Felbatol

Generic Name: Felbamate
Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 2-Phenyltrimethylene ester carbamic acid
Molecular Formula: C11H14N2O4
CAS Number: 25451-15-4

Warning(s)

  • Aplastic Anemia
  • Risk of aplastic anemia in patients receiving felbamate appears to be at least 40–100 times higher than that in general population (about 2–5 cases per million untreated individuals per year).21 22 26 27 31

  • Potentially fatal; current estimated overall case fatality rate for untreated individuals with aplastic anemia ranges from 20–30%, but rates as high as 70% have been reported in the past.19 27

  • Limit use to patients whose seizure disorder is so severe that the benefits of therapy outweigh the substantial risk of aplastic anemia.26 27 31 (See Seizure Disorders under Uses.)

  • Clinical manifestation of aplastic anemia (e.g., bleeding, infection) usually develops without premonitory clinical or laboratory signs after several months of therapy (range: 5–30 weeks).27 Routine blood tests are unreliable but may, nevertheless, result in early detection of the syndrome in some patients.27 (See Hematologic Effects under Cautions.)

  • Hepatic Failure
  • Risk of acute hepatic failure resulting in death or hepatic transplantation reported at an estimated rate of about 6 cases per 75,000 patient years of use.a Actual rate believed to be considerably higher.a 27

  • Severe hepatic dysfunction followed by hepatic failure reported as early as 3 weeks after initiation of felbamate; has resulted in death or hepatic transplantation in about 67% of reported cases, usually within 5 weeks of the onset of signs and symptoms of hepatic failure.a Prodromal symptoms (e.g., anorexia, malaise, other GI symptoms) and/or dark urine may or may not precede onset of jaundice.a

  • Do not initiate therapy in patients with active liver disease, abnormal baseline serum transaminase concentrations, or a history of hepatic dysfunction.a

  • Periodic serum transaminase testing has not been proven to prevent serious injury but may, nevertheless, result in early detection of the syndrome in some patients.a (See Hepatic Effects under Cautions.)

Introduction

Anticonvulsant; a dicarbamate derivative.1 3 4 5 20

Uses for Felbatol

Seizure Disorders

Not indicated as a first-line antiepileptic therapy; should be used only in patients whose seizure disorder is refractory to alternative safer therapy and is so severe that the benefits of felbamate therapy are believed to outweigh the substantial risk of aplastic anemia26 27 31 or acute hepatic failure.27 28 29 (See Boxed Warning.)

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Management (alone or in combination with other anticonvulsants) of partial seizures with or without secondary generalization in adults and adolescents ≥14 years of age.1 8 12 13 14 19 20 21 22 25

Management (in combination with other anticonvulsants) of partial and generalized seizures associated with Lennox-Gastaut syndrome in children 2–14 years of age1 15 16 17 20 21 25 (designated an orphan drug by FDA for this use).2

Felbatol Dosage and Administration

General

  • Prior to initiation of therapy, discuss the risks associated with use of felbamate with the patient, parent, or guardian and obtain written informed consent.27 32

  • Obtain expert hematologic consultation prior to initiation of therapy and whenever any hematologic abnormality is detected during the course of therapy.19 27

  • Abrupt withdrawal may result in increased seizure frequency;1 withdraw gradually and reduce dosage slowly.27 (See Withdrawal Seizures under Cautions.)

Administration

Oral Administration

Tablets

Administer orally in 3 or 4 divided doses without regard to meals.27

Suspension

Administer orally in 3 or 4 divided doses;27 effect of food on absorption of the suspension has not been evaluated.27 Shake well before administration.27

Dosage

When adding to an existing anticonvulsant regimen, add gradually while reducing the dosage(s) of other anticonvulsant(s).1 (See Specific Drugs under Interactions.)

Pediatric Patients

Lennox-Gastaut Syndrome
Adjunctive Therapy
Oral

Children 2–14 years of age: Initially, 15 mg/kg daily administered in 3 or 4 divided doses.1 15 Dosage may be increased by 15 mg/kg daily at weekly intervals to a maximum dosage of 45 mg/kg daily administered in 3 or 4 divided doses.1 15

As felbamate is added to the anticonvulsant regimen, the dosage(s) of other anticonvulsant(s) must be gradually decreased, initially by at least 20%;1 15 19 further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary as felbamate dosage is increased.1 19

Partial Seizures With or Without Secondary Generalization
Oral

Adolescents ≥14 years of age should receive dosages recommended for adults.1 (See Adults under Dosage and Administration.)

Adults

Partial Seizures With or Without Secondary Generalization
Monotherapy
Oral

Initially, 1.2 g daily administered in 3 or 4 divided doses.1 Titrate previously untreated patients under close clinical supervision, increasing dosage in 600-mg daily increments every 2 weeks to 2.4 g daily based on clinical response and thereafter to 3.6 g daily if clinically indicated.a Felbamate has not been evaluated systematically as initial monotherapy.1

Conversion to Felbamate Monotherapy
Oral

Initially, 1.2 g daily administered in 3 or 4 divided doses.1 At the same time, reduce the dosage(s) of concomitantly administered anticonvulsant(s) by 33%.a At week 2, increase the felbamate dosage to 2.4 g daily while reducing the dosage(s) of other anticonvulsant(s) by up to an additional 33% of their baseline dosage(s).a At week 3, increase the felbamate dosage to 3.6 g daily and continue to reduce the dosage(s) of other anticonvulsant(s) as clinically indicated.a

Adjunctive Therapy
Oral

Initially, 1.2 g daily administered in 3 or 4 divided doses.1 Dosage may be increased by 1.2-g daily increments at weekly intervals to a maximum of 3.6 g daily administered in 3 or 4 divided doses.1

As felbamate is added to the anticonvulsant regimen, the dosage(s) of other anticonvulsant(s) must be gradually decreased, initially by at least 20%;1 15 19 further reductions in dosage(s) of concomitant anticonvulsant(s) may be necessary as felbamate dosage is increased.1 19

More rapid titration of felbamate dosage (e.g., increasing dosage to 3.6 g daily over a 3-day period) occasionally has been employed.1 8 11 14

Prescribing Limits

Pediatric Patients

Lennox-Gastaut Syndrome
Oral

Children 2–14 years of age: Maximum 45 mg/kg daily.1 15

Partial Seizures With or Without Secondary Generalization
Oral

Adolescents ≥14 years of age: Maximum 3.6 g daily.1 8 11 14

Adults

Partial Seizures With or Without Secondary Generalization
Oral

Maximum 3.6 g daily.1 8 11 14

Special Populations

Renal Impairment

Reduce initial and maintenance dosages by 50%.a Adjunctive therapy with drugs that affect plasma felbamate concentrations, especially other anticonvulsants, may warrant further reductions in felbamate daily dosage in patients with renal dysfunction.a

Cautions for Felbatol

Contraindications

  • History of any blood dyscrasia or hepatic dysfunction.27

  • Known hypersensitivity to felbamate, other carbamates, or any ingredient in the formulation.27

Warnings/Precautions

Warnings

Hematologic Effects

Increased risk of potentially fatal aplastic anemia.21 22 26 27 31 (See Boxed Warning.)

Risk factors for development of aplastic anemia not identified; no known documented effective means to monitor patients so as to avoid and/or reduce the risk of aplastic anemia.22 26 27 31

Obtain expert hematologic consultation prior to initiation of therapy and whenever any hematologic abnormality is detected during therapy.19 27

Full hematologic evaluations (e.g., CBC) recommended by manufacturer before initiation of felbamate therapy, at frequent intervals during therapy, and for a substantial period of time following discontinuance of therapy.27

If any evidence of bone marrow depression occurs, discontinue the drug.27 Patients remain at risk for a variable, and unknown, period of time following drug discontinuance.27

Hepatic Effects

Increased risk of acute hepatic failure resulting in death or hepatic transplantation.a (See Boxed Warning.)

