Drugs List

Therapeutic Indications

Uses

Epilepsy - grand mal
Seizure prevention & treatment during/after neurosurgery &/or head injury
Status epilepticus
Ventricular arrhythmias

Control of status epilepticus of the tonic-clonic (grand mal) type.

Prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury.

Treatment of cardiac arrhythmias where first line therapy is not effective. It is of particular value where these are digitalis induced.

Administration

For intravenous and intramuscular route only.

Parenteral phenytoin should be injected slowly and directly into a large vein through a large gauge needle or intravenous catheter at a rate not exceeding 1mg/kg per minute (maximum 50mg per minute). Each injection or infusion of phenytoin should be preceded by and followed by an injection of sodium chloride 0.9% injection through the same needle or catheter to avoid local venous irritation due to the alkalinity of the solution.

For intravenous infusion, dilute to a concentration not exceeding 10mg/ml with sodium chloride 0.9% and give into a large vein through an in-line filter (0.22 micron to 0.50 micron) at a rate not exceeding 1mg/kg per minute (maximum 50mg per minute).

Phenytoin injection is suitable for administration provided it is not hazy and no precipitate has formed. Only a clear solution should be used. A faint yellow colouration may develop but has no effect on the potency.

Reconstitution

For use as an infusion, the phenytoin injection should be diluted with 50ml to 100ml of sodium chloride 0.9% injection. The final concentration of the phenytoin solution should not exceed 10mg/ml. Commence the administration, immediately after the infusion has been prepared and complete the administration within one hour of preparation. An in-line filter (0.22 microns to 0.50microns should be used).

Incompatibilities

Phenytoin injection should not be mixed with other drugs as there is risk of precipitation of phenytoin acid.

Contraindications

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
Hypoalbuminaemia
Patients over 65 years
Severe illness
Suicidal ideation
Breastfeeding
Diabetes mellitus
Elevated serum bilirubin
Hepatic impairment
Hypotension
Pregnancy
Severe cardiac failure
Severe ischaemic heart disease

Patients at risk of suicide should be closely supervised
Sodium content of formulation may be significant
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
Increased risk of osteomalacia; consider vitamin D supplement
May precipitate or aggravate absence and myoclonic seizures
Contains alcohol
Injection contains propylene glycol
Caution in changing formulations containing phenytoin and phenytoin sodium
If adverse reactions occur, reduce rate or temporarily stop infusion
Resuscitation facilities must be immediately available
Monitor antidiabetic drug treatment
Monitor blood pressure regularly
Monitor ECG
Monitor for Antiepileptic Hypersensitivity Syndrome
Monitor for mental changes, suicidal depression and antisocial behaviour
Monitor patient for signs and symptoms of respiratory depression
Monitor serum folate levels - add supplements if necessary
Monitor serum folate levels at least every six months
Plasma level monitoring may be useful: refer to local guidelines
Refer women considering pregnancy for specialist advice and monitoring
Advise patients/carers to seek medical advice if suicidal intent develops
Discontinue immediately following signs of acute hepatotoxicity
Discontinue treatment if DRESS is suspected
Discontinue treatment if Stevens-Johnson Syndrome suspected
Discontinue treatment if toxic epidermal necrolysis is suspected
May affect results of some laboratory tests
Avoid abrupt withdrawal
Discontinue treatment if rash occurs
Discontinue immediately if Antiepileptic Hypersensitivity Syndrome occurs
Consider reducing initial dose in the 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

Patients should be aware of the risks of developing Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) if alternative diagnosis for the signs and symptoms of HSS and DRESS cannot be determined, treatment should be discontinued.

Obtain serum drug levels at the first sign of toxicity. Plasma levels of phenytoin above the optimal range may produce confusional states such as delirium, psychosis or encephalopathy, reduce dose if serum levels are excessive and if symptoms persist with the recommendation of discontinuing treatment.

Long-term treatment with phenytoin is associated with decreased bone mineral density, resulting in an increased risk of developing osteopenia, osteoporosis and fractures in at-risk patients (those immobilised for long periods or who have inadequate sun exposure or dietary calcium intake). Consider vitamin D supplementation for all at-risk patients on long-term treatment.

The presence of the HLAB* 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 HLAB*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.

Phenytoin may cause lowered serum levels of calcium and folic acid. It is recommended that serum folate levels be measured at least every six months, and folic acid supplements given if necessary.

