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  • CLASSES

    MS Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral potassium channel blocker, also known as 4-aminopyridine
    Indicated to improve walking in adult patients with multiple sclerosis (MS); results are independent of immunomodulatory drug therapies
    Major dose-limiting side effect is seizures; patients with moderate to severe renal dysfunction cannot receive the drug

    COMMON BRAND NAMES

    Ampyra

    HOW SUPPLIED

    Ampyra/Dalfampridine Oral Tab ER: 10mg

    DOSAGE & INDICATIONS

    For improved walking (i.e., improved walking speed) in patients with multiple sclerosis.
    Oral dosage
    Adults

    10 mg PO every 12 hours. No additional benefit was noted with doses greater than 10 mg twice daily, and adverse effects including seizures were more frequent with higher doses. During clinical trials, a benefit was noted as an increase in walking speed, and a benefit was observed across all 4 major types of multiple sclerosis disease courses. Most patients were also taking immunomodulatory drugs (e.g.,  interferons, glatiramer acetate, or natalizumab). The magnitude of improvement in walking ability was independent of concomitant treatment with an immunomodulatory drug.

    MAXIMUM DOSAGE

    Adults

    20 mg/day PO, administered as 10 mg every 12 hours.

    Geriatric

    20 mg/day PO, administered as 10 mg every 12 hours.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCl 51 to 80 mL/minute: No dose adjustment is needed; however, use with caution. Dalfampridine plasma concentrations with a 10 mg PO twice daily dose in these patients may approach those observed at a dose of 15 mg twice daily in patients with normal renal function, which is a dose that may be associated with an increased seizure risk.
    CrCl 50 mL/minute or less: Use is contraindicated.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer whole. Do not divide, crush, chew, or dissolve the extended-release, film-coated tablets.
    May administer with or without food.
    Administer tablets every 12 hours; an approximate 12-hour interval is needed between doses. Do not administer more than 10 mg every 12 hours; dalfampridine causes seizures in a dose-dependent fashion.
    Missed dose: If a dose is missed, do not administer double or extra doses.

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Ampyra :
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Avoid concomitant use of dalfampridine 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 in order to reduce the potential for dose-related adverse reactions, including convulsions.

    History of angioedema

    Dalfampridine can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. The drug is contraindicated in patients with a history of hypersensitivity to dalfampridine, 4-aminopyridine, or other aminopyridine hypersensitivity. This includes a history of angioedema to the drug. Inform patients of the signs and symptoms of anaphylaxis and angioedema and instruct them to discontinue dalfampridine and seek immediate medical care should these signs and symptoms occur.

    Seizure disorder, seizures

    Dalfampridine is contraindicated for use by patients with a history of seizures or a seizure disorder. Seizures were noted with dalfampridine, and the seizure risk increases with increasing dalfampridine doses. Patients with a seizure history or with evidence of epileptiform activity on an EEG were excluded from trials. The seizure risk from dalfampridine in patients with epileptiform activity on EEG is unknown and may be substantially higher. If a seizure occurs, discontinue dalfampridine, and do not restart the drug.

    Geriatric, renal failure, renal impairment

    Estimate creatinine clearance using the Cockroft-Gault equation in all patients before and at least annually during dalfampridine receipt, even if serum creatinine appears normal. Dalfampridine is substantially excreted by the kidney, and the seizure risk is greater with increased drug exposure. The clearance of dalfampridine is significantly correlated with creatinine clearance. Dalfampridine is contraindicated for use by patients with renal failure or moderate to severe renal impairment defined as a CrCl of 50 mL/min or less. The possible benefits of dalfampridine treatment should be weighed against the risk of seizures in patients with mild renal impairment (CrCl 51 to 80 mL/minute), as dalfampridine plasma levels may approach those that may be associated with an increased risk of seizures. Because geriatric patients are more likely to have decreased renal function, it is particularly important to know the estimated CrCl in these patients.

