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warnings and cautions
5 WARNINGS AND PRECAUTIONS Dalfampridine can cause seizures; the risk of seizures increases with increasing dalfampridine doses; discontinue dalfampridine and do not restart if a seizure occurs ( 5.1 ) Avoid concomitant use with other forms of 4-aminopyridine (4AP, fampridine), since the active ingredient is the same ( 5.3 ) Dalfampridine can cause anaphylaxis. Discontinue and do not restart dalfampridine extended-release tablets if this occurs ( 5.4 ) 5.1 Seizures 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 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. Dalfampridine 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 dalfampridine clinical studies. Permanently discontinue dalfampridine in patients who have a seizure while on treatment. Dalfampridine is contraindicated in patients with a history of seizures [see Contraindications (4) ] . 5.2 Renal Impairment 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 is 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) ] . 5.3 Concurrent 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 in order to reduce the potential for dose-related adverse reactions. 5.4 Anaphylaxis 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 is 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 and seek immediate medical care should these signs and symptoms occur.
6 ADVERSE REACTIONS 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 )] 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 ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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 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 and that led to discontinuation more frequently compared to placebo were headache (dalfampridine 0.5%, placebo 0%), balance disorder (dalfampridine 0.5%, placebo 0%), dizziness (dalfampridine 0.5%, placebo 0%), and confusional state (dalfampridine 0.3%, placebo 0%). Table 1 lists adverse reactions that occurred in ≥2% of patients treated with dalfampridine 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-Treated Adult MS Patients and More Frequent with Dalfampridine 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 has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with dalfampridine 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 in patients with MS as follows: dalfampridine 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). 6.2 Postmarketing 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.