Anticonvulsants and Rectal Use: Best Practices


Seizures are a rare but serious complication at end of life. The incidence of seizure occurrence in hospice patients is not known. Patients at an increased risk for seizures are those with brain cancer, cerebrovascular disease, metabolic abnormalities, certain genetic disorders and/or pre-existing seizure disorders.1 Anticonvulsant therapy should continue, if possible, for patients with a history of seizures, brain tumors with experience of seizures, or a history of status epilepticus.

Up to 40% of patients with brain tumors have a seizure at the time of diagnosis. Another 20% develop seizures during the course of the illness. In the past, anticonvulsants were commonly started at the time of brain tumor diagnosis, however they have not been found to prevent seizures. Guidelines published by the American Academy of Neurology do not support seizure prophylaxis. Based on the lack of evidence for benefit, anticonvulsants can be safely discontinued in patients with brain tumors who have never had a seizure.1,2

Most acute seizures are short-lived and terminate spontaneously. The exception is status epilepticus (SE), defined as a crisis in which seizure activity is abnormal, prolonged and refractory to management. Guidelines for managing SE recommend the use of intravenous medications and suggest that neurological, respiratory and cardiovascular monitoring be available. Considering many hospice patients reside at home, these resources may not always be available or easily accessible. In addition, many patients on maintenance therapy may lose the ability to swallow reliably. The ability to administer medication via alternate routes is important to avoid hospital or hospice IPU admission for seizure management.3


  • Intractable nausea and vomiting
  • GI obstruction
  • Dysphagia
  • Esophageal stricture or malignancy
  • Loss of consciousness
  • Refusing oral medications or spitting out tablets


  • Avoiding painful injections
  • Administration of drugs that don’t have a SUBCUT/IM/IV dosage form
  • Ability to continue treatment with medications essential to comfort


  • Not all drugs are absorbed rectally4
  • Tablets and capsules administered rectally may vary in how they dissolve. It depends on presence of stool in the rectum and hydration status.
  • Suppositories may be expelled prematurely and not provide the total drug dose
  • The patient and family/caregiver may have concerns regarding the patient’s privacy or feel embarrassed by rectal administration 


The diazepam gel preparation (Diastat®) is the only commercially available rectal formulation approved for seizures. Several studies found effective the use of diazepam solution for injection and compounded diazepam suppositories administered rectally.5-12

There is evidence of feasibility of short-term substitution per rectum (PR) for:

  • Carbamazepine (Tegretol®)13-18
  • Lamotrigine (Lamictal®)19,20
  • Levetiracetam (Keppra®)21,22
  • Phenobarbital23-29
  • Topiramate (Topamax®)30
  • Valproic acid (Depakene®)31-42

Limited evidence suggests PR is not an effective route for:

  • Clonazepam (Klonopin®)43-48
  • Felbamate (Felbatol®)49
  • Gabapentin (Neurontin®)50
  • Lorazepam (Ativan®) 50-52
  • Midazolam (Versed®)50,53-62
  • Oxcarbazepine (Trileptal®)63-66
  • Phenytoin (Dilantin®)50,67-70

No evidence exists to support nor refute the PR route for:

  • Brivaracetam (Briviact®)
  • Divalproex (Depakote®)
  • Eslicarbazepine (Aptiom®)
  • Ethosuximide (Zarontin®)
  • Ezogabine (Potiga®)
  • Lacosamide (Vimpat®)
  • Perampanel (Fycompa®)
  • Pregabalin (Lyrica®)
  • Primidone (Mysoline®)
  • Rufinamide (Banzel®)
  • Tiagabine (Gabitril®)
  • Vigabatrin (Sabril®)
  • Zonisamide (Zonegran®)

In patients receiving anticonvulsants for managing seizure disorders, maintaining therapeutic concentrations of the drug is necessary for optimal seizure control.4 When literature does not support rectal administration in humans, or literature does not exist, consider using an alternative route of administration or a medication with more supporting evidence. However, in the absence of literature, one can consider trying rectal administration of a drug based on the following properties: 4

  • Surface area of absorption
  • Rectal retention time
  • Absorption rate, considering lipid solubility of drug and the amount of nonionized drug at site
  • Time available for rectal drug release/drug dissolution


Download a copy of this month’s case study to share with your colleagues or to keep for personal reference.



  1. Connelly J, Weissman D. Fast Facts and Concepts #229. Seizure management in the dying patient. June 2018. Article link
  2. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurol. 2000; 54:1886-1893
  3. Droney J, Hall E. Status epilepticus in a hospice inpatient setting. J Pain Symptom Manage. 2008; 36(1): 97-105.
  4. Anderson GD, Saneto RP. Current oral and non-oral routes of antiepileptic drug delivery. Adv Drug Del Rev. 2012;54:911-918.
  5. Moolenaar F, et al. Biopharmaceutics of rectal administration of drugs in man IX. Comparative biopharmaceutics of diazepam after single rectal, oral, and intravenous administration in man. Inter J Pharmaceutics. 1980 Apr;5(2): 127-137.
  6. Calderon Gonzalez R. Emergency management of convulsions and prevention of status epilepticus with rectal diazepam administered by parents. Boletin medico del Hospital Infantil de Mexico. 1991;48(7):469-473.
  7. Dhillon S, Ngwane E, Richens A. Rectal absorption of diazepam in epileptic children. Arch Dis Child. 1982;57(4):264-267.
  8. Dhillon S, Oxley J, Richens A. Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients. Br J Clin Pharmacol. 1982;13(3):427-432.
  9. Kanto J. Plasma concentrations of diazepam and its metabolites after per oral, intramuscular, and rectal administration. Correlation between plasma concentration and sedatory effect of diazepam. Int J Clin Pharmacol Biopharm. 1975;12(4):427-432.
  10. Knudsen FU. Plasma-diazepam in infants after rectal administration in solution and by suppository. Acta Paediatr Scand. 1977;66(5):563-567.
  11. Knudsen FU. Rectal administration of diazepam in solution in the acute treatment of convulsions in infants and children. Arch Dis Child. 1979;54(11):855-857.
  12. Milligan NM, et al. A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients. J Neurol Neurosurg Psychiatry. 1984;47(3):235-240.
  13. Arvidsson J, Nilsson HL, Sandstedt P, Steinwall G, Tonnby B, Flesch G. Replacing carbamazepine slow-release tablets with carbamazepine suppositories: a pharmacokinetic and clinical study in children with epilepsy. J Child Neurol. 1995;10(2):114-117.
  14. El-Kamel A, El-Khatib M. Thermally reversible in situ gelling carbamazepine liquid suppository. Drug Deliv. 2006;13(2):143-148.
  15. Neuvonen PJ, Tokola O. Bioavailability of rectally administered carbamazepine mixture. Br J Clin Pharmacol. 1987;24(6):839-841.
  16. Graves NM, et al. Relative bioavailability of rectally administered carbamazepine suspension in humans. Epilepsia. 1985;26(5):429-433.
  17. Graves NM, Kriel RL. Rectal administration of antiepileptic drugs in children. Pediatr Neurol. 1987;3(6):321-326.
  18. Storey P, Trumble M. Rectal doxepin and carbamazepine therapy in patients with cancer. N Engl J Med. 1992;327(18):1318-1319.
  19. Birnbaum AK, et al. Rectal absorption of lamotrigine compressed tablets. Epilepsia. 2000;41(7):850-853.
  20. Birnbaum AK, et al. Relative bioavailability of lamotrigine chewable dispersible tablets administered rectally. Pharmacother. 2001;21(2):158-162.
  21. Davis MP, et al. Symptom control in cancer patients: The clinical pharmacology and therapeutic role of suppositories and rectal suspensions. Support Care Cancer. 2002 Mar;10(2):117-38.
  22. Dunteman E. Levetiracetam administered by the rectal route is effective in treating neuropathic pain. J Pain 2004;5(3):S50.
