Phenytoin (Dilantin) is used to treat partial and generalized tonic clinic seizures. It is available in different formulations. Intravenous phenytoin is used to treat patients with uncontrolled seizures and those with status epilepticus while oral formulations are used as maintenance treatment.
Phenytoin is ineffective in treating absence seizures which are a specific form of seizures and not easily recognizable.
Phenytoin (Dilantin) Uses:
- It is used to treat uncontrolled generalized seizures, status epilepticus, post-traumatic seizures (off-label), and partial/ focal seizures.
Phenytoin (Dilantin) Dose in Adults
HLA-B*1502 allele testing
- It is best to perform an HLA-B*1502 allele testing before phenytoin is administered, especially in high-risk ethnic groups such as Asians (to prevent severe skin reactions).
- For those who can not perform the test and even in patients in whom the test is negative, should be observed for skin-related side effects of phenytoin.
Drug Levels:
- Drug levels monitoring is also recommended 2 hours after the IV loading dose, 24 hours after the oral loading dose, and about 1 to 3 weeks after dose adjustment. keep the drug levels between 10 to 20 mg/L.
- In conditions where free levels may be more important than the bound form such as in kidney disease or hypoalbuminemia, the free or unbound levels should be between 1 to 2 mg/L.
Administering Phenytoin:
- It is important to monitor the vitals (BP, pulse, and cardiac monitoring) when administering phenytoin. The rate of infusion should not exceed 50 mg/minute.
- In situations where rapid infusion is required, it is best to administer fosphenytoin.
- The oral dose should not exceed 400 mg to ensure proper absorption.
Phenytoin (Dilantin) Dose in patients with a head injury:
|
Treatment |
Dose |
Frequency |
Maximum Dose |
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Craniotomy, seizure prophylaxis |
Loading dose: 15 mg per kg IV |
Once prior to the incision |
2 g |
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Postoperative prophylaxis |
5-6 mg per kg per day IV or oral |
2-3 divided doses |
300-400 mg (adjust based on response and serum concentrations) |
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Note:
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Phenytoin (Dilantin) Dose in the Focal (partial) and generalized seizures:
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Seizure Type |
Dose |
Route |
Loading Dose |
Maintenance Dose |
Maximum Dose |
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Focal (partial) onset seizures and generalized onset seizures |
Fixed dosing |
Oral extended-release capsule |
Optional: 1 g split into 3 doses (300 mg, 300 mg, and 400 mg) at 2-hour intervals |
Initial: 100 mg three to four times daily |
Not clear |
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Weight-based dosing (off-label): |
IV, Oral |
Optional: Usual total loading dose is 1 to 1.5 g; the maintenance dose should start 8 to 12 hours after the loading dose |
Initial: 4 to 7 mg/kg/day in two to four divided doses |
Care should be taken with maintenance doses greater than 600 mg daily. |
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Note:
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Phenytoin (Dilantin) Dose in preventing early posttraumatic seizure after Traumatic brain injury (off-label):
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Usage |
Loading Dose |
Maintenance Dose |
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Early seizure prophylaxis (for high-risk patients) |
17-20 mg/kg at a rate of ≤50 mg/min IV The Max dose is 2 gm |
100 mg every 8 hours or 5 mg/kg/day oral or IV |
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Note: Consult institutional protocols if dosing is center-specific. Prophylaxis is often used for a brief period, such as 7 days or less. |
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Phenytoin (Dilantin) Dose as an alternative agent in the treatment of Status epilepticus (convulsive and non-convulsive):
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Treatment for |
Phenytoin Loading Dose |
|
Convulsive Status Epilepticus |
20 mg/kg at a rate of 25 to 50 mg/min along with a parenteral benzodiazepine; decrease infusion rate if adverse effects occur. Administer 20 minutes after initial therapy |
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Non-Convulsive Status Epilepticus |
Administer immediately after initial therapy. Dosage same as for convulsive status epilepticus |
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Loading Dose (Phenytoin naive) |
10 minutes following the loading dose, if necessary, provide an extra dose of 5 to 10 mg/kg. Maximum total loading dose: 30 mg/kg |
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Maintenance Dose |
Start 8 to 12 hours after the loading dose. IV or Oral: 100 mg every 8 hours or 5 mg/kg/day rounded up to the nearest hundredth of a milligram. Prophylaxis is often used for a brief period of time, such as 7 days or less. |
Note: If fosphenytoin is available, it should be used instead of phenytoin because it is more quickly delivered and better tolerated.
- Discontinuation of therapy:
Patients who have to switch to another antiepileptic should do it very slowly. It is recommended to taper the dose over 2 to 6 weeks while simultaneously introducing another seizure medication and titrating the doses.
Rapid discontinuation may be necessary if side effects are a concern.
- Dosage form conversions:
|
Conversion |
Dosage Adjustment |
Monitoring |
|
IV to oral capsule formulations |
Use the same overall daily dose |
Dosage modifications and more frequent serum monitoring may be necessary due to 10% lower bioavailability of oral capsules |
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Phenytoin Soidum to Base |
Phenytoin sodium 100 mg to phenytoin base 92 mg |
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Phenytoin base (Suspension and tablets) to phenytoin sodium (Capsules) |
Dosage changes may be required |
Closer serum monitoring may be necessary |
Phenytoin (Dilantin) Dose in Children
When deciding on the right amount of medicine, doctors consider how well the patient is doing and how much of the drug is in their blood. Usually, doctors don't change how much medicine the patient takes more often than once a week.
If a patient takes phenytoin base (in the form of chewable tablets or oral solution), they are getting a bit more of the active ingredient compared to phenytoin sodium (which is found in capsules). This means that if the patient switches from one form to the other, the doctor might need to adjust the dose and check the patient's blood more often.
Phenytoin (Dilantin) Dose in the treatment of Status epilepticus:
|
Recommendations |
Loading Dose |
Maintenance Dose |
|
Manufacturer labeling |
15 to 20 mg/kg |
Start after 12 hours |
|
Alternate dosing: AAP, NCS recommendations |
20 mg/kg Max dose: 1000 mg Extra load: 5 to 10 |
Start after 12 hours |
Note:
- Maintenance therapy dosage adjustments are typically made no more than once every seven days, and the appropriate dosage should be determined based on clinical response and serum concentrations.
- Some experts suggest switching to a different medication after a total loading dose of 20 mg/kg has been given. However, an additional load of 5 to 10 mg/kg may be used if status epilepticus is not controlled.
Phenytoin (Dilantin) Dose in the Seizures:
Loading Dose: Oral and IV
- Divided into three doses given every 2-4 hours if the patient is already taking phenytoin
- Dosage: 15-20 mg/kg
Maintenance Therapy: Oral and IV
- Initial dosage: 5 mg/kg/day in divided doses (based on dosage form)
- Usual range: 4-8 mg/kg/day
- Maximum daily dose: 300 mg/day
- The dosing interval depends on the product type
Dosing Based on Ideal Body Weight (IBW)
|
Age Group |
Dosage Range (mg/kg/day) |
|
6 months to 3 years |
8-10 |
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4 to 6 years |
5-9 |
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7 to 9 years |
7-8 |
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10 to 16 years |
6-7 |
Immediate and Extended-release preparations:
- Divide immediate-release formulations into two or three doses per day.
- A double-blind, placebo-controlled trial of 102 pediatric patients showed no significant difference in seizure control.
(Note: Dosage adjustments may be necessary and should be based on individual response and serum concentration monitoring.)
Phenytoin (Dilantin) Dose to prevent seizures in traumatic brain injury:
|
Route |
Initial Dose |
Frequency |
|
IV |
18 mg/kg over 20 minutes |
Majority of pediatric patients: every 12 hours; adolescent patients with long half-life: every 24 hours |
Other Information:
- Preventive phenytoin treatment may reduce the frequency of seizures, as shown in a retrospective study.
