`
`INFATABS®
`Dilantin®
`(Phenytoin Chewable Tablets, USP)
`NOT FOR ONCE-A-DAY DOSING
`
`DESCRIPTION
`Dilantin (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring.
`The chemical name is 5,5-diphenyl-2,4-imidazolidinedione, having the following structural formula:
`
`Each Dilantin Infatab, for oral administration, contains 50 mg phenytoin, USP. Also contains: D&C
`yellow No. 10, Al lake; FD&C yellow No. 6, Al lake; flavor; saccharin sodium, USP; confectioner's
`sugar, NF; talc, USP; magnesium stearate, NF; and purified water, USP.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`Phenytoin is an antiepileptic 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 posttetanic potentiation at synapses. Loss of
`posttetanic 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.
`
`Pharmacokinetics and Drug Metabolism
`Clinical studies using Dilantin Infatabs have shown an average plasma half-life of 14 hours with a range
`of 7 to 29 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after
`initiation of therapy with recommended doses of 300 mg/day.
`When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after
`treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that
`equilibrium or steady-state will have been achieved. Trough levels provide information about clinically
`effective serum level range and confirm patient compliance and are obtained just prior to the patient's
`next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side
`effects and are obtained at the time of expected peak concentration. For Dilantin Infatabs, peak levels
`occur 1½ to 3 hours after administration.
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`Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and
`20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with
`lower serum levels of phenytoin.
`In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may
`be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with
`unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels
`result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in
`metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard
`doses, presents a difficult clinical problem. Serum level determinations in such patients may be
`particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in
`patients whose protein binding characteristics differ from normal.
`Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the
`intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly
`with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is
`hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small
`incremental doses may increase the half-life and produce very substantial increases in serum levels,
`when these are in the upper range. The steady-state level may be disproportionately increased, with
`resultant intoxication, from an increase in dosage of 10% or more.
`Clinical studies show that chewed and unchewed Dilantin Infatabs are bioequivalent, yield
`approximately equivalent plasma levels, and are more rapidly absorbed than 100 mg Dilantin
`Kapseals®.
`
`Special Populations
`
`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 (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more
`useful in these patient populations.
`
`Age
`Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age
`relative to that in patients 20–30 years of age). Phenytoin dosing requirements are highly variable and
`must be individualized (see DOSAGE AND ADMINISTRATION).
`
`Gender and Race
`Gender and race have no significant impact on phenytoin pharmacokinetics.
`
`Pediatrics
`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 to 8 mg/kg. Children
`over 6 years and adolescents may require the minimum adult dose (300 mg/day).
`
`INDICATIONS AND USAGE
`Dilantin Infatabs (Phenytoin Chewable Tablets, USP) are indicated for the control of generalized tonic-
`clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and
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`treatment of seizures occurring during or following neurosurgery. Phenytoin serum level determinations
`may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and
`CLINICAL PHARMACOLOGY sections).
`
`CONTRAINDICATIONS
`Phenytoin is contraindicated in those patients with a history of hypersensitivity to phenytoin or its
`inactive ingredients, or other hydantoins.
`Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic
`response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase
`inhibitors.
`
`WARNINGS
`
`Effects of Abrupt Withdrawal
`Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the
`judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative
`antiepileptic medication arises, this should be done gradually. In the event of an allergic or
`hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case,
`alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class.
`
`Suicidal Behavior and Ideation
`Antiepileptic drugs (AEDs), including Dilantin Infatabs, increase the risk of suicidal thoughts or
`behavior in patients taking these drugs for any indication. Patients treated with any AED for any
`indication should be monitored for the emergence or worsening of depression, suicidal thoughts or
`behavior, and/or any unusual changes in mood or behavior.
`Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different
`AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted
`Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to
`placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate
`of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24%
`among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal
`thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in
`the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about
`drug effect on suicide.
`The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
`starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most
`trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior
`beyond 24 weeks could not be assessed.
`The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
`The finding of increased risk with AEDs of varying mechanisms of action and across a range of
`indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary
`substantially by age (5–100 years) in the clinical trials analyzed.
`Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
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`Table 1 Risk by indication for antiepileptic drugs in the pooled analysis
`Risk Difference:
`Indication
`Placebo Patients
`Drug Patients
`Relative Risk:
`Additional Drug
`with Events Per
`with Events Per
`Incidence of
`Patients with
`1000 Patients
`1000 Patients
`Events in Drug
`Events Per 1000
`Patients/Incidence
`Patients
`in Placebo
`Patients
`3.5
`1.5
`1.9
`1.8
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`1.0
`5.7
`1.0
`2.4
`
`3.4
`8.5
`1.8
`4.3
`
`2.4
`2.9
`0.9
`1.9
`
`The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
`clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the
`epilepsy and psychiatric indications.
