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dalfampridine er 10 mg tablet generic ampyra

In stock Manufacturer ASCEND LABORATO 67877044460
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Uses

Multiple Sclerosis

Dalfampridine is used to improve walking in patients with multiple sclerosis (MS). Dalfampridine has been designated an orphan drug by the US Food and Drug Administration (FDA) for relief of symptoms of multiple sclerosis. In clinical studies in MS patients who received the recommended dalfampridine dosage, walking improvement was demonstrated by increased walking speed in a timed 25-foot walk (T25FW). In those who responded to dalfampridine (approximately 35-43%), walking speed increased 25-29% and was maintained until the drug was discontinued.

Although only a portion of MS patients appear to respond to dalfampridine treatment with increased walking speed, improved walking during such treatment has been demonstrated in all MS disease types (relapsing remitting, primary progressive, secondary progressive, progressive relapsing). It is not clear what magnitude of improvement in walking speed results in improved walking ability or quality of life. Although consistent improvements in walking speed were shown to be associated with improvements on a patient self-assessment of ambulatory disability (12-item Multiple Sclerosis Walking Scale; MSWS-12), the average MSWS-12 score during dalfampridine treatment was not different than that reported with placebo. Improvement in walking speed reported with dalfampridine is independent of concomitant therapy with biologic response modifiers used for the management of MS (interferon, glatiramer acetate, natalizumab).

Data are insufficient regarding the safety and efficacy of dalfampridine for the management of other MS symptoms (e.g., motor function assessed using manual muscle testing, visual function, cognitive function, fatigue).

Clinical Experience

FDA labeling for use of dalfampridine for improved walking in MS patients is based on results of 2 randomized, double-blind, placebo-controlled phase 3 studies involving 540 adults with MS who had a mean disease duration of approximately 13 years, a mean Kurtzke Expanded Disability Status Scale (EDSS) score of 6, and had the ability to walk 25 feet in 8-45 seconds at baseline. The primary measure of efficacy in both studies was walking speed (feet per second) as measured by the T25FW, using a responder analysis that assessed consistency of improvement during treatment. Treatment responders were defined as those who had walking speeds for at least 3 visits (out of a possible 4 visits) during the double-blind treatment period that were faster than the maximum speed achieved during any of the 5 visits outside the treatment period.

One study (study 1, MS-F203) involved 301 adults with MS who were randomized to receive 14 weeks of dalfampridine extended-release tablets (10 mg twice daily) or placebo. Most patients (67%) were receiving stable therapy with a biologic response modifier used for the management of MS (interferon, glatiramer acetate). Patients with a history of seizures or evidence of epileptiform activity on EEG screening, those with onset of an MS exacerbation within the past 60 days, and pregnant and breast-feeding women were excluded. Approximately 35% of patients receiving dalfampridine were responders compared with 8% of those receiving placebo. In responders, the increase in walking speed was maintained throughout the treatment period and the increase from baseline averaged 25.2% (0.5 feet per second) in those who received dalfampridine compared with 4.7% (0.1 feet per second) in those who received placebo.

The other study (study 2, MS-F204) involved 239 adults with MS who were randomized to receive 9 weeks of dalfampridine extended-release tablets (10 mg twice daily) or placebo. In addition to the same inclusion and exclusion criteria used in study 1, study 2 excluded patients with severe renal impairment. Most patients (59%) were receiving stable therapy with a biologic response modifier used for the management of MS (interferon, glatiramer acetate). Approximately 43% of patients receiving dalfampridine were responders compared with 9% of those receiving placebo. The mean increase in walking speed ranged from 21-27% in those who responded to dalfampridine and 7-9% in those who responded to placebo.

Dosage and Administration

General

Estimated creatinine clearance should be determined prior to initiating dalfampridine and monitored at least annually during dalfampridine therapy. Because mild renal impairment is common in adults 50 years of age or older, estimating creatinine clearance is particularly important in this age group.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Restricted Distribution

Distribution of dalfampridine is restricted; the drug is available only through certain specialty pharmacies. Specific information regarding the dalfampridine distribution process is available from the manufacturer at 888-881-1918 or http://www.ampyra.com.

Administration

Dalfampridine is administered orally as an extended-release tablet. The drug may be given with or without food.

Dalfampridine doses should be given approximately 12 hours apart.

The extended-release tablets should be swallowed whole and should not be divided, crushed, chewed, or dissolved.

If a dose is missed, patients should not double the dosage or take extra doses. The next dose should be taken at the regularly scheduled time.

Dosage

The recommended oral dosage of dalfampridine used to improve walking in adults with multiple sclerosis (MS) is 10 mg twice daily administered as an extended-release tablet. The doses should be given approximately 12 hours apart.

The maximum recommended adult dosage of dalfampridine is 10 mg twice daily. Higher dosage should not be used since it does not result in additional therapeutic benefit and is associated with an increased risk of adverse reactions (e.g., seizures).(See Seizures under Cautions: Warnings/Precautions.)

