APO-DIMETHYL FUMARATE

2 Recommended Dose and Dosage Adjustment 01/2023 7 WARNINGS AND PRECAUTIONS, Hematologic 05/2024 7 WARNINGS AND PRECAUTIONS, Immune 01/2023 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 ....................................................................................................................

1 Pediatrics ........................................................................................................................ 2 Geriatrics ........................................................................................................................

4 2 CONTRAINDICATIONS ....................................................................................................... 4 4 DOSAGE AND ADMINISTRATION .......................................................................................

1 Dosing Considerations .................................................................................................... 2 Recommended Dose and Dosage Adjustment ................................................................ 4 Administration ................................................................................................................

5 Missed Dose ................................................................................................................... 6 5 OVERDOSAGE ...................................................................................................................

6

, Clinical Trial Adverse Reactions). Administration of APO-DIMETHYL FUMARATE with food or a temporary dose reduction to 240 mg/day may improve tolerability in patients who experience gastrointestinal adverse events (see 4 DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Dimethyl fumarate has not been evaluated in patients with severe active gastrointestinal disease and caution should be exercised when treating these patients. Hematologic APO-DIMETHYL FUMARATE may decrease lymphocyte counts (see 8 ADVERSE REACTIONS, Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data).

In the MS placebo-controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate then remained stable at this reduced level for the duration of treatment. 91 x APO-DIMETHYL FUMARATE (dimethyl fumarate delayed-release capsules) Page 8 of 42 109/L).

8 x 109/L for at least six months. 5 x 109/L with continued therapy. Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. 2 Pharmacodynamics. The following precautions should be taken: • Prior to initiating treatment with APO-DIMETHYL FUMARATE, obtain a complete blood count (CBC), including lymphocytes, if no recent (within 6 months) result is available.

A CBC, including lymphocytes, is also recommended after 6 months of treatment, then every 6 to 12 months, and as clinically indicated. 5 x 109/L persisting for more than 6 months. • Assess the benefit-risk in patients who experience moderate lymphopenia for more than 6 months.

• In patients with lymphocyte counts below lower limit of normal (LLN) as defined by local laboratory reference range, regular monitoring of absolute lymphocyte counts is recommended. Additional factors that might further augment the individual PML risk should be considered (see also Progressive Multifocal Leukoencephalopathy below).

• In all cases of lymphopenia, lymphocyte counts should be followed until recovery. Where APO-DIMETHYL FUMARATE treatment has been stopped, decisions about whether or not to restart APO-DIMETHYL FUMARATE should be individualized based on clinical circumstances.

• A CBC is also recommended prior to switching patients to other therapies that are known to reduce lymphocyte counts to avoid additive immune effects (see 8 ADVERSE REACTIONS, Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data).

• Patients with pre-existing low lymphocyte counts, and patients concomitantly taking other immunomodulating treatments, were excluded from the multiple sclerosis clinical trials. , immunodeficiency syndrome), due to the potential risk of additive immune system effects.

Hepatic/Biliary During clinical trials in patients with multiple sclerosis, elevations in liver transaminases (ALT and AST) > 1 x the upper limit of normal (ULN) and less than 3 x ULN occurred more frequently in patients treated with dimethyl fumarate than in patients that received placebo.

The increased incidence of elevations of hepatic transaminases in patients treated with dimethyl APO-DIMETHYL FUMARATE (dimethyl fumarate delayed-release capsules) Page 9 of 42 fumarate relative to placebo was primarily seen during the first 6 months of treatment (see 8 ADVERSE REACTIONS, Clinical Trial Adverse Reactions, Hepatic Transaminases).

Prior to initiating treatment with APO-DIMETHYL FUMARATE, serum aminotransferase, alkaline phosphatase and total bilirubin levels should be obtained (within 6 months). During treatment, evaluation of transaminases is recommended after 6 months of treatment, then every 6 to 12 months, and as clinically indicated.

Discontinue APO-DIMETHYL FUMARATE if clinically significant liver injury induced by APO- DIMETHYL FUMARATE is suspected. Clinically significant cases of liver injury have been reported in patients treated with dimethyl fumarate in the postmarketing setting.

The onset has ranged from a few days to several months after initiation of treatment with dimethyl fumarate. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed.

These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients.

Immune Infections:

Treatment with APO-DIMETHYL FUMARATE should not be initiated in patients with signs and symptoms of a serious infection. Decreases in lymphocyte counts observed in patients treated with dimethyl fumarate in clinical trials were not associated with increased frequencies of infections.

However, due to the potential risk of infections in patients who develop sustained lymphopenia, patients should be […]

, Hematologic 05/2024 7 WARNINGS AND PRECAUTIONS, Immune 01/2023 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 .................................................................................................................... 1 Pediatrics ........................................................................................................................

2 Geriatrics ........................................................................................................................ 4 2 CONTRAINDICATIONS .......................................................................................................

4 4 DOSAGE AND ADMINISTRATION ....................................................................................... 1 Dosing Considerations ....................................................................................................

2 Recommended Dose and Dosage Adjustment ................................................................ 4 Administration ................................................................................................................

5 Missed Dose ................................................................................................................... 6 5 OVERDOSAGE ...................................................................................................................

6 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING....................................... 6 7 WARNINGS AND PRECAUTIONS ........................................................................................ 1 Special Populations .......................................................................................................

1 Pregnant Women .................................................................................................. 2 Breast-feeding .......................................................................................................

3 Pediatrics ............................................................................................................... 4 Geriatrics ...............................................................................................................

13 8 ADVERSE REACTIONS ...................................................................................................... 1 Adverse Reaction Overview ..........................................................................................

2 Clinical Trial Adverse Reactions .................................................................................... 3 Less Common Clinical Trial Adverse Reactions ............................................................. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data......................................................................................................................................

5 Post-Market Adverse Reactions .................................................................................... 18 9 DRUG INTERACTIONS ......................................................................................................

2 Drug Interactions Overview .......................................................................................... 4 Drug-Drug Interactions .................................................................................................

5 Drug-Food Interactions ................................................................................................. 22 10 CLINICAL PHARMACOLOGY .............................................................................................

1 Mechanism of Action .................................................................................................... 2 Pharmacodynamics.......................................................................................................

3 Pharmacokinetics ......................................................................................................... 24 11 STORAGE, STABILITY AND DISPOSAL ...............................................................................

26 12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 26 PART II: SCIENTIFIC INFORMATION ........................................................................................

27 13 PHARMACEUTICAL INFORMATION ................................................................................. 27 14 CLINICAL TRIALS ..............................................................................................................

1 Clinical Trials by Indication ........................................................................................... 3 Comparative Bioavailability Studies ..............................................................................

31 15 MICROBIOLOGY .............................................................................................................. 33 16 NON-CLINICAL TOXICOLOGY ...........................................................................................

33 17 SUPPORTING PRODUCT MONOGRAPHS.......................................................................... 35 PATIENT MEDICATION INFORMATION ................................................................................... 36 APO-DIMETHYL FUMARATE […]