EPANUTIN READY MIXED PARENTERAL

4). Continuous monitoring of the electrocardiogram and blood pressure is essential. Cardiac resuscitative equipment should be available. The patient should be observed for signs of respiratory depression. If administration of intravenous Epanutin does not terminate seizures, the use of other measures, including general anaesthesia, should be considered.

Because of the risks of cardiac and local toxicity associated with intravenous phenytoin, oral phenytoin should be used whenever possible. There is a relatively small margin between full therapeutic effect and minimally toxic doses of this drug.

Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 mcg/mL and 20 mcg/mL (40-80 micromoles/l). e. serial epilepsy, injection of intravenous diazepam or a short acting barbiturate is recommended because of their rapid onset of action, prior to administration of Epanutin.

Following the use of diazepam in patients having continuous seizures and in the initial management of serial epilepsy a loading dose of Epanutin 10 mg/kg - 15 mg/kg should be injected slowly intravenously, at a rate not exceeding 50 mg/min in adults (this will require approximately 20 minutes in a 70 kg patient).

The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6 to 8 hours. Absorption of phenytoin in neonates is unreliable after oral administration, but a loading dose of 15 mg/kg - 20 mg/kg of Epanutin intravenously will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range (10 mcg/ml - 20 mcg/ml).

Determination of phenytoin serum levels is advised when using Epanutin in the management of status epilepticus and in the subsequent establishing of maintenance dosage. The clinically effective level is usually 10 mcg/mL – 20 mcg/mL although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin.

Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. 5 mg per kg - 5 mg per kg of bodyweight intravenously initially, repeated once if necessary.

The solution should be injected slowly, intravenously and at a uniform rate which should not exceed 1 ml (50 mg/min).

Neurosurgery:

In a patient who has not previously received the drug, Parenteral Epanutin 100 mg - 200 mg (2-4 ml) may be administered intramuscularly at approximately 4-hour intervals prophylactically during neurosurgery and continued during the post- operative period for 48-72 hrs.

The dosage should then be reduced to a maintenance dose of 300 mg and adjusted according to serum level estimations. If the patient requires more than a week of intramuscular Epanutin, alternative routes should be explored such as gastric intubation.

For time periods less than one week, the patient switched from intramuscular administration should receive one half the original oral dose for the same period of time the patient received Epanutin intramuscularly. Measurement of serum levels is of value as a guide to an appropriate adjustment of dosage.

Other clinical conditions:

It is not possible to set forth a universally applicable dosage schedule. The intravenous route (IV) of administration is preferred. Dosage and dosing interval will, of necessity, be determined by the needs of the individual patient.

Factors such as previous antiepileptic therapy, seizure control, age and general medical condition must be considered. Notwithstanding the slow absorption of Epanutin, when given intramuscularly, its use in certain conditions may be appropriate.

When short-term intramuscular administration is necessary for a patient previously stabilised orally, compensating dosage adjustments are essential to maintain therapeutic serum levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels.

When returned to oral administration, the dose should be reduced by 50% of the original oral dose, for the same period of time the patient received Epanutin intramuscularly, to prevent excessive serum levels due to continued release from intramuscular tissue sites.

2. Parenteral substitution for oral phenytoin therapy Epanutin Ready Mixed Parenteral contains phenytoin sodium whereas Epanutin Suspension and Epanutin Infatabs contain phenytoin. Although 100 mg of phenytoin sodium is equivalent to 92 mg of phenytoin on a molecular weight basis, these molecular equivalents are not necessarily biologically equivalent.

Physicians should therefore exercise care in those situations where it is necessary to change the dosage form and serum level monitoring is advised. 5 - 5 mg/kg intravenously Infusion rate: Not to exceed a rate of 50 mg/min Patients with Renal or Hepatic Disease: See section

8 Skin and subcutaneous tissue disorders).. 4 Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)), occurrence of rash and should be monitored closely for skin reactions. Patients should seek medical advice from their physician immediately when observing any indicative signs or symptoms.

The highest risk for occurrence of SJS or TEN is within the first weeks of treatment. g. progressive skin rash often with blisters or mucosal lesions) are present, Epanutin treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug.

Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of Epanutin, Epanutin must not be re-started in this patient at any time. If the rash is of a milder type (measles-like or scarlantiniform), therapy may be resumed after the rash has completely disappeared.

If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. The risk of serious skin reactions and other hypersensitivity reactions to phenytoin may be higher in black patients. Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of human leukocyte antigen 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 drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

Case-control, genome-wide association studies in Taiwanese, Japanese, Malaysian and Thai patients have identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant. Literature reports suggest that the combination of phenytoin, cranial irradiation, and the gradual reduction of corticosteroids may be associated with the development of erythema multiforme and/or SJS and/or TEN.

CYP2C9 metabolism:

CYP2C9 metabolism Phenytoin is metabolised by the CYP450 CYP2C9 enzyme. Patients who are carriers of the decreased function CYP2C9*2 or CYP2C9*3 variants (intermediate or poor metabolizers of CYP2C9 substrates) may be at risk of increased phenytoin plasma concentrations and subsequent toxicity.

In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles, close monitoring of clinical response is advised and monitoring of plasma phenytoin concentrations may be required.

Angioedema:

Angioedema has been reported in patients treated with phenytoin and fosphenytoin. 8 Immune system disorders).

