Dalfampridine: Package Insert and Label Information (Page 2 of 3)

11 DESCRIPTION

Dalfampridine, USP is a potassium channel blocker, available in 10 mg tablet strength. Each tablet contains 10 mg dalfampridine, formulated as an extended-release tablet for twice-daily oral administration. Dalfampridine is also known by its chemical name, 4-aminopyridine, with the following structure:

spl-dalfampridine-structure

Dalfampridine extended-release tablets are available in 10 mg strength and are white to off-white, round, biconvex, beveled edged, film-coated tablets imprinted with “429” in black ink on one side and plain on the other side, containing 10 mg of dalfampridine. Inactive ingredients consist of hypromellose, povidone, microcrystalline cellulose and magnesium stearate. The film-coating contains hypromellose, talc, ethyl cellulose, triacetin and titanium dioxide. The imprinting ink contains shellac glaze, iron oxide black, n-butyl alcohol, propylene glycol and ammonium hydroxide.
Dalfampridine, USP is a white to off-white crystalline powder with a molecular weight of 94.1, CAS 504-24-5, and a molecular formula of C5 H6 N2 . At ambient conditions, dalfampridine is soluble in water, methanol, acetone, tetrahydrofuran, isopropanol, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, and ethanol.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

The mechanism by which dalfampridine exerts its therapeutic effect has not been fully elucidated. Dalfampridine is a broad spectrum potassium channel blocker. In animal studies, dalfampridine has been shown to increase conduction of action potentials in demyelinated axons through inhibition of potassium channels.

12.2 Pharmacodynamics

Dalfampridine extended-release tablets do not prolong the QTc interval and does not have a clinically important effect on QRS duration.

12.3 Pharmacokinetics

Absorption and Distribution

Orally administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of dalfampridine extended-release tablets have not been assessed, but relative bioavailability is 96% when compared to an aqueous oral solution. The extended-release tablet delays absorption of dalfampridine relative to the solution formulation, giving a slower rise to a lower peak concentration (Cmax ), with no effect on the extent of absorption (AUC). Single dalfampridine extended-release tablet 10 mg doses administered to healthy volunteers in a fasted state gave peak concentrations ranging from 17.3 ng/mL to 21.6 ng/mL occurring 3 to 4 hours post-administration (Tmax ). In comparison, Cmax with the same 10 mg dose of dalfampridine in an oral solution was 42.7 ng/mL and occurred approximately 1.3 hours after dosing. Exposure increased proportionally with dose.

Dalfampridine is largely unbound to plasma proteins (97 to 99%). The apparent volume of distribution is 2.6 L/kg.

There is no apparent difference in pharmacokinetic parameter values following administration of dalfampridine extended-release tablets to either healthy volunteers or patients with MS.

When dalfampridine is taken with food, there is a slight increase in Cmax (12 to 17%) and a slight decrease in AUC (4 to 7%). These changes in exposure are not clinically significant, and therefore the drug may be taken with or without food [see Dosage and Administration (2.2)].

Metabolism and Elimination

Dalfampridine and metabolites elimination is nearly complete after 24 hours, with 95.9% of the dose recovered in urine and 0.5% recovered in feces. Most of the excreted radioactivity in urine was parent drug (90.3%). Two metabolites were identified: 3-hydroxy­-4-aminopyridine (4.3%) and 3-hydroxy-4-aminopyridine sulfate (2.6%). These metabolites have been shown to have no pharmacologic activity on potassium channels.

The apparent elimination half-life of dalfampridine following administration of the dalfampridine extended-release tablets is 5.2 to 6.5 hours. The plasma half-life of the sulfate conjugate is approximately 7.6 hours and the half-life of 3-hydroxy-4­-aminopyridine could not be calculated because concentrations for most subjects were close to or below the limit of quantitation.

In vitro studies with human liver microsomes indicate that CYP2E1 was the major enzyme responsible for the 3-hydroxylation of dalfampridine. The identity of the CYP enzymes suspected of playing a minor role in the 3-hydroxylation of dalfampridine could not be established unequivocally.

Specific Populations

Pediatric

The safety and effectiveness in patients younger than 18 years of age have not been established.

Geriatric

A population pharmacokinetic analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to necessitate a modification of dose.

Gender

A population pharmacokinetic analysis suggested that female patients would be expected to have higher maximum dalfampridine plasma concentration than male patients. The magnitude of these differences is small and does not necessitate any dose modification.

Renal Impairment [see Contraindications (4) and Warnings and Precautions (5.2)].

