Gralise (Gabapentin ER)

December 2011

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)
Unknown MOA
Does not affect the following receptors:
–GABA
–BZD
–NMDA
–Alpha
–Beta
"Gabapentin." Facts & Comparisons eAnswers. Wolters
Kluwer Health, Apr. 2011. Web. 28 Nov. 2011.
GABA
–Cannabinoid
–Dopamine
–Histamine
–Serotonin
–Opioid
Gabapentin

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
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.
websters-online-dictionary.org
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
long-term effects of these treatments.”

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
Neurontin Timeline. http://www.hkllp.com/neurontin/neurontin-timeline/
January 2011 – Gralise
TM
(gabapentin ER, by
Depomed, Inc.) approved for PHN
April 2011 – Gabapentin REMS discontinued

8. GRALISE
TM
ER Technology: AcuForm
TM
(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
"Depomed: Leader in Gastric Retention Technology." Drug
Delievery Technology 9.3 (2009): 56-57. Print.
Drug Cost #90
Gralise
TM
300mg $217
gabapentin 300mg $19
Neurontin
®
300 mg $200
Lyrica
®
100mg $260
Drugstore.com

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

10. GABAPENTIN ER DOSING
Initiate and titrate as follows, taken once daily with the evening meal

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

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
Covidien | | Confidential
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)

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

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

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

17. TREATMENT GROUPS
*Active treatment groups were escalated
from 300mg to 1800mg over 15 days
Covidien | | Confidential
Daily (“QD”) - Gabapentin ER 1800mg

with the evening meal*
BID (“DD”) - Gabapentin ER 600mg with breakfast,
1200mg with the evening meal*
Placebo

18. BASELINE CHARACTERISTICS
Covidien | | Confidential

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

20. Covidien | | Confidential

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

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

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

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
Covidien | | Confidential
Off-label uses?
 Alternative therapy for PHN?

27. REFERENCES
Covidien | | Confidential
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.

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