Subject: COX-2 Selective NSAIDs

Status	Drug	PR-B/D	PR	PR-QL	PR-AL	ST	M EX‡	TOC§
NC	Celebrex®  (celecoxib)		X	X			X

Policy:

1. Precertification Criteria

Under some plans, including plans that use an open or closed formulary, COX-2 selective NSAIDs are subject to precertification as specifically described below.  

A. Celebrex is subject to precertification.  If precertification requirements apply, Aetna considers Celebrex to be medically necessary for those members who meet the following precertification criteria:

For Celebrex 100 mg and 200 mg

1. One of the following:

a. Age greater than 60
OR
b. Concomitant use of warfarin (Coumadin®) or other antiplatelet therapy
OR
c. Concomitant use of chronic oral (systemic) corticosteroid therapy
OR
d. Documented history of ulcer disease or GI bleed;
OR
e. Documented history of significant GI disease requiring therapy with an H2 receptor antagonist (cimetidine/Tagamet®, famotidine/Pepcid®, nizatidine/Axid®, ranitidine/ Zantac®) or a proton pump inhibitor (AcipHex®, Nexium®, omeprazole/Prilosec®, Prevacid®, Protonix®)

NOTE: Significant GI diseases can include:

Duodenal ulcer - active ulcer; maintenance of healed ulcer
Gastric ulcer - active benign; maintenance
Gastrojejunal ulcer - active; maintenance
NSAID-induced gastric ulcer - healing; risk reduction for recurrence
Peptic ulcer disease
Stress ulcer/surgical prophylaxis
Barrett's esophagus
Crohn's disease
Erosive esophagitis - active, maintenance, healed
Gastric residual reduction
Gastrointestinal bleed
GERD - moderate to severe with symptoms (treatment, maintenance, screening)
H. pylori, treatment
Hypersecretory conditions, including Zollinger-Ellison Syndrome
Laryngopharyngeal reflux

OR

f. Documented history of NSAID-induced GI adverse effects, necessitating discontinuation of NSAID therapy AND addition of a proton pump inhibitor (AcipHex, Nexium, omeprazole/Prilosec, Prevacid, Protonix) or misoprostol  (Cytotec®)
OR
g. A documented diagnosis of Juvenile rheumatoid arthritis

For Celebrex 400mg

1. Documented diagnosis of FAP (Familial Adenomatous Polyposis)

AND

B. Celebrex may be subject to quantity limits.

According to the manufacturer, Celebrex can be dosed up to a maximum daily dose at the interval(s) as indicated in the table below. A quantity of each drug will be considered medically necessary as indicated in the table below, if member fulfills criteria A as indicated above


Drug	Maximum Daily Dose/ Dosing Interval	Dosage Strength	Quantity Limits
Celebrex	200 mg/ once daily	100 mg	Up to 60 capsules in 30 days
Celebrex	200 mg/ once or twice daily	200 mg	Up to 30 capsules in 30 days
Celebrex	800 mg/ twice daily	400 mg	Up to 60 capsules in 30 days





For coverage of additional quantities, a member's treating physician must request prior authorization through the Aetna Pharmacy Management Precertification Unit. Additional quantities of Celebrex will be considered medically necessary for those members who meet the following criteria:

 

For Celebrex 400 mg:

• Member’s physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for use of a higher dose.

 

For Celebrex 100 mg and 200 mg:

• Documented diagnosis of rheumatoid arthritis (RA) (approvable dose is 200 mg twice daily or 60 capsules (200mg) per 30 days) OR
• Failure of 200mg QD (approvable dose is 200 mg twice daily or 60 capsules (200mg) per 30 days) OR,
• Documented diagnosis of acute pain (approvable dose is 200 mg twice daily or 60 capsules (200 mg) per 30 days; 30 day limit)
Member’s physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for use of a higher dose


2. Medical Exception Criteria

Celebrex is currently a Not Covered Part D drug under the Aetna Medicare Prescription Drug Plan.* Therefore, it is excluded from coverage for members enrolled in prescription drug benefit plans that use a closed formulary, unless a medical exception is granted.  Aetna considers Celebrex to be medically necessary for those members who meet the following criteria:

For Celebrex 100 mg and 200 mg

1. One of the following:

a. Age greater than 60 OR
b. Concomitant use of warfarin (Coumadin®) or other antiplatelet therapy OR
c. Concomitant use of chronic oral (systemic) corticosteroid therapy OR
d. Documented history of ulcer disease or GI bleed; OR
e. Documented history of significant GI disease requiring therapy with an H2
receptor antagonist (cimetidine/Tagamet®, famotidine/Pepcid®,
nizatidine/Axid®, ranitidine/ Zantac®) or a proton pump inhibitor (AcipHex®,
Nexium®, omeprazole/Prilosec®, Prevacid®, Protonix®)

NOTE: Significant GI diseases can include:

Duodenal ulcer - active ulcer; maintenance of healed ulcer
Gastric ulcer - active benign; maintenance
Gastrojejunal ulcer - active; maintenance
NSAID-induced gastric ulcer - healing; risk reduction for recurrence
Peptic ulcer disease
Stress ulcer/surgical prophylaxis
Barrett's esophagus
Crohn's disease
Erosive esophagitis - active, maintenance, healed
Gastric residual reduction
Gastrointestinal bleed
GERD - moderate to severe with symptoms (treatment, maintenance, screening)
H. pylori, treatment
Hypersecretory conditions, including Zollinger-Ellison Syndrome
Laryngopharyngeal reflux

OR

f. Documented history of NSAID-induced GI adverse effects, necessitating
discontinuation of NSAID therapy AND addition of a proton pump inhibitor
(AcipHex, Nexium, omeprazole/Prilosec, Prevacid, Protonix) or misoprostol 
(Cytotec®)

OR

g.   A documented diagnosis of Juvenile rheumatoid arthritis

For Celebrex 400mg

1. Documented diagnosis of FAP (Familial Adenomatous Polyposis)

Special Notes:

On April 7, 2005, the FDA posted the following information:

1. What is FDA announcing today?

In follow-up to the February 16-18, 2005, joint meeting of FDA's Arthritis and Drug Safety and Risk Management Advisory Committees, convened to discuss the safety of the "COX-2 selective nonsteroidal anti-inflammatory drugs and related agents," we are announcing our planned regulatory actions for Bextra, Celebrex, and the non-selective prescription and over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs).

We have concluded that the overall risk versus benefit profile for Bextra is unfavorable and we have requested that Pfizer, the manufacturer, voluntarily withdraw the drug from the market. Pfizer has agreed to suspend sales and marketing of Bextra in the U.S., pendng further discussions with the agency. We are requesting that manufacturers of all marketed prescription NSAIDs, including Celebrex, a COX-2 selective NSAID, revise the labeling (package insert) for their products to include a boxed warning and a Medication Guide. The boxed warning will highlight the potential for increased risk of cardiovascular (CV) events and the well-described, serious, and potentially life threatening gastrointestinal (GI) bleeding associated with these drugs.

We are asking manufacturers of OTC NSAIDs to revise their labeling to include more specific information about the potential GI and CV risks, and information to assist consumers in the safe use of the drug. This includes instructions about which patients should seek the advice of a physician before using these drugs, stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a physician, and a warning about potential skin reactions.
We anticipate that our actions will lead to careful and appropriate use of these drugs to maximize their potential benefits and minimize their risks.

2. To what products does FDA's decision apply and what is being requested?

The decision applies to the marketed COX-2 selective drugs (Bextra and Celebrex) as well as the non-selective NSAIDs. A detailed chart listing the chemical name and trade names for the products affected by this announcement is attached and also can be found at http://www.fda.gov/cder/drug/infopage/cox2/default.htm#list.

For the COX-2 selective inhibitor drugs, we have determined the following:
" Bextra (valdecoxib tablets):  FDA has concluded that the overall risk versus benefit profile is unfavorable at this time and has requested the manufacturer of Bextra, Pfizer, Inc., to voluntarily withdraw Bextra from the market. This request is based on:

• the lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trials that FDA believes may be relevant to chronic use,
• reports of serious and potentially life-threatening skin reactions, including deaths, in patients using Bextra. The risk of these serious skin reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use, and
• the lack of any demonstrated advantages for Bextra compared with other NSAIDs.

Pfizer has agreed to suspend sales and marketing of Bextra in the U.S. pending further discussions with the agency.