Severe cardiotoxic reactions due to arrhythmias have been reported. Complications are most common in elderly or gravely ill patients but have also been reported in adults and children with no underlying cardiac disease or comorbidities within recommended doses and infusion rates. All patients must undergo careful cardiac (including respiratory) monitoring during administration of intravenous loading doses. If adverse effects develop, a reduction in infusion rate or discontinuation of treatment may be needed.

Pregnancy and Lactation

Pregnancy

Use phenytoin sodium with caution in pregnancy.

Phenytoin sodium crosses the placenta, studies on the use of phenytoin sodium in pregnancy have shown to cause congenital abnormalities such as foetal hydantoin syndrome, cleft palate and heart malformations. It is suggested to increase folic acid during pregnancy, especially in the very early stages. Briggs (2015) suggests pregnant women should take 4mg to 5mg of folic acid each day to help prevent any adverse effects on foetal neurodevelopment such as neural tube defects.

If phenytoin sodium is administered in pregnancy, it is recommended that an expanded prenatal diagnosis should be carried out, including anatomical ultrasound diagnosis to rule out major disturbances of structural development. It is also recommended to monitor serum phenytoin levels to guide any necessary dose adjustments during pregnancy as drug plasma concentration is decreased due to phenytoin accumulating in fatty tissues, which is believed to be a cause for an increased occurrence of seizures during pregnancy (Schaefer et al, 2015).

It is recommended to use other drugs as the first drug of treatment during pregnancy as phenytoin sodium has up three times greater risks to the foetus of developing adverse effects (Briggs et al, 2015), therefore if phenytoin sodium is administered, the lowest possible dose is suggested in order to decrease the likelihood of foetal anomalies. Studies have shown when vitamin K is administered to the mother before delivery and neonate after birth, it can help prevent and correct neonatal coagulation as phenytoin can cause clotting problems due to vitamin k deficiency.

The manufacturer suggests to only administer phenytoin sodium injection if the potential benefit to the mother outweighs any potential risk to the foetus.

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 phenytoin with caution in breastfeeding.

Phenytoin is excreted into breast milk. Studies have shown that an infant may be exposed to a maximum of 10% of the maternal weight-related dose via the mother's milk, which is normally less than 5% of a paediatric phenytoin dose (Schaefer et al, 2015). Briggs (2015) states that there is little risk to the nursing infant if maternal levels are kept in the therapeutic range, there have been reports of drowsiness and methemoglobinemia, however no other reports of serious adverse effects. Hale (2014) suggests if phenytoin is used during breastfeeding, the infants plasma levels should be monitored.

The manufacturer suggests to avoid the use of phenytoin 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

Acne
Agranulocytosis
Aplastic anaemia
Asterixis
Ataxia
Benign lymph node hyperplasia
Bone marrow depression
Bullous eruption
Chorea
Coarse facial features
Confusion
Constipation
Decrease in bone mineral density
Depression of atrioventricular nodal conduction
Dermatitis
Dizziness
Drowsiness
Dupuytren's contracture
Dyskinesia
Dystonia
Enlargement of lips
Exfoliative rash
Fever
Fractures
Gingival hypertrophy and tenderness
Granulocytopenia
Headache
Hepatitis
Hepatotoxicity
Hirsutism
Hodgkin's disease
Hypersensitivity reactions
Hypertrichosis
Immunoglobulin abnormalities
Impaired co-ordination
Inflammation (injection site)
Insomnia
Interstitial nephritis
Irritation (injection site)
Leucopenia
Liver damage
Lymphadenopathy
Lymphoma
Macrocytosis
Megaloblastic anaemia
Morbilliform eruption
Nausea
Necrosis (injection site)
Nervousness
Nystagmus
Osteopenia
Osteoporosis
Pancytopenia
Paraesthesia
Periarteritis nodosa
Peyronie's disease
Pneumonitis
Polyarthropathy
Polyneuropathy
Pseudolymphoma
Purpuric dermatitis
Rash
Respiratory arrest
Scarlatiniform rash
Seizures
Serum sickness
Sloughing of tissue
Slurred speech
Stevens-Johnson syndrome
Systemic lupus erythematosus
Tenderness (injection site)
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Twitching
Ventricular fibrillation
Vertigo
Vomiting

Presentation

Parenteral formulation of phenytoin sodium.

Drugs List

Therapeutic Indications

Uses

Epilepsy - grand mal
Seizure prevention & treatment during/after neurosurgery &/or head injury
Status epilepticus
Ventricular arrhythmias

Control of status epilepticus of the tonic-clonic (grand mal) type.

Prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury.

Treatment of cardiac arrhythmias where first line therapy is not effective. It is of particular value where these are digitalis induced.

