FLURBIPROFEN

4 Geriatrics 03/2022 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. 9

1 Adverse Reaction Overview The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly.

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. Adverse reaction information was derived from patients who received flurbiprofen in blinded - controlled and open-label clinical trials, and from world wide marketing experience and from publications.

In the tables below, rates of the more common events (greater than 1%) and many of the less common events (less than 1%) represent clinical study results. Of the 4123 patients in premarketing studies, 2954 were treated for at least 1 month, 1448 for at least 3 months, 948 for at least 6 months, 356 for at least 1 year, and 100 for at least 2 years.

The adverse reaction figures represent the percent of treated patients (N=4123) reporting an adverse reaction. Reactions listed in column 2 of the following table occurred in <1% of patients in the clinical trials or were reported during post-marketing experience from other countries.

Reactions listed in column 3 have been reported in patients taking flurbiprofen under circumstances that do not permit a clear attribution of the reaction to flurbiprofen. INCIDENCE GREATER THAN 1% INCIDENCE LESS THAN 1% (CAUSAL RELATIONSHIP PROBABLE) INCIDENCE LESS THAN 1% (CAUSAL RELATIONSHIP UNKNOWN) FLURBIPROFEN (flurbiprofen) Page 19 of 41 INCIDENCE GREATER THAN 1% INCIDENCE LESS THAN 1% (CAUSAL RELATIONSHIP PROBABLE) INCIDENCE LESS THAN 1% (CAUSAL RELATIONSHIP UNKNOWN) CARDIOVASCULAR Heart failure, hypertension, vascular disease and vasodilation.

4 Geriatrics 03/2022 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. 9 7 WARNINGS AND PRECAUTIONS ..................................................................................

1 Special Populations .......................................................................................... 18 8 ADVERSE REACTIONS ..................................................................................................

1 Adverse Reaction Overview .............................................................................. 2 Clinical Trial Adverse Reactions ........................................................................ 5 Post-Market Adverse Reactions ........................................................................

20 9 DRUG INTERACTIONS.................................................................................................. 2 Drug Interactions Overview .............................................................................. 3 Drug-Behavioural Interactions ..........................................................................

4 Drug- Drug Interactions .................................................................................... 5 Drug-Food Interactions .................................................................................... 6 Drug-Herb Interactions.....................................................................................

7 Drug-Laboratory Test Interactions .................................................................... 25 10 CLINICAL PHARMACOLOGY ......................................................................................... 1 Mechanism of Action .......................................................................................

2 Pharmacodynamics .......................................................................................... 3 Pharmacokinetics............................................................................................. 26 11 STORAGE, STABILITY AND DISPOSAL ...........................................................................