- Preventive phenytoin may be used in pediatric patients with severe traumatic brain injuries to minimize the incidence of early post-traumatic seizures, but it does not lower the risk of long-term seizures or enhance neurological outcomes according to current recommendations.
Phenytoin (Dilantin) Pregnancy Risk Category: D
Phenytoin can cross the placenta and increase the risk of congenital malformations or other adverse outcomes in fetuses. Maternal use of phenytoin during pregnancy should be avoided to reduce the chance of developing cleft palate or poor cognitive outcomes.
Women who become pregnant while on phenytoin may need dose adjustments to maintain their clinical response. Monotherapy is preferred to reduce the risk of congenital malformations. Folic acid supplementation is recommended during pregnancy to lower the chance of major congenital malformations.
Hormonal contraceptives may become less effective when taken with phenytoin.
Breastfeeding during phenytoin therapy should be decided after considering the risks to infants and the benefits to mothers.
Phenytoin (Dilantin) Dose in Kidney Disease:
Monitor total and free serum concentration in patients with renal failure as it is difficult to read the serum concentration in kidney disease.
Phenytoin (Dilantin) Dose in Liver Disease:
Adjustment in the dose may be required as it is metabolized in the liver and its clearance from the body may also be decreased. Serum levels should be monitored and dosing adjustments should be made accordingly.
Side effects of Phenytoin (Dilantin):
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Cardiovascular: |
Central Nervous System: |
Dermatologic: |
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Endocrine & Metabolic: |
Hematologic & Oncologic: |
Local: |
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Gastrointestinal: |
Genitourinary: |
Hepatic: |
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Neuromuscular & Skeletal: |
Ophthalmic: |
Miscellaneous: |
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Contraindications to Phenytoin (Dilantin):
You cannot take phenytoin if you have had a bad reaction to it in the past or are allergic to it or any of its ingredients. It is also not safe to use if you are taking delavirdine.
Phenytoin injections are not recommended if you have certain heart conditions like sinoatrial block, Adams-Stokes syndrome, second or third-degree heart blocks, or sinus bradycardia.
The Canadian labeling for oral phenytoin includes additional contraindications like second- and third-degree heart blocks, longer QT interval, Adams-Stokes syndrome, or other heart rhythm disorders, sinoatrial block, and sinus bradycardia.
Warnings and precautions:
- Blood dyscrasias:
Hematologic reactions may occur, including granulocytopenia, thrombocytopenia, agranulocytosis, and leukopenia, which can be fatal.
Patients with a history of adverse hematologic reactions may be at higher risk. Symptoms such as fever, sore throats, mouth ulcers, infections, and petechial hemorrhage should be reported to the healthcare provider promptly.
- Bone effects:
Long-term use of phenytoin may lower vitamin D levels and cause hypophosphatemia, hypocalcemia, osteoporosis, osteomalacia, decreased bone mineral density, and bone fractures.
Patients may need to take calcium and vitamin D supplements and have their bone health monitored.
- Cardiovascular events:
Intravenous phenytoin should be administered slowly to avoid hypotension, severe cardiac arrhythmias, and cardiac arrest.
Adult patients should not receive more than 50 mg/minute intravenous, and pediatric patients should be administered intravenously at a rate of 1 to 3 mg/kg/minute, or 50 mg/minute, whichever is faster.
Patients with underlying heart disease may be at higher risk and should be monitored closely. Those with sinoatrial block and 2nd or 3rd degree heart block should not receive it.
- Dermatologic reactions
Phenytoin can cause severe skin reactions that may be fatal, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis. These reactions can occur around 28 days after starting the treatment.
People of Asian origin may have a higher risk of developing severe skin reactions to phenytoin due to genetic factors. If you notice a rash or any other sign of severe skin reaction, stop taking phenytoin immediately.
- Extravasation:
When giving phenytoin through an IV, make sure the catheter or needle is in the right place. Phenytoin can cause skin damage if it leaks out of the vein. If this happens, you may need surgery to fix it.
Calculate the dose of phenytoin before administering it. Avoid injecting phenytoin into small veins.
Sometimes, after an IV injection of phenytoin, the limb can become discolored, swollen, and painful. To prevent this, inject phenytoin slowly into a large vein using a large needle and flush it with saline.
- Hepatotoxicity:
Acute liver toxicity and dysfunction may occur. Symptoms may include jaundice, increased blood transaminase, leukocytosis, and hepatomegaly.
Acute hepatotoxicity can lead to rapid recovery or fatal results. Stop taking phenytoin immediately if acute hepatotoxicity occurs, and do not re-administer.
Patients with hepatic impairment should be cautious and their serum concentrations should be monitored at a free (unbound) level
- Hypersensitivity:
Hypersensitivity and angioedema have been reported. Stop taking phenytoin immediately if hypersensitivity reactions occur.
Patients who are hypersensitive to certain drugs (such as succinimides, barbiturates, and carbamazepine) should consider alternative treatment.
- Lymphadenopathy:
It may occur locally or globally, including benign lymphoma pseudolymphoma, and lymphoma. The cause-and-effect relationship is unclear.
- Multiorgan hypersensitivity reactions:
Phenytoin and some other antiepileptic drugs have been linked to potentially fatal multiorgan hypersensitivity reactions.
Monitor for possible manifestations in lymphatic, hepatic, and renal organ systems. It may be necessary to gradually discontinue and convert to alternative therapy.
- Suicidal thoughts:
According to a pooled analysis of antiepileptic drug trials, there was a higher incidence of suicide ideation and behavior in patients treated with the drugs compared to those who received a placebo, regardless of the indication for treatment.
The rate of such events was 0.43 percent among patients treated with the drug and 0.24 percent among those who received a placebo. This increased risk was observed as early as one week after starting the medication and persisted throughout the trial period (which typically lasted less than 24 weeks).
Therefore, it is important to be vigilant for any changes in behavior or thoughts that could indicate depression or suicidal ideation while taking antiepileptic drugs. If such symptoms occur, it is essential to inform your healthcare provider right away
- Diabetes:
Patients with diabetes mellitus should use phenytoin with caution as it can interfere with insulin release and increase serum sugar levels.
- Hypoalbuminemia:
Patients with low serum albumin levels should use phenytoin with caution as it can increase the pharmacologic response. Monitor with serum concentrations that are unbound.
- Hypothyroidism:
Patients with hypothyroidism should be treated with caution as chronic administration of phenytoin can alter the thyroid hormone serum levels.
- Porphyria:
Cases of porphyria can be exacerbated by the use of phenytoin.
- Renal impairment:
Patients with impaired renal function should use phenytoin with caution and their serum concentrations should be monitored at a free (unbound) level.
