PHENYTOIN SODIUM MILPHARM

Phenytoin Sodium Milpharm 100 mg film-coated tablets contain phenytoin sodium. 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. Posology Dosage should be individualised as there may be wide interpatient variability in phenytoin serum levels with equivalent dosage.

Phenytoin should be introduced in small dosages with gradual increments until control is achieved or until toxic effects appear. In some cases serum level determinations may be necessary for optimal dosage adjustments - the clinically effective level is usually 10-20mg/l (40-80 micromoles/l) although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin.

With recommended dosage a period of seven to ten days may be required to achieve steady state serum levels with Phenytoin and changes in dosage should not be carried out at intervals shorter than seven to ten days. Maintenance of treatment should be the lowest dose of anticonvulsant consistent with control of seizures.

Adult Dosage for Seizures:

Initially 3 to 4mg/kg/day with subsequent dosage adjustment if necessary. For most adults a satisfactory maintenance dose will be 200 to 500mg daily in single or divided doses. Exceptionally, a daily dose outside this range may be indicated.

Dosage should normally be adjusted according to serum levels where assay facilities exist.

Adult Dosage for Trigeminal Neuralgia:

The clinically effective dose has not been established in clinical trials. In adults, 300- 500 mg given in divided daily doses have been reported in the literature. Dosing should be adjusted based on clinical response. Determination of serum phenytoin level is advised.

Levels of total phenytoin should not exceed 20 mcg/ml. 2 Pharmacokinetic properties-Age). As with adults the dosage of Phenytoin sodium tablets should be titrated to the patient's individual requirements using the same guidelines. As elderly patients tend to receive multiple drug therapies, the possibility of drug interactions should be borne in mind.

Infants and Children:

Initially, 5mg/kg/day in two divided doses, with subsequent dosage individualised to a maximum of 300mg daily. A recommended daily maintenance dosage is usually 4 mg/kg to 8 mg/kg.

Neonates:

The absorption 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.

Patients with Renal or Hepatic Disease:

Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound concentration of phenytoin may be elevated in patients with hyperbilirubinemia.

Unbound phenytoin concentrations may be more useful in these patient populations (see section

The following adverse reactions have been reported with phenytoin (frequency unknown – cannot be estimated from available data): Immune system reactions: Anaphylactoid reaction, and anaphylaxis.

Central Nervous System:

Adverse reactions in this body system are common and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased co-ordination, mental confusion. 4 Special warnings and precautions for use – Central Nervous System Effect).

Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, taste perversion, headache, paraesthesia and somnolence have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs.

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Gastrointestinal System:

Nausea, vomiting and constipation. 4 Special warnings and precautions for use – Hepatic Injury) Skin and subcutaneous tissue disorders: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes.

A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. 4 Special warnings and precautions for use – Serious Dermatologic Reactions). Urticaria also has been reported.

Connective Tissue System:

Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hirsutism, hypertrichosis, Peyronie's Disease and Dupuytren's contracture may occur rarely.

Haemopoietic System:

Haemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression, pure red cell aplasia.

Macrocytosis and megaloblastic anaemia have occurred. 4 Special warnings and precautions for use – Hematopoietic Effect). ). 4 Special warnings and precautions for use - Angioedema).

Investigations:

Thyroid function test abnormal Other: Polyarthropathy, interstitial nephritis, pneumonitis.

Musculoskeletal System:

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with phenytoin. The mechanism by which phenytoin affects bone metabolism has not been identified. However, phenytoin has been shown to induce the CYP450 enzyme, which can affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3.

This may lead to Vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients. Other disorders of bone metabolism such as hypocalcemia, hypophosphatemia and decreased levels of Vitamin D metabolites have also been reported.

Paediatric population The adverse event profile of phenytoin is generally similar between children and adults, however, gingival hyperplasia occurs more frequently in paediatric patients and in patients with poor oral hygiene. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

General). Method of administration For oral administration only. 1, or other hydantoins. 4. Special warnings and precautions for use General Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence seizures are present together, combined drug therapy is needed.

Phenytoin may affect glucose metabolism and inhibit insulin release. Hyperglycaemia has been reported in association with toxic levels. Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes. Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus.

When, in the judgement of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anti-epileptic 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 anti-epileptic drug not belonging to the hydantoin chemical class. Phenytoin may precipitate or aggravate absence seizures and myoclonic seizures. 5). Women of childbearing potential Phenytoin may cause foetal harm when administered to a pregnant woman.

6). Phenytoin Sodium film-coated tablets should not be used in women of childbearing potential unless the benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options. Before the initiation of treatment with phenytoin in a woman of childbearing potential, pregnancy testing should be considered.

Women of childbearing potential should be fully informed of the potential risk to the foetus if they take phenytoin during pregnancy. 6). Women of childbearing potential should be counselled to contact her doctor immediately if she becomes pregnant or thinks she may be pregnant and is taking phenytoin.

Women of childbearing potential should use effective contraception during treatment and for one month after stopping treatment. 6). Suicide Suicidal ideation and behaviour have been reported in patients treated with anti- epileptic agents in several indications.

A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Phenytoin Sodium.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

9), but also at recommended phenytoin doses and levels. Hypersensitivity Syndrome / Drug Reaction with Eosinophilia and Systemic Symptoms Hypersensitivity syndrome (HSS) or drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients taking anticonvulsant drugs, including phenytoin.

Some of these events have been fatal or life threatening. HSS/DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, myositis or pneumonitis.

Initial symptoms may resemble an acute viral infection. Other common manifestations include arthralgias, jaundice, hepatomegaly, leukocytosis, and eosinophilia. The interval between the first drug exposure and symptoms is usually 2 to 4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months.

If such signs and symptoms occur, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative etiology for the signs and symptoms cannot be established. Patients at higher risk for developing HSS/DRESS include black patients, patients who have experienced this syndrome in the past (with phenytoin or other anticonvulsant drugs), patients who have a family history of this syndrome, and immunosuppressed patients.

The syndrome is more severe in previously sensitized individuals. 8 undesirable effects – Skin and subcutaneous tissue disorders), exfoliative dermatitis, Stevens - Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) and DRESS which can be fatal.

4 Special warnings and precautions for use – Hypersensitivity Syndrome/Drug Reaction with Eosinophilia […]

1, or other hydantoins.