Aptiom (Page 2 of 7)

5.2 Serious Dermatologic Reactions

Serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with APTIOM use. Serious and sometimes fatal dermatologic reactions, including TEN and SJS, have also been reported in patients using oxcarbazepine or carbamazepine which are chemically related to APTIOM. The reporting rate of these reactions associated with oxcarbazepine use exceeds the background incidence rate estimates by a factor of 3- to 10-fold. The reporting rates for Aptiom have not been determined.

Risk factors for the development of serious and potentially fatal dermatologic reactions with APTIOM use have not been identified.

If a patient develops a dermatologic reaction while taking APTIOM, discontinue APTIOM use, unless the reaction is clearly not drug-related. Patients with a prior dermatologic reaction with oxcarbazepine, carbamazepine, or APTIOM should ordinarily not be treated with APTIOM [see Contraindications (4)].

5.3 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking APTIOM. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. APTIOM should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. Patients with a prior DRESS reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM [see Contraindications (4)].

5.4 Anaphylactic Reactions and Angioedema

Rare cases of anaphylaxis and angioedema have been reported in patients taking APTIOM. Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with APTIOM, the drug should be discontinued. Patients with a prior anaphylactic-type reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM [see Contraindications (4)].

5.5 Hyponatremia

Clinically significant hyponatremia (sodium <125 mEq/L) can develop in patients taking APTIOM.

Measurement of serum sodium and chloride levels should be considered during maintenance treatment with APTIOM, particularly if the patient is receiving other medications known to decrease serum sodium levels, and should be performed if symptoms of hyponatremia develop (e.g., nausea/vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness/spasms, obtundation, or increase in seizure frequency or severity). Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing use. In clinical trials, patients whose treatment with APTIOM was discontinued because of hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment.

In the controlled adult adjunctive epilepsy trials, 4/415 patients (1.0%) treated with 800 mg and 6/410 (1.5%) patients treated with 1200 mg of APTIOM had at least one serum sodium value less than 125 mEq/L, compared to none of the patients assigned to placebo. A higher percentage of APTIOM-treated patients (5.1%) than placebo-treated patients (0.7%) experienced decreases in sodium values of more than 10 mEq/L. These effects were dose-related and generally appeared within the first 8 weeks of treatment (as early as after 3 days). Serious, life-threatening complications were reported with APTIOM-associated hyponatremia (as low as 112 mEq/L) including seizures, severe nausea/vomiting leading to dehydration, severe gait instability, and injury. Some patients required hospitalization and discontinuation of APTIOM. Concurrent hypochloremia was also present in patients with hyponatremia. Hyponatremia was also observed in adult monotherapy trials and in pediatric trials. Depending on the severity of hyponatremia, the dose of APTIOM may need to be reduced or discontinued.

5.6 Neurological Adverse Reactions

Dizziness and Disturbance in Gait and Coordination

APTIOM causes dose-related increases in adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, ataxia, vertigo, balance disorder, gait disturbance, nystagmus, and abnormal coordination) [see Adverse Reactions (6.1)]. In controlled adult adjunctive epilepsy trials, these events were reported in 26% and 38% of patients randomized to receive APTIOM at doses of 800 mg and 1200 mg/day, respectively, compared to 12% of placebo-treated patients. Events related to dizziness and disturbance in gait and coordination were more often serious in APTIOM-treated patients than in placebo-treated patients (2% vs. 0%), and more often led to study withdrawal in APTIOM-treated patients than in placebo-treated patients (9% vs. 0.7%). There was an increased risk of these adverse reactions during the titration period (compared to the maintenance period) and there also may be an increased risk of these adverse reactions in patients 60 years of age and older compared to younger adults. Nausea and vomiting also occurred with these events. Adverse reactions related to dizziness and disturbance in gait and coordination were also observed in adult monotherapy trials and pediatric trials.

The incidence of dizziness was greater with the concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine in adult and pediatric trials. Therefore, consider dosage modifications of both APTIOM and carbamazepine if these drugs are used concomitantly [see Dosage and Administration (2.3)].

Somnolence and Fatigue

APTIOM causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy). In the controlled adult adjunctive epilepsy trials, these events were reported in 13% of placebo patients, 16% of patients randomized to receive 800 mg/day APTIOM, and 28% of patients randomized to receive 1200 mg/day APTIOM. Somnolence and fatigue-related events were serious in 0.3% of APTIOM-treated patients (and 0 placebo patients) and led to discontinuation in 3% of APTIOM-treated patients (and 0.7% of placebo-treated patients). Somnolence and fatigue-related reactions were also observed in adult monotherapy trials and in pediatric trials.

Cognitive Dysfunction

APTIOM causes dose-dependent increases in cognitive dysfunction-related events in adults (memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, and psychomotor retardation). In the controlled adult adjunctive epilepsy trials, these events were reported in 1% of placebo patients, 4% of patients randomized to receive 800 mg/day APTIOM, and 7% of patients randomized to receive 1200 mg/day APTIOM. Cognitive dysfunction-related events were serious in 0.2% of APTIOM-treated patients (and 0.2% of placebo patients) and led to discontinuation in 1% of APTIOM-treated patients (and 0.5% of placebo-treated patients). Cognitive dysfunction events were also observed in adult monotherapy trials.

Visual Changes

APTIOM causes dose-dependent increases in events related to visual changes including diplopia, blurred vision, and impaired vision. In the controlled adult adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive APTIOM compared to 6% of placebo patients. Eye events were serious in 0.7% of APTIOM-treated patients (and 0 placebo patients) and led to discontinuation in 4% of APTIOM-treated patients (and 0.2% of placebo-treated patients). There was an increased risk of these adverse reactions during the titration period (compared to the maintenance period) and also in patients 60 years of age and older (compared to younger adults). The incidence of diplopia was greater with the concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine (up to 16% vs. 6%, respectively) [see Dosage and Administration (2.3)]. Similar adverse reactions related to visual changes were also observed in adult monotherapy trials and in pediatric trials.

Hazardous Activities

Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of APTIOM is known.

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