Dosage

Theoretically 100mg of phenytoin sodium is equivalent to 92mg of phenytoin on a molecular weight basis. These molecular equivalents are not necessarily biologically equivalent. Physicians should take care when changing patients between different formulations, monitoring is advised.

Adults

Children

Neonates

Additional Dosage Information

Administration

For intravenous and intramuscular route only.

Parenteral phenytoin should be injected slowly and directly into a large vein through a large gauge needle or intravenous catheter at a rate not exceeding 1mg/kg per minute (maximum 50mg per minute). Each injection or infusion of phenytoin should be preceded by and followed by an injection of sodium chloride 0.9% injection through the same needle or catheter to avoid local venous irritation due to the alkalinity of the solution.

For intravenous infusion, dilute to a concentration not exceeding 10mg/ml with sodium chloride 0.9% and give into a large vein through an in-line filter (0.22 micron to 0.50 micron) at a rate not exceeding 1mg/kg per minute (maximum 50mg per minute).

Phenytoin injection is suitable for administration provided it is not hazy and no precipitate has formed. Only a clear solution should be used. A faint yellow colouration may develop but has no effect on the potency.

Reconstitution

For use as an infusion, the phenytoin injection should be diluted with 50ml to 100ml of sodium chloride 0.9% injection. The final concentration of the phenytoin solution should not exceed 10mg/ml. Commence the administration, immediately after the infusion has been prepared and complete the administration within one hour of preparation. An in-line filter (0.22 microns to 0.50microns should be used).

Incompatibilities

Phenytoin injection should not be mixed with other drugs as there is risk of precipitation of phenytoin acid.

Contraindications

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
Hypoalbuminaemia
Patients over 65 years
Severe illness
Suicidal ideation
Breastfeeding
Diabetes mellitus
Elevated serum bilirubin
Hepatic impairment
Hypotension
Pregnancy
Severe cardiac failure
Severe ischaemic heart disease

Patients at risk of suicide should be closely supervised
Sodium content of formulation may be significant
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
Increased risk of osteomalacia; consider vitamin D supplement
May precipitate or aggravate absence and myoclonic seizures
Contains alcohol
Injection contains propylene glycol
Caution in changing formulations containing phenytoin and phenytoin sodium
If adverse reactions occur, reduce rate or temporarily stop infusion
Resuscitation facilities must be immediately available
Monitor antidiabetic drug treatment
Monitor blood pressure regularly
Monitor ECG
Monitor for Antiepileptic Hypersensitivity Syndrome
Monitor for mental changes, suicidal depression and antisocial behaviour
Monitor patient for signs and symptoms of respiratory depression
Monitor serum folate levels - add supplements if necessary
Monitor serum folate levels at least every six months
Plasma level monitoring may be useful: refer to local guidelines
Refer women considering pregnancy for specialist advice and monitoring
Advise patients/carers to seek medical advice if suicidal intent develops
Discontinue immediately following signs of acute hepatotoxicity
Discontinue treatment if DRESS is suspected
Discontinue treatment if Stevens-Johnson Syndrome suspected
Discontinue treatment if toxic epidermal necrolysis is suspected
May affect results of some laboratory tests
Avoid abrupt withdrawal
Discontinue treatment if rash occurs
Discontinue immediately if Antiepileptic Hypersensitivity Syndrome occurs
Consider reducing initial dose in the 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

Patients should be aware of the risks of developing Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) if alternative diagnosis for the signs and symptoms of HSS and DRESS cannot be determined, treatment should be discontinued.

Obtain serum drug levels at the first sign of toxicity. Plasma levels of phenytoin above the optimal range may produce confusional states such as delirium, psychosis or encephalopathy, reduce dose if serum levels are excessive and if symptoms persist with the recommendation of discontinuing treatment.

Long-term treatment with phenytoin is associated with decreased bone mineral density, resulting in an increased risk of developing osteopenia, osteoporosis and fractures in at-risk patients (those immobilised for long periods or who have inadequate sun exposure or dietary calcium intake). Consider vitamin D supplementation for all at-risk patients on long-term treatment.

The presence of the HLAB* 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 HLAB*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.

Phenytoin may cause lowered serum levels of calcium and folic acid. It is recommended that serum folate levels be measured at least every six months, and folic acid supplements given if necessary.

Severe cardiotoxic reactions due to arrhythmias have been reported. Complications are most common in elderly or gravely ill patients but have also been reported in adults and children with no underlying cardiac disease or comorbidities within recommended doses and infusion rates. All patients must undergo careful cardiac (including respiratory) monitoring during administration of intravenous loading doses. If adverse effects develop, a reduction in infusion rate or discontinuation of treatment may be needed.

