Fosphenytoin Sodium

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Overview

What is Fosphenytoin Sodium?

Fosphenytoin Sodium Injection, USP is a prodrug intended for parenteral administration; its active metabolite is phenytoin. 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE). The amount and concentration of fosphenytoin is always expressed in terms of mg PE.

The pharmacological class of the fosphenytoin sodium is hydantoin derivative, and the therapeutic class is anticonvulsant.

Fosphenytoin Sodium Injection, USP is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE, for intravenous or intramuscular administration. The concentration of each vial is 50 mg PE/mL. Fosphenytoin Sodium Injection, USP is supplied in vials as a ready-mixed solution in Water for Injection, USP, and Tromethamine, USP (TRIS), buffer adjusted to pH 8.3 to 9.3 with either Hydrochloric Acid, NF, or Sodium Hydroxide, NF. Fosphenytoin Sodium Injection, USP is a clear, colorless to pale yellow, sterile solution.

The chemical name of fosphenytoin is 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidinedione disodium salt. The molecular structure of fosphenytoin is:

The molecular weight of fosphenytoin is 406.24.

What does Fosphenytoin Sodium look like?

What are the available doses of Fosphenytoin Sodium?

Injection: 50 mg phenytoin sodium equivalents (PE)/mL available as:

What should I talk to my health care provider before I take Fosphenytoin Sodium?

How should I use Fosphenytoin Sodium?

Fosphenytoin Sodium Injection, USP is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin Sodium Injection, USP can also be substituted, short-term, for oral phenytoin. Fosphenytoin Sodium Injection, USP should be used only when oral phenytoin administration is not possible

Use caution when administering Fosphenytoin Sodium Injection because of the risk of dosing errors

Phenytoin Sodium Equivalents (PE)

The dose, concentration, and infusion rate of Fosphenytoin Sodium Injection 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. Fosphenytoin Sodium Injection 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 Fosphenytoin Sodium Injection 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 ten-fold overdoses of Fosphenytoin Sodium Injection since each of the vials actually contains a total of 100 mg PE (2 mL vial) or 500 mg PE (10 mL vial). Ensure the appropriate volume of Fosphenytoin Sodium Injection is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some Fosphenytoin Sodium Injection medication errors from occurring.

What interacts with Fosphenytoin Sodium?

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What are the warnings of Fosphenytoin Sodium?

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What are the precautions of Fosphenytoin Sodium?

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What are the side effects of Fosphenytoin Sodium?

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What should I look out for while using Fosphenytoin Sodium?

Fosphenytoin Sodium Injection is contraindicated in patients with:

The rate of intravenous Fosphenytoin Sodium Injection administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Fosphenytoin Sodium Injection. 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 might happen if I take too much Fosphenytoin Sodium?

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with Fosphenytoin Sodium Injection.

Because Fosphenytoin Sodium Injection is a prodrug of phenytoin, the following information about phenytoin overdosage may be helpful. Initial symptoms of acute phenytoin toxicity are nystagmus, ataxia, and dysarthria. Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma, and hypotension. Death is caused by respiratory and circulatory depression. The lethal dose of phenytoin in adults is estimated to be 2 to 5 grams. The lethal dose in pediatrics is not known.

There are marked variations among individuals with respect to serum phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 20 µg/mL, ataxia at 30 µg/mL, and dysarthria and lethargy appear when the serum concentration is over 40 µg/mL. However, phenytoin concentrations as high as 50 µg/mL have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in serum phenytoin concentrations over 100 µg/mL, with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported after overdosage.

Formate and phosphate are metabolites of Fosphenytoin Sodium Injection and therefore may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with severe anion-gap metabolic acidosis. Large amounts of phosphate, delivered rapidly, could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. Ionized free calcium levels can be measured and, if low, used to guide treatment.

Treatment:

The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin (the active metabolite of Fosphenytoin Sodium Injection) is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children.

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

How should I store and handle Fosphenytoin Sodium?

