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PHENYTOIN HIKMA is a brand name for Phenytoin. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Status epilepticus and series of seizures - Prophylaxis of seizures occurring in connection with neurosurgery. N.B. Phenytoin Hikma is not effective in absence status epilepticus or in the prophylaxis and treatment of febrile convulsions.
Verbatim from this product's MHRA label. Tap a section to expand.
Dosage instructions The therapeutic range for plasma concentration is generally between 10 and 20 micrograms/ml phenytoin; concentrations over 25 micrograms/ml phenytoin may be in the toxic range. Status epilepticus and series of seizures Continuous monitoring of ECG, blood pressure and neurological status and regular determination of plasma phenytoin concentrations is essential.
In addition, resuscitation facilities should be readily available. 5 ml/min (equivalent to 23 mg phenytoin per minute). If the seizures do not stop after 20 to 30 minutes, the dose can be repeated. 5 to 6 hours up to a maximum daily dose of 17 mg/kg bodyweight (or 6 ampoules - equivalent to 1380 mg phenytoin), to achieve rapid saturation.
At a maximum daily dose of 17 mg/kg bodyweight, this is equivalent to Bodyweight Ampoules Phenytoin 41 kg 3 690 mg 54 kg 4 920 mg 68 kg 5 1150 mg 81 kg 6 1380 mg Children up to 12 years of age On day 1 the maximum daily dose is 30 mg/kg bodyweight, on day 2 20 mg/kg bodyweight, on day 3 10 mg/kg bodyweight.
The maximum injection rate is 1 mg/kg bodyweight per minute. 5 ml/min (equivalent to 23 mg phenytoin per minute). Children up to 12 years of age receive 5 to 6 mg/kg bodyweight. Rate of injection is reduced according to the weight/age of the child.
At a daily dose of 5 mg/kg bodyweight, this is equivalent to Bodyweight ml Phenytoin 9 kg 1 46 mg 18 kg 2 92 mg 28 kg 3 138 mg 37 kg 4 184 mg 46 kg 5 230 mg At a daily dose of 6 mg/kg bodyweight, this is equivalent to Bodyweight ml Phenytoin 8 kg 1 46 mg 15 kg 2 92 mg 23 kg 3 138 mg 31 kg 4 184 mg 38 kg 5 230 mg 46 kg 6 276 mg Duration of administration Duration of administration is dependent on the underlying disease and the course of the illness.
If the medicinal product is well-tolerated, it can be used indefinitely. Switching preparations Due to the relatively narrow therapeutic range and the varying bioavailability of the numerous pharmaceutical preparations, when changing from one preparation to another containing phenytoin, the phenytoin-plasma concentrations must be monitored closely.
If the dose is kept the same, steady state (constant plasma concentration) can be expected after 5 to 14 days. After switching to an oral formulation, treatment should be monitored monthly during the first three months, and then six-monthly.
The following adverse reactions have been reported with phenytoin (frequency unknown – cannot be estimated from available data): Signs of toxicity are associated with cardiovascular and central nervous system depression.
Blood and lymphatic system disorders:
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 and aplastic anaemia.
While macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy. Pure red cell aplasia has been reported with a frequency not known. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease.
Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. g. fever, rash and liver involvement.
In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Frequent blood counts should be carried out during treatment with phenytoin.
Immune system reactions:
Anaphylactoid reaction and anaphylaxis. 4) has been reported and may in rare cases be fatal (the syndrome may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, polyarteritis nodosa, and immunoglobulin abnormalities may occur.
, Local Toxicity (including Purple Glove Syndrome)). 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 AV 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. Phenytoin Hikma should not be administered: - if the patient already has severe damage to the blood cells and bone marrow - within the first three months after myocardial infarction and in case of cardiac output failure (left ventricular ejection fraction < 35%).
4 Special warnings and precautions for use Phenytoin Hikma should not be used in case of: - cardiac insufficiency - impaired pulmonary function - severe hypotension (systolic blood pressure less than 90 mm Hg) - Bradycardia (less than 50 beats per minute) - sinuatrial block and grade I AV block - atrial fibrillation and atrial flutter General: In adults, intravenous administration should not exceed 50 mg per minute.
In neonates, the drug should be administered at a rate of 1-3 mg/kg/min. Phenytoin Hikma is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present together, combined drug therapy is needed.
Phenytoin Hikma is not indicated for seizures due to hypoglycaemia or other metabolic causes. The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression.
Severe cardiotoxic reactions and fatalities due to depression of atrial and ventricular conduction and ventricular fibrillation, respiratory arrest and tonic seizures have been reported particularly in older people or gravely ill patients, if the preparation is given too rapidly or in excess.
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 AV 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. Phenytoin Hikma should not be administered: - if the patient already has severe damage to the blood cells and bone marrow - within the first three months after myocardial infarction and in case of cardiac output failure (left ventricular ejection fraction < 35%).
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Phenytoin-plasma concentration, blood count, liver enzymes (GOT, GPT, gamma-GT), alkaline phosphatase and additionally in children thyroid function should be monitored. Therefore the dose (if possible) should be reduced slowly and the new antiepileptic medicinal product started at a low dose and gradually increased.
Abrupt withdrawal of Phenytoin Hikma may increase seizure frequency or lead to status epilepticus. 4). Impaired renal and hepatic functions require careful monitoring. Phenytoin Hikma should be used with caution in patients with hypoproteinaemia, as reduced plasma protein binding may lead to an increase in the free phenytoin fraction (without increasing the total serum concentration of phenytoin).
Increase in the free phenytoin fraction may enhance the risk of nervous system disorders.
Elderly (over 65 years):
As for adults; however, complications may occur more readily in elderly patients.
Neonates:
In neonates it has been shown that absorption of phenytoin is unreliable after oral administration. Phenytoin Hikma should be injected slowly intravenously at a rate of 1-3 mg/kg/min at dose of 15-20 mg/kg. This will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range of 10- 20 mg/l.
Infants and children:
As for adults, children tend to metabolise phenytoin more rapidly than adults. This should be considered when determining dosage regimens; monitoring serum levels is therefore particularly beneficial in such cases. Method of administration The solution for injection is for intravenous use only as absorption is delayed and unreliable after intramuscular administration.
Phenytoin Hikma should be injected slowly directly into a large vein through a large-gauge needle or intravenous catheter. Subcutaneous or venous perivascular or intra-arterial injection should be avoided, as the alkaline phenytoin solution for injection can cause tissue necrosis.
The solution for injection must not be mixed with other solutions, as phenytoin can crystallise out. Before use, the ampoules should be checked for precipitation and discolouration. The product should not be used if a precipitate or haziness develops in the solution in the ampoule.
Phenytoin Hikma is suitable for use as long as it remains free of haziness and precipitate. A precipitate might form if the product has been kept in a refrigerator or freezer. This precipitate will dissolve if allowed to stand at room […]
Several individual case reports have suggested that there may be an increased, although still rare, incidence of hypersensitivity reactions, including skin rash and hepatotoxicity, in black patients. Endocrine disorders Disturbance of thyroid function may occur, especially in children Nervous system disorders: Adverse reactions in this body system are common and are usually dose-related.
Reactions include nystagmus, diplopia, ataxia, slurred speech, decreased coordination, mental confusion, memory disorder, cognitive disorder, paraesthesia, somnolence, drowsiness and vertigo. Dizziness, insomnia, transient nervousness, increasing irritability, motor twitchings, taste perversion and headache have also been observed.
There have also been rare reports of phenytoin-induced dyskinesia, including chorea, dystonia, tremor, and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. There are occasional reports of irreversible cerebellar dysfunction associated with severe phenytoin overdosage or long-term plasma concentrations of phenytoin above 25 μg/ml.
A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Long-term treatment with phenytoin concomitant with other anticonvulsive drugs, especially velproic acied, may lead to signs of encephalopathy: increased seizure frequency, listlessness, stupor, muscular hypoptonia, choreatiform dyskinesias and severe general changes on the EEG.
Tonic seizures have also been reported.
Cardiac disorders:
Rare – asystole due to inhibition of the sinus node, conduction blockade and suppression of the ventricular escape rhythm in patients with total AV block, especially when phenytoin is administered intravenously. Proarhythmic effects in the form of changes or increases in cardiac arrythmias can occur which can lead to severe impairment of cardiac activity or even cardiac arrest.
With intravenous administration in particular, decreased blood pressure, deterioration in existing heart and respiratory failure can occur. In isolated cases ventricular fibrillation has been triggered. Atrial fibrillation and flutter is not cured by phenytoin.
However, as AV node refractory time can be shortened, acceleration in ventricular rate is possible. Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation.
Severe complications are most commonly encountered in older people or gravely ill patients.
Respiratory, thoracic and mediastinal disorders:
Alterations in respiratory function including respiratory arrest may occur. Pneumonitis.
Gastrointestinal disorders:
Acute hepatic failure, toxic hepatitis, liver damage, vomiting, nausea, constipation.
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. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus.
4). Hyperpigmentation (chloasma).
Musculoskeletal and connective tissue disorders:
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. Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hirsutism, hypertrichosis, Peyronie's disease and Dupuytren's contracture may occur rarely.
Polyarthropathy.
Renal and urinary disorders:
Interstitial nephritis.
General disorders and administration site conditions:
Local irritation, inflammation, tenderness, […]
Hypotension usually occurs when the drug is administered rapidly by the intravenous route. Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin. Soft tissue irritation may vary from slight tenderness to extensive necrosis, sloughing and in rare instances has led to amputation.
Subcutaneous or perivascular injection should be avoided because of the highly alkaline nature of the solution. Intravenous Phenytoin Hikma should be used with caution in patients with hypotension and severe myocardial insufficiency.
The intramuscular route is not recommended for the treatment of status epilepticus because of slow absorption. Serum levels of phenytoin in the therapeutic range cannot be rapidly achieved by this method. Phenytoin Hikma may precipitate or aggravate absence seizures and myoclonic seizures.
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgement of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic 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 antiepileptic drug not belonging to the hydantoin chemical class.
Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Herbal preparations containing St. 5). Phenytoin Hikma is highly protein bound and extensively metabolised by the liver.
Reduced maintenance dosage to prevent accumulation and toxicity may therefore be required in patients with impaired liver function. Where protein binding is reduced, as in uraemia, total serum phenytoin levels will be reduced accordingly.
However, the pharmacologically active free drug concentration is unlikely to be altered. Therefore, under these circumstances therapeutic control may be achieved with total phenytoin levels below the normal range of 10-20 mg/l. Dosage should not exceed the minimum necessary to control convulsions.
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.
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 metabolisers 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.
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 […]