RUZURGI

1 Dosing Considerations The following situations may affect dosing of RUZURGI (amifampridine)  Dosing should be individualized based on disease severity, patient response, and patient population.  RUZURGI is extensively metabolized/acetylated by N-acetyltransferase 2 (NAT2).

RUZURGI (amifampridine tablets) Product Monograph Page 5 of 29 Therefore, RUZURGI should be initiated at the lowest recommended starting dose possible in patients who are known NAT2 slow acetylators (see DOSAGE AND ADMINISTRATION (3), Recommended Dose and Dosage Adjustment; WARNINGS AND PRECAUTIONS (6), Hepatic/Billiary/Pancreatic; ACTION AND CLINICAL PHARMACOLOGY (9), Genetic Polymorphism).

 RUZURGI can accumulate in patients with renal impairment. In patients with mild and moderate renal impairment, RUZURGI should be initiated at the lowest possible dose and titrated slowly to clinical effect while monitoring for adverse reactions and tolerability.

Additional caution should be exercised when dosing patients with severe renal impairment. No dosing recommendations can be made for patients with end-stage renal disease or those receiving dialysis (see WARNINGS AND PRECAUTIONS (6), Renal; ACTION AND CLINICAL PHARMACOLOGY (9), Renal Impairment).

 To avoid the risk of overdose, RUZURGI should not be taken with other forms of amifampridine or with other aminopyridines (see CONTRAINDICATIONS (2)).  Caution is advised if administering RUZURGI to patients with risk factors for torsade de pointes or in combination with drugs known to prolong QT interval (see WARNINGS AND PRECAUTIONS (6), Cardiovascular; DRUG INTERACTIONS (8); ACTION AND CLINICAL PHARMACOLOGY (9), Pharmacodynamics).

2 Recommended Dose and Dosage Adjustment Dosing should be individualized based on disease severity, patient response, and patient population. The dose should be gradually titrated to the optimal effective dose with the minimum of side effects.

Once achieved, this optimal dose should be maintained, and dosing frequency should be adjusted, as needed. Patients 6 years of age and older RUZURGI should be initiated at the lowest possible dose and titrated slowly to effect while closely monitoring tolerability and adverse events.

The recommended oral dose is based on body weight (see Table 1). 5 mg* to 5 mg increments, divided in up to 5 doses per day 10 mg 40 mg All patients weighing 45 kg or more 10 mg to 20 mg daily, in divided doses (2 to 3 times per day) Increase daily in 5 mg to 10 mg increments, divided in up to 5 doses per day 20 mg 80 mg Some patients may benefit from a total daily dose of 100 mg.

3) for method to achieve these doses. RUZURGI (amifampridine tablets) Product Monograph Page 6 of 29 Known N-acetyltransferase 2 (NAT2) Slow Acetylators: The recommended starting dosage in patients weighing less than 45 kg who are known NAT2 slow acetylators is 5 mg daily taken orally in divided doses, 2 to 3 times per day.

2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials 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 is useful for identifying drug-related adverse events and for approximating rates. 2 times greater than the maximum recommended total daily dose) to 52 healthy adult volunteers (see ACTION AND CLINICAL PHARMACOLOGY (9), Cardiac Electrophysiology).

Adverse reactions that occurred during RUZURGI treatment and with incidence at least 2% greater than placebo treatment are displayed in Table 3. RUZURGI (amifampridine tablets) Product Monograph Page 11 of 29 Table 3 – Adverse Reactions Occurring in ≥1% of Subjects During Ruzurgi Treatment and with at Least 2% Greater Incidence than Placebo System Organ Class (SOC) Adverse Reactions Ruzurgi (n=52) % Placebo (n=49) % Gastrointestinal Disorders Oral dysaesthesia 29 0 Abdominal pain* 25 0 Dyspepsia 17 2 Nausea 10 2 Diarrhea 2 0 General Disorders and Administration Site Conditions Chest discomfort 2 0 Musculoskeletal and Connective Tissue Disorders Back pain 8 2 Muscle spasms 6 2 Pain in extremity 2 0 Nervous System Disorders Dysaesthesia 48 2 Dizziness 12 0 Hypoesthesia 6 0 Dysgeusia 2 0 Paresthesia 2 0 Respiratory, Thoracic and Mediastinal Disorders Hiccups 2 0 Vascular Disorders Hot flush 2 0 Hypotension 2 0 * Includes abdominal pain and upper abdominal pain.

RUZURGI (amifampridine tablets) Product Monograph Page 12 of 29 Subjects classified as slow acetylators based on genotyping for variants of the N- acetyltransferase 2 (NAT2) gene were more likely to experience adverse reactions during RUZURGI treatment than intermediate or rapid acetylators (see ACTION AND CLINICAL PHARMACOLOGY (9), Genetic Polymorphism).

Cardiovascular QTc Interval Prolongation:

RUZURGI can cause QTc interval prolongation in N- acetyltransferase 2 slow acetylators (see ACTION AND CLINICAL PHARMACOLOGY (9), Electrocardiography). Drugs that prolong the QTc increase the risk of torsade de pointes, a polymorphic ventricular tachyarrhythmia.

Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by a drug. Torsade de pointes can be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.

Caution should be observed if RUZURGI is administered to patients who have risk factors for torsade de pointes. , myocardial infarction, heart failure); history of arrhythmias; bradycardia (<50 beats per minute); and electrolyte disorders.

Hypokalemia, hypocalcemia, and hypomagnesemia should be corrected prior to initiation or continuation of RUZURGI. Endocrine and Metabolism Exposure of RUZURGI is increased in patients who are N-acetyltransferase (NAT2) slow acetylators (see ACTION AND CLINICAL PHARMACOLOGY (9)).

Therefore, initiate RUZURGI in patients who are known NAT2 slow acetylators at the lowest recommended starting dose and monitor for adverse reactions. Dose titration should be based on clinical response and tolerability (see DOSAGE AND ADMINISTRATION (3), Recommended Dose and Dosage Adjustment).

Hepatic/Biliary/Pancreatic The effects of RUZURGI have not been studied under controlled conditions in patients or volunteers with any degree of hepatic impairment. Since RUZURGI is extensively metabolized/acetylated by N-acetyltransferase 2 (NAT2), hepatic impairment can cause an increase in exposure.

Therefore, initiate RUZURGI in patients with mild and moderate hepatic impairment using the lowest recommended initial single and total daily doses. Additional caution and monitoring of adverse reactions is recommended for patients with severe hepatic impairment (see DOSAGE AND ADMINISTRATION (3) and ACTION AND CLINICAL PHARMACOLOGY (9), Special Populations and Conditions, Hepatic Impairment).

RUZURGI (amifampridine) is contraindicated in patients who:  Are hypersensitive to this drug or to any ingredient in its formulation, including any non- medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING (5);  Have history of seizures;  Are taking other forms of amifampridine or other aminopyridines.