Fosphenytoin (Page 4 of 8)

5.13 Renal or Hepatic Disease or Hypoalbuminemia

Because the fraction of unbound phenytoin (the active metabolite of fosphenytoin sodium injection) 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 IV 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.

5.14 Exacerbation of Porphyria

In view of isolated reports associating phenytoin (the active metabolite of fosphenytoin sodium injection) with exacerbation of porphyria, caution should be exercised in using fosphenytoin sodium injection in patients suffering from this disease.

5.15 Teratogenicity and Other Harm to the Newborn

Fosphenytoin sodium injection may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin (the active metabolite of fosphenytoin sodium injection) may increase the risks for congenital malformations and other adverse developmental outcomes [see Use in Specific Populations (8.1)].

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma.

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

5.16 Hyperglycemia

Hyperglycemia, resulting from the inhibitory effect of phenytoin (the active metabolite of fosphenytoin sodium injection) on insulin release, has been reported. Phenytoin may also raise the serum glucose concentrations in diabetic patients.

5.17 Serum Phenytoin Levels above Therapeutic Range

Serum levels of phenytoin (the active metabolite of fosphenytoin sodium injection) sustained above the therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Fosphenytoin sodium injection dose reduction is indicated if serum levels are excessive; if symptoms persist, administration of fosphenytoin sodium injection should be discontinued.

6 ADVERSE REACTIONS

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

• Cardiovascular Risk Associated with Rapid Infusion [see Warnings and Precautions (5.2)]
• Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.3)]
• Serious Dermatologic Reactions [see Warnings and Precautions (5.4)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.5)]
• Hypersensitivity [see Warnings and Precautions (5.6)]
• Angioedema [see Warnings and Precautions (5.7)]
• Hepatic Injury [see Warnings and Precautions (5.8)]
• Hematopoietic Complications [see Warnings and Precautions (5.9)]
• Sensory Disturbances [see Warnings and Precautions (5.10)]
• Local Toxicity (Including Purple Glove Syndrome) [see Warnings and Precautions (5.11)]
• Exacerbation of Porphyria [see Warnings and Precautions (5.14)]
• Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.15)]
• Hyperglycemia [see Warnings and Precautions (5.16)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The more important adverse clinical reactions caused by the IV use of fosphenytoin sodium injection or phenytoin are cardiovascular collapse and/or CNS 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 [see Warnings and Precautions (5.2)]. The adverse reactions most commonly observed with the use of fosphenytoin sodium injection in clinical trials were nystagmus, dizziness, pruritus, somnolence, and ataxia. With one exception, these reactions are commonly associated with the administration of IV phenytoin. Pruritus, however, was seen much more often following fosphenytoin sodium injection administration and occurred more often with IV fosphenytoin sodium administration than with IM fosphenytoin sodium administration. These reactions 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 infusion. Some patients experienced symptoms for hours. These reactions did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen [see Warnings and Precautions (5.10)]. Approximately 2% of the 859 patients 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 Reactions Following IV Fosphenytoin Sodium Injection: The incidence of adverse reactions tended to increase as both dose and infusion rate increased. In particular, at doses of ≥15mg PE/kg and rates ≥150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates.

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.

Incidence in Controlled Clinical Trials — IV Administration to Adult Patients with Epilepsy or Neurosurgical Patients: Table 4 lists adverse reactions that occurred in at least 2% of patients treated with IV fosphenytoin sodium injection at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and fosphenytoin sodium injection administration would have resulted in equivalent systemic exposure to phenytoin.

TABLE 4. Adverse Reaction Incidence Following IV Administration at the Maximum Dose and Rate to Adult Patients with Epilepsy or Neurosurgical Patients (Events in at Least 2% of Fosphenytoin Sodium Injection-Treated Patients)