Hepatic Injury:

The liver is the chief site of biotransformation of phenytoin. Toxic hepatitis and liver damage have been reported and may, in rare cases, be fatal. Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin.

4 Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)). Patients with impaired liver function, older patients, or those who are gravely ill may show early signs of toxicity. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes.

In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. The risk of hepatotoxicity and other hypersensitivity reactions to phenytoin may be higher in black patients.

Haematopoietic System:

Haematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression.

Central Nervous System Effect:

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium”, “psychosis”, or “encephalopathy”, or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum drug level determinations are recommended.

Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of therapy with phenytoin is recommended.

Metabolic Effect:

Phenytoin may affect glucose metabolism and inhibit insulin release. Hyperglycaemia has been reported. Caution is advised when treating diabetic patients. In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Women of Childbearing Potential:

Phenytoin may cause foetal harm when administered to a pregnant woman. 6). The magnitude of the risk to the foetus is unknown when phenytoin use is of short duration (emergency situations). Epanutin should not be used in women of childbearing potential except where there is a clinical need and when possible, the woman should be informed of the potential risk to the foetus associated with the use of phenytoin during pregnancy.

In emergency situations, the risk of harm to the foetus should be assessed in view of the condition being treated for […]

4. 2 – Special Populations – Age). As for adults, however, complications may occur more readily in older people.

Paediatric population:

It has been shown that younger children tend to metabolise phenytoin more rapidly than adults, with metabolism in older children (adolescents) approaching that of adults and absorption of phenytoin in neonates is unreliable after oral administration.

This should be borne in mind when determining dosage regimens; the use of serum level monitoring being particularly beneficial in such cases. * PAEDIATRIC POPULATION Indication Dose Phenytoin Sodium Injection Posology Loading Dosage: 15 - 20 mg/kg intravenously Infusion rate: 1 - 3 mg/kg/min, not exceeding 50 mg/min, whichev is slower Status Epilepticus Maintenance Dosage: 2 to 4 mg/kg administered 12 hours after the loading dose and then continued every 12 hours (4 to 8 mg/kg/day) Infusion rate: 1 - 2 mg/kg/min, not exceeding 50 mg/min, whichev is slower Loading Dosage: 10 -15 mg/kg intravenously Infusion rate: 1 - 2 mg/kg/min, not exceeding 50 mg/min, whichev is slower Neurosurgery and/or severe head injury Maintenance Dosage: 2 to 4 mg/kg administered every 12 hours Infusion rate:1 - 2 mg/kg/min, not exceeding 50 mg/min, whichev is slower Cardiac Arrhythmia The clinically effective dose has not been established.

2.

Status Epilepticus:

Loading dose: 15 - 20 mg/kg of Epanutin administered intravenously will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range (10 mcg/ml - 20 mcg/ml). The drug should be injected slowly intravenously at a rate of 1 - 3 mg/kg/min not exceeding 50 mg/min, whichever is slower.

Maintenance Dose:

Initial maintenance dose of Epanutin is 2 to 4 mg/kg and should be given 12 hours after the loading dose and then continued every 12 hours (4 to 8 mg/kg/day). The subsequent maintenance doses should be guided by serum phenytoin levels and clinical response.

The drug should be injected slowly intravenously at a rate of 1 - 2 mg/kg/min not exceeding 50 mg/min, whichever is slower.

Method of administration For parenteral administration:

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Parenteral Epanutin is suitable for use as long as it remains free of haziness and precipitate.

Upon refrigeration or freezing a precipitate might form; this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. Only a clear solution should be used. A faint yellow colouration may develop; however, this has no effect on the potency of this solution.

Because of the risk of local toxicity, intravenous phenytoin should be injected slowly directly into a large peripheral or central vein through a large-gauge needle or intravenous catheter. 4. Local Toxicity (including Purple Glove Syndrome)).

Parenteral Epanutin should neither be mixed with other drugs nor be added to dextrose or dextrose-containing solutions due to the potential for precipitation of phenytoin acid.

Instructions for dilution:

For infusion administration the parenteral phenytoin should be diluted in 50 - 100 ml of normal saline, with the final concentration of phenytoin in the solution not exceeding 10 mg/ml. Administration should commence immediately after the mixture has been prepared and must be completed within one hour (the infusion mixture should not be refrigerated).

6) The diluted form is suitable for use as long as it remains free of haziness and precipitate.

Precautions to be taken before handling:

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. For infusion administration the parenteral phenytoin should be diluted in saline.

50 microns) should be used. 6mg/kg of propylene glycol. 4). 1, or other hydantoins. Intra- arterial administration must be avoided in view of the high pH of the preparation. Because of its effect on ventricular automaticity, phenytoin is contra-indicated in sinus bradycardia, sino-atrial block, and second and third degree atrioventricular A-V block, and patients with Adams-Stokes syndrome.

Co-administration of phenytoin is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non nucleoside reverse transcriptase inhibitors. 4 Special warnings and precautions for use General: In adults, intravenous administration should not exceed 50 mg/min.

2 Paediatric population). Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures […]

1, or other hydantoins. Intra- arterial administration must be avoided in view of the high pH of the preparation. Because of its effect on ventricular automaticity, phenytoin is contra-indicated in sinus bradycardia, sino-atrial block, and second and third degree atrioventricular A-V block, and patients with Adams-Stokes syndrome.

Co-administration of phenytoin is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non nucleoside reverse transcriptase inhibitors.