Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`CEREBYX®
`
` (Fosphenytoin Sodium Injection)
`
` WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION
`
` RATES
`The rate of intravenous CEREBYX administration should not exceed 150 mg phenytoin
`sodium equivalents (PE) per minute because of the risk of severe hypotension and cardiac
`
`
`arrhythmias. Careful cardiac monitoring is needed during and after administering
`
`intravenous CEREBYX. Although the risk of cardiovascular toxicity increases with
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`
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`infusion rates above the recommended infusion rate, these events have also been reported
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`at or below the recommended infusion rate. Reduction in rate of administration or
`
`
`discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND
`
`ADMINISTRATION).
`
`
`DESCRIPTION
`
`CEREBYX® (fosphenytoin sodium injection) 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.
`
`
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`CEREBYX 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. CEREBYX is
`
`
`supplied in vials as a ready-mixed solution in Water for Injection, USP, and Tromethamine, USP
`
`(TRIS), buffer adjusted to pH 8.6 to 9.0 with either Hydrochloric Acid, NF, or Sodium
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`Hydroxide, NF. CEREBYX is a clear, colorless to pale yellow, sterile solution.
`
`
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`The chemical name of fosphenytoin is 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4­
`
`imidazolidinedione disodium salt. The molecular structure of fosphenytoin is:
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`The molecular weight of fosphenytoin is 406.24.
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` IMPORTANT NOTE: Throughout all CEREBYX® 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
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`
`
`
`
`Reference ID: 3431387
`
`1
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`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 1
`
`

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`
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`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`
`
` Care should be taken to ensure that CEREBYX is always prescribed and dispensed in
`
`
`
`
`
` phenytoin sodium equivalent (PE) (see DOSAGE AND ADMINISTRATION).
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`CLINICAL PHARMACOLOGY
`
`Introduction
`
`
`Following parenteral administration of CEREBYX, 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 CEREBYX is administered under
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`conditions of use recommended in this labeling.
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`Mechanism of Action
`
`
`Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are
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`attributable to phenytoin. After IV administration to mice, fosphenytoin blocked the tonic phase
`of maximal electroshock seizures at doses equivalent to those effective for phenytoin. In addition
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`to its ability to suppress maximal electroshock seizures in mice and rats, phenytoin exhibits
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`anticonvulsant activity against kindled seizures in rats, audiogenic seizures in mice, and seizures
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`produced by electrical stimulation of the brainstem in rats. The cellular mechanisms of phenytoin
`
`thought to be responsible for its anticonvulsant actions include modulation of voltage-dependent
`sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation
`
`of voltage-dependent calcium channels of neurons, and enhancement of the sodium-potassium
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`ATPase activity of neurons and glial cells. The modulation of sodium channels may be a primary
`anticonvulsant mechanism because this property is shared with several other anticonvulsants in
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`addition to phenytoin.
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`Pharmacokinetics and Drug Metabolism
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`Fosphenytoin
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`Absorption/Bioavailability: Intravenous: When CEREBYX is administered by IV infusion,
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`maximum plasma fosphenytoin concentrations are achieved at the end of the infusion.
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`Fosphenytoin has a half-life of approximately 15 minutes. Intramuscular: Fosphenytoin is
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`
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`completely bioavailable following IM administration of CEREBYX. Peak concentrations occur
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`at approximately 30 minutes postdose. Plasma fosphenytoin concentrations following IM
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`administration are lower but more sustained than those following IV administration due to the
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`time required for absorption of fosphenytoin from the injection site.
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`Distribution: Fosphenytoin is extensively bound (95% to 99%) to human plasma proteins,
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`primarily albumin. Binding to plasma proteins is saturable with the result that the percent bound
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`decreases as total fosphenytoin concentrations increase. Fosphenytoin displaces phenytoin from
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`
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`Reference ID: 3431387
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`2
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 2
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`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`protein binding sites. The volume of distribution of fosphenytoin increases with CEREBYX
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`
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`dose and rate, and ranges from 4.3 to 10.8 liters.
