Fosphenytoin sodium parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Parenteral formulations of fosphenytoin sodium.
Drugs List
Therapeutic Indications
Uses
Epilepsy - grand mal
Epilepsy - short-term use as replacement therapy
Seizure prevention & treatment during/after neurosurgery &/or head injury
Status epilepticus
Dosage
The amount and concentration of fosphenytoin should always be expressed in terms of phenytoin sodium equivalents (PE) to avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). 1.5mg of fosphenytoin is equivalent to 1mg PE.
Fosphenytoin sodium should not be administered for more than five days.
When treating status epilepticus consider using alternative anticonvulsants if fosphenytoin sodium does not terminate seizures.
Adults
Status Epilepticus
Loading Dose
IV diazepam or lorazepam should be administered prior to administration of fosphenytoin to obtain rapid seizure control in patients with continuous seizure activity.
15mg PE/kg administered as a single dose by IV infusion at a recommended rate of 100mg to 150mg PE/minute. The rate of IV infusion should not exceed 150mg PE/minute.
Maintenance Dose
Recommended 4mg to 5mg PE/kg per day given by IV infusion or by IM injection in one or two divided doses at a recommended rate of IV infusion 50mg to 100mg PE/minute. The rate of IV infusion should not exceed 100mg PE/minute. Cumulative daily dose should not exceed 4mg to 5mg PE/kg per day.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Treatment or Prophylaxis of Seizures
Loading Dose
10mg to 15mg PE/kg given as a single dose by IV infusion or IM injection at a recommended rate of IV infusion 50mg to 100mg PE/minute. The rate of IV infusion should not exceed 100mg PE/minute.
Maintenance Dose
Recommended 4mg to 5mg PE/kg per day may be given by IV infusion or IM injection in one or two divided doses at a recommended rate of IV infusion 50mg to 100mg PE/minute. The rate of IV infusion should not exceed 100mg PE/minute.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Temporary Substitution of Oral Phenytoin Therapy with Fosphenytoin
The same dose and dosing frequency as for oral phenytoin therapy should be used and can be administered by IV infusion or by IM injection. The recommended rate of IV infusion for temporary substitution dosing is 50mg to 100mg PE/minute and should not exceed 100mg PE/minute.
Therapeutic drug monitoring may be useful whenever switching between products and/or routes of administration. Doses should be adjusted according to patient response and trough plasma phenytoin concentrations.
Elderly
(See Dosage; Adult)
A 10% to 25% dose reduction or rate reduction may be considered with careful monitoring of the patient.
Children
Children aged 5 to 18 years
Fosphenytoin may be administered to children aged 5 years and above by IV infusion only, at the same mg PE/kg dose used for adults.
Status Epilepticus
Loading Dose
IV diazepam or lorazepam should be administered prior to administration of fosphenytoin to obtain rapid seizure control in patients with continuous seizure activity.
15mg PE/kg (alternate sources suggest up to 20mg PE/kg) administered as a single dose by IV infusion at a recommended rate of 2mg to 3mg PE/kg/minute. The rate of IV infusion should not exceed 3mg PE/kg/minute or 150mg PE/minute, whichever is the slowest.
Maintenance Dose
Recommended 4mg to 5mg PE/kg per day given by IV infusion or by IM injection in one or two divided doses at a recommended rate of IV infusion 1mg to 2mg PE/kg/minute. The rate of IV infusion should not exceed 2mg PE/kg/minute or 100mg PE/minute, whichever is the slowest. Cumulative daily dose should not exceed 4mg to 5mg PE/kg per day.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Treatment or Prophylaxis of Seizures
Loading Dose
10mg to 15mg PE/kg given as a single dose by IV infusion or IM injection at a recommended rate of IV infusion 1mg to 2mg PE/kg/minute. The rate of IV infusion should not exceed 2mg PE/kg/minute or 100mg PE/minute, whichever is the slowest.
Maintenance Dose
Recommended 4mg to 5mg PE/kg per day may be given by IV infusion or IM injection in one or two divided doses at a recommended rate of IV infusion 1mg to 2mg PE/kg/minute. The rate of IV infusion should not exceed 2mg PE/kg/minute or 100 mg PE/minute, whichever is the slowest.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Temporary Substitution of Oral Phenytoin Therapy with Fosphenytoin
The same dose and dosing frequency as for oral phenytoin therapy should be used and can be administered by IV infusion or by IM injection. The recommended rate of IV infusion for temporary substitution dosing is 1mg to 2mg PE/kg/minute and should not exceed 2mg PE/kg/minute or 100mg PE/minute, whichever is the slowest.
Therapeutic drug monitoring may be useful whenever switching between products and/or routes of administration. Doses should be adjusted according to patient response and trough plasma phenytoin concentrations.
Patients with Renal Impairment
A 10% to 25% dose reduction or rate reduction may be considered with careful monitoring of the patient.
Patients with Hepatic Impairment
A 10% to 25% dose reduction or rate reduction may be considered with careful monitoring of the patient.
Administration
For administration by intravenous infusion or intramuscular injection.
Only the intravenous route should be used in emergency situations such as status epilepticus.
