Ampyra

Ampyra information, interactions and side effects, AMPYRA (dalfampridine) Extended Release tablets are available in a 10 mg strength and are white to off-white, biconvex, oval shaped, film-coated, non-scored tablets with flat edge, debossed with “A10” on one side, containing 10 mg of dalfampridine. Inactive ingredients consist of colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.

Dalfampridine is a fine white powder with a molecular weight of 94.1, CAS 504-24-5, and a molecular formula of C5H6N2. At ambient conditions, dalfampridine is soluble in water, methanol, acetone, tetrahydrofuran, isopropanol, acetonitrile, N,Ndimethylformamide, dimethylsulfoxide, and ethanol.

AMPYRA (dalfampridine) is a potassium channel blocker, available in a 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:

ampyra

INDICATIONS

AMPYRA (dalfampridine) is indicated as a treatment to improve walking in patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed.

DOSAGE AND ADMINISTRATION

The maximum recommended dose of AMPYRA is one 10 mg tablet twice daily, taken with or without food, and should not be exceeded. Doses should be taken approximately 12 hours apart. Tablets should only be taken whole; do not divide, crush, chew, or dissolve. Patients should not take double or extra doses if a dose is missed.

Estimated creatinine clearance (CrCl) should be known before initiating treatment with AMPYRA, and monitored at least annually during treatment with AMPYRA. CrCl can be estimated using the following equation (multiply by 0.85 for women):

CrCl = (140 – age) x weight(kg)/ SerumCr(mg / dl) x 72

In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA 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. As mild renal impairment is common after age 50, estimating CrCl is particularly important in these patients. The potential benefits of AMPYRA should be carefully considered against the risk of seizures in these patients.

No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse reactions and discontinuations because of adverse reactions were more frequent at higher doses.

HOW SUPPLIED

Dosage Forms And Strengths

AMPYRA is available in a 10 mg strength and is a film-coated, white to off-white, biconvex, oval shaped, non-scored tablet with flat edge, debossed with “A10” on one side.

Storage And Handling

AMPYRA (dalfampridine) Extended Release Tablets, 10 mg are film-coated, white to off-white, biconvex, oval shaped, non-scored tablets with flat edge. The tablets are identified by a debossed code “A10” on one side and are available in bottles of 60.

NDC 10144-427-60 bottles of 60 tablets

Store at 25°C (77°F). Excursions permitted 15–30°C (59–86°F).

SIDE EFFECTS

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.

The following adverse reactions are described in more detail in the WARNINGS AND PRECAUTIONS section of the label: Seizures, Anaphylaxis, and Urinary Tract Infections.

Controlled Clinical Trials Experience

In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%; placebo 0%), dizziness (AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%).

Table 1 lists adverse reactions that occurred in ≥ 2% of patients treated with AMPYRA 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 AMPYRA treated MS patients, and more frequent with AMPYRA compared to placebo in controlled clinical trials

 

Adverse Reaction Placebo
(N=238)
10 mg twice
(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

AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA 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 AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13–0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21–6.28).

DRUG INTERACTIONS

In humans, dalfampridine is eliminated predominantly unchanged by the kidneys. No clinically significant drug interaction was identified. In particular, no interaction was identified between dalfampridine and baclofen.

PRECAUTIONS

Seizures

AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9–14 weeks duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 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.

AMPYRA has 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 AMPYRA clinical studies. AMPYRA should be discontinued and not restarted in patients who experience a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures.

Renal Impairment

AMPYRA 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, AMPYRA is contraindicated in these patients.

In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA 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.

Concurrent Treatment with Other Forms of 4-Aminopyridine

AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Patients should discontinue use of any product containing 4-aminopyridine prior to initiating treatment with AMPYRA in order to reduce the potential for dose-related adverse reactions.

Anaphylaxis

AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. Patients should be informed of the signs and symptoms of anaphylaxis and instructed to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur.

Urinary Tract Infections

Urinary tract infections (UTIs) were reported more frequently as adverse reactions in controlled studies in patients receiving AMPYRA 10 mg twice daily (12%) as compared to placebo (8%). UTIs in AMPYRA-treated patients should be evaluated and treated as clinically indicated.

