ARTHROTEC

1 Dosing Considerations Use of ARTHROTEC should be limited to the lowest effective dose for the shortest possible duration of treatment in order to minimize the potential risk for cardiovascular or gastrointestinal adverse events (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS ).

4 Geriatrics). g. hypertension, hyperlipidemia, diabetes mellitus and smoking). These patients should be treated with ARTHROTEC only after careful consideration (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX). • Renal Insufficiency: In patients with mild to moderate renal insufficiency, the lowest dose of ARTHROTEC should be considered, and patients should be monitored closely (see 7 WARNINGS AND PRECAUTIONS – Renal).

5mL/sec) (see 2 CONTRAINDICATIONS). • Hepatic Insufficiency: If ARTHROTEC must be used in patients with mild to moderate hepatic impairment, these patients must be closely monitored (see 7 WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic).

ARTHROTEC is contraindicated in patients with significant hepatic impairment or active liver disease (see 2 CONTRAINDICATIONS). Diclofenac metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. 2 Drug Interactions Overview).

g. antibiotics, anti-epileptics). 2 Recommended Dose and Dosage Adjustment • Use of ARTHROTEC should be limited to the lowest effective dose and the shortest possible duration of treatment in every patient (see 7 WARNINGS AND PRECAUTIONS).

• The recommended daily oral dose of ARTHROTEC (diclofenac sodium plus misoprostol) for treating the signs and symptoms of rheumatoid arthritis and osteoarthritis is 100 mg administered as two divided doses (50 mg twice per day) (see 7 WARNINGS AND PRECAUTIONS – Cardiovascular).

• The recommended maximum daily dose is 100 mg. 4 Administration ARTHROTEC should be taken immediately after a meal or with food or milk and the tablets should be swallowed whole. 5 Missed Dose If a dose of ARTHROTEC is missed, the next dose should be taken at the regular time.

The dose should not be doubled.

1 Adverse Reaction Overview The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.

Most fatal gastrointestinal events occur in the elderly or debilitated patients. Gastrointestinal adverse events can develop at any time in the course of the therapy. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.

The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

In clinical trials, 3549 arthritic patients have been treated with ARTHROTEC (diclofenac sodium plus misoprostol), 506 of whom received ARTHROTEC for more than one year. A total of 285 patients have been treated with ARTHROTEC 75 in clinical trials for a duration of up to 12 weeks.

0 1 A50 = Arthrotec 50 2 D50 = Diclofenac 50mg 3 A75 = Arthrotec 75 4 D75 = Diclofenac 75 mg *Patients must have experienced ulceration in order to enter study. 1 Clinical Trial Adverse Reactions – Pediatrics At the time of authorization, no clinical trials in the pediatric population have been conducted.

3 Less Common Clinical Trial Adverse Reactions The following adverse events were reported by 1% or less of the subjects receiving ARTHROTEC. Causal relationships between ARTHROTEC and these events have not been established but cannot be excluded.

Body as a Whole: hot flushes, malaise, rigors Blood and lymphatic system disorders: leukopenia and thrombocytopenia Cardiovascular: palpitation and syncope Female reproductive disorders: menstrual disorder, intermenstrual bleeding, dysmenorrhea, leukorrhea, vaginal bleeding, breast pain and uterine cramping.

1 pregnant women 02/2022 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 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 5 4 DOSAGE AND ADMINISTRATION ................................................................................. 7 5 OVERDOSAGE..............................................................................................................

7 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8 7 WARNINGS AND PRECAUTIONS .................................................................................. 17 8 ADVERSE REACTIONS ................................................................................................

21 9 DRUG INTERACTIONS ................................................................................................ 25 10 CLINICAL PHARMACOLOGY .......................................................................................

26 11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 28 12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 28 PART II: SCIENTIFIC INFORMATION .......................................................................................