Risk factors for development of hepatic failure not identified; no known documented effective means to monitor patients so as to avoid and/or reduce the risk of acute hepatic failure.27

Monitor serum transaminase (ALT, AST) concentrations prior to initiation of therapy and periodically thereafter (precise schedule for monitoring based on clinician’s judgment).a Time course for progression from normal hepatic function to hepatic failure currently unknown.a

If serum ALT or AST concentrations increase to ≥2 times ULN or if clinical signs and symptoms suggestive of hepatic failure occur, discontinue felbamate immediately and monitor hepatic function until values return to normal.a

Do not reinitiate therapy in patients who develop evidence of hepatocellular injury and are withdrawn from felbamate for any reason.a

Withdrawal Seizures

Abrupt withdrawal may result in increased seizure frequency;27 withdraw gradually and reduce dosage slowly.1

To minimize the risk of adverse withdrawal effects, decrease dosage at 4- to 5-day intervals in increments that are one-third of the baseline daily dosage; according to this schedule, therapy usually can be discontinued over a period of 8–10 days.19 23

If the clinician determines that abrupt discontinuance is necessary, felbamate therapy may be stopped without gradual decreases in dosage provided that the patient receives adequate doses of another anticonvulsant.23

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Severe dermatologic reactions (i.e., toxic epidermal necrolysis,27 Stevens-Johnson syndrome1 20 ) and photosensitivity1 reported rarely.a c

Specific Populations

Pregnancy

Category C.1 b

Lactation

Distributed into milk;27 use with caution, if at all, in nursing women.b

Pediatric Use

Safety and efficacy for the management of Lennox-Gastaut syndrome not established in children <2 years of age.27 Safety and efficacy for the management of partial seizures with or without secondary generalization not established in children and adolescents <14 years of age.27

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.27 Consider the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease and other drug therapy observed in the elderly.27

Renal Impairment

Use with caution; decreased clearance; dosage adjustments necessary.a (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

When used as adjunctive therapy in children, anorexia, vomiting, insomnia, headache, and somnolence.1 16

When used as monotherapy or adjunctive therapy in adults, anorexia, nausea, vomiting, insomnia, and headache; dizziness and somnolence also are frequent during adjunctive therapy.1 11 12 14 20

Interactions for Felbatol

Partially metabolized by CYP isoenzymes,27 d principally CYP3A4 and CYP2E1.d e May possibly induce CYP3A4 and inhibit CYP2C19.d

Drugs Affecting Hepatic Microsomal Enzymes

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma felbamate concentrations).27 d

Inhibitors of CYP3A4: Pharmacokinetic interaction unlikely.e

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction (decreased plasma substrate concentrations).e

Substrates of CYP2C19: Potential pharmacokinetic interaction (increased plasma substrate concentrations).e

Specific Drugs

Drug

Interaction

Comment

Antacids

Pharmacokinetic interaction unlikely27

Carbamazepine

Increased felbamate clearance; steady-state trough concentrations of felbamate decreased approximately 40%27

Decreased steady-state plasma carbamazepine concentrations and increased steady-state plasma carbamazepine epoxide concentrations27

Reduce carbamazepine dosage by 20–33%27

Contraceptives, oral (e.g., low-dose combinations containing ethinyl estradiol and gestodene [not commercially available in the US])

Decreased gestodene AUC; intermenstrual bleeding reporteda

No clinically relevant effect on ethinyl estradiol pharmacokineticsa

Monitor and adjust dosages accordinglya

Erythromycin

Effect on felbamate pharmacokinetics unlikelya

Phenobarbital

Possible decreased plasma felbamate concentrationsa

Increased plasma phenobarbital concentrationsa

Reduce phenobarbital dosage by 20–33%a

Phenytoin

Felbamate clearance doubled; steady-state trough concentrations of felbamate decreased approximately 45%27

Increased steady-state plasma phenytoin concentrations27

Reduce phenytoin dosage by 20–33%27

Valproate

No clinically important effect on plasma felbamate concentrations27

Increased steady-state plasma valproate concentrations27

Reduce valproate dosage by 20–33%27

Felbatol Pharmacokinetics

Absorption

Bioavailability

Well absorbed after oral administration.27 Oral bioavailability estimated to be ≥90%.d

Commercially available tablets and oral suspension are bioequivalent to the capsule formulation used in clinical trials; pharmacokinetic profiles of the tablets and oral suspension are similar.1

Food

Food has no effect on absorption of tablets; effect of food on absorption of the suspension has not been evaluated.27

Distribution

Extent

Crosses the placenta in rats.1

Distributed into human milk.27

Plasma Protein Binding

22–25% (principally albumin).27

Elimination

Metabolism

Undergoes partial hepatic metabolism via N-glucuronidation, oxidation, and hydroxylation mediated by CYP3A4 and 2E1;d monocarbamate, p-hydroxy, and 2-hydroxy metabolites appear to contribute little, if any, to the anticonvulsant action of the drug.1 4 6

