Sanbetoin

Phenytoin sodium.

Each extended-release capsule contains: Phenytoin Sodium 100 mg.

Pharmacology: Phenytoin is an anticonvulsant drug, which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, Phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at the synaptic levels. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.
Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.

SANBETOIN is indicated for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and for the prevention and treatment of seizures occurring during or following neurosurgery. SANBETOIN has also been used in the treatment of trigeminal neuralgia.

General: Phenytoin sustained release capsules is formulated with the sodium salt of Phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.
Dosage should be individualized to provide maximum benefit. In some cases serum drug level determinations may be necessary for optimal dosage adjustments.
Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 mcg/mL and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of Phenytoin. With recommended dosage, a period of 7 to 10 days may be required to achieve steady-state serum levels with Phenytoin, and changes in dosage (increase or decrease) should not be carried out at intervals shorter than 7 to 10 days.
Adult Dosage: Divided daily dosage: Patients who have received no previous treatment may be started on 300 mg daily, to be taken in three equally divided doses, and the dosage then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be 300 mg to 400 mg daily, to be taken in three to four equally divided doses respectively. An increase up to 600 mg daily may be made if necessary.
Non-emergency oral loading dose in adult patients: An oral loading dose of SANBETOIN may be used for non-emergency initiation of therapy in adults who require rapid steady state serum levels, and for whom intravenous administration is not desirable. This dosing regimen should be reserved for patients in a clinic or hospital setting where SANBETOIN serum levels can be closely monitored. Patients with a history of renal or liver disease should not receive the oral loading regimen.
The recommended oral loading dose is 1 g of SANBETOIN divided into three doses (400 mg, 300 mg, 300 mg) and administered at 2-hour intervals. Normal maintenance dosage is then instituted 24 hours after the loading dose, with frequent serum level determinations.
Pediatric Dosage: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 mg/kg to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day). If the daily dosage cannot be divided equally, the larger dose should be given at bedtime.
Dosing in Special Populations: Patients with Renal or Hepatic Disease, see Precautions.
Elderly Patients: Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 g to 5 g. The initial symptoms are nystagmus, ataxia and dysarthria. Other signs are tremor, hyperreflexia, somnolence, drowsiness, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.
There are marked variations among individuals with respect to Phenytoin serum levels where toxicity may occur.
Treatment: Treatment is non-specific since there is no known antidote.
The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since Phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.
In acute overdosage, the possibility of the presence of other CNS depressants, including alcohol, should be borne in mind.

Phenytoin is contraindicated in patients who are hypersensitive to Phenytoin or its inactive ingredients, or other hydantoins. Co-administration of Phenytoin with Delavirdine is contraindicated due to the potential for loss of virologic response and possible resistance to Delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