Therapeutic Drug Monitoring
Prior to complete conversion, immunoanalytical techniques may significantly overestimate plasma phenytoin concentrations due to cross reactivity with fosphenytoin.
Chromatographic assay methods (e.g. HPLC) accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. It is advised that blood samples to assess phenytoin concentration should not be obtained for at least 2 hours after IV fosphenytoin infusion or 4 hours after IM fosphenytoin injection.
Optimal seizure control without clinical signs of toxicity occurs most often with plasma total phenytoin concentration of between 10 and 20 mg/l (40 and 80 micromoles/l) or plasma unbound phenytoin concentrations between 1 and 2 mg/l (4 and 8 micromoles/l).
Plasma phenytoin concentrations sustained above the optimal range may produce signs of acute toxicity.
Phenytoin capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as fosphenytoin, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase when IM or IV fosphenytoin is substituted for oral phenytoin therapy. However, it is not necessary to adjust the initial doses when substituting oral phenytoin with fosphenytoin or vice versa.
Therapeutic drug monitoring may be useful whenever switching between products and/or routes of administration.
Measure the plasma concentration of unbound phenytoin as levels may be elevated in patients with hyperbilirubinaemia.
Contraindications
Children under 5 years
Non-paced sinus node dysfunction
Porphyria
Second degree atrioventricular block
Sinoatrial exit block
Sinus bradycardia
Stokes-Adams attacks
Third degree atrioventricular block
Precautions and Warnings
Debilitation
East Asian ancestry
Elderly
Hypoalbuminaemia
Restricted phosphate intake
Severe illness
Suicidal ideation
Acute phase of cerebrovascular accident
Breastfeeding
Diabetes mellitus
Elevated serum bilirubin
Hepatic impairment
Hypotension
Pregnancy
Renal impairment
Severe ischaemic heart disease
Patients at risk of suicide should be closely supervised
Reduce dose in patients with hepatic impairment
Reduce dose in patients with renal impairment
Advise ability to drive/operate machinery may be affected by side effects
Confirm HLA-B 1502 status in Han Chinese & Thai patients before initiating
Folic acid 5mg daily required pre-conception to end of 1st trimester
Resuscitation facilities must be immediately available
Determine drug plasma levels at first sign of acute toxicity
Monitor blood pressure and ECG continuously throughout treatment
Monitor patient for 30 minutes after administration
Monitor respiratory function
Plasma level monitoring may be useful: refer to local guidelines
Reduce dose or discontinue if excessive hypotension occurs
Refer women considering pregnancy for specialist advice and monitoring
Advise patient to report any unusual swelling of the lymph nodes
Advise patient to seek immediate medical advice if rash occurs
Advise patients/carers to seek medical advice if suicidal intent develops
Consider discontinuation and/or dose reduction in acute toxicity
Discontinue immediately following signs of acute hepatotoxicity
Risk of developing lymphoproliferative disorders
May affect results of some laboratory tests
Abrupt withdrawal may precipitate status epilepticus
Discontinue if angioedema occurs
Discontinue if drug-related rash or other hypersensitivity reactions occur
Prescription should state dose in terms of phenytoin sodium equivalent (PE)
Reduce dose in elderly
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Neonate exposed in utero: Administer vitamin K at birth
Pregnancy: Administer vitamin K in the last few weeks of pregnancy
Monitor ECG, blood pressure and respiratory function continuously throughout the duration of infusion and for thirty minutes after. The patient should also be monitored throughout the period where plasma phenytoin concentrations are maximised.
Fosphenytoin is not effective in absence seizures. If tonic-clonic seizures are present simultaneously with absence seizures, combined drug therapy is recommended.
Discontinue permanently if serious rash occurs (i.e. exfoliative, purpuric or bullous, or suspected lupus erythematosus, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis or toxic epidermal necrolysis). Mild rashes may have treatment resumed once the rash has disappeared. If the rash reappears upon resuming treatment, treatment should be discontinued permanently.
Published literature suggests an increased (although still rare) risk of hypersensitivity reactions in black patients.
Discontinue if patient is diagnose with Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Patients at increased risk of HSS/DRESS include black patients, patients with a personal or family history, and immuno-suppressed patients.
The presence of the HLA-B* 1502 allele may be associated with an increased risk of developing Stevens Johnson syndrome in patients of Thai and Han Chinese origin when treated with phenytoin. Use only if the benefits outweigh the risks in patients known to be positive for this allele. The frequency of HLA-B*1502 is extremely low in the Caucasian and Japanese population, therefore it is not possible to conclude on risk association, and adequate information about risk association in other ethnicities is currently not available.
Pregnancy and Lactation
Pregnancy
Use fosphenytoin sodium with caution in pregnancy.
At the time of writing there is limited published information regarding the use of fosphenytoin sodium during pregnancy. It is suggested that the frequency of seizures may increase due to the pharmacokinetics of phenytoin, therefore plasma phenytoin concentrations should be measured throughout pregnancy for appropriate dose adjustments as it can accumulate in fatty tissues.
