Extended-release gabapentin was approved in 2011 for the treatment of postherpetic neuralgia. A clinical trial compared once daily and twice daily dosing of extended-release gabapentin to placebo. While the primary endpoint was not statistically significant, secondary endpoints showed benefits for pain, sleep interference, and global impression of change with gabapentin. Further studies are needed to definitively establish efficacy and identify optimal dosing for postherpetic neuralgia.

1. Extended-Release Gabapentin:
A medication overview and its
use in postherpetic neuralgia
Kyle A. Amelung
Pharm.D. Candidate, 2012
St. Louis College of Pharmacy
Preceptor: Tina M. Purcell, Pharm.D., PMP
Medical Affairs

2. OBJECTIVES
 Discuss the history of gabapentin in
the marketplace
 Describe gabapentin pharmacology
and the ER dosage form
 Explain postherpetic neuralgia
 Understand a clinical trial focusing
on ER gabapentin
Covidien | | Confidential

3. GABAPENTIN PHARMACOLOGY
 Structurally related to GABA
(gamma-Aminobutyric acid)
GABA  Unknown MOA
 Does not affect the following receptors:
– GABA – Cannabinoid
– BZD – Dopamine
– NMDA – Histamine
– Alpha – Serotonin
– Beta – Opioid
Gabapentin
"Gabapentin." Facts & Comparisons eAnswers. Wolters
Kluwer Health, Apr. 2011. Web. 28 Nov. 2011.

4. GABAPENTIN PHARMACOKINETICS
 Absorption: Not dose-proportional;
Slight effect of food on rate and
extent
 Distribution: <3% binds to plasma protein;
VD of ~60 L after 150mg IV infusion
 Metabolism: Not metabolized
 Excretion: Elimination half-life of 5 to 7 hours;
Renally excreted as unchanged
drug
"Gabapentin." Facts & Comparisons eAnswers. Wolters
Kluwer Health, Apr. 2011. Web. 28 Nov. 2011.

5. ADVERSE DRUG REACTIONS
Covidien | | Confidential

6. POSTHERPETIC NEURALGIA (PHN)
 Follows the healing of herpes zoster rash (shingles)
 A neuropathic pain syndrome, with pain >3 months
Guideline Recommendations
 First line – TCAs, gabapentin, opioids,
pregabalin, and topical lidocaine patches
 Aspirin (in cream) and capsaicin are
“possibly effective” but the magnitude of
benefit is low
 Intrathecal methylprednisolone may be
considered
 “There is insufficient evidence at this
time to make any recommendations on the websters-online-dictionary.org
long-term effects of these treatments.”
Dubinsky et al. Practice parameter: treatment of postherpetic neuralgia: an evidence-
based report of the Quality Standards Subcommittee of the American Academy of
Neurology. Neurology 2004 Sep 28;63(6):959-65. Reaffirmed February 2008.

7. GABAPENTIN TIMELINE
 December 1993 – Neurontin® (gabapentin, by Parke-Davis) approved
for adjunctive therapy in the treatment of partial seizures in adults
 October 2000 – Neurontin® approved
for use in children >3 years of age
 May 2002 – Neurontin® approved for
postherpetic neuralgia (PHN)
 October 2004 – Generic gabapentin becomes available
 January 2011 – GraliseTM (gabapentin ER, by
Depomed, Inc.) approved for PHN
 April 2011 – Gabapentin REMS discontinued
Neurontin Timeline. http://www.hkllp.com/neurontin/neurontin-timeline/

8. GRALISETM
ER Technology: AcuFormTM (proprietary)
– Polymers that, upon contact with the gastric
fluid, swell by a factor of 3x and retain the
medication in the stomach over 6 to 8 hours
Drug Cost #90
GraliseTM 300mg $217
gabapentin 300mg $19
Neurontin® 300 mg $200
Lyrica® 100mg $260
Drugstore.com
"Depomed: Leader in Gastric Retention Technology." Drug
Delievery Technology 9.3 (2009): 56-57. Print.

9. ACUFORMTM TECHNOLOGY AND COVIDIEN
November 2008  Covidien granted worldwide rights from Depomed
to utilize AcuformTM technology for the development of up to 4
opioid/APAP products , costing $5.5M upfront
October 2009  1st formulation delivered
December 2009  2nd formulation delivered
September 2010  1st formulation entered clinical development
November 2010  Contract expires; Depomed no longer required to
perform formulation work on the remaining two products.
DepoMed (2011). 10-K Annual Report 2011.
Retrieved November 30, 2011 from Wikiinvest, Web.

10. GABAPENTIN ER DOSING
Initiate and titrate as follows, taken once daily with the evening meal
Gralise.com
In the setting of renal insufficiency:
CrCl (mL/min) Max Dose
 If dose is reduced or
≥ 60 1,800 mg discontinued, taper
30 to 60 600 to 1,800 mg gradually over a
< 30 Do not administer minimum of 1 week
On hemodialysis Do not administer
"Gabapentin." Facts & Comparisons eAnswers. Wolters
Kluwer Health, Apr. 2011. Web. 28 Nov. 2011.

11. CLINICAL TRIAL
Gabapentin extended-release tablets for the treatment
of patients with postherpetic neuralgia: a randomized,
double-blind, placebo-controlled, multicentre study.
Wallace MS, G Irving, and VE Cowles. Clin Drug Investig. 2010;30(11):765-76.
Depomed. Inc – Funded and designed the study
and directed the data analysis.
Depomed and Solvay Pharmaceuticals. Inc.
(now part of Abbott) participated in the collection
and interpretation of data, in the writing of the
manuscript and in the decision to submit the
manuscript for publication.

12. OBJECTIVE AND PRIMARY ENDPOINT
Objective:
Determine the efficacy and safety of
gabapentin ER in the treatment of PHN, and
determine optimal frequency of administration
Primary Endpoint:
The mean change of average daily pain
(ADP) score from baseline to week 10 using
baseline observation carried forward (BOCF)
Covidien | | Confidential

13. Baseline Observation Carried Forward (BOCF)
vs. Last Observation Carried Forward (LOCF)
BOCF
Baseline Week 2 Week 6 Week 8 Week 10 Recorded
9 8 7 6 5 5
9 8 7 - - 9
LOCF
Baseline Week 2 Week 6 Week 8 Week 10 Recorded
9 8 7 6 5 5
9 8 7 - - 7
Covidien | | Confidential

14. SECONDARY ENDPOINTS
 Changes to week 10 ADP score using last
observation carried forward (LOCF)
 Average daily sleep interference
score using LOCF
 Short-Form McGill Pain
Questionnaire score
 Neuropathic Pain Scale score
Brief Pain Inventory score
End-of-study Patient- and Clinical-
Global Impression of Change
Covidien | | Confidential

15. Exclusion Criteria
STUDY DESIGN Previously unresponsive to
gabapentin or pregabalin
Past gabapentin allergy/ADR
Inclusion Criteria Neurolytic/neurosurgical treatment for
>18 years of age PHN
Neuropathic pain >3 months Severe pain from non-PHN source
after healing of acute herpes Use on injected anesthetics or
zoster skin rash corticosteroids within 30 days
Continued to experience pain Immunocompromised
intensity >4/10 after 7 day CrCl <50 ml/min
study baseline period
Gastric reduction surgery
Substance abuse in past 12 months
All patients taking Any skin condition that could alter
sensation in the area affected by PHN
medications effecting PHN
pain underwent a 5-half-life Pregnant
washout period.
Covidien | | Confidential

16. STUDY DESIGN
Average daily pain and average daily sleep
interference scores recorded in an electronic log
Questionnaires and scales
completed in clinic at weeks 0, 2, 4,
8, and 10
Covidien | | Confidential

17. TREATMENT GROUPS
Daily (“QD”) - Gabapentin ER 1800mg
with the evening meal*
BID (“DD”) - Gabapentin ER 600mg with breakfast,
1200mg with the evening meal*
Placebo
*Active treatment groups were escalated
from 300mg to 1800mg over 15 days
Covidien | | Confidential

18. BASELINE CHARACTERISTICS
Covidien | | Confidential

19. 407 randomized
QD = 134 DD = 135 DD = 131
(ITT) (ITT) (ITT)
QD = DD = Placebo
111 102 =101
Covidien | | Confidential

20. Covidien | | Confidential

21. RESULTS – PRIMARY ENDPOINT
P = 0.255
P = 0.110
Baseline Observation Carried Forward
Covidien | | Confidential

22. RESULTS – SECONDARY ENDPOINT
P = 0.154
P = 0.032
Last Observation Carried Forward
Covidien | | Confidential

23. RESULTS – SECONDARY ENDPOINT
P = 0.152
P = 0.001
Covidien | | Confidential

24. SAFETY ENDPOINTS
Covidien | | Confidential

25. AUTHORS’ CONCLUSIONS
 The primary endpoint not reaching statistical significance “was
probably due to the unexpectantly large reduction in LS mean
ADP scores in the placebo group.”
 “The magnitude of treatment effects observed was greater in
the group of patients who received a QD dose compared to
those who received DD therapy.”
 External validity may be limited since they “excluded patients
who previously did not tolerate gabapentin or pregabalin.”
 “…many of the secondary endpoints suggested the potential for
benefits of gabapentin ER…”
 “Further studies are needed…”
Covidien | | Confidential

26. MY CONCLUSIONS
Strengths: Limitations:
Daily vs. TID Efficacy not definitive
Sleep hygiene improvements External Validity?
Cost vs. Dosing Frequency
Clinically Significant?
Safety
Off-label uses?
 Alternative therapy for PHN?
Covidien | | Confidential

27. REFERENCES
 Neurontin Timeline. http://www.hkllp.com/neurontin/neurontin-timeline/
 "Gabapentin." Facts & Comparisons eAnswers. Wolters Kluwer Health,
Apr. 2011. Web. 28 Nov. 2011.
 Dubinsky et al. Practice parameter: treatment of postherpetic neuralgia:
an evidence-based report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2004 Sep 28;63(6):959-65.
Reaffirmed February 2008.
 "Depomed: Leader in Gastric Retention Technology." Drug Delievery
Technology 9.3 (2009): 56-57. Print.
 DepoMed (2011). 10-K Annual Report 2011. Retrieved November 30,
2011 from Wikiinvest, Web.
 Wallace MS, G Irving, and VE Cowles. Gabapentin extended-release
tablets for the treatment of patients with postherpetic neuralgia: a
randomized, double-blind, placebo-controlled, multicentre study. Clin Drug
Investig. 2010;30(11):765-76.
Covidien | | Confidential

28. Extended-Release Gabapentin:
An medication overview
and trial focus
Kyle A. Amelung
Pharm.D. Candidate, 2012
St. Louis College of Pharmacy
Preceptor: Tina M. Purcell, Pharm.D., PMP
Medical Affairs