`Anyone considering prescribing Dilantin Infatabs or any other AED must balance the risk of suicidal
`thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which
`AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of
`suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the
`prescriber needs to consider whether the emergence of these symptoms in any given patient may be
`related to the illness being treated.
`Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
`thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of
`the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of
`suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported
`immediately to healthcare providers.
`
`Serious Dermatologic Reactions
`Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
`Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms
`is usually within 28 days, but can occur later. Dilantin should be discontinued at the first sign of a rash,
`unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug
`should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should
`be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see
`DRESS/Multiorgan hypersensitivity below).
`Studies in patients of Chinese ancestry have found a strong association between the risk of developing
`SJS/TEN and the presence of 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 other antiepileptic drugs associated with
`SJS/TEN, including phenytoin. Consideration should be given to avoiding phenytoin as an alternative
`for carbamazepine in patients positive for HLA-B*1502.
`The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate
`clinical vigilance and patient management. The role of other possible factors in the development of, and
`morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications,
`comorbidities, and the level of dermatologic monitoring have not been studied.
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`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
`hypersensitivity, has been reported in patients taking antiepileptic drugs, including Dilantin. Some of
`these events have been fatal or life-threatening. 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, or myositis sometimes resembling an
`acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression,
`other organ systems not noted here may be involved. It is important to note that early manifestations of
`hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If
`such signs or symptoms are present, the patient should be evaluated immediately. Dilantin should be
`discontinued if an alternative etiology for the signs or symptoms cannot be established.
`
`Hypersensitivity
`Dilantin and other hydantoins are contraindicated in patients who have experienced phenytoin
`hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally
`similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and
`oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of
`hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members,
`consider alternatives to Dilantin.
`
`Hepatic Injury
`Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported
`with Dilantin. These events may be part of the spectrum of DRESS or may occur in isolation. Other
`common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels,
`leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from
`prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Dilantin should be
`immediately discontinued and not readministered.
`
`Hematopoietic System
`Hematopoietic complications, some fatal, have occasionally been reported in association with
`administration of Dilantin. 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 of
`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 antiepileptic drugs.
`
`Effects on Vitamin D and Bone
`The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral
`density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic
`metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels,
`which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should
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`be given to screening with bone-related laboratory and radiological tests as appropriate and initiating
`treatment plans according to established guidelines.
`
`Effects of Alcohol Use on Phenytoin Serum Levels
`Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease
`serum levels.
`
`Exacerbation of Porphyria
`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.
`
`Usage in Pregnancy
`
`Clinical
`Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered
`phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be
`valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see
`PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will
`probably be indicated.
`Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking
`the drug, the patient should be apprised of the potential harm to the fetus.
`Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse
`developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and
`cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth
`abnormalities (including microcephaly), and mental deficiency have been reported among children born
`to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during
`pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in
`children whose mothers received phenytoin during pregnancy. The overall incidence of malformations
`for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during
`pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative
`contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are
`uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to
`particular antiepileptic drugs.
`Patients should consult with their physicians to weigh the risks and benefits of phenytoin during
`pregnancy.
`Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of
`vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-
`induced condition can be prevented with vitamin K administration to the mother before delivery and to
`the neonate after birth.
`
`Nonclinical
`Administration of phenytoin to pregnant animals resulted in teratogenicity (increased incidences of fetal
`malformations) and other developmental toxicity (including embryofetal death, growth impairment, and
`behavioral abnormalities) in multiple animal species at clinically relevant doses.
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`PRECAUTIONS
`
`General
`The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function,
`elderly patients, or those who are gravely ill may show early signs of toxicity.
`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. If early signs of dose-related CNS toxicity develop, plasma levels
`should be checked immediately.
`Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported.
`Phenytoin may also raise the serum glucose level in diabetic patients.
`Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate
`diagnostic procedures should be performed as indicated.
`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.
`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.
`Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of
`phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is
`recommended. (See WARNINGS section.)
`
`Information for Patients
`Inform patients of the availability of a Medication Guide, and instruct them to read the Medication
`Guide prior to taking Dilantin. Instruct patients to take Dilantin only as prescribed.
`Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed
`dosage regimen, and of informing the 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 made aware of the early toxic signs and symptoms of potential hematologic,
`dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited
`to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or
`purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The
`patient should be advised that, because these signs and symptoms may signal a serious reaction, that
`they must report any occurrence immediately to a physician. In addition, the patient should be advised
`that these signs and symptoms should be reported even if mild or when occurring after extended use.
`Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking
`the physician's advice.
`The importance of good dental hygiene should be stressed in order to minimize the development of
`gingival hyperplasia and its complications.
`Patients, their caregivers, and families should be counseled that AEDs, including Dilantin Infatabs, may
`increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
`emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the
`emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be
`reported immediately to healthcare providers.
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`Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
`Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic
`drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see
`PRECAUTIONS: Pregnancy section).
`
`Laboratory Tests
`Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.
`Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to
`20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).
`
`Drug Interactions
`Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement.
`Phenytoin is metabolized by hepatic cytochrome 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.
`Serum level determinations for phenytoin are especially helpful when possible drug interactions are
`suspected.
`The most commonly occurring drug interactions are listed below:
`Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should
`be consulted.
`
`Drugs that affect phenytoin concentrations
`• Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-
`epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles
`(fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol,
`chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine,
`H -antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines,
`2
`salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine,
`sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
`• Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g.,
`bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse,
`diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John's
`Wort, sucralfate, theophylline, and vigabatrin.
`• Administration of phenytoin with preparations that increase gastric pH (e.g., supplements or antacids
`containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the
`absorption of phenytoin. In most cases where interactions were seen, the effect is a decrease in
`phenytoin levels when the drugs are taken at the same time. When possible, phenytoin and these
`products should not be taken at the same time of day.
`• Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium
`valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid, and
`sodium valproate serum levels is unpredictable.
`• The addition or withdrawal of these agents in patients on phenytoin therapy may require an
`adjustment of the phenytoin dose to achieve optimal clinical outcome.
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`Drugs affected by phenytoin
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`• Drugs that should not be coadministered with phenytoin: Delavirdine (see
`CONTRAINDICATIONS).
`• Drugs whose efficacy is impaired by phenytoin include: azoles, (fluconazole, ketoconazole,
`itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide,
`irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide,
`theophylline, and vitamin D.
`• Increased and decreased PT/INR responses have been reported when phenytoin is coadministered
`with warfarin.
`• Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV
`antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic
`agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin,
`chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone,
`mexiletine,nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin and verapamil.
`• Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the
`active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may
`increase the concentration of amprenavir.
`• Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking
`agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients
`chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-
`depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from
`neuromuscular blockade than expected, and infusion rate requirements may be higher.
`• The addition or withdrawal of phenytoin during concomitant therapy with these agents may require
`adjustment of the dose of these agents to achieve optimal clinical outcome.
`
`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 decrease serum concentrations of T4. It may also 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).
`Care should be taken when using immunoanalytical methods to measure plasma phenytoin
`concentrations.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis
`See WARNINGS (Hematopoietic System) section
`In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and
`rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in
`male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The
`highest doses tested in these studies were associated with peak plasma phenytoin levels below human
`therapeutic concentrations.
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`In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at
`doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120
`mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the
`lowest dose tested. No increases in tumor incidence were observed in rats.
`
`Mutagenesis
`Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster
`ovary (CHO) cells.
`In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and
`the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid
`exchange assay in CHO cells.
`
`Fertility
`Phenytoin has not been adequately assessed for effects on male or female fertility.
`
`Pregnancy
`
`Pregnancy Category D
`See WARNINGS section.
`To provide information regarding the effects of in utero exposure to Dilantin Infatabs, physicians are
`advised to recommend that pregnant patients taking Dilantin Infatabs enroll in the NAAED Pregnancy
`Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients
`themselves. Information on the registry can also be found at the website
`http://www.aedpregnancyregistry.org/.
`
`Nursing Mothers
`Infant breast-feeding is not recommended for women taking this drug because phenytoin appears to be
`secreted in low concentrations in human milk.
`
`Pediatric Use
`See DOSAGE AND ADMINISTRATION section.
`
`Geriatric Use
`Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY:
`Special Populations).
`
`ADVERSE REACTIONS
`
`Body as a Whole
`Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages
`paragraph below) and DRESS (see WARNINGS) have been observed. Anaphylaxis has also been
`reported.
`There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis
`nodosa, and immunoglobulin abnormalities.
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`Nervous System
`The most common adverse reactions encountered with phenytoin therapy are nervous system reactions
`and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased
`coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness,
`motor twitchings, paresthesias, and headaches 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.
`
`Digestive System
`Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the
`lips, and gingival hyperplasia.
`
`Skin and Appendages
`Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or
`morbilliform rashes. A morbill