Phenytoin: Drug Interactions
Risk Category C drugs can be continued but need monitoring:
|
Drug |
Interaction with Phenytoin: Risk Category C |
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Acemetacin |
May increase serum levels of phenytoin-fosphenytoin. |
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Acetaminophen |
Phenytoin can reduce serum levels of acetaminophen, leading to lower efficacy and an increased risk of hepatotoxicity due to the production of a hazardous metabolite. |
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Albendazole |
Phenytoin can lower serum concentrations of albendazole's active metabolite(s). |
|
Alcohol (Ethyl) |
May intensify phenytoin's CNS depressive effects and either increase or decrease phenytoin serum levels, depending on the amount and duration of alcohol consumption. |
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Amiodarone |
Phenytoin can reduce amiodarone serum levels, while amiodarone can increase phenytoin serum levels. |
|
Amphetamines |
May lower serum levels of phenytoin. |
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Bazedoxifene |
Phenytoin can decrease serum levels of bazedoxifene, potentially reducing its effectiveness or increasing the risk of endometrial hyperplasia if used in combination with estrogen therapy. |
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Benperidol |
CYP3A4 inducers (strong), including phenytoin, can decrease serum concentrations of benperidol. |
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Benzhydrocodone |
CYP3A4 inducers (strong), including phenytoin, can decrease serum levels of benzhydrocodone, particularly hydrocodone concentrations. |
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Benzodiazepines |
Phenytoin can increase serum levels of benzodiazepines, with long-term treatment posing a greater risk than short-term use. Alprazolam is an exception. |
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Bleomycin |
May lower serum levels of phenytoin. |
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CYP3A4 inducers (strong) and P-glycoprotein/ABCB1 inducers can decrease serum levels of Brentuximab vedotin's active constituent, monomethyl auristatin E (MMAE). |
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Brivaracetam |
Serum levels may be reduced by phenytoin. Brivaracetam may raise the level of phenytoin in the blood. |
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Buprenorphine |
Serum concentration may decrease after taking CYP3A4 Inducers (Strong). |
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Busulfan |
Serum concentration may be lowered by phenytoin. |
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Calcifediol |
Serum concentration may drop in response to CYP3A4 Inducers (Strong). |
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Cannabidiol |
Serum concentration may drop in response to CYP3A4 Inducers (Strong). |
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Cannabis |
Serum concentrations may be reduced by strong CYP3A4 inducers. Serum concentrations of tetrahydrocannabinol and cannabidiol may fall. |
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Carbonic Anhydrase Inhibitors |
May intensify the hazardous or harmful effects of phenytoin-fosphenytoin. Brinzolamide and dorzolamide are exceptions. |
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Cefazolin |
Phenytoin's affinity for proteins might be reduced. |
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Celiprolol |
Serum concentration may drop in response to P-glycoprotein/ABCB1 Inducers. |
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Chloramphenicol (Systemic) |
Serum levels may be reduced by phenytoin (Systemic). |
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Chlorpheniramine |
Chloramphenicol serum levels may rise in response to phenytoin (Systemic). The serum levels of phenytoin may rise when using chloramphenicol (Systemic). May raise the serum level of phenytoin-fosphenytoin. |
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Chlorpropamide |
Serum levels may be reduced by CYP3A4 Inducers (Strong). May reduce Phenytoin's therapeutic impact. |
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Ciprofloxacin (Systemic) |
Serum levels of phenytoin may be reduced by the antibiotic systemic ciprofloxacin. |
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Cladribine |
P-glycoprotein/ABCB1 Inducers may lower the level of Cladribine in the serum. |
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Clindamycin (Systemic) |
CYP3A4 Inducers (Strong) may lower the level of Clindamycin in the blood (Systemic). |
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Clonazepam |
Serum levels may be reduced by phenytoin. Phenytoin concentrations may also change in response to clonazepam. |
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Codeine |
Serum concentrations of the active metabolite(s) of codeine may be lowered by CYP3A4 Inducers (Strong). |
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Corticosteroids (Systemic) |
Strong CYP3A4 Inducers may lower the level of corticosteroids in the blood (Systemic). Hydrocortisone (Systemic), prednisolone (Systemic), and prednisone are exceptions. |
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Cosyntropin |
May intensify phenytoin's hepatotoxic effects. |
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CYP2C19 Inducers (Moderate) |
May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). |
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CYP2C19 Inhibitors (Moderate) |
May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors). |
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CYP2C9 Inhibitors (Moderate) |
May decrease the metabolism of CYP2C9 Substrates |
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Dapsone |
May intensify the harmful/toxic effects of methemoglobinemia |
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Darunavir |
May lower the level of phenytoin in the serum |
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Dexketoprofen |
May intensify the harmful effects of phenytoin-fosphenytoin |
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Dexmethylphenidate |
Phenytoin serum levels can rise |
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Diazoxide |
May lower the level of phenytoin in the serum |
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Diethylstilbestrol |
CYP3A4 inducers (strong) may reduce serum levels |
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Disopyramide |
Disopyramide's serum levels may drop when phenytoin is taken |
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Doxercalciferol |
Active metabolites may be present in higher serum levels with CYP3A4 inducers (strong) |
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Doxofylline |
The serum concentration of doxofylline may be reduced by the drug fosphenytoin-phenytoin |
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Dronabinol |
The serum concentration of dronabinol may drop in response to CYP3A4 inducers (strong) |
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Edoxaban |
The serum concentration of edoxaban may be lowered by P-glycoprotein/ABCB1 inducers |
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Elagolix |
Elagolix's serum levels may be reduced by CYP3A4 inducers (strong) |
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Eslicarbazepine |
Eslicarbazepine's serum levels may drop when phenytoin is taken; eslicarbazepine may raise the level of phenytoin in the blood |
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Estriol |
Strong CYP3A4 inducers may lower serum estriol concentrations (systemic/topical) |
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Ethosuximide |
Ethosuximide's serum levels may drop if you take phenytoin; ethosuximide may raise the level of phenytoin in the blood |
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Etizolam |
CYP3A4 inducers (strong) may lower the level of etizolam in your blood |
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Evogliptin |
Evogliptin's serum levels may be reduced by CYP3A4 inducers (strong) |
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Fentanyl |
The blood concentration of fentanyl may drop when CYP3A4 inducers (strong) are taken |
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Flunarizine |
Flunarizine's serum levels may be lowered by phenytoin |
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Fluorouracil |
Phenytoin serum levels can rise |
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Fluoxetine |
Phenytoin serum levels can rise |
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Fluvoxamine |
Phenytoin serum levels can rise |
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Folic Acid |
Phenytoin serum levels can rise |
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Fosamprenavir |
May lower the level of phenytoin in the serum; serum levels of fosamprenavir may rise in response to phenytoin |
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Gestrinone |
The serum concentration of gestrinone may drop when taking fosphenytoin-phenytoin |
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Halothane |
