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苯妥英口服混悬剂DILANTIN ORAL SUSP（PHENYTOIN）

2013-03-10 16:46:08 作者：新特药房来源：互联网浏览次数：121 文字大小：【大】【中】【小】

简介： 部分中文苯妥英钠处方资料（仅供参考）药品名称：苯妥英钠英文药名：Phenytoin Sodium 其他名称：Dihycon、Diphenylhydantoin、苯妥英、二苯乙内酰胺、二苯乙内酰脲、Dilantin、Dilantin Sodium、S ...

关键字：苯妥英口服混悬剂狄兰汀口服混悬剂 DILANTIN ORAL SUSP

部分中文苯妥英钠处方资料（仅供参考）
药品名称：苯妥英钠
英文药名：Phenytoin Sodium
其他名称：Dihycon、Diphenylhydantoin、苯妥英、二苯乙内酰胺、二苯乙内酰脲、Dilantin、Dilantin Sodium、Sodium Phenytoin、大伦丁、大仑丁、二苯乙内酰脲钠、奇非宁。
药理作用：
本品为己内酰脲类抗癫痫药，作用机制尚不完全清楚。本品对大脑皮层运动区有高度选择性抑制作用，防止异常放电的传播，为控制癫痫大发作首选药物之一。主要用于抗癫痫大发作、颞叶癫痫等局限性发作，对精神运动性发作效果次之，对小发作无效。近年证明，本品能增加脑中7-氨基丁酸(GABA)的含量。此外，本品为膜抑制性药物，电生理作用与盐酸利多卡因相似。主要是抑制心肌的自律性，对心肌的应激性和收缩性无明显抑制作用，且有加快房室传导的作用，可用于室性早搏或心动过速、洋地黄中毒引起的心律紊乱。本品口服吸收较慢，主要在小肠吸收，约4-12小时血药浓度达峰值，有效血药浓度为10-20μg／m1，静注15分钟达峰值，蛋白结合率约为85％-90％主要由肝脏代谢，肾脏排出，碱性尿排泄加快。还可以抗神经痛，以及可抑制皮肤成纤维细胞合成或分泌胶原酶用于治疗隐形营养不良性大疱性表皮松解症；静脉用药可扩张周围血管，降低轻度高血压。
临床应用：
用于全身强直阵挛性发作，复杂部分性发作(精神运动性发作，颞叶癫痫)，单纯部分性发作(局限性发作)和癫痫持续状态。还用于治疗三叉神经痛及心律失常。
禁忌症
(1)孕妇禁用。
(2)频率极快的心动过速、高度房室传导阻滞、充血性心力衰竭、严重心肌损害及有过敏反应者禁用。
不良反应
本品不良反应少。长期用药或血药浓度超过30μg／ml。
(1)精神神经系统：眼球震颤，共济失调，神志模糊，构音障碍，行为改变，视觉障碍、精神错乱、癫痫发作次数增多，眩晕，失眠，头痛等。
(2)消化系统：恶心，呕吐，胃炎，大便色淡，齿龈增生，罕见肝功能损害。
(3)血液：白细胞减少，粒细胞缺乏及骨髓抑制所致全血细胞减少，巨幼细胞贫血，紫癜。
(4)皮肤：常有皮疹反应。
(5)肌肉骨骼系统：罕见骨折、骨质疏松。
(6)泌尿生殖系统：尿色加深。
(7)血糖升高。
制剂规格
妥英钠片 (1)50mg。(2)100mg。
注射用苯妥英钠 (1)100mg。(2)250mg。
注意事项
(1)定期检查血象。
(2)糖尿病患者可因用本药血糖升高，需调整降血糖药剂量。
(3)长期服用，应注意测定血钙，必要时补充维生素D。
(4)口服需7-10日才可达到有效的血药浓度。
(5)骤然停药可能诱发癫痫发作。
(6)癫痫大、小发作混合型患者须与抗小发作药合用。
(7)静注时以注射用水溶解成5％-10％溶液，缓慢注入，以25-50mg/分钟为宜，速度太快或用量过大可产生低血压、房室传导阻滞、心动过缓、心脏停搏、心室颤动或完全性房室传导阻滞、呼吸抑制等。
(8)静滴时先用注射用水溶解，再用生理盐水或葡萄糖液稀释。
(9)经静注后如仍有偶发早搏，可肌注或口服维持。
(10)肌注吸收差，易引起局部坏死，故不用。
(11)肝功能不全者及哺乳期妇女、老年人慎用。
(12)静注处常有疼痛，并易致静脉栓塞、故宜选较粗的静脉注射。
(13)本品为肝酶诱导剂，与肾上腺皮质激素、口服避孕药、环孢菌素、洋地黄类、雌激素、左旋多巴及奎尼丁等药物合用，可使后者药物疗效下降。
(14)抗凝剂(如双香豆素)、氯霉素、异烟肼、保泰松、磺胺类等合用，可降低苯妥英钠的代谢，使其血药浓度增高。
(15)本品与利多卡因、普萘洛尔合用可加强对心脏的抑制作用。
(16)苯妥英钠与长马西平合用，可降低后者的血药浓度。
(17)长期饮酒可降低苯妥英钠的疗效。
(18)本品极易潮解，故应避湿，避光保存。
Dilantin-125
Generic Name: phenytoin
Dosage Form: oral suspension
Dilantin-125®
(Phenytoin Oral Suspension, USP)
(FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE)
Dilantin-125 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 5 ml of suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6.
Dilantin-125 - 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
The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 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-125 Suspension, peak levels occur 1½–3 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.
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 for Dilantin-125
Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.
Contraindications
Dilantin is contraindicated in those patients with a history of hypersensitivity to phenytoin, 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 anticonvulsant 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, 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.
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 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
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.
Preclinical
Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
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 instructed to use an accurately calibrated measuring device when using this medication to ensure accurate dosing.
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, 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 µg/mL (unbound phenytoin concentrations of 1 to 2 µg/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, which may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (felbamate, topiramate, oxcarbazepine), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), chloramphenicol, chlordiazepoxide, cimetidine, diazepam, disulfiram, estrogens, ethosuximide, fluorouracil, fluoxetine, fluvoxamine, H2-antagonists, halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides, ticlopidine, tolbutamide, trazodone, and warfarin.
