These Highlights Do Not Include All The Information Needed To Use Vigadrone ®

Dosing

Use the lowest dosage and shortest exposure to VIGADRONE consistent with clinical objectives [see Warnings and Precautions (5.1)].

The VIGADRONE dosing regimen depends on the indication, age group, weight, and dosage form (tablets or powder for oral solution) [see Dosage and Administration (2.2, 2.3)]. Patients with impaired renal function require dose adjustment [see Dosage and Administration (2.4)].

Monitoring of VIGADRONE plasma concentrations to optimize therapy is not helpful.

Vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. It is not possible to predict the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of vigabatrin (e.g., incrementation of dose, drug-seeking behavior).

VIGADRONE causes edema in adults. Pediatric clinical trials were not designed to assess edema but observed incidence of edema based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo.

Pooled data from controlled trials demonstrated increased risk among vigabatrin patients compared to placebo patients for peripheral edema (vigabatrin 2%, placebo 1%), and edema (vigabatrin 1%, placebo 0%). In these studies, one vigabatrin and no placebo patients discontinued for an edema related AE. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

In North American controlled trials in adults, 6% of patients (16/280) receiving vigabatrin and 2% of patients (3/188) receiving placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or RBC indices. Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in vigabatrin and placebo treated patients, respectively, and a mean decrease in hematocrit of about 1% in vigabatrin treated patients compared to a mean gain of about 1% in patients treated with placebo.

In controlled and open label epilepsy trials in adults and pediatric patients, 3 vigabatrin patients (0.06%, 3/4,855) discontinued for anemia and 2 vigabatrin patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%.

VIGADRONE (vigabatrin, USP) is an oral antiepileptic drug and is available as a white, film- coated 500 mg tablet.

The chemical name of vigabatrin, a racemate consisting of two enantiomers, is (±) 4-amino-5-hexenoic acid. The molecular formula is C ₆H ₁₁NO ₂and the molecular weight is 129.16. It has the following structural formula:

Vigabatrin, USP is a white to off-white powder which is freely soluble in water, slightly soluble in methyl alcohol, very slightly soluble in ethyl alcohol and chloroform, and insoluble in toluene and hexane. The pH of a 1% aqueous solution is about 6.9. The n-octanol/water partition coefficient of vigabatrin is about 0.011 (log P=-1.96) at physiologic pH. Vigabatrin, USP melts with decomposition in a 3-degree range within the temperature interval of 171°C to 176°C. The dissociation constants (pK _a) of vigabatrin are 4 and 9.7 at room temperature (25°C).

Each VIGADRONE tablet contains 500 mg of vigabatrin. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate (potato) and isopropyl alcohol. The tablet coating ingredients are hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.

Approved dissolution test specifications differ from USP.

Following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation. However, as with all AEDs, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see Warnings and Precautions (5.6)].

VIGADRONE causes weight gain in adult and pediatric patients.

Data pooled from randomized controlled trials in adults found that 17% (77/443) of vigabatrin patients versus 8% (22/275) of placebo patients gained ≥7% of baseline body weight. In these same trials, the mean weight change among vigabatrin patients was 3.5 kg compared to 1.6 kg for placebo patients.

Data pooled from randomized controlled trials in pediatric patients with refractory complex partial seizures found that 47% (77/163) of vigabatrin patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight.

In all epilepsy trials, 0.6% (31/4,855) of vigabatrin patients discontinued for weight gain. The long-term effects of vigabatrin related weight gain are not known. Weight gain was not related to the occurrence of edema.

VIGADRONE ^®(vigabatrin, USP) tablets, 500 mg for oral use are white to off-white, oval, film-coated, biconvex tablets, debossed with "ZNV" on one side and scored on the other side. They are supplied as follows:

• Bottles of 100, NDC 0245-6001-11

Intramyelinic Edema (IME) has been reported in postmortem examination of infants being treated for infantile spasms (IS) with vigabatrin.

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have also been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and evoked potentials (EP) in adult epilepsy patients have demonstrated no clear-cut abnormalities [see Warnings and Precautions (5.3)].

Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory EP.

Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin-treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long-term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. Administration of vigabatrin to juvenile dogs produced vacuolar changes in the brain gray matter (including the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children [see Use in Specific Populations (8.1, 8.4)].

In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5 to 7.

Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring.