Dalfampridine has been used for up to 9-14 weeks in clinical studies.

Special Populations

Renal Impairment

Dalfampridine clearance is decreased in patients with renal impairment and is correlated with creatinine clearance. The drug is contraindicated in patients with moderate or severe renal impairment (creatinine clearance 50 mL/minute or less).

In adults with mild renal impairment (creatinine clearance 51-80 mL/minute) receiving the recommended dalfampridine dosage (10 mg twice daily), plasma concentrations of the drug may approach those reported with dosages that may be associated with an increased risk of seizures. Potential benefits of dalfampridine should be carefully weighed against the risk of seizures when considering use of the drug in patients with mild renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) The manufacturer does not provide dosage recommendations for patients with mild renal impairment. Dalfampridine is only available as an extended-release tablet containing 10 mg of the drug.

Hepatic Impairment

Dalfampridine pharmacokinetics have not been evaluated in adults with hepatic impairment. Hepatic impairment is not expected to affect the pharmacokinetics or dosage recommendations for the drug.

Adults 50 Years of Age or Older

Modification of dalfampridine dosage is not necessary based solely on age. However, the drug is eliminated by the kidneys and the fact that mild renal impairment is common in adults 50 years of age or older should be considered.(See Renal Impairment under Dosage and Administration: Special Populations.)

Cautions

Contraindications

History of seizures.(See Seizures under Cautions: Warnings/Precautions.)

Moderate or severe renal impairment (creatinine clearance 50 mL/minute or less).(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Warnings/Precautions

Sensitivity Reactions

Anaphylactic reactions have been reported rarely in patients receiving dalfampridine.

If an anaphylactic or other serious allergic reaction occurs, dalfampridine should be discontinued and should not be restarted.

Seizures

Dalfampridine can cause seizures.

Postmarketing reports indicate that the majority of seizures have occurred in patients receiving the recommended dalfampridine dosage (generally within days to weeks after starting the drug) and in patients without a history of seizures. Some patients had been receiving other drugs that could have increased the risk of seizures or lowered the seizure threshold; in addition, age-related renal dysfunction and resultant increases in plasma dalfampridine concentrations could have contributed to the risk of seizures.

Use of a high dalfampridine dosage (e.g., 15 or 20 mg twice daily) increases the risk of seizures. In open-label extension studies in patients with multiple sclerosis (MS), the incidence of seizures was more than 4 times greater at a dosage of 15 mg twice daily compared with that reported with the recommended dosage (10 mg twice daily).

Altered mental state, confusion, and seizures (including status epilepticus requiring intensive supportive care) have been reported following dalfampridine overdosage.

Dalfampridine is contraindicated in patients with a prior history of seizures. The drug has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on EEG; such patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on EEG is unknown and could be substantially higher than that observed in clinical trials.

Although the risk of seizures in patients with mild renal impairment (creatinine clearance 51-80 mL/minute) who receive the usual dosage of dalfampridine is unknown, plasma concentrations of the drug in such patients may approach those reported with dosages that may be associated with an increased risk of seizures.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

If a seizure occurs, dalfampridine should be discontinued and should not be restarted.

Concurrent Treatment with Other Aminopyridines

Because of increased risk of dose-related adverse effects, dalfampridine should not be used in patients receiving other aminopyridines, including extemporaneously prepared formulations; dalfampridine formerly was known as fampridine (4-aminopyridine, 4-AP).

Prior to initiation of dalfampridine therapy, any product containing fampridine or 4-aminopyridine should be discontinued, since the active ingredient is the same.

Urinary Tract Infections

Urinary tract infections (UTIs) have been reported more frequently in patients receiving dalfampridine (12%) than in patients receiving placebo (8%).

If a UTI occurs in a patient receiving dalfampridine, it should be evaluated and treated as clinically indicated.

Specific Populations

Pregnancy

Category C.

In animal studies, decreased offspring viability and growth were reported at a dalfampridine dosage similar to the maximum recommended human dosage.

Lactation

Not known whether dalfampridine is distributed into human milk. Discontinue nursing or the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

There is insufficient experience with use of dalfampridine in geriatric patients 65 years of age or older to determine whether such individuals respond differently than younger individuals.

Dalfampridine is substantially eliminated by kidneys; geriatric patients are more likely to have decreased renal function. Because the risk of adverse reactions (including seizures) may be greater in patients with impaired renal function, it is particularly important to determine estimated creatinine clearance in geriatric patients prior to initiation of dalfampridine.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Hepatic Impairment

Dalfampridine pharmacokinetics have not been evaluated in patients with hepatic impairment. However, hepatic impairment is not expected to affect pharmacokinetics or dosage recommendations of the drug.

Renal Impairment

Clearance of dalfampridine is decreased in patients with renal impairment and is correlated with creatinine clearance.

Prior to dalfampridine therapy, the estimated creatinine clearance should be determined (e.g., Cockcroft-Gault equation). Estimated creatine clearance also should be determined at least annually during dalfampridine therapy.