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`Metabolism and Elimination: The conversion half-life of fosphenytoin to phenytoin is
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`
`approximately 15 minutes. The mechanism of fosphenytoin conversion has not been determined,
`but phosphatases probably play a major role. Fosphenytoin is not excreted in urine. Each mmol
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`of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate (see CLINICAL
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`PHARMACOLOGY, Introduction and PRECAUTIONS, Phosphate Load for Renally Impaired
`Patients).
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`Phenytoin (after CEREBYX administration)
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`In general, IM administration of CEREBYX generates systemic phenytoin concentrations that are
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`similar enough to oral phenytoin sodium to allow essentially interchangeable use. The
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`pharmacokinetics of fosphenytoin following IV administration of CEREBYX, however, are
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`complex, and when used in an emergency setting (eg, status epilepticus), differences in rate of
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`availability of phenytoin could be critical. Studies have therefore empirically determined an
`infusion rate for CEREBYX that gives a rate and extent of phenytoin systemic availability
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`similar to that of a 50 mg/min phenytoin sodium infusion. A dose of 15 to 20 mg PE/kg of
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`CEREBYX infused at 100 to 150 mg PE/min yields plasma free phenytoin concentrations over
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`time that approximate those achieved when an equivalent dose of phenytoin sodium
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`(eg, parenteral DILANTIN®) is administered at 50 mg/min (see DOSAGE AND
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`ADMINISTRATION, WARNINGS).
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` FIGURE 1. Mean plasma unbound phenytoin concentrations following IV administration of
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` 1200 mg PE CEREBYX infused at 100 mg PE/min (triangles) or 150 mg PE/min
` (squares) and 1200 mg Dilantin infused at 50 mg/min (diamonds) to healthy
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` subjects (N = 12). Inset shows time course for the entire 96-hour sampling period.
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`
`Reference ID: 3431387
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`3
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 3
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`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`
`
` Following administration of single IV CEREBYX doses of 400 to 1200 mg PE, mean maximum
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`
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`total phenytoin concentrations increase in proportion to dose, but do not change appreciably with
`changes in infusion rate. In contrast, mean maximum unbound phenytoin concentrations increase
`with both dose and rate.
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`Absorption/Bioavailability: Fosphenytoin is completely converted to phenytoin following IV
`
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`administration, with a half-life of approximately 15 minutes. Fosphenytoin is also completely
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`converted to phenytoin following IM administration and plasma total phenytoin concentrations
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`peak in approximately 3 hours.
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`Distribution: Phenytoin is highly bound to plasma proteins, primarily albumin, although to a
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`lesser extent than fosphenytoin. In the absence of fosphenytoin, approximately 12% of total
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`plasma phenytoin is unbound over the clinically relevant concentration range. However,
`fosphenytoin displaces phenytoin from plasma protein binding sites. This increases the fraction
`of phenytoin unbound (up to 30% unbound) during the period required for conversion of
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`fosphenytoin to phenytoin (approximately 0.5 to 1 hour postinfusion).
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`Metabolism and Elimination: Phenytoin derived from administration of CEREBYX is
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`extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5­
`phenylhydantoin and its glucuronide; little unchanged phenytoin (1%–5% of the CEREBYX
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`dose) is recovered in urine. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9
`and CYP2C19. Phenytoin hepatic metabolism is saturable, and following administration of
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`single IV CEREBYX doses of 400 to 1200 mg PE, total and unbound phenytoin AUC values
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`increase disproportionately with dose. Mean total phenytoin half-life values (12.0 to 28.9 hr)
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`following CEREBYX administration at these doses are similar to those after equal doses of
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`parenteral Dilantin and tend to be greater at higher plasma phenytoin concentrations.