The safety and effectiveness of vigabatrin as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age [s ee Clinical Pharmacology (12.3), Clinical Studies (14.1)]. The dosing recommendation in this population varies according to age group and is weight-based [see Dosage and Administration (2.2)]. Adverse reactions in this pediatric population are similar to those observed in the adult population [see Adverse Reactions (6.1)]. The safety and effectiveness of vigabatrin as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see Dosage and Administration (2.3), Clinical Studies (14.2)] .

Safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established.

Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use [s ee Clinical Studies (14.2)].

Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with vigabatrin have been observed [see Warnings and Precautions (5.3, 5.4)].

Clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients.

Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Oral administration of a single dose of 1.5 g of vigabatrin to elderly (≥65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

None.

The following serious and otherwise important adverse reactions are described elsewhere in labeling:

• Permanent Vision Loss [see BOXED WARNING, Warnings and Precautions (5.1)]
• Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions (5.3)]
• Neurotoxicity [see Warnings and Precautions (5.4)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
• Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions (5.6)]
• Anemia [see Warnings and Precautions (5.7)]
• Somnolence and Fatigue [see Warnings and Precautions (5.8)]
• Peripheral Neuropathy [see Warnings and Precautions (5.9)]
• Weight Gain [see Warnings and Precautions (5.10)]
• Edema [see Warnings and Precautions (5.11)]

Decreased phenytoin plasma levels: dosage adjustment may be needed ( 7.1)

The initial daily dosing is 50 mg/kg/day given in two divided doses (25 mg/kg twice daily); subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days, up to a maximum of 150 mg/kg/day given in 2 divided doses (75 mg/kg twice daily) [see Use in Specific Populations (8.4)].

Table 2 provides the volume of the 50 mg/mL dosing solution of vigabatrin for oral solution that should be administered as individual doses in infants of various weights.

In patients with infantile spasms, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time [see Warnings and Precautions (5.1)].

In a controlled clinical study in patients with infantile spasms, vigabatrin was tapered by decreasing the daily dose at a rate of 25 mg/kg to 50 mg/kg every 3 to 4 days [see Warnings and Precautions (5.6)].

Dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 2 years of age and older and adults with mild (creatinine clearance >50 to 80 mL/min), moderate (creatinine clearance >30 to 50 mL/min) and severe (creatinine clearance >10 to 30 mL/min) renal impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Vigabatrin displayed linear pharmacokinetics after administration of single doses ranging from 0.5 g to 4 g, and after administration of repeated doses of 0.5 g and 2.0 g twice daily. Bioequivalence has been established between the oral solution and tablet formulations. The following PK information (T _max, half-life, and clearance) of vigabatrin was obtained from stand-alone PK studies and population PK analyses.

The effectiveness of vigabatrin as monotherapy was established for infantile spasms in two multicenter controlled studies. Both studies were similar in terms of disease characteristics and prior treatments of patients and all enrolled infants had a confirmed diagnosis of infantile spasms.

VIGADRONE is indicated for the treatment of:

• Refractory Complex Partial Seizures as adjunctive therapy in patients 2 years of age and older who have responded inadequately to several alternative treatments; VIGADRONE is not indicated as a first line agent ( 1.1)
• Infantile Spasms – monotherapy in infants 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss ( 1.2)

VIGADRONE is unlikely to affect the efficacy of steroid oral contraceptives [see Clinical Pharmacology (12.3)].

The precise mechanism of vigabatrin's anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system.

No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation.

Vigabatrin is not a controlled substance.

VIGADRONE is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see Warnings and Precautions (5.1)].

Store at 20° to 25°C (68 to 77°F). [See USP Controlled Room Temperature].

VIGADRONE can cause permanent vision loss. Because of this risk and because, when it is effective, VIGADRONE provides an observable symptomatic benefit; patient response and continued need for treatment should be periodically assessed.

Based upon adult studies, 30 percent or more of patients can be affected with bilateral concentric visual field constriction ranging in severity from mild to severe. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can result in disability. In some cases, VIGADRONE also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from VIGADRONE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.

Because assessing vision may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in these patients. For this reason, the understanding of the risk is primarily based on the adult experience. The possibility that vision loss from vigabatrin may be more common, more severe, or have more severe functional consequences in infants and children than in adults cannot be excluded.

The onset of vision loss from VIGADRONE is unpredictable and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.