The pharmacokinetics of dalfampridine was studied in 9 male and 11 female subjects with varying degrees of renal function. Elimination of the drug is significantly correlated with the creatinine clearance. Total body clearance of dalfampridine was reduced by about 45 % in patients with mild renal impairment (CrCl 51 to 80 mL/min), by about 50% in patients with moderate renal impairment (CrCl = 30 to 50 mL/min), and by about 75% in patients with severe renal impairment (CrCl < 30 mL/min). The terminal half-life of dalfampridine is about 3.3 times longer in patients with severe renal impairment but is not prolonged in patients with mild or moderate renal impairment.

Hepatic Impairment

The pharmacokinetics of dalfampridine in hepatically impaired subjects has not been studied. Since dalfampridine is primarily excreted unchanged in the urine, hepatic impairment is not expected to significantly affect dalfampridine pharmacokinetics or recommended dosing.

Race

There were too few non-Caucasians in the patient population to evaluate the effect of race.

Drug Interactions

Effects of Coadministered Drugs on Dalfampridine

Interferon

Dalfampridine kinetics were not affected by coadministration of subcutaneous injections of 8 million units interferon beta-1b.

Baclofen

Based on a population analysis, dalfampridine kinetics were not affected by baclofen.

Cimetidine

In a single-dose clinical study, 23 healthy volunteers took the OCT2 inhibitor cimetidine 400 mg every 6 hours concurrently with dalfampridine 10 mg single dose. The test-reference ratio for AUC0–∞ was 125% (90% confidence interval: 121% to 130%) due to a reduction in the clearance of dalfampridine [see Drug Interactions (7.1)].

Effects of Dalfampridine on Coadministered Drugs

In vitro data with human liver microsomes showed that dalfampridine was not a direct or time-dependent inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Dalfampridine is not likely to affect the pharmacokinetics of drugs that are substrates of these enzymes.

Other in vitro studies with cultured human hepatocytes with 0.025 μM, 0.25 μM, 2.5 μM, and 25 μM dalfampridine had little or no effect on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 enzyme activities. Consequently, the potential for dalfampridine to induce human hepatocytes at therapeutic concentrations is remote.

In vitro , dalfampridine is not a substrate or an inhibitor for the p-glycoprotein transporter. The pharmacokinetics of dalfampridine extended-release tablets are unlikely to be affected by drugs that inhibit the p-glycoprotein transporter, and dalfampridine is not likely to affect the pharmacokinetics of drugs that are substrates of the p-glycoprotein transporter.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


Carcinogenesis
Two-year dietary carcinogenicity studies of dalfampridine were conducted in mice and rats. In mice, the doses tested (approximately 2, 12.5, and 80 mg/kg/day) were associated with plasma exposures (AUC) up to 11 times the plasma AUC in humans at the maximum recommended human dose (MRHD) of 20 mg/day. There was no evidence of drug-related carcinogenicity.

In rats, the doses tested (approximately 2, 6, and 18 mg/kg/day) were approximately 1, 3, and 9 times the MRHD on a body surface area (mg/m2) basis. There was a significant increase in uterine polyps at the highest dose tested.

Mutagenesis
Dalfampridine was negative in in vitro (bacterial reverse mutation, mouse lymphoma tk , chromosomal aberration) and in vivo ( mouse bone marrow, rat erythrocyte micronucleus) genetic toxicology assays.

Impairment of Fertility

Oral administration of dalfampridine (0, 1, 3, and 9 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through early pregnancy (to gestation day 13) or throughout pregnancy and lactation resulted in no adverse effects on fertility. Reduced offspring viability and body weight were observed at 9 mg/kg/day. The no-effect dose for adverse effects on fertility (9 mg/kg/day) and reproductive performance (3 mg/kg/day) are 4 times and similar to, respectively, the MRHD on a mg/m2 basis.

14 CLINICAL STUDIES

The effectiveness of dalfampridine extended-release tablets in improving walking in patients with multiple sclerosis was evaluated in two adequate and well controlled trials involving 540 patients. Patients in these two clinical trials had a mean disease duration of 13 years and a mean Kurtzke Expanded Disability Status Scale (EDSS) score of 6.

Trial 1 was a randomized, placebo-controlled, parallel group, 21-week study (one week post screening, two-week, single-blind placebo run-in, 14-week double-blind treatment, and 4-week no treatment follow-up) in 301 patients with multiple sclerosis at 33 centers in the U.S. and Canada: 229 patients assigned to dalfampridine extended-release tablets 10 mg twice daily and 72 patients assigned to placebo. A total of 283 patients (212 dalfampridine extended-release tablets and 71 placebo) completed all study visits. Patient inclusion criteria included the ability to walk 25 feet in 8 to 45 seconds. Patient exclusion criteria included a history of seizures or evidence of epileptiform activity on a screening EEG, and onset of an MS exacerbation within 60 days.

