Tofacitinib

Tofacitinib is a Disease-Modifying Antirheumatic Drugs (DMARDs) agent belonging to the pharmacological class of Janus kinase (JAK) inhibitors.

Tofacitinib is FDA-approved for the treatment of moderate to severe rheumatoid arthritis (RA), ulcerative colitis (UC), psoriatic arthritis (PA), and polyarticular course juvenile idiopathic arthritis (pcJIA).

Tofacitinib is rapidly absorbed upon oral intake, undergoes hepatic metabolism primarily via CYP3A4, and eventually gets eliminated primarily through urine in its unchanged form.

Tofacitinib's most common side effects include upper respiratory tract infections, headache, diarrhoea, and nasopharyngitis.

Tofacitinib is available as a tablets and oral solution.

The molecule is available in India, Brazil, the United States, Canada, the United Kingdom, Australia, Germany, France, Italy, Japan, and Mexico.

Tofacitinib is a Disease-Modifying Antirheumatic Drugs (DMARDs) agent belonging to the pharmacological class of Janus kinase (JAK) inhibitors.

A dysregulation of pro-inflammatory cytokines such as IFN-alpha, IFN-beta, IL7, IL15, IL21, and IL6 typifies an autoimmune condition called rheumatoid arthritis. Through the Janus kinase signalling pathway, cytokine signalling promotes immune cell recruitment and activation, leading to tissue inflammation and joint damage.

A partial and reversible inhibitor of Janus kinase (JAK), Tofacitinib stops the body from reacting to cytokine signals. Tofacitinib suppresses the phosphorylation and activation of STATs by blocking JAKs. The JAK-STAT signalling pathway regulates the cells' transcription in hematopoiesis and immune cell function. To reduce inflammation, Tofacitinib inhibits the JAK-STAT pathway therapeutically. Evidence, though, suggests it might also be effective through other channels.

The time required for Tofacitinib to show its effect is typically observed within a few weeks to months after administration.

The duration of effectiveness for Tofacitinib has yet to be established. It varies based on individuals and depends on the condition being treated.

Tofacitinib's peak plasma concentration (Cmax) usually reaches approximately 1- 2 hours after oral administration (Tmax).

Tofacitinib is available as a tablets and oral solution.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it. Doing this may release the entire dosage at once, raising the risk of adverse effects.

Oral solutions: Shake the oral solution, measure the prescribed dose, and swallow it without diluting or mixing it with anything.

As the physician recommends, take the medication orally once or twice; as directed.

Tofacitinib treats specific arthritis types (like psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis) by reducing joint pain, tenderness, and swelling. It's also effective for managing ulcerative colitis symptoms such as rectal bleeding, diarrhea, and stomach pain.

It is also used in pediatrics for active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients aged more than 2 years.

Tofacitinib can be indicated for various health conditions:

Orally: Patients typically take Tofacitinib orally in tablet form and oral solution, following healthcare professional guidance for once or twice daily intake with or without food. The prescribing doctor provides specific instructions based on the treated condition. Patients should adhere to these directions, ensuring consistency in dosage and timing and managing potential food interactions to maximize the medication's effectiveness and safety.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 5mg, 10mg; extended-release: 11mg, 22mg

Oral solution: 1mg/mL

Tofacitinib is available in the form of tablets and oral solutions.

Tofacitinib: 5 mg PO BID

Tofacitinib extended-release: 11 mg PO qDay

Tofacitinib: 5 mg PO BID

Tofacitinib extended-release: 11 mg PO qDay

Tofacitinib

Induction

10 mg PO BID for a minimum of eight weeks; in accordance with the therapeutic response, assess patients and switch to maintenance medication.

For a maximum of 16 weeks, if necessary, continue taking 10 mg BID; if sufficient therapeutic benefit is not obtained after 16 weeks, stop taking it.

Maintenance

5 mg PO BID; patients who stop responding to maintenance therapy may be eligible for 10 mg BID (limited to a shorter duration).

Utilize the lowest dose that works well to keep the response going.

Tofacitinib extended-release

Induction

22 mg PO qDay for at least eight weeks; based on the patient's reaction to treatment, assess them and move them to maintenance medication.

For a maximum of 16 weeks, if necessary, continue taking 22 mg once daily; if sufficient therapeutic benefit is not obtained after 16 weeks, stop taking it.