The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.

In patients with refractory complex partial seizures, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time [see Dosage and Administration (2.2), Warnings and Precautions (5.6)].

In patients with infantile spasms, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time [see Dosage and Administration (2.3), Warnings and Precautions (5.6)].

VIGADRONE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. The interaction of other types of irreversible vision damage with vision damage from VIGADRONE has not been well-characterized but is likely adverse.

VIGADRONE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.

Vigabatrin causes symptoms of peripheral neuropathy in adults. Pediatric clinical trials were not designed to assess symptoms of peripheral neuropathy but observed incidence of symptoms based on pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of vigabatrin patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of vigabatrin treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms was related to duration of vigabatrin treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of vigabatrin.

• Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with Infantile Spasms receiving vigabatrin ( 5.3, 5.4)
• Suicidal behavior and ideation: Antiepileptic drugs, including VIGADRONE, increase the risk of suicidal thoughts and behavior ( 5.5)
• Withdrawal of AEDs: Taper dose to avoid withdrawal seizures ( 5.6)
• Anemia: Monitor for symptoms of anemia ( 5.7)
• Somnolence and fatigue: Advise patients not to drive or operate machinery until they have gained sufficient experience on VIGADRONE ( 5.8)

VIGADRONE causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of VIGADRONE on their ability to perform such activities.

Pooled data from two vigabatrin controlled trials in adults demonstrated that 24% (54/222) of vigabatrin patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of vigabatrin patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of vigabatrin patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue.

Pooled data from three vigabatrin controlled trials in pediatric patients demonstrated that 6% (10/165) of vigabatrin patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of vigabatrin patients experienced fatigue compared to 7% (7/104) of placebo patients. No vigabatrin patients discontinued from clinical trials due to somnolence or fatigue.

Refractory Complex Partial Seizures

• Adults (17 years of age and older): Initiate at 1,000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3,000 mg/day (1,500 mg twice daily) ( 2.2)
• Pediatric (2 to 16 years of age): The recommended dosage is based on body weight and administered as two divided doses ( 2.2)
• The dosage may be increased in weekly intervals, depending on response ( 2.2)
• Dose patients weighing more than 60 kg according to adult recommendations ( 2.2)

Infantile Spasms

• Initiate at a daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every 3 days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to a maximum daily dose of 150 mg/kg (75 mg/kg twice daily) ( 2.3)

Renal Impairment: Dose adjustment recommended ( 2.4, 8.5, 8.6)

VIGADRONE is available only through a restricted distribution program called the Vigabatrin REMS Program, because of the risk of permanent vision loss.

Notable requirements of the Vigabatrin REMS Program include the following:

• Prescribers must be certified by enrolling in the program, agreeing to counsel patients on the risk of vision loss and the need for periodic monitoring of vision, and reporting any event suggestive of vision loss to www.vigabatrinREMS.com
• Patients must enroll in the program.
• Pharmacies must be certified and must only dispense to patients authorized to receive VIGADRONE.

Further information is available at www.vigabatrinREMS.com or call 1-866-244-8175.

VIGADRONE tablets, 500 mg for oral use are white to off-white, oval, film-coated, biconvex tablets, debossed with "ZNV" on one side and scored on the other side.

There is no specific antidote for VIGADRONE overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient.

In an in vitrostudy, activated charcoal did not significantly adsorb vigabatrin.

The effectiveness of hemodialysis in the treatment of VIGADRONE overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.

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.

In U.S. and primary non-U.S. clinical studies of 4,079 vigabatrin-treated patients, the most common (≥5%) adverse reactions associated with the use of vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash.

The adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression.

In patients with infantile spasms, the adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia.

The following adverse reactions have been identified during post approval use of vigabatrin. 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. Adverse reactions are categorized by system organ class.

Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes

Ear Disorders: Deafness

Endocrine Disorders: Delayed puberty

Gastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitis

General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure

Hepatobiliary Disorders: Cholestasis

Nervous System Disorders: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia

Psychiatric Disorders: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder

Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor

Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia

• Pregnancy: Based on animal data, may cause fetal harm ( 8.1)
• Lactation: VIGADRONE is excreted in human milk ( 8.2)

• VIGADRONE can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, VIGADRONE also can damage the central retina and may decrease visual acuity [see Warnings and Precautions (5.1)].
• The onset of vision loss from VIGADRONE is unpredictable and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.
• Symptoms of vision loss from VIGADRONE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.
• The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.
• Vision assessment is recommended at baseline (no later than 4 weeks after starting VIGADRONE), at least every 3 months during therapy, and about 3 to 6 months after the discontinuation of therapy.
• Once detected, vision loss due to VIGADRONE is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss.
• Consider drug discontinuation, balancing benefit and risk, if vision loss is documented.
• Risk of new or worsening vision loss continues as long as VIGADRONE is used. It is possible that vision loss can worsen despite discontinuation of VIGADRONE.
• Because of the risk of vision loss, VIGADRONE should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 3 months of initiation and within 2 to 4 weeks of initiation for patients with infantile spasms, or sooner if treatment failure becomes obvious. Patient response to and continued need for VIGADRONE should be periodically reassessed.
• VIGADRONE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks.
• VIGADRONE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.
• Use the lowest dosage and shortest exposure to VIGADRONE consistent with clinical objectives [see Dosage and Administration (2.1)].

Because of the risk of permanent vision loss, VIGADRONE is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vigabatrin REMS Program [see Warnings and Precautions (5.2)]. Further information is available at www.vigabatrinREMS.com or call 1-866-244-8175.

Advise patients and caregivers to read the FDA-approved patient labeling (Medication Guide).

VIGADRONE is primarily eliminated through the kidney.

Antiepileptic drugs (AEDs), including VIGADRONE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing VIGADRONE, or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

VIGADRONE decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by VIGADRONE may preclude the use of these markers, especially ALT, to detect early hepatic injury.

VIGADRONE may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

As with all AEDs, VIGADRONE should be withdrawn gradually. However, if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered. Patients and caregivers should be told not to suddenly discontinue VIGADRONE therapy.

In controlled clinical studies in adults with complex partial seizures, vigabatrin was tapered by decreasing the daily dose 1,000 mg/day on a weekly basis until discontinued.

In a controlled study in pediatric patients with complex partial seizures, vigabatrin was tapered by decreasing the daily dose by one third every week for three weeks.

In a controlled clinical study in patients with infantile spasms, vigabatrin was tapered by decreasing the daily dose at a rate of 25 to 50 mg/kg every 3 to 4 days .

VIGADRONE is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see Warnings and Precautions (5.1)]. VIGADRONE is not indicated as a first line agent for complex partial seizures.

NDC 0245-6001-11

VIGADRONE™

(vigabatrin Tablets, USP)

500 mg

PHARMACIST:

Dispense the enclosed

Medication Guide to

each patient.

100 Tablets

Rx only

UPSHER-SMITH

Vigabatrin showed no carcinogenic potential in mouse or rat when given in the diet at doses up to 150 mg/kg/day for 18 months (mouse) or at doses up to 150 mg/kg/day for 2 years (rat). These doses are less than the maximum recommended human dose (MRHD) for infantile spasms (150 mg/kg/day) and for refractory complex partial seizures (3 g/day) on a mg/m ²basis.

Vigabatrin was negative in in vitro(Ames, CHO/HGPRT mammalian cell forward gene mutation, chromosomal aberration in rat lymphocytes) and in in vivo (mouse bone marrow micronucleus) assays.

No adverse effects on male or female fertility were observed in rats at oral doses up to 150 mg/kg/day (approximately ½ the MRHD of 3 g/day on a mg/m ²basis for refractory complex partial seizures).

Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine.

Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care.

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin.

In a retrospective epidemiologic study in infants with infantile spasms (N=205), the prevalence of MRI changes was 22% in vigabatrin-treated patients versus 4% in patients treated with other therapies. In this study, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied.

Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development, and brain histopathological changes were observed in dogs exposed to vigabatrin during the juvenile period of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

The specific pattern of signal changes observed in patients 6 years and younger was not observed in older pediatric and adult patients treated with vigabatrin. In a blinded review of MRI images obtained in prospective clinical trials in patients with refractory complex partial seizures (CPS) 3 years and older (N=656), no difference was observed in anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo treated patients. In the post-marketing setting, MRI changes have also been reported in patients 6 years of age and younger being treated for refractory CPS.

For adults treated with VIGADRONE, routine MRI surveillance is unnecessary as there is no evidence that vigabatrin causes MRI changes in this population.

