RUZURGI Tablet Ref.[11071] Active ingredients: Amifampridine

5.1 Seizures

RUZURGI can cause seizures. Seizures have been observed in patients with and without a history of seizures taking RUZURGI at the recommended doses, and at various times after initiation of treatment. Many of the patients were taking medications or had comorbid medical conditions that may have lowered the seizure threshold [see Drug Interactions (7.1)]. Seizures may be dose-dependent. Because seizure events were captured retrospectively from expanded access programs, it is not possible to reliably estimate their frequency with use of RUZURGI. Consider discontinuation or dose-reduction of RUZURGI in patients who have a seizure while on treatment. RUZURGI is contraindicated in patients with a history of seizures.

5.2 Hypersensitivity

In clinical trials, hypersensitivity reactions and anaphylaxis associated with RUZURGI administration have not been reported. Anaphylaxis has been reported in patients taking another aminopyridine; therefore, it may occur with RUZURGI. If anaphylaxis occurs, administration of RUZURGI should be discontinued and appropriate therapy initiated.

The following serious adverse reactions are described elsewhere in the labeling:

• Seizures [see Warnings and Precautions (5.1)]
• Hypersensitivity [see Warnings and Precautions (5.2)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In a double-blind, 3-way crossover, pharmacology study to assess the effects of RUZURGI on QTc interval prolongation, RUZURGI was administered at doses greater than the maximum recommended dose (120 mg administered as 4 equal doses of 30 mg at 4-hour intervals) to 52 healthy adult volunteers [see Clinical Pharmacology (12.2)]. Adverse reactions that occurred in at least 5% of subjects during RUZURGI treatment and with incidence at least 2% greater than during placebo treatment are displayed in Table 2.

Table 2. Adverse Reactions Occurring in at Least 5% of Subjects During RUZURGI Treatment and With at Least 2% Greater Incidence Than Placebo:

^* Includes paresthesia, dysesthesia, and oral dysesthesias.
^** Includes abdominal pain and upper abdominal pain.

Subjects classified as poor metabolizers based on rate of metabolism were more likely to experience adverse reactions during RUZURGI treatment than intermediate or normal metabolizers [see Clinical Pharmacology (12.5)].

Expanded Access Experience

In expanded access programs, 162 patients with LEMS (54% female) were treated with RUZURGI. Among patients with available exposure data, the median duration of treatment was 1.7 years (range 1 day to 27.6 years) for a total of 766.4 person years. Patient age at the time RUZURGI was initiated ranged from 21 to 84 years (mean 58.7 years). The median of the maximum total daily dosage was 75 mg/day.

In general, the most frequent adverse reactions observed in the expanded access programs were similar to those observed in the QT study. Additionally, the following adverse reactions were reported in ≥5% of patients: falls, diarrhea, pneumonia, dyspnea, arthralgia, asthenia, depression, dysphagia, headache, insomnia, vision blurred, anemia, anxiety, constipation, feeling cold, gastroesophageal reflux disease, and pain. Because these reactions were captured retrospectively from expanded access programs, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Pediatric Patients (6 to Less than 17 Years of Age)

Safety of RUZURGI was evaluated in pediatric LEMS and non-LEMS patients 6 to less than 17 years of age who were treated in expanded access programs. There were 15 patients ages 6 to less than 17 years who received RUZURGI, of whom 9 received RUZURGI for at least 1 year. Adverse reactions reported in pediatric patients 6 to less than 17 years of age were similar to those seen in adult patients.

7.1 Drugs that Lower Seizure Threshold

The concomitant use of RUZURGI and drugs that lower seizure threshold may lead to an increased risk of seizures [see Warnings and Precautions (5.1)]. The decision to administer RUZURGI concomitantly with drugs that lower the seizure threshold should be carefully considered in light of the severity of the associated risks.

7.2 Drugs with Cholinergic Effects

The concomitant use of RUZURGI and drugs with cholinergic effects (e.g., direct or indirect cholinesterase inhibitors) may increase the cholinergic effects of RUZURGI and of those drugs and increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].

Risk Summary

There are no data on the developmental risk associated with the use of RUZURGI in pregnant women.

Animal studies to assess the potential adverse effects of amifampridine on embryofetal development have not been conducted.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Risk Summary

There are no data on the presence of amifampridine or the 3-N-acetyl-amifampridine metabolite in human milk, the effects on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RUZURGI and any potential adverse effects on the breastfed infant from RUZURGI or from the underlying maternal condition.

Safety and effectiveness of RUZURGI have been established in patients 6 to less than 17 years of age. Use of RUZURGI in patients 6 to less than 17 years of age is supported by evidence from adequate and well-controlled studies of RUZURGI in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients, and safety data from pediatric patients 6 to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

Renal clearance is an elimination pathway for amifampridine and the inactive metabolite, 3-N-acetyl amifampridine [see Clinical Pharmacology (12.3)]. Therefore, in patients with renal impairment, RUZURGI should be initiated at the lowest recommended starting dosage and patients should be closely monitored for adverse reactions [see Dosage and Administration (2.3)]. Consider dosage modification or discontinuation of RUZURGI for patients with renal impairment as needed based on clinical effect and tolerability. No dosage recommendations for RUZURGI can be made for patients with end-stage renal disease (CLcr<15 mL/min or patients requiring dialysis).

The effects of RUZURGI have not been studied in patients with hepatic impairment. RUZURGI is extensively metabolized by N-acetyltransferase 2 (NAT2), and hepatic impairment may cause an increase in exposure. Therefore, initiate RUZURGI in patients with any degree of hepatic impairment at the lowest recommended starting dosage and monitor for adverse reactions [see Dosage and Administration (2.4)]. Consider dosage modification or discontinuation of RUZURGI for patients with hepatic impairment as needed based on clinical effect and tolerability.

8.8 NAT2 Poor Metabolizers

Exposure of RUZURGI is increased in patients who are N-acetyltransferase 2 (NAT2) poor metabolizers [see Clinical Pharmacology (12.5)]. Therefore, initiate RUZURGI in patients who are known NAT2 poor metabolizers at the lowest recommended starting dosage and monitor for adverse reactions [see Dosage and Administration (2.5)]. Consider dosage modification of RUZURGI for patients who are known NAT2 poor metabolizers as needed based on clinical effect and tolerability.