Fosphenytoin (Page 3 of 8)

5.3 Withdrawal Precipitated Seizure, Status Epilepticus

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

5.4 Serious Dermatologic Reactions

Fosphenytoin sodium can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin (the active metabolite of fosphenytoin sodium)-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.5)]. The onset of symptoms is usually within 28 days, but can occur later. Fosphenytoin sodium injection should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a severe cutaneous adverse reaction, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of SCARs.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding fosphenytoin sodium injection as an alternative for carbamazepine patients positive for HLA-B*1502.

The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

5.5 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 antiepileptic drugs, including phenytoin and fosphenytoin sodium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, 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. Fosphenytoin sodium injection should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.6 Hypersensitivity

Fosphenytoin sodium and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.7)]. Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to fosphenytoin sodium injection.

5.7 Angioedema

Angioedema has been reported in patients treated with phenytoin and fosphenytoin sodium injection in the postmarketing setting. Fosphenytoin sodium injection should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Fosphenytoin sodium injection should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

5.8 Hepatic Injury

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin (the active metabolite of fosphenytoin sodium injection). These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.5)]. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, fosphenytoin sodium injection should be immediately discontinued and not re-administered.

5.9 Hematopoietic Complications

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin (the active metabolite of fosphenytoin sodium injection). These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports that have suggested a relationship between phenytoin and the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS [see Warnings and Precautions (5.5)].

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

5.10 Sensory Disturbances

Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered

IV fosphenytoin sodium injection at a dose of 1,200 mg PE at the maximum rate of administration (150 mg PE/min). The severe sensory disturbance lasted from 3 to 50 minutes in 6 of these subjects and for 14 hours in the seventh subject. In some cases, milder sensory disturbances persisted for as long as 24 hours. The location of the discomfort varied among subjects with the groin mentioned most frequently as an area of discomfort. In a separate cohort of 16 normal volunteers (taken from 2 other studies) who were administered IV fosphenytoin sodium injection at a dose of 1,200 mg PE at the maximum rate of administration (150 mg PE/min), none experienced severe disturbances, but most experienced mild to moderate itching or tingling. Patients administered fosphenytoin sodium injection at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree. The occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion. The effect of continuing infusion unaltered in the presence of these sensations is unknown. No permanent sequelae have been reported thus far. The pharmacologic basis for these positive sensory phenomena is unknown, but other phosphate ester drugs, which deliver smaller phosphate loads, have been associated with burning, itching, and/or tingling predominantly in the groin area.

5.11 Local Toxicity (Including Purple Glove Syndrome)

Edema, discoloration, and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous fosphenytoin sodium injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection.

5.12 Phosphate Load

The phosphate load provided by fosphenytoin sodium injection (0.0037 mmol phosphate/mg PE fosphenytoin sodium injection) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment.

5.13 Renal or Hepatic Disease or Hypoalbuminemia

Because the fraction of unbound phenytoin (the active metabolite of fosphenytoin sodium injection) is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients. After IV administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events.

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