Dosing

Use the lowest dosage and shortest exposure to VIGADRONE consistent with clinical objectives [see Warnings and Precautions (5.1)].

The VIGADRONE dosing regimen depends on the indication, age group, weight, and dosage form (tablets or powder for oral solution) [see Dosage and Administration (2.2, 2.3)]. Patients with impaired renal function require dose adjustment [see Dosage and Administration (2.4)].

Monitoring of VIGADRONE plasma concentrations to optimize therapy is not helpful.

Vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. It is not possible to predict the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of vigabatrin (e.g., incrementation of dose, drug-seeking behavior).

VIGADRONE causes edema in adults. Pediatric clinical trials were not designed to assess edema but observed incidence of edema based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo.

Pooled data from controlled trials demonstrated increased risk among vigabatrin patients compared to placebo patients for peripheral edema (vigabatrin 2%, placebo 1%), and edema (vigabatrin 1%, placebo 0%). In these studies, one vigabatrin and no placebo patients discontinued for an edema related AE. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

In North American controlled trials in adults, 6% of patients (16/280) receiving vigabatrin and 2% of patients (3/188) receiving placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or RBC indices. Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in vigabatrin and placebo treated patients, respectively, and a mean decrease in hematocrit of about 1% in vigabatrin treated patients compared to a mean gain of about 1% in patients treated with placebo.

In controlled and open label epilepsy trials in adults and pediatric patients, 3 vigabatrin patients (0.06%, 3/4,855) discontinued for anemia and 2 vigabatrin patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%.

VIGADRONE (vigabatrin, USP) is an oral antiepileptic drug and is available as a white, film- coated 500 mg tablet.

The chemical name of vigabatrin, a racemate consisting of two enantiomers, is (±) 4-amino-5-hexenoic acid. The molecular formula is C ₆H ₁₁NO ₂and the molecular weight is 129.16. It has the following structural formula:

Vigabatrin, USP is a white to off-white powder which is freely soluble in water, slightly soluble in methyl alcohol, very slightly soluble in ethyl alcohol and chloroform, and insoluble in toluene and hexane. The pH of a 1% aqueous solution is about 6.9. The n-octanol/water partition coefficient of vigabatrin is about 0.011 (log P=-1.96) at physiologic pH. Vigabatrin, USP melts with decomposition in a 3-degree range within the temperature interval of 171°C to 176°C. The dissociation constants (pK _a) of vigabatrin are 4 and 9.7 at room temperature (25°C).

Each VIGADRONE tablet contains 500 mg of vigabatrin. The inactive ingredients are magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate (potato) and isopropyl alcohol. The tablet coating ingredients are hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.

Approved dissolution test specifications differ from USP.

Following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation. However, as with all AEDs, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see Warnings and Precautions (5.6)].

VIGADRONE causes weight gain in adult and pediatric patients.

Data pooled from randomized controlled trials in adults found that 17% (77/443) of vigabatrin patients versus 8% (22/275) of placebo patients gained ≥7% of baseline body weight. In these same trials, the mean weight change among vigabatrin patients was 3.5 kg compared to 1.6 kg for placebo patients.

Data pooled from randomized controlled trials in pediatric patients with refractory complex partial seizures found that 47% (77/163) of vigabatrin patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight.

In all epilepsy trials, 0.6% (31/4,855) of vigabatrin patients discontinued for weight gain. The long-term effects of vigabatrin related weight gain are not known. Weight gain was not related to the occurrence of edema.

VIGADRONE ^®(vigabatrin, USP) tablets, 500 mg for oral use are white to off-white, oval, film-coated, biconvex tablets, debossed with "ZNV" on one side and scored on the other side. They are supplied as follows:

• Bottles of 100, NDC 0245-6001-11

Intramyelinic Edema (IME) has been reported in postmortem examination of infants being treated for infantile spasms (IS) with vigabatrin.

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have also been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and evoked potentials (EP) in adult epilepsy patients have demonstrated no clear-cut abnormalities [see Warnings and Precautions (5.3)].

Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory EP.

Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin-treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long-term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. Administration of vigabatrin to juvenile dogs produced vacuolar changes in the brain gray matter (including the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children [see Use in Specific Populations (8.1, 8.4)].

In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5 to 7.

Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring.