Maintenance

11 mg PO qDay; in patients who do not respond to maintenance treatment, consider 22 mg qDay (limited to shorter duration).

To maintain response, use the lowest effective dose required.

Tofacitinib: 5 mg PO BID

Tofacitinib extended release: 11 mg PO qDay

It should be caution Ly used in elderly patients due to a higher risk of infection

If the overall lymphocyte count is less than 500 cells/mm3, do not begin.

OR Hgb <9 g/dL OR ANC <1000 cells/mm3.

Biologic disease-modifying antirheumatic medications (DMARDs) or strong immunosuppressants (such as azathioprine or cyclosporine) combined with RA, PsA, or AS are not advised.

UC: Combining this medication with potent immunosuppressants (such as cyclosporine or azathioprine) or biological therapies is not advised.

While taking this medication, avoid grapefruit or grapefruit juice as it could impact its effectiveness. Maintain a healthy lifestyle with regular, gentle exercises and a balanced diet rich in antioxidants like berries, spinach, and dark chocolate. To diminish inflammation, consume flavonoid-containing foods like soy, berries, and green tea. Refrain from smoking and limit alcohol intake to minimize potential interactions and reduce specific side effects.

The dietary restriction should be individualized as per patient requirements.

Treatment with Tofacitinib can lower lymphocyte counts below baseline by approximately 10% over 12 months, associated with increased treated and severe infections for counts below 500 cells/mm³. Do not initiate treatment if the lymphocyte count is less than 500 cells/mm³.

Tofacitinib use may cause neutropenia (ANC <2000 cells/mm³). Avoid treatment if ANC falls below 1000 cells/mm³. Suspend dosing for persistent 500-1000 cells/mm³ ANC; avoid Tofacitinib if <500 cells/mm³. Regularly monitor ANC levels.

Caution is advised if hemoglobin is <9 g/dL before starting Tofacitinib. Interrupt treatment for <8 g/dL or >2 g/dL drop. Monitor haemoglobin levels every 3 months and adjust treatment accordingly.

Tofacitinib usage may elevate liver enzymes; promptly investigate and suspend treatment if drug-induced liver injury is suspected.

Tofacitinib causes dose-dependent lipid increases (total cholesterol, LDL, HDL). Assess lipid parameters after 4-8 weeks and manage according to hyperlipidemia guidelines like the NCEP.

The adverse reactions related to Tofacitinib can be categorized as

Common Adverse Effects: Upper respiratory tract infections, headache, diarrhoea, hypertension, and nausea.

Less Common Adverse Effects: Anemia, hyperlipidemia, liver enzyme elevations, and respiratory tract infections.

Rare Adverse Effects: Severe infections, malignancies, thrombosis, gastrointestinal perforation, and interstitial lung disease.

Immune system abnormalities: Hypersensitivity to drugs

The clinically relevant drug interactions of Tofacitinib are briefly summarized here.

The common side effects of Tofacitinib include: -

Infection of the upper respiratory tract

headache

diarrhoea

nasopharyngitis is an inflammation of the nasal passages and throat.

vomiting

cold

elevated blood pressure

Pregnancy Category C (FDA): Use caution if the benefits outweigh the risks.

There are no sufficient well-controlled studies in pregnant women. Tofacitinib clinical programs reported instances of congenital disabilities and miscarriages.

Animal studies indicate Tofacitinib's potential impact on fetal development. Pregnant rats and rabbits exposed to Tofacitinib during organogenesis showed feticidal and teratogenic effects at 146 times and 13 times the human dose of 5 mg BID, respectively. In rats, Tofacitinib led to reduced live litter size, postnatal survival, and pup weights at approximately 73 times the human dose. As observed in rat studies, females of reproductive potential using Tofacitinib may experience decreased fertility.

Encourage women who are able to get pregnant to use an effective form of birth control during and for a period of time more fantastic than four weeks following the last dose of medication. Inform them to notify the physician immediately if they become pregnant or suspect one while receiving treatment.

The drug's excretion in human milk remains unknown. Rat studies show higher drug concentrations in rat milk than in the mother's blood. Women should avoid breastfeeding during treatment. A decision should be made either to cease breastfeeding or to discontinue therapy, as there is insufficient data to evaluate the drug's impact on the breastfed child.