• Celebrex (celecoxib tablets): We have concluded that the benefits of Celebrex outweigh the potential risks in properly selected and informed patients. FDA has decided to allow Celebrex to remain and has asked Pfizer to take the actions listed below:
  • Revise the Celebrex label to include a boxed warning containing the class NSAID warnings and contraindication about CV and GI risk, plus specific information on the controlled clinical trial data that demonstrate an increased risk of adverse CV events for celecoxib.
  • Encourage practitioners to use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
  • Include a Medication Guide as part of the labeling. It will be required to be given at the time the drug is dispensed to inform patients of the potential for CV and GI risk associated with NSAIDS, in general, and Celebrex specifically. The Medication Guide will inform patients of the need to discuss with their doctor the risks and benefits of using NSAIDs and the importance of using the lowest effective dose for the shortest duration possible.
  • Commit to conduct a long-term study of the safety of Celebrex compared to naproxen and other appropriate drugs.
    
• Vioxx (rofecoxib tablets and suspension): Vioxx was voluntarily removed from the market by Merck in September 2004. FDA will carefully review any proposal from Merck for resumption of marketing of Vioxx, and would likely discuss the review with the new FDA Drug Safety Oversight Board and an Advisory Committee before making a final decision.
• Non-selective NSAIDs
• Based upon the available data, FDA has concluded that an increased risk of CV events may be a class effect for NSAIDs. There are a number of non-selective NSAIDs currently approved for marketing in the United States. Long term controlled clinical trials have not been conducted with most of these NSAIDs. However, the available data suggests that use of these drugs may increase CV risk.

To further evaluate the potential for increased CV risk, all sponsors of non-selective NSAIDs will be asked to conduct and submit to FDA a comprehensive review and analysis of pertinent available controlled clinical trial databases.

In addition, FDA is requesting labeling changes for prescription and OTC non-selective NSAIDs. Because the use and labeling for the prescription products is different from those available without a prescription, they are addressed separately.

Prescription Non-Selective NSAIDs

Based on the available data, the FDA will request the manufacturers of all prescription products containing non-selective NSAIDs to revise their product labeling to include:

• A boxed warning regarding the potential serious adverse CV events and the serious, and potentially life-threatening GI adverse events associated with the use of this class of drugs.
• A contraindication for use in patients who have recently undergone coronary artery bypass surgery.
• A Medication Guide for patients to help make them aware of the potential for CV and GI adverse events associated with the use of this class of drugs. The Medication Guide will inform patients of the need to discuss with their doctor the risks and benefits of using NSAIDs and the importance of using the lowest effective dose for the shortest duration possible if treatment with an NSAID is warranted in an individual patient.

For further information, go to websites http://www.fda.gov/bbs/topics/news/2005/NEW01171.html and http://www.fda.gov/cder/drug/infopage/COX2/COX2qa.htm

* Coverage is provided through a Medicare Prescription Drug Plan Sponsor with a Medicare contract and benefits, limitations, service areas and premiums are subject to change on January 1 of each year.

Place of Service:

Outpatient

The above policy is based on the following references:

1. Subcommittee on Osteoarthritis Guidelines, Recommendations for the Medical Management of Osteoarthritis of the HIP and Knee, Arthritis & Rheumatism, September 2000; Vol 43(9):1905-1915.
2. Bloom BJ.  New drug therapies for the pediatric rheumatic diseases.  Current Opinion in Rheumatology. 2001;13:410-4.
3. American Collegeof Rheumatology Ad Hoc Committee on Clinical Guidelines.  Guidelines for the Management of Rheumatoid Arthritis.  Arthritis and Rheumatism. 1996;39:713-22.
4. American Collegeof Rheumatology Ad Hoc Committee on Clinical Guidelines.  Guidelines for Monitoring Drug Therapy in Rheumatoid Arthritis.  Arthritis and Rheumatism. 1996;39:723-31.
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17. Dear Health Care Professional letter (Celebrex product labeling update), Searle and Pfizer, May 1999.
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22. Jackson, LM, Hawkey, CJ, COX-2 Selective Nonsteroidal Anti-inflammatory Drugs, Do They Really Offer Any Advantages, ADIS Drugs, 2000 Jun;59(6):1207-1216.
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Property of Aetna Inc. All rights reserved. Pharmacy Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

September 28, 2006