The safety and effectiveness of vigabatrin as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age [s ee Clinical Pharmacology (12.3), Clinical Studies (14.1)]. The dosing recommendation in this population varies according to age group and is weight-based [see Dosage and Administration (2.2)]. Adverse reactions in this pediatric population are similar to those observed in the adult population [see Adverse Reactions (6.1)]. The safety and effectiveness of vigabatrin as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see Dosage and Administration (2.3), Clinical Studies (14.2)] .

Safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established.

Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use [s ee Clinical Studies (14.2)].

Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with vigabatrin have been observed [see Warnings and Precautions (5.3, 5.4)].

Clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients.

Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Oral administration of a single dose of 1.5 g of vigabatrin to elderly (≥65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

None.

The following serious and otherwise important adverse reactions are described elsewhere in labeling:

• Permanent Vision Loss [see BOXED WARNING, Warnings and Precautions (5.1)]
• Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions (5.3)]
• Neurotoxicity [see Warnings and Precautions (5.4)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
• Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions (5.6)]
• Anemia [see Warnings and Precautions (5.7)]
• Somnolence and Fatigue [see Warnings and Precautions (5.8)]
• Peripheral Neuropathy [see Warnings and Precautions (5.9)]
• Weight Gain [see Warnings and Precautions (5.10)]
• Edema [see Warnings and Precautions (5.11)]

Decreased phenytoin plasma levels: dosage adjustment may be needed ( 7.1)

The initial daily dosing is 50 mg/kg/day given in two divided doses (25 mg/kg twice daily); subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days, up to a maximum of 150 mg/kg/day given in 2 divided doses (75 mg/kg twice daily) [see Use in Specific Populations (8.4)].

Table 2 provides the volume of the 50 mg/mL dosing solution of vigabatrin for oral solution that should be administered as individual doses in infants of various weights.

In patients with infantile spasms, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time [see Warnings and Precautions (5.1)].

In a controlled clinical study in patients with infantile spasms, vigabatrin was tapered by decreasing the daily dose at a rate of 25 mg/kg to 50 mg/kg every 3 to 4 days [see Warnings and Precautions (5.6)].

Dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 2 years of age and older and adults with mild (creatinine clearance >50 to 80 mL/min), moderate (creatinine clearance >30 to 50 mL/min) and severe (creatinine clearance >10 to 30 mL/min) renal impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Vigabatrin displayed linear pharmacokinetics after administration of single doses ranging from 0.5 g to 4 g, and after administration of repeated doses of 0.5 g and 2.0 g twice daily. Bioequivalence has been established between the oral solution and tablet formulations. The following PK information (T _max, half-life, and clearance) of vigabatrin was obtained from stand-alone PK studies and population PK analyses.

The effectiveness of vigabatrin as monotherapy was established for infantile spasms in two multicenter controlled studies. Both studies were similar in terms of disease characteristics and prior treatments of patients and all enrolled infants had a confirmed diagnosis of infantile spasms.

VIGADRONE is indicated for the treatment of:

• Refractory Complex Partial Seizures as adjunctive therapy in patients 2 years of age and older who have responded inadequately to several alternative treatments; VIGADRONE is not indicated as a first line agent ( 1.1)
• Infantile Spasms – monotherapy in infants 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss ( 1.2)

VIGADRONE is unlikely to affect the efficacy of steroid oral contraceptives [see Clinical Pharmacology (12.3)].

The precise mechanism of vigabatrin's anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system.

No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation.

Vigabatrin is not a controlled substance.

VIGADRONE is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see Warnings and Precautions (5.1)].

Store at 20° to 25°C (68 to 77°F). [See USP Controlled Room Temperature].

VIGADRONE can cause permanent vision loss. Because of this risk and because, when it is effective, VIGADRONE provides an observable symptomatic benefit; patient response and continued need for treatment should be periodically assessed.

Based upon adult studies, 30 percent or more of patients can be affected with bilateral concentric visual field constriction ranging in severity from mild to severe. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can result in disability. In some cases, VIGADRONE also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from VIGADRONE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.

Because assessing vision may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in these patients. For this reason, the understanding of the risk is primarily based on the adult experience. The possibility that vision loss from vigabatrin may be more common, more severe, or have more severe functional consequences in infants and children than in adults cannot be excluded.

The onset of vision loss from VIGADRONE is unpredictable and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.

The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.

