DALFAMPRIDINE — dalfampridine tablet, extended release
Sun Pharmaceutical Industries, Inc.
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 [see Clinical Studies (14)].
The maximum recommended dosage of dalfampridine extended-release tablets 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.
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.
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):
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 [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Dalfampridine extended-release tablets are contraindicated in patients with moderate or severe renal impairment (CrCl≤50 mL/min).
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.
The use of dalfampridine extended-release tablets are contraindicated in the following conditions:
- History of seizure [see Warnings and Precautions (5.1)]
- Moderate or severe renal impairment (CrCl ≤ 50 mL/min) [see Warnings and Precautions (5.2)]
- History of hypersensitivity to dalfampridine or 4-aminopyridine; reactions have included anaphylaxis [see Warnings and Precautions (5.4)]
Dalfampridine extended-release tablets 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 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 postmarketing 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 have experience a seizure while on treatment. Dalfampridine extended-release tablets are contraindicated in patients with a history of seizures [see Contraindications (4)].
Dalfampridine is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.3)].
Because patients with moderate to severe renal impairment (CrCl ≤ 50 mL/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 [see Contraindications (4)].
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 [see Warnings and Precautions (5.1)].
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.
Dalfampridine extended-release tablets 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 following serious adverse reactions are described in more detail elsewhere in the labeling:
- Seizures [see Warnings and Precautions (5.1)]
- Anaphylaxis [see Warnings and Precautions (5.4)]
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|
|Multiple sclerosis relapse||3||4|
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).
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.
Concurrent treatment with OCT2 inhibitors, such as cimetidine, may cause increased exposure to dalfampridine [see Clinical Pharmacology (12.3)]. Elevated levels of dalfampridine increase the risk of seizures [see Warnings and Precautions (5.1, 5.2)]. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine extended-release tablets should be considered against the risk of seizures in these patients.
No interaction was identified between dalfampridine and baclofen [see Clinical Pharmacology (12.3)].
There are no adequate data on the developmental risk associated with use of dalfampridine in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at clinically relevant doses [see Data]. 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.
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/m2) 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/m2 basis.
There are no data on the presence of dalfampridine in human milk, the effects of dalfampridine on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dalfampridine and any potential adverse effects on the breastfed infant from dalfampridine or from the underlying maternal condition.
Safety and effectiveness in patients younger than 18 years of age have not been established.
Clinical studies of dalfampridine extended-release tablets 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.
Dalfampridine 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 [see Warnings and Precautions (5.2)].
Clearance of dalfampridine is decreased in patients with renal impairment and is significantly correlated with creatinine clearance (CrCl) [see Clinical Pharmacology (12.3)]. Dalfampridine extended-release tablets are contraindicated in patients with moderate or severe renal impairment (CrCl ≤ 50 mL/min) [see Contraindications (4)]. The risk of seizures in patients with mild renal impairment (CrCl 51 to 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 dalfampridine extended-release tablets [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].
Three cases of overdose were reported in controlled clinical trials with dalfampridine extended-release tablets, 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.
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