------------WARNINGS AND PRECAUTIONS---------------
`• SABRIL causes permanent vision loss (5.1)
`• Abnormal MRI signal changes have been reported
`
`in some infants with IS receiving SABRIL (5.3)
`• Antiepileptic drugs, including SABRIL, increase
`the risk of suicidal thoughts and behavior (5.5)
`• Dose should be tapered gradually to avoid
`withdrawal seizures (5.6)
`• SABRIL causes anemia (5.7)
`• SABRIL causes somnolence and fatigue (5.8)
`• SABRIL causes peripheral neuropathy (5.9)
`
`• SABRIL causes weight gain (5.10)
`
`
`• SABRIL causes edema (5.11)
`
`
`----------------ADVERSE REACTIONS-------------------------
`Most common adverse reactions (change of ≥5% over
`
`placebo) in addition to permanent vision loss in adult
`controlled trials with vigabatrin were fatigue,
`somnolence, nystagmus, tremor, vision blurred,
`memory impairment, weight gain, arthralgia, abnormal
`coordination, and confusional state (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS,
`contact Lundbeck Inc. at 1-800-455-1141 or
`www.lundbeckinc.com or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`--------------------DRUG INTERACTIONS----------------------
`• Decreased phenytoin plasma levels have been
`
`reported (7.1)
`
`
`
`
`
`
`
`
`---------------USE IN SPECIFIC POPULATIONS------------
`• Pregnancy: Based on animal data, may cause
`fetal harm. Pregnancy registry available (8.1)
`• Nursing Mothers: SABRIL is excreted in human
`milk (8.2)
`• Renal Impairment: Dose adjustment
`recommended (2.2, 8.4, 8.5)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`and FDA-approved patient labeling (Medication
`
`Guide).
`
`
`Issued: 08/07/09
`
`
`
`FDA-approved labeling 8/21/09
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information
`needed to use SABRIL safely and effectively. See
`
`full prescribing information for SABRIL.
`
`SABRIL® (vigabatrin) Tablets
`
`
`For Oral Administration Only
`Initial U.S. Approval: Pending
`
`
`
` Only
`
`
`WARNING: VISION LOSS
`
`See full prescribing information for
`complete boxed warning
`
`
`• SABRIL causes progressive and permanent bilateral
`
`concentric visual field constriction in a high percentage
`of patients. In some cases, SABRIL may also reduce
`visual acuity.
`• Risk increases with total dose and duration of use, but
`no exposure to SABRIL is known that is free of risk of
`vision loss
`• Risk of new and worsening vision loss continues as long
`as SABRIL is used, and possibly after discontinuing
`
`SABRIL
`• Periodic vision testing is required for patients on
`SABRIL, but cannot reliably prevent vision damage
`• Because of the risk of permanent vision loss, SABRIL is
`available only through a special restricted distribution
`program
`
`
`
`
`
`
`----------------INDICATIONS AND USAGE-------------------
`SABRIL is an antiepileptic drug (AED) indicated for:
`• Refractory Complex Partial Seizures in Adults
`
`(1.1). It should be used as adjunctive therapy in
`patients who have responded inadequately to
`
`
`several alternative treatments.
`
`
`-------------DOSAGE AND ADMINISTRATION--------------
`• Refractory Complex Partial Seizures in Adults:
`
`Initiate therapy at 500 mg twice daily, increasing
`total daily dose per instructions. The
`recommended dose is 1.5 grams twice daily (2.1).
