Di-hyden

Di-hyden Uses, Dosage, Side Effects, Food Interaction and all others data.

Di-hyden acts as an anticonvulsant by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses; thus stabilising neuronal membranes and decreasing seizure activity. It acts as an antiarrhythmic by extending the effective refractory period and suppressing ventricular pacemaker automaticity, shortening action potential in the heart.

Di-hyden is an anticonvulsant with a narrow therapeutic index. Although the recommended therapeutic range is cited to be between 10-20 mg/L, differences in albumin levels, genetics, comorbidities, and body composition can make achieving an ideal phenytoin dose challenging. For example, studies have confirmed that phenytoin metabolism is impacted by CYP2C9 genotype polymorphisms and possibly by CYP2C19 genotype polymorphisms (the latter has not been as extensively studied).

It is worth nothing that although phenytoin is highly protein bound, only the fraction unbound is able to exert a pharmacological effect. Therefore, factors that reduce or increase the percentage of protein bound phenytoin (for example: concomitant administration of drugs that can cause displacement from protein binding sites) can have a marked impact on phenytoin therapy.

Trade Name Di-hyden
Availability Prescription only
Generic Phenytoin
Phenytoin Other Names Diphenylhydantoin, Fenitoina, Phentytoin, Phenytoin, Phenytoine, Phenytoinum
Related Drugs gabapentin, clonazepam, lorazepam, lamotrigine, diazepam, pregabalin, Lyrica, topiramate, Ativan, levetiracetam
Weight 100mg
Type Tablet
Formula C15H12N2O2
Weight Average: 252.268
Monoisotopic: 252.089877638
Protein binding

Phenytoin is roughly 90% protein bound.

Groups Approved, Vet approved
Therapeutic Class Adjunct anti-epileptic drugs
Manufacturer French Pharmaceutical Group
Available Country Pakistan
Last Updated: September 19, 2023 at 7:00 am
Di-hyden
Di-hyden

Uses

Parenteral Di-hyden is used for the treatment of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Intravenous Di-hyden can also be substituted, as short-term use, for oral phenytoin. Parenteral Di-hyden should be used only when oral Di-hyden administration is not possible

Di-hyden is also used to associated treatment for these conditions: Complex Partial Seizures, Grand Mal Status Epilepticus, Grand mal Generalized tonic-clonic seizure, Jacksonian epilepsy, Partial-Onset Seizures, Petit Mal Epilepsy, Post-Traumatic Seizure Disorder, Seizures, Status; Epilepticus, Tonic-clonic, Temporal Lobe Epilepsy (TLE), Convulsive disorders

How Di-hyden works

Although phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated. Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels.

Di-hyden is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes. More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials.

Dosage

Di-hyden dosage

Oral:Epilepsy:

  • Adult: Initially, 3-4 mg/kg daily as single dose or in divided doses. Alternatively, 150-300 mg daily increased gradually to 600 mg daily if necessary. Maintenance: 200-500 mg daily.
  • Child: Initially, 5 mg/kg daily in 2-3 divided doses. Maintenance: 4-8 mg/kg daily in divided doses. Max dose: 300 mg daily.

Intravenous:Tonic-clonic status epilepticus:

  • Adult: Adjunctive therapy with a benzodiazepine (e.g. diazepam): 10-15 mg/kg by slow inj or intermittent infusion at a max rate of 50 mg/min. Maintenance: 100 mg IV (or orally) given every 6-8 hr.
  • Child: Neonates: 20 mg/kg as a loading dose, then 2.5-5 mg/kg bid; 1 mth-12 yr: 18 mg/kg as a loading dose, then 2.5-5 mg/kg bid; >12 yr: 18 mg/kg as a loading dose, then up to 100 mg 3-4 times daily.

Should be taken with food. When administering to patients on nasogastric or other enteral feeds, do not administer feeds 2 hr before or after a dose. Be consistent throughout therapy in relation to feed times. Do not switch dosage forms/brands w/o prior consideration.

Side Effects

Hypersensitivity, lack of appetite, headache, dizziness, tremor, transient nervousness, insomnia, GI disturbances (e.g. nausea, vomiting, constipation), tenderness and hyperplasia of the gums, acne, hirsutism, coarsening of the facial features, rashes, osteomalacia. Di-hyden toxicity as manifested as a syndrome of cerebellar, vestibular, ocular effects, notably nystagmus, diplopia, slurred speech, and ataxia; also with mental confusion, dyskinesias, exacerbations of seizure frequency, hyperglycaemia. Solutions for inj may cause local irritation or phlebitis. Prolonged use may produce subtle effects on mental function and cognition, especially in children.

Toxicity

The experience of phenytoin toxicity is not limited to situations of acute ingestion, but may also occur due to drug interactions or due to physiological circumstances that impact serum albumin (ie. kidney disease) or drug metabolism. Other changes that may result in phenytoin toxicity include pregnancy, malnutrition and malignancy.