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect from light.Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as round white tablets debossed ‘490’ on one side and plain on the other side. Each tablet contains 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate and are supplied as:Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP controlled room temperature].Manufactured by: ANI Pharmaceuticals, Inc.Baudette, MN 56623 Repackaged by: Proficient Rx LPThousand Oaks, CA 913209981 Rev 10/17Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as round white tablets debossed ‘490’ on one side and plain on the other side. Each tablet contains 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate and are supplied as:Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP controlled room temperature].Manufactured by: ANI Pharmaceuticals, Inc.Baudette, MN 56623 Repackaged by: Proficient Rx LPThousand Oaks, CA 913209981 Rev 10/17Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as round white tablets debossed ‘490’ on one side and plain on the other side. Each tablet contains 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate and are supplied as:Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP controlled room temperature].Manufactured by: ANI Pharmaceuticals, Inc.Baudette, MN 56623 Repackaged by: Proficient Rx LPThousand Oaks, CA 913209981 Rev 10/17Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as round white tablets debossed ‘490’ on one side and plain on the other side. Each tablet contains 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate and are supplied as:Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP controlled room temperature].Manufactured by: ANI Pharmaceuticals, Inc.Baudette, MN 56623 Repackaged by: Proficient Rx LPThousand Oaks, CA 913209981 Rev 10/17Diphenoxylate Hydrochloride and Atropine Sulfate Tablets USP are available as round white tablets debossed ‘490’ on one side and plain on the other side. Each tablet contains 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate and are supplied as:Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP controlled room temperature].Manufactured by: ANI Pharmaceuticals, Inc.Baudette, MN 56623 Repackaged by: Proficient Rx LPThousand Oaks, CA 913209981 Rev 10/17

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

Non-Clinical Toxicology

Fosphenytoin Sodium Injection is contraindicated in patients with:

The rate of intravenous Fosphenytoin Sodium Injection administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Fosphenytoin Sodium Injection. 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

Alcohol

Alcohol may increase the CNS depressant effects of diphenoxylate hydrochloride and atropine sulfate and may cause drowsiness (see ). Avoid concomitant use of diphenoxylate hydrochloride and atropine sulfate tablets with alcohol.

Other Drugs that Cause CNS Depression

The concurrent use of diphenoxylate hydrochloride and atropine sulfate with other drugs that cause CNS depression (e.g., barbiturates, benzodiazepines, opioids, buspirone, antihistamines, muscle relaxants), may potentiate the effects of diphenoxylate hydrochloride and atropine sulfate (see ). Either diphenoxylate hydrochloride and atropine sulfate tablets or the other interacting drug should be chosen, depending on the importance of the drug to the patient. If CNS-acting drugs cannot be avoided, monitor patients for CNS adverse reactions.

MAO Inhibitors

Diphenoxylate may interact with monoamine oxidase inhibitors (MAOIs) and precipitate a hypertensive crisis. Avoid use of diphenoxylate hydrochloride and atropine sulfate tablets in patients who take MAOIs and monitor for signs and symptoms of hypertensive crisis (headache, hyperthermia, hypertension).

Phenytoin Sodium Equivalents (PE)

Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial.

Doses of Fosphenytoin Sodium Injection are always expressed in terms of milligrams of phenytoin sodium equivalents (mg PE). 1 mg PE is equivalent to 1 mg phenytoin sodium.

Do not, therefore, make any adjustment in the recommended doses when substituting Fosphenytoin Sodium Injection for phenytoin sodium or vice versa. For example, if a patient is receiving 1000 mg PE of Fosphenytoin Sodium Injection, that is equivalent to 1000 mg of phenytoin sodium.

Concentration of 50 mg PE/mL

Medication errors associated with Fosphenytoin Sodium Injection have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin Sodium Injection is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Errors 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 ten-fold overdoses of Fosphenytoin Sodium Injection since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of Fosphenytoin Sodium Injection should always be expressed in milligrams of phenytoin equivalents (mg PE) . Additionally, when ordering and storing Fosphenytoin Sodium Injection, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg PE/ 10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of Fosphenytoin Sodium Injection is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some Fosphenytoin Sodium Injection medication errors from occurring.

The following serious adverse reactions are described elsewhere in the labeling:

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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