Dalfampridine

Dalfampridine Extended-Release Tablets are indicated as a treatment to improve walking in adult patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed . Dalfampridine Extended-Release Tablets are a potassium channel blocker indicated to improve walking in adult patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed ( 1 , 14 ).

The maximum recommended dosage is 10 mg twice daily (approximately 12 hours apart). There is no evidence of additional benefit with doses greater than 10 mg twice daily. Adverse reactions, including seizures, were more frequent at higher doses. Take with or without food. Administer tablets whole; do not divide, crush, chew, or dissolve Patients should not take double or extra doses if they miss a dose. Estimated creatinine clearance (CrCl) should be known before initiating treatment with Dalfampridine Extended-Release Tablets. In patients with mild renal impairment (CrCl 51 to 80 mL/min), Dalfampridine Extended-Release Tablets may reach plasma levels associated with a greater risk of seizures, and the potential benefits of Dalfampridine Extended-Release Tablets should be carefully considered against the risk of seizures in these patients ( 2.3 , 5.2 , 8.6 )

2.1Dosage Information The

maximum recommended dosage of Dalfampridine Extended-Release Tablet is one 10 mg tablet twice daily and should not be exceeded. Take doses approximately 12 hours apart. There is no evidence of additional benefit at doses greater than 10 mg twice daily. Adverse reactions, including seizures, and discontinuations because of adverse reactions were more frequent at higher doses.

2.2Administration Instructions Dalfampridine Extended-Release Tablets

can be taken with or without food. Administer tablets whole; do not divide, crush, chew, or dissolve Dalfampridine Extended-Release Tablets. If a dose is missed, patients should not take double or extra doses.

2.3Renal Monitoring Prior to and During Treatment

Estimated creatinine clearance (CrCl) should be known before initiating treatment with Dalfampridine Extended-Release Tablets, and monitored at least annually during treatment with Dalfampridine Extended-Release Tablets. CrCl can be estimated using the following equation (multiply by 0.85 for women): CrCl = (140 - age ) × weight ( kg ) SerumCr ( mg / dl )× 72

2.4Dosage in Patients with Renal Impairment In

patients with mild renal impairment (CrCl 51 to 80 mL/min), Dalfampridine Extended-Release Tablets plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that is 1.5 times the maximum recommended dose and may be associated with an increased risk of seizures. As mild renal impairment is common after age 50, estimating CrCl is particularly important in these patients. The potential benefits of Dalfampridine Extended-Release Tablets should be carefully considered against the risk of seizures in these patients . Dalfampridine Extended-Release Tablets are contraindicated in patients with moderate or severe renal impairment (CrCl≤50 mL/min).

Dalfampridine can cause seizures; the risk of seizures increases with increasing Dalfampridine Extended-Release Tablets doses; discontinue Dalfampridine Extended-Release Tablets and do not restart if a seizure occurs Avoid concomitant use with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same Dalfampridine can cause anaphylaxis. Discontinue and do not restart Dalfampridine Extended-Release Tablets if this occurs

5.1Seizures Dalfampridine

can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily (2 times the maximum recommended dosage) in controlled clinical studies of 9 to 14 weeks duration with Dalfampridine Extended-Release Tablets in patients with MS. In open-label extension trials in MS patients, the incidence of seizures during treatment with Dalfampridine Extended-Release Tablets 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported.

The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy. Dalfampridine Extended-Release Tablets have not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially higher than that observed in Dalfampridine Extended-Release Tablets clinical studies.

Permanently discontinue Dalfampridine Extended-Release Tablets in patients who experience have a seizure while on treatment. Dalfampridine Extended-Release Tablets are contraindicated in patients with a history of seizures .

5.2Renal Impairment Dalfampridine

is eliminated through the kidneys primarily as unchanged drug . Because patients with moderate to severe renal impairment (CrCl ≤50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, Dalfampridine Extended-Release Tablets are contraindicated in these patients . In patients with mild renal impairment (CrCl 51 to 80 mL/min), dalfampridine plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures .

5.3Concurrent Treatment with Other Forms of

4-Aminopyridine Avoid concomitant use with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Instruct patients to discontinue use of any product containing 4-aminopyridine prior to initiating treatment with Dalfampridine Extended-Release Tablets in order to reduce the potential for dose-related adverse reactions.

5.4Anaphylaxis Dalfampridine

can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. Dalfampridine Extended-Release Tablets are contraindicated in patients with a history of hypersensitivity to dalfampridine or 4-aminopyridine.

Inform patients of the signs and symptoms of anaphylaxis and instruct them to discontinue Dalfampridine Extended-Release Tablets and seek immediate medical care should these signs and symptoms occur.

The use of Dalfampridine Extended-Release Tablets are contraindicated in the following conditions: History of seizure Moderate or severe renal impairment (CrCl≤50 mL/min) History of hypersensitivity to dalfampridine or 4-aminopyridine; reactions have included anaphylaxis History of seizure Moderate or severe renal impairment (CrCl≤50 mL/min) History of hypersensitivity to dalfampridine or 4-aminopyridine

8.1Pregnancy Risk Summary There

are no adequate data on the developmental risk associated with use of Dalfampridine Extended-Release Tablets in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at clinically relevant doses . In the U.S. 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.

Data Animal Data Oral administration of dalfampridine to pregnant rats and rabbits throughout organogenesis resulted in no evidence of developmental toxicity in either species. The highest doses tested (10 mg/kg/day in rats, 5 mg/kg/day in rabbits), which were associated with maternal toxicity, are approximately 5 times the MRHD on a body surface area (mg/m 2 ) basis. Oral administration of dalfampridine (0, 1, 3, and 9 to 6 mg/kg/day; high dose reduced during the second week of dosing) to female rats throughout pregnancy and lactation resulted in decreased offspring viability at the highest dose tested and decreased body weight in offspring at the mid and high doses.

The no-effect dose for pre-and postnatal developmental toxicity in rats (1 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

The following serious adverse reactions are described in more detail elsewhere in the labeling: Seizures Anaphylaxis The most common adverse events (incidence ≥2% and at a rate greater than the placebo rate) for dalfampridine were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain. To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience 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 three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with Dalfampridine Extended-Release Tablets 10 mg twice daily experienced one or more adverse reactions leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The adverse reactions leading to discontinuation of at least 2 patients treated with Dalfampridine Extended-Release Tablets and that led to discontinuation more frequently compared to placebo were headache (Dalfampridine Extended-Release Tablets 0.5%, placebo 0%), balance disorder (Dalfampridine Extended-Release Tablets 0.5%, placebo 0%), dizziness (Dalfampridine Extended-Release Tablets 0.5%, placebo 0%), and confusional state (Dalfampridine Extended-Release Tablets 0.3%, placebo 0%).

Table 1 lists adverse reactions that occurred in ≥2% of patients treated with Dalfampridine Extended-Release Tablets 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials. Table 1: Adverse Reactions with an Incidence ≥2% of Dalfampridine Extended-Release Tablets Treated Adult MS Patients, and More Frequent with Dalfampridine Extended-Release Tablets Compared to Placebo in Controlled Clinical Trials Adverse Reaction Placebo (N=238) % Dalfampridine Extended-Release Tablets 10 mg twice daily (N=400) % Urinary tract infection 8 12 Insomnia 4 9 Dizziness 4 7 Headache 4 7 Nausea 3 7 Asthenia 4 7 Back pain 2 5 Balance disorder 1 5 Multiple sclerosis relapse 3 4 Paresthesia 3 4 Nasopharyngitis 2 4 Constipation 2 3 Dyspepsia 1 2 Pharyngolaryngeal pain 1 2 Other Adverse Reactions Dalfampridine Extended-Release Tablets have been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with Dalfampridine Extended-Release Tablets for over six months, 501 for over one year and 352 for over two years.

The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with Dalfampridine Extended-Release Tablets in patients with MS as follows: Dalfampridine Extended-Release Tablets 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13 to 0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21 to 6.28).

6.2Postmarketing Experience The

following adverse reactions have been identified during post approval use with dalfampridine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: vomiting, vertigo.