Elimination Route

Excreted principally in urine (90%) as unchanged drug (40–50%), unidentified metabolites and conjugates (40%), and monocarbamate, p-hydroxy, and 2-hydroxy metabolites (15%).27

Half-life

Terminal half-life is approximately 20–23 hours.27

Special Populations

Renal impairment decreases total body clearance by 40–50% and prolongs half-life by 9–15 hours.a

Effects of hepatic impairment on felbamate pharmacokinetics have not been evaluated.27

Stability

Storage

Oral

Suspension and Tablets

Tight containers at 20–25°C.a

Actions

  • Structurally related to but pharmacologically distinct from meprobamate, an anxiolytic agent.3 5 7 20

  • Exact mechanism of action of anticonvulsant effect not known, but available data suggest that the drug increases seizure threshold and reduces seizure spread.1 4 6 20

  • Exhibits a spectrum of anticonvulsant activity that is pharmacologically distinct from the spectra of other currently available agents.1 4 6 7 20

  • Weak inhibitor in vitro at GABA receptors and benzodiazepine receptors.1

Advice to Patients

  • Risk of aplastic anemia; importance of notifying clinicians if signs of infection, bleeding, easy bruising, or signs of anemia (e.g., fatigue, weakness, lassitude) occur.27

  • Risk of hepatic failure; importance of immediately notifying clinicians if signs of liver dysfunction (e.g., jaundice, anorexia, GI complaints, malaise) occura and of adhering to prescribed schedule of liver function tests.27

  • Importance of women informing their clinician if they are or plan to become pregnant or to breast-feed.27

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.27

  • Importance of informing patients of other important precautionary information.27 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Felbamate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

600 mg/5 mL

Felbatol (with polysorbate 80 parabens saccharin sodium and sorbitol)

Medpointe

Tablets

400 mg

Felbatol (scored)

Medpointe

600 mg

Felbatol (scored)

Medpointe

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Felbatol 400MG Tablets (MEDA PHARMACEUTICALS): 90/$447.01 or 100/$494.99

Felbatol 600MG/5ML Suspension (MEDA PHARMACEUTICALS): 237/$590.01 or 711/$1,741.97

Felbatol 600MG Tablets (MEDA PHARMACEUTICALS): 90/$519.01 or 270/$1,532.94

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Wallace Laboratories. Felbatol (felbamate) tablets and oral suspension prescribing information. Cranbury, NJ; 1993 Jul 31.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 30, 1993. Rockville, MD; 1993 Jul.

3. Pugh CB, Garnett WR. Current issues in the treatment of epilepsy. Clin Pharm. 1991; 10:335-58. [IDIS 280238] [PubMed 2049897]

4. Graves NM, Leppik IE. Antiepileptic medications in development. DICP. 1991; 25:978-86. [IDIS 285278] [PubMed 1949977]

5. Brodie MJ, Porter RJ. New and potential anticonvulsants. Lancet. 1990; 336:425-6. [IDIS 269909] [PubMed 1974955]

6. Anon. Felbamate. Phase III Prof. 1992; 2: 14-9.

7. Brodie MJ. Felbamate: a new antiepileptic drug. Lancet. 1993; 341:1445-6. [IDIS 316235] [PubMed 8099147]

8. Sachdeo R, Kramer LD, Rosenberg A et al. Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol. 1992; 32:386-92. [IDIS 302873] [PubMed 1416808]

9. Wilner AN. Efficacy of felbamate monotherapy. Ann Neurol. 1993; 33:661. [IDIS 315259] [PubMed 8498849]

10. Sachdeo R. Efficacy of felbamate monotherapy. Ann Neurol. 1993; 33:661-2. [IDIS 315259] [PubMed 8498849]

11. Faught E, Sachdeo RC, Remler MP et al. Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology. 1993; 43:688-92. [IDIS 313030] [PubMed 8469323]

12. Leppik IE, Dreifuss FE, Pledger GW et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology. 1991; 41:1785-9. [IDIS 291232] [PubMed 1944909]

13. Theodore WH, Raubertas RF, Porter RJ et al. Felbamate: a clinical trial for complex partial seizures. Epilepsia. 1991; 32:392-7. [IDIS 283681] [PubMed 2044501]

14. Bourgeois B, Leppik IE, Sackellares JC et al. Felbamate: a double-blind controlled trial in patients undergoing presurgical evaluation of partial seizures. Neurology. 1993; 43:693-6. [IDIS 313031] [PubMed 8469324]

15. The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med. 1993; 328:29-33. [IDIS 307291] [PubMed 8347179]

16. Snodgrass SR. Felbamate therapy in the Lennox-Gastaut syndrome. N Engl J Med. 1993; 328:1641. [IDIS 315141] [PubMed 8487814]

17. Ritter FJ. Felbamate therapy in the Lennox-Gastaut syndrome. N Engl J Med. 1993; 328:1641.

18. Pledger GW, Kramer LD. Clinical trials of investigational antiepileptic drugs: monotherapy designs. Epilepsia. 1991; 32:716-21. [PubMed 1915182]

19. Wallace, Princeton, NJ: Personal communication.

20. Anon. Felbamate. Med Lett Drugs Ther. 1993; 35:107-8. [PubMed 8232064]

21. Cruzan S. From the FDA electronic bulletin board: suspension of Felbatol use urged. Rockville, MD: Food and Drug Administration; 1994 Aug 1.

22. Costin JC. Dear doctor letter regarding recommendation for the immediate withdrawal of patients from treatment with Felbatol (felbamate). Cranbury, NJ: Wallace Laboratories; 1994 Aug 1.

23. Neumann E. Dear doctor letter regarding the recommended procedure for the discontinuation of Felbatol (felbamate). Cranbury, NJ: Wallace Laboratories; 1994 Aug 1.

24. Flanagan HP III. Dear pharmacist letter regarding suspension of Felbatol (felbamate) therapy. Cranbury, NJ: Wallace Laboratories; 1994 Aug.

25. Cruzan S. From the FDA electronic bulletin board: felbamate approved for epilepsy. Rockville, MD: Food and Drug Administration; 1993 Aug 2.

26. Costin JC. Dear doctor letter regarding revised prescribing information for Felbatol. Cranbury, NJ: Wallace Laboratories; 1994 Aug 26.

27. Wallace Laboratories. Felbatol (felbamate) tablets 400 mg and 600 mg and oral suspension 600 mg/5 mL prescribing information. Cranbury, NJ; 1994 Oct.

28. Costin JC. Dear doctor letter regarding recommendation for monitoring liver function tests in patients being treated with Felbatol (felbamate). Cranbury, NJ: Wallace Laboratories; 1994 Sep 21.

29. Cruzan S. FDA Talk Paper T94-46. Felbatol update. Rockville, MD: Food and Drug Administration; 1994 Sep 27.

30. Ahmad SR. Felbamate and aplastic anemia. Lancet. 1994; 344:465.

31. Nightingale SL. From the Food and Drug Administration: recommendation to immediately withdraw patients from treatment with felbamate. JAMA. 1994; 272:995. [PubMed 8089899]

32. Costin JC. Dear doctor letter regarding revised prescribing information for Felbatol. Cranbury, NJ: Wallace Laboratories; 1994 Oct 26.

33. Flanagan HP III. Dear pharmacist letter regarding revised prescribing information for Felbatol. Cranbury, NJ: Wallace Laboratories; 1994 Oct 26.

34. US Food and Drug Administration. Medwatch web site. 1999.

a. MedPointe Pharmaceuticals. Felbatol (felbamate) tablets 400 mg and 600 mg and oral suspension 600 mg/5 mL prescribing information. Somerset, NJ; 2002 Dec.

b. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Baltimore, MD: Williams & Wilkins; 2002:537-8.

c. French J, Smith M, Faught E et al. Practice advisory: the use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 1999; 52:1540-5. [PubMed 10331676]

d. Hachad H, Ragueneau-Majlessi I, Levy RH. New antiepileptic drugs: review on drug interactions. Ther Drug Monit. 2002; 24:91-103. [PubMed 11805729]

e. Glue P, Banfield CR, Perhach JL et al. Pharmacokinetic interactions with felbamate. In vitro-in vivo correlation. Clin Pharmacokinet. 1997; 33:214-24. [PubMed 9314612]

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