Sesquient (fosphenytoin sodium) Seizure Medication Interactions

What is Sesquient, and how does it work?

Generic drug: fosphenytoin sodium

Brand name: Sesquient

Sesquient (fosphenytoin sodium) is an anticonvulsant used to treat generalized tonic-clonic status epilepticus in adult patients and to prevent and treat seizures occurring during neurosurgery in adult patients and for short-term substitution for oral phenytoin in patients 2 years of age and older.

What are the side effects of Sesquient?

Side effects of Sesquient include:

itching,
Involuntary eye movements (nystagmus),
dizziness,
sleepiness,
vomiting (in children),
loss of coordination,
ringing in the ears,
nausea, and
low blood pressure

Antiepileptic drugs such as
Sesquient should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus.

WARNING

CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES

The rate of intravenous Sesquient administration should not exceed 150 mg
phenytoin sodium equivalents (PE) per minute in adults because of the risk of
severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed
during and after administering intravenous Sesquient.

Although the risk of
cardiovascular toxicity increases with infusion rates above the recommended
infusion rate, these events have also been reported at or below the recommended
infusion rate. Reduction in rate of administration or discontinuation of dosing
may be needed.

What is the dosage for Sesquient?

Important Administration Instructions To Avoid Dosing Errors

Use caution when administering Sesquient because of the risk of dosing errors.

Phenytoin Sodium Equivalents (PE)

The dose, concentration, and infusion rate of Sesquient should always be expressed as phenytoin sodium equivalents (PE).
There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Sesquient should always be prescribed and dispensed in phenytoin sodium equivalent units (PE).
The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).

Concentration Of 50 mg PE/mL

Do not confuse the concentration of Sesquient with the total amount of drug in the vial.
Errors, including fatal overdoses, have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two-or tenfold overdoses of Sesquient since each of the vials actually contains a total of 100 mg PE (2 mL ) or 500 mg PE (10 mL).
Ensure the appropriate volume of Sesquient is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some Sesquient medication errors from occurring.

Preparation

Prior to intravenous infusion, dilute Sesquient in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 mg PE/mL to 25 mg PE/mL.
The maximum concentration of Sesquient in any solution should be 25 mg PE/mL.
When Sesquient is given as an intravenous infusion, Sesquient needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min in adults or 0.4 mg PE/kg/min in pediatric patients 2 years to less than 17 years of age.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Drug product with particulate matter or discoloration should not be used.
The diluted Sesquient solution is stable for 4 hours at room temperature.
For single-dose only. After opening, any unused product should be discarded.

Status Epilepticus In Adults

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for Sesquient should be no greater than 150 mg PE/min in adults. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential, and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of Sesquient infusions.
Because the full antiepileptic effect of phenytoin, whether given as Sesquient or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an intravenous benzodiazepine, will usually be necessary for the control of status epilepticus.
The loading dose should be followed by maintenance doses of either Sesquient or phenytoin [see Non-Emergent Loading And Maintenance Dosing In Adult And Pediatric Patients below].
If administration of Sesquient does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
See Table 1 for status epilepticus dosing in adult patients.

Table 1. Status Epilepticus Loading Dosages in Adult Patients

PopulationDosageInfusion RateAdults (17 years of age and older)15 mg PE/kg to 20 mg PE/kg100 mg PE/min to 150mg PE/min, do not exceed a maximum rate of 150 mg PE/min

Non-Emergent Loading And Maintenance Dosing In Adult And Pediatric Patients

Rate of Administration
- Adult Patients (17 years of age and older): Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for Sesquient should not exceed 150 mg PE/min in adults.
- Pediatric Patients (2 years to less than 17 years of age): Because of the betadex sulfobutyl ether sodium ingredient in Sesquient, the rate of administration for Sesquient should not exceed 0.4 mg PE/kg/min in pediatric patients. The rate of administration of intravenous Sesquient in pediatric patients differs from that of other intravenous fosphenytoin products.
Monitoring: Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential, and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 10 to 20 minutes after the end of Sesquient infusions).
After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin [see Laboratory Tests And Monitoring Levels below].
See Table 2 and Table 3 for adult and pediatric non-emergent loading and maintenance dosing, respectively.

Table 2. Non-emergent Loading Dosages

PopulationDosageInfusion RateAdults (17 years of age and older)15 mg PE/kg to 20 mg PE/kg100 mg PE/min to 150mg PE/min, do not exceed a maximum rate of 150 mg PE/min

Table 3. Maintenance Dosages

PopulationDosageInfusion RateAdultInitial Maintenance Dosage:
4 mg PE/kg/day to 6 mg PE/kg/day in divided dosesNot to exceed a maximum rate of 150 mg PE/minPediatric (2 years to less than 17 years of age)Initial Maintenance Dosage:
2 mg PE/kg to 4 mg PE/kg (dose given 12 hours after the loading dose)Not to exceed a maximum rate of 0.4 mg PE/kg/minMaintenance Dosage after Initial Maintenance Dosage:
4 mg PE/kg/day to 8 mg PE/kg/day in divided doses (continued every 12 hours after initial maintenance dose)Not to exceed a maximum rate of 0.4 mg PE/kg/min

Laboratory Tests And Monitoring Levels

Laboratory Tests

Sesquient (or phenytoin) doses are usually selected to attain therapeutic serum total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).
Following Sesquient administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete.
This occurs within approximately 2 hours after the end of intravenous infusion.
Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx/TDxFLx (fluorescence polarization) and Emit 2000 (enzyme multiplied), may significantly overestimate serum phenytoin concentrations because of cross-reactivity with fosphenytoin.
The error is dependent on serum phenytoin and fosphenytoin concentration (influenced by Sesquient dose, route and rate of administration, and time of sampling relative to dosing), and analytical method.
Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin.
Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin.
However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved.

