Phenytoin

Registered South African indications:

• Seizures
• Arrhythmias (inj)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Porphyria
• Sinus bradycardia (inj)
• Sino-atrial block (inj)
• Second and third degree atrioventricular block (inj)
• Adams-Stokes syndrome (inj)
• Intra-arterial administration (inj)
• Coadministration with delavirdine

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Not indicated for seizures due to hypoglycaemia or other metabolic causes
• Avoid abrupt withdrawal
• May precipitate or aggravate absence seizures and myoclonic seizures
• Black patients
• Diabetes mellitus
• Hypotension (inj)
• Severe myocardial insufficiency (inj)
• Galactose intolerance (cap)
• Lapp lactase deficiency (cap)
• Glucose-galactose malabsorption (cap)

Forms avail. in SA and covered in this monograph: cap, tab, inj, sus

Status epilepticus

Loading dose 

• IV: 20mg/kg; Max rate: 50mg/min

Maintenance

• Oral (cap, tab, sus)/IV: 100mg, 8hrly

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Dilute IV in 0.9% sodium chloride, concentration 4g/l, admin. Max: 50mg/min with cardiac monitioring, use within 1hr of mixing

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Determination of phenytoin serum levels is advised. The clinically effective level is usually 10-20μg/l

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Seizures

• Oral: 15mg/kg as a single oral dose to reach a therapeutic range of 10-20μg/mL
• Oral (cap, tab): 300mg at night; Titrate at 7-10 day intervals; Usual maintenance dose: 300-400mg/24hrs; Max: 600mg/24hrs
• Oral (sus): 125mg, 8hrly; Titrate at 7-10 day intervals; Max: 625mg/24hrs

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Phenytoin can be loaded in patients not in status epilepticus as a single dose to achieve a faster rise into the therapeutic range

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Dosages in excess of 300mg at night can be split into a 12hrly dose

Dosage adjustment should be guided by phenytoin serum levels

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It may be useful to supplement with folate to minimise gum hypertophy

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Prevention of seizures following neurosurgery - Phenytoin naive patients

• IM: 100-200mg (2-4 ml), 4hrly during neurosurgery and continued during the postoperative period for 48-72hrs; Thereafter reduce to maintenance dose: 300mg and adjusted according to serum level estimations

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IM therapy should generally be limited to 1 week

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Trigeminial neuralgia

• Oral (sus, cap, tab): 100-300mg/day, in divided doses; Serum levels should not exceed 20μg/ml

Digitalis-induced ventricular tachyarrythmias

• IV: 100mg, given slowly; Repeat at intervals of 5 mins if needed; Max: 15mg/kg

Paed. forms avail. in SA and covered in this monograph: inj, cap, sus

Status epilepticus

Loading dose

• IV: 18mg/kg infused over 20min in glucose free solution; Max rate: 1-3mg/kg/min or 50mg/min, whichever is slower

Maintenance

• Oral (sus, cap)/IV: Usual maintenance range: 4-8mg/kg

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Determination of phenytoin serum levels is advised

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Cardiac monitoring essential; If bradycardia, hypotension or arrhythmias develop, stop infusion until stable then restart at 2/3 starting dose

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In neonates admin rate: Max: 1-3 mg/kg/min

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Seizures

• Oral (sus, cap): 5mg/kg, dly in 2 divided doses; Titrate at 7-10 day intervals; Usual maintenance dose: 4-8mg/kg; Max: 300mg/24hrs

Digitalis-induced ventricular tachyarrythmias

• IV: 1.5mg/kg, given slowly; Repeat at intervals of 5 mins if needed; Max: 15mg/kg

Pregnancy

• Caution
• Phenytoin crosses the placenta
• There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans. Genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or foetus
• Anticonvulsants including phenytoin may produce congenital abnormalities in the offspring of a small number of epileptic patients. The exact role of drug therapy in these abnormalities is unclear and genetic factors, in some studies, have also been shown to be important. Phenytoin should only be used during pregnancy, especially in early pregnancy, if in the judgement of the physician the potential benefits clearly outweigh the risk
• In addition to the reports of increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other antiepileptic drugs, there have more recently been reports of a foetal hydantoin syndrome. This consists of prenatal growth deficiency, microencephaly and mental deficiency in children born to mothers who have received phenytoin, barbiturates, alcohol, or trimethadione. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes
• There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy
• An increase in seizure frequency during pregnancy occurs in a proportion of patients, and this may be due to altered phenytoin absorption or metabolism. Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to an appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated
• Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenytoin. Vitamin K1 has been shown to prevent or correct this defect and may be given to the mother before delivery and to the neonate after birth

Breastfeeding

• Caution
• Phenytoin is excreted in breast milk
• If maternal plasma levels are within the therapeutic range, and considering the daily volume of milk taken by the infant, it is unlikely that the infant will be exposed to clinically significant phenytoin concentrations
• A decision to breastfeed during phenytoin therapy must be made taking into account the risk of phenytoin exposure to the child and the benefit of therapy for the mother

Renal Impairment

• Caution; no dose adjustment recommended

Hepatic Impairment

• Status epilepticus: Mild to severe: No dose adjustment recommended
  Dose adjustment not required for loading and maintenance dose during emergency therapy
• Mild to moderate (Child-Pugh class A or B): Caution; no dose adjustment recommended
  Phenytoin (therapeutic-concentration) plasma TDM must be requested
• Severe (Child-Pugh class C): Caution; no dose adjustment recommended
  Lower doses or less frequent dosing may be required if Phenytoin (therapeutic-concentration) plasma TDM is above the upper limits of normal ranges. Immediately discontinue phenytoin in patients who develop acute hepatotoxicity and do not re-administer
  Closer serum monitoring is required in hepatic impairment

