FOSPHENYTOIN PRESCRIBING INFORMATION PDF

Sections or subsections omitted from the full prescribing information are not listed. Careful cardiac monitoring is needed during and after administering intravenous fosphenytoin sodium. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed [see Dosage and Administration 2.

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Intramuscular administration of Cerebyx should ordinarily not be used in pediatric patients. Following Cerebyx administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after intramuscular IM injection.

The error is dependent on serum phenytoin and fosphenytoin concentration influenced by Cerebyx dose, route and rate of administration, and time of sampling relative to dosing , and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin.

However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration 2. Parenteral Substitution for Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, Cerebyx can be substituted for oral phenytoin at the same total daily phenytoin sodium equivalents PE dose.

For this reason, serum phenytoin concentrations may increase modestly when IM or IV Cerebyx is substituted for oral phenytoin sodium therapy.

In controlled trials, IM Cerebyx was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing. Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia Because the fraction of unbound phenytoin the active metabolite of Cerebyx 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.

This has the potential to increase the frequency and severity of adverse events [see Warnings and Precautions 5. Dosing in Geriatrics The clearance of phenytoin the active metabolite of Cerebyx is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology Dosing during Pregnancy Decreased serum concentrations of phenytoin the active metabolite of Cerebyx may occur during pregnancy because of altered phenytoin pharmacokinetics [see Clinical Pharmacology Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the Cerebyx dosage should be adjusted as necessary.

Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations 8. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction. Dosage Forms and Strengths Cerebyx Injection is a clear, colorless to pale yellow solution available as 50 mg phenytoin sodium equivalents PE per mL in: 10 mL single-dose injection vials, each containing mg phenytoin sodium equivalents 2 mL single-dose injection vials, each containing mg phenytoin sodium equivalents Contraindications Cerebyx is contraindicated in patients with: A history of hypersensitivity to Cerebyx or its inactive ingredients, or to phenytoin or other hydantoins [see Warnings and Precautions 5.

Reactions have included angioedema. Sinus bradycardia, sino-atrial block, second and third degree A-V block, or Adams-Stokes syndrome because of the effect of parenteral phenytoin or Cerebyx on ventricular automaticity. A history of prior acute hepatotoxicity attributable to Cerebyx or phenytoin [see Warnings and Precautions 5.

Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. Doses of Cerebyx are always expressed in terms of milligrams of phenytoin sodium equivalents mg PE. Do not, therefore, make any adjustment in the recommended doses when substituting Cerebyx for phenytoin sodium or vice versa.

For example, if a patient is receiving mg PE of Cerebyx, that is equivalent to mg of phenytoin sodium. These errors have resulted in two- or ten-fold overdoses of Cerebyx since each vial actually contains a total of mg PE or mg PE.

In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of Cerebyx should always be expressed in milligrams of phenytoin equivalents mg PE [see Dosage and Administration 2. Additionally, when ordering and storing Cerebyx, consider displaying the total drug content i. Care should be taken to ensure the appropriate volume of Cerebyx is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some Cerebyx medication errors from occurring.

Cardiovascular Risk Associated with Rapid Infusion Rapid intravenous administration of Cerebyx increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias.

Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.

Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate.

As non-emergency therapy, intravenous Cerebyx should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV Cerebyx, oral phenytoin should be used whenever possible.

Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac and respiratory monitoring is needed during and after the administration of intravenous Cerebyx. Reduction in rate of administration or discontinuation of dosing may be needed. 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.

The onset of symptoms is usually within 28 days, but can occur later. Cerebyx 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. Some of these events have been fatal or life-threatening. 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. Cerebyx should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Hypersensitivity Cerebyx and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications 4 and Warnings and Precautions 5.

Additionally, consider alternatives to structurally similar drugs such as carboxamides e. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Cerebyx. Cerebyx should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.

Cerebyx should be discontinued permanently if a clear alternative etiology for the reaction cannot be established. Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin the active metabolite of Cerebyx. 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, Cerebyx should be immediately discontinued and not re-administered. Hematopoietic Complications Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin the active metabolite of Cerebyx. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

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. 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. 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. 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.

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 Cerebyx injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection. Phosphate Load The phosphate load provided by Cerebyx 0. Renal or Hepatic Disease or Hypoalbuminemia Because the fraction of unbound phenytoin the active metabolite of Cerebyx 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.

This has the potential to increase the frequency and severity of adverse events. Exacerbation of Porphyria In view of isolated reports associating phenytoin the active metabolite of Cerebyx with exacerbation of porphyria, caution should be exercised in using Cerebyx in patients suffering from this disease.

Teratogenicity and Other Harm to the Newborn Cerebyx may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin the active metabolite of Cerebyx may increase the risks for congenital malformations and other adverse developmental outcomes [see Use in Specific Populations 8. Increased frequencies of major malformations such as orofacial clefts and cardiac defects , and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities including microcephaly , and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy.

There have been several reported cases of malignancies, including neuroblastoma. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Slow Metabolizers of Phenytoin A small percentage of individuals who have been treated with phenytoin the active metabolite of Cerebyx have been shown to metabolize the drug slowly.

Slow metabolism may be caused by limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related central nervous system CNS toxicity develop, serum levels should be checked immediately.

Hyperglycemia Hyperglycemia, resulting from the inhibitory effect of phenytoin the active metabolite of Cerebyx on insulin release, has been reported. Phenytoin may also raise the serum glucose concentrations in diabetic patients. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Cerebyx dose reduction is indicated if serum levels are excessive; if symptoms persist, administration of Cerebyx should be discontinued.

Adverse Reactions.

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FOSPHENYTOIN PRESCRIBING INFORMATION PDF

Following CEREBYX administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after intramuscular IM injection. The error is dependent on serum phenytoin and fosphenytoin concentration influenced by CEREBYX dose, route and rate of administration, and time of sampling relative to dosing , and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration 2.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

Albendazole decreases active metabolite , chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients. This can be done by calling the tollfree number , and must be done by patients themselves. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities including microcephaly , and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data ]. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

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