  23. Moolenaar F, Koning B, Huizinga T. Biopharmaceutics of rectal administration of drugs in man: Absorption rate and bioavailability of phenobarbital and its sodium salt from rectal dosage forms. Inter J Pharmaceutics.1979;4:99-109.
  24. Graves, et al. Relative Bioavailability of rectally administered phenobarbital sodium parenteral solution. Ann Pharmacotherapy. 1989 July/Aug;23:565-568
  25. Graves NM, et al. Relative bioavailability of rectally administered phenobarbital sodium parenteral solution. Dicp. 1989;23(7-8):565-568.
  26. Heimann G, Neuwald F, Gladtke E. Rectal absorption of phenobarbital in children as affected by different vehicles. Arzneimittelforschung. 1978;28(6):1023-1026.
  27. Matsukura M, et al. Bioavailability of phenobarbital by rectal administration. Pediatr Pharmacol (New York). 1981;1(3):259-265.
  28. Minkov E, et al. Biopharmaceutical investigation of rectal suppositories. Part 2: Pharmaceutical and biological availability of phenobarbital and phenobarbital-sodium. Pharmazie. 1985;40(4):257-259.
  29. Yukawa E, et al. Population pharmacokinetic investigation of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants. J Clin Pharm Ther. 2005;30(2):159-163.
  30. Conway JM, et al. Relative bioavailability of topiramate administered rectally. Epilepsy Res. 2003;54(2-3):91-96.
  31. Battino D, et al. Comparison of the effectiveness of several formulations of sodium valproate: Tablets, enteric-coated capsules, solutions and rectal capsules. Ital J Neurol Sci. 1982;3(3):197-200.
  32. Cloyd JC, Kriel RL. Bioavailability of rectally administered valproic acid syrup. Neurology. 1981;31(10):1348-1352.
  33. Holmes GB, et al. Absorption of valproic acid suppositories in human volunteers. Arch Neurol. 1989;46(8):906-909.
  34. Issakainen J, Bourgeois BF. Bioavailability of sodium valproate suppositories during repeated administration at steady state in epileptic children. Eur J Pediatr. 1987;146(4):404-407.
  35. Kanazawa O, Sengoku A, Kawai I. Treatment of childhood epilepsy with rectal valproate: case reports and pharmacokinetic study. Brain Dev. 1987;9(6):615-620.
  36. Matsumura S, Shima T, Okada Y, et al. Serum concentration of valproic acid after rectal administration. Neurol Med Chir (Tokyo). 1988;28(5):473-476.
  37. Moolenaar F, Greving WJ, Huizinga T. Absorption rate and bioavailability of valproic acid and its sodium from rectal dosage forms. Eur J Clin Pharmacol. 1980;17(4):309-315.
  38. Scanabissi E, et al. Rectal administration of sodium valproate in children. Ital J Neurol Sci. 1984;5(2):189-193.
  39. Thorpy MJ. Rectal valproate syrup and status epilepticus. Neurology. 1980;30(10):1113-.
  40. Vajda FJE, et al. Rectal administration of sodium valproate in status epilepticus. Neurology. 1978;28(9):897-899.
  41. Vajda FJE, Symington GR, Bladin PF. Rectal valproate in intractable status epilepticus. Lancet. 1977:359-360.
  42. Yoshiyama Y, Nakano S, Ogawa N. Chronopharmacokinetic study of valproic acid in man: comparison of oral and rectal administration. J Clin Pharmacol.1989;29(11):1048-1052.
  43. Netter JC, et al. Intrarectal clonazepam in children. Plasma and CSF levels. Pediatrie (Bucur). 1988;43(7):603-605.
  44. Klosterskov Jensen P, Abild K, Nohr Poulsen M. Serum concentration of clonazepam after rectal administration. Acta Neurol Scand. 1983;68(6):417-420.
  45. Rylance GW, Poulton J, Cherry RC, Cullen RE. Plasma concentrations of clonazepam after single rectal administration. Arch Dis Child. 1986;61(2):186-188.