Phenytoin serum levels can rise |
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Hydrocodone |
CYP3A4 inducers (strong) may lower the level of hydrocodone in the blood |
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Hydrocortisone |
CYP3A4 inducers (strong) may lower the level of hydrocortisone |
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Ifosfamide |
CYP3A4 inducers (strong) may lower active metabolite levels, while inducers may raise them. |
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Lacosamide |
Antiepileptic drugs (Sodium Channel Blockers) increase the risk of harmful effects. |
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Letermovir |
May lower the serum level of phenytoin-fosphenytoin. |
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Leucovorin Calcium-Levoleucovorin |
May lower the level of phenytoin in the serum. |
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Levetiracetam |
Fosphenytoin-phenytoin may reduce serum concentration. |
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Levodopa-Containing Products |
Fosphenytoin-phenytoin may reduce therapeutic effects. |
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Levomefolate |
May lower the level of phenytoin in the serum. |
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Levomethadone |
Phenytoin may reduce levomethadone serum levels. |
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Lithium |
Phenytoin may intensify lithium's harmful effects. |
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Local Anesthetics |
Local anaesthetics may have toxic effects amplified by associated agents. |
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Loop Diuretics |
Phenytoin may lessen diuretic action. |
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Lumacaftor |
May decrease/increase the serum concentration of CYP2C9/2C19 substrates. |
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Mebendazole |
Phenytoin may decrease the serum concentration. |
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Meperidine |
Phenytoin may reduce serum levels. |
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Methadone |
Phenytoin may reduce methadone serum levels. |
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Methotrexate |
May lower the serum level of phenytoin-fosphenytoin. |
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Methylfolate |
May make methotrexate more concentrated in the blood. |
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Methylphenidate |
Fosphenytoin-phenytoin may increase free medication levels. |
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Metronidazole |
May lower/raise serum levels of phenytoin. |
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Mexiletine |
May lower the level of phenytoin in the serum. |
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Mianserin |
Phenytoin may lower serum levels, while it may raise them in response to metronidazole. |
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Miconazole |
May lower the level of phenytoin in the serum. |
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Multivitamins/Minerals (with ADEK, Folate, Iron) |
May lower the serum level of phenytoin-fosphenytoin. |
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Nelfinavir |
May decrease the serum concentration of phenytoin. |
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Neuromuscular-Blocking Agents (Nondepolarizing) |
Fosphenytoin-phenytoin may diminish or enhance the neuromuscular-blocking effect and decrease serum concentration. |
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Nitric Oxide |
Combinations with methemoglobinemia-associated agents may enhance toxic effects. |
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Omeprazole |
Phenytoin may decrease the serum concentration of omeprazole, and vice versa. |
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Orlistat |
May decrease the serum concentration of anticonvulsants. |
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P-glycoprotein/ABCB1 Substrates |
P-glycoprotein/ABCB1 inducers may decrease serum concentration. Exceptions: Betrixaban; Edoxaban. |
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Phenobarbital |
Phenytoin may enhance CNS depressant effect; phenobarbital may decrease serum concentration of Phenytoin; Phenytoin may increase serum concentration of phenobarbital. |
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Phenytoin |
May increase metabolism of Primidone, decrease serum concentration of quinidine and Rufinamide, and increase Serum concentration of Sertraline. |
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Phenylbutazone |
May increase serum concentration of Fosphenytoin-Phenytoin. |
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Platinum Derivatives |
May decrease serum concentration of Fosphenytoin-Phenytoin. |
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Polatuzumab Vedotin |
CYP3A4 Inducers (Strong) may decrease serum concentration of Polatuzumab Vedotin. |
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Prednisolone |
CYP3A4 Inducers (Strong) may decrease serum concentration of prednisolone (Systemic). |
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Prednisone |
CYP3A4 Inducers (Strong) may decrease serum concentration of prednisone. |
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Prilocaine |
Methemoglobinemia Associated Agents may enhance adverse/toxic effect of Prilocaine. |
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Primidone |
Phenytoin may increase metabolism of Primidone. |
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Propacetamol |
Fosphenytoin-Phenytoin may decrease serum concentrations of active metabolites of Propacetamol. |
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Propafenone |
CYP3A4 Inducers (Strong) may decrease serum concentration of Propafenone. |
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Pyridoxine |
May increase metabolism of Phenytoin. |
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Quinidine |
Phenytoin may decrease serum concentration of quinidine. |
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Ramelteon |
CYP3A4 Inducers (Strong) may decrease serum concentration of Ramelteon. |
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Reboxetine |
CYP3A4 Inducers (Strong) may decrease serum concentration of Reboxetine. |
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Rifapentine |
May decrease serum concentration of CYP2C9 Substrates (High risk with Inducers). |
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Rufinamide |
Phenytoin may decrease serum concentration of Rufinamide. |
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Ruxolitinib |
CYP3A4 Inducers (Strong) may decrease serum concentration of Ruxolitinib. |
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Saxagliptin |
CYP3A4 Inducers (Strong) may decrease serum concentration of saxagliptin. |
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Sertraline |
May increase serum concentration of Phenytoin. |
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Sodium Nitrite |
Methemoglobinemia Associated Agents may enhance adverse/toxic effect of Sodium Nitrite. |
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Sufentanil |
CYP3A4 Inducers (Strong) may decrease serum concentration of sufentanil. |
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Sulfadiazine |
May increase serum concentration of Fosphenytoin-Phenytoin. |
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Sulfinpyrazone |
May increase serum concentration of Fosphenytoin-Phenytoin. |
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Sulthiame |
May increase serum concentration of Fosphenytoin-Phenytoin. |
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Tacrolimus (Systemic) |
Phenytoin may decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Phenytoin. |
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Tetrahydrocannabinol |
CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. |
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Tetrahydrocannabinol and Cannabidiol |
CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. |
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Thiothixene |
Fosphenytoin-Phenytoin may decrease the serum concentration of Thiothixene. |
|
Thyroid Products |
Phenytoin may decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites. |
|
Ticlopidine |
May increase the serum concentration of Phenytoin. |
|
Tolbutamide |
May decrease the protein binding of Fosphenytoin-Phenytoin. Specifically concentrations of free phenytoin may be increased. |
|
Topiramate |
May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Topiramate. |
|
Tramadol |
CYP3A4 Inducers (Strong) may decrease the serum concentration of tramadol. |
|
Trazodone |
Phenytoin may decrease the serum concentration of trazodone. Trazodone may increase the serum concentration of Phenytoin. |
|
Tropisetron |
CYP3A4 Inducers (Strong) may decrease the serum concentration of Tropisetron. |
|
Udenafil |
CYP3A4 Inducers (Strong) may decrease the serum concentration of Udenafil. |
|
Valproate Products |