In patients with refractory complex partial seizures, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time [see Dosage and Administration (2.2), Warnings and Precautions (5.6)].

In patients with infantile spasms, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time [see Dosage and Administration (2.3), Warnings and Precautions (5.6)].

VIGADRONE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. The interaction of other types of irreversible vision damage with vision damage from VIGADRONE has not been well-characterized but is likely adverse.

VIGADRONE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.

Vigabatrin causes symptoms of peripheral neuropathy in adults. Pediatric clinical trials were not designed to assess symptoms of peripheral neuropathy but observed incidence of symptoms based on pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of vigabatrin patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of vigabatrin treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms was related to duration of vigabatrin treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of vigabatrin.

• Abnormal MRI signal changes and intramyelinic edema have been reported in some infants with Infantile Spasms receiving vigabatrin ( 5.3, 5.4)
• Suicidal behavior and ideation: Antiepileptic drugs, including VIGADRONE, increase the risk of suicidal thoughts and behavior ( 5.5)
• Withdrawal of AEDs: Taper dose to avoid withdrawal seizures ( 5.6)
• Anemia: Monitor for symptoms of anemia ( 5.7)
• Somnolence and fatigue: Advise patients not to drive or operate machinery until they have gained sufficient experience on VIGADRONE ( 5.8)

VIGADRONE causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of VIGADRONE on their ability to perform such activities.

Pooled data from two vigabatrin controlled trials in adults demonstrated that 24% (54/222) of vigabatrin patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of vigabatrin patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of vigabatrin patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue.

Pooled data from three vigabatrin controlled trials in pediatric patients demonstrated that 6% (10/165) of vigabatrin patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of vigabatrin patients experienced fatigue compared to 7% (7/104) of placebo patients. No vigabatrin patients discontinued from clinical trials due to somnolence or fatigue.

Refractory Complex Partial Seizures

• Adults (17 years of age and older): Initiate at 1,000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3,000 mg/day (1,500 mg twice daily) ( 2.2)
• Pediatric (2 to 16 years of age): The recommended dosage is based on body weight and administered as two divided doses ( 2.2)
• The dosage may be increased in weekly intervals, depending on response ( 2.2)
• Dose patients weighing more than 60 kg according to adult recommendations ( 2.2)

Infantile Spasms

• Initiate at a daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every 3 days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to a maximum daily dose of 150 mg/kg (75 mg/kg twice daily) ( 2.3)

Renal Impairment: Dose adjustment recommended ( 2.4, 8.5, 8.6)

VIGADRONE is available only through a restricted distribution program called the Vigabatrin REMS Program, because of the risk of permanent vision loss.

Notable requirements of the Vigabatrin REMS Program include the following:

• Prescribers must be certified by enrolling in the program, agreeing to counsel patients on the risk of vision loss and the need for periodic monitoring of vision, and reporting any event suggestive of vision loss to www.vigabatrinREMS.com
• Patients must enroll in the program.
• Pharmacies must be certified and must only dispense to patients authorized to receive VIGADRONE.

Further information is available at www.vigabatrinREMS.com or call 1-866-244-8175.

VIGADRONE tablets, 500 mg for oral use are white to off-white, oval, film-coated, biconvex tablets, debossed with "ZNV" on one side and scored on the other side.

There is no specific antidote for VIGADRONE overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient.

In an in vitrostudy, activated charcoal did not significantly adsorb vigabatrin.

The effectiveness of hemodialysis in the treatment of VIGADRONE overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.

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.

In U.S. and primary non-U.S. clinical studies of 4,079 vigabatrin-treated patients, the most common (≥5%) adverse reactions associated with the use of vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash.

The adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression.

In patients with infantile spasms, the adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia.

The following adverse reactions have been identified during post approval use of vigabatrin. 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. Adverse reactions are categorized by system organ class.

Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes

Ear Disorders: Deafness

Endocrine Disorders: Delayed puberty

Gastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitis

General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure

Hepatobiliary Disorders: Cholestasis

Nervous System Disorders: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia

Psychiatric Disorders: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder

Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor

Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia

• Pregnancy: Based on animal data, may cause fetal harm ( 8.1)
• Lactation: VIGADRONE is excreted in human milk ( 8.2)

• VIGADRONE can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, VIGADRONE also can damage the central retina and may decrease visual acuity [see Warnings and Precautions (5.1)].
• The onset of vision loss from VIGADRONE is unpredictable and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.
• Symptoms of vision loss from VIGADRONE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.
• The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.
• Vision assessment is recommended at baseline (no later than 4 weeks after starting VIGADRONE), at least every 3 months during therapy, and about 3 to 6 months after the discontinuation of therapy.
• Once detected, vision loss due to VIGADRONE is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss.
• Consider drug discontinuation, balancing benefit and risk, if vision loss is documented.
• Risk of new or worsening vision loss continues as long as VIGADRONE is used. It is possible that vision loss can worsen despite discontinuation of VIGADRONE.
• Because of the risk of vision loss, VIGADRONE should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 3 months of initiation and within 2 to 4 weeks of initiation for patients with infantile spasms, or sooner if treatment failure becomes obvious. Patient response to and continued need for VIGADRONE should be periodically reassessed.
• VIGADRONE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks.
• VIGADRONE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.
• Use the lowest dosage and shortest exposure to VIGADRONE consistent with clinical objectives [see Dosage and Administration (2.1)].

Because of the risk of permanent vision loss, VIGADRONE is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vigabatrin REMS Program [see Warnings and Precautions (5.2)]. Further information is available at www.vigabatrinREMS.com or call 1-866-244-8175.

Advise patients and caregivers to read the FDA-approved patient labeling (Medication Guide).

VIGADRONE is primarily eliminated through the kidney.

Antiepileptic drugs (AEDs), including VIGADRONE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing VIGADRONE, or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

VIGADRONE decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by VIGADRONE may preclude the use of these markers, especially ALT, to detect early hepatic injury.

VIGADRONE may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

As with all AEDs, VIGADRONE should be withdrawn gradually. However, if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered. Patients and caregivers should be told not to suddenly discontinue VIGADRONE therapy.

In controlled clinical studies in adults with complex partial seizures, vigabatrin was tapered by decreasing the daily dose 1,000 mg/day on a weekly basis until discontinued.

In a controlled study in pediatric patients with complex partial seizures, vigabatrin was tapered by decreasing the daily dose by one third every week for three weeks.

In a controlled clinical study in patients with infantile spasms, vigabatrin was tapered by decreasing the daily dose at a rate of 25 to 50 mg/kg every 3 to 4 days .

VIGADRONE is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see Warnings and Precautions (5.1)]. VIGADRONE is not indicated as a first line agent for complex partial seizures.

NDC 0245-6001-11

VIGADRONE™

(vigabatrin Tablets, USP)

500 mg

PHARMACIST:

Dispense the enclosed

Medication Guide to

each patient.

100 Tablets

Rx only

UPSHER-SMITH

Vigabatrin showed no carcinogenic potential in mouse or rat when given in the diet at doses up to 150 mg/kg/day for 18 months (mouse) or at doses up to 150 mg/kg/day for 2 years (rat). These doses are less than the maximum recommended human dose (MRHD) for infantile spasms (150 mg/kg/day) and for refractory complex partial seizures (3 g/day) on a mg/m ²basis.

Vigabatrin was negative in in vitro(Ames, CHO/HGPRT mammalian cell forward gene mutation, chromosomal aberration in rat lymphocytes) and in in vivo (mouse bone marrow micronucleus) assays.

No adverse effects on male or female fertility were observed in rats at oral doses up to 150 mg/kg/day (approximately ½ the MRHD of 3 g/day on a mg/m ²basis for refractory complex partial seizures).

Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine.

Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care.

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin.

In a retrospective epidemiologic study in infants with infantile spasms (N=205), the prevalence of MRI changes was 22% in vigabatrin-treated patients versus 4% in patients treated with other therapies. In this study, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied.

Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development, and brain histopathological changes were observed in dogs exposed to vigabatrin during the juvenile period of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

The specific pattern of signal changes observed in patients 6 years and younger was not observed in older pediatric and adult patients treated with vigabatrin. In a blinded review of MRI images obtained in prospective clinical trials in patients with refractory complex partial seizures (CPS) 3 years and older (N=656), no difference was observed in anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo treated patients. In the post-marketing setting, MRI changes have also been reported in patients 6 years of age and younger being treated for refractory CPS.

For adults treated with VIGADRONE, routine MRI surveillance is unnecessary as there is no evidence that vigabatrin causes MRI changes in this population.