Monitoring Levels

Trough levels provide information about clinically effective serum level range and are obtained just prior to the patient’s next scheduled dose.
Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration.
Therapeutic effect without clinical signs of toxicity occurs more often with serum total phenytoin concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin.
In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosing In Patients With Renal Or Hepatic Impairment Or Hypoalbuminemia below].

Parenteral Substitution For Oral Phenytoin Therapy

Because of the risks of cardiac and local toxicity associated with intravenous Sesquient, oral phenytoin should be used whenever possible.
When treatment with oral phenytoin is not possible, Sesquient can be substituted for oral phenytoin at the same total daily phenytoin sodium equivalents (PE) dose.
Dilantin capsules are approximately 90% bioavailable by the oral route.
Phenytoin, derived from administration of Sesquient, is 100% bioavailable by the intravenous route.
For this reason, serum phenytoin concentrations may increase modestly when Sesquient is substituted for oral phenytoin sodium therapy.
The rate of administration for Sesquient should be no greater than 150 mg PE/min in adults and 0.4 mg PE/kg/min in pediatric patients.

Dosing In Patients With Renal Or Hepatic Impairment Or Hypoalbuminemia

Because the fraction of unbound phenytoin (the active metabolite of Sesquient) 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.
After intravenous Sesquient administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance.
This has the potential to increase the frequency and severity of adverse events.
Closely monitor serum creatinine levels and estimated glomerular filtration rate (eGFR) in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m²) receiving intravenous Sesquient. If serum creatinine level increases occur, consider changing to oral phenytoin.

Dosing In Geriatrics

The clearance of phenytoin (the active metabolite of Sesquient) is decreased slightly in elderly patients and lower or less frequent dosing may be required.

Dosing During Pregnancy

Decreased serum concentrations of phenytoin (the active metabolite of Sesquient) may occur during pregnancy because of altered phenytoin pharmacokinetics.
Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the Sesquient dosage should be adjusted as necessary.
Postpartum restoration of the original dosage will probably be indicated.
Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

What drugs interact with Sesquient?

Fosphenytoin is extensively bound to human plasma proteins. Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin.
Although, it is unknown whether this could result in clinically significant effects, caution is advised when administering
Sesquient with other drugs that significantly bind to serum albumin.
The most significant drug interactions following administration of
Sesquient are expected to occur with drugs that interact with phenytoin.
Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement.
Phenytoin is primarily metabolized by hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism.
Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity.
Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.
Phenytoin or Sesquient is a potent inducer of hepatic drug-metabolizing enzymes.

Drugs That Affect Phenytoin Or Sesquient

Table 5 includes commonly occurring drug interactions that affect phenytoin (the active metabolite of
Sesquient) concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.

The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

Table 5. Drugs That Affect Phenytoin Concentrations

Interacting AgentExamplesDrugs that may increase phenytoin serum levels Antiepileptic drugsEthosuximide, felbamate, oxcarbazepine, methsuximide, topiramate AzolesFluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agentsCapecitabine, fluorouracil AntidepressantsFluoxetine, fluvoxamine, sertraline Gastric acid reducing agentsH₂ antagonists (cimetidine), omeprazole SulfonamidesSulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazoletrimethoprim OtherAcute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarinDrugs that may decrease phenytoin serum levels Antineoplastic agents usually in combinationBleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agentsFosamprenavir, nelfinavir, ritonavir Antiepileptic drugsCarbamazepine, vigabatrin OtherChronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort,^a theophyllineDrugs that may either increase or decrease phenytoin serum levels Antiepileptic drugsPhenobarbital, valproate sodium, valproic acid^a The induction potency of St. John’s wort may vary widely based on preparation.

Drugs Affected By Phenytoin Or Sesquient

Table 6 includes commonly occurring drug interactions affected by phenytoin (the active metabolite of
Sesquient). However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.

Table 6: Drugs Affected by Phenytoin

Interacting AgentExamplesDrugs whose efficacy is impaired by phenytoin  AzolesFluconazole, ketoconazole, itraconazole, posaconazole, voriconazole  Antineoplastic agentsIrinotecan, paclitaxel, teniposide  DelavirdinePhenytoin can substantially reduce the concentrations of delavirdine. This can
lead to loss of virologic response and possible resistance.  Neuromuscular blocking agentsCisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.
Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.  WarfarinIncreased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.  OtherCorticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin DDrugs whose level is decreased by phenytoin  Antiepileptic drugs^aCarbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine  Antilipidemic agentsAtorvastatin, fluvastatin, simvastatin  Antiviral agentsEfavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavirFosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir  Calcium channel blockersNifedipine, nimodipine, nisoldipine, verapamil  OtherAlbendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine^a The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.

Drug/Laboratory Test Interactions

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations following
Sesquient administration.

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Is Sesquient safe to use while pregnant or breastfeeding?

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as
Sesquient, during pregnancy.
Physicians are advised to recommend that pregnant patients taking
Sesquient enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
It is not known whether fosphenytoin is secreted in human milk. Following administration of phenytoin (the active metabolite of
Sesquient), phenytoin is secreted in human milk.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for
Sesquient and any potential adverse effects on the breastfed infant from
Sesquient or from the underlying maternal condition.