symptoms associated with various autoimmune diseases. 

tofacitinib is administered orally and is rapidly absorbed, with peak plasma concentrations reached within 1-2 hours after administration. The medication is metabolized in the liver and eliminated primarily through the feces, with a smaller amount excreted in the urine. The half-life of tofacitinib is approximately 3 hours, and steady-state concentrations are reached within 5 days of daily dosing.  

Pharmacodynamics: 

The pharmacodynamics of tofacitinib is related to its mechanism of action as a Janus kinase (JAK) inhibitor. JAKs are intracellular tyrosine kinases that are activated by cytokines and growth factors, leading to the phosphorylation and activation of downstream signaling pathways. This activation results in the production of pro-inflammatory cytokines, which contribute to the pathogenesis of autoimmune diseases. 

tofacitinib inhibits JAKs, including JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), which are involved in the signaling pathways of various cytokines, such as interleukin-6 (IL-6), interleukin-12 (IL-12), and interferon-gamma (IFN-gamma). By blocking the activity of JAKs, tofacitinib reduces the production of pro-inflammatory cytokines and interferes with the activation and differentiation of immune cells, such as T cells, B cells, and natural killer (NK) cells.

This leads to a reduction in inflammation and helps to alleviate the symptoms associated with autoimmune diseases. The pharmacodynamic effects of tofacitinib can be observed within hours of administration and persist for up to 24 hours. tofacitinib has been shown to reduce disease activity and improve clinical outcomes in patients with rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

The medication also has immunomodulatory effects that may be beneficial in other autoimmune and inflammatory diseases. In summary, tofacitinib inhibits JAKs and interferes with cytokine signaling pathways, leading to a reduction in inflammation and improvement in clinical outcomes in various autoimmune diseases.   

Pharmacokinetics: 

Absorption 

tofacitinib is administered orally, and its absorption is rapid and complete, with a bioavailability of approximately 74%. The drug can be given with or without food, and food does not significantly affect its absorption. 

Distribution 

tofacitinib has a high plasma protein binding of approximately 40%, mainly to albumin and alpha-1 acid glycoprotein. The drug distributes widely into tissues, and the volume of distribution at steady state is 115 L. 

Metabolism 

tofacitinib is metabolized mainly by the liver through oxidative metabolism, primarily via the cytochrome P450 (CYP) 3A4 enzyme system. The major metabolites of tofacitinib are less pharmacologically active than the parent compound. 

Elimination and excretion 

tofacitinib and its metabolites are primarily eliminated through fecal excretion, with a small amount excreted in the urine. Approximately 30% of the dose is excreted unchanged in the feces, and less than 1% is excreted unchanged in the urine. The elimination half-life of tofacitinib is approximately 3 hours. 

Special populations: In patients with mild to moderate renal impairment, no dose 

Administration: 

tofacitinib is available as an oral tablet and should be taken according to the prescribed dose and schedule. The tablets should be administered whole and can be taken with or without food. 

The recommended dose of tofacitinib depends on the condition being treated: 

• Rheumatoid arthritis: The starting dose is typically 5 mg twice daily. Depending on the patient’s response to therapy, the dose may be increased to 10 mg twice daily. 
• Psoriatic arthritis: The usual recommended dose is 5 mg twice daily. 
• Ulcerative colitis: The starting dose is typically 10 mg twice daily for 8 weeks, followed by a maintenance dose of 5 mg or 10 mg twice daily. 

Patient information leaflet 

Generic Name: tofacitinib 

Pronounced: (toh-fuh-SIT-uh-nib) 

Why do we use tofacitinib? 

• Rheumatoid arthritis: tofacitinib is FDA-approved to treat rheumatoid arthritis in adults who have not responded well to methotrexate or cannot tolerate it. 
• Psoriatic arthritis: tofacitinib is FDA-approved to treat active psoriatic arthritis in patients who have not responded well to disease-modifying antirheumatic drugs (DMARDs). 
• Ulcerative colitis: tofacitinib is FDA-approved to treat moderate to severe active ulcerative colitis in adults who have not responded well to other medications, such as corticosteroids, immunosuppressants, or TNF blockers. 
• Systemic lupus erythematosus (SLE): tofacitinib is being studied for its potential use in treating SLE. Early research has shown promise in reducing disease activity and improving symptoms in patients with SLE.