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`Special Populations
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`Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in
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`patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of
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`total phenytoin plasma concentrations should be made with caution (see DOSAGE AND
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`ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient
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`populations. After IV administration of CEREBYX to patients with renal and/or hepatic disease,
`or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased
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`without a similar increase in phenytoin clearance. This has the potential to increase the frequency
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`and severity of adverse events (see PRECAUTIONS).
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`Age: The effect of age was evaluated in patients 5 to 98 years of age. Patient age had no
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`
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`significant impact on fosphenytoin pharmacokinetics. Phenytoin clearance tends to decrease with
`
`increasing age (20% less in patients over 70 years of age relative to that in patients 20–30 years
`
`of age). Phenytoin dosing requirements are highly variable and must be individualized (see
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`DOSAGE AND ADMINISTRATION).
`
`
`
`
`Reference ID: 3431387
`
`
`4
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 4
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`

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`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`Gender and Race: Gender and race have no significant impact on fosphenytoin or phenytoin
`pharmacokinetics.
`
` Pediatrics: The safety and efficacy of CEREBYX in pediatric patients have not been established.
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`Clinical Studies
`
`Infusion tolerance was evaluated in clinical studies. One double-blind study assessed infusion-
`site tolerance of equivalent loading doses (15–20 mg PE/kg) of CEREBYX infused at 150 mg
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`
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`PE/min or phenytoin infused at 50 mg/min. The study demonstrated better local tolerance (pain
`and burning at the infusion site), fewer disruptions of the infusion, and a shorter infusion period
`for CEREBYX-treated patients (Table 1).
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` TABLE 1. Infusion Tolerance of Equivalent Loading Doses of IV CEREBYX and IV Phenytoin
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` IV Phenytoin
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` N=22
`90%
`67%
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` 44 min
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` IV CEREBYX
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`
` N=90
`9%a
`21%
`
`13 min
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` Local Intolerance
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` Infusion Disrupted
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`
` Average Infusion Time
`aPercent of patients
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`CEREBYX-treated patients, however, experienced more systemic sensory disturbances (see
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`PRECAUTIONS, Sensory Disturbances). Infusion disruptions in CEREBYX-treated patients
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`were primarily due to systemic burning, pruritus, and/or paresthesia while those in phenytoin­
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` treated patients were primarily due to pain and burning at the infusion site (see Table 1). In a
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` double-blind study investigating temporary substitution of CEREBYX for oral phenytoin, IM
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` CEREBYX was as well-tolerated as IM placebo. IM CEREBYX resulted in a slight increase in
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` transient, mild to moderate local itching (23% of patients vs 11% of IM placebo-treated patients
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`
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` at any time during the study). This study also demonstrated that equimolar doses of IM
` CEREBYX may be substituted for oral phenytoin sodium with no dosage adjustments needed
`
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` when initiating IM or returning to oral therapy. In contrast, switching between IM and oral
` phenytoin requires dosage adjustments because of slow and erratic phenytoin absorption from
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` muscle.
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`INDICATIONS AND USAGE
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` CEREBYX is indicated for the control of generalized tonic-clonic status epilepticus and
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` prevention and treatment of seizures occurring during neurosurgery. CEREBYX can also be
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` substituted, short-term, for oral phenytoin. CEREBYX should be used only when oral phenytoin
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` administration is not possible. CEREBYX must not be given orally.
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` CONTRAINDICATIONS
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`
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` CEREBYX is contraindicated in patients who have demonstrated hypersensitivity to CEREBYX
` or its ingredients, or to phenytoin or other hydantoins. Because of the effect of parenteral
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`
`Reference ID: 3431387
`
`
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 5
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`
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`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`
`
` phenytoin on ventricular automaticity, CEREBYX is contraindicated in patients with sinus
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` bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome.
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` Coadministration of CEREBYX is contraindicated with delavirdine due to potential for loss of
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` virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse
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` transcriptase inhibitors.
