INFATABS® Dilantin® (Phenytoin Chewable Tablets, USP)
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`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.
`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.
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`Age
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`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 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.
`
`Indication
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`Table 1 Risk by indication for antiepileptic drugs in the pooled analysis
`Placebo Patients with
`Drug Patients with
`Relative Risk: Incidence
`Events Per 1000 Patients
`Events Per 1000 Patients
`of Events in Drug
`Patients/Incidence in
`Placebo Patients
`3.5
`1.5
`1.9
`1.8
`
`3.4
`8.5
`1.8
`4.3
`
`1.0
`5.7
`1.0
`2.4
`
`Risk Difference:
`Additional Drug
`Patients with Events Per
`1000 Patients
`2.4
`2.9
`0.9
`1.9
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`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.
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`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.
`
`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 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
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`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.
`
`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.
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`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.
`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),
`2
`halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, 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.
`
`Drugs affected by phenytoin
`• 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).
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`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.
`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.
`
`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 morbilliform rash
`(measles-like) is the most common; other types of derma