May decrease the protein binding of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Valproate Products. |
|
Vigabatrin |
May decrease the serum concentration of Phenytoin. |
|
Vincristine |
Phenytoin may decrease the serum concentration of vincristine. Vincristine may decrease the serum concentration of Phenytoin. |
|
Vindesine |
May decrease the serum concentration of Phenytoin. |
|
Zolpidem |
CYP3A4 Inducers (Strong) may decrease the serum concentration of Zolpidem. |
|
Zonisamide |
Phenytoin may decrease the serum concentration of Zonisamide. |
|
Zuclopenthixol |
CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. |
Risk Category D drugs need dose modification and strict monitoring:
|
Drug name |
Effect of interaction |
Management |
|
Abiraterone acetate |
Decreased serum concentration of abiraterone acetate |
Avoid whenever possible. If unavoidable, increase dosing frequency from once to twice daily during concomitant use. |
|
Acalabrutinib |
Decreased serum concentration of acalabrutinib |
Avoid co-administration of strong cyp3a inducers. If unavoidable, increase acalabrutinib dose to 200mg twice daily. |
|
Afatinib |
P-glycoprotein/abcb1 inducers decreased serum concentration of afatinib |
Increase afatinib dose by 10mg as tolerated if requiring chronic use of p-gp inducers; reduce to original dose 2-3 days after stopping inducers. Avoid combination if possible (per canadian labeling). |
|
Antifungal agents (azole derivatives, systemic) |
May increase or decrease serum concentration of phenytoin |
Concomitant therapy with itraconazole, voriconazole, or ketoconazole and phenytoin should probably be avoided. Consider selecting alternative antifungal therapy. Exceptions: isavuconazonium sulfate. |
|
Aripiprazole |
Decreased serum concentration of aripiprazole |
Double oral aripiprazole dose and closely monitor. Reduce dose if inducer is discontinued. Avoid use of strong cyp3a4 inducers for more than 14 days with extended-release injectable aripiprazole. |
|
Aripiprazole lauroxil |
Decreased serum concentration of active metabolite(s) of aripiprazole lauroxil |
Increase dose of aripiprazole lauroxil from 441 mg to 662 mg if used with strong cyp3a4 inducer for more than 14 days. No dose adjustment is necessary for higher doses of aripiprazole lauroxil. |
|
Bictegravir |
Decreased serum concentration of bictegravir |
Consider using alternative anticonvulsant with concurrent use of bictegravir, emtricitabine, and tenofovir alafenamide. Monitor closely if combination must be used. |
|
Brexpiprazole |
Decreased serum concentration of brexpiprazole |
Gradually double brexpiprazole dose over 1 to 2 weeks if used with strong cyp3a4 inducer. |
|
Buspirone |
Decreased serum concentration of buspirone |
Consider alternatives. Monitor for reduced buspirone effects and increase doses as needed if coadministration is deemed necessary. |
|
Cabozantinib |
Strong cyp3a4 inducers may decrease serum concentration |
Adjust dose if coadministered |
|
Calcium channel blockers |
May increase serum concentration of phenytoin. Phenytoin may decrease the serum concentration of calcium channel blockers |
Monitor for toxicity or decreased efficacy |
|
Canagliflozin |
Phenytoin may decrease serum concentration |
Consider increasing canagliflozin dose or use alternatives |
|
Capecitabine |
May increase serum concentration of phenytoin |
Monitor closely for toxicity |
|
Carbamazepine |
May decrease serum concentration of phenytoin. Phenytoin may decrease serum concentration of carbamazepine |
Monitor for decreased efficacy |
|
Caspofungin |
Inducers of drug clearance may decrease serum concentration |
Consider increased caspofungin dose when coadministered with inducers |
|
Cimetidine |
May increase serum concentration of fosphenytoin-phenytoin |
Consider using alternative h2-antagonist. Monitor for toxic effects of hydantoin anticonvulsants if cimetidine is initiated/dose increased |
|
Clarithromycin |
Strong cyp3a4 inducers may increase serum concentration of active metabolite(s) of clarithromycin |
Consider alternative antimicrobial therapy for patients receiving a cyp3a inducer |
|
Colesevelam |
May decrease serum concentration of phenytoin |
Administer phenytoin at least 4 hours prior to colesevelam |
|
Cyclosporine |
Phenytoin may increase metabolism of cyclosporine |
Monitor cyclosporine levels and adjust dose accordingly |
|
Cyp2c19 inducers |
May increase metabolism of cyp2c19 substrates |
Consider alternative for one of the interacting drugs |
|
Cyp3a4 substrates |
Strong cyp3a4 inducers may increase metabolism of cyp3a4 substrates |
Consider alternative for one of the interacting drugs |
|
Dabrafenib |
May decrease serum concentration of cyp2c9 and cyp2c19 substrates |
Seek alternatives to substrates if possible |
|
Dasatinib |
Strong cyp3a4 inducers may decrease serum concentration |
Avoid if possible or consider increasing dasatinib dose and monitor closely |
|
Deferasirox |
Phenytoin may decrease serum concentration |
Avoid if possible; if used, consider 50% increase in initial deferasirox dose and monitor closely |
|
Dexamethasone |
Phenytoin may decrease serum concentration. Dexamethasone may decrease serum concentration of phenytoin |
Monitor closely |
|
Disulfiram |
May increase the serum concentration of phenytoin |
Avoid concomitant use if possible. Phenytoin dose adjustment may be necessary. Monitor phenytoin response and concentrations closely |
|
Doxorubicin (conventional) |
Cyp3a4 inducers (strong) may decrease the serum concentration |
Seek alternatives to strong cyp3a4 inducers. Consider avoiding this combination. |
|
Doxorubicin (conventional) |
P-glycoprotein/abcb1 inducers may decrease the serum concentration |
Seek alternatives to p-glycoprotein inducers when possible. Consider avoiding this combination. |
|
Doxycycline |
Phenytoin may decrease the serum concentration |
Monitor doxycycline response and concentrations closely |
|
Efavirenz |
Phenytoin may decrease the serum concentration of efavirenz. Efavirenz may increase the serum concentration of phenytoin |
Monitor both drug concentrations closely |
|
Eravacycline |
Cyp3a4 inducers (strong) may decrease the serum concentration |
Increase eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong cyp3a4 inducers |
|
Estrogen derivatives (contraceptive) |
Phenytoin may diminish the therapeutic effect |
Use an alternative, nonhormonal means of contraception |
|
Etoposide |
Cyp3a4 inducers (strong) may decrease the serum concentration |
Seek alternatives to strong cyp3a4-inducing medications when possible. Monitor patients closely for diminished etoposide response and need for etoposide dose increases. |
|
Etoposide phosphate |
Cyp3a4 inducers (strong) may decrease the serum concentration |
Seek alternatives to strong cyp3a4-inducing medications when possible. Monitor patients closely for diminished etoposide phosphate response. |
|
Everolimus |
Cyp3a4 inducers (strong) may decrease the serum concentration |
Avoid concurrent use if possible. Double the daily dose using increments of 5 mg or less if coadministration cannot be avoided. Monitor everolimus serum concentrations closely |
|
Exemestane |
Cyp3a4 inducers (strong) may decrease the serum concentration |
Consider using an increased dose (50 mg/day) in patients receiving concurrent strong cyp3a4 inducers. |
|
Ezogabine |
Fosphenytoin-phenytoin may decrease the serum concentration |
Consider increasing the ezogabine dose when adding phenytoin. Monitor patients closely for adequate ezogabine therapy. |
|
Felbamate |
May increase the serum concentration of phenytoin. Phenytoin may decrease the serum concentration of felbamate |
Decrease phenytoin dose when adding felbamate. Additional reductions may be needed if felbamate dose is increased or as otherwise guided by monitoring. |
|
Floxuridine |
May increase the serum concentration of phenytoin |
Monitor floxuridine response and concentrations closely |
|
Fluconazole |
May increase the serum concentration of phenytoin |
Monitor fluconazole and phenytoin concentrations closely |
|
Fluorouracil (systemic) |
May increase the serum concentration of phenytoin |
Monitor fluorouracil response and concentrations closely |
|
Gefitinib |
Cyp3a4 inducers (strong) may decrease the serum concentration |
Increase gefitinib dose to 500 mg daily in patients receiving strong cyp3a4 inducers. Care |
|
Guanfacine |
Strong CYP3A4 Inducers may decrease serum concentration |
Increase dose by up to double when initiating, or gradually increase over 1 to 2 weeks if initiating inducer therapy in patient already taking guanfacine |
|
HMG-coa Reductase Inhibitors (Statins) |
Phenytoin may decrease serum concentration (exceptions: Pitavastatin; Rosuvastatin) |
|
|
Imatinib |
Strong CYP3A4 Inducers may decrease serum concentration |
Avoid concurrent use if possible, if not, increase imatinib dose by at least 50% and monitor closely |
|
Isoniazid |
May increase serum concentration of Phenytoin |
Consider alternatives, or monitor for increased phenytoin concentration/effects with isoniazid initiation/dose increase, or decreased concentrations/effects with isoniazid discontinuation/dose decrease |
|
Ixabepilone |
Strong CYP3A4 Inducers may decrease serum concentration |
