Tofacit XR11 mg

Established / FDA-Approved Uses

• Rheumatoid arthritis (RA): Moderately to severely active RA in adults who have had an inadequate response or intolerance to methotrexate. Tofacit XR may be used as monotherapy or in combination with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs).
• Psoriatic arthritis (PsA): Active PsA in adults who have had an inadequate response or intolerance to methotrexate or other DMARDs, usually used in combination with a non-biologic DMARD such as methotrexate.
• Ulcerative colitis (UC): Moderately to severely active UC in adults who have had an inadequate response, loss of response, or intolerance to a TNF blocker.
• Polyarticular course juvenile idiopathic arthritis (pJIA): Active pJIA in children 2 years of age and older.

Important Limitation

Tofacit XR is not recommended for use in combination with biologic DMARDs (e.g. TNF blockers, IL-1 or IL-6 antagonists) or with potent immunosuppressants such as azathioprine or cyclosporine, because of the possibility of increased immunosuppression and increased risk of infection.

Given the extensive boxed warnings associated with Tofacit XR (see Precautions and Warnings), it is generally reserved for patients who have not responded adequately to other therapies, and the lowest effective dose should be used for the shortest duration consistent with treatment goals.

Tofacit XR is an oral Janus kinase (JAK) inhibitor used to treat certain chronic inflammatory and autoimmune conditions, including rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis.

By blocking JAK enzymes involved in the signaling of multiple inflammatory cytokines, Tofacit XR reduces the immune-driven inflammation responsible for joint damage and gastrointestinal mucosal injury in these diseases. Because it works by suppressing part of the immune system, Tofacit XR carries important safety warnings, including increased risks of serious infection, malignancy, major cardiovascular events, and blood clots, and its use requires careful patient selection and monitoring.

Janus Kinase (JAK) Inhibitor / Immunosuppressant (targeted synthetic DMARD)

Tofacitinib is a small-molecule Janus kinase (JAK) inhibitor. It works intracellularly to modulate the signaling of cytokines and growth factors that are important for immune cell function, hematopoiesis, and inflammation.

At clinically relevant concentrations, Tofacitinib preferentially inhibits signaling by receptors that associate with JAK1 and/or JAK3, with functional selectivity over receptors that signal via pairs of JAK2. This inhibition blocks the phosphorylation and activation of signal transducers and activators of transcription (STATs), which in turn reduces the transcription of genes involved in the inflammatory cascade seen in rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

Tofacitinib is well absorbed orally, metabolized primarily in the liver via CYP3A4 (with a minor contribution from CYP2C19), and eliminated through both hepatic metabolism and renal excretion, with an elimination half-life of approximately 3 hours for the immediate-release formulation.

Clinically Significant Drug Interactions

• Strong CYP3A4 inhibitors (e.g. ketoconazole): Increase Tofacit XR plasma concentrations; the Tofacit XR dose should be reduced when co-administered.
• Combined moderate CYP3A4 and strong CYP2C19 inhibitors (e.g. fluconazole): Also increase Tofacit XR exposure and require dose reduction.
• Strong CYP3A4 inducers (e.g. rifampin): Substantially reduce Tofacit XR efficacy by lowering plasma concentrations; co-administration with Tofacit XR is not recommended.
• Biologic DMARDs (TNF blockers, IL-1/IL-6 antagonists, abatacept) and potent immunosuppressants (azathioprine, cyclosporine, tacrolimus): Combining these with Tofacit XR increases the risk of serious infection and additive immunosuppression; concurrent use is not recommended.
• Live vaccines: Concurrent use with Tofacit XR should be avoided due to the risk of disseminated infection from the vaccine strain — see Precautions and Warnings.

Inform your physician and pharmacist of all prescription and over-the-counter medicines, herbal products, and supplements before starting Tofacit XR.

Common Side Effects

• Upper respiratory tract infection and nasopharyngitis (common cold-type symptoms)
• Headache
• Diarrhea
• Elevated blood pressure
• Elevated cholesterol/lipid levels
• Rash
• Herpes zoster (shingles)

Serious Side Effects

Serious infections, malignancy, major adverse cardiovascular events, and blood clots (venous and arterial thrombosis) can occur with Tofacit XR — these are subjects of the FDA boxed warnings; see Precautions and Warnings for details and warning signs to watch for. Other serious but less common effects include gastrointestinal perforation, significant elevations in liver enzymes, and low blood counts (lymphopenia, neutropenia, anemia).

Seek prompt medical attention for signs of infection (fever, chills, persistent cough), chest pain or shortness of breath, one-sided limb swelling or pain, sudden weakness or vision changes, or unusual bleeding while taking Tofacit XR.

