DRUG INTERACTIONS

 Drugs that lower seizure threshold: The concomitant use of FIRDAPSE and drugs that lower seizure threshold may lead to an increased risk of seizures. 

The decision to administer FIRDAPSE concomitantly with drugs that lower the seizure threshold should be carefully considered in light of the severity of the associated risks.

Drugs with cholinergic effects:                                                                                     The concomitant use of FIRDAPSE and drugs with cholinergic effects (e.g., direct or indirect cholinesterase inhibitors) may increase the cholinergic effects of FIRDAPSE and of those drugs, and increase the risk of adverse reactions. 

BRIEF SUMMARY

AMIFAMPRIDINE (Nov 2018)

Indn-         To treat Lambert-Eaton myasthenic syndrome (LEMS)  in adults

Comp-          Tablets: 10 mg, functionally scored    * Starting dosage is 15 mg daily for patients with renal impairment, hepatic impairment, and in known N-acetyltransferase 2 (NAT2) poor metabolizers                                                                                               Dosage can be increased by 5 mg daily every 3 to 4 days. Dosage is not to exceed a maximum of 80 mg daily. The maximum single dose is 20 mg

ADR-      The most common (> 10%) adverse reactions are: paresthesia, upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension, and muscle spasms.

CI-    FIRDAPSE is contraindicated in patients with:  A history of seizures  Hypersensitivity to amifampridine or another aminopyridine   

WARNINGS-

 Seizures:                                                                                                            FIRDAPSE can cause seizures. Consider discontinuation or dose-reduction of FIRDAPSE in patients who have a seizure while on treatment.

Pat Infm-

Risk of Seizures- Inform patients that FIRDAPSE can cause seizures, and to notify their healthcare provider if they experience a seizure                                             

 Hypersensitivity- Instruct patients to inform their healthcare provider if they have signs or symptoms of hypersensitivity, and to seek emergency help if symptoms of anaphylaxis occur 

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  54

WARNINGS AND PRECAUTIONS

 Seizures:                                                                                                            FIRDAPSE can cause seizures. Consider discontinuation or dose-reduction of FIRDAPSE in patients who have a seizure while on treatment.

ADVERSE REACTIONS

 The most common (> 10%) adverse reactions are: paresthesia, upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension, and muscle spasms.

WARNINGS AND PRECAUTIONS

 Seizures:                                                                                                            FIRDAPSE can cause seizures. Consider discontinuation or dose-reduction of FIRDAPSE in patients who have a seizure while on treatment.

 Hypersensitivity reactions:                                                                                              If a hypersensitivity reaction such as anaphylaxis occurs, FIRDAPSE should be discontinued and appropriate therapy initiated. 

 PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Risk of Seizures

Inform patients that FIRDAPSE can cause seizures, and to notify their healthcare provider if they experience a seizure 

Hypersensitivity

Instruct patients to inform their healthcare provider if they have signs or symptoms of hypersensitivity, and to seek emergency help if symptoms of anaphylaxis occur 

FIRDAPSE Dosing

Instruct patients to take FIRDAPSE exactly as prescribed.

Patients should carefully followthe dose escalation schedule provided by their healthcare provider to safely achieve the therapeutic dosage 

Inform patients that the tablets may be divided in half at the score, if needed.

Instruct patients not to take a double dose to make up for a missed dose.

Drug Interactions

Instruct patients to notify their healthcare provider prior to starting any new medication, including over-the-counter drugs 

. Storage

Advise patients to store FIRDAPSE at 68ºF to 77ºF (20ºC to 25ºC).

Distributed by Catalyst Pharmaceuticals, Inc., Coral Gables, FL 33134.

FIRDAPSE is a trademark of Catalyst Pharmaceuticals, Inc.

Catalyst and the Catalyst logo are trademarks of Catalyst Pharmaceuticals, Inc. © 201X Catalyst Pharmaceuticals, Inc. – All rights reserved.

 CLINICAL PHARMACOLOGY

1 .Mechanism of Action

The mechanism by which amifampridine exerts its therapeutic effect in LEMS patients has not been fully elucidated. Amifampridine is a broad spectrum potassium channel blocker.

2 Pharmacodynamics

The effect of FIRDAPSE on QTc interval prolongation was studied in a double blind, randomized, placebo and positive controlle d study in 52 healthy individuals who are slow acetylators.

At an exposure 2-fold the expected maximum therapeutic exposure of amifampridine, FIRDAPSE did not prolong QTc to any clinically relevant extent.

3. Pharmacokinetics

The pharmacokinetics of amifampridine are similar between healthy individuals and LEMS patients.

Following single and multiple doses, AUC, Cmax and Cmin were highly variable between individuals. FIRDAPSE exposure increased proportionally with dose across the range of 20 mg to 80 mg single oral doses.

Absorption

Amifampridine peak plasma concentration is reached 20 minutes to 1 hour after administration.

Food does not have a clinically significant effect on the exposure of amifampridine.

