VIMPAT 50 MG Oral Tablet
Generic Name: LACOSAMIDE
Brand Name: Vimpat
- Substance Name(s):
- LACOSAMIDE
DRUG INTERACTIONS
7 Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between VIMPAT and carbamazepine, valproate, digoxin, metformin, omeprazole, or an oral contraceptive containing ethinylestradiol and levonorgestrel.
There was no evidence for any relevant drug-drug interaction of VIMPAT with common AEDs in the placebo-controlled clinical trials in patients with partial-onset seizures [see Clinical Pharmacology (12.3) ].
The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system.
OVERDOSAGE
10 10.1 Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans There is limited clinical experience with VIMPAT overdose in humans.
The highest reported accidental overdose of VIMPAT during clinical development was 1200 mg/day which was non-fatal.
The types of adverse events experienced by patients exposed to supratherapeutic doses during the trials were not clinically different from those of patients administered recommended doses of VIMPAT.
There has been a single case of intentional overdose by a patient who self-administered 12 grams VIMPAT along with large doses of zonisamide, topiramate, and gabapentin.
The patient presented in a coma and was hospitalized.
An EEG revealed epileptic waveforms.
The patient recovered 2 days later.
10.2 Treatment or Management of Overdose There is no specific antidote for overdose with VIMPAT.
Standard decontamination procedures should be followed.
General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient.
A Certified Poison Control Center should be contacted for up to date information on the management of overdose with VIMPAT.
Standard hemodialysis procedures result in significant clearance of VIMPAT (reduction of systemic exposure by 50% in 4 hours).
Hemodialysis has not been performed in the few known cases of overdose, but may be indicated based on the patient’s clinical state or in patients with significant renal impairment.
DESCRIPTION
11 The chemical name of lacosamide, the single (R)-enantiomer, is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC).
Lacosamide is a functionalized amino acid.
Its molecular formula is C13H18N2O3 and its molecular weight is 250.30.
The chemical structure is: Lacosamide is a white to light yellow powder.
It is sparingly soluble in water and slightly soluble in acetonitrile and ethanol.
Chemical Structure 11.1 VIMPAT Tablets VIMPAT tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and dye pigments as specified below: VIMPAT tablets are supplied as debossed tablets and contain the following coloring agents: 50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake 100 mg tablets: yellow iron oxide 150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide 200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake 11.2 VIMPAT Injection VIMPAT injection is a clear, colorless, sterile solution containing 10 mg lacosamide per mL for intravenous infusion.
One 20-mL vial contains 200 mg of lacosamide drug substance.
The inactive ingredients are sodium chloride and water for injection.
Hydrochloric acid is used for pH adjustment.
VIMPAT injection has a pH of 3.5 to 5.0.
11.3 VIMPAT Oral Solution VIMPAT oral solution contains 10 mg of lacosamide per mL.
The inactive ingredients are purified water, sorbitol solution, glycerin, polyethylene glycol, carboxymethylcellulose sodium, acesulfame potassium, methylparaben, flavoring (including natural and artificial flavors, propylene glycol, aspartame, and maltol), anhydrous citric acid and sodium chloride.
CLINICAL STUDIES
14 14.1 Effectiveness in Partial-Onset Seizures The efficacy of VIMPAT as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter trials in adult patients.
Patients enrolled had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs.
During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days.
In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days.
84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.
Study 1 compared doses of VIMPAT 200, 400, and 600 mg/day with placebo.
Study 2 compared doses of VIMPAT 400 and 600 mg/day with placebo.
Study 3 compared doses of VIMPAT 200 and 400 mg/day with placebo.
In all three trials, following an 8-week Baseline Phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose (a 1-step back-titration of VIMPAT 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the Titration Phase).
During the Titration Phase in all 3 trials, treatment was initiated at 100 mg/day (50 mg given twice daily) and increased in weekly increments of 100 mg/day to the target dose.
The Titration Phase lasted 6 weeks in Study 1 and Study 2 and 4 weeks in Study 3.
In all three trials, the Titration Phase was followed by a Maintenance Phase that lasted 12 weeks, during which patients were to remain on a stable dose of VIMPAT.
A reduction in 28 day seizure frequency (Baseline to Maintenance Phase) as compared to the placebo group was the primary variable in all three trials.
The criteria for statistical significance was p<0.05.
A statistically significant effect was observed with VIMPAT treatment (Figure 1) at doses of 200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2).
Subset evaluations of VIMPAT demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).
Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial 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 seizure frequency), while a negative value indicates a worsening from Baseline (ie., an increase in 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 VIMPAT groups compared to the placebo group.
For example, 40% of patients randomized to VIMPAT (400 mg/day) experienced a 50% or greater reduction in seizure frequency, compared to 23% 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 Figure
HOW SUPPLIED
16 /STORAGE AND HANDLING VIMPAT (lacosamide) Tablets 50 mg are pink, oval, film-coated tablets debossed with “SP” on one side and “50” on the other.
They are supplied as follows: Bottles of 60 NDC54868-6077-0 16.1 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).
[See USP Controlled Room Temperature].
Do not freeze Vimpat injection or oral solution.
Discard any unused Vimpat oral solution remaining after seven (7) weeks of first opening the bottle.
GERIATRIC USE
8.5 Geriatric Use There were insufficient numbers of elderly patients enrolled in partial-onset seizure trials (n=18) to adequately assess the effectiveness of VIMPAT in this population.
In healthy subjects, the dose and body weight normalized pharmacokinetic parameters AUC and Cmax were approximately 20% higher in elderly subjects compared to young subjects.
The slightly higher lacosamide plasma concentrations in elderly subjects are possibly caused by differences in total body water (lean body weight) and age-associated decreased renal clearance.
No VIMPAT dose adjustment based on age is considered necessary.
Caution should be exercised for dose titration in elderly patients.
DOSAGE FORMS AND STRENGTHS
3 50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), and 200 mg (blue) film-coated tablets 200 mg/20mL injection 10 mg/mL oral solution 50 mg (pink), 100 mg (dark yellow), 150 mg (salmon), 200 mg (blue) film-coated tablets (3) 200 mg/20 mL single-use vial for intravenous use (3) 10 mg/mL oral solution (3)
MECHANISM OF ACTION
12.1 Mechanism of Action The precise mechanism by which VIMPAT exerts its antiepileptic effects in humans remains to be fully elucidated.
In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.
Lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth.
The role of CRMP-2 binding in seizure control is unknown.
INDICATIONS AND USAGE
1 VIMPAT is indicated for: Partial-onset seizures (1.1): Tablets and oral solution are indicated for adjunctive therapy in patients ≥17 years.
Injection is indicated as short term replacement when oral administration is not feasible in these patients.
1.1 Partial-Onset Seizures VIMPAT (lacosamide) tablets and oral solution are indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged 17 years and older.
VIMPAT (lacosamide) injection for intravenous use is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged 17 years and older when oral administration is temporarily not feasible.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of VIMPAT in pediatric patients <17 years have not been established.
Lacosamide has been shown in vitro to interfere with the activity of CRMP-2, a protein involved in neuronal differentiation and control of axonal outgrowth.
Potential adverse effects on CNS development can not be ruled out.
Administration of lacosamide to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).
The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide exposure (AUC) approximately 0.5 times the human plasma AUC at the maximum recommended human dose of 400 mg/day.
PREGNANCY
8.1 Pregnancy Pregnancy Category C Lacosamide produced developmental toxicity (increased embryofetal and perinatal mortality, growth deficit) in rats following administration during pregnancy.
Developmental neurotoxicity was observed in rats following administration during a period of postnatal development corresponding to the third trimester of human pregnancy.
These effects were observed at doses associated with clinically relevant plasma exposures.
Lacosamide has been shown in vitro to interfere with the activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth.
Potential adverse effects on CNS development can not be ruled out.
There are no adequate and well-controlled studies in pregnant women.
VIMPAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral administration of lacosamide to pregnant rats (20, 75, or 200 mg/kg/day) and rabbits (6.25, 12.5, or 25 mg/kg/day) during the period of organogenesis did not produce any teratogenic effects.
However, the maximum doses evaluated were limited by maternal toxicity in both species and embryofetal death in rats.
These doses were associated with maternal plasma lacosamide exposures [area under the plasma-time concentration curve; (AUC)] ≈2 and 1 times (rat and rabbit, respectively) that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
When lacosamide (25, 70, or 200 mg/kg/day) was orally administered to rats throughout gestation, parturition, and lactation, increased perinatal mortality and decreased body weights were observed in the offspring at the highest dose.
The no-effect dose for pre- and post-natal developmental toxicity in rats (70 mg/kg/day) was associated with a maternal plasma lacosamide AUC approximately equal to that in humans at the MRHD.
Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory).
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 rats was associated with a plasma lacosamide AUC approximately 0.5 times that in humans at the MRHD.
Pregnancy Registry UCB, Inc.
has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with VIMPAT.
To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling 1-888-537-7734 (toll free).
Physicians are also advised to recommend that pregnant patients taking VIMPAT enroll in the North American Antiepileptic Drug 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/.
NUSRING MOTHERS
8.3 Nursing Mothers Studies in lactating rats have shown that lacosamide and/or its metabolites are excreted in milk.
It is not known whether VIMPAT is excreted in human milk.
Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue VIMPAT, taking into account the importance of the drug to the mother.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation (5.1) Patients should be advised that VIMPAT may cause dizziness and ataxia.
(5.2) Caution is advised for patients with known cardiac conduction problems [e.g., second-degree atrioventricular (AV) block], who are taking drugs known to induce PR interval prolongation, or with severe cardiac disease such as myocardial ischemia or heart failure.
(5.3) Patients should be advised that VIMPAT may cause syncope.
(5.4) In patients with seizure disorders, VIMPAT should be gradually withdrawn to minimize the potential of increased seizure frequency.
(5.5) Multiorgan Hypersensitivity Reactions (5.6) Phenylketonurics (5.7) 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VIMPAT, 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 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 of events 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 treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.
The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 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 1.9 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.
Anyone considering prescribing VIMPAT or any other AED must balance this risk with the risk of untreated illness.
Epilepsy and many other illnesses for which antiepileptics 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.
5.2 Dizziness and Ataxia Patients should be advised that VIMPAT may cause dizziness and ataxia.
Accordingly, they should be advised not to drive a car or to operate other complex machinery until they are familiar with the effects of VIMPAT on their ability to perform such activities.
In patients with partial-onset seizures taking 1 to 3 concomitant AEDs, dizziness was experienced by 25% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%).
Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared to 2% of placebo patients).
The onset of dizziness and ataxia was most commonly observed during titration.
There was a substantial increase in these adverse events at doses higher than 400 mg/day.
[see Adverse Reactions/Table 2 (6.1) ] 5.3 Cardiac Rhythm and Conduction Abnormalities PR interval prolongation Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in patients and in healthy volunteers.
[see Clinical Pharmacology (12.2)] In clinical trials in patients with partial-onset epilepsy, asymptomatic first-degree atrioventricular (AV) block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT and 0% (0/364) of patients randomized to receive placebo.
In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.5% (5/1023) of patients receiving VIMPAT and 0% (0/291) of patients receiving placebo.
Second degree or higher AV block has been reported in postmarketing experience in epilepsy patients.
When VIMPAT is given with other drugs that prolong the PR interval, further PR prolongation is possible.
Patients should be made aware of the symptoms of second-degree or higher AV block (e.g.
slow or irregular pulse, feeling of lightheadedness and fainting) and told to contact their physician should any of these occur.
VIMPAT should be used with caution in patients with known conduction problems (e.g.
marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), or with severe cardiac disease such as myocardial ischemia or heart failure.
In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state, is recommended.
Atrial fibrillation and Atrial flutter In the short-term investigational trials of VIMPAT in epilepsy patients, there were no cases of atrial fibrillation or flutter, however, both have been reported in open label epilepsy trials and in postmarketing experience.
In patients with diabetic neuropathy, 0.5% of patients treated with VIMPAT experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients.
VIMPAT administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease.
Patients should be made aware of the symptoms of atrial fibrillation and flutter (e.g., palpitations, rapid pulse, shortness of breath) and told to contact their physician should any of these symptoms occur.
5.4 Syncope In the short-term controlled trials of VIMPAT in epilepsy patients with no significant system illnesses, there was no increase in syncope compared to placebo.
In the short-term controlled trials of VIMPAT in patients with diabetic neuropathy, 1.2% of patients who were treated with VIMPAT reported an adverse reaction of syncope or loss of consciousness, compared to 0% of placebo-treated patients with diabetic neuropathy.
Most of the cases of syncope were observed in patients receiving doses above 400 mg/day.
The cause of syncope was not determined in most cases.
However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia.
5.5 Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, VIMPAT should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency in patients with seizure disorders.
5.6 Multiorgan Hypersensitivity Reactions One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to VIMPAT during clinical development.
The event occurred in a healthy volunteer, 10 days after stopping VIMPAT treatment.
The subject was not taking any concomitant medication and potential known viral etiologies for hepatitis were ruled out.
The subject fully recovered within a month, without specific treatment.
The case is consistent with a delayed multiorgan hypersensitivity reaction.
Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology.
Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, or DRESS) have been reported with other anticonvulsants and typically, although not exclusively, present with fever and rash associated with other organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis.
Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur.
If this reaction is suspected, VIMPAT should be discontinued and alternative treatment started.
5.7 Phenylketonurics VIMPAT oral solution contains aspartame, a source of phenylalanine.
A 200 mg dose of VIMPAT oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION [See Medication Guide] Patients should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking VIMPAT.
Patients should be instructed to take VIMPAT only as prescribed.
17.1 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including VIMPAT, 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 about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
17.2 Dizziness and Ataxia Patients should be counseled that VIMPAT use may cause dizziness, double vision, abnormal coordination and balance, and somnolence.
Patients taking VIMPAT should be advised not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with VIMPAT.
17.3 Cardiac Rhythm and Conduction Abnormalities Patients should be counseled that VIMPAT is associated with electrocardiographic changes that may predispose to irregular beat and syncope, particularly in patients with underlying cardiovascular disease, with heart conduction problems or who are taking other medications that affect the heart.
Patients who develop syncope should lay down with raised legs until recovered and contact their health care provider.
17.4 Multiorgan Hypersensitivity Reactions Patients should be aware that VIMPAT may cause serious hypersensitivity reactions affecting multiple organs such as the liver and kidney.
VIMPAT should be discontinued if a serious hypersensitivity reaction is suspected.
Patients should also be instructed to report promptly to their physicians any symptoms of liver toxicity (e.g.
fatigue, jaundice, dark urine).
17.5 Pregnancy Registry UCB, Inc.
has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with VIMPAT.
To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling 1-888-537-7734 (toll free).
Patients should also be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant.
This Registry is collecting information about the safety of AEDs during pregnancy.
To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations (8.1) ].
DOSAGE AND ADMINISTRATION
2 VIMPAT may be taken with or without food.
When using VIMPAT oral solution, it is recommended that a calibrated measuring device be obtained and used.
A household teaspoon or tablespoon is not an adequate measuring device.
Healthcare providers should recommend a device that can measure and deliver the prescribed dose accurately, and provide instructions for measuring the dosage.
Partial-onset seizures (2.1): Initially, give 50 mg twice daily (100 mg/day).
The dose may be increased, based on clinical response and tolerability, at weekly intervals by 100 mg/day given as two divided doses to a daily dose of 200 to 400 mg/day.
VIMPAT injection may be given without further dilution or mixed in compatible diluent and should be administered intravenously over a period of 30 to 60 minutes.
(2.1) Oral-Intravenous Replacement therapy (2.1): When switching from oral VIMPAT, the initial total daily intravenous dosage of VIMPAT should be equivalent to the total daily dosage and frequency of oral VIMPAT.
At the end of the intravenous treatment period, the patient may be switched to VIMPAT oral administration at the equivalent daily dosage and frequency of the intravenous administration.
See full prescribing information for compatibility and stability (2.1) and dosing in patients with renal impairment (2.2) and hepatic impairment (2.3) .
2.1 Partial-Onset Seizures VIMPAT can be initiated with either oral or intravenous administration.
The initial dose should be 50 mg twice daily (100 mg per day).
VIMPAT can be increased at weekly intervals by 100 mg/day given as two divided doses up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient response and tolerability.
In clinical trials, the 600 mg daily dose was not more effective than the 400 mg daily dose, and was associated with a substantially higher rate of adverse reactions.
[see Clinical Studies (14.1) ] Switching from Oral to Intravenous Dosing When switching from oral VIMPAT, the initial total daily intravenous dosage of VIMPAT should be equivalent to the total daily dosage and frequency of oral VIMPAT and should be infused intravenously over a period of 30 to 60 minutes.
There is experience with twice daily intravenous infusion for up to 5 days.
Switching from Intravenous to Oral Dosing At the end of the intravenous treatment period, the patient may be switched to VIMPAT oral administration at the equivalent daily dosage and frequency of the intravenous administration.
Compatibility and Stability VIMPAT injection can be administered intravenously without further dilution or may be mixed with diluents.
VIMPAT injection was found to be physically compatible and chemically stable when mixed with the following diluents for at least 24 hours and stored in glass or polyvinyl chloride (PVC) bags at ambient room temperature 15-30°C (59-86°F).
Diluents: Sodium Chloride Injection 0.9% (w/v) Dextrose Injection 5% (w/v) Lactated Ringer’s Injection The stability of VIMPAT injection in other infusion solutions has not been evaluated.
Product with particulate matter or discoloration should not be used.
Any unused portion of VIMPAT injection should be discarded.
2.2 Patients with Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment.
A maximum dose of 300 mg/day VIMPAT is recommended for patients with severe renal impairment [creatinine clearance (CLCR) ≤30mL/min] and in patients with endstage renal disease.
VIMPAT is effectively removed from plasma by hemodialysis.
Following a 4-hour hemodialysis treatment, dosage supplementation of up to 50% should be considered.
In all renally impaired patients, the dose titration should be performed with caution.
[see Use in Specific Populations (8.6) ] 2.3 Patients with Hepatic Impairment The dose titration should be performed with caution in patients with hepatic impairment.
A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.
VIMPAT use is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ].