The P-I-E-N-O Parkinsn's List Drug Database
phenytoin / DilantinTM
ANTICONVULSANT:
Description: Phenytoin is an oral and parenteral hydantoin anticonvulsant first synthesized in 1908. Although it has been used in many diverse conditions, its only approved use is as an anticonvulsant, specifically, for the prophylactic management of tonic-clonic (grand mal) seizures and partial seizures with complex symptomatology (psychomotor seizures). It may be used alone or with phenobarbital or other anticonvulsants. Phenytoin also can be used to prevent seizures occurring during surgery but is not used for pure absence (petit mal) seizures. Phenytoin has been used for many other conditions including treatment of diabetic neuropathy and treatment of digitalis-induced cardiac arrhythmias although its efficacy in these conditions is questionable. Since the release of digoxin immune Fab (see separate monograph), phenytoin is seldom used for digitalis cardiac toxicity. Phenytoin possesses significant toxicity and is difficult to dose in some patients. In addition, switching patients from one dosage form of phenytoin to another may produce significant changes in phenytoin bioavailability. Phenytoin was originally approved by the FDA in 1939. A new dosage form of phenytoin (e.g., phosphenytoin) is currently under investigation.
Mechanism of Action: Anticonvulsant drugs can elevate the seizure threshold and/or limit the spread of seizure discharge. Phenytoin exerts its anticonvulsant effect mainly by limiting the spread of seizure activity and reducing seizure propagation, unlike phenobarbital and carbamazepine, which elevate the seizure threshold. Because phenytoin does not elevate the seizure threshold, it is less effective against drug-induced or electroconvulsive-induced seizures. Phenytoin's anticonvulsant effects are mediated through effects on sodium channels on the neuronal cell membrane. Phenytoin exerts its anticonvulsant effects with less CNS sedation than does phenobarbital. In toxic concentrations, phenytoin is excitatory and can induce seizures. Phenytoin is also a weak antiarrhythmic. Antiarrhythmic actions are also mediated through effects on sodium channels, in this case, in Purkinje fibers.
Pharmacokinetics: Phenytoin is administered orally and parenterally. Phenytoin dosage forms are available as either phenytoin acid (tablets and oral suspension) or phenytoin sodium (capsules and injection). Phenytoin sodium contains 8% less phenytoin than does phenytoin acid. Due to phenytoin's unique metabolism, switching patients from phenytoin sodium to phenytoin acid without adjusting the dose to account for this 8% difference could lead to phenytoin toxicity. When using phenytoin oral suspension, it is important to note that concomitant administration with enteral nutritional products will significantly reduce phenytoin bioavailability.
Phenytoin pharmacokinetics are complex and make its clinical use difficult. Oral absorption of phenytoin is slow and variable. Time to reach peak concentration varies with the size of the dose, and bioavailability depends on the dosage form and the presence of food in the GI tract. Rapid-release dosage forms reach peak concentrations in 1.5-6 hours, whereas a dose of sustained-release capsules may not reach peak concentrations for 12 hours. Extremely large oral doses (e.g., 1600 mg) require more than 24 hours to reach a peak concentration.
Phenytoin is distributed into CSF, saliva, semen, GI fluids, and bile. Phenytoin crosses the placenta and is distributed into breast milk. Fetal plasma concentrations are similar to maternal concentrations. The drug is about 95% bound to plasma protein, but less in patients with renal failure or hypoproteinemia. Phenytoin serum concentrations are routinely used to guide therapy. It is important to measure unbound phenytoin concentrations in patients with renal failure or hypoalbuminemia.
Metabolism is also highly variable. Phenytoin is one of only a few drugs in which metabolic capacity can be saturated at therapeutic concentrations. Below the saturation point, phenytoin is eliminated in a linear, first-order process. Above the saturation point, elimination is much slower and occurs via a zero-order process. Because of this saturable metabolism, it is inaccurate to report a fixed value for phenytoin half-life; it can range from 7-42 hours, depending on the clinical setting. In addition, small increases in dose can produce large increases in plasma concentrations. Metabolism occurs in the liver and produces inactive metabolites. Liver disease can reduce the clearance of phenytoin or, paradoxically, increase its clearance if protein binding is significantly decreased. Less than 5% of phenytoin is eliminated renally.
CONTRAINDICATIONS/PRECAUTIONS: Parenteral phenytoin is contraindicated in patients with cardiac function impairment because of the affects on ventricular automaticity may cause ventricular arrhythmias. These conditions include Adams-Stokes syndrome, second and third degree AV block, sino-arterial block, and sinus bradycardia. Parenteral phenytoin should also be used with caution in patients with cardiac disease, because it can cause atrial and ventricular conduction depression, ventricular fibrillation, and reduce cardiac output. Cardiac effects are thought to be secondary to the propylene glycol (PEG) diluent of the parenteral product. These reactions occur more often in the elderly or in very ill patients. In these patient populations, phenytoin should be infused no faster than 25 mg/minute, ideally at a rate of 5-10 mg/minute.
Hematotoxicity can occur during therapy with phenytoin, so hematological status (leukocyte and platelet counts) should be monitored closely. Phenytoin should be used cautiously in patients with hematological disease. Leukopenia, agranulocytosis, and pancytopenia increase the risk of infection in these patients.
Phenytoin should be used with caution in patients with dental disease. Phenytoin can cause myelosuppression and there may be an increased risk of infection. Dental work should be performed prior to initiating phenytoin therapy or deferred until blood counts return to normal. Patients should be instructed on proper oral hygiene.
Intramuscular injections should not be administered to patients receiving phenytoin. IM injections may cause bleeding, bruising, or hematomas due to phenytoin-induced thrombocytopenia.
Intramuscular administration of phenytoin is not recommended when oral or intravenous access is available. IM phenytoin has a delayed absorption, therefore it is not recommended for patients in status epilepticus. Parenteral phenytoin has an alkaline pH (pH=12) and causes a high degree of local irritation and pain when administered IM.
Phenytoin is a known teratogen. It is classified by the FDA as category D for use during pregnancy. It should not be prescribed to pregnant women unless the potential benefit outweighs the risk to the fetus. Women taking phenytoin should be counseled regarding the risks to the fetus should they become pregnant. If a woman taking phenytoin does become pregnant, there is debate as to what course of action is best; other anticonvulsants also have been associated with fetal disorders, and seizures themselves can be equally harmful. While it is true that women receiving anticonvulsants usually deliver normal infants, the risk versus the benefit should be weighed carefully in each situation.
Phenytoin enters breast milk. Although women taking phenytoin should be counseled about breast-feeding, the risk to a nursing infant appears to be less than that for a fetus.
Phenytoin should be used with caution in patients with intermittent porphyria because it can exacerbate this condition.
Phenytoin is eliminated via hepatic metabolism. Dose adjustments may be necessary in patients with hepatic disease. Patients with severe hepatic dysfunction can have decreased phenytoin clearance or, paradoxically, if hypoalbuminemia exists, phenytoin clearance can be increased due to more unbound drug being available for metabolism.
Phenytoin should be used with caution in patients with alcoholism. Ethanol can induce hepatic oxidative enzymes which metabolize phenytoin, decreasing serum concentrations. Fever, temperatures greater than 101F for more than 24 hours, can also induce hepatic oxidative enzymes decreasing phenytoin serum concentrations. Patients with renal failure or renal impairment leading to significant elevations of blood urea nitrogen also should be monitored for phenytoin toxicity. High serum concentrations of urea displace phenytoin from protein-binding sites. Unbound phenytoin concentrations should be monitored in patients with uremia or hypoalbuminemia. Dose adjustments may be necessary in patients with renal disease.
Cranial irradiation administered to patients receiving phenytoin has been associated with erythema multiforme and/or Stevens-Johnson syndrome (see Adverse Reactions). Phenytoin should be used cautiously, if at all, in patients receiving radiation therapy.
Phenytoin can stimulate glucagon secretion and can impair insulin secretion. Either of these effects could cause serum glucose to rise. There are case reports of hyperglycemia and even DKA occurring as a result of phenytoin administration. Blood sugar should be monitored closely when phenytoin is administered to patients with diabetes mellitus.
Patients with thyroid disease, especially hypothyroidism, should be monitored for signs of hypothyroidism. Phenytoin has been shown to cause a decrease in circulating levels of thyroid hormone with a corresponding rise in TSH in patients previously stabilized on replacement therapy.
A lupus-like syndrome has been described for phenytoin. Whether phenytoin administration will exacerbate preexisting idiopathic systemic lupus erythematosus (SLE) is unclear. Because the mechanism of drug-induced lupus differs from idiopathic SLE, it may be safe to administer phenytoin to patients with preexisting disease, keeping in mind that worsening of the condition is possible.
DRUG INTERACTIONS: Phenytoin can stimulate hepatic microsomal enzymes. This action enhances the clearance of other drugs metabolized via this pathway. Drugs that may be affected include: corticosteroids, estrogens, oral contraceptives, cyclosporine, cardiac glycosides, disopyramide, felodipine, levodopa, lidocaine, methadone, mexiletine, quinidine, theophylline, and some anticonvulsants. Phenytoin interacts with the oral anticoagulants dicoumarol and warfarin, although warfarin does not appear to be affected to the same degree as dicoumarol. Phenytoin can interact with any of these drugs not only when it is added to therapy but also when it is discontinued and its enzyme induction actions subside.
Phenytoin clearance can be affected by drugs that either stimulate or inhibit hepatic microsomal enzymes. Drugs that stimulate hepatic metabolism of phenytoin include rifampin and some anticonvulsants. Drugs that inhibit phenytoin metabolism include amiodarone, chloramphenicol, cimetidine, disulfiram, fluconazole, and isoniazid, INH. Isoniazid appears to inhibit the hepatic metabolism of phenytoin in a dose-dependent manner and this is more likely to occur in patients who are slow acetylators.D Fluoxetine has been shown to increase phenytoin serum concentrations, possibly due to inhibition of phenytoin hepatic metabolism. Phenytoin toxicity has been described in several patients after the addition of fluoxetine. Interactions between phenytoin and paroxetine, an antidepressant related to fluoxetine, have also been reported. Phenytoin and paroxetine have each been shown to reduce the AUC of the other. The clinical significance of this is uncertain. Omeprazole also can inhibit phenytoin metabolism, but only if large omeprazole doses are used. Sulfamethizole can inhibit phenytoin metabolism. Other more commonly used sulfonamides, such as sulfamethoxazole or sulfisoxazole, do not appear to possess clinically significant interactions with phenytoin however trimethoprim may significantly decrease phenytoin clearance. Isolated reports of decreased phenytoin metabolism secondary to influenza vaccine exist, but this interaction appears to be rare.
Phenytoin interacts with other anticonvulsants in a variety of ways. Phenytoin is a mild, albeit significant, inducer of hepatic microsomal enzymes. The activity of other anticonvulsants metabolized via this pathway can be affected when phenytoin is either added or discontinued. Anticonvulsants that may be susceptible to interactions with phenytoin include carbamazepine, clonazepam, phenobarbital, and primidone. These anticonvulsants may also affect phenytoin metabolism. Regarding phenytoin and carbamazepine, phenytoin can decrease carbamazepine concentrations while carbamazepine has little effect on phenytoin concentrations. Regarding phenytoin and clonazepam, phenytoin causes significant decreases in clonazepam concentrations but the effects of clonazepam on phenytoin serum concentrations are variable. Regarding phenytoin and phenobarbital, phenytoin may cause phenobarbital concentrations to rise, while phenobarbital has variable effects on phenytoin metabolism. It is likely that other barbiturates interact with phenytoin similarly. Regarding phenytoin and primidone, phenytoin will accelerate primidone metabolism, but clinicians should note that primidone is metabolized to phenobarbital. Finally, valproic acid also can inhibit phenytoin metabolism and displace phenytoin from protein-binding sites.
Phenytoin can add to the CNS-depressant effects of ethanol and other CNS depressants including benzodiazepines, HA-blockers, and opiate agonists. In addition, acute ingestion of ethanol can increase the clearance of phenytoin, thus reducing its effectiveness.
Oral absorption of phenytoin can be reduced by any of the following: antacids containing magnesium, calcium carbonate, or aluminum; calcium salts; or enteral feeding products. Calcium salts can form complexes that are nonabsorbable. It is not clear how enteral feeding solutions reduce absorption of phenytoin. Although many contain magnesium and calcium, tube feedings may decrease phenytoin's GI residence time, preventing it from being absorbed completely. Sucralfate can decrease the oral absorption of phenytoin if used concomitantly. Although the magnitude of this interaction is not great, an occasional patient may be affected. Separating the administration of phenytoin and enteral feeding products, antacids, or calcium salts by at least 2 hours will help avoid this interaction.
Large doses of salicylates (i.e., more than 2000 mg/day) can displace phenytoin from protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, unbound drug may also be more rapidly cleared by the liver.
Patients stabilized on dopamine infusions can experience sudden hypotension and/or cardiac arrest if IV phenytoin is administered. At least two deaths have occurred as a result of this interaction. Intravenous phenytoin should be administered extremely cautiously, if at all, to critically ill patients receiving dopamine infusions. It is unclear if oral phenytoin can produce a similar reaction in patients receiving dopamine.
Phenytoin can increase the risk of developing hepatotoxicity from inhalation general anesthetics such as enflurane, halothane, and methoxyflurane.
Phenytoin can reportedly decrease the bioavailability of itraconazole although data describing this interaction are scant.
The interaction between phenytoin and folic acid, vitamin BE is complex. Folic acid administration has been blamed for accelerating phenytoin metabolism and causing a decline in seizure control. In addition, the activity of phenytoin may depend on some degree of folate depletion or inhibition of folate conversion to a form that is readily transported into the brain. Folic acid administration alone, especially in excessive amounts, can cause seizures in animals. Unless patients develop hematologic signs of folate deficiency, folic acid (especially doses of 5 mg/day or more) should not be routinely administered to patients receiving phenytoin because it could counteract the therapeutic effects of phenytoin. Although less information is available, folinic acid (leucovorin) also should be used with caution in patients receiving phenytoin.
ADVERSE REACTIONS: NOTE: Phenytoin is a toxic drug. Many organ systems can potentially be affected.
Many adverse CNS reactions can occur during phenytoin therapy including dizziness, drowsiness, nystagmus, ataxia, lethargy, coma, seizures, choreoathetosis, and dystonia. The severity of these adverse reactions increases as serum concentrations of phenytoin increase. While lethargy, dizziness, and drowsiness may occur at therapeutic serum concentrations, ataxia, coma, and drug-induced seizures usually occur at supra-therapeutic concentrations. In a small study, phenytoin-induced seizures occurred most often in patients with serum phenytoin concentrations of 50 ęg/ml or higher.
Adverse GI effects of phenytoin therapy include nausea/vomiting, constipation, abdominal pain, and anorexia. Taking the drug with food may reduce some symptoms, however, clinicians should keep in mind that oral administration with continuous nasogastric feedings can significantly impair phenytoin bioavailability. Gingival hyperplasia is a adverse reaction in children and young adults, especially during long-term therapy. Emphasis should be placed on good oral hygiene and gum massage. Cataracts have also been rarely reported after long-term therapy.
Adverse dermatological reactions to phenytoin occur in 5-10% of patients and can present as maculopapular rash, or a more serious response such as bullous rash; exfoliative dermatitis; purpura; erythema multiforme; Stevens-Johnson syndrome; or toxic epidermal necrolysis. These conditions may be a result of a severe hypersensitivity reaction to hydantoins. Minor reactions, such as rash, can develop in the first few weeks of therapy and should be investigated promptly. More serious reactions can develop up to 12 weeks after initiation of therapy, and early intervention can prevent severe adverse effects. Skin hyperpigmentation caused by an increase in melanin of the basal layer and dispersion of melanin granules has been seen and is more common in women than in men. Phenytoin can produce hypertrichosis or hirsutism (unusual growth of hair) in some patients. This reaction is generally confined to the extremities but can affect the trunk and face and may be irreversible. Severe dermatologic reactions to phenytoin are infrequent. Some evidence suggests that erythema multiforme is more likely in patients who undergo radiation therapy while receiving phenytoin.
Lupus-like symptoms have been described for phenytoin. Whether phenytoin administration will exacerbate preexisting idiopathic systemic lupus erythematosus (SLE) is unclear.
Various lymph node reactions have been reported with phenytoin therapy. These include lymphoid hyperplasia, pseudolymphoma, pseudo-pseudolymphoma, and lymphoma. If lymphadenopathy develops, the patient should be closely monitored for an extended period and, when possible, alternative anticonvulsant therapy used.
The actions of phenytoin on control of blood sugar are complex. Phenytoin can interfere with glucose metabolism. Phenytoin can stimulate glucagon secretion and can impair insulin secretion. Either of these effects could cause serum glucose to rise. Case reports exist of hyperglycemia and even DKA occurring as a result of phenytoin administration.D Blood sugar should be monitored closely when phenytoin is administered to patients with diabetes.