Elimination

Amifampridine is eliminated primarily through metabolism to 3-N-acetyl-amifampridine and to a smaller extent through the kidneys. The terminal half-life ranges from 1.8 to 2.5 hours in healthy subjects.

Metabolism

Amifampridine is extensively metabolized by N-acetyltransferase 2 (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite.

Excretion

Following administration of FIRDAPSE to healthy subjects, 93% to 100% of the administered dose was eliminated in the urine as amifampridine or 3-N-acetyl amifampridine over 24 hours.

Specific Populations

Patients with Renal Impairment

Pharmacokinetic data are available from a study of 24 otherwise healthy subjects with impaired renal function who received a single 10-mg dose of FIRDAPSE.

The exposure of amifampridine (measured as AUC) was 2- to 3-fold higher in subjects with moderate (CLcr 30-59 mL/min) or severe (CLcr 15-29 mL/min) renal impairment than in subjects with normal renal function (CLcr greater than or equal to 90 mL/min).

Compared with subjects with normal renal function, subjects with mild renal impairment (CLcr 60-89 mL/min) had a 36% increase in exposure.

Therefore, FIRDAPSE should be initiated at the lowest recommended starting dosage (15 mg/day) in patients with renal impairment, and such patients should be closely monitored for adverse reactions. .Cmax was marginally affected by renal impairment. 

 Pharmacogenomics

Genetic variants in the N-acetyltransferase gene 2 (NAT2) affect the rate and extent of FIRDAPSE metabolism.

Poor metabolizers, also referred to as “slow acetylators” (i.e., carriers of two reduced function alleles), have 3.5- to 4.5-fold higher Cmax, and 5.6- to 9­ fold higher AUC than normal metabolizers, also referred to as “fast/rapid acetylators” (i.e., carriers of two normal function alleles).

Therefore, FIRDAPSE should be initiated at the lowest recommended starting dosage (15 mg/day) in known NAT2 poor metabolizers, and such patients should be closely monitored for adverse reactions.

In the general population, the NAT2 poor metabolizer phenotype prevalence is 40–60% in the White and African American populations, and in 10–30% in Asian ethnic populations (individuals of Japanese, Chinese, or Korean descent).

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

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

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 

The background risk of major birth defects and miscarriage for the indicated population is unknown.

2. Lactation Risk Summary

There are no data on the presence of FIRDAPSE 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 FIRDAPSE and any potential adverse effects on the breastfed infant from FIRDAPSE or from the underlying maternal condition.

3. Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Reference ID: 4355888

4.Geriatric Use

Clinical studies of FIRDAPSE did not include sufficient numbers of subjects aged 65 and over (19 of 63 patients in Studies 1 and 2) to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

5. Renal Impairment

Renal clearance is an elimination pathway for amifampridine and the inactive metabolite, 3-N-acetyl amifampridine, and exposure of amifampridine is higher in subjects with renal impairment.

Therefore, in patients with renal impairment, FIRDAPSE should be initiated at the lowest recommended starting dosage (15 mg/day), and patients should be closely monitored for adverse reactions 

Consider dosage modification or discontinuation of FIRDAPSE for patients with renal impairment as needed based on clinical effect and tolerability.

The safety, efficacy, and pharmacokinetics of amifampridine have not been studied in patients with end-stage renal disease (CLcr <15 mL/min or patients requiring dialysis). No dosage recommendation for FIRDAPSE can be made for patients with end-stage renal disease.

6.Hepatic Impairment

The effects of FIRDAPSE have not been studied in patients with hepatic impairment. FIRDAPSE is extensively metabolized by Nacetyltransferase 2 (NAT2) and hepatic impairment may cause an increase in exposure.

Therefore, initiate FIRDAPSE in patients with any degree of hepatic impairment at the lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions 

Consider dosage modification or discontinuation of FIRDAPSE for patients with hepatic impairment as needed based on clinical effect and tolerability.

7. NAT2 Poor Metabolizers

Exposure of FIRDAPSE is increased in patients who are N-acetyltransferase 2 (NAT2) poor metabolizers 

Therefore, initiate FIRDAPSE in patients who are known NAT2 poor metabolizers at the lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions 

Consider dosage modification of FIRDAPSE for patients who are known NAT2 poor metabolizers as needed based on clinical effect and tolerability.

 OVERDOSAGE

Overdose with FIRDAPSE was not reported during clinical studies.

In a case report, a 65-year-old patient with LEMS inadvertently received a total daily amifampridine dose of 360 mg/day (more than 4 times the maximum recommended total daily dose) and was hospitalized for general weakness, paresthesia, nausea, vomiting, and palpitations.

The patient developed convulsions and paroxysmal supraventricular tachycardia, and four days after admission, experienced cardiac arrest. The patient was resuscitated and ultimately recovered following withdrawal of amifampridine.

Patients with suspected overdose with FIRDAPSE should be monitored for signs or symptoms of exaggerated FIRDAPSE adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.