Vigabatrin

Vigabatrin is part of the drug class:

• Fatty acid derivatives

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of vigabatrin there are no specific foods that you must exclude from your diet when receiving vigabatrin.
 

Adults with complex partial seizure: The recommended dose of vigabatrin in adults is 3 g/day (1.5 g twice daily). Your healthcare provider will likely prescribe a low dose to start, and then gradually increase your dose.

Babies with infantile spasms: The recommended starting dose of vigabatrin is 50 mg/kg/day given in two divided doses and can be gradually increased by 25-50 mg/kg/day increments every 3 days up to a maximum of 150 mg/kg/day.

Vigabatrin is an anti-epileptic medicine, also called an anticonvulsant.

Vigabatrin is used in combination with other medications to treat complex partial seizures in adults and children who are at least 10 years old. The powder form of vigabatrin is used to treat infantile spasms in babies and children between the ages of 1 month and 2 years.

Vigabatrin can cause serious side effects and should be used only by people who have been unable to control their seizures with several other medications.

Vigabatrin may also be used for purposes not listed in this medication guide.

Vigabatrin is available only from a certified pharmacy under a special program called SHARE. You must be registered in the program and agree to have vision exams every 3 months while taking vigabatrin. Be sure you understand the risks and benefits of taking this medicine.

Some people taking vigabatrin have developed vision problems within weeks to years after starting treatment. Vision loss caused by vigabatrin may be permanent, and you may notice only mild symptoms at first. Talk to your doctor about this possibility.

You should not use vigabatrin if you are allergic to it.

To make sure vigabatrin is safe for you, tell your doctor if you have:

• vision problems;

• kidney disease;

• anemia (low red blood cells); or

• a history of depression, mood disorder, mental illness, or suicidal thoughts or actions.

Some people have thoughts about suicide while taking seizure medication. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Follow your doctor's instructions about taking seizure medication if you are pregnant. Seizure control is very important during pregnancy, and having a seizure could harm both mother and baby. Do not start or stop taking this medicine without your doctor's advice, and tell your doctor right away if you become pregnant.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of vigabatrin on the baby.

Vigabatrin can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using vigabatrin.

Other drugs may interact with vigabatrin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Not extensively metabolized by hepatic CYP isoenzymes.1

Induces CYP2C9; does not appear to induce or inhibit other hepatic CYP isoenzymes.1 19 24

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2C9: potential pharmacokinetic interaction (decreased plasma substrate concentrations).1 19 22 24 25 42

Substrates of other CYP isoenzymes: clinically important interactions unlikely.1 19 22 24 25 42

Drugs associated with Serious Adverse Ophthalmic Effects

Avoid concurrent use with other drugs associated with serious adverse ophthalmic effects (e.g., retinopathy, glaucoma) unless benefits clearly outweigh risks.1 54

Specific Drugs and Laboratory Tests

Storage

Oral

20–25°C.1

20–25°C.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.

Pharmacodynamics

Effects on Electrocardiogram

There is no indication of a QT/QTc prolonging effect of Vigabatrin 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 Vigabatrin (3 g and 6 g) and placebo. Peak concentrations for 6.0 g Vigabatrin were approximately 2-fold higher than the peak concentrations following the 3.0 g single oral dose.

Pharmacokinetics

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

Absorption

Following oral administration, Vigabatrin is essentially completely absorbed. The time to maximum concentration (Tmax) is approximately 1 hour for children (10 years – 16 years) and adults, and approximately 2.5 hours for infants (5 months – 2 years). There was little accumulation with multiple dosing in adult and pediatric patients. 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.

Distribution

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 terminal half-life of Vigabatrin is about 5.7 hours for infants (5 months – 2 years), 9.5 hours for children (10 years – 16 years), and 10.5 hours for adults. Following administration of [14]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.

Specific Populations

Geriatric

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 [see Use in Specific Populations (8.5)].

Pediatric

The clearance of Vigabatrin is 2.4 L/hr for infants (5 months – 2 years), 5.8 L/hr for children (10 years – 16 years) and 7 L/hr for adults.

Gender

No gender differences were observed for the pharmacokinetic parameters of Vigabatrin in patients.

Race

No specific study was conducted to investigate the effects of race on Vigabatrin 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.

Renal Impairment

Mean AUC increased by 30% and the terminal half-life increased by 55% (8.1 hr vs 12.5 hr) in adult patients with mild renal impairment (CLcr from >50 to 80 mL/min) in comparison to normal subjects.

Mean AUC increased by two-fold and the terminal half-life increased by two-fold in adult patients with moderate renal impairment (CLcr from >30 to 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 adult patients with severe renal impairment (CLcr from >10 to 30 mL/min) in comparison to normal subjects.

Adult patients with renal impairment

Dosage adjustment, including starting at a lower dose, is recommended for adult patients with any degree of renal impairment [see Use in Specific Populations (8.6) and Dosage and Administration (2.4)].

Infants with renal impairment

Information about how to adjust the dose in infants with renal impairment is unavailable.

Pediatric patients 10 years and older with renal impairment

Although information is unavailable on the effects of renal impairment on Vigabatrin clearance in pediatric patients 10 years and older, dosing can be calculated based upon adult data and an established formula [see Use in Specific Populations (8.6) and Dosage and Administration (2.4)].

Hepatic Impairment

Vigabatrin is not significantly metabolized. The pharmacokinetics of Vigabatrin in patients with impaired liver function has not been studied.

Drug Interactions

Phenytoin

A 16% to 20% average reduction in total phenytoin plasma levels was reported in adult 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 [see Drug Interactions (7.1)].

Clonazepam

In a study of 12 healthy adult volunteers, clonazepam (0.5 mg) co-administration had no effect on Vigabatrin (1.5 g twice daily) concentrations. Vigabatrin increases the mean Cmax of clonazepam by 30% and decreases the mean Tmax by 45% [see Drug Interactions (7.1)].

Other AEDs

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 [see Drug Interactions (7.1)].

Alcohol

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.

Oral Contraceptives

In a double-blind, placebo-controlled study using a combination oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg 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 [see Drug Interactions (7.2)].

How Supplied

Vigabatrin for Oral Solution, USP 500 mg packets contain a white to off-white powder.

NDC 49884-358-03         Carton of 50 unit dose packets

Storage and Handling

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

Vigabatrin for Oral Solution, USP 500 mg Packet Label

Vigabatrin for Oral Solution, USP 500 mg - Carton of 50 unit dose packets Label

Resynthesis of GABA-T dependent: Variable (not strictly correlated to serum concentrations)

Half-Life Elimination

Prolonged in renal impairment

Pediatric patients:

5 months to 2 years: ~5.7 hours

4 to 14 years: ~5.5 hours (Sabril Canadian product monograph)

10 to 16 years: 9.5 hours

Adult patients: 10.5 hours

Refractory complex partial seizures: Oral: Initial: 500 mg twice daily; increase daily dose by 500 mg increments at weekly intervals based on response and tolerability. Recommended dose: 1.5 g twice daily. Note: To taper, decrease dose by 1 g daily on a weekly basis. Withdraw therapy if a substantial clinical benefit is not observed within 3 months of treatment initiation; discontinue therapy if evidence of treatment failure becomes obvious earlier than 3 months.

Concerns related to adverse effects:

• Anemia: Use has been associated with decreased hemoglobin and hematocrit; cases of significantly reduced hemoglobin (<8 g/dL) and/or hematocrit (<24%) have been reported.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Edema: Peripheral edema and edema independent of hypertension, heart failure, weight gain, renal or hepatic dysfunction has been reported.

• Neurotoxicity: Patients must be closely monitored for potential neurotoxicity (observed in animal models but not established in adults).

• Peripheral neuropathy: Peripheral neuropathy manifesting as numbness or tingling in the toes or feet, reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles, has been reported in adult patients.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

• Vision loss: [US Boxed Warning]: Vigabatrin causes permanent vision loss in infants, children, and adults. Due to the risk of vision loss and because vigabatrin, provides an observable symptomatic benefit when it is effective, the patient who fails to show substantial clinical benefit within a short period of time after initiation of treatment (2 to 4 weeks for infantile spasms; <3 months for refractory complex partial seizures), should be withdrawn from therapy. If in the clinical judgment of the prescriber evidence of treatment failure becomes obvious earlier in treatment, vigabatrin should be discontinued at that time. Patient response to and continued need for treatment should be periodically assessed. The onset of vision loss is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time during treatment, even after months or years. The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss. It is possible that vision loss can worsen despite discontinuation. Assessment of vision loss is difficult in children and the frequency and extent of vision loss in infants and children is poorly characterized. Most data are available in adult patients. Vigabatrin causes permanent bilateral concentric visual field constriction in >30% of patients ranging in severity from mild to severe, including tunnel vision to within 10 degrees of visual fixation, and can result in disability. In some cases, vigabatrin can damage the central retina and may decrease visual acuity. Symptoms of vision loss are unlikely to be recognized by the patient or caregiver before loss is severe. Vision loss of milder severity, although potentially unrecognized by the patient or caregiver, may still adversely affect function. Vision should be assessed to the extent possible at baseline (no later than 4 weeks after initiation), at least every 3 months during therapy and at 3 to 6 months after discontinuation. Once detected, vision loss is not reversible; even with frequent monitoring, it is expected that some patients will develop severe vision loss. In patients who cannot be tested, treatment may continue according to clinical judgement, with appropriate patient counseling. Vigabatrin 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 vigabatrin has not been well-characterized, but is likely adverse. Vigabatrin should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks. The lowest dose and shortest exposure should be used that is consistent with clinical objectives. 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.

• Weight gain: Use has been associated with an average weight gain of 3.5 kg in adults and ≥7% of baseline body weight in pediatric patients.

Disease-related concerns:

• Psychiatric behavior: Use with caution in patients with a history of psychosis (psychotic/agitated reactions may occur more frequently), depression, or behavioral problems.

• Renal impairment: Use with caution in patients with renal impairment; modify dose in children (≥10 years) and adults with renal impairment (CrCl <80 mL/minute).

• Seizures: May cause an increase in seizure frequency in some patients; use with particular caution in patients with myoclonic seizures, which may be more prone to this effect.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly as moderate to severe sedation and confusion have been reported; consider dose and/or frequency adjustments as renal clearance may be decreased.

Other warnings/precautions:

• Appropriate use: Vigabatrin is not indicated as a first-line agent for complex partial seizures.

• MRI abnormalities: Abnormal MRI changes have been reported in some infants. Resolution of MRI changes usually occurs with discontinuation of therapy. MRI changes were not seen in older children and adult patients.

• REMS program: Because of the risk of permanent vision loss, vigabatrin is only available through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) program. Under the Vigabatrin REMS program, only prescribers and pharmacies registered with the program are able to prescribe and distribute vigabatrin. Vigabatrin may only be dispensed to patients who are enrolled in and meet all conditions of the Vigabatrin REMS program. Call 866-244-8175 or visit http://www.vigabatrinREMS.com for further information.

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.