Trial 2 was a randomized, placebo-controlled, parallel group, 14-week study (one week post-screening, two weeks of single-blind, placebo run-in, nine weeks of double-blind treatment, and two weeks of no-treatment follow-up) in 239 patients with multiple sclerosis at 39 centers in the U.S. and Canada: 120 patients assigned to 10 mg twice daily and 119 assigned to placebo. A total of 227 patients (113 dalfampridine extended-release tablets and 114 placebo) completed all study visits. The patient inclusion and exclusion criteria used in Trial 1 were employed in Trial 2, and in addition patients with severe renal impairment were also excluded.

The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed 25-foot Walk (T25FW), using a responder analysis. A responder was defined as a patient who showed faster walking speed for at least three visits out of a possible four during the double-blind period than the maximum value achieved in the five non-double-blind no treatment visits (four before the double-blind period and one after).

A significantly greater proportion of patients taking dalfampridine extended-release tablets 10 mg twice daily were responders, compared to patients taking placebo, as measured by the T25FW (Trial 1: 34.8% vs. 8.3%; Trial 2: 42.9% vs. 9.3%). The increased response rate in the dalfampridine extended-release tablets group was observed across all four major types of MS disease course.

During the double-blind treatment period, a significantly greater proportion of patients taking dalfampridine extended-release tablets 10 mg twice daily had increases in walking speed of at least 10%, 20%, or 30% from baseline, compared to placebo (Figure 1 and Figure 2).

Figure 1: Average walking speed change (%) from baseline during the double-blind phase of Trial 1

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Figure 2: Average walking speed change (%) from baseline during the double-blind phase of Trial 2

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In Trial 1 and Trial 2, consistent improvements in walking speed were shown to be associated with improvements on a patient self-assessment of ambulatory disability, the 12-item Multiple Sclerosis Walking Scale (MSWS-12), for both drug and placebo treated patients. However, a drug-placebo difference was not established for that outcome measure.

The majority of patients in these trials (63%) were using immunomodulatory drugs (interferons, glatiramer acetate, or natalizumab), but the magnitude of improvement in walking ability was independent of concomitant treatment with these drugs. No differences in effectiveness based on degree of impairment, age, gender, or body mass index were detected. There were too few non-Caucasians in the patient population to evaluate the effect of race.

16 HOW SUPPLIED/STORAGE AND HANDLING

Dalfampridine extended-release tablets, 10 mg are white to off-white, round, biconvex, beveled edged, film-coated tablets imprinted with “429” in black ink on one side and plain on the other side. They are available as:

Bottles of 60 with Child-resistant Cap ………….….. NDC 62756-429-86

Store dalfampridine extended-release tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Risk of Seizures
Inform patients that dalfampridine extended-release tablets can cause seizures, and that they must discontinue use of dalfampridine extended-release tablets if they experience a seizure [see Warnings and Precautions (5.1)].
Dalfampridine Extended-Release Tablets dosing
Instruct patients to take dalfampridine extended-release tablets exactly as prescribed. Instruct patients not to take a double dose after they miss a dose, as this would increase their risk of seizure. Instruct patients not to take more than 2 tablets in a 24-hour period and to make sure that there is an approximate 12-hour interval between doses [see Dosage and Administration (2.1, 2.2)].
Anaphylaxis
Advise patients to discontinue dalfampridine extended-release tablets and seek medical care if they develop signs and symptoms of anaphylaxis [see Warnings and Precautions (5.4)].

Effects on Driving or Using Machinery

Counsel patients that central nervous system-related adverse reactions, such as vertigo and dizziness, associated with the use of dalfampridine extended-release tablets might impair their ability to drive or use machinery should they develop these symptoms.

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 dalfampridine extended-release tablets at 25°C (77°F), with excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Advise patients to safely throw away dalfampridine extended-release tablets those are out of date or no longer needed.

MEDICATION GUIDE

Dispense with Medication Guide available at: https://www.sunpharma.com/usa/products
Dalfampridine

(dal-FAM-pri-deen)

Extended-Release Tablets

Read this Medication Guide before you start taking dalfampridine extended-release tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about dalfampridine extended-release tablets?

Dalfampridine extended-release tablets can cause seizures.

  • You could have a seizure even if you never had a seizure before.
  • Your chance of having a seizure is higher if you take too many dalfampridine extended-release tablets or if your kidneys have a mild decrease of function, which is common after age 50.
  • Your doctor may do a blood test to check how well your kidneys are working, if that is not known before you start taking dalfampridine extended-release tablets.
    • Do not take dalfampridine extended-release tablets if you have ever had a seizure.
    • Before taking dalfampridine extended-release tablets tell your doctor if you have kidney problems.
    • Take dalfampridine extended-release tablets exactly as prescribed by your doctor. See “How should I take dalfampridine extended-release tablets?”

Stop taking dalfampridine extended-release tablets and call your doctor right away if you have a seizure while taking dalfampridine extended-release tablets.

