LEFLUNOMIDE

2 Recommended Dose and Dosage Adjustment Loading Dose Due to the long half-life in patients with rheumatoid arthritis and recommended dosing interval (24 hr), a loading dose is needed to yield steady-state concentrations more rapidly.

It is recommended that LEFLUNOMIDE therapy be initiated with a loading dose of one 100 mg tablet per day for 3 days. Maintenance Therapy Daily dosing of 20 mg is recommended for treatment of patients with rheumatoid arthritis. A small cohort of patients (n=104) treated with 25 mg/day experienced a greater incidence of side LEFLUNOMIDE Page 6 of 77 effects: alopecia, weight loss, liver enzyme elevations.

Doses higher than 20 mg/day are not recommended. If dosing at 20 mg/day is not well tolerated clinically, the dose may be decreased to 10 mg daily. Due to the prolonged half-life of the active metabolite of leflunomide, patients should be carefully observed after dose reduction since it may take several weeks for metabolite levels to decline (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section).

A treatment effect may be evident after 4 weeks and may further improve up to 4 to 6 months after start of treatment. Geriatric Use (≥ 65 years) No dosage adjustment is needed in patients over 65 years of age. Pediatrics Use (< 18 years) The use in patients less than 18 years of age is contraindicated.

Dose Modification for Patients with Renal ImpairmentBecause the kidney plays a role in the elimination of leflunomide, and without sufficient studies of the use of leflunomide in patients with renal insufficiency, caution should be used when considering the administration of LEFLUNOMIDE to patients with mild renal insufficiency (see 2 CONTRAINDICATIONS section).

4 Administration LEFLUNOMIDE tablets should be swallowed whole, with sufficient liquid. LEFLUNOMIDE can be taken with or without food, without regard to meals, at the same time everyday. 5 Missed Dose If the patient forgot to take a tablet of LEFLUNOMIDE they should be advised to take it as soon as they remember, unless it is nearly time for their next dose.

The patient should be advised not to double-up on the next dose to make up for the missed dose.

section). The most frequent adverse events observed were diarrhea, abdominal pain, leucopenia, anemia and elevated liver function tests. In the event of relevant overdose or toxicity, cholestyramine or activated charcoal administration is recommended.

LEFLUNOMIDE Page 7 of 77 Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of A771726 by approximately 40% in 24 hours and by 49- 65% in 48 hours (see 7 WARNINGS AND PRECAUTIONS, General, Washout Procedures section).

Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite, A771726, by 37% in 24 hours and by 48% in 48 hours.

These washout procedures may be repeated if clinically necessary. Studies with both hemodialysis and CAPD (chronic ambulatory peritoneal dialysis) indicate that A771726, the primary metabolite of leflunomide, is not dialyzable. For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1- 844-764-7669).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 1 – Dosage Forms, Strengths, Composition and Packaging Route of Administration Dosage Form/ Strength/ Composition Non-medicinal Ingredients oral film-coated tablets 10 mg and 20 mg Colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxide yellow, lactose anhydrous, lactose monohydrate impalpable, magnesium stearate, polyethylene glycol, povidone, pregelatinized starch, polydextrose, polysorbate 80, talc, titanium dioxide and triethyl citrate.

, Perioperative Considerations 03/2026 7 WARNINGS AND PRECAUTIONS, Skin 03/2026 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES .............................................................................................

2 TABLE OF CONTENTS................................................................................................................ 2 PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................

4 1 INDICATIONS ............................................................................................................. 4 2 CONTRAINDICATIONS ................................................................................................

4 4 DOSAGE AND ADMINISTRATION................................................................................ 6 5 OVERDOSAGE ............................................................................................................

6 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................... 7 7 WARNINGS AND PRECAUTIONS ................................................................................. 18 8 ADVERSE REACTIONS ...............................................................................................

23 9 DRUG INTERACTIONS............................................................................................... 31 10 CLINICAL PHARMACOLOGY ..................................................................................... 32 11 STORAGE, STABILITY AND DISPOSAL ........................................................................

34 12 SPECIAL HANDLING INSTRUCTIONS ......................................................................... 34 PART II: SCIENTIFIC INFORMATION ........................................................................................

LEFLUNOMIDE is contraindicated in: • Patients with known hypersensitivity to leflunomide (especially previous Stevens- Johnson syndrome, toxic epidermal necrolysis or erythema multiforme), to teriflunomide or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging section. , AIDS) (see 7 WARNINGS AND PRECAUTIONS, Immune section). • Patients with impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid arthritis.

• Patients with serious infections. • Patients with moderate to severe renal insufficiency because the kidney plays a role in the elimination of leflunomide. , Disease Modifying Antirheumatic Drugs [DMARDs] such as methotrexate) given the possible risk of increased hepatotoxicity and the role of the liver in activation, elimination and recycling of leflunomide (see 9 DRUG INTERACTIONS section).

LEFLUNOMIDE Page 5 of 77 While the mechanism of action of leflunomide and methotrexate are different, their pharmacodynamic action of interfering with cell division is similar. Concomitant treatment with methotrexate and/or other liver and bone marrow toxic medications is associated with an increased risk of serious hepatic or marrow reactions and requires strict vigilance in monitoring (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests section).

If a switch in treatment from LEFLUNOMIDE to another hepatotoxic DMARD is required the washout and monitoring must be adhered to as mentioned in the WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests and General, Washout procedures section).

g. in nephrotic syndrome). Since the active metabolite of leflunomide, A771726, is highly protein-bound and cleared via hepatic metabolism and biliary secretion. 02 mg/L). Pregnancy must be excluded before start of treatment with LEFLUNOMIDE (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Pregnancy section).