Elderly

• Caution; no dose adjustment recommended
  Lower or less frequent dosing may be required

Porphyria Information

• Porphyrinogenic (P)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Nystagmus
• Ataxia
• Slurred speech
• Decreased coordination 
• Mental confusion
• Cerebellar atrophy 
• Dizziness
• Vertigo
• Insomnia
• Transient nervousness
• Motor twitchings
• Headache
• Paraesthesia
• Somnolence 
• Taste perversion 
• Dyskinesias
• Irreversible cerebellar dysfunction 
• Sensory peripheral polyneuropathy 

Cardiovascular Disorders

• Severe cardiotoxic reactions (inj)
• Atrial and ventricular conduction depression (inj)
• Ventricular fibrillation (inj)

Respiratory Disorders

• Pulmonary infiltrates
• Fibrosis
• Alterations in respiratory function
• Respiratory arrest
• Pneumonitis

Gastrointestinal Disorders

• Acute hepatic failure
• Toxic hepatitis
• Nausea and vomiting
• Constipation 
• Gingival hyperplasia

Hepatobiliary Disorders

• Toxic hepatitis
• Hepatic damage

Genitourinary Disorders  

• Interstitial nephritis
• Peyronie's disease

Skin and Subcutaneous Tissue Disorders

• Scarlatiniform rashes
• Morbilliform rashes
• Dermatitis 
• Bullous
• Exfoliative dermatitis
• Purpuric dermatitis
• Lupus erythematosus
• Severe cutaneous adverse reactions 
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis 
• Coarsening of the facial features
• Enlargement of the lips
• Gingival hyperplasia
• Hirsutism
• Hypertrichosis
• Peyronie's Disease 
• Dupuytren's contracture 
• Soft tissue irritation and inflammation at site of injection (inj)
• Purple glove syndrome (inj)

Musculoskeletal Disorders

• Decreased bone mineral density
• Osteopenia
• Osteoporosis 
• Osteomalacia
• Bone fractures
• Polyarthropathy

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Leucopenia
• Granulocytopenia
• Agranulocytosis
• Pancytopenia 
• Bone marrow suppression
• Aplastic anaemia
• Macrocytosis anaemia
• Megaloblastic anaemia 
• Lymphadenopathy  
• Benign lymph node hyperplasia
• Pseudolymphoma 
• Lymphoma
• Hodgkin's disease 
• Hypersensitivity syndrome
• Drug reaction with eosinophilia and systemic symptoms
• Systemic lupus erythematosus
• Polyarteritis nodosa
• Immunoglobulin abnormalities
• Hypersensitivity reactions
• Skin rash 
• Hepatotoxicity in black patients
• Anaphylactoid reaction 
• Anaphylaxis

• CYP2C9 substrates
• CYP2C19 substrates
• Antidiabetic agents  
• Diazoxide
• Dopamine (inj)
• Lignocaine (inj)
• Beta blockers (inj)  
• Alcohol
• Anti-inflammatory agents
• Anaesthetics
• Antibacterial agents
• Anticonvulsants
• Antifungal agents
• Antineoplastic agents
• Benzodiazepines
• Psychotropic agents
• Calcium channel blockers
• Histamine antagonists
• HMG-CoA reductase inhibitors
• Oestrogens
• Tacrolimus
• Proton pump inhibitors
• Serotonin reuptake inhibitors
• Antiulcer agents
• Antiretrovirals
• Theophylline
• Reserpine
• Folic acid
• St. John's Wort
• Antihelminthics
• Corticosteroids
• Coumarin anticoagulants
• Cyclosporine
• Furosemide
• Oral contraceptives
• Immunosuppressant agents
• Neuromuscular blocking agents
• Opioid analgesics
• Antidepressants
• Vitamin D

None routine. Specific cases may require

• Phenytoin serum levels
• Full blood count
• Mental status
• ECG (inj)
• Blood pressure (inj)

Capsule 100mg, Suspension - EML (Primary)

Injection 250mg/5ml - EML (Hospital)

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Neonates

The aborption of phenytoin following oral administration in neonates is unpredictable. Furthermore, the metabolism of phenytoin may be depressed. It is therefore especially important to monitor serum levels in the neonate

Phenytoin sodium inhibits the spread of seizure activity in the motor cortex by promoting sodium efflux from neurons. It stabilises the threshold against hyperexcitability caused by environmental changes or excessive stimulation capable of reducing membrane sodium gradient. This includes the reduction of post tetanic potentiation of synapses. Loss of post tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin thereby reduces the over-activity of brain stem centres responsible for the tonic phase of grand mal seizures.

Phenytoin sodium's antiarrhythmic action may be attributed to the normalization of influx of sodium and calcium to cardiac Purkinje fibres. Abnormal ventricular automaticity and membrane responsiveness are decreased. It also shortens the refractory period, and therefore shortens the QT interval and the duration of the action potential.  

Tablets 50mg

• Epanutin infatabs (Pfizer) originator

Tablet 100mg

• Epanutin (Pfizer) originator
• Phenytoin (Pharmacare)

Capsule 100mg

• Epanutin (UpJohn) originator
• Phenytoin Sodium ( Pharmacare)

Suspension (per 5ml) 125mg

• Epanutin forte (Pfizer) originator

Injection (per 5ml) 250mg

• Epanutin ready mix parenteral (UpJohn) originator
• Phlexy (Dezzo)