What are dalfampridine extended-release tablets?

Dalfampridine extended-release tablets are prescription medicines used to help improve walking in adults with multiple sclerosis (MS). This was shown by an increase in walking speed.

It is not known if dalfampridine extended-release tablets are safe or effective in children less than 18 years of age.

Who should not take dalfampridine extended-release tablets?

Do not take dalfampridine extended-release tablets if you:

  • have ever had a seizure
  • have certain types of kidney problems
  • are allergic to dalfampridine (4-aminopyridine), the active ingredient in dalfampridine extended-release tablets

What should I tell my doctor before taking dalfampridine extended-release tablets?

Before you take dalfampridine extended-release tablets, tell your doctor if you:

  • have any other medical conditions
  • are taking compounded 4-aminopyridine (fampridine, 4-AP)
  • are taking any other medicines, including over-the-counter medicines such as cimetidine
  • are pregnant or plan to become pregnant. It is not known if dalfampridine extended-release tablets will harm your unborn baby.
  • are breast-feeding or plan to breast-feed. It is not known if dalfampridine passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you take dalfampridine extended-release tablets.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take dalfampridine extended-release tablets?

  • Take dalfampridine extended-release tablets exactly as your doctor tells you to take it. Do not change your dose of dalfampridine extended-release tablets.
  • Take one dalfampridine extended-release tablet 2 times each day about 12 hours apart. Do not take more than 2 dalfampridine extended-release tablets in a 24-­hour period.
  • Take dalfampridine extended-release tablets whole. Do not break, crush, chew or dissolve dalfampridine extended-release tablets before swallowing. If you cannot swallow dalfampridine extended-release tablets whole, tell your doctor.
  • Dalfampridine is released slowly over time. If the tablet is broken, the medicine may be released too fast. This can raise your chance of having a seizure.
  • Dalfampridine extended-release tablets can be taken with or without food.
  • If you miss a dose of dalfampridine extended-release tablets, do not make up the missed dose. Do not take 2 doses at the same time. Take your next dose at your regular scheduled time.
  • If you take too many dalfampridine extended-release tablets, call your doctor or go to the nearest hospital emergency room right away.
  • Do not take dalfampridine extended-release tablets together with other aminopyridine medications, including compounded 4-AP (sometimes called 4­-aminopyridine, fampridine).

What should I avoid while taking dalfampridine extended-release tablets?

Dalfampridine extended-release tablets may cause dizziness or vertigo. If you have these symptoms, do not drive, operate machinery, or do other dangerous activities.

What are the possible side effects of dalfampridine extended-release tablets?

Dalfampridine extended-release tablets may cause serious side effects, including:

  • serious allergic reactions. Stop taking dalfampridine extended-release tablets and call your doctor right away or get emergency medical help if you have:
    • shortness of breath or trouble breathing
    • swelling of your throat or tongue
    • hives

See “What is the most important information I should know about dalfampridine extended-release tablets?”

The most common side effects of dalfampridine extended-release tablets include:

  • urinary tract infection
  • trouble sleeping (insomnia)
  • dizziness
  • headache
  • nausea
  • weakness
  • back pain
  • problems with balance
  • multiple sclerosis relapse
  • burning, tingling or itching of your skin
  • irritation in your nose and throat
  • constipation
  • indigestion
  • pain in your throat

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of dalfampridine extended-release tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
How should I store dalfampridine extended-release tablets?

  • Store dalfampridine extended-release tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).
  • Safely throw away dalfampridine extended-release tablets those are out of date or no longer needed.

Keep dalfampridine extended-release tablets and all medicines out of the reach of children.

General Information about the safe and effective use of dalfampridine extended-release tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use dalfampridine extended-release tablets for a condition for which it was not prescribed. Do not give dalfampridine extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about dalfampridine extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about dalfampridine extended-release tablet that is written for health professionals.
For more information, call 1-800-818-4555.

What are the ingredients in dalfampridine extended-release tablets?

Active ingredient: dalfampridine, USP (previously called fampridine)

Inactive ingredients: hypromellose, povidone, microcrystalline cellulose and magnesium stearate. The film-coating contains hypromellose, talc, ethyl cellulose, triacetin and titanium dioxide. The imprinting ink contains shellac glaze, iron oxide black, n-butyl alcohol, propylene glycol and ammonium hydroxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Dispense with Medication Guide available at: https://www.sunpharma.com/usa/products

Distributed by:
Sun Pharmaceutical Industries, Inc.
Cranbury, NJ 08512
Manufactured by:
Sun Pharmaceutical Industries Ltd.
Survey No. 259/15,
Dadra-396 191, (U.T. of D & NH), India.
ISS. 12/2021
PGPI0316B

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