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Fosphenytoin
Overview
What is Fosphenytoin?
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.
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. 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, and tromethamine (TRIS), buffer adjusted to pH 8.6 to 9.0 with either hydrochloric acid, or sodium hydroxide. 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:
IMPORTANT NOTE: Throughout all fosphenytoin sodium injection product labeling, the amount and concentration of fosphenytoin are always expressed in terms of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa.
Care should be taken to ensure that fosphenytoin sodium injection is always prescribed and dispensed in phenytoin sodium equivalents (PE) (see
).
What does Fosphenytoin look like?
What are the available doses of Fosphenytoin?
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What should I talk to my health care provider before I take Fosphenytoin?
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How should I use Fosphenytoin?
Fosphenytoin sodium injection is indicated for the control of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium can also be substituted, short-term, for oral phenytoin. Fosphenytoin sodium should be used only when oral phenytoin administration is not possible. Fosphenytoin sodium must not be given orally.
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).
Do not confuse the concentration of fosphenytoin sodium injection with the total amount of drug in the vial.
Caution must be used when administering fosphenytoin sodium injection due to the risk of dosing errors (see ). Medication errors associated with fosphenytoin 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. Both vials contain a concentration of 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 of the vials 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, 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 is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some fosphenytoin medication errors from occurring.
Prior to IV infusion, dilute fosphenytoin sodium injection in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL. The maximum concentration of fosphenytoin in any solution should be 25 mg PE/mL. When fosphenytoin is given as an intravenous infusion, fosphenytoin needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
What interacts with Fosphenytoin?
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What are the warnings of Fosphenytoin?
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What are the precautions of Fosphenytoin?
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What are the side effects of Fosphenytoin?
The more important adverse clinical events caused by the IV use of fosphenytoin sodium injection or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for fosphenytoin sodium injection, it should not exceed 150 mg PE/min. The adverse clinical events most commonly observed with the use of fosphenytoin sodium injection in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following fosphenytoin sodium injection administration and occurred more often with IV fosphenytoin sodium injection administration than with IM fosphenytoin sodium injection administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of fosphenytoin sodium injection infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see ). Approximately 2% of the 859 individuals who received fosphenytoin sodium injection in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).
Dose and Rate Dependency of Adverse Events Following IV Fosphenytoin Sodium Injection:
Incidence in Controlled Clinical Trials
All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the tables and listings below with the frequencies representing the proportion of individuals exposed to fosphenytoin sodium injection or comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.
Incidence in Controlled Clinical Trials - IV Administration To Patients with Epilepsy or Neurosurgical Patients
TABLE 2. Treatment-Emergent Adverse Event Incidence Following IV Administration at the Maximum Dose and Rate to Patients
with Epilepsy or Neurosurgical Patients (Events in at Least 2% of Fosphenytoin Sodium Injection-Treated Patients)
Incidence in Controlled Trials - IM Administration to Patients with Epilepsy:
TABLE 3. Treatment-Emergent Adverse Event Incidence Following Substitution of IM Fosphenytoin Sodium Injection
for Oral Phenytoin Sodium in Patients with Epilepsy (Events in at Least 2% of Fosphenytoin Sodium Injection-Treated Patients)
| IV Fosphenytoin Sodium Injection | IV Phenytoin | |
| Adverse Event | N=90 | N=22 |
| Pelvic Pain | 4.4 | 0 |
| Asthenia | 2.2 | 0 |
| Back Pain | 2.2 | 0 |
| Headache | 2.2 | 4.5 |
| Hypotension | 7.7 | 9.1 |
| Vasodilatation | 5.6 | 4.5 |
| Tachycardia | 2.2 | 0 |
| Nausea | 8.9 | 13.6 |
| Tongue Disorder | 4.4 | 0 |
| Dry Mouth | 4.4 | 4.5 |
| Vomiting | 2.2 | 9.1 |
| Nystagmus | 44.4 | 59.1 |
| Dizziness | 31.1 | 27.3 |
| Somnolence | 20 | 27.3 |
| Ataxia | 11.1 | 18.2 |
| Stupor | 7.7 | 4.5 |
| Incoordination | 4.4 | 4.5 |
| Paresthesia | 4.4 | 0 |
| Extrapyramidal Syndrome | 4.4 | 0 |
| Tremor | 3.3 | 9.1 |
| Agitation | 3.3 | 0 |
| Hypesthesia | 2.2 | 9.1 |
| Dysarthria | 2.2 | 0 |
| Vertigo | 2.2 | 0 |
| Brain Edema | 2.2 | 4.5 |
| Pruritus | 48.9 | 4.5 |
| Tinnitus | 8.9 | 9.1 |
| Diplopia | 3.3 | 0 |
| Taste Perversion | 3.3 | 0 |
| Amblyopia | 2.2 | 9.1 |
| Deafness | 2.2 | 0 |
| IM Fosphenytoin Sodium Injection | Oral Phenytoin Sodium | |
| Adverse Event | N=179 | N=61 |
| Headache | 8.9 | 4.9 |
| Asthenia | 3.9 | 3.3 |
| Accidental Injury | 3.4 | 6.6 |
| Nausea | 4.5 | 0 |
| Vomiting | 2.8 | 0 |
| Ecchymosis | 7.3 | 4.9 |
| Nystagmus | 15.1 | 8.2 |
| Tremor | 9.5 | 13.1 |
| Ataxia | 8.4 | 8.2 |
| Incoordination | 7.8 | 4.9 |
| Somnolence | 6.7 | 9.8 |
| Dizziness | 5 | 3.3 |
| Paresthesia | 3.9 | 3.3 |
| Reflexes Decreased | 2.8 | 4.9 |
| Pruritus | 2.8 | 0 |
Adverse Events During All Clinical Trials
Fosphenytoin sodium injection has been administered to 859 individuals during all clinical trials. All adverse events seen at least twice are listed in the following, except those already included in previous tables and listings. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 individuals; infrequent adverse events are those occurring in 1/100 to 1/1,000 individuals.
