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News+Views: Rectal Administration of Anticonvulsants

There is a need for alternative routes of administration in hospice and palliative care patients who often suffer from nausea and vomiting, dysphagia, gastrointestinal obstruction, and mental status changes, all of which may limit intake of oral medications.  Compared to common alternative routes such as the intravenous and intramuscular routes, the rectal route of administration has certain practical advantages, as it does not require extensive patient or caregiver education and can be administered in the comfort of one’s own home. In addition, it is generally less expensive when compared to topical, subcutaneous, or intravenous routes.1

Rectal administration may also partially bypass first-pass metabolism, as the absorbed drug from the lower region of the rectum directly enters systemic circulation.2 However, factors such as defecation, pH, solubility, and particle size can all affect rectal absorption.2 Furthermore, patient acceptability and compliance may be a limiting factor in rectal administration.

Seizure management generally requires maintaining consistent plasma concentrations of antiepileptic drugs. In those who cannot tolerate oral administration, the rectal route may be appropriate if a continuous need for anticonvulsant therapy exists. The rectal administration of varying anticonvulsants has been explored to a limited degree - findings from studies are presented below.

Phenytoin

Phenytoin is typically administered orally or intravenously. Although the IM route is available, it is not commonly used due to erratic absorption.1 Likewise, rectal absorption is not reliable.

A pilot crossover study including five healthy patients was conducted to observe the absorption of rectally administered phenytoin. Patients received 7 mg/kg rounded to the lowest 25 mg of phenytoin sodium injection solution rectally or intravenously with a one week wash-out. Blood samples were taken at timed intervals to assess plasma concentration. The mean bioavailability was calculated to be 24.4% +/- 13.4 %.1 Out of the five patients, four patients reported preferring the rectal route to intravenous.1

Another study was conducted to determine the bioavailability of a phenytoin suppository compounded in a polyethylene glycol base. Six healthy subjects were given 8 mL of 125 mg/5 mL oral phenytoin solution and suppositories containing 200 mg phenytoin in 2 mL of polybase (polyethylene glycol 400, polyethylene glycol 8000, and polysorbate 80). Participants administered phenytoin either rectally or orally, and repeated with the other formulation following a one week wash-out. Out of the six participants, only four had detectable plasma levels following rectal administration.3 In addition, the median maximum rectal concentration was significantly lower that of the oral (o.4 vs 1.9 mcg / ml, p=0.028).3

At this time the evidence is limited and yields unreliable results. One study suggested that the rectal route may be a well tolerated alternative. However, due to the narrow therapeutic window of phenytoin and the impracticality of frequently monitoring plasma concentrations, rectal administration is not recommended.

Conclusion: Do not administer rectally.

Valproic Acid

In contrast, valproic acid has several studies that demonstrate consistent bioavailability when administered rectally.

One study compared the plasma concentrations following oral and rectal administration of 5oo mg of valproic acid in six healthy males. Participants received 500 mg or valproic acid orally or by rectal suppository one week apart. The study found that mean rectal absorption was roughly 80% of that of oral, ranging from 69% to 88%.4 In addition, at 2 hours following administration, over 90% had been absorbed rectally.4 There were no adverse effects reported other than urge to defecate in two participants.

Another study compared the pharmacokinetics of oral and rectal valproic acid. Participants ingested 600 mg sodium valproate dissolved in water orally and received a micro-enema solution of 600 mg sodium valproate rectally in a crossover model. The mean peak plasma concentrations were 60.2 mcg/mL after 1.5 hours for oral administration and 53.3 mcg/mL after 2 hours.5 The difference was not statistically significant (p>0.05).5 The area under the curve (AUC) was also not significantly different between the two routes, indicating complete absorption of valproic acid.5 In addition, the absorption following administration of valproic acid with sodium valproate suppositories in a fatty base was comparable to that of oral administration (p>0.05).5

Conclusion: Valproic acid and sodium valproate are good candidates for rectal administration.

Oxcarbazepine

An open label, randomized, cross-over study was performed to determine the bioavailability and tolerability of oxcarbazepine oral solution (300 mg/5 mL)  administered rectally. Two participants received 300 mg doses and eight participants received 450 mg doses of oxcarbazepine with a minimum of a two week washout period. The bioavailability following rectal administration was 8% of that following oral administration, most likely due to the low solubility of oxcarbazepine in water.6

Conclusion: It is unlikely that oxcarbazepine will reach sufficient therapeutic levels rectally.