General: Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Phenytoin is not indicated for seizures due to hypoglycemia or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin 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 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 anticonvulsant drug not belonging to the hydantoin chemical class.
A small percentage of individuals who have been treated with Phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction, it appears to be genetically determined.
Acute alcoholic intake may increase Phenytoin serum levels, while chronic alcoholic use may decrease serum levels.
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 hyperalbuminemia. Unbound Phenytoin concentrations may be more useful in these patient populations.
Suicide: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents in several indications. A small increased risk of suicidal ideation and behavior. The mechanism of the risk is not known and the available data do not exclude the possibility of an increased risk for Phenytoin.
Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms: Hypersensitivity syndrome (HSS) or drug reaction with eosinophilia and systemic symptoms (DRESS) has been occurred in patients taking anticonvulsant drugs, including Phenytoin. Some of these events have been fatal or life threatening.
Hypersensitivity syndrome (HSS) or drug reaction with eosinophilia and Systemic Symptoms (DRESS) typically, although not exclusively, present fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, haematological 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.
Serious Dermatologic Reactions: Phenytoin can cause rare, serious skin adverse events, such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin reactions may occur without warning, patients should be alert for the occurrence of rash and other symptoms of HSS/DRESS, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The physician should advise the patient to discontinue treatment if the rash appears.
If the rash is of a milder type (measles-like or scarlatiniform), 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, literature report suggests that may be higher in black patients. The literature suggests that the combination of Phenytoin, cranial irradiation, and a gradual decrease in corticosteroids can lead to the development of erythema multiform, and/or SJS, and/or TEN.
Hepatic Injury: The liver is the chief site of biotransformation of Phenytoin.
Toxic hepatitis and liver damage may occurred rarely, can be fatal.
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been occurred with Phenytoin. These incidents usually occur within the first 2 months of treatment and may be associated with HSS/DRESS. Patients with impaired liver function, elderly 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.
Hematopoietic System: Hematopoietic complications, some fatal, have occasionally been occurred in association with administrations of Phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression.
There have been a number of reports suggesting a relationship between Phenytoin and the development of lymphadenopathy (local or generalized) 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. Lymph node involvement may occur with or without symptoms and signs resembling HSS/DRESS. 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 anticonvulsant drugs.
While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to Folic Acid therapy. If Folic Acid is added to Phenytoin therapy, a decrease in seizure control may occur.
Central Nervous System: 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 can caused exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.
Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin also may raise serum glucose levels in diabetic patients.
Musculoskeletal Effect: Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are thought to 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.
Women of Childbearing Potential: Phenytoin may cause fetal harm when administered to a pregnant women. Prenatal exposure to Phenytoin may increase the risks for congenital malformations and other adverse development outcomes.
Fertility: In animal studies, Phenytoin had no direct effect on fertility.
Information for the Patient: Patient taking Phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen and of informing their physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
Patients should be cautioned on the use of other drugs or alcoholic beverages without first seeking their physician's advice.
Patients should be instructed to call their physician if skin rash develops.
The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.
Effects on Ability to Drive and Use Machines: Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that this medication does not affect their ability to engage in these activities.
Use in Pregnancy: Phenytoin crosses the placenta in humans.
There is an association between the use of anticonvulsant drugs by women with epilepsy and a higher incidence of birth defects in children born to these women. There are also a possible similar association with the use of all known anticonvulsant drugs.
A higher incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. 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 fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of child-bearing potential.
In addition there is also increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving Phenytoin and other anticonvulsant drugs, there have been occurred of a fetal hydantoin syndrome. This consists of pre-natal dysmorphic facial features, nail and digit hypoplasia, growth deficiency (including microcephaly) 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.
Phenytoin should only be used in women of childbearing potential and pregnant women if the potential benefit outweighs the risk. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options.
An increase in seizure frequency during pregnancy occurs in a high proportion of patients because of 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 Phenobarbital and/or phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother before delivery and to the neonate after birth.
Women of childbearing potential who are not planning a pregnancy should be advised regarding the use of effective contraception during treatment. Phenytoin may result in a failure of the therapeutic effect of hormonal contraceptives.
Phenytoin is teratogenic in rats, mice and rabbits.
Use in Lactation: Breast-feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Phenytoin concentration in breast milk is approximately one-third of the corresponding maternal plasma concentration.

Women of Childbearing Potential: Phenytoin may cause fetal harm when administered to a pregnant women. Prenatal exposure to Phenytoin may increase the risks for congenital malformations and other adverse development outcomes.
Fertility: In animal studies, Phenytoin had no direct effect on fertility.
Usage in Pregnancy: Phenytoin crosses the placenta in humans.
There is an association between the use of anticonvulsant drugs by women with epilepsy and a higher incidence of birth defects in children born to these women. There are also a possible similar association with the use of all known anticonvulsant drugs.
A higher incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. 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 fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of child-bearing potential.
In addition there is also increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving Phenytoin and other anticonvulsant drugs, there have been occurred of a fetal hydantoin syndrome. This consists of pre-natal dysmorphic facial features, nail and digit hypoplasia, growth deficiency (including microcephaly) 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.
Phenytoin should only be used in women of childbearing potential and pregnant women if the potential benefit outweighs the risk. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options.
An increase in seizure frequency during pregnancy occurs in a high proportion of patients because of 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 Phenobarbital and/or phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother before delivery and to the neonate after birth.
Women of childbearing potential who are not planning a pregnancy should be advised regarding the use of effective contraception during treatment. Phenytoin may result in a failure of the therapeutic effect of hormonal contraceptives.
Phenytoin is teratogenic in rats, mice and rabbits.
Usage in Nursing Mothers: Breast-feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Phenytoin concentration in breast milk is approximately one-third of the corresponding maternal plasma concentration.