Pregnancy: Animal reproduction studies with Tofacit XR have shown adverse effects on the fetus at high exposures, and adequate, well-controlled studies in pregnant women are lacking. Tofacit XR should be used during pregnancy only if the potential benefit to the mother clearly justifies the potential risk to the fetus, and only under close physician supervision. Women who become pregnant while taking Tofacit XR should notify their physician promptly; enrollment in a pregnancy exposure registry may be recommended where available.

Lactation: Tofacit XR passes into breast milk in animal studies, and breastfeeding is generally advised against during treatment and for a period after the last dose. Discuss the risks and benefits of breastfeeding with your physician, who may recommend an alternative feeding method during therapy.

Boxed Warnings

Tofacit XR carries U.S. FDA boxed (black box) warnings for the following:

• Serious infections: Serious infections leading to hospitalization or death have occurred, including tuberculosis (including reactivation of latent TB), invasive fungal infections, and bacterial, viral, and other opportunistic infections. Screen for latent tuberculosis before starting Tofacit XR and monitor throughout treatment; do not start Tofacit XR in patients with an active infection.
• Increased mortality: In a large safety study of patients with rheumatoid arthritis aged 50 years and older with at least one cardiovascular risk factor, Tofacit XR was associated with a higher rate of all-cause mortality compared with TNF-blocker therapy.
• Malignancy: Lymphomas and other malignancies, including skin cancers, have been observed in patients treated with Tofacit XR. Periodic skin examination is recommended, particularly in patients at increased risk of skin cancer.
• Major adverse cardiovascular events (MACE): Increased risk of heart attack, stroke, and cardiovascular death has been observed with Tofacit XR, particularly in patients 50 years and older with at least one additional cardiovascular risk factor.
• Thrombosis: Cases of deep vein thrombosis, pulmonary embolism, and arterial thrombosis, some fatal, have occurred with Tofacit XR, especially at higher doses and in patients with underlying thrombosis risk factors. Seek urgent care for symptoms such as sudden shortness of breath, chest pain, or leg swelling/pain.

Other Warnings and Precautions

• Laboratory monitoring: Baseline and periodic monitoring of complete blood count (lymphocytes, neutrophils, hemoglobin), liver function tests, and lipid panel is required during Tofacit XR therapy; dose interruption or discontinuation is advised for significant abnormalities.
• Live vaccines: Avoid live/attenuated vaccines during treatment with Tofacit XR; ensure vaccinations, including for herpes zoster, are brought up to date before starting therapy where possible.
• Gastrointestinal perforation: Use with caution in patients with risk factors for GI perforation (e.g. history of diverticulitis, concurrent NSAID or corticosteroid use).
• Hepatic effects: Elevations in liver enzymes can occur; use caution when initiating in patients with pre-existing liver disease.
• Lipid changes: Increases in total cholesterol, LDL, and HDL may occur; assess lipid parameters approximately 4-8 weeks after starting therapy and manage according to clinical guidelines.

Do not start, stop, or change the dose of Tofacit XR without consulting your physician, given the extent of these safety considerations.

There is no specific antidote for Tofacit XR overdose. In case of a suspected overdose of Tofacit XR, seek immediate medical attention or contact a poison control center. Treatment is supportive, with monitoring for signs and symptoms of adverse reactions (such as infection, unusual bleeding/clotting, or cardiovascular symptoms). Because Tofacit XR undergoes significant non-renal clearance, hemodialysis is of limited value in removing the drug from the body. Do not attempt to manage a Tofacit XR overdose at home.

Store at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

Pediatric Use

Tofacit XR is approved for polyarticular course juvenile idiopathic arthritis in children 2 years of age and older, using weight-based dosing (see Dosage and Administration). Safety and efficacy in children below 2 years of age, and for indications other than pJIA, have not been established.

Geriatric Use

Patients 65 years and older, and particularly those 50 years and older with at least one cardiovascular risk factor, are at increased risk of serious infection, malignancy, major cardiovascular events, and mortality with Tofacit XR — see Precautions and Warnings. Use the lowest effective dose in elderly patients and monitor closely.

Renal Impairment

Dose reduction of Tofacit XR is required in patients with moderate to severe renal impairment — see Dosage and Administration.

Hepatic Impairment

Dose reduction of Tofacit XR is required in moderate hepatic impairment; use in severe hepatic impairment is not recommended.

Janus Kinase (JAK) Inhibitors; Targeted Synthetic Disease-Modifying Antirheumatic Drugs (tsDMARDs); Immunosuppressants