Carbamazepine

Carbamazepine is rectally absorbed and has been used successfully to treat cluster seizures and generalized tonic-clonic status epilepticus.7

Nine healthy male volunteers received a 6 mg / kg dose of carbamazepine via oral tablet, oral suspension, and rectal suspension two weeks apart. Eight participants were included in analyses. Differences in total absorption, maximum plasma concentration, and time to peak concentration were statistically non-significant (p>0.05).8 Although rectal absorption was slower than absorption following oral suspension, this was associated with a reduction in reported adverse effects.8 Seven out of eight of the patients who received the oral suspension reported adverse effects such as lightheadedness, unsteadiness, and nystagmus.8 In contrast, the only adverse effects reported with rectal administration was the feeling of needing to defecate.8

Another study treated seven patients with cluster seizures and generalized tonic-clonic status epilepticus, following acute intervention, rectally with 400 mg aliquots of oral Tegretol syrup (100 mg/5 mL). All participants had termination of seizures prior to receiving carbamazepine rectally.7 All patients were seizure free following carbamazepine administration, and all but one patient achieved therapeutic levels between 5 to 10 hours.7

Conclusion: Carbamazepine is effective and tolerated well when given rectally.

Gabapentin

Rectal administration of gabapentin is not recommended.

Rectal absorption was studied in two children who had been taking gabapentin.  Prior to surgery these children received a single weight based dose orally, and then rectally. Rectal dosage forms were prepared by dissolving the contents of gabapentin capsules in 5 mL of tap water. The study found that serum levels gradually decreased following rectal administration, and therefore concluded that there was no measurable absorption.9 The authors state that the rectal route may not be viable because gabapentin is absorbed through active transport.9

Conclusion: Gabapentin is not absorbed rectally.

Levetiracetam

UCB Inc., the original manufacturer of Keppra does not approve breaking or crushing Keppra tablets for rectal administration. The current evidence of rectally administered levetiracetam is inconclusive.

A case study was presented at the American Epilepsy Society meeting in December 2005. A 56 year old male intubated in the ICU for seizures. Due to declining oral tolerance, he was given the same dose of levetiracetam (2000 mg twice daily) rectally starting day 8. The plasma concentration one hour prior to rectal administration was 36.8 mg/L.10 The study found that the steady state trough prior to the fourth dose of rectal levetiracetam was 16.4 mg/L.10 Irritation was not observed.

Per the manufacturer inquiry, one study by Dunteman et al. administered 500 mg Keppra tablets covered with water soluble lubricant rectally, every 12 hours, to seven patients in either oncology/palliative care or the ICU with severe pain. Of the seven patients, four patients had confirmed blood levels of absorption via rectal route.11

Conclusion: Levetiracetam is absorbed with significant (>50%) reduction in plasma levels.

Phenobarbital

Plasma phenobarbital concentrations were measured in six volunteers following oral or rectal administration of 200 mg phenobarbital or 219 mg sodium phenobarbital in aqueous solution. Despite the delay in absorption, the total rectal absorption was comparable to oral absorption in both phenobarbital and sodium phenobarbital 6.5 hours following administration.12 However, a much more significant delay in absorption with phenobarbital in fatty suppository dosage form was observed in vivo.12

Conclusion: Total rectal absorption of phenobarbital is comparable to that of oral absorption, but the slow speed of absorption, particularly with compounded suppositories, make it a poor choice for treatment of acute seizures.

Topiramate

In a randomized, open-label, cross-over study twelve healthy men and women received either 100 or 200 mg topiramate tablet orally or 200 mg rectal suspension prepared by crushing the 200 mg oral tablet. Patients received the other formulation after a 2 week wash-out. The relative bioavailability of rectally administered topiramate was 0.95 +/- 0.17.13 Plasma concentrations and time to peak plasma concentration was not significantly different between the oral and rectal routes.13 The study found that the 2.78 mg topiramate dissolved in 1 mL of water, indicating that despite low solubility a significant amount of drug was absorbed.13 Further studies may yield better results by using a more concentrated rectal solution.

Conclusion: In healthy adults, topiramate was rectally absorbed to a similar extent when compared to oral dosage forms.

Lamotrigine

One single-blind crossover study involving twelve healthy individuals analyzed the pharmacokinetics of lamotrigine administered rectally. Participants were randomly assigned to receive either 100 mg lamotrigine compressed tablet orally or suspension prepared from 100 mg lamotrigine compressed tablet rectally. Blood samples were drawn for plasma concentration analysis. Participants received the other formulation after 2 weeks. There were no significant adverse effects reported, and the suspension was tolerated well.14 However, the average plasma concentration was significantly lower after rectal administration compared to oral administration (0.3 mcg/mL vs 0.83 mcg/mL, p<0.001) with a relative bioavailability of 0.63 +/- 0.33.14

Another study of similar design performed in the same lab found that the relative rectal bioavailability of lamotrigine chewable dispersible tablets was 0.52 +/- o.23.15 Participants in both studies were required to empty the bowel by administering Fleet’s enema the night before rectal administration. However, the findings from these studies suggest that rectal lamotrigine may potentially benefit patients requiring an alternative route of administration.

Conclusion: Lamotrigine is absorbed rectally, though not to the same degree as it is orally.

Not studied:

Tiagabine

Lacosamide

Primidone

Written by: Heesun Stephanie Park, Midwestern University PharmD Candidate – 2018

Reviewed by: Joe Solien, PharmD, BCPP, BCGP, Vice President – Clinical Services OnePoint Patient Care

References

  1. Chang, S. W., da Silva, J. H., & Kuhl, D. R. (1999). Absorption of rectally administered phenytoin: a pilot study. Annals of Pharmacotherapy, 33(7-8), 781-786.
  2. De Boer, A. G., Moolenaar, F., De Leede, L. G. J., & Breimer, D. D. (1982). Rectal drug administration. Clinical Pharmacokinetics, 7(4), 285-311.
  3. Burstein, A. H., Fisher, K. M., McPherson, M. L., & Roby, C. A. (2000). Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 20(5), 562-567.
  4. Holmes, G. B., Rosenfeld, W. E., Graves, N. M., Remmel, R. P., Carlson, G. H., & Kriel, R. D. (1989). Absorption of valproic acid suppositories in human volunteers. Archives of neurology, 46(8), 906-909.
  5. Moolenaar, F., Greving, W. J., & Huizinga, T. (1980). Absorption rate and bioavailability of valproic acid and its sodium salt from rectal dosage forms. European journal of clinical pharmacology, 17(4), 309-315.
  6. Clemens, P. L., Cloyd, J. C., Kriel, R. L., & Remmel, R. P. (2007). Relative bioavailability, metabolism and tolerability of rectally administered oxcarbazepine suspension. Clinical drug investigation, 27(4), 243-250.
  7. Patel, V., Cordato, D. J., Malkan, A., & Beran, R. G. (2014). Rectal carbamazepine as effective long-acting treatment after cluster seizures and status epilepticus. Epilepsy & Behavior, 31, 31-33.
  8. Graves, N. M., Kriel, R. L., Jones‐Saete, C., & Cloyd, J. C. (1985). Relative bioavailability of rectally administered carbamazepine suspension in humans. Epilepsia, 26(5), 429-433.
  9. Kriel, R. L., Birnbaum, A. K., Cloyd, J. C., Ricker, B. J., Saete, C. J., & Caruso, K. J. (1997). Failure of absorption of gabapentin after rectal administration. Epilepsia, 38(11), 1242-1244.
  10. Gustafson MC, Penovich PE, Frost MD. Levetiracetam absorption after rectal administration: 2 case reports. Epilepsia. 2005; 46(Suppl 8):211. [Abstract 2.357] Presented at: American Epilepsy Society Annual Meeting, Dec 2-5, 2005. Washington, USA.
  11. Dunteman E. Levetiracetam administered by the rectal route is effective in treating neuropathic pain. [Abstract 766]. Presented at the Second Joint Scientific Meeting of the American Pain Society and Canadian Pain Society. May 6-9, 2004. Vancouver, Canada. Per manufacturer inquiry, January 2015.
  12. Leppik, I. E., & Patel, S. I. (2015). Intramuscular and rectal therapies of acute seizures. Epilepsy & Behavior, 49, 307-312.
  13. Conway, J. M., Birnbaum, A. K., Kriel, R. L., & Cloyd, J. C. (2003). Relative bioavailability of topiramate administered rectally. Epilepsy research, 54(2-3), 91-96.
  14. Birnbaum, A. K., Kriel, R. L., Burkhardt, R. T., & Remmel, R. P. (2000). Rectal absorption of lamotrigine compressed tablets. Epilepsia, 41(7), 850-853.
  15. Birnbaum, A. K., Kriel, R. L., Im, Y., & Remmel, R. P. (2001). Relative bioavailability of lamotrigine chewable dispersible tablets administered rectally. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 21(2), 158-162.

 

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