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`WARNINGS
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`DOSES OF CEREBYX ARE ALWAYS EXPRESSED IN TERMS OF MILLIGRAMS OF
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`PHENYTOIN SODIUM EQUIVALENTS (mg PE) 1 MG PE IS EQUIVALENT TO 1 MG
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`PHENYTOIN SODIUM.
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`DO NOT, THEREFORE, MAKE ANY ADJUSTMENT IN THE RECOMMENDED
`
`
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`DOSES WHEN SUBSTITUTING CEREBYX FOR PHENYTOIN SODIUM OR VICE
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`
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`VERSA. FOR EXAMPLE, IF A PATIENT IS RECEIVING 1000 MG PE OF CEREBYX,
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`THAT IS EQUIVALENT TO 1000 MG OF PHENYTOIN SODIUM.
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`The following warnings are based on experience with CEREBYX or phenytoin.
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` Dosing Errors
`
`Do not confuse the amount of drug to be given in PE with the concentration of the drug in
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` the vial.
`
` Medication errors associated with CEREBYX have resulted in patients receiving the wrong dose
` of fosphenytoin. CEREBYX is marketed in 2 mL vials containing a total of 100 mg PE and 10
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`
` mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/ mL.
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` Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to
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` mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten­
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` fold overdoses of CEREBYX since each vial actually contains a total of 100 mg PE or 500 mg
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`
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`PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize
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` confusion, the prescribed dose of CEREBYX should always be expressed in milligrams of
` phenytoin equivalents (mg PE) (see Dosage and Administration). Additionally, when ordering
`
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` and storing CEREBYX, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500
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`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
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` should be taken to ensure the appropriate volume of CEREBYX is withdrawn from the vial
`
`
` when preparing the drug for administration. Attention to these details may prevent some
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`
`
` CEREBYX medication errors from occurring.
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` Status Epilepticus Dosing Regimen
`
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` Because of the increased risk of adverse cardiovascular reactions associated with rapid
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` administration, do not administer CEREBYX at a rate greater than 150 mg PE/min.
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` The dose of IV CEREBYX (15 to 20 mg PE/kg) that is used to treat status epilepticus is
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` administered at a maximum rate of 150 mg PE/min. The typical CEREBYX infusion
` administered to a 50 kg patient would take between 5 and 7 minutes. Note that the delivery
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`Reference ID: 3431387
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`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 6
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`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`of an identical molar dose of phenytoin using parenteral Dilantin or generic phenytoin
`sodium injection cannot be accomplished in less than 15 to 20 minutes because of the
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`untoward cardiovascular effects that accompany the direct intravenous administration of
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`phenytoin at rates greater than 50 mg/min.
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`If rapid phenytoin loading is a primary goal, IV administration of CEREBYX is preferred
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`because the time to achieve therapeutic plasma phenytoin concentrations is greater following IM
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`than that following IV administration (see DOSAGE AND ADMINISTRATION).
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`Cardiovascular Risk Associated with Rapid Infusion
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`As non-emergency therapy, intravenous CEREBYX should be administered more slowly.
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`Because of the risks of cardiac and local toxicity associated with IV CEREBYX, oral
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`phenytoin should be used whenever possible.
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`Because adverse cardiovascular reactions have occurred during and after infusions, careful
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`cardiac monitoring is needed during and after the administration of intravenous
`
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`CEREBYX. Reduction in rate of administration or discontinuation of dosing may be
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`
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`needed.
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`Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac
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`arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular
`
`tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death.
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`Severe complications are most commonly encountered in critically ill patients, elderly patients,
`
`and patients with hypotension and severe myocardial insufficiency. However, cardiac events
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`have also been reported in adults and children without underlying cardiac disease or
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`comorbidities and at recommended doses and infusion rates.
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`Withdrawal Precipitated Seizure, Status Epilepticus
`
`Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased
`seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need
`
`
`for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication
`arises, this should be done gradually. However, in the event of an allergic or hypersensitivity
`
`reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative
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` therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.