Di-hyden toxicity most often affects the cardiovascular and nervous systems. The most common presentation of toxicity depends on the route of administration. Cardiovascular adverse effects are most commonly linked to intravenous phenytoin administration, whereas neurological adverse effects are more common with oral phenytoin administration.

Neurotoxicity is usually dependent on serum concentrations. When concentrations range from 10-20 mg/L, mild nystagmus and lateral gaze may occur, while more significant nystagmus is associated with concentrations ranging from 20-30 mg/L. At concentrations of 30-40 mg/L, slurred speech, tremor, nausea, vomiting and ataxia have been reported. In more serious cases where serum levels range from 40-50 mg/L patients are at risk of lethargy, confusion and hyperactivity, and at levels beyond 50 mg/L, coma and seizures may occur.

Di-hyden is classified as an antiarrhythmic and can cause SA and AV nodal blocks as well as dysrhythmias due to its effect on voltage-gated sodium channels. Further, since phenytoin is poorly soluble, the parenteral form is administered with propylene glycol, which is a cardiac depressant. The infusion rate of parenteral phenytoin should not exceed 50 mg per minute due to the risk of hypotension, bradycardia, and asystole.

Treatment for phenytoin toxicity is non-specific and centres around supportive care. One dose of activated charcoal may be used to prevent phenytoin absorption in cases of acute ingestion.

Although hemodialysis is moderately effective at removing phenytoin, it is not normally recommended due to the risks associated with the procedure, and the general effectiveness of supportive care.

Precaution

Cardiovascular disease, e.g. sinus bradycardia, heart blocks; DM; hepatic impairment; hypoalbuminemia; porphyria; seizures (may increase frequency of petit mal seizures); debilitated patients; elderly. Caution in IV admin in hypotension, heart failure or MI, monitor BP and ECG during therapy. IV must be given slowly (too rapid admin may cause hypotension, CNS depression, cardiac arrhythmias and impaired heart conduction). Extravasation and intra-arterial admin must be avoided. Do not discontinue abruptly (may increase seizure frequency), unless safety concerns require a more rapid withdrawal. May impair ability to drive or operate machinery.

Interaction

Effects with other sedative drugs or ethanol may be potentiated. Enhances toxic effects of paracetamol, lithium. Increased risk of osteomalacia with acetazolamide. Decreased serum levels/effects with acyclovir, antineoplastics, benzodiazeines, ciprofloxacin, CYP2C9 inducers (e.g. carbamazepine), CYP2C19 inducers (e.g. rifampin), folic acid, vigabatrin. Increased serum concentrations with allopurinol, capecitabine, cimetidine, CYP2C9 inhibitors (e.g. fluconazole), CYP2C19 inhibitors (e.g. delavirdine), disulfiram, methylphenidate, metronidazole, omeprazole, SSRI, trazodone, trimethoprim. Increases metabolism of antiarrhythmics, anticonvulsants, antipsychotics, beta-blockers, calcium channel blockers, chloramphenicol, corticosteroids, doxycycline, oestrogens, HMG-CoA reductase inhibitors, methadone, theophylline, TCAs. Decreases levels/effects of clozapine, ciclosporin, tacrolimus, CYP2B6 substrates (e.g. bupropion, selegiline), CYP2C8 substrates (e.g. amiodarone), CYP2C9 substrates (e.g. celecoxib), CYP2C19 substrates (e.g. citalopram), CYP3A4 substrates (e.g. benzodiazepines), digoxin, itraconazole, levodopa, neuromuscular-blocking agents, thyroid hormones, topiramate. Increases levels/effect of dopamine, ticlopidine. Valproic acid may displace phenytoin from binding sites; and affect phenytoin serum concentrations. Transiently increases the hypothrombinaemia response to warfarin initially, followed by an inhibition of the response.

Food Interaction

  • Avoid alcohol. Alcohol may increase or decrease serum levels of phenytoin.
  • Take separate from antacids. Take at least 2 hours before or after antacids. Taking this medication with antacids can reduce absorption.
  • Take with food. Food reduces irritation and increases bioavailability.

[Moderate] ADJUST DOSING INTERVAL: Di-hyden bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings.

The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and

Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels.

Chronic consumption of alcohol may decrease plasma phenytoin levels.

The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration.

Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible.

Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings.

Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained.

In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

Volume of Distribution

The volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.

Elimination Route

Given its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing. Di-hyden is completely absorbed. Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively. It should be noted that absorption can be markedly prolonged in situations of acute ingestion.

Half Life

Oral administration: The half-life of phenytoin ranges from 7 to 42 hours, and is 22 hours on average.

Intravenous administration: The half-life of phenytoin ranges from 10-15 hours.

Clearance

The clearance of phenytoin is non-linear. At lower serum concentrations (less than 10 mg/L), elimination is characterized by first order kinetics. As plasma concentrations increase, the kinetics shift gradually towards zero-order, and finally reach zero-order kinetics once the system is saturated.