Body as a whole: 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 coordination, and mental confusion. Cerebellar atrophy may occurred in the regulation of elevated Phenytoin levels and/or long-term use of Phenytoin. Dizziness, vertigo, insomnia, transient nervousness, motor twitching, headache, paresthesia, and somnolence have also been observed.
There are also 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.
Connective Tissue System: Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hypertrichosis, and Peyronie's disease.
Gastrointestinal System: Acute hepatic failure, toxic hepatitis, liver damage, vomiting, nausea, and constipation.
Hematopoietic System: Hematopoietic complications, some fatal, have occasionally been occurred in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. Macrocytosis and megaloblastic anemia have also occurred. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have also occurred.
Immunologic: Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.
Dermatologic System: 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 that may be fatal have included bullous, exfoliative, or purpuric dermatitis, lupus erythematosus, Stevens-John Syndrome, and toxic epidermal necrolysis (TEN).
Special Senses: Taste perversion.
Musculoskeletal System: Bone fractures and osteomalacia have been associated with long term (> 10 years) use of phenytoin by patients with chronic epilepsy. Osteoporosis and other disorders of bone metabolism, such as hypocalcemia, hypophosphatemia and decreased levels of vitamin D metabolites have also been occurred.

Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome (CYP) P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating Phenytoin concentrations and enhance the risk of drug toxicity.
Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes and may reduce the levels of drugs metabolized by these enzymes.
There are many drugs that may increase or decrease serum Phenytoin levels or that Phenytoin may affect. Serum level determinations for Phenytoin are especially helpful when possible drug interactions are suspected.
The most commonly occurring drug interactions are listed as follows.
Drugs that may increase Phenytoin serum levels: See Table 1.


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Drugs that may decrease Phenytoin serum levels: See Table 2.


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Molindone hydrochloride contains ions, which interfere with the absorption of Phenytoin. Ingestion times of Phenytoin and calcium preparations, including antacid preparations containing calcium, should be staggered to prevent absorption problems.
Phenytoin concentration should be monitored during co-administration with Nelfinavir, as Nelfinavir may reduce Phenytoin plasma concentration.
Drugs that may either increase or decrease Phenytoin serum levels: See Table 3.


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Similarly, the effect of Phenytoin on Carbamazepine, Phenobarbital, Valproic Acid and Sodium Valproate serum levels is unpredictable.
Drugs whose serum levels and/or effects may be altered by Phenytoin: See Table 4.


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Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and Phenytoin dosage may need to be adjusted.
Drug-enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected Phenytoin plasma levels. It is therefore suggested that Phenytoin not be administered concomitantly with an enteral feeding preparation.
More frequent serum Phenytoin level monitoring may be necessary in these patients.
Drug Laboratory Test Interactions: Phenytoin may cause decreased serum levels of protein bound iodine (PBI). It also may produce lower than normal values for Dexamethasone or Metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline Phosphatase, and gamma-glutamyl transpeptidase (GGT). Phenytoin may affect blood calcium and blood sugar metabolism tests.

Store below 30°C. Protect from light and moisture.

Anticonvulsants

N03AB02 - phenytoin ; Belongs to the class of hydantoin derivatives antiepileptics.

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