Drugs, which may decrease phenytoin levels, include: carbamazepine, chronic alcohol abuse, nelfinavir, reserpine, ritonavir, and sucralfate.
Ingestion times of phenytoin and antacid preparations containing calcium should be staggered in patients with low serum phenytoin levels to prevent absorption problems.
Drugs which 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
Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, vitamin D, and warfarin.
Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
Phenytoin decreases plasma concentrations of certain HIV antivirals (amprenavir, efavirenz, Kaletra (lopinavir/ritonavir), indinavir, nelfinavir, ritonavir, saquinavir), and anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine).
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
See WARNINGS section for information on carcinogenesis.
Pregnancy
Pregnancy Category D; See WARNINGS section.
To provide information regarding the effects of in utero exposure to Dilantin, physicians are advised to recommend that pregnant patients taking Dilantin 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 manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, 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
Nausea, vomiting, constipation, enlargement of the lips, gingival hyperplasia, toxic hepatitis and liver damage.
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 dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see WARNINGS section). There have also been reports of hypertrichosis.
Hematologic and Lymphatic System
Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported (see WARNINGS section).
Special Senses
Altered taste sensation including metallic taste.
Urogenital
Peyronie's disease
Overdosage
The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, 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 plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery.
Treatment
Treatment is nonspecific 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 other CNS depressants, including alcohol, should be borne in mind.
DOSAGE AND ADMINISTRATION
FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE
Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. 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.
General
Dosage should be individualized to provide maximum benefit. In some cases serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.
Adult Dose
Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125 Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary.
Dosing in 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. Unbound phenytoin concentrations may be more useful in these patient populations.
Elderly Patients
Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
Pediatric
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).
How is Dilantin-125 Supplied
N 0071-2214-20—Dilantin-125® Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL with a maximum alcohol content not greater than 0.6 percent, an orange suspension with an orange-vanilla flavor; available in 8-oz bottles.
Store at controlled room temperature 20°–25°C (68°–77°F). [See USP.] Protect from freezing and light.
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原产地英文商品名:
DILANTIN ORAL SUSP 125MG/5ML 237MLS(8OZ)/BOTTLE
原产地英文药品名:
PHENYTOIN
中文参考商品译名:
狄兰汀口服混悬剂 125毫克/5毫升 237毫升(8盎司)/瓶
中文参考药品译名:
苯妥英
生产厂家中文参考译名:
派德药厂
生产厂家英文名:
PARKE DAVIS