`
`
` Serious Dermatologic Reactions
` Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN)
`
`
`
`
` and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset
` of symptoms is usually within 28 days, but can occur later. CEREBYX should be discontinued
`
`
`
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` at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest
`
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`
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` SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
`
`
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` If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with
`
` Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).
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` Studies in patients of Chinese ancestry have found a strong association between the risk of
`
` developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B
`
` gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a
`
`
`
`
`
`Reference ID: 3431387
`
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`IPR2014-01126
`RCT EX. 2010 page 7
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`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`risk factor for the development of SJS/TEN in patients of Asian ancestry taking other
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`
`antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be
`
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`given to avoiding CEREBYX as an alternative for carbamazepine patients positive for HLA­
`
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`B*1502.
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` The use of HLA-B*1502 genotyping has important limitations and must never substitute for
`
` appropriate clinical vigilance and patient management. The role of other possible factors in the
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` development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose,
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`
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` compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring
`
`
` have not been studied.
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
`
` hypersensitivity
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
`
` hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin and
`CEREBYX. Some of these events have been fatal or life-threatening. DRESS typically, although
`not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other
`organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis,
`or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because
`this disorder is variable in its expression, other organ systems not noted here may be involved. It
`
`
`is important to note that early manifestations of hypersensitivity, such as fever or
`
`lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are
`
`present, the patient should be evaluated immediately. CEREBYX should be discontinued if an
`
`alternative etiology for the signs or symptoms cannot be established.
`
`
`Hypersensitivity
`
`CEREBYX and other hydantoins are contraindicated in patients who have experienced phenytoin
`
`
`hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to
`
`
`structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides,
`
`and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history
`
`
`of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family
`
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`
`
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`members, consider alternatives to CEREBYX.
`
`
`Hepatic Injury
`
`Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been
`
`
`
`
`
`reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in
`
`isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum
`transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin
`
`
`hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute
`
`
`hepatotoxicity, CEREBYX should be immediately discontinued and not readministered.
`
`Hematopoietic System
`
`Hematopoietic complications, some fatal, have occasionally been reported in association with
`administration of phenytoin. These have included thrombocytopenia, leukopenia,
`granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.
`
`
`
`
`
`Reference ID: 3431387
`
`8
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`
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 8
`
`

`
`
`
`
`
`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`There have been a number of reports that have suggested a relationship between phenytoin and
`the development of lymphadenopathy (local or generalized), including benign lymph node
`
`hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect
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`relationship has not been established, the occurrence of lymphadenopathy indicates the need to
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`differentiate such a condition from other types of lymph node pathology. Lymph node
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`involvement may occur with or without symptoms and signs resembling DRESS. In all cases of
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`lymphadenopathy, follow-up observation for an extended period is indicated and every effort
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`should be made to achieve seizure control using alternative antiepileptic drugs.
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`Alcohol Use
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`Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use
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`may decrease plasma concentrations.
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` Usage in Pregnancy
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` Clinical:
`
` Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered
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` phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be
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` valuable in the management of pregnant women as a guide to appropriate adjustment of dosage
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` (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage
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`
` will probably be indicated.
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`Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while
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`taking the drug, the patient should be apprised of the potential harm to the fetus.
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`
` Prenatal exposure to phenytoin may increase the risks for congenital malformations and other
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`
`
` adverse developmental outcomes. Increased frequencies of major malformations (such as
` orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit
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`hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been
`reported among children born to epileptic women who took phenytoin alone or in combination
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`with other antiepileptic drugs during pregnancy. There have also been several reported cases of
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`malignancies, including neuroblastoma, in children whose mothers received phenytoin during
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`pregnancy. The overall incidence of malformations for children of epileptic women treated with
`antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two-to three-fold
`that in the general population. However, the relative contributions of antiepileptic drugs and
`other factors associated with epilepsy to this increased risk are uncertain and in most cases it has
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`not been possible to attribute specific developmental abnormalities to particular antiepileptic
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`drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin
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`during pregnancy.
