Recent reports of serious eye infections following intravitreal injection with Genentech's Avastin (bevacizumab) could lead to increased FDA scrutiny of compounding pharmacies that repackage the drug for this off-label use.

A crackdown on compounding pharmacies that supply intravitreal bevacizumab injections, coupled with publicity surrounding the adverse event reports, also could push more health care providers to use Lucentis (ranibizumab), Genentech's more expensive VEGF-inhibitor specifically intended for use in the eye.

Genentech has tried to curb compounding pharmacies' access to Avastin in the past, (Also see "Genentech Clarifies Avastin Off-Label Policy; Wholesale Distributors Key" - Pink Sheet, 21 December, 2007.), but reaction to the announcement of the adverse events could reduce the supply of repurposed Avastin by reducing demand.

If providers, patients and payers become more wary of off-label Avastin, then number of compounding pharmacies repackaging it could drop, regardless of whether FDA turns a more watchful eye towards their operations.

"The Common Link For The Infections Is The Pharmacy"

In an Aug. 30 alert to healthcare providers, FDA said it has been notified by the Florida Department of Health of a cluster of Streptococcus endophthalmitis infections in three clinics following intravitreal injections of repackaged Avastin.

Investigators traced the tainted injections to a pharmacy in Hollywood, Fla., the agency said. The pharmacy repackaged the Avastin from sterile injectable 100 mg/4 mL, single-use, preservative-free vials into individual 1 mL single-use syringes and distributed the repackaged product to multiple eye clinics.

"To date, FDA is aware of at least 12 patients in at least three of these clinics who had eye infection," the agency said. Although all of these patients had visual deficits prior to their injections with Avastin, some lost all remaining vision in the treated eye due to the endophthalmitis, which is an infection affecting the interior of the eyeball.

"The agency and Florida health officials continue to investigate the cause of the infection," FDA said. "While the investigation is not yet complete, the common link for the infections is the pharmacy that repackaged the Avastin and the single lot of Avastin used in the re-packaging."

The agency does not identify the Hollywood pharmacy at the center of the infection cluster.

In its Aug. 24 enforcement report, FDA announced that Walgreens Pharmacy, doing business as Chroniscript, recalled all lots of Avastin 0.1 mL syringes due to microbial contamination with Streptococcus oralis.

A Walgreens spokesman said the syringes were supplied to a limited number of physician offices in Miami-Dade and Broward counties in Florida.

The city of Hollywood is located in Broward County.

While FDA's alert only discusses the adverse events reported in Florida, four cases of serious eye infection also have been reported with Avastin intravitreal injections at the Tennessee Valley Healthcare System, which is part of the Department of Veterans Affairs. The four cases were identified at the end of March, a hospital spokesman said.

Avastin vs. Lucentis

Avastin is approved for treating colorectal, lung, brain, kidney and breast cancers, although the Center for Drug Evaluation and Research is in the process of trying to withdraw the metastatic breast cancer claim for failure to verify efficacy in this indication.

The biologi is not approved for treating ocular disorders but is used off-label in microdoses compounded by pharmacists to treat wet age-related macular degeneration and diabetic macular edema. The cost for each injection is about $50.

The use of Avastin off-label for eye disorders has presented a commercial challenge for Genentech, which developed Lucentis, a closely related agent, specifically for use in the eye. Lucentis is indicated for wet-AMD and macular edema following retinal vein occlusion. However, its cost far exceeds that of Avastin, running about $2,000 per dose. Medicare covers both agents but pays far more for Lucentis injections even though Avastin is more widely used.

One-year data from the National Institute of Health's widely anticipated CATT trial pitting Avastin against Lucentis for treatment of wet-AMD showed that the drugs had equivalent effects on visual acuity when administered according to the same schedule. In terms of efficacy, the results gave physicians and payers little incentive to encourage use of the more expensive Lucentis (Also see "Lucentis And Avastin Stack Up In CATT, Forcing Genentech/Novartis To Play Defense" - Pink Sheet, 28 April, 2011.).

Seeking to combat off-label use of the cheaper bevacizumab, Genentech and