Lacosamide

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Pregnancy category: C

Lactation: Unknown if distributed in breast milk; use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Serious side effects have been reported with lacosamide. See the “ Drug Precautions” section.

Common side effects of lacosamide include the following:

• headache
• dizziness
• drowsiness
• nausea
• tremor
• blurred vision

This is not a complete list of lacosamide side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

No lacosamide drug interactions have been identified. However, you should tell your doctor about all the medications you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Tell your doctor if you are pregnant or plan to get pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories- A, B,C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Lacosamide belongs to category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

The recommended dose of lacosamide for the treatment of partial-onset seizures is 50 mg twice a day. The dose may be increased at weekly intervals up to 400 mg a day in two divided doses.

Lacosamide is an anti-epileptic drug, also called an anticonvulsant.

Lacosamide is used together with other medications to treat partial-onset seizures in people with epilepsy who are at least 17 years old.

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

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Other drugs may interact with lacosamide, 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.

Anticonvulsant; a functionalized amino acid.1 4 5 6 22 23 34

Seizure Disorders

Management (in combination with other anticonvulsants) of partial-onset seizures in patients ≥17 years of age with epilepsy.1 2 3 4 20 24 36

IV lacosamide is used as a short-term alternative to oral therapy in patients in whom oral administration of the drug is temporarily not feasible (e.g., patients undergoing surgical procedures, those experiencing difficulty swallowing, those with acute GI disorders).1 20 24 36

Neuropathic Pain

Oral lacosamide has been studied in the treatment of pain associated with diabetic peripheral neuropathy (DPN)† in several short- and long-term clinical trials; additional controlled trials needed to confirm efficacy and safety.14 15 16 17 18 38 43

In the U.S.

• Vimpat

Available Dosage Forms:

• Tablet
• Solution

Therapeutic Class: Anticonvulsant

Lacosamide is used together with other medicines to help control partial seizures (convulsions) in the treatment of epilepsy. It acts on the central nervous system (CNS) to reduce the number and severity of seizures. However, lacosamide cannot cure epilepsy and will only work to control seizures for as long as you continue to take it.

lacosamide is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For lacosamide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to lacosamide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of lacosamide in children younger than 17 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of lacosamide in the elderly. However, elderly patients are more likely to have age-related heart, kidney, or liver problems, which may require caution in patients receiving lacosamide.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking lacosamide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using lacosamide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Amitriptyline
• Amlodipine
• Atazanavir
• Atenolol
• Betaxolol
• Bisoprolol
• Calcifediol
• Carteolol
• Carvedilol
• Celiprolol
• Chlordiazepoxide
• Cinnarizine
• Clevidipine
• Diltiazem
• Dolasetron
• Eslicarbazepine Acetate
• Esmolol
• Felodipine
• Isradipine
• Labetalol
• Levobunolol
• Lopinavir
• Metipranolol
• Metoprolol
• Nadolol
• Nebivolol
• Nicardipine
• Nifedipine
• Nimodipine
• Nisoldipine
• Orlistat
• Oxprenolol
• Penbutolol
• Pindolol
• Practolol
• Propranolol
• Quinine
• Ritonavir
• Saquinavir
• Sotalol
• Timolol
• Verapamil

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of lacosamide. Make sure you tell your doctor if you have any other medical problems, especially:

• Brugada syndrome (genetic disease) or
• Depression, history of or
• Drug abuse or dependence, history of or
• Heart attack or
• Heart block or
• Heart disease (eg, heart failure, myocardial ischemia) or
• Heart rhythm problems (eg, prolonged PR interval) or
• Mental illness, history of or
• Sick sinus syndrome (type of abnormal heart rhythm), without pacemaker—Use with caution. May make these conditions worse.

• Diabetic neuropathy (nerve problem caused by diabetes) or
• Heart or blood vessel disease—May increase risk for more serious side effects.

• Kidney disease, severe or
• Liver disease, mild to moderate—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Liver disease, severe—Should not be used in patients with this condition.

• Phenylketonuria (PKU)—The oral liquid contains aspartame (a source of phenylalanine), which can make this condition worse.

Strong CYP3A4 or CYP2C9 Inhibitors

Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have a significant increase in exposure to Lacosamide tablets. Dose reduction may be necessary in these patients.

Concomitant Medications that Prolong PR Interval

Lacosamide should be used with caution in patients on concomitant medications that prolong PR interval, because of a risk of AV block or bradycardia, e.g., beta-blockers and calcium channel blockers. In such patients, obtaining an ECG before beginning Lacosamide tablets, and after Lacosamide is titrated to steady-state, is recommended.

Mechanism of Action

The precise mechanism by which Lacosamide 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.

Pharmacodynamics

A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses.

Cardiac Electrophysiology

Electrocardiographic effects of Lacosamide were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin). Lacosamide did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration. Lacosamide produced a small, dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax. The placebo-subtracted maximum increase in PR interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients who participated in the controlled trials, the placebo-subtracted mean maximum increase in PR interval for a 400 mg/day Lacosamide tablets dose was 3.1 ms in patients with partial-onset seizures and 9.4 ms for patients with diabetic neuropathy.

Pharmacokinetics

The pharmacokinetics of Lacosamide has been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment.

Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. The maximum Lacosamide plasma concentrations occur approximately 1 to 4 hour post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration. Pharmacokinetics of Lacosamide are dose proportional (100-800 mg) and time invariant, with low inter- and intra-subject variability. Compared to Lacosamide the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hours).

Absorption and Bioavailability

Lacosamide is completely absorbed after oral administration. The oral bioavailability of Lacosamide tablets is approximately 100%. Food does not affect the rate and extent of absorption. After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet.

In a trial comparing the oral tablet with an oral solution containing 10 mg/mL Lacosamide, bioequivalence between both formulations was shown.

Distribution

The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. Lacosamide is less than 15% bound to plasma proteins.

Metabolism and Elimination

Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation.

After oral and intravenous administration of 100 mg [14C]-Lacosamide approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The major compounds excreted were unchanged Lacosamide (approximately 40% of the dose), its O-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%). The plasma exposure of the major human metabolite, O-desmethyl-Lacosamide, is approximately 10% of that of Lacosamide. This metabolite has no known pharmacological activity.

The CYP isoforms mainly responsible for the formation of the major metabolite (O-desmethyl) are CYP3A4, CYP2C9, and CYP2C19. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.

There is no enantiomeric interconversion of Lacosamide.

Special Populations

Renal Impairment

Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.

The AUC of Lacosamide was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min) and 60% in severely (CLCR≤30 mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80 mL/min), whereas Cmax was unaffected. Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of Lacosamide is reduced by approximately 50% [see Dosage and Administration (2.3)].

Hepatic Impairment

Lacosamide undergoes metabolism. Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of Lacosamide (approximately 50-60% higher AUC compared to healthy subjects). The pharmacokinetics of Lacosamide have not been evaluated in severe hepatic impairment [see Dosage and Administration (2.4)].

Geriatric

In the elderly (>65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18-64 years). This may be related to body weight and decreased renal function in elderly subjects.

Gender

Lacosamide clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of Lacosamide.

Race

There are no clinically relevant differences in the pharmacokinetics of Lacosamide between Asian, Black, and Caucasian subjects.

CYP2C19 Polymorphism

There are no clinically relevant differences in the pharmacokinetics of Lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that Lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.

Drug interactions

In Vitro Assessment of Drug Interactions

In vitro metabolism studies indicate that Lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4. Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.

In vitro data suggest that Lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.

Lacosamide was not a substrate or inhibitor for P-glycoprotein.

Lacosamide is a substrate of CYP3A4, CYP2C9, and CYP2C19. Patients with renal or hepatic impairment who are taking strong inhibitors of CYP3A4 and CYP2C9 may have increased exposure to Lacosamide.

Since <15% of Lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.

In Vivo Assessment of Drug Interactions

• Drug interaction studies with AEDs
  • Effect of Lacosamide on concomitant AEDs
    Lacosamide 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.
    The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of Lacosamide tablets at any dose.
  • Effect of concomitant AEDs on Lacosamide
    Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day Lacosamide. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of Lacosamide tablets in a healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in Lacosamide plasma concentrations when Lacosamide tablets were coadministered with carbamazepine, phenobarbital or phenytoin.
• Drug-drug interaction studies with other drugs
  • Digoxin
    There was no effect of Lacosamide (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects.
  • Metformin
    There were no clinically relevant changes in metformin levels following coadministration of Lacosamide (400 mg/day).
    Metformin (500 mg three times a day) had no effect on the pharmacokinetics of Lacosamide (400 mg/day).
  • Omeprazole
    Omeprazole is a CYP2C19 substrate and inhibitor.
    There was no effect of Lacosamide (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that Lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.
    Omeprazole at a dose of 40 mg once daily had no effect on the pharmacokinetics of Lacosamide tablets (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.
  • Midazolam
    Midazolam is a 3A4 substrate.
    There was no effect of Lacosamide (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.
  • Oral Contraceptives
    There was no influence of Lacosamide (400 mg/day) on the pharmacodynamics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that a 20% increase in ethinylestradiol Cmax was observed.
  • Warfarin
    Co-administration of Lacosamide (400 mg/day) with warfarin (25 mg single dose) did not result in a clinically relevant change in the pharmacokinetic and pharmacodynamic effects of warfarin in a study in healthy male subjects.

NDC 51991-348-06

CV

Lacosamide Tablets

50 mg

60 Tablets
Rx Only

PHARMACIST: DISPENSE WITH THE ACCOMPANYING
MEDICATION GUIDE TO EACH PATIENT

Breckenridge
Pharmaceutical, Inc.

NDC 51991-351-06

CV

Lacosamide Tablets

200 mg

60 Tablets
Rx Only

PHARMACIST: DISPENSE WITH THE ACCOMPANYING
MEDICATION GUIDE TO EACH PATIENT

Breckenridge
Pharmaceutical, Inc.

AUC is increased by ~50% to 60% in patients with moderate hepatic impairment (Child-Pugh class B).

Use caution when titrating dose.

Mild to moderate renal impairment (CrCl >30 mL/minute): No dosage adjustment necessary. However, in patients with renal impairment taking concomitant strong CYP3A4 and/or CYP2C9 inhibitors, dosage reduction may be necessary.

Severe renal impairment (CrCl ≤30 mL/minute): Maximum dose: 300 mg/day. Further dosage reduction/limitation may be necessary with concomitant use of strong CYP3A4 and/or CYP2C9 inhibitors.

End-stage renal disease (ESRD) requiring hemodialysis: Maximum dose: 300 mg/day. Further dosage reduction/limitation may be necessary with concomitant use of strong CYP3A4 and/or CYP2C9 inhibitors. Removed by hemodialysis; after 4-hour hemodialysis treatment, a supplemental dose of up to 50% should be considered.

Use caution when titrating dose.

Mild to moderate hepatic impairment: Maximum dose: 300 mg/day. Further dosage reduction/limitation may be necessary in patients taking concomitant strong CYP3A4 and/or CYP2C9 inhibitors.

Severe hepatic impairment: Use is not recommended.

Injection: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. Stable when mixed with compatible diluents (NS, LR, D5W) for up to 4 hours at room temperature. Discard any unused portion.

Oral solution, tablets: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze oral solution. Discard any unused portion of oral solution after 7 weeks.

Adverse events were observed in animal reproduction studies. Information related to pregnancy outcomes following maternal use of lacosamide is limited (Hoeltzenbein 2011). In general, maternal polytherapy with antiepileptic drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of women taking antiepileptic medications may be at an increased risk of adverse events (Harden and Meader 2009).

Patients exposed to lacosamide during pregnancy are encouraged to enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, loss of strength and energy, headache, blurred vision, nausea, vomiting, diarrhea, dry mouth, or sweating a lot. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), seizures, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), change in balance, memory impairment, severe dizziness, passing out, bradycardia, tachycardia, abnormal heartbeat, tremors, diplopia, shortness of breath, agitation, irritability, panic attacks, mood changes, enlarged lymph nodes, angina, burning or numbness feeling, urinary retention, or change in amount of urine passed (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Safety and efficacy have not been established in patients younger than 17 years.

Consult WARNINGS section for additional precautions.

Animal studies have revealed evidence of increased embryofetal mortality, perinatal mortality, and growth deficit. There are no controlled data in human pregnancy. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Pregnancy Registries: 1) UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with this drug. To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrolment in the UCB AED Pregnancy Registry by calling 1-888-537-7734. 2) Physicians are advised to recommend that pregnant patients taking this drug enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at http://www.aedpregnancyregistry.org.

This drug should be used during pregnancy only if the benefit outweighs the risk. AU TGA pregnancy category: B3 US FDA pregnancy category: C