    Pregnancy

    There are no adequate and well-controlled studies of dalfampridine use 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. Dalfampridine 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 an mg/m2 basis. The effect of dalfampridine on labor and delivery in humans is unknown.[43980]

    Breast-feeding

    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 (e.g., seizures) in a nursing infant from dalfampridine, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

    Children, infants

    The safety and efficacy of dalfampridine in infants, children, and adolescents less than 18 years of age have not been established.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0-0.3
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 3.0-3.0
    confusion / Early / 0-1.0

    Mild

    infection / Delayed / 12.0-12.0
    insomnia / Early / 9.0-9.0
    nausea / Early / 7.0-7.0
    headache / Early / 7.0-7.0
    dizziness / Early / 7.0-7.0
    asthenia / Delayed / 7.0-7.0
    back pain / Delayed / 5.0-5.0
    pharyngitis / Delayed / 4.0-4.0
    paresthesias / Delayed / 4.0-4.0
    dyspepsia / Early / 2.0-2.0
    vomiting / Early / Incidence not known
    vertigo / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
    Amifampridine: (Major) Avoid use of dalfampridine and amifampridine together, due to duplicative effects and an increased risk for serious side effects, such as seizures. Both drugs are aminopyridine class potassium channel blockers. Both drugs increase the seizure risk.
    Bupropion: (Moderate) Due to additive risks for seizure, extreme caution when coadministering bupropion with other drugs that lower seizure threshold (e.g., dalfampridine). Use low initial doses and increase the dose gradually. Monitor for seizure activity. Consider benefits against the risk of seizures. Consider alternatives to bupropion. Additionally, bupropion inhibits OCT2 in vitro, but the clinical relevance is not certain. Concurrent treatment with OCT2 inhibitors, such as bupropion, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients.
    Bupropion; Naltrexone: (Moderate) Due to additive risks for seizure, extreme caution when coadministering bupropion with other drugs that lower seizure threshold (e.g., dalfampridine). Use low initial doses and increase the dose gradually. Monitor for seizure activity. Consider benefits against the risk of seizures. Consider alternatives to bupropion. Additionally, bupropion inhibits OCT2 in vitro, but the clinical relevance is not certain. Concurrent treatment with OCT2 inhibitors, such as bupropion, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients.
    Cimetidine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as cimetidine, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients. Consider alternatives to cimetidine.
    Dolutegravir: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
    Dolutegravir; Lamivudine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
    Dolutegravir; Rilpivirine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
    Trilaciclib: (Moderate) Consider the potential benefits of treatment versus the risk of seizures if concomitant use of trilaciclib and dalfampridine is necessary. Trilaciclib is an OCT2 and MATE inhibitor that may increase dalfampridine exposure; elevated dalfampridine exposure may increase the risk of seizures.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of dalfampridine use 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. Dalfampridine 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 an mg/m2 basis. The effect of dalfampridine on labor and delivery in humans is unknown.[43980]

    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 (e.g., seizures) in a nursing infant from dalfampridine, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

    MECHANISM OF ACTION

    Dalfampridine is a broad spectrum potassium channel blocker. The mechanism of dalfampridine's therapeutic effect has not been fully elucidated. In animals, inhibition of potassium channels increased action potential conduction in demyelinated axons.

    PHARMACOKINETICS

    Dalfampridine is administered orally. It is mostly unbound to plasma proteins. The apparent volume of distribution is 2.6 L/kg. The CYP2E1 isoenzyme is 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. Two inactive metabolites are present: 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate, but these are not pharmacologically active. The clearance of dalfampridine is significantly correlated with creatinine clearance. Dalfampridine and metabolite elimination is nearly complete after 24 hours, with 95.9% of the dose recovered in urine and 0.5% recovered in feces. The elimination half-life is 5.2 to 6.5 hours.[43980]
     
    Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2E1, OCT2
    CYP2E1 is the major enzyme responsible for the metabolism of dalfampridine. In vitro, dalfampridine is not an inducer or 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. Further, dalfampridine is neither a substrate nor an inhibitor of P-glycoprotein. Dalfampridine appears to be a substrate for organic cation transporter 2 (OCT2); concurrent treatment with OCT2 inhibitors (e.g., cimetidine) may cause increased exposure to dalfampridine and may increase the risk of seizures.[43980]

    Oral Route

    Absorption of dalfampridine is rapid and complete. The relative bioavailability is 96% as compared with an aqueous oral solution. After administration of a 10 mg tablet to healthy patients in the fasted state, the maximum serum concentration (Cmax) of 17.3 to 21.6 ng/mL occurs in 3 to 4 hours. If dalfampridine is taken with food, a 12% to 17% increase in Cmax and a 4% to 7% decrease in AUC occurs; these changes in exposure are not clinically significant, and dalfampridine can be taken with or without food. Exposure of dalfampridine increases proportionally with dose.