Avoid whenever possible, or gradually increase ixabepilone dose from 40 mg/m to 60 mg/m as tolerated if must be used |
|
Lamotrigine |
Phenytoin may decrease serum concentration |
|
|
Larotrectinib |
Strong CYP3A4 Inducers may decrease serum concentration |
Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer half-life. |
|
Lefamulin |
Strong CYP3A4 Inducers may decrease serum concentration |
Avoid concomitant use unless benefits outweigh risks |
|
Lefamulin (Intravenous) |
Strong CYP3A4 Inducers may decrease serum concentration |
Avoid concomitant use unless benefits outweigh risks |
|
Linagliptin |
P-glycoprotein/ABCB1 Inducers may decrease serum concentration |
Strongly consider alternative to any strong P-glycoprotein inducer, or monitor patients closely for reduced effectiveness |
|
Lopinavir |
Phenytoin may decrease the serum concentration of lopinavir. Lopinavir may decrease the serum concentration of phenytoin. |
Avoid once-daily administration of lopinavir/ritonavir if used together with phenytoin. |
|
Manidipine |
Cyp3a4 inducers (strong) may decrease the serum concentration of manidipine. |
Consider avoiding concomitant use of manidipine and strong cyp3a4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. |
|
Maraviroc |
Cyp3a4 inducers (strong) may decrease the serum concentration of maraviroc. |
Increase maraviroc adult dose to 600 mg twice daily when used with strong cyp3a4 inducers. Do not use maraviroc with strong cyp3a4 inducers in patients with crcl less than 30 ml/min. |
|
Mefloquine |
May diminish the therapeutic effect of anticonvulsants. Mefloquine may decrease the serum concentration of anticonvulsants. |
Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. |
|
Methylprednisolone |
Cyp3a4 inducers (strong) may decrease the serum concentration of methylprednisolone. |
Consider methylprednisolone dose increases in patients receiving strong cyp3a4 inducers and monitor closely for reduced steroid efficacy. |
|
Metyrapone |
Phenytoin may decrease the serum concentration of metyrapone. |
Increase metyrapone dosage substantially in the oral metyrapone test. |
|
Mirodenafil |
Cyp3a4 inducers (strong) may decrease the serum concentration of mirodenafil. |
Consider avoiding the concomitant use of mirodenafil and strong cyp3a4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. |
|
Osimertinib |
Cyp3a4 inducers (strong) may decrease the serum concentration of osimertinib. |
|
|
Oxcarbazepine |
Fosphenytoin-phenytoin may decrease serum concentrations of the active metabolite(s) of oxcarbazepine. |
Consider increasing the initial adult oxcarbazepine extended-release tablet (oxtellar xr) dose to 900 mg/day. |
|
Paliperidone |
Inducers of cyp3a4 (strong) and p-glycoprotein may decrease the serum concentration of paliperidone. |
Avoid using the 3-month extended-release injectable suspension (invega trinza) with inducers of both cyp3a4 and p-glycoprotein during the 3-month dosing interval if possible. Consider using extended-release tablets. |
|
Perampanel |
Phenytoin may decrease the serum concentration of perampanel. |
Increase the perampanel starting dose to 4 mg/day when perampanel is used with phenytoin/fosphenytoin. |
|
Pitolisant |
Cyp3a4 inducers (strong) may decrease the serum concentration of pitolisant. |
For patients taking a strong cyp3a4 inducer, increase the pitolisant dose over 7 days to double the original dose. |
|
Progestins |
Phenytoin may diminish the therapeutic effect of progestins (contraceptive). |
Use of an alternative, nonhormonal contraceptive is recommended. |
|
Quetiapine |
Cyp3a4 inducers (strong) may decrease the serum concentration of quetiapine. |
Increase the quetiapine dose (as much as 5 times the regular dose) to maintain therapeutic benefit. |
|
Quinine |
Phenytoin may decrease the serum concentration of quinine. |
Monitor patients for response, especially with any changes to phenytoin therapy. |
|
Radotinib |
Cyp3a4 inducers (strong) may decrease the serum concentration of radotinib. |
Consider alternatives to this combination when possible. |
|
Rifampin |
May decrease the serum concentration of phenytoin. |
Monitor closely for decreased serum phenytoin concentrations following rifampin initiation/dose increase, or increased concentrations and toxic effects following rifampin discontinuation/dose decrease. |
|
Risperidone |
Cyp3a4 inducers (strong) may decrease the serum concentration of risperidone. |
Consider increasing the dose of oral risperidone (to no more than double the original dose) if a strong cyp3a4 inducer is initiated. |
|
Ritonavir |
Phenytoin may decrease the serum concentration of ritonavir. |
Monitor patients closely for changes in serum concentrations and adjust the doses accordingly. |
|
Rolapitant |
Cyp3a4 inducers (strong) may decrease the serum concentration of rolapitant. |
Avoid rolapitant use in patients requiring chronic administration of strong cyp3a4 inducers. |
|
Sirolimus |
Cyp3a4 inducers (strong) may decrease the serum concentration of sirolimus. |
Avoid concomitant use of strong cyp3a4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. |
|
Sulfamethoxazole |
May increase the serum concentration of phenytoin. |
Monitor closely for changes in serum phenytoin concentrations and adjust the doses accordingly. |
|
Sunitinib |
Cyp3a4 inducers (strong) may decrease the serum concentration of sunitinib. |
Avoid when possible. If such a combination cannot be avoided, sunitinib dose increases are recommended, and vary by indication. |
|
Tadalafil |
Cyp3a4 inducers (strong) may decrease the serum concentration of tadalafil. |
Monitor for decreased effectiveness of tadalafil - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong cyp3a4 inducer. |
|
Tamoxifen |
Cyp3a4 inducers (strong) may decrease serum concentrations of the active metabolite(s) of tamoxifen. Cyp3a4 inducers (strong) may decrease the serum concentration of tamoxifen. |
Consider alternatives to concomitant use of strong cyp3a4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen. |
|
Tegafur |
May increase the serum concentration of fosphenytoin-phenytoin. |
Phenytoin dose reductions may be necessary when used together with fluorouracil, which is the active metabolite of tegafur. |
|
Temsirolimus |
Phenytoin may decrease the serum concentration of temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). |
Temsirolimus prescribing information recommends against coadministration with strong cyp3a4 inducers such as phenytoin; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. |
|
Teniposide |
Phenytoin may decrease the serum concentration of teniposide. |
Consider alternatives to combined treatment with phenytoin and teniposide due to the potential for decreased teniposide concentrations. If the combination cannot be avoided, monitor teniposide response closely. |
|
Theophylline derivatives |
Phenytoin may decrease the serum concentration of theophylline derivatives. Theophylline derivatives may decrease the serum concentration of phenytoin. |
Seek alternatives when possible. If used together, monitor for decreased concentrations/effects of phenytoin or theophylline if the other agent is initiated/dose increased, or increased concentrations/effects if the other is discontinued/dose decreased. Exceptions: dyphylline. |
|
Thiotepa |
Cyp3a4 inducers (strong) may increase serum concentrations of the active metabolite(s) of thiotepa. Cyp3a4 inducers (strong) may decrease the serum concentration of thiotepa. |
Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong cyp3a4 inducers. If concomitant use is unavoidable, monitor for adverse effects. |
|
Tiagabine |
Cyp3a4 inducers (strong) may decrease the serum concentration of tiagabine. |
Approximately 2-fold higher tiagabine doses and a more rapid dose titration will likely be required in patients concomitantly taking a strong cyp3a4 inducer. |
|
Tipranavir |
Phenytoin may decrease the serum concentration of tipranavir. Tipranavir may decrease the serum concentration of phenytoin. |
- |
|
Topotecan |
Fosphenytoin-phenytoin may decrease the serum concentration of topotecan. |
Monitor topotecan response closely, and consider alternatives to phenytoin when possible. No specific guidelines for topotecan dose adjustment are available. |
|
Trimethoprim |
May increase the serum concentration of phenytoin. Phenytoin may decrease the serum concentration of trimethoprim. |
Consider alternatives to this combination when possible, to avoid potential decreased trimethoprim efficacy and increased phenytoin concentrations/effects. Monitor patients receiving this combination closely for both of these possible effects. |
|
Vemurafenib |
Cyp3a4 inducers (strong) may decrease the serum concentration of vemurafenib. |
Avoid concurrent use of vemurafenib with a strong cyp3a4 inducer and replace with another agent when possible. If a strong cyp3a4 inducer is indicated and unavoidable, the dose of vemurafenib may be increased by 240 mg (1 tablet) as tolerated. |
|
Vilazodone |
Cyp3a4 inducers (strong) may decrease the serum concentration of vilazodone. |
Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong cyp3a4 inducers for > 14 days. Reduce to the original vilazodone dose over 1-2 weeks after inducer discontinuation. |
|
Vitamin k antagonists |
