gralise (gabapentin er)

Extended-Release Gabapentin:A medication overview and its

use in postherpetic neuralgia

Kyle A. AmelungPharm.D. Candidate, 2012

St. Louis College of Pharmacy

Preceptor: Tina M. Purcell, Pharm.D., PMPMedical Affairs

OBJECTIVES

Discuss the history of gabapentin in the marketplace

Describe gabapentin pharmacology and the ER dosage form

Explain postherpetic neuralgiaUnderstand a clinical trial focusing

on ER gabapentin

Covidien | | Confidential

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

– OpioidGabapentin

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


ADVERSE DRUG REACTIONS


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.”

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 – GraliseTM (gabapentin ER, by Depomed, Inc.) approved for PHN

April 2011 – Gabapentin REMS discontinued

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

"Depomed: Leader in Gastric Retention Technology." Drug Delievery Technology 9.3 (2009): 56-57. Print.

Drug Cost #90

GraliseTM 300mg $217

gabapentin 300mg $19

Neurontin® 300 mg $200

Lyrica® 100mg $260Drugstore.com

ACUFORMTM 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 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.

GABAPENTIN ER DOSINGInitiate and titrate as follows, taken once daily with the evening meal


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

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 collectionand interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication.

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)

Baseline Observation Carried Forward (BOCF) vs. Last Observation Carried Forward (LOCF)


BOCF

LOCF

Baseline Week 2 Week 6 Week 8 Week 10 Recorded

9 8 7 6 5 5

9 8 7 - - 9

Baseline Week 2 Week 6 Week 8 Week 10 Recorded

9 8 7 6 5 5

9 8 7 - - 7

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


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


Exclusion CriteriaPreviously 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.

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

TREATMENT GROUPS

*Active treatment groups were escalated from 300mg to 1800mg over 15 days


Daily (“QD”) - Gabapentin ER 1800mg with the evening meal*

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

Placebo

BASELINE CHARACTERISTICS



QD =111

DD =102

Placebo =101

407 randomized

QD = 134(ITT)

DD = 135(ITT)

DD = 131(ITT)

RESULTS – PRIMARY ENDPOINT


P = 0.255P = 0.110

Baseline Observation Carried Forward

RESULTS – SECONDARY ENDPOINT


Last Observation Carried Forward

P = 0.154P = 0.032

RESULTS – SECONDARY ENDPOINT


P = 0.152

P = 0.001

SAFETY ENDPOINTS


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…”


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?

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.

Extended-Release Gabapentin:An medication overview

and trial focus

Kyle A. AmelungPharm.D. Candidate, 2012

St. Louis College of Pharmacy

Preceptor: Tina M. Purcell, Pharm.D., PMPMedical Affairs

gralise (gabapentin er)

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