Dalfampridine is contraindicated in patients with moderate or severe renal impairment (creatinine clearance 50 mL/minute or less).

In patients with mild renal impairment (creatinine clearance 51-80 mL/minute), the potential benefits of dalfampridine should be carefully weighed against the risk of seizures. Plasma concentrations attained in patients with mild renal impairment receiving the recommended dalfampridine dosage (10 mg twice daily) may approach those seen with 15 mg twice daily, a dosage that may be associated with an increased risk of seizures.(See Seizures under Cautions: Warnings/Precautions.)

Because mild renal impairment is common in adults 50 years of age or older, even when serum creatinine is normal, it is particularly important that estimated creatinine clearance be determined in this age group.

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving dalfampridine include urinary tract infections, insomnia, dizziness, headache, nausea, asthenia, tremor, fatigue, upper respiratory tract infection, back pain, balance disorder, MS relapse or worsening, paresthesia, muscle spasm, peripheral edema, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Dalfampridine is metabolized by cytochrome P-450 (CYP) isoenzyme 2E1 and, possibly, other unidentified CYP isoenzymes.

In vitro studies indicate that dalfampridine does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5 and does not induce 1A2, 2B6, 2C9, 2C19, 2E1, or 3A4/5.

Pharmacokinetic interactions are unlikely with drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.

Drugs Affecting or Affected by P-glycoprotein Transport

Dalfampridine is not an inhibitor or substrate of the P-glycoprotein transport system and pharmacokinetic interactions are unlikely with drugs that are inhibitors or substrates of this transport system.

Interferon Beta

Concomitant use of dalfampridine and subcutaneous interferon beta-1b does not affect the pharmacokinetics of dalfampridine.

Pharmacokinetics

Absorption

Bioavailability

Dalfampridine is rapidly and completely absorbed from the GI tract.

The bioavailability of dalfampridine extended-release tablets is 96% compared with an extemporaneously prepared aqueous oral solution of immediate-release dalfampridine (formerly known as fampridine [4-aminopyridine, 4-AP]).

Dalfampridine extended-release tablets result in delayed absorption and a slower increase to lower peak plasma concentrations compared with an aqueous oral solution of the drug, but the extent of absorption (area under the concentration-time curve [AUC]) is not affected.

Plasma concentrations and AUC of dalfampridine increase proportionally with dose.

The pharmacokinetics of dalfampridine in adults with multiple sclerosis (MS) are similar to that reported in healthy adults.

In adults 29-56 years of age with MS who received a single 10-mg dalfampridine extended-release tablet, the mean peak plasma concentration was 25.23 ng/mL and was attained 3.92 hours after the dose. In healthy fasting adults, a single 10-mg extended-release tablet of the drug resulted in peak concentrations of 17.3-21.6 ng/mL and occurred 3-4 hours after the dose.

Food

Administration of a dalfampridine extended-release tablet with food results in a 12-17% increase in peak plasma concentrations and a 4-7% decrease in AUC of the drug; this is not considered clinically important.

Distribution

Extent

Studies using IV dalfampridine indicate the drug is distributed into CSF.

It is not known whether dalfampridine is distributed into human milk.

Plasma Protein Binding

Dalfampridine is 1-3% bound to plasma proteins.

Elimination

Metabolism

A small portion of dalfampridine dose is metabolized by cytochrome P-450 (CYP) isoenzymes to 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate. These metabolites have no pharmacologic activity on potassium channels. In vitro studies indicate CYP2E1 is the major enzyme responsible for 3-hydroxylation of dalfampridine; other unidentified CYP enzymes play a minor role in 3-hydroxylation of the drug.

Elimination Route

Following oral administration, 95.9% of a dalfampridine dose is eliminated in urine and 0.5% is eliminated in feces.

The majority of the dose is eliminated in urine (90.3%) as unchanged dalfampridine; 4.3% is eliminated as 3-hydroxy-4-aminopyridine and 2.6% is eliminated as 3-hydroxy-4-aminopyridine sulfate.

Half-life

The half-life of dalfampridine is 5.2-6.5 hours. The half-life of 3-hydroxy-4-aminopyridine sulfate is 7.6 hours.

Special Populations

Clearance of dalfampridine is modestly decreased with increasing age; this age-related decrease is not considered clinically important.

Females may have higher maximum dalfampridine plasma concentrations than males; this is not considered clinically important.

Total body clearance of dalfampridine is reduced about 45% in adults with mild renal impairment (creatinine clearance 51-80 mL/minute), about 50% in those with moderate renal impairment (creatinine clearance 30-50 mL/minute), and about 75% in those with severe renal impairment (creatinine clearance less than 30 mL/minute). Mean half-life in otherwise healthy adults with mild or moderate renal impairment is 7.4 or 8.1 hours, respectively; mean half-life in those with severe renal impairment is 14.3 hours.

The pharmacokinetics of dalfampridine have not been evaluated in patients with hepatic impairment; however, hepatic impairment is not expected to have a clinically important effect on pharmacokinetics of the drug.

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