Body as a Whole:
Frequent
Cardiovascular
Frequent
Digestive
Endocrine
Hematologic and Lymphatic:
Infrequent
Metabolic and Nutritional:
Frequent
Musculoskeletal:
Frequent
Nervous:
Frequent
Respiratory
Skin and Appendages
Special Senses:
Frequent
Urogenital:
Infrequent
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of fosphenytoin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
There have been post-marketing reports of anaphylactoid reaction and anaphylaxis.
Other Phenytoin-Associated Adverse Events:
Dyskinesia.
What should I look out for while using Fosphenytoin?
Fosphenytoin sodium injection is contraindicated in patients who have demonstrated hypersensitivity to fosphenytoin sodium injection or its ingredients, or to phenytoin or other hydantoins. Because of the effect of parenteral phenytoin on ventricular automaticity, fosphenytoin sodium injection is contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome. Coadministration of fosphenytoin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.
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 1,000 mg PE OF FOSPHENYTOIN SODIUM, THAT IS EQUIVALENT TO 1,000 mg OF PHENYTOIN SODIUM.
The following warnings are based on experience with fosphenytoin sodium injection or phenytoin.
What might happen if I take too much Fosphenytoin?
Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin.
The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.
Because fosphenytoin sodium injection is a prodrug of phenytoin, the following information 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. Depression of respiratory and circulatory systems leads to death. There are marked variations among individuals with respect to plasma phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, and dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL. However, phenytoin concentrations as high as 50 mcg/mL have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in plasma phenytoin concentrations over 100 mcg/mL, with complete recovery.
Treatment is nonspecific since there is no known antidote to fosphenytoin sodium injection or phenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
Formate and phosphate are metabolites of fosphenytoin 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.
How should I store and handle Fosphenytoin?
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.Fosphenytoin Sodium Injection, USP is supplied as follows:This container closure is not made with natural rubber latex.Both sizes of vial contain tromethamine (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection. Fosphenytoin Sodium Injection, USP should always be prescribed in phenytoin sodium equivalents (PE) (see ).1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.The brand names mentioned in this document are the trademarks of their respective owners.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Following parenteral administration of fosphenytoin sodium injection, fosphenytoin is converted to the anticonvulsant phenytoin. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin include those of phenytoin. However, the hydrolysis of fosphenytoin to phenytoin yields two metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which is in turn metabolized via a folate dependent mechanism. Although phosphate and formaldehyde (formate) have potentially important biological effects, these effects typically occur at concentrations considerably in excess of those obtained when fosphenytoin sodium injection is administered under conditions of use recommended in this labeling.
Non-Clinical Toxicology
Fosphenytoin sodium injection is contraindicated in patients who have demonstrated hypersensitivity to fosphenytoin sodium injection or its ingredients, or to phenytoin or other hydantoins. Because of the effect of parenteral phenytoin on ventricular automaticity, fosphenytoin sodium injection is contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome. Coadministration of fosphenytoin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.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 1,000 mg PE OF FOSPHENYTOIN SODIUM, THAT IS EQUIVALENT TO 1,000 mg OF PHENYTOIN SODIUM.
The following warnings are based on experience with fosphenytoin sodium injection or phenytoin.
Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.
Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.
Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 20 mg/wk) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.
Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored.
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.
Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Use of methotrexate with penicillins should be carefully monitored.
The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfa-salazine) should be closely monitored for possible increased risk of hepatotoxicity.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.
Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate.
Trimethoprim/sulfa-methoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.
Sensory Disturbances
Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered IV fosphenytoin sodium injection at a dose of 1,200 mg PE at the maximum rate of administration (150 mg PE/min). The severe sensory disturbance lasted from 3 to 50 minutes in 6 of these subjects and for 14 hours in the seventh subject. In some cases, milder sensory disturbances persisted for as long as 24 hours. The location of the discomfort varied among subjects with the groin mentioned most frequently as an area of discomfort. In a separate cohort of 16 normal volunteers (taken from 2 other studies) who were administered IV fosphenytoin sodium injection at a dose of 1,200 mg PE at the maximum rate of administration (150 mg PE/min), none experienced severe disturbances, but most experienced mild to moderate itching or tingling. Patients administered fosphenytoin sodium injection at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree. The occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion. The effect of continuing infusion unaltered in the presence of these sensations is unknown. No permanent sequelae have been reported thus far. The pharmacologic basis for these positive sensory phenomena is unknown, but other phosphate ester drugs, which deliver smaller phosphate loads, have been associated with burning, itching, and/or tingling predominantly in the groin area.
The more important adverse clinical events caused by the IV use of fosphenytoin sodium injection or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for fosphenytoin sodium injection, it should not exceed 150 mg PE/min. The adverse clinical events most commonly observed with the use of fosphenytoin sodium injection in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following fosphenytoin sodium injection administration and occurred more often with IV fosphenytoin sodium injection administration than with IM fosphenytoin sodium injection administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of fosphenytoin sodium injection infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see ). Approximately 2% of the 859 individuals who received fosphenytoin sodium injection in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).
Dose and Rate Dependency of Adverse Events Following IV Fosphenytoin Sodium Injection:
Reference
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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