Aptiom (Page 3 of 7)

5.7 Withdrawal of AEDs

As with all antiepileptic drugs, APTIOM should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus, but if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

5.8 Drug Induced Liver Injury

Hepatic effects, ranging from mild to moderate elevations in transaminases (>3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (>2 times the upper limit of normal) have been reported with APTIOM use. Baseline evaluations of liver laboratory tests are recommended. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury. APTIOM should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

5.9 Abnormal Thyroid Function Tests

Dose-dependent decreases in serum T3 and T4 (free and total) values have been observed in patients taking APTIOM. These changes were not associated with other abnormal thyroid function tests suggesting hypothyroidism. Abnormal thyroid function tests should be clinically evaluated.

5.10 Hematologic Adverse Reactions

Rare cases of pancytopenia, agranulocytosis, and leukopenia have been reported during postmarketing use in patients treated with APTIOM. Discontinuation of APTIOM should be considered in patients who develop pancytopenia, agranulocytosis, or leukopenia.

6 ADVERSE REACTIONS

The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:

  • Suicidal Behavior and Ideation [see Warnings and Precautions (5.1)]
  • Serious Dermatologic Reactions [see Warnings and Precautions (5.2)]
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.3)]
  • Anaphylactic Reactions and Angioedema [see Warnings and Precautions (5.4)]
  • Hyponatremia [see Warnings and Precautions (5.5)]
  • Neurological Adverse Reactions [see Warnings and Precautions (5.6)]
  • Drug Induced Liver Injury [see Warnings and Precautions (5.8)]
  • Abnormal Thyroid Function Tests [see Warnings and Precautions (5.9)]
  • Pancytopenia, Agranulocytosis, and Leukopenia [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Patients

In monotherapy trials in patients with partial-onset seizures [Study 1 and Study 2, see Clinical Studies (14.1) ], 365 patients received APTIOM, of whom 225 were treated for longer than 12 months and 134 for longer than 24 months. Of the patients in those trials, 95% were between 18 and 65 years old; 48% were male, and 84% were Caucasian. Across controlled and uncontrolled trials in patients receiving adjunctive therapy for partial-onset seizures, 1195 patients received APTIOM, of whom 586 were treated for longer than 6 months and 462 for longer than 12 months. In the placebo controlled adjunctive therapy trials in patients with partial-onset seizures (Study 3, Study 4 and Study 5), 1021 patients received APTIOM. Of the patients in those trials, approximately 95% were between 18 and 60 years old, approximately 50% were male, and approximately 80% were Caucasian.

Monotherapy Historical Control Trials

In the monotherapy epilepsy trials (Study 1 and Study 2), 13% of patients randomized to receive APTIOM at the recommended doses of 1200 mg and 1600 mg once daily discontinued from the trials as a result of an adverse event. The adverse reaction most commonly (≥1% on APTIOM) leading to discontinuation was hyponatremia.

Adverse reactions observed in these studies were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies. Because these studies did not include a placebo control group, causality could not be established.

Dizziness, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase compared with the Titration Phase.

Adjunctive Therapy Controlled Trials

In the controlled adjunctive therapy epilepsy trials (Study 3, Study 4, and Study 5), the rate of discontinuation as a result of any adverse reaction was 14% for the 800 mg dose, 25% for the 1200 mg dose, and 7% in subjects randomized to placebo. The adverse reactions most commonly (≥1% in any APTIOM treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were dizziness, nausea, vomiting, ataxia, diplopia, somnolence, headache, blurred vision, vertigo, asthenia, fatigue, rash, dysarthria, and tremor.

The most frequently reported adverse reactions in patients receiving APTIOM at doses of 800 mg or 1200 mg (≥4% and ≥2% greater than placebo) were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.

Table 4 gives the incidence of adverse reactions that occurred in ≥2% of subjects with partial-onset seizures in any APTIOM treatment group and for which the incidence was greater than placebo during the controlled clinical trials. Adverse reactions during titration were less frequent for patients who began therapy at an initial dose of 400 mg for 1 week and then increased to 800 mg compared to patients who initiated therapy at 800 mg.

Table 4: Adverse Reactions Incidence in Pooled Controlled Clinical Trials of Adjunctive Therapy in Adults (Events ≥2% of Patients in the APTIOM 800 mg or 1200 mg Dose Group and More Frequent Than in the Placebo Group)
Placebo APTIOM
800 mg 1200 mg
(N=426) % (N=415) % (N=410) %
Ear and labyrinth disorders Vertigo <1 2 6
Eye disorders Diplopia Blurred vision Visual impairment 211 962 1151
Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Abdominal pain Gastritis 53311<1 1064222 1610222<1
General disorders and administration site conditions Fatigue Asthenia Gait disturbance Peripheral edema 42<11 4222 7321
Infections and Infestations Urinary tract infections 1 2 2
Injury, poisoning and procedural complications Fall 1 3 1
Metabolism and nutrition disorders Hyponatremia <1 2 2
Nervous system disorders Dizziness Somnolence Headache Ataxia Balance disorder Tremor Dysarthria Memory impairment Nystagmus 9892<110<1<1 201113432111 281815634222
Psychiatric disorders Depression Insomnia 21 12 32
Respiratory, thoracic and mediastinal disorders Cough 1 2 1
Skin and subcutaneous tissue disorders Rash 1 1 3
Vascular disorders Hypertension 1 1 2

Pediatric Patients (4 to 17 Years of Age)

Clinical studies of pediatric patients 4 to 17 years of age were conducted which support the safety and tolerability of APTIOM for the treatment of partial-onset seizures. Across studies in pediatric patients with partial-onset seizures, 393 patients ages 4 to 17 years received APTIOM, of whom 265 received APTIOM for at least 1 year. Adverse reactions reported in clinical studies of pediatric patients 4 to 17 years of age were similar to those seen in adult patients.

Other Adverse Reactions with APTIOM Use

Compared to placebo, APTIOM use was associated with slightly higher frequencies of decreases in hemoglobin and hematocrit, increases in total cholesterol, triglycerides, and LDL, and increases in creatine phosphokinase.

Adverse Reactions Based on Gender and Race

No significant gender differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.

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