Pregnancy and Lactation

Pregnancy

Use phenytoin sodium with caution in pregnancy.

Phenytoin sodium crosses the placenta, studies on the use of phenytoin sodium in pregnancy have shown to cause congenital abnormalities such as foetal hydantoin syndrome, cleft palate and heart malformations. It is suggested to increase folic acid during pregnancy, especially in the very early stages. Briggs (2015) suggests pregnant women should take 4mg to 5mg of folic acid each day to help prevent any adverse effects on foetal neurodevelopment such as neural tube defects.

If phenytoin sodium is administered in pregnancy, it is recommended that an expanded prenatal diagnosis should be carried out, including anatomical ultrasound diagnosis to rule out major disturbances of structural development. It is also recommended to monitor serum phenytoin levels to guide any necessary dose adjustments during pregnancy as drug plasma concentration is decreased due to phenytoin accumulating in fatty tissues, which is believed to be a cause for an increased occurrence of seizures during pregnancy (Schaefer et al, 2015).

It is recommended to use other drugs as the first drug of treatment during pregnancy as phenytoin sodium has up three times greater risks to the foetus of developing adverse effects (Briggs et al, 2015), therefore if phenytoin sodium is administered, the lowest possible dose is suggested in order to decrease the likelihood of foetal anomalies. Studies have shown when vitamin K is administered to the mother before delivery and neonate after birth, it can help prevent and correct neonatal coagulation as phenytoin can cause clotting problems due to vitamin k deficiency.

The manufacturer suggests to only administer phenytoin sodium injection if the potential benefit to the mother outweighs any potential risk to the foetus.

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 phenytoin with caution in breastfeeding.

Phenytoin is excreted into breast milk. Studies have shown that an infant may be exposed to a maximum of 10% of the maternal weight-related dose via the mother's milk, which is normally less than 5% of a paediatric phenytoin dose (Schaefer et al, 2015). Briggs (2015) states that there is little risk to the nursing infant if maternal levels are kept in the therapeutic range, there have been reports of drowsiness and methemoglobinemia, however no other reports of serious adverse effects. Hale (2014) suggests if phenytoin is used during breastfeeding, the infants plasma levels should be monitored.

The manufacturer suggests to avoid the use of phenytoin 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

Acne
Agranulocytosis
Aplastic anaemia
Asterixis
Ataxia
Benign lymph node hyperplasia
Bone marrow depression
Bullous eruption
Chorea
Coarse facial features
Confusion
Constipation
Decrease in bone mineral density
Depression of atrioventricular nodal conduction
Dermatitis
Dizziness
Drowsiness
Dupuytren's contracture
Dyskinesia
Dystonia
Enlargement of lips
Exfoliative rash
Fever
Fractures
Gingival hypertrophy and tenderness
Granulocytopenia
Headache
Hepatitis
Hepatotoxicity
Hirsutism
Hodgkin's disease
Hypersensitivity reactions
Hypertrichosis
Immunoglobulin abnormalities
Impaired co-ordination
Inflammation (injection site)
Insomnia
Interstitial nephritis
Irritation (injection site)
Leucopenia
Liver damage
Lymphadenopathy
Lymphoma
Macrocytosis
Megaloblastic anaemia
Morbilliform eruption
Nausea
Necrosis (injection site)
Nervousness
Nystagmus
Osteopenia
Osteoporosis
Pancytopenia
Paraesthesia
Periarteritis nodosa
Peyronie's disease
Pneumonitis
Polyarthropathy
Polyneuropathy
Pseudolymphoma
Purpuric dermatitis
Rash
Respiratory arrest
Scarlatiniform rash
Seizures
Serum sickness
Sloughing of tissue
Slurred speech
Stevens-Johnson syndrome
Systemic lupus erythematosus
Tenderness (injection site)
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Twitching
Ventricular fibrillation
Vertigo
Vomiting

Effects on Laboratory Tests

Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may also produce lower than normal values for dexamethasone or metapyrone tests.

Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, gamma glutamyl transpeptidase and lowered serum levels of calcium and folic acid.

Phenytoin may affect blood sugar metabolism tests.

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: June 2017

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Summary of Product Characteristics: Epanutin Ready Mixed Parenteral. Pfizer Ltd. Revised September 2017.

Summary of Product Characteristics: Phenytoin Injection BP. Hospira UK Ltd. Revised April 2017.

Summary of Product Characteristics: Phenytoin 250mg/5ml solution for injection. Beacon Pharmaceuticals. Revised March 2016.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 08 June 2017