Phenytoin is potentially hepatotoxic, although this is an uncommon occurrence. It can cause benign elevated hepatic enzymes or more serious manifestations of hepatitis such as focal necrosis and hepatomegaly. The histologic pattern usually resembles hepatocellular necrosis similar to viral hepatitis. Cholestasis with jaundice can occur. Heptatotoxicity may also be a component of a severe hypersensitivity reaction. Careful investigation should be made of any complaint suggestive of hepatic injury.
Various blood dyscrasias can develop from phenytoin use. These include thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia, macrocytosis, and megaloblastic anemia. Although macrocytosis and megaloblastic anemia usually respond to therapy with folic acid, folic acid should not be administered indiscriminantly to patients receiving phenytoin due to its potential detrimental effects on phenytoin efficacy (see Drug Interactions). Some evidence suggests aplastic anemia secondary to phenytoin administration is due to a highly reactive arene oxide metabolite and the inability to detoxify this metabolite.
Long-term therapy with phenytoin can lead to osteomalacia secondary to its interference with vitamin D metabolism.
Phenytoin has been associated with sexual dysfunction including libido decrease, impotence, and priapism.
Phenytoin rarely causes renal complications. Reports of glomerulonephritis, interstitial nephritis, proteinuria, and nephrotic syndrome have been reported.
Phenytoin injection contains 40% propylene glycol, a substance that, when infused into dogs, has caused cardiac arrhythmias. Too rapid IV administration of phenytoin can produce cardiac arrhythmias, hypotension, and/or death. IV phenytoin should be administered no faster than 50 mg/min to minimize this risk. Phenytoin injection has a pH of 12. Pain and inflammation (vasculitis) are examples of an injection site reaction that can occur with IV administration. Phenytoin should never be administered IM because it precipitates at the injection site, producing delayed and erratic absorption.
PATIENT INFORMATION:
What do phenytoin capsules do?
Phenytoin (DilantinTM KapsealsTM ) helps to control seizures (convulsions) in certain types of epilepsy. Phenytoin can help to prevent seizures occurring during or after surgery. Generic phenytoin capsules are available. NOTE: Phenytoin can affect many organs or tissues in your body. Phenytoin has many possible side effects; read patient information carefully before use.
What should my doctor, dentist, or pharmacist know before I take phenytoin?
They need to know if you have any of these conditions:
How should I take this medicine?
Take phenytoin capsules by mouth. Follow the directions on the prescription label. Swallow the capsules with a drink of water. If you are taking extended-release capsules, swallow them whole; do not crush or chew. Take phenytoin with food if it upsets your stomach. Take your doses at regular intervals. Do not take your medicine more often than directed.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is less than four hours to your next dose, take only that dose. If you only take a dose once a day and do not remember until the next day, miss that dose and resume your normal schedule. Do not take double or extra doses.
What other medicines can interact with phenytoin?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking phenytoin?
Serious side effects with phenytoin include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with phenytoin include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take phenytoin?
Visit your doctor for regular checks on your progress. Your doctor may schedule regular blood tests, because phenytoin therapy needs careful monitoring. Do not stop taking phenytoin suddenly; this increases the risk of seizures. Because your condition and the use of phenytoin carry some risk, it is a good idea to carry an identification card, necklace or bracelet with details of your condition, medications and doctor.
Different brands of phenytoin may not act in the same way in your body, and increase the risk of seizures. Ask your doctor before you make any change from your regular brand of phenytoin.
You may feel dizzy or drowsy. Do not drive, use machinery, or do anything that needs mental alertness until you know how phenytoin affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient. Alcohol can make you more dizzy, increase flushing and rapid heartbeats. Avoid alcoholic drinks.
If you are going to have surgery, tell your doctor or pharmacist that you are taking phenytoin.
Birth control pills (contraceptive pills) may not work properly while you are taking phenytoin; use another method of birth control.
Phenytoin can cause unusual growth of gum tissues; visit your dentist regularly. Problems can arise if you need dental work, and in the day to day care of your teeth. Try to avoid damage to your teeth and gums when you brush or floss your teeth.
Do not take antacids at the same time as phenytoin. If you get an upset stomach and want to take an antacid or medicine for diarrhea, make sure there is an interval of 2 to 3 hours before or after you took phenytoin.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Keep container tightly closed. Throw away any unused medicine after the expiration date.
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