The safety and effectiveness of Tofacitinib Oral Solution for treating active pcJIA have been established in patients 2 to 17 years of age.

Polyarticular Course Juvenile Idiopathic Arthritis

≥2 years

Oral solution

10 to< 20 kg: 3.2 mg oral BID

20 to < 40 kg: 4 mg oral BID

Oral solution or tablet

More than 40 kg: 5 mg PO BID

Coadministration with strong CYP3A4 inhibitors, OR a moderate CYP3A4 inhibitor(s) with a strong CYP2C19 inhibitor(s)

pcJIA

If taking 3.2 mg BID, switch to 3.2 mg qDay; for 4 mg BID, change to 4 mg qDay; for 5 mg BID, switch to 5 mg qDay.

As per FDA, the safety and efficacy of Tofacitinib in elderly patients above 65 have not been extensively studied or established. Further research is essential to understand its potential benefits and risks in this specific demographic.

When treating patients with diabetes, caution should be exercised because the diabetic population generally has a higher incidence of infection.

Mild impairment: No dosage adjustment is required.

Moderate and Severe Impairment: Patients treated with Tofacitinib who had moderate to severe renal impairment had higher blood concentrations of the medication than patients treated with Tofacitinib who had normal renal function. Consequently, patients with moderate to severe renal impairment (but not limited to those with severe insufficiency who are receiving hemodialysis) should have their dosage of Tofacitinib Oral Solution adjusted.

Mild impairment: No dosage adjustment is required.

Moderate Impairment: Patients treated with Tofacitinib with mild hepatic impairment had higher blood concentrations of the medication than those treated with Tofacitinib who had normal liver function. Specific adverse reactions may be more likely at higher blood concentrations. Therefore, patients with moderate hepatic impairment are advised to adjust their dosage of Tofacitinib Oral Solution.

Severe Impairment: Not recommended in patients with severe hepatic impairment; Not studied.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Tofacitinib.

Overconsumption of Tofacitinib could lead to severe headaches, gastrointestinal issues like diarrhea, nausea, potential infections, elevated liver enzymes, and abnormal blood counts.

There is no specific antidote or treatment for overdosage of Tofacitinib, so treatment typically involves symptomatic and supportive measures. If ingestion is recent, activated charcoal is likely to limit absorption.

It's crucial to continually monitor for signs of toxicity: severe headaches, gastrointestinal distress, infections, altered liver enzymes, or abnormal blood counts. Regularly monitor vital signs, blood counts, and liver function. In severe overdose or adverse effects, provide supportive care and appropriate medical intervention based on observed symptoms. Continuously monitor and offer comprehensive medical care to mitigate potential complications from Tofacitinib overdose.

Tofacitinib (5 mg or 10 mg twice daily) elicited rapid ACR20 responses within two weeks of treatment in placebo-controlled rheumatoid arthritis trials, indicating a 20% or more significant reduction in joint pain, disability, and inflammation. Improved performance was more important than with a placebo. Tuberculosis screening is recommended before starting Tofacitinib, and close monitoring of infections is advised during treatment. Therapy should not be continued if there are active infections; if they are severe, it must be stopped. Since Tofacitinib is linked to a higher risk of lymphoma and other cancers, checking liver function and blood components is essential. It changes immune cells, causes a sharp decline in C-reactive protein, and maintains a drop in CRP after stopping the medication—all of which suggest that its pharmacodynamic effects may last longer than its half-life.

The conventional tablet form of the drug is rapidly and effectively absorbed upon oral administration. The bioavailability reaches 74%, exhibiting a peak plasma concentration within 0.5-1 hour for the conventional tablet and oral solution, while the extended-release tablet takes approximately 4 hours.

It gets evenly distributed between red blood cells and plasma, boasting a substantial volume of distribution at 87 litres. Roughly 40% of the drug binds to plasma proteins, primarily albumin.

Hepatic metabolism via the CYP3A4 enzyme, and to a lesser extent, the CYP2C19 isoenzyme, transforms the compound into inactive metabolites.

Following metabolic processes, approximately 30% of the drug is eliminated through urine, maintaining its unchanged chemical structure. The elimination half-life spans about 3 hours for the conventional tablet and oral solution, while the extended-release tablet exhibits a longer half-life of approximately 6-8 hours.