1 The study was not designed to assess comparative safety.
BODY SYSTEM Adverse Event	IV Fosphenytoin Sodium InjectionN=90	IV Phenytoin1 N=22
BODY AS A WHOLE
Pelvic Pain	4	0
Asthenia	2	0
Back Pain	2	0
Headache	2	5
CARDIOVASCULAR
Hypotension	8	9
Vasodilatation	6	5
Tachycardia	2	0
DIGESTIVE
Nausea	9	14
Tongue Disorder	4	0
Dry Mouth	4	5
Vomiting	2	9
NERVOUS
Nystagmus	44	59
Dizziness	31	27
Somnolence	20	27
Ataxia	11	18
Stupor	8	5
Incoordination	4	5
Paresthesia	4	0
Extrapyramidal Syndrome	4	0
Tremor	3	9
Agitation	3	0
Hypesthesia	2	9
Dysarthria	2	0
Vertigo	2	0
Brain Edema	2	5
SKIN AND APPENDAGES
Pruritus	49	5
SPECIAL SENSES
Tinnitus	9	9
Diplopia	3	0
Taste Perversion	3	0
Amblyopia	2	9
Deafness	2	0

Incidence in Clinical Trials — IV Administration to Pediatric Patients with Epilepsy or Neurosurgical Patients: The overall incidence of adverse reactions and the types of adverse reactions seen were similar among children and adults treated with fosphenytoin sodium injection. In an open-label, safety, tolerability, and pharmacokinetic study of fosphenytoin in pediatric subjects (neonates through age 16), the following adverse reactions occurred at a frequency of at least 5% in 96 subjects treated with intravenous fosphenytoin sodium injection: vomiting (21%), nystagmus (18%), ataxia (10%), fever (8%), nervousness (7%), pruritus (6%), somnolence (6%), hypotension (5%), and rash (5%).

Incidence in Controlled Trials — IM Administration to Adult Patients with Epilepsy: Table 5 lists adverse reactions that occurred in at least 2% of fosphenytoin sodium injection-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either IM fosphenytoin sodium injection substituted for oral phenytoin or continuing oral phenytoin. Both treatments were administered for 5 days.

TABLE 5. Adverse Reaction Incidence Following Substitution of IM Fosphenytoin Sodium Injection for Oral Phenytoin in Adult Patients with Epilepsy (Events in at Least 2% of Fosphenytoin Sodium Injection-Treated Patients)

1 The study was not designed to assess comparative safety.
BODY SYSTEM Adverse Event	IM Fosphenytoin Sodium InjectionN=179	OralPhenytoin1 N=61
BODY AS A WHOLE
Headache	9	5
Asthenia	9	3
DIGESTIVE
Nausea	5	0
Vomiting	3	0
HEMATOLOGIC AND LYMPHATIC
Ecchymosis	7	5
NERVOUS
Nystagmus	15	8
Tremor	10	13
Ataxia	8	8
Incoordination	8	5
Somnolence	7	10
Dizziness	5	3
Paresthesia	4	3
Reflexes Decreased	3	5
SKIN AND APPENDAGES
Pruritus	3	0

Adverse Events During Clinical Trials in Adult and Pediatric Patients

Fosphenytoin sodium injection has been administered to approximately 900 individuals during clinical trials. 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: fever, injection-site reaction, infection, chills, face edema, injection-site pain; Infrequent: sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis.

Cardiovascular: Frequent: hypertension; Infrequent: cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation, sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly, cerebral infarct, postural hypotension, pulmonary embolus, QT interval prolongation, thrombophlebitis, ventricular extrasystoles, congestive heart failure.

Digestive: Frequent: constipation; Infrequent: dyspepsia, diarrhea, anorexia, gastrointestinal hemorrhage, increased salivation, liver function tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis, ileus.

Endocrine: Infrequent: diabetes insipidus.

Hematologic and Lymphatic: Infrequent: thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia [see Warnings and Precautions (5.9)].

Laboratory Test Abnormality: Phenytoin (the active metabolite of fosphenytoin sodium injection) may cause increased serum levels of glucose and alkaline phosphatase.

Metabolic and Nutritional: Frequent: hypokalemia; Infrequent: hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis.

Musculoskeletal: Frequent: myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia.

Nervous: Frequent: reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness; Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis.

Respiratory: Frequent: pneumonia; Infrequent: pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased, epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis.

Skin and Appendages: Frequent: rash; Infrequent: maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule.

Special Senses: Infrequent: visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss.

Urogenital: Infrequent: urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis.