2.6.1 Interferences in Epelin Immunoassays
Epelin (diphenylhydantoin) was first introduced as an anticonvulsant agent in 1938, and it is one of the most widely used anticonvulsant drugs. Immunoassays are used in clinical laboratories for TDM of Epelin, and in general, these assays are robust, with few reported interferences. One of the potential interferences in immunochemical measurements of Epelin is cross-reactivity of the major Epelin metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) and its glucuronide conjugate with Epelin immunoassays. HPPH is the primary metabolite of Epelin, and it is readily conjugated to glucuronide (HPPG), which is excreted in urine. It is estimated that 60–90% of the administered dose of Epelin can by recovered in the urine as HPPG . This cross-reactivity is particularly important in patients with renal insufficiency because of the increased concentration of metabolites. A 1981 study showed significant interference of metabolites with Epelin immunoassays . However, newer monoclonal antibody-based immunoassays are less affected by Epelin metabolites. Tutor-Crespo et al. compared Epelin concentrations determined by two immunoassays (FPIA and EMIT) with values determined by HPLC for determination of Epelin using specimens from 36 patients receiving Epelin. These patients had renal function ranging from normal to severe renal insufficiency (glomerular filtration rate 10–102 mL/min of creatinine clearance). The authors used a deviation of 15% in value as clinically significant, and they concluded that immunoassays provided accurate results in therapeutic monitoring of Epelin in patients with renal insufficiency . Datta et al. studied the analytical performance of a turbidimetric assay on the ADVIA 1650 analyzer and reported that the Epelin assay had very low cross-reactivity (5–8%) with the HPPH metabolite and virtually no cross-reactivity with oxaprozin. Oxaprozin interference in some older Epelin immunoassays had been reported ( Table 2.4 ).
Table 2.4 . Common Interferences in Immunoassays for TCAs
Michael Stewart, Reviewed by Sid Dajani | Last edited 4 Jan 2018 | Certified by The Information Standard
Try to keep your regular doctor's appointments. Your doctor may need to test your blood to decide the correct dose for you.
You need to take Epelin regularly. Do not stop taking it unless your doctor tells you to.
Different formulations and brands of Epelin can act in a slightly different way in your body. Each time you collect a prescription, check to make sure your supply looks the same as you have had before. If not, please ask your pharmacist to check your prescription for you.
For the Consumer
Applies to Epelin: oral capsule extended release, oral suspension, oral tablet chewable
Other dosage forms:
Along with its needed effects, Epelin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking Epelin:
- Decreased coordination
- mental confusion
- slurred speech
- trouble with breathing, speaking, or swallowing
- unsteadiness, trembling, or other problems with muscle control or coordination
- Inability to move the eyes
- increased blinking or spasms of the eyelid
- shakiness and unsteady walk shakiness in the legs, arms, hands, or feet
- sticking out of the tongue
- trembling or shaking of the hands or feet
- twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
- uncontrolled twisting movements of the neck, trunk, arms, or legs
- unusual facial expressions
Incidence not known
- Abdominal or stomach pain
- bleeding gums
- blistering, peeling, or loosening of the skin
- blisters, hives, or itching
- bloating of the abdomen or stomach
- blood in the urine or stools
- bloody, black, or tarry stools
- chest pain
- cough or hoarseness
- dark urine
- difficulty with moving
- fainting spells
- fever with or without chills
- general feeling of discomfort or illness
- general feeling of tiredness or weakness
- hair loss
- high fever
- irregular heartbeat
- irritation in the mouth
- joint or muscle pain
- light-colored stools
- lower back or side pain
- muscle stiffness
- nausea or vomiting
- numbness, tingling, or pain in the hands or feet
- painful or difficult urination
- pale skin
- pinpoint red spots on the skin
- red skin lesions, often with a purple center
- red, irritated eyes
- redness and swelling of the gums
- skin blisters
- skin rash
- sore throat
- sores, ulcers, or white spots on the lips or in the mouth
- swollen, painful, or tender lymph glands in the neck, armpit, or groin
- unusual bleeding or bruising
- unusual tiredness
- upper right abdominal or stomach pain
- weight loss
- yellow eyes or skin
Some side effects of Epelin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
- Trouble sleeping
- uncontrolled eye movements
Incidence not known
- Difficulty having a bowel movement (stool)
- enlarged lips
- feeling of constant movement of self or surroundings
- increased hair growth on the forehead, back, arms, or legs
- pain of the penis on erection
- sensation of spinning
3. Who can and can't take Epelin
Epelin can be taken by adults and children of any age.
Epelin is not suitable for some people.
To make sure Epelin is safe for you, tell your doctor if you:
- have ever had an allergic reaction to Epelin or other medicines in the past
- have liver or kidney problems
- have a blood disorder called porphyria
- cannot have alcohol - Epelin liquid contains a small amount of alcohol
- have had a rash caused by Epelin in the past
- are pregnant or planning to become pregnant
- have ever had an allergic reaction to carmoisine (E122) or sunset yellow (E110) - some brands of Epelin liquid and tablets contain these
- have an intolerance to or cannot absorb some sugars - some brands of Epelin tablets contain sugars
Mechanism of Injury
The liver injury caused by Epelin appears to be due to a hypersensitivity reaction and resembles typical cases of immunoallergic hepatotoxicity. This syndrome is more common in blacks than whites, but few other risk factors have been established. In some populations, the risk of injury correlates with the presence of HLA-B*1502. Epelin is metabolized by CYP 450 system to arene oxide, which may represent the toxic or immunogenic intermediate.
Epelin absorption is erratic, slow and incomplete from both the gastrointestinal tract and intramuscular injection sites. The half-life is 3–4 h.
When the level of Epelin reaches the toxic level, the patient may manifest with a febrile reaction and bradycardia. If the patient receives Epelin intravenously, they may experience hypotension or low blood pressure. Oral intake of the drug is associated with the presence of gingival hyperplasia .
18. How is dosage of anticonvulsants adjusted in patients with CKD?
Epelin is a highly protein-bound drug. In patients receiving dialysis or in patients with CKD and significant proteinuria, the free fraction of Epelin (free Epelin) is elevated, although plasma Epelin levels seem low. If not adjusted, total Epelin levels are of little value. In patients receiving dialysis, the monitoring of free concentration is recommended for a target plasma concentration of 1 to 2 mcg/mL.
If unable to obtain a free Epelin level, the following equations can be used to adjust the serum concentrations based on either reduced albumin levels or presence of kidney failure (CrCl •
Hypoproteinemia: Cadjusted = Cmeasured/
AKI and dialysis: Cadjusted = Cmeasured/
Case 1. Acute immunoallergic hepatitis 3 weeks after starting Epelin.
A 25 year old man was started on Epelin (100 mg thrice daily) for new onset seizures and developed fever, mobilliform pruritic rash and fatigue 3 weeks later. He was treated symptomatically and maintained on anticonvulsant therapy until 2 weeks later when he was admitted for worsening rash and jaundice. He had no other medical illnesses, no history of liver disease, drank little alcohol and was taking no other medications except salicylates for fever. On examination, he had a generalized erythematous rash and facial edema. His temperature was 39.5 o C and he had mild cervical, axillary and inguinal adenopathy. He was jaundiced, but had no hepatomegaly or peripheral signs of liver disease. Laboratory tests showed elevations in serum enzymes and bilirubin (Table). The total white count was 18,200/μL with 13% eosinophils and 13% atypical lymphocytes. An abdominal ultrasound was normal without splenomegaly or biliary abnormalities. He tested negative for markers of hepatitis A, B and C as well as cytomegalovirus, Epstein-Barr and herpes simplex viruses. Serological tests for syphilis were negative. Epelin was stopped. Initially, the prothromin time was prolonged (20.4 sec, control 11 sec), but it corrected in the following week (and after vitamin K injections). The skin rash became desquamative. A liver biopsy showed changes of acute hepatitis with some granulomata and moderate cholestasis. In follow up six weeks after onset, the rash had resolved, he was asymptomatic and all laboratory tests (white counts and liver tests) were normal.
What other drugs will affect Dilantin?
Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.
Many drugs can interact with Epelin. Not all possible interactions are listed here. TELL YOUR DOCTOR ABOUT ALL OTHER MEDICINES YOU USE, and any you start or stop using during treatment with Dilantin. This includes prescription and over-the-counter medicines, vitamins, and herbal products.