Patient Counseling Information

Risk of Seizures

Inform patients that AMPYRA can cause seizures, and that they must discontinue use of AMPYRA if they experience a seizure.

AMPYRA dosing

Instruct patients to take AMPYRA 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.

Anaphylaxis

Advise patients to discontinue AMPYRA and seek medical care if they develop signs and symptoms of anaphylaxis.

Storage

Advise patients to store AMPYRA at 25°C (77°F), with excursions permitted to 15–30°C (59–86°F). Advise patients to safely throw away AMPYRA that is out of date or no longer needed.

Nonclinical Toxicology

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 (doses of 1, 3, and 9 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females up to day 13 of gestation or day 21 of lactation resulted in no adverse effects on fertility. Reduced offspring viability and body weight were observed at 9 mg/kg/day. The mid dose (a no-effect dose) was similar to the MRHD on a mg/m² basis.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of AMPYRA in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at doses similar to the maximum recommended human dose (MRHD) of 20 mg/day. AMPYRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In developmental toxicity studies in rats and rabbits, dalfampridine was administered orally at doses up to 10 and 5 mg/kg/day, respectively, during the period of organogenesis. These doses are approximately 5 times the MRHD on a body surface area (mg/m²) basis. No evidence of developmental toxicity was found in either species at the highest doses tested, which were maternally toxic. Oral administration of dalfampridine (at doses of 1, 3, and 9 to 6 mg/kg/day; high dose reduced during the second week of dosing) to rats throughout the pregnancy and lactation periods resulted in decreased offspring survival and growth. The no-effect dose for pre- and postnatal developmental toxicity in rats (1 mg/kg) is approximately 0.5 times the MRHD on a mg/m² basis.

Labor and delivery

The effect of AMPYRA on labor and delivery in humans is unknown.

Nursing mothers

It is not known whether dalfampridine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dalfampridine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

Safety and effectiveness of AMPYRA in patients younger than 18 years of age have not been established.

Geriatric use

Clinical studies of AMPYRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. A population PK analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to necessitate a modification of dose with age. Other reported clinical experience has identified no differences in responses between the elderly and younger patients.

AMPYRA is known to be substantially excreted by the kidneys and the risk of adverse reactions, including seizures, is greater with increasing exposure of dalfampridine. Because elderly patients are more likely to have decreased renal function, it is particularly important to know the estimated creatinine clearance (CrCl) in these patients.

Impaired Renal Function

Clearance of dalfampridine is decreased in patients with renal impairment and is significantly correlated with creatinine clearance (CrCl). AMPYRA is contraindicated in patients with moderate or severe renal impairment (CrCl ≤ 50 mL/min). The risk of seizures in patients with mild renal impairment (CrCl 51–80 mL/min) is unknown, but dalfampridine plasma levels in these patients may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures. If unknown, estimated creatinine clearance should be calculated prior to initiating treatment with AMPYRA.

OVERDOSE

Three cases of overdose were reported in controlled clinical trials with AMPYRA, involving two MS patients. The first patient took six times the currently recommended dose (60 mg) and was taken to the emergency room with altered mental state. The second patient took 40 mg doses on two separate occasions. In the first instance, she experienced a complex partial seizure and, in the second instance, a period of confusion. Both patients recovered by the following day without sequelae.

Several cases of overdose are found in the scientific literature in which various formulations of dalfampridine were used, resulting in numerous adverse events including seizure, confusion, tremulousness, diaphoresis, and amnesia. In some instances, patients developed status epilepticus, requiring intensive supportive care and were responsive to standard therapy for seizures. In one published case report, an MS patient who ingested 300 mg of 4-aminopyridine (dalfampridine) developed a condition that resembled limbic encephalitis. This patient developed weakness, reduced awareness, memory loss, hypophonic speech, and temporal lobe hyperintensities on MRI. The patient’s speech and language and ambulation improved over time, and an MRI at 4 months after the overdose no longer showed signal abnormalities. At one year, the patient continued to have difficulty with short term memory and learning new tasks.

CONTRAINDICATIONS

The use of AMPYRA is contraindicated in the following conditions:

  • History of seizure
  • Moderate or severe renal impairment (CrCl ≤ 50 mL/min)
  • History of hypersensitivity to AMPYRA or 4-aminopyridine
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