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`Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of
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`
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` vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This
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` drug-induced condition can be prevented with vitamin K administration to the mother before
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` delivery and to the neonate after birth.
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`
`
`
`
`
`Reference ID: 3431387
`
`9
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`
`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 9
`
`

`
`
`
`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`Preclinical: Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal
`
`
`anomalies), death, growth retardation, and functional impairment (chromodacryorrhea,
` hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during
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`
` pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg
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` PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2
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`basis), which produced peak maternal plasma phenytoin concentrations of approximately 20
`µg/mL or greater. Maternal toxicity was often associated with these doses and plasma
`concentrations, however, there is no evidence to suggest that the developmental effects were
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`secondary to the maternal effects. The single occurrence of a rare brain malformation at a non­
`maternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on
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`a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in
`rats were similar to those which have been reported following administration of phenytoin to
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` pregnant rats. No effects on embryo-fetal development were observed when rabbits were given
`up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on
`
`
` a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported
` following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the
`
`
` maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
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`PRECAUTIONS
`General: (CEREBYX specific)
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`Sensory Disturbances
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`Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers
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`administered IV CEREBYX at a dose of 1200 mg PE at the maximum rate of administration
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`
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`(150 mg PE/min). The severe sensory disturbance lasted from 3 to 50 minutes in 6 of these
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`subjects and for 14 hours in the seventh subject. In some cases, milder sensory disturbances
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`persisted for as long as 24 hours. The location of the discomfort varied among subjects with the
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`groin mentioned most frequently as an area of discomfort. In a separate cohort of 16 normal
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`volunteers (taken from 2 other studies) who were administered IV CEREBYX at a dose of 1200
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`
`mg PE at the maximum rate of administration (150 mg PE/min), none experienced severe
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`disturbances, but most experienced mild to moderate itching or tingling. Patients administered
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`CEREBYX at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of
`
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`some degree. The occurrence and intensity of the discomfort can be lessened by slowing or
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`temporarily stopping the infusion. The effect of continuing infusion unaltered in the presence of
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`these sensations is unknown. No permanent sequelae have been reported thus far. The
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`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
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`tingling predominantly in the groin area.
`
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`Local toxicity (Purple Glove Syndrome)
`
`
`Edema, discoloration, and pain distal to the site of injection (described as “purple glove
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`syndrome”) have also been reported following peripheral intravenous CEREBYX injection. This
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`
`
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`may or may not be associated with extravasation. The syndrome may not develop for several
`
`days after injection.
`
`
`
`
`Reference ID: 3431387
`
`
`10
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`
`Actavis v. Research Corp. Techs.
`IPR2014-01126
`RCT EX. 2010 page 10
`
`

`
`
`
`Cerebyx NDA 020450
`FDA Approved Labeling Text Jan 2014
`
`
`Phosphate Load
`
` The phosphate load provided by CEREBYX (0.0037 mmol phosphate/mg PE CEREBYX)
`
`
`
`should be considered when treating patients who require phosphate restriction, such as those with
`severe renal impairment.
`
`
` IV Loading in Renal and/or Hepatic Disease or in Those with Hypoalbuminemia
`
`
`
`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 (see CLINICAL PHARMACOLOGY: Special Populations, and DOSAGE AND
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`ADMINISTRATION: Dosing in Special Populations).
`
`
`General: (phenytoin associated)
`
`CEREBYX is not indicated for the treatment of absence seizures.
`
`
`
`
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`A small percentage of individuals who have been treated with phenytoin have been shown to
`
`metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack
`
`
`of induction; it appears to be genetically determined.
`
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`Phenytoin has been infrequently associated with the exacerbation of porphyria. Caution should
`
`
`be exercised when CEREBYX is used in patients with this disease.
`
`
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`Hyperglycemia, resulting from phenytoin’s inhibitory effect on insulin release, has been reported.
`Phenytoin may also raise the serum glucose concentrations in diabetic patients.
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`Plasma