`• Dose adjustment recommended in renally
`
`
`impaired patients (2.2)
`• Reduce dose gradually upon discontinuation (2.3)
`
`
`
`------------DOSAGE FORM AND STRENGTHS------------
`
`Tablet: 500 mg (3.1)
`
`--------------------CONTRAINDICATIONS---------------------
`None (4)
`
`
`
`
`
`ARGENTUM Exhibit 1210
`Argentum Pharmaceuticals LLC v. Research Corporation Technologies, inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`FDA-approved labeling 8/21/09
`
`
`3
`
`
`4
`5
`
`
`
`
`
`
`
`
`6
`
`
`
`7
`
`FULL PRESCRIBING INFORMATION: CONTENTS
`WARNING: VISION LOSS
`1
`INDICATIONS AND USAGE
`
`1.1
`Refractory Complex Partial Seizures in Adults
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`Refractory Complex Partial Seizures in Adults
`
`2.1
`2.2
`Patients with Renal Impairment
`
`2.3
`General Dosing Considerations
`
`DOSAGE FORMS AND STRENGTHS
`
`3.1
`Tablet
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`Vision Loss (see BOXED WARNING)
`
`
`5.2
`Distribution Program for SABRIL
`
`5.3
`Magnetic Resonance Imaging (MRI) Abnormalities
`
`Neurotoxicity
`
`5.4
`
`Suicidal Behavior and Ideation
`
`5.5
`5.6
`Withdrawal of Antiepileptic Drugs (AEDs)
`
`5.7
`Anemia
`5.8
`Somnolence and Fatigue
`
`Peripheral Neuropathy
`
`5.9
`
`5.10
`Weight Gain
`5.11
`Edema
`ADVERSE REACTIONS
`
`Adverse Reactions in Clinical Trials
`
`6.1
`6.2
`Post Marketing Experience
`
`DRUG INTERACTIONS
`7.1
`Phenytoin
`7.2
`Other AEDs
`7.3
`Clonazepam
`7.4
`Oral Contraceptives
`7.5
`Drug-Laboratory Test Interactions
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`
`8.1
`
`Nursing Mothers
`
`8.2
`8.3
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Renal Impairment
`DRUG ABUSE AND DEPENDENCE
`
`9.1
`Controlled Substance Class
`
`9.2
`Abuse
`9.3
`Dependence
`OVERDOSAGE
`
`Signs, Symptoms, and Laboratory Findings of Overdosage
`
`10.1
`10.2
`Treatment or Management for Overdosage
`
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`12.1
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.1
`
`CLINICAL STUDIES
`
`Complex Partial Seizures in Adults
`
`14.1
`
`REFERENCES
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1
`SABRIL Tablet
`
`PATIENT COUNSELING INFORMATION
`17.1
`Vision Loss
`17.2
`Suicidal Thinking and Behavior
`
`17.3
`Use in Pregnancy
`
`17.4
`Withdrawal of SABRIL Therapy
`
`17.5
`FDA-Approved Medication Guide
`
`
`14
`
`15
`16
`
`17
`
`
`
`
`
`
`
`
`8
`
`
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`10
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`11
`12
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`13
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`
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`49
`50
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`
`Page 00002
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`
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`
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`
`
`
`
`
`
`
`
`

`
`
`
`
`
`
`
`
`
` WARNING: VISION LOSS
`
`
`
` • SABRIL causes permanent bilateral concentric visual field constriction in 30 percent or
`more of patients that ranges in severity from mild to severe, including tunnel vision to
`within 10 degrees of visual fixation, and can result in disability. In some cases, SABRIL
`also can damage the central retina and may decrease visual acuity.
`• The onset of vision loss from SABRIL is unpredictable, and can occur within weeks of
`starting treatment or sooner, or at any time during 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
`• Vision testing at baseline (no later than 4 weeks after starting SABRIL) and at least
`every 3 months during therapy is required for adults on SABRIL. Vision testing is also
`required about 3 to 6 months after the discontinuation of SABRIL therapy. Once
`
`detected, vision loss due to SABRIL is not reversible. It is expected that, even with
`frequent monitoring, some patients will develop severe vision loss.
`• It is possible that vision loss can worsen despite discontinuation of SABRIL
`• Because of the risk of vision loss, SABRIL should be withdrawn from patients who fail
`to show substantial clinical benefit within 3 months of initiation, or sooner if treatment
`failure becomes obvious. Patient response to and continued need for SABRIL should
`be periodically reassessed.
`• Symptoms of vision loss from SABRIL 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, can still adversely affect function.
`• SABRIL 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
`SABRIL has not been well-characterized, but is likely adverse.
`• SABRIL 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
`• The lowest dose and shortest exposure to SABRIL should be used that is consistent
`with clinical objectives
`
`
`
`
`Because of the risk of permanent vision loss, SABRIL is available only through a special
`restricted distribution program called SHARE, by calling 1-888-45-SHARE. Only
`prescribers and pharmacies registered with SHARE may prescribe and distribute SABRIL.
`In addition, SABRIL may be dispensed only to patients who are enrolled in and meet all
`conditions of SHARE [see WARNINGS AND PRECAUTIONS, Distribution Program for
`
`SABRIL (5.2)].
`
`
`INDICATIONS AND USAGE
`
`
`
`1
`
`1.1 Refractory Complex Partial Seizures in Adults
`SABRIL® is indicated as adjunctive therapy for adult patients with refractory
`complex partial seizures (CPS) who have inadequately responded to several
`alternative treatments and for whom the potential benefits outweigh the risk of
`
`
`
`
`
`Page 00003
`
`

`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`vision loss [see WARNINGS AND PRECAUTIONS, Vision Loss (5.1)]. SABRIL is
`not indicated as a first line agent for complex partial seizures.
`
`2
`
`2.1 Refractory Complex Partial Seizures in Adults
`SABRIL 500 mg tablets should be given as twice daily oral administration with or
`without food. Therapy should be initiated at 1 g/day (500 mg twice daily). Total
`daily dose may be increased in 500 mg increments at weekly intervals depending
`on response. The recommended dose of SABRIL in adults is 3 g/day (1.5 g
`twice daily). A 6 g/day dose has not been shown to confer additional benefit
`compared to the 3 g/day dose and is associated with an increased incidence of
`adverse events.
`
`2.2 Patients with Renal Impairment
`SABRIL is primarily eliminated through the kidney. In patients with renal
`impairment, dose adjustments should be made as follows:
`
`In patients with mild renal impairment (CLcr >50 to 80 mL/min), the dose should
`be decreased by 25%; in patients with moderate renal impairment (CLcr >30 to
`50 mL/min), the dose should be decreased by 50%; and in patients with severe
`renal impairment (CLcr >10 to <30 mL/min), the dose should be decreased by
`75%.
`
`CLcr in mL/min may be estimated from a serum creatinine (mg/dL) determination
`using the following formula:
`
`CLcr *= [140-age (years)]×weight (kg)/72×serum creatinine (mg/dL)]
`*[×0.85 for female patients]
`
`
`The effect of dialysis on SABRIL clearance has not been adequately studied.
`
`
`[see CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Impairment (12.3)
`and USE IN SPECIFIC POPULATIONS, Renal Impairment (8.5)].
`
`2.3 General Dosing Considerations
`
`SABRIL should be withdrawn gradually. In controlled clinical studies in adults
`with CPS, vigabatrin was tapered by decreasing the daily dose 1 g/day on a
`weekly basis until discontinued [see WARNINGS AND PRECAUTIONS,
`Withdrawal of Antiepileptic Drugs (AEDs) (5.6)].
`
`
`
`
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Tablet
`3.1
`
`500 mg Tablet.
`
`
`
`
`Page 00004
`
`

`
`CONTRAINDICATIONS
`
`
`
`4
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`5.1 Vision Loss (see BOXED WARNING)
`
`Because of the risk of vision loss and because SABRIL, when it is effective,
`
`provides an observable symptomatic benefit, a patient who fails to show
`substantial clinical benefit within 3 months of initiation of treatment, should
`be withdrawn from SABRIL. If in the clinical judgment of the prescriber
`evidence of treatment failure becomes obvious earlier than 3 months,
`treatment with SABRIL should be discontinued at that time. Patient
`
`response to and continued need for treatment should be periodically
`assessed.
`
`Monitoring of Vision
`
`Monitoring of vision by an ophthalmic professional with expertise in visual field
`interpretation and the ability to perform dilated indirect ophthalmoscopy of the
`retina is required. Vision testing at baseline (no later than 4 weeks after starting
`SABRIL) and at least every 3 months is required for adults on SABRIL. Vision
`testing is also required about 3 to 6 months after the discontinuation of SABRIL
`therapy.
`
`The diagnostic approach should be individualized for the patient and clinical
`situation, but for all patients attempts to monitor vision periodically must be
`documented under the SHARE program. Perimetry is recommended, preferably
`by automated threshold visual field testing. Additional testing may also include
`electrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., optical
`coherence tomography [OCT]), and/or other methods appropriate for the patient.
`In patients in whom vision testing is not possible, treatment may continue
`according to clinical judgment, with appropriate patient counseling and with
`documentation in the SHARE program of the inability to test vision. Because of
`variability, results from ophthalmic monitoring must be interpreted with caution,
`and repeat testing is recommended if results are abnormal or uninterpretable.
`Repeat testing in the first few weeks of treatment is recommended to establish if,
`and to what degree, reproducible results can be obtained, and to guide selection
`of appropriate ongoing monitoring for the patient.
`
`The onset and progression of vision loss from SABRIL is unpredictable, and it
`may occur or worsen precipitously between tests. Once detected, vision loss
`due to SABRIL is not reversible. It is expected that even with frequent monitoring,
`some SABRIL patients will develop severe vision loss.
`
`5.2 Distribution Program for SABRIL
`
`
`
`
`
`Page 00005
`
`

`
`
`
`SABRIL is available only under a special restricted distribution program called
`the SHARE program. Under the SHARE program, only prescribers and
`pharmacies registered with the program are able to prescribe and distribute
`SABRIL. In addition, SABRIL may be dispensed only to patients who are enrolled
`in and meet all conditions of SHARE. Contact the SHARE program at 1-888-45­
`SHARE.
`
`To enroll in SHARE, prescribers must understand the risks of SABRIL and
`complete the SHARE Prescriber Enrollment and Agreement Form indicating
`agreement to:
`
`
`• Enroll all patients in SHARE
`• Review the SABRIL Medication Guide with every patient
`• Educate patients on the risks of SABRIL, including the risk of vision loss
`[see BOXED WARNING: VISION LOSS]
`• Order and review vision assessments at initiation of SABRIL treatment
`and every 3 months during therapy
`• Remove patients from SABRIL therapy if the patients do not experience
`meaningful reduction in seizures
`• Counsel patients who fail to comply with the program requirements
`• Remove patients from SABRIL therapy who fail to comply with the
`
`program requirements after appropriate counseling
`
`
`
`
`
`5.3 Magnetic Resonance Imaging (MRI) Abnormalities
`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 for
`Infantile Spasms (IS) with vigabatrin. In a retrospective epidemiologic study in
`infants with IS (N=205), the prevalence of these changes was 21.5% in
`vigabatrin-treated patients versus 4.1% in patients treated with other therapies.
`
`In the study above, 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 (including convulsions and hypomyelination) was observed in rats
`exposed to vigabatrin during late gestation and the neonatal and juvenile periods
`of development. The relationship between these findings and the abnormal MRI
`findings in infants treated for IS with vigabatrin is unknown [see WARNINGS
`AND PRECAUTIONS, Neurotoxicity (5.4) and USE IN SPECIFIC
`POPULATIONS, Pregnancy (8.1)].
`
`
`
`
`Page 00006
`
`

`
`The specific pattern of signal changes observed in IS patients was not observed
`in older children and adult patients treated with vigabatrin for CPS. In a blinded
`review of MRI images obtained in prospective clinical trials in patients with 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
`patients.
`
`
`
`
`
`For adults treated with SABRIL, routine MRI surveillance is unnecessary as there
`is no evidence that vigabatrin causes MRI changes in this population.
`
`5.4 Neurotoxicity
`
`Vacuolization, 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, vacuolization 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.
`Vacuolization in adult animals was correlated with alterations in MRI and
`changes in visual and somatosensory evoked potentials (EP).
`
`Administration of vigabatrin to rats during the neonatal and juvenile periods of
`development produced vacuolar changes in the gray matter (areas 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, retinal dysplasia, and
`neurobehavioral abnormalities (convulsions, neuromotor impairment, learning
`deficits) were also observed following vigabatrin treatment of young rats. These
`effects occurred at doses associated with plasma vigabatrin levels substantially
`lower than those achieved clinically in infants and children.
`
`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 5-7.
`
`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.
`
`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 for IS
`with vigabatrin. Studies of the effects of vigabatrin on MRI and EP in adult
`
`
`
`Page 00007
`
`

`
`epilepsy patients have demonstrated no clear-cut abnormalities [see WARNINGS
`AND PRECAUTIONS, MRI Abnormalities (5.3)].
`
`
`
`5.5 Suicidal Behavior and Ideation
`Antiepileptic drugs (AEDs), including SABRIL, 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 (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and
`relative risk by indication for all evaluated AEDs.
`
`Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
`Indication
`Placebo Patients Drug Patients
`
` Relative Risk: Incidence Risk Difference:
`
` Additional Drug
`with Events per
`with Events per
`of Drug Events in Drug
`Patients with Events
`1000 Patients
`1000 Patients
`Patients/Incidence in
`Placebo Patients
`per 1000 Patients
`3.5
`2.4
`1.5
`2.9
`1.9
`0.9
`1.8
`1.9
`
`Epilepsy
`Psychiatric
`Other
`Total
`
`1.0
`5.7
`1.0
`2.4
`
`
`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.
`
`
`3.4
`8.5
`1.8
`4.3
`
`
`
`Page 00008
`
`

`
`
`
`Anyone considering prescribing SABRIL 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.
`
`
`5.6 Withdrawal of Antiepileptic Drugs (AEDs)
`
`As with all AEDs, SABRIL should be withdrawn gradually. In controlled clinical
`studies in adults with CPS, SABRIL was tapered by decreasing the daily dose 1
`g/day on a weekly basis until discontinued [see DOSAGE AND
`ADMINISTRATION, General Dosing Considerations (2.3), PATIENT
`COUNSELING INFORMATION, Withdrawal of SABRIL Therapy (17.4)].
`
`5.7 Anemia
`In North American controlled trials, 5.7% of patients (16/280) receiving SABRIL
`and 1.6% 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 SABRIL
`and placebo-treated patients, respectively, and in hematocrit of about 1% in
`Sabril treated patients compared to a gain of about 1% in patients treated with
`placebo.
`
`In controlled and open label epilepsy trials, 3 SABRIL patients (0.06%, 3/4855)
`discontinued for anemia and 2 SABRIL patients experienced unexplained
`declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%.
`
`5.8 Somnolence and Fatigue
`SABRIL 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 SABRIL on their ability to perform such activities.
`
`Pooled data from two SABRIL controlled trials demonstrated that 24% (54/222)
`of SABRIL patients experienced somnolence compared to 10% (14/135) of
`
`placebo patients. In those same studies, 28% of SABRIL patients experienced
`fatigue compared to 15% (20/135) of placebo patients. Almost 1% of SABRIL
`
`
`
`Page 00009
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`

`
`
`
`patients discontinued from clinical trials for somnolence and almost 1%
`discontinued for fatigue.
`
`
`5.9 Peripheral Neuropathy
`SABRIL causes symptoms of peripheral neuropathy. In a pool of North American
`controlled and uncontrolled epilepsy studies, 4.2% (19/457) of SABRIL patients
`developed signs and/or symptoms of peripheral neuropathy. In the subset of
`North American placebo-controlled epilepsy trials, 1.4% (4/280) of SABRIL
`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 theses signs and symptoms
`were related to duration of SABRIL treatment, cumulative dose, or if the findings
`of peripheral neuropathy were completely reversible upon discontinuation of
`SABRIL.
`
`5.10 Weight Gain
`SABRIL causes weight gain. Data pooled from randomized controlled trials found
`that 17% (77/443) of SABRIL patients versus 8% (22/275) of placebo patients
`gained ≥7% of baseline body weight. In these same trials, the mean weight
`change among SABRIL patients was 3.5 kg compared to 1.6 kg for placebo
`patients. In all epilepsy trials, 0.6% (31/4855) of SABRIL patients discontinued for
`weight gain. The long term effects of SABRIL related weight gain are not known.
`Weight gain was not related to the occurrence of edema.
`
`5.11 Edema
`SABRIL causes edema. Pooled data from controlled trials demonstrated
`increased risk among SABRIL patients compared to placebo patients for
`peripheral edema (SABRIL 2%, placebo 1%), and edema (SABRIL 1%, placebo
`0%). In these studies, one SABRIL and no placebo patients discontinued for an
`edema related AE. 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.
`
`
`6
`ADVERSE REACTIONS
`SABRIL causes permanent damage to vision in a high percentage of patients
`[see BOXED WARNING: VISION LOSS and WARNINGS AND PRECAUTIONS,
`Vision Loss (5.1)].
`
`
`
`
`
`Page 00010
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`

`
`
`
`6.1 Adverse Reactions in Clinical Trials
`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.
`
`Adverse Reactions in U.S. and Primary Non-U.S. Clinical Studies
`In U.S. and primary non-U.S. clinical studies of 4,079 SABRIL treated patients,
`the most commonly observed (≥5%) adverse reactions associated with the use of
`SABRIL in combination with other AEDs were headache (18%), somnolence
`(17%), fatigue (16%), dizziness (15%), convulsion (11%), nasopharyngitis (10%),
`weight increased (10%), upper respiratory tract infection (10%), visual field defect
`(9%), depression (8%), tremor (7%), nystagmus (7%), nausea (7%), diarrhea
`(7%), memory impairment (7%), insomnia (7%), irritability (7%), coordination
`
`abnormal (7%), vision blurred (6%), diplopia (6%), vomiting (6%), influenza (6%),
`pyrexia (6%), and rash (6%).
`
`The adverse reactions most commonly associated with SABRIL treatment
`discontinuation in ≥1% of patients were convulsion (1.4%) and depression
`(1.5%).
`
`Most Common Adverse Reactions in Controlled Clinical Trials
`
`
`
`
`
`Refractory Complex Partial Seizures in Adults
`Table 2 lists the treatment emergent adverse reactions that occurred in ≥2%
`and more than one patient per SABRIL-treated group and that occurred more
`frequently than in placebo patients from 2 U.S. add-on clinical studies of
`refractory CPS in adults.
`
`
`
`
`
`
`
`
`Table 2. Treatment Emergent Adverse Reactions Occurring in
`≥2% and More than One Patient per SABRIL-Treated Group
`and More Frequently than in Placebo Patients (Studies 024
`and 025)
`Body System
`
`Preferred Term
`
`Placebo
`(N=135)
`n(%)
`
`
`
`2 (1)
`2 (1)
`
`7 (5)
`4 (3)
`0 (0)
`0 (0)
`
`10 (7)
`11 (8)
`8 (6)
`
`SABRIL
`6 g/day
`
`(N=43)
`n(%)
`
`
`0 (0)
`2 (5)
`
`7 (16)
`7 (16)
`1 (2)
`2 (5)
`
`
`7 (16)
`1 (2)
`4 (9)
`
`
`
`SABRIL
`3 g/day
`
`(N=134)
`n(%)
`
`
`3 (2)
`3 (2)
`
`
`18 (13)
`9 (7)
`3 (2)
`0 (0)
`
`
`14 (10)
`
`13 (10)
`9 (7)
`
`
`
`Ear Disorders
`Tinnitus
`Vertigo
`Eye Disorders
`
`Vision blurred
`Diplopia
`Asthenopia
`Eye pain
`Gastrointestinal Disorders
`Diarrhoea
`
`Nausea
`Vomiting
`
`Page 00011
`
`

`
`Table 2. Treatment Emergent Adverse Reactions Occurring in
`≥2% and More than One Patient per SABRIL-Treated Group
`and More Frequently than in Placebo Patients (Studies 024
`and 025)
`Body System
`
`Preferred Term
`
`
`
`Placebo
`(N=135)
`n(%)
`
`
`4 (3)
`2 (1)
`4 (3)
`1 (1)
`2 (1)
`3 (2)
`1 (1)
`
`
`21 (16)
`9 (7)
`2 (1)
`1 (1)
`4 (3)
`2 (1)
`0 (0)
`0 (0)
`
`
`14 (10)
`8 (6)
`
`5 (4)
`0 (0)
`2 (1)
`
`3 (2)
`1 (1)
`2 (1)
`0 (0)
`
`
`1 (1)
`4 (3)
`
`4 (3)
`3 (2)
`5 (4)
`2 (1)
`2 (1)
`1 (1)
`
`
`42 (31)
`
`18 (13)
`
`23 (17)
`12 (9)
`11 (8)
`4 (3)
`
`SABRIL
`3 g/day
`
`(N=134)
`n(%)
`
`11 (8)
`7 (5)
`6 (4)
`5 (4)
`4 (3)
`3 (2)
`3 (2)
`
`
`31 (23)
`8 (6)
`7 (5)
`7 (5)
`6 (4)
`2 (1)
`3 (2)
`0 (0)
`
`
`19 (14)
`10 (7)
`
`SABRIL
`6 g/day
`
`(N=43)
`n(%)
`
`2 (5)
`2 (5)
`2 (5)
`1 (2)
`1 (2)
`2 (5)
`0 (0)
`
`
`17 (40)
`
`5 (12)
`3 (7)
`3 (7)
`3 (7)
`2 (5)
`0 (0)
`2 (5)
`
`4 (9)
`4 (9)
`
`3 (7)
`2 (5)
`2 (5)
`
`2 (5)
`1 (2)
`1 (2)
`1 (2)
`
`
`2 (5)
`
`6 (14)
`
`2 (5)
`3 (7)
`1 (2)
`2 (5)
`4 (9)
`0 (0)
`
`
`11 (26)
`
`11 (26)
`
`11 (26)
`
`8 (19)
`7 (16)
`7 (16)
`
`
`
`7 (5)
`5 (4)
`0 (0)
`
`4 (3)
`2 (1)
`1 (1)
`0 (0)
`
`
`2 (1)
`8 (6)
`
`
`14 (10)
`6 (4)
`8 (6)
`4 (3)
`1 (1)
`4 (3)
`
`
`44 (33)
`
`29 (22)
`
`32 (24)
`
`17 (13)
`
`20 (15)
`9 (7)
`
`
`
`Constipation
`Abdominal pain upper
`Dyspepsia
`Stomach discomfort
`Abdominal pain
`Toothache
`Abdominal distension
`General Disorders
`Fatigue
`Gait disturbance
`Asthenia
`Oedema peripheral
`Fever
`Chest pain
`Thirst
`Malaise
`Infections
`Nasopharyngitis
`Upper respiratory tract
`infection
`Influenza
`Urinary tract infection
`Bronchitis
`
`Injury
`Contusion
`Joint sprain
`
`Muscle strain
`Wound secretion
`Metabolism and Nutrition
`Disorders
`Increased appetite
`Weight increased
`Musculoskeletal Disorders
`Arthralgia
`Back pain
`
`Pain in extremity
`Myalgia
`Muscle twitching
`Muscle spasms
`Nervous System Disorders
`Headache
`Somnolence
`Dizziness
`Nystagmus
`
`Tremor
`Memory impairment
`
`Page 00012
`
`

`
`Table 2. Treatment Emergent Adverse Reactions Occurring in
`≥2% and More than One Patient per SABRIL-Treated Group
`and More Frequently than in Placebo Patients (Studies 024
`and 025)
`Body System
`
`Preferred Term
`
`
`
`Placebo
`(N=135)
`n(%)
`
`
`Coordination abnormal
`Disturbance in attention
`Sensory disturbance
`Hyporeflexia
`Paraesthesia
`Lethargy
`Hyperreflexia
`Hypoaesthesia
`Sedation
`
`Status epilepticus
`
`Dysarthria
`Postictal state
`
`Sensory loss
`Psychiatric Disorders
`Irritability
`Depression
`Confusional state
`
`Anxiety
`Depressed mood
`Thinking abnormal
`Abnormal behaviour
`Expressive language
`
`disorder
`
`Nervousness
`Abnormal dreams
`Reproductive System
`Dysmenorrhoea
`Erectile dysfunction
`Respiratory and Thoracic
`Disorders
`Pharyngolaryngeal pain
`Cough
`Pulmonary congestion
`
`Sinus headache
`
`Skin and Subcutaneous
`Tissue Disorders
`Rash
`
`