Phenytoin may enhance the anticoagulant effect of vitamin k antagonists. Vitamin k antagonists may increase the serum concentration of phenytoin. |
Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (inr and signs/symptoms of bleeding) when using this combination. |
|
Vortioxetine |
Cyp3a4 inducers (strong) may decrease the serum concentration of vortioxetine. |
Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. |
|
Zaleplon |
Cyp3a4 inducers (strong) may decrease the serum concentration of zaleplon. |
Consider the use of an alternative hypnotic that is not metabolized by cyp3a4 in patients receiving strong cyp3a4 inducers. If zaleplon is combined with a strong cyp3a4 inducer, monitor for decreased effectiveness of zaleplon. |
Risk Category X: Avoid combining Phenytoin and the following drugs:
|
Drug |
Drug Interaction Category X: Effect of CYP3A4 Inducers (Strong) |
|
Abemaciclib |
Decrease serum concentration |
|
Alpelisib |
Decrease serum concentration |
|
Antihepaciviral Combination Products |
Decrease serum concentration |
|
Apixaban |
Decrease serum concentration |
|
Apremilast |
Decrease serum concentration |
|
Aprepitant |
Decrease serum concentration |
|
Artemether |
Decrease serum concentration of active metabolite(s) |
|
Asunaprevir |
Decrease serum concentration |
|
Axitinib |
Decrease serum concentration |
|
Bedaquiline |
Decrease serum concentration |
|
Benznidazole |
Enhance adverse/toxic effect of products containing propylene glycol |
|
Betrixaban |
Decrease serum concentration |
|
Bortezomib |
Decrease serum concentration |
|
Bosutinib |
Decrease serum concentration |
|
Brigatinib |
Decrease serum concentration |
|
Cariprazine |
Decrease serum concentration |
|
Ceritinib |
Decrease serum concentration |
|
Clozapine |
Decrease serum concentration |
|
Cobicistat |
Decrease serum concentration |
|
Cobimetinib |
Decrease serum concentration |
|
Copanlisib |
Decrease serum concentration |
|
Crizotinib |
Decrease serum concentration |
|
Dabigatran Etexilate |
Decrease serum concentration; avoid concurrent use with P-glycoprotein inducers |
|
Daclatasvir |
Decrease serum concentration |
|
Darolutamide |
Decrease serum concentration |
|
Dasabuvir |
Decrease serum concentration |
|
Deflazacort |
Decrease serum concentration of active metabolite(s) |
|
Delamanid |
Decrease serum concentration |
|
Delavirdine |
Phenytoin may decrease serum concentration of Delavirdine; Delavirdine may increase serum concentration of Phenytoin |
|
Dienogest |
Decrease serum concentration; avoid use for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer |
|
Dolutegravir |
Decrease serum concentration |
|
Doravirine |
Decrease serum concentration |
|
Dronedarone |
Decrease serum concentration |
|
Duvelisib |
Decrease serum concentration |
|
Medication |
Interaction with CYP3A4 Inducers (Strong) |
|
Elbasvir |
Decreased serum concentration |
|
Eliglustat |
Decreased serum concentration |
|
Elvitegravir |
Decreased serum concentration |
|
Encorafenib |
Decreased serum concentration |
|
Entrectinib |
Decreased serum concentration |
|
Enzalutamide |
Decreased serum concentration |
|
Erdafitinib |
Decreased serum concentration |
|
Erlotinib |
Increased serum concentration, decreased serum concentration, management: avoid use or adjust dose |
|
Etravirine |
Decreased serum concentration |
|
Fedratinib |
Decreased serum concentration |
|
Flibanserin |
Decreased serum concentration |
|
Fosaprepitant |
Decreased serum concentration |
|
Fosnetupitant |
Decreased serum concentration |
|
Fostamatinib |
Decreased serum concentration |
|
Fotemustine |
Decreased serum concentration |
|
Gemigliptin |
Decreased serum concentration |
|
Gilteritinib |
Decreased serum concentration |
|
Glasdegib |
Decreased serum concentration |
|
Glecaprevir and Pibrentasvir |
Decreased serum concentration |
|
Grazoprevir |
Decreased serum concentration |
|
Ibrutinib |
Decreased serum concentration |
|
Idelalisib |
Decreased serum concentration |
|
Irinotecan Products |
Decreased serum concentration |
|
Isavuconazonium Sulfate |
Decreased serum concentration |
|
Itraconazole |
Decreased serum concentration |
|
Ivabradine |
Decreased serum concentration |
|
Ivacaftor |
Decreased serum concentration |
|
Ivosidenib |
Decreased serum concentration |
|
Ixazomib |
Decreased serum concentration |
|
Lapatinib |
Decreased serum concentration, management: consider titrating dose gradually |
|
Ledipasvir |
Decreased serum concentration |
|
Lorlatinib |
Decreased serum concentration |
|
Drug |
Interaction |
|
Lumefantrine |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Lurasidone |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Macimorelin |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Macitentan |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Midostaurin |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Mifepristone |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Naldemedine |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Naloxegol |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Neratinib |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Netupitant |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Nifedipine |
May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of nifedipine |
|
Nilotinib |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Nimodipine |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Nintedanib |
Combined Inducers of CYP3A4 and P-glycoprotein may decrease its serum concentration |
|
Nisoldipine |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Olaparib |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Palbociclib |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Panobinostat |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Pazopanib |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Pexidartinib |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Pimavanserin |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Piperaquine |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Ponatinib |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Praziquantel |
CYP3A4 Inducers (Strong) may decrease its serum concentration. Use of praziquantel with strong CYP3A4 inducers is contraindicated. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion |
|
Pretomanid |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Ranolazine |
CYP3A4 Inducers (Strong) may decrease its serum concentration |
|
Regorafenib |
CYP3A4 Inducers (Strong) may decrease |
|
Regorafenib |
Decreased serum concentration |
|
Ribociclib |
Decreased serum concentration |
|
Rilpivirine |
Decreased serum concentration; may require dose adjustment |
|
Rivaroxaban |
Decreased serum concentration; increased risk of thrombotic events |
|
Roflumilast |
Decreased serum concentration; U.S. prescribing information recommends against combination with strong CYP3A4 inducers |
|
Romidepsin |
Decreased serum concentration |
|
Simeprevir |
Decreased serum concentration |
|
Sofosbuvir |
Decreased serum concentration |
|
Sonidegib |
Decreased serum concentration |
|
Sorafenib |
Decreased serum concentration |
|
Stiripentol |
Decreased serum concentration of phenytoin |
|
Tasimelteon |
Decreased serum concentration |
|
Tenofovir Alafenamide |
Decreased serum concentration; consider dose adjustment |
|
Ticagrelor |
Decreased serum concentration of active metabolite(s); consider alternative therapy or use with caution |
|
Tofacitinib |
Decreased serum concentration |
|
Tolvaptan |
Decreased serum concentration; increased doses may be needed if concurrent use is necessary |
|
Toremifene |
Decreased serum concentration |
|
Trabectedin |
Decreased serum concentration |
|
Ulipristal |
Decreased serum concentration |
|
Upadacitinib |
Decreased serum concentration |
|
Valbenazine |
Decreased serum concentration |
|
Vandetanib |
Decreased serum concentration |
|
Velpatasvir |
Decreased serum concentration; P-glycoprotein/ABCB1 inducers may decrease serum concentration |
|
Venetoclax |
Decreased serum concentration |
|
Vincristine (Liposomal) |
Decreased serum concentration; P-glycoprotein/ABCB1 inducers may decrease serum concentration |
|
Vinflunine |
Decreased serum concentration |
|
Vorapaxar |
Decreased serum concentration |
|
Voxilaprevir |
Decreased serum concentration |
|
Drug |
Management with CYP3A4 Inducers (Strong) |
|
Roflumilast |
U.S. prescribing information recommends against combination with strong CYP3A4 inducers |
|
Sofosbuvir |
Avoid concurrent use with P-glycoprotein/ABCB1 inducers |
|
Ticagrelor |
Consider alternative therapy or use with caution |
|
Tolvaptan |
Increased doses may be needed if concurrent use is necessary |
|
Tenofovir Alafenamide |
Consider dose adjustment |
Monitoring parameters:
- Complete Blood Count (CBC)
- Liver function tests
- Assessment of vitamin D status for patients on chronic use
- Monitoring for suicidality, such as depression or behavioral changes, including suicidal thoughts
- Measuring plasma phenytoin concentrations, with free phenytoin concentrations is recommended for patients with renal impairment and/or hypoalbuminemia. Adjusted total concentration may be determined based on equations in adult patients if free phenytoin concentrations are unavailable. Trough concentrations are generally recommended for routine monitoring.
