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vigabatrin tablet, film coated
FULL PRESCRIBING INFORMATION
WARNING: VISION LOSS
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)].
1 INDICATIONS AND USAGE
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 vision loss [see WARNINGS AND PRECAUTIONS, Vision Loss (5.1)]. SABRIL is not indicated as a first line agent for complex partial seizures.
2 DOSAGE AND ADMINISTRATION
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)]x weight (kg)/72x serum creatinine (mg/dL)]
*[x 0.85 for female patients]
The effect of dialysis on SABRIL clearance has not been adequately studied.
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SABRIL should be withdrawn gradually.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)].
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
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:
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)].
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.
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.
IME has been reported in a vigabatrin treated infant on postmortem examination. The infant had hypoxic ischemic brain injury and abnormalities of myelin prior to vigabatrin treatment.
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 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.
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 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)].
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 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 these 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.
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)].
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.
6.2 Post Marketing Experience
The following serious adverse events have been reported since approval and use of SABRIL worldwide. All serious adverse events that are not listed above as adverse events reported in clinical trials, that are not relatively common in the population and are not too vague to be useful are listed in this section. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Events 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
Endocrine: Delayed puberty
Gastrointestinal: Gastrointestinal hemorrhage, esophagitis
General: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure
Nervous System: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis
Psychiatric: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder
Respiratory: Laryngeal edema, pulmonary embolism, respiratory failure, stridor
Skin and Subcutaneous Tissue: Angioedema, maculo-papular rash, pruritus
7 DRUG INTERACTIONS
For detailed information about Drug Interactions see CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions (12.3).
A 16% to 20% average reduction in total phenytoin plasma levels was reported in controlled clinical studies.
7.2 Other AEDs
There are no clinically significant pharmacokinetic interactions between SABRIL and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin.
In a study of 12 healthy volunteers, clonazepam (0.5 mg) co-administration had no effect on SABRIL (1.5 g twice daily) concentrations. SABRIL increases the mean Cmax of clonazepam by 30% and decreases the mean tmax by 45%.
7.5 Drug-Laboratory Test Interactions
SABRIL 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 SABRIL may preclude the use of these markers, especially ALT, to detect early hepatic injury.
SABRIL 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).
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C. Vigabatrin produced developmental toxicity, including teratogenic and neurohistopathological effects, when administered to pregnant animals at clinically relevant doses. In addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy. There are no adequate and well-controlled studies in pregnant women. SABRIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of vigabatrin (oral doses of 50 to 200 mg/kg) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryo-fetal death; these findings were observed in two separate studies. The no-effect dose for teratogenicity and embryolethality in rabbits (100 mg/kg) is approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a body surface area (mg/m2) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for embryo-fetal toxicity in rats (50 mg/kg) is approximately 1/5 the MRHD on a mg/m2 basis. Oral administration of vigabatrin (50, 100, 150 mg/kg) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. A no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg) is approximately 1/5 the MRHD on a mg/m2 basis.
In a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in malformations (including cleft palate) was observed at both doses.
Oral administration of vigabatrin (5, 15, or 50 mg/kg) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.
Pregnancy Registry: To provide information regarding the effects of in utero exposure to SABRIL, physicians are advised to recommend that pregnant patients taking SABRIL enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
8.3 Nursing Mothers
Vigabatrin is excreted in human milk. Because of the potential for serious adverse reactions from vigabatrin in nursing infants [see WARNINGS AND PRECAUTIONS, MRI Abnormalities (5.3) and Neurotoxicity (5.4)], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and efficacy of SABRIL in pediatric patients (<16 years of age) with CPS has not been established.
Oral administration of vigabatrin (5, 15, or 50 mg/kg) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.
8.5 Geriatric Use
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 CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Impairment (12.3) and DOSAGE AND ADMINISTRATION, Patients with Renal Impairment (2.2)].
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
8.6 Renal Impairment
Dose adjustment, including initiating treatment with a lower dose, is necessary in patients with mild (creatinine clearance >50-80 mL/min), moderate (creatinine clearance >30-50 mL/min) and severe (creatinine clearance >10-30 mL/min) renal impairment [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Impairment (12.3) and DOSAGE AND ADMINISTRATION, Patients with Renal Impairment (2.2)].
9 DRUG ABUSE AND DEPENDENCE
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).
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, Withdrawal of Antiepileptic Drugs (AEDs) (5.6) and PATIENT COUNSELING INFORMATION, Withdrawal of SABRIL Therapy (17.4)].
10.1 Signs, Symptoms, and Laboratory Findings of Overdosage
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.
10.2 Treatment or Management for Overdosage
There is no specific antidote for SABRIL 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 patients.
In an in vitro study, activated charcoal did not significantly adsorb vigabatrin.
The effectiveness of hemodialysis in the treatment of SABRIL 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%.
SABRIL (vigabatrin) is available as a white, film-coated tablet for oral administration. Each tablet contains 500 mg vigabatrin. Tablets also contain as inactive ingredients: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycols, povidone, sodium starch glycolate, and titanium dioxide. Vigabatrin is an oral antiepileptic drug with the chemical name (±) 4-amino-5-hexenoic acid. It is a racemate consisting of two enantiomers. The molecular formula is C6H11NO2 and the molecular weight is 129.16.
Vigabatrin 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 melts with decomposition in a 3-degree range within the temperature interval of 171 °C to 176 °C. The dissociation constants (pKa) of vigabatrin are 4 and 9.7 at room temperature (25 °C).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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 y-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.
Effects on Electrocardiogram
There is no indication of a QT/QTc prolonging effect of SABRIL in single doses up to 6.0 g. In a randomized, placebo-controlled, crossover study, 58 healthy subjects were administered a single oral dose of SABRIL (3 g and 6 g) and placebo. Peak concentrations for 6.0 g SABRIL were approximately 2-fold higher than the peak concentrations following the 3.0 g single oral dose.
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 with a half-life of about 7.5 hours. Bioequivalence has been established between the oral solution and tablet formulations.
Following oral administration, vigabatrin is essentially completely absorbed. Time to maximum concentration (tmax) is approximately 1 hour following single and multiple doses. There was little accumulation with multiple dosing. A food effect study involving administration of vigabatrin to healthy volunteers under fasting and fed conditions indicated that the Cmax was decreased by 33%, tmax was increased to 2 hours, and AUC was unchanged under fed conditions [see DOSAGE AND ADMINISTRATION (2)].
Vigabatrin does not bind to plasma proteins. Vigabatrin is widely distributed throughout the body; mean steady-state volume of distribution is 1.1 L/Kg (CV = 20%).
Metabolism and Elimination
Vigabatrin is not significantly metabolized; it is eliminated primarily through renal excretion. The half-life of vigabatrin is about 7.5 hours. Following administration of C-vigabatrin to healthy male volunteers, about 95% of total radioactivity was recovered in the urine over 72 hours with the parent drug representing about 80% of this. Vigabatrin induces CYP2C9, but does not induce other hepatic cytochrome P450 enzyme systems.
Pharmacokinetics in Special Populations
The renal clearance of vigabatrin in healthy elderly patients (≥ 65 years of age) was 36% less than those in healthy younger patients. This finding is confirmed by an analysis of data from a controlled clinical trial.
No gender differences were observed for the pharmacokinetic parameters of vigabatrin in patients.
No specific study was conducted to investigate the effects of race on SABRIL pharmacokinetics. A cross study comparison between 23 Caucasian and 7 Japanese patients who received 1, 2, and 4 g of vigabatrin indicated that the AUC, Cmax, and half-life were similar for the two populations. However, the mean renal clearance of Caucasians (5.2 L/hr) was about 25% higher than the Japanese (4.0 L/hr). Inter-subject variability in renal clearance was 20% in Caucasians and was 30% in Japanese.
Mean AUC increased by 30% and the terminal half-life increased by 55% (8.1 hr vs 12.5 hr) in patients with mild renal impairment (CLcr from >50-80 mL/min) in comparison to normal subjects.
Mean AUC increased by two-fold and the terminal half-life increased by two-fold in patients with moderate renal impairment (CLcr from >30-50 mL/min) in comparison to normal subjects.
Mean AUC increased by 4.5-fold and the terminal half-life increased by 3.5-fold in patients with severe renal impairment (CLcr from >10-30 mL/min) in comparison to normal subjects.
Dosage adjustment, including starting at a lower dose, is recommended for patients with any degree of renal impairment [see USE IN SPECIFIC POPULATIONS, Renal Impairment (8.6) and DOSAGE AND ADMINISTRATION, Patients with Renal Impairment (2.2)].
Vigabatrin is not significantly metabolized. The pharmacokinetics of vigabatrin in patients with impaired liver function have not been studied.
A 16% to 20% average reduction in total phenytoin plasma levels was reported in controlled clinical studies. In vitro drug metabolism studies indicate that decreased phenytoin concentrations upon addition of vigabatrin therapy are likely to be the result of induction of cytochrome P450 2C enzymes in some patients. Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated.
When co-administered with vigabatrin, phenobarbital concentration (from phenobarbital or primidone) was reduced by an average of 8% to 16%, and sodium valproate plasma concentrations were reduced by an average of 8%. These reductions did not appear to be clinically relevant. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin.
In a study of 12 healthy volunteers, clonazepam (0.5 mg) co-administration had no effect on SABRIL (1.5 g twice daily) concentrations. SABRIL increases the mean Cmax of clonazepam by 30% and decreases the mean tmax by 45%.
Co-administration of ethanol (0.6 g/kg) with vigabatrin (1.5 g twice daily) indicated that neither drug influences the pharmacokinetics of the other.
In a double-blind, placebo-controlled study using a combination oral contraceptive containing 30 μg ethinyl estradiol and 150 μg levonorgestrel, vigabatrin (3 g/day) did not interfere significantly with the cytochrome P450 isoenzyme (CYP3A)-mediated metabolism of the contraceptive tested. Based on this study, vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives. Additionally, no significant difference in pharmacokinetic parameters (elimination half-life, AUC, Cmax, apparent oral clearance, time to peak, and apparent volume of distribution) of vigabatrin were found after treatment with ethinyl estradiol and levonorgestrel.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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) of 3 g/day on a mg/m2 basis.
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 1/2 the MRHD on a mg/m2 basis).
14 CLINICAL STUDIES
14.1 Complex Partial Seizures in Adults
The effectiveness of SABRIL as adjunctive therapy in adult patients with CPS was established in two U.S. multicenter, double-blind, placebo-controlled, parallel-group clinical studies. A total of 357 adults (age 18 to 60 years) with CPS, with or without secondary generalization were enrolled (Studies 1 and 2). Patients were required to be on an adequate and stable dose of an anticonvulsant, and have a history of failure on an adequate regimen of carbamazepine or phenytoin. Patients had a history of about 8 seizures per month (median) for about 20 years (median) prior to entrance into the study. These studies were not capable by design of demonstrating direct superiority of SABRIL over any other anticonvulsant added to a regimen to which the patient had not adequately responded. Further, in these studies patients had previously been treated with a limited range of anticonvulsants.
The primary measure of efficacy was the patient's reduction in mean monthly frequency of complex partial seizures plus partial seizures secondarily generalized at end of study compared to baseline.
Study 1 (N=174) was a randomized, double-blind, placebo-controlled, dose-response study consisting of an 8-week baseline period followed by an 18-week treatment period. Patients were randomized to receive placebo or 1, 3, or 6 g/day vigabatrin administered twice daily. During the first 6 weeks following randomization, the dose was titrated upward beginning with 1 g/day and increasing by 0.5 g/day on days 1 and 5 of each subsequent week in the 3 g/day and 6 g/day groups, until the assigned dose was reached.
Results for the primary measure of effectiveness, reduction in mean monthly frequency of Complex Partial Seizures, are shown in Table 4. The 3 g/day and 6 g/day dose groups were statistically significantly superior to placebo, but the 6 g/day dose was not superior to the 3 g/day dose.
Figure 1 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in complex partial seizure frequency was consistently higher for the SABRIL 3 and 6 g/day groups compared to the placebo group. For example, 51% of patients randomized to SABRIL 3 g/day and 53% of patients randomized to Sabril 6 g/day experienced a 50% or greater reduction in seizure frequency, compared to 9% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.
Figure 1. Percent Reduction from Baseline in Seizure Frequency
Study 2 (N=183 randomized, 182 evaluated for efficacy) was a randomized, double-blind, placebo-controlled, parallel study consisting of an 8-week baseline period and a 16-week treatment period. During the first 4 weeks following randomization, the dose of vigabatrin was titrated upward beginning with 1 g/day and increased by 0.5 g/day on a weekly basis to the maintenance dose of 3 g/day.
Results for the primary measure of effectiveness, reduction in mean monthly complex partial seizure frequency, are shown in Table 5. Vigabatrin 3 g/day was statistically significantly superior to placebo in reducing seizure frequency.
Figure 2 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the SABRIL 3 g/day group compared to the placebo group. For example, 39% of patients randomized to SABRIL (3 g/day) experienced a 50% or greater reduction in complex partial seizure frequency, compared to 21% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.
Figure 2. Percent Reduction from Baseline in Seizure Frequency
For both studies, there was no difference in the effectiveness of vigabatrin between male and female patients. Analyses of age and race were not possible as nearly all patients were between the ages of 18 to 65 and Caucasian.
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (17.5)
Patients must be informed of the availability of a Medication Guide. Patients must be instructed to read the Medication Guide prior to initiating treatment with SABRIL and with each prescription refill. Doctors must review the SABRIL Medication Guide with every patient prior to initiation of treatment. Patients should be instructed to take SABRIL only as prescribed.
17.1 Vision Loss
Patients should be informed of the risk of permanent vision loss, particularly loss of peripheral vision, from SABRIL, and the need for monitoring vision [see WARNINGS AND PRECAUTIONS, Vision Loss (5.1)].
Monitoring of vision, including assessment of visual fields and visual acuity, is required for adults at baseline (no later than 4 weeks after starting SABRIL) and at least every 3 months while on therapy unless after repeated attempts it is not possible. In those 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. Patients should be informed that if baseline or subsequent vision is not normal, SABRIL should only be used if the benefits of SABRIL treatment clearly outweigh the risks of additional vision loss.
Patients should understand that vision testing may be insensitive and may not detect vision loss before it is severe. Patients should also understand that if vision loss is documented, such loss is irreversible.
Patients should be informed that if changes in vision are suspected, they should notify their physician immediately.
17.2 Suicidal Thinking and Behavior
Patients, their caregiver(s), and families should be counseled that AEDs, including SABRIL, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Behaviors of concern should be reported immediately to healthcare providers [see WARNINGS AND PRECAUTIONS, Suicidal Behavior and Ideation (5.5)].
17.3 Use in Pregnancy
Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy [see USE IN SPECIFIC POPULATIONS, Pregnancy (8.1), and Nursing Mothers (8.3)].
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see USE IN SPECIFIC POPULATIONS, Pregnancy (8.1)]. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
17.4 Withdrawal of SABRIL Therapy
Patients should be told not to suddenly discontinue SABRIL therapy. As with all AEDs, withdrawal should be gradual. 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.
In all people who take SABRIL:
Because SABRIL might cause vision loss, it is available to doctors and patients only under a special program called SHARE. As part of the SHARE program, among other things, your doctor will have to test your or your baby's vision frequently while you or your baby are being treated with SABRIL, and even after you or your baby stops treatment. You also have to agree to be in the SHARE program, and agree to have your or your baby's vision tested regularly. Your doctor will explain the details of the SHARE program to you.
MRI changes. Brain pictures taken by magnetic resonance imaging (MRI) show changes in some babies after they are given SABRIL. It is not known if these changes are harmful.
Risk of suicidal thoughts or actions. Like other antiepileptic drugs, SABRIL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500 people taking it. Call a doctor right away if you have any of these symptoms, especially if they are new, worse, or worry you:
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
How can I watch for early symptoms of suicidal thoughts and actions?
Do not stop SABRIL without first talking to a healthcare provider.
SABRIL can be prescribed only to people who are enrolled in a program called SHARE. Before you or your baby can begin taking SABRIL, you must read and agree to all of the instructions in the SHARE program.
What is SABRIL?
SABRIL Tablets is a prescription medicine used along with other treatments to treat adults with CPS if:
SABRIL should not be the first medicine used to treat your CPS.
SABRIL for Oral Solution is a prescription medicine used to treat babies, one month to two years old who have IS, if you and your doctor decide the possible benefits of taking SABRIL are more important than the possible risk of vision loss.
If you are an adult with CPS, you must sign an agreement form before you can receive SABRIL.
If you are the parent or caregiver of a baby with IS, you must sign an agreement form before your baby can receive SABRIL.
What should I tell my doctor before starting SABRIL?
If you are an adult with CPS, before taking SABRIL tell your doctor if you have or had:
If you become pregnant while taking SABRIL, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy.
Before giving SABRIL to your baby, tell the doctor about all of your baby's medical conditions, including if your baby has or ever had:
Tell your doctor about all the medicines you or your baby take, including prescription and non-prescription medicines, vitamins, and herbal supplements. SABRIL and other medicines may affect each other causing side effects.
How should I take SABRIL?
If you are an adult with CPS:
If you are giving SABRIL to your baby for IS:
What should I avoid while taking SABRIL?
SABRIL causes sleepiness and tiredness. Adults taking SABRIL should not drive, operate machinery, or perform any hazardous task, unless you and your doctor have decided that you can do these things safely.
What are the possible side effects of SABRIL?
SABRIL can cause serious side effects. See "What is the most important information I should know about SABRIL?"
These other serious side effects happen in adults. It is not known if these side effects also happen in babies who take SABRIL.
If you are an adult with CPS, SABRIL may make certain types of seizures worse. Tell your doctor right away if your seizures get worse.
The most common side effects of SABRIL in adults include:
If you are giving SABRIL to your baby for IS
SABRIL may make certain types of seizures worse. You should tell your baby's doctor right away if your baby's seizures get worse. Tell your baby's doctor if you see any changes in your baby's behavior.
The most common side effects of SABRIL in babies and young children include:
Tell your doctor if you or your baby have any side effect that bother you or that does not go away. These are not all the possible side effects of SABRIL. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store SABRIL?
Store SABRIL tablets and SABRIL packets at room temperature, between 68 °F to 77 °F (20 °C to 25 °C).
Keep SABRIL tablets and SABRIL powder in the container they come in.
Keep SABRIL and all medicines out of the reach of children.
General information about SABRIL
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SABRIL for a condition for which it was not prescribed. Do not give SABRIL to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about SABRIL. If you would like more information about SABRIL, talk with your doctor. You can ask your pharmacist or doctor for information about SABRIL that is written for health professionals. For more information, go to www.SABRIL.net or call 1-800-455-1141.
What are the ingredients in SABRIL?
Active Ingredient: vigabatrin.
Inactive Ingredients in SABRIL tablets: hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycols, povidone, sodium starch glycolate, and titanium dioxide.
Inactive Ingredient in SABRIL powder: povidone.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Marketed by: Lundbeck Inc., Deerfield, IL 60015, U.S.A.
® Trademark of Lundbeck Inc.
Issued: August 2009
vigabatrin tablet, film coated
|Marketing Category||Application Number or Monograph Citation||Marketing Start Date||Marketing End Date|
|Labeler - Lundbeck Inc. (018343595)|
|Patheon Pharmaceuticals Inc.||005286822||ANALYSIS, MANUFACTURE|
Revised: 04/2010 Lundbeck Inc.
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2017
|Over-the-counter (OTC) Drugs|