Studies have shown phenytoin to cause teratogenic effects including cleft palate, heart defects and growth abnormalities as well as some adverse effects on neurodevelopment causing mental deficiency.
Briggs (2015) states that the epileptic pregnant women taking phenytoin, either alone or in combination with other anticonvulsants, has a two to three times greater risk for delivering a child with congenital defects over the general population, however the potential benefit of phenytoin to the mother outweighs any potential risk to the foetus.
Schaefer (2015) agrees with Briggs (2015) stating that although phenytoin is not the preferred antiepileptic drug of choice during pregnancy, it is acceptable to continue with phenytoin therapy as long as the condition is being well managed.
Treatment with phenytoin is not an indication for termination, but an expanded prenatal diagnosis should be considered, including anatomical ultrasound diagnosis to rule out major disturbances of structural development. The lowest possible dose should be administered to help prevent seizures in order to lessen the likelihood of foetal anomalies. It is recommended that vitamin K1 should be administered during the last four weeks of pregnancy to decrease the risks of coagulation disturbances in the foetus (Schaefer et al, 2015). Although there is limited effective evidence, it is also recommended to administer folic acid during pregnancy to help protect the foetus against teratogenic effects suggesting it enhances antiepileptic metabolism reducing the drug concentrations in the mother (Schaefer et al, 2015).
The manufacturer states the patient should be well informed of the potential risks to the foetus if fosphenytoin sodium is used during pregnancy.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Use fosphenytoin sodium with caution in breastfeeding.
At the time of writing there is limited published information regarding the use of fosphenytoin during breastfeeding. It is not known whether fosphenytoin is excreted in breast milk, however phenytoin is excreted in breast milk in low concentrations that Briggs (2015) states poses little risk to the infant if kept within the therapeutic range.
Studies with phenytoin have shown that an infant may be exposed to a maximum of 10% of the maternal weight-related dose excreted in breast milk, which is normally less than 5% of a paediatric phenytoin dose (Schaefer et al, 2015). Another study in one infant reported swallowing difficulties, methemoglobinemia, drowsiness and decreased sucking activity, but no other reports of adverse effects with the use of phenytoin during breastfeeding have been located (Briggs et al, 2015).
The manufacturer states the use of fosphenytoin sodium is not recommended during breastfeeding.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Abnormal thinking
Abnormal vision
Acute generalised exanthematous pustulosis
Agranulocytosis
Anaphylactic reaction
Angioedema
Aplastic anaemia
Asterixis
Asthenia
Asystole
Ataxia
AV conduction disorders
Blurred vision
Bone marrow depression
Bradycardia
Cardiotoxicity
Cardiovascular collapse
Chills
Chorea
CNS depression
Coarse facial features
Confusion
Constipation
Decrease in bone mineral density
Decreased reflexes
Disturbances of appetite
Dizziness
Drowsiness
Dry mouth
Dupuytren's contracture
Dysarthria
Dysgeusia
Dyskinesia
Dystonia
Ear disorder
Ecchymosis
Enlargement of lips
Euphoria
Extrapyramidal effects
Fractures
Gingival hyperplasia
Granulocytopenia
Headache
Heart block
Hepatitis
Hepatocellular damage
Hirsutism
Hyperglycaemia
Hyperreflexia
Hypersensitivity reactions
Hypertrichosis
Hypoacusis
Hypoaesthesia
Hypotension
Immunoglobulin abnormalities
Inco-ordination
Insomnia
Interstitial nephritis
Leucopenia
Liver damage
Local pain (injection site)
Local reaction at injection site
Lymphadenopathy
Muscle spasm
Muscle weakness
Nausea
Nystagmus
Osteopenia
Osteoporosis
Pain - generalised
Pancytopenia
Paraesthesia
Periarteritis nodosa
Peripheral neuropathy
Peyronie's disease
Pneumonitis
Polyarthropathy
Pruritus
Purpura exfoliative dermatitis
Rash
Respiratory arrest
Respiratory depression
Seizures
Slurred speech
Somnolence
Stevens-Johnson syndrome
Stupor
Systemic lupus erythematosus
Taste disturbances
Thrombocytopenia
Tingling in extremities
Tinnitus
Toxic epidermal necrolysis
Transient nervousness
Tremor
Twitching
Vasodilatation
Ventricular fibrillation
Vertigo
Vomiting
Effects on Laboratory Tests
Concentration of serum T4 may be decreased as well as artefacts in dexamethasone or metyrapone tests. Phenytoin has also been shown to affect blood calcium and blood sugar metabolism tests and may increase blood glucose or serum concentrations of alkaline phosphatase and gamma glutamyl transpeptidase (GGT).
Phenytoin has the potential to lower serum folate levels.
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: May 2017
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 8th edition (2008) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Summary of Product Characteristics: Pro-Epanutin concentrate for infusion/solution for injection. Pfizer Limited. Revised July 2021.
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 21 August 2017
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
FDB Disclaimer : FDB Multilex is intended for the use of healthcare professionals and is provided on the basis that the healthcare professionals will retain FULL and SOLE responsibility for deciding what treatment to prescribe or dispense for any particular patient or circumstance.