- For IV use, continuous cardiac monitoring (rate, rhythm, blood pressure) and observation during administration are recommended. Blood pressure and pulse should be monitored every 15 minutes for 1 hour after administration, and infusion site reactions should be monitored as well. It is important to consult individual institutional policies and procedures for further guidance.
How to administer Phenytoin (Dilantin)?
- Oral:
Immediate-release tablets: Divide the daily dose into two to three doses, and take with or without food. If you cannot divide the dose equally, take the higher dose at bedtime.
- Chewable tablets: Chew well before swallowing, or swallow whole.
Suspension: Shake well before using. Use a calibrated oral dosing device to measure and administer the dosage. Patients receiving continuous nasogastric feeds should have their phenytoin suspension administered separately, with a two-hour gap before and after each dose.
Extended-release capsules: Take the capsule whole, with or without food, every 12 or 24 hours as prescribed by your healthcare provider.
- IM:
Do not administer phenytoin via intramuscular injection. Use fosphenytoin instead.
- IV:
Fosphenytoin can be used instead of phenytoin in hemodynamically unstable or status epilepticus patients.
Phenytoin can be administered directly via IV injection, but it is preferred to administer it via an infusion pump undiluted or diluted with normal saline as an IV piggyback (IVPB).
Use a large-gauge catheter to administer phenytoin directly into large central or peripheral veins.
If diluted with normal saline, the infusion must be completed within four hours.
The maximum IV dose is 50 mg per minute, but patients with high sensitivities should be given phenytoin at a slower rate (20 mg per minute).
If using IV for oral replacement, administer the dose at a slower rate.
An in-line filter of 0.22- to 0.55-micron size is recommended for IVPB solutions to prevent precipitation.
To avoid irritation, always inject normal saline via the same IV catheter or needle used for IV administration.
- SubQ:
Do not administer phenytoin via subcutaneous injection to prevent tissue damage.
Use Vesicant to ensure that the catheter or needle is correctly placed before and during IV infusions, and avoid extravasation.
- Extravasation management:
To manage extravasation, it is important to stop the infusion immediately and gently aspirate the extravasated solution without flushing the line. Next, remove the needle or cannula and elevate the affected extremity while applying dry heat.
Monitor the area closely for signs of tissue sloughing or compartment syndrome. There is inconsistent information regarding the use of antidotes, with some sources recommending against their use and others suggesting hyaluronidase for refractory cases.
If deemed appropriate, hyaluronidase can be administered in four separate injections of 0.2 mL of a 15 unit/mL solution using a 25-gauge needle to the area of extravasation.
Mechanism of action of Phenytoin (Dilantin):
Stabilizes neuronal cells and decreases seizure activity through increasing efflux or decreasing the number of sodium ions across cell membranes in the motor cortex during the generation of nerve impulses. This prolongs the effective refractory time and suppresses ventricular rate-maker automaticity. It also reduces heart action potential.
|
Onset of Action |
IV: ~0.5 to 1 hour |
|
Absorption |
Oral: Slow, variable; dependent on product formulation; decreased in neonates |
|
Protein Binding |
Neonates: ≥80 percent (≤20 percent free); Infants: ≥85 percent (≤15 percent free); Adults: 87.8 percent to 91.9 percent |
|
Metabolism |
Major metabolite (via oxidation) HPPA undergoes enterohepatic recycling and elimination in urine as glucuronides |
|
Bioavailability |
IM: 83 percent to ~100 percent (single dose); IV: 100 percent; Oral (dependent on the product and/or salt): 70 percent to 95 percent |
|
Half-life elimination |
Range: 7 to 42 hours; newborns (PNA <weak ): Apparent half-life greatly prolonged (clearance decreased) and then rapidly accelerates to infant levels by 5 weeks of life. |
|
Time to peak, serum (formulation dependent) |
Oral: Extended-release capsule: 4 to 12 hours; Immediate-release preparation: 1.5 to 3 hours |
|
Excretion |
Urine (<5 percent as unchanged drug); as glucuronides |
|
Clearance |
Highly variable, dependent upon intrinsic hepatic function and dose administered; increased clearance and decreased serum concentrations with febrile illness |
International Brand Names of Phenytoin:
- Dilantin
- Tremytoine
- Aleviatin
- Antisacer
- Clerin
- Clerin LR
- Cumatil
- Decatona
- DiHydan
- Difetoin
- Dilantin
- Dintoina
- Diphedan
- Ditoin
- Dilantin Infatabs
- Phenytek
- Phenytoin Infatabs
- APO-Phenytoin Sodium
- Dilantin
- Dilantin Infatabs
- Dilantin-125
- Dilantin-30
- NOVO-Phenytoin
- TARO-Phenytoin
- Epamin
- Epanutin
- Epilan-D
- Epilax
- Epinat
- Epinotid
- Epinotin
- Epitoin
- Eptoin
- Felantin
- Fenatoin NM
- Fenevit
- Fenidantoin S
- Fenitin
- Fenitron
- Fenytoin
- Fomiken
- Hidanil
- Hidantin
- Hidantoína
- Hydantin
- Hydantoin
- Hydantol
- Ikaphen
- Ipanten
- Kutoin
- Lantidin
- Lehydan
- Pepsytoin-100
- Phenhydan
- Phenilep
- Phenlin
- Phentolep
- Pyoredol
- Sinergina
- Sizatoin
- Utoin
- Xentoin
Phenytoin Brand Names in Pakistan:
|
Phenytoin Injection 250 mg in Pakistan |
|
|
Epigran |
Atco Laboratories Limited |
|
Phenytoin Injection 30 mg/ml in Pakistan |
|
|
Fentin |
Geofman Pharmaceuticals |
|
Phenytoin Suspension 30 mg/5ml in Pakistan |
|
|
Dilantin |
Pfizer Laboratories Ltd. |
|
Epilantin |
Pharmedic (Pvt) Ltd. |
|
Epitoin |
Adamjee Pharmaceuticals (Pvt) Ltd. |
|
Phenytoin Tablets 100 mg in Pakistan |
|
|
Di-Hyden |
French Pharmaceutical Group |
|
Epilantin |
Pharmedic (Pvt) Ltd. |
|
Epitoin |
Adamjee Pharmaceuticals (Pvt) Ltd. |
|
Phenytoin Sodium Capsules 100 mg in Pakistan |
|
|
Dilantin |
Pfizer Laboratories Ltd. |
|
Phenton-S |
Swiss Pharmaceuticals (Pvt) Ltd. |
|
Shalentin |
Shifa Laboratories.(Pvt) Ltd. |
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