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warnings and cautions
5 WARNINGS AND PRECAUTIONS Seizures: AMPYRA can cause seizures; the risk of seizures increases with increasing AMPYRA doses; AMPYRA is contraindicated in patients with a prior history of seizure; discontinue AMPYRA use if seizure occurs ( 5.1 ) Renally impaired patients: 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 AMPYRA 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 ( 4 , 5.1 , 5.2 ); estimated CrCl should be known before initiating treatment with AMPYRA ( 4 , 5.2 , 8.6 ) AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same ( 5.3 ) Urinary tract infections were reported more frequently as adverse reactions in patients receiving AMPYRA 10 mg twice daily compared to placebo ( 5.4 ) 5.1 Seizures AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4) ] . 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. There was one seizure seen in the placebo group (0.4%) and at a dose of 10 mg twice daily (0.25%), no seizure seen at 15 mg twice daily and 2 seizures (3.5%) seen at 20 mg twice daily. 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). 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 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. 5.2 Renal Impairment AMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology, Special Populations (12.4) ]. Because patients with renal impairment would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, AMPYRA is contraindicated in patients with moderate or severe renal impairment [Creatinine Clearance (CrCl) ≤50mL/min] [see Contraindications (4) ] . 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 [see Warnings and Precautions, Seizures (5.1) ] . If unknown, CrCl should be estimated prior to initiating treatment with AMPYRA. CrCl can be estimated using the following equation (multiply by 0.85 for women): CrCl = (140 - age ) × weight ( kg ) SerumCr ( mg / dl ) × 72 5.3 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. 5.4 Urinary Tract Infections Urinary tract infections were reported more frequently as adverse reactions in controlled studies in patients receiving AMPYRA 10 mg twice daily (12%) as compared to placebo (8%).
6 ADVERSE REACTIONS 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 and Urinary Tract Infections. The most common adverse events (incidence ≥2% and at a rate greater than the placebo rate) for AMPYRA in MS patients 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 Acorda Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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) AMPYRA 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% 6.2 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).