Elimination Route

The majority of phenytoin is excreted as inactive metabolites in the bile. An estimated 1-5% of phenytoin is eliminated unchanged in the urine.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Di-hyden Sodium is contraindicated in patients with:

  • A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins
  • Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity.
  • A history of prior acute hepatotoxicity attributable to phenytoin
  • Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Special Warning

Pediatric Use: A loading dose of 15 to 20 mg/kg of Di-hyden intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Di-hyden should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower

Geriatric Use: Di-hyden clearance tends to decrease with increasing age. Lower or less frequent dosing may be required

Renal and Hepatic Impairment Or Hypoalbuminemia: The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

Acute Overdose

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, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is caused by respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum 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 serum 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. Irreversible cerebellar dysfunction and atrophy have been reported.

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.

Storage Condition

Intravenous: Store at room temperature of 15-30°C.Oral:

  • Tablet/capsule: Store below 30°C. Protect from light and moisture;
  • Oral suspension: Store at room temperature of 20-25°C, do not freeze, protect from light.

Innovators Monograph

You find simplified version here Di-hyden

Di-hyden contains Phenytoin see full prescribing information from innovator Di-hyden Monograph, Di-hyden MSDS, Di-hyden FDA label

FAQ

What is Di-hyden used for?

Di-hyden is used to treat epilepsy. It can also be used to treat trigeminal neuralgia, a type of nerve pain that affects your face.

How safe is Di-hyden?

Many people can take Di-hyden safely for several months or years. But there are some side effects that might happen over a long time.

How does Di-hyden work?

Di-hyden works by slowing down impulses in the brain that cause seizures.

What are the common side effects of Di-hyden?

Common side effects of Di-hyden are include:

  • headaches.
  • feeling drowsy, sleepy or dizzy.
  • feeling nervous, unsteady or shaky.
  • feeling or being sick (nausea or vomiting)
  • constipation.
  • sore or swollen gums.
  • mild skin rash.

Is Di-hyden safe during pregnancy?

If Di-hyden is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential harm to the fetus.

Is Di-hyden safe during breastfeeding?

Di-hyden is considered compatible with breastfeeding, with rarely reported side effects and low infant serum levels if maternal concentrations remain within the therapeutic range.

Can I drink alcohol with Di-hyden?

Yes, you can usually drink alcohol with Di-hyden. But it may make you feel sleepy or tired, and alcohol and hangovers can bring on seizures in some people with epilepsy.

Can I drive after taking Di-hyden?

Do not drive, ride a bike or operate machinery until you feel more alert. If they do not go within a week or two, your doctor may reduce your dose or increase it more slowly.

When should be taken of Di-hyden?

Di-hyden are usually taken two or three times a day. The extended-release capsules are usually taken one to four times a day. Take Di-hyden at around the same time(s) every day.

How long does Di-hyden take to work?

Di-hyden usually takes around 4 weeks for Di-hyden to work properly.

How long does Di-hyden stay in my system?

When taken orally,Di-hyden has a 22-hour plasma half-life and peaks 4 to 12 hours after ingestion. With intravenous administration, that half-life drops to 10 to 15 hours.

Is Di-hyden a lifelong drug?

Di-hyden oral capsule is used for long-term treatment. It comes with serious risks if you don't take it as prescribed.

How long should Di-hyden be administered?

Give Di-hyden over 30-40 minutes. In patients who are elderly, or have pre-existing cardiac disease, give phenytoin over 60 minutes. Adminstration should commence immediately after the mixture has been prepared and completed within 1 hour.

Can Di-hyden cause brain damage?

Cerebellar atrophy may be seen in  barnd exposed patients with epilepsy in the absence of generalized tonic-clonic seizures or preexistent brain damage.

When can I stop taking Di-hyden?

If you're taking Di-hyden for trigeminal neuralgia and your pain goes away, your doctor will slowly reduce your dose as low as possible, or may even stop it.

Can Di-hyden cause liver damage?

Di-hyden may cause liver damage.

Do I take Di-hyden on an empty stomach?

barnd can be taken with food or on an empty stomach. Try to take it the same way each day, since taking this with food may change the time it takes to be absorbed. Do not take antacids or medicine for diarrhea within 2 to 3 hours of taking Di-hyden.

Can Di-hyden cause heart problems?

Di-hyden cause cardiac rhythm disturbances, hypotension, and cardiac arrest is rarely recognized.

Can Di-hyden cause kidney stones?

Di-hyden can cause clinically relevant urolithiasis leading to significant morbidity and even mortality.

Who should not take Di-hyden?

You should not use Di-hyden if you are allergic to it, or if you have ever had. Tell your doctor if you have ever had Some people have thoughts about suicide while taking Di-hyden. Your doctor will need to check your progress at regular visits.

What happens if I miss a dose?

Take Di-hyden as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose?

Seek emergency medical attention. An overdose of phenytoin can be fatal. Overdose symptoms may include twitching eye movements, slurred speech, loss of balance, tremor, muscle stiffness or weakness, nausea, vomiting, feeling light-headed, fainting, and slow or shallow breathing.

*** Taking medicines without doctor's advice can cause long-term problems.
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