  46. Woody RC, Laney SM. Rectal anticonvulsants in pediatric practice. Pediatr Emerg Care. 1988;4(2):112-116.
  47. Mpimbaza A, et al. Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics. 2008;121:e58–e64.
  48. Scott RC, et al. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: A randomised trial. Lancet. 1999;353: 623–626.
  49. Grossmann R, Maytal J, Fernando J. Rectal administration of felbamate in a child with Lennox–Gastaut syndrome. Neurology. 1994; 44:1979.
  50. Kriel RL, et al. Failure of absorption of gabapentin after rectal administration. Epilepsia. 1990;38:1242-1244.
  51. Appleton R, et al. Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev Med Child Neurol. 1995 Aug;37(8):682-8.
  52. Mitchell WG, Crawford TO. Lorazepam is the treatment of choice for status epilepticus. J Epilepsy. 1990;3(1):7-10.
  53. Aydintug YS, Okcu KM, Guner Y, Gunaydin Y, Sencimen M. Evaluation of oral or rectal midazolam as conscious sedation for pediatric patients in oral surgery. Mil Med. 2004; 169(4):270-273.
  54. Clausen TG, et al. Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration. Br J Clin Pharmacol. 1988;25(4):457-463.
  55. Houi N, et al. Premedication with midazolam in infants. A comparison of different modes of administration. Cah Anesthesiol. 1992;40(3):167-170.
  56. Khazin V, Ezra S, Cohen A. Comparison of rectal to intranasal administration of midazolam for premedication of children. Mil Med. 1995;160(11):579-581.
  57. Kogan A, et al. Premedication with midazolam in young children: a comparison of four routes of administration. Paediatr Anaesth. 2002;12(8):685-689.
  58. Krafft TC, et al. Experience with midazolam as sedative in the dental treatment of uncooperative children. J Dent Child. 1993;60(4-5):295-299.
  59. Lejus C, et al. Midazolam for premedication in children: nasal vs. rectal administration. Eur J Anaesthesiol. 1997;14(3):244-249.
  60. Malinovsky JM, et al. Plasma concentrations of midazolam after i.v., nasal or rectal administration in children. Br J Anaesth. 1993;70(6):617-620.
  61. Malinovsky JM, et al. Premedication with midazolam in children. Effect of intranasal, rectal and oral routes on plasma midazolam concentrations. Anaesthesia. 1995;50(4):351-354.
  62. Pohl B, Schmicker F, Hofmockel R. Oral and rectal premedication of children with midazolam. Anaesthesiol Reanim. 2002;27(3):60-67.
  63. Clemens PL, et al. Relative bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension. Clinical Drug Investigation. 2007;27(4):243-250.
  64. van der Kuy PH, Koppejan EH, Wirtz JJ. Rectal absorption of oxcarbazepine. Pharm World Sci. 2000;22(4):165-166.
  65. Brouard A, et al. Rectal administration of carbamazepine gel. Clin. Pharm.1990; 9:13–14.
  66. Johannessen SI, et al. Serum concentration profile studies of tablets and suppositories of valproate and carbamazepine in healthy subjects and patients with epilepsy. In: R. Levy, et al (eds.), Metabolism of Antiepileptic Drugs, Raven Press, New York, 1984, pp. 61–71.
  67. Burstein AH, et al. Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base. Pharmacother. 2000;20(5):562-567.
  68. Chang SW, da Silva JH, Kuhl DR. Absorption of rectally administered phenytoin: a pilot study. Ann Pharmacother. 1999;33(7-8):781-786.
  69. Kerr D. Re: Practical use of rectal medications in palliative care. J Pain Symptom Manage. 1997;13(5):250.
  70. Moolenaar F, et al. Manipulation of rectal absorption rate of phenytoin in man. Pharm World Sci. 1981;3(1):1051-1056.