Vigadrone Drug Information
Generic name: VIGABATRIN
Anti-epileptic Agent [EPC]
Uses of Vigadrone
Refractory Complex Partial Seizures (CPS)
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. VIGADRONE is not indicated as a first line agent for complex partial seizures.
Infantile Spasms (IS)
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.
Dosage & Administration of Vigadrone
| 10 kg to 15 kg | 350 mg |
|---|---|
| Greater than 15 kg to 20 kg | 450 mg |
| Greater than 20 kg to 25 kg | 500 mg |
| Greater than 25 kg to 60 kg | 500 mg |
Side Effects of Vigadrone
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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. Refractory Complex Partial Seizures Adults Table 5 lists the adverse reactions that occurred in ≥2% and more than one patient per vigabatrin treated group and that occurred more frequently than in placebo patients from 2 U.S. adjunctive clinical studies of refractory CPS in adults. Table 5. Adverse Reactions in Pooled, Adjunctive Trials in Adults with Refractory Complex Partial Seizures Vigabatrin dosage (mg/day) Body System Adverse Reaction 3,000 % 6,000 % Placebo % Ear Disorders Tinnitus 2 0 1 Vertigo 2 5 1 Eye Disorders Blurred vision 13 16 5 Diplopia 7 16 3 Asthenopia 2 2 0 Eye pain 0 5 0 Gastrointestinal Disorders Diarrhea 10 16 7 Nausea 10 2 8 Vomiting 7 9 6 Constipation 8 5 3 Upper abdominal pain 5 5 1 Dyspepsia 4 5 3 Stomach discomfort 4 2 1 Abdominal pain 3 2 1 Toothache 2 5 2 Abdominal distension 2 0 1 General Disorders Fatigue 23 40 16 Gait disturbance 6 12 7 Asthenia 5 7 1 Edema peripheral 5 7 1 Fever 4 7 3 Chest pain 1 5 1 Thirst 2 0 0 Malaise 0 5 0 Infections Nasopharyngitis 14 9 10 Upper respiratory tract infection 7 9 6 Influenza 5 7 4 Urinary tract infection 4 5 0 Bronchitis 0 5 1 Injury Contusion 3 5 2 Joint sprain 1 2 1 Muscle strain 1 2 1 Wound secretion 0 2 0 Metabolism and Nutrition Disorders Increased appetite 1 5 1 Weight gain 6 14 3 Musculoskeletal Disorders Arthralgia 10 5 3 Back pain 4 7 2 Pain in extremity 6 2 4 Myalgia 3 5 1 Muscle twitching 1 9 1 Muscle spasms 3 0 1 Nervous System Disorders Headache 33 26 31 Somnolence 22 26 13 Dizziness 24 26 17 Nystagmus 13 19 9 Tremor 15 16 8 Memory impairment 7 16 3 Abnormal coordination 7 16 2 Disturbance in attention 9 0 1 Sensory disturbance 4 7 2 Hyporeflexia 4 5 1 Paraesthesia 7 2 1 Lethargy 4 7 2 Hyperreflexia 4 2 3 Hypoaesthesia 4 5 1 Sedation 4 0 0 Status epilepticus 2 5 0 Dysarthria 2 2 1 Postictal state 2 0 1 Sensory loss 0 5 0 Psychiatric Disorders Irritability 7 23 7 Depression 6 14 3 Confusional state 4 14 1 Anxiety 4 0 3 Depressed mood 5 0 1 Abnormal thinking 3 7 0 Abnormal behavior 3 5 1 Expressive language disorder 1 7 1 Nervousness 2 5 2 Abnormal dreams 1 5 1 Reproductive System Dysmenorrhea 9 5 3 Erectile dysfunction 0 5 0 Respiratory and Thoracic Disorders Pharyngolaryngeal pain 7 14 5 Cough 2 14 7 Pulmonary congestion 0 5 1 Sinus headache 6 2 1 Skin and Subcutaneous Tissue Disorders Rash 4 5 4 Pediatrics 2 to 16 years of age Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving vigabatrin or placebo as adjunctive therapy for refractory complex partial seizures.
Adverse reactions that are listed occurred in at least 2% of vigabatrin-treated patients and more frequently than placebo. The median vigabatrin dose was 49.4 mg/kg (range of 8 to 105.9 mg/kg). Table 6. Adverse Reactions in Pooled, Adjunctive Trials in Pediatric Patients 3 to 16 Years of Age with Refractory Complex Partial Seizures Body System Adverse Reaction All Vigabatrin % Placebo % Eye Disorders Diplopia 3 2 Blurred vision 2 0 Gastrointestinal Disorders Upper abdominal pain 4 3 Constipation 2 1 General Disorders Fatigue 10 7 Infections and Infestations Upper respiratory tract infection 15 11 Influenza 7 3 Otitis media 6 4 Streptococcal pharyngitis 4 3 Viral gastroenteritis 2 0 Investigations Weight gain 15 2 Nervous System Disorders Somnolence 6 5 Nystagmus 4 3 Tremor 4 2 Status epilepticus 2 1 Psychiatric Disorders Abnormal behavior 7 6 Aggression 6 2 Disorientation 3 0 Safety of vigabatrin for the treatment of refractory CPS in patients 2 years of age is expected to be similar to pediatric patients 3 to 16 years of age. Infantile Spasms In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in >5% of patients receiving vigabatrin and that occurred more frequently than in placebo patients were somnolence (vigabatrin 45%, placebo 30%), bronchitis (vigabatrin 30%, placebo 15%), ear infection (vigabatrin 10%, placebo 5%), and acute otitis media (vigabatrin 10%, placebo 0%). In a dose response study of low-dose (18 to 36 mg/kg/day) versus high-dose (100 to 148 mg/kg/day) vigabatrin, no clear correlation between dose and incidence of adverse reactions was observed.
The adverse reactions (≥5% in either dose group) are summarized in Table 7. Table 7. Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms Body System Adverse Reaction Vigabatrin Low Dose % Vigabatrin High Dose % Eye Disorders (other than field or acuity changes) Strabismus 5 5 Conjunctivitis 5 2 Gastrointestinal Disorders Vomiting 14 20 Constipation 14 12 Diarrhea 13 12 General Disorders Fever 29 19 Infections Upper respiratory tract infection 51 46 Otitis media 44 30 Viral infection 20 19 Pneumonia 13 11 Candidiasis 8 3 Ear infection 7 14 Gastroenteritis viral 6 5 Sinusitis 5 9 Urinary tract infection 5 6 Influenza 5 3 Croup infectious 5 1 Metabolism and Nutrition Disorders Decreased appetite 9 7 Nervous System Disorders Sedation 19 17 Somnolence 17 19 Status epilepticus 6 4 Lethargy 5 7 Convulsion 4 7 Hypotonia 4 6 Psychiatric Disorders Irritability 16 23 Insomnia 10 12 Respiratory Disorders Nasal congestion 13 4 Cough 3 8 Skin and Subcutaneous Tissue Disorders Rash 8 11
Post Marketing Experience
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
Warnings & Cautions for Vigadrone
Permanent Vision Loss
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. 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. 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. 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 recommended. Because vision testing in infants is difficult, vision loss may not be detected until it is severe.
For patients receiving VIGADRONE, vision assessment is recommended at baseline (no later than 4 weeks after starting VIGADRONE), at least every 3 months while on therapy, and about 3 to 6 months after the discontinuation of therapy. The diagnostic approach should be individualized for the patient and clinical situation. In adults and cooperative pediatric patients, perimetry is recommended, preferably by automated threshold visual field testing.
Additional testing may also include electrophysiology (e.g., electroretinography ), retinal imaging (e.g., optical coherence tomography ), and/or other methods appropriate for the patient. In patients who cannot be tested, treatment may continue according to clinical judgment, with appropriate patient counseling. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat assessment is recommended if results are abnormal or uninterpretable.
Repeat assessment 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 VIGADRONE is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to VIGADRONE is not reversible.
It is expected that even with frequent monitoring, some VIGADRONE patients will develop severe vision loss. Consider drug discontinuation, balancing benefit and risk, if vision loss is documented. It is possible that vision loss can worsen despite discontinuation of VIGADRONE.
Vigabatrin
REMS Program 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.
Magnetic Resonance Imaging (MRI) Abnormalities in Infants 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. 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.
Neurotoxicity 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.
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. 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.
Suicidal Behavior and Ideation 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. Table 4. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Drug Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5
Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4
4.3 1.8
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.
Withdrawal of Antiepileptic Drugs (AEDs) 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.
Anemia
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%.
Somnolence and Fatigue
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.
Peripheral Neuropathy 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. 5.10 Weight Gain 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. 5.11 Edema 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.
Drug Interactions with Vigadrone
Antiepileptic Drugs Phenytoin
Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since VIGADRONE may cause a moderate reduction in total phenytoin plasma levels. Clonazepam VIGADRONE may moderately increase the C max of clonazepam resulting in an increase of clonazepam-associated adverse reactions. Other AEDs There are no clinically significant pharmacokinetic interactions between vigabatrin 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.
Oral Contraceptives
VIGADRONE is unlikely to affect the efficacy of steroid oral contraceptives.
Drug-Laboratory Test Interactions
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).
Pregnancy Safety for Vigadrone
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including VIGADRONE, during pregnancy. Encourage women who are taking VIGADRONE during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself.
Risk Summary There are no adequate data on the developmental risk associated with the use of VIGADRONE in pregnant women. Limited available data from case reports and cohort studies pertaining to VIGADRONE use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on animal data, VIGADRONE use in pregnant women may result in fetal harm.
When administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, 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 (see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data Animal Data Administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. The no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately ½ the maximum recommended human dose (MRHD) of 3 g/day on a body surface area (mg/m 2 ) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations.
The no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1 / 5 the MRHD on a mg/m 2 basis. Oral administration of vigabatrin (50, 100, 150 mg/kg/day) 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/day) is approximately 1 / 5 the MRHD on a mg/m 2 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 fetal malformations (including cleft palate) was observed at both doses. Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4 to 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/day) 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.
Pediatric Use of Vigadrone
Pediatric Use 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. The dosing recommendation in this population varies according to age group and is weight-based. Adverse reactions in this pediatric population are similar to those observed in the adult population.
The safety and effectiveness of vigabatrin as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established . 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. Abnormal MRI signal changes and Intramyelinic Edema (IME) in infants and young children being treated with vigabatrin have been observed. Juvenile Animal Toxicity Data Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4 to 65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities.
The no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (AUC) substantially less than those measured in pediatric patients at recommended doses. In dogs, oral administration of vigabatrin (30 or 100 mg/kg/day) during selected periods of juvenile development (postnatal days 22 to 112) produced neurohistopathological abnormalities (brain gray matter vacuolation). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. A no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg/day) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses.
Overdosage Information for Vigadrone
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.
Management of Overdosage
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 vitro study, 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%.
Clinical Studies of Vigadrone
Complex Partial Seizures Adults
The effectiveness of vigabatrin as adjunctive therapy in adult patients 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 complex partial seizures, 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 vigabatrin 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 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 monthly frequency of complex partial seizures, are shown in Table 8. 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. Table 8. Median Monthly Frequency of Complex Partial Seizures Including one patient with simple partial seizures with secondary generalization only N Baseline Endstudy Placebo 45 9.0 8.8 1 g/day Vigabatrin 45 8.5 7.7 3 g/day Vigabatrin 41 8.5 3.7 p<0.05 compared to placebo 6 g/day Vigabatrin 43 8.5
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 vigabatrin 3 and 6 g/day groups compared to the placebo group.
For example, 51% of patients randomized to vigabatrin 3 g/day and 53% of patients randomized to vigabatrin 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 Figure 1 Study 2 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 monthly complex partial seizure frequency, are shown in Table 9. Vigabatrin 3 g/day was statistically significantly superior to placebo in reducing seizure frequency. Table 9. Median Monthly Frequency of Complex Partial Seizures N Baseline Endstudy Placebo 90 9.0 7.5 3 g/day Vigabatrin 92 8.3 5.5 p<0.05 compared to placebo 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 vigabatrin 3 g/day group compared to the placebo group. For example, 39% of patients randomized to vigabatrin (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. Figure 2 Pediatric patients 3 to 16 years of age Vigabatrin was studied in three double-blind, placebo-controlled, parallel-group studies in 269 patients who received vigabatrin and 104 patients who received placebo. No individual study was considered adequately powered to determine efficacy in pediatric patients age 3 years and above.
The data from all three pediatric studies were pooled and used in a pharmacometric bridging analysis using weight-normalized doses to establish efficacy and determine appropriate dosing. All three studies were randomized, double-blind, placebo-controlled, parallel-group, adjunctive-treatment studies in patients aged 3 to 16 years with uncontrolled complex partial seizures with or without secondary generalization. The study period included a 6 to 10 week baseline phase and a 14 to 17 week treatment phase (composed of a titration and maintenance period). The pharmacometric bridging approach consisted of defining a weight-normalized dose-response, and showing that a similar dose-response relationship exists between pediatric patients and adult patients when vigabatrin was given as adjunctive therapy for complex partial seizures.
Dosing recommendations in pediatric patients 2 to 16 years of age were derived from simulations utilizing these pharmacometric dose-response analyses.
Infantile Spasms
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. Study 1 Study 1 (N=221) was a multicenter, randomized, low-dose high-dose, parallel-group, partially-blind (caregivers knew the actual dose but not whether their child was classified as low or high dose; EEG reader was blinded but investigators were not blinded) study to evaluate the safety and efficacy of vigabatrin in patients <2 years of age with new-onset infantile spasms.
Patients with both symptomatic and cryptogenic etiologies were studied. The study was comprised of two phases. The first phase was a 14 to 21 day partially-blind phase in which patients were randomized to receive either low-dose (18 to 36 mg/kg/day) or high-dose (100 to 148 mg/kg/day) vigabatrin.
Study drug was titrated over 7 days, followed by a constant dose for 7 days. If the patient became spasm-free on or before day 14, another 7 days of constant dose was administered. The primary efficacy endpoint of this study was the proportion of patients who were spasm-free for 7 consecutive days beginning within the first 14 days of vigabatrin therapy.
Patients considered spasm-free were defined as those patients who remained free of spasms (evaluated according to caregiver response to direct questioning regarding spasm frequency) and who had no indication of spasms or hypsarrhythmia during 8 hours of CCTV EEG recording (including at least one sleep-wake-sleep cycle) performed within 3 days of the seventh day of spasm freedom and interpreted by a blinded EEG reader. Seventeen patients in the high-dose group achieved spasm freedom compared with 8 patients in the low dose group. This difference was statistically significant (p=0.0375). Primary efficacy results are shown in Table 10. Table 10. Spasm Freedom by Primary Criteria (Study 1) Vigabatrin Treatment Group 18 to 36 mg/kg/day n (%) 100 to 148 mg/kg/day n (%) p=0.0375 Note: Primary criteria were evaluated based on caregiver assessment plus CCTV EEG confirmation within 3 days of the seventh day of spasm freedom.
Patients who Achieved Spasm Freedom 8 17 Study 2 Study 2 (N=40) was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisting of a pre-treatment (baseline) period of 2 to 3 days, followed by a 5-day double-blind treatment phase during which patients were treated with vigabatrin (initial dose of 50 mg/kg/day with titration allowed to 150 mg/kg/day) or placebo. The primary efficacy endpoint in this study was the average percent change in daily spasm frequency, assessed during a pre-defined and consistent 2-hour window of evaluation, comparing baseline to the final 2 days of the 5-day double-blind treatment phase. No statistically significant differences were observed in the average frequency of spasms using the 2-hour evaluation window.
However, a post-hoc alternative efficacy analysis, using a 24-hour clinical evaluation window found a statistically significant difference in the overall percentage of reductions in spasms between the vigabatrin group (68.9%) and the placebo group (17.0%) (p=0.030). 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. The 38/68 infants in the study who had responded to vigabatrin therapy (complete cessation of spasms and hypsarrhythmia) continued vigabatrin therapy for a total duration of 6 months therapy. The 38 infants who responded were then followed for an additional 18 months after discontinuation of vigabatrin to determine their clinical outcome.
A post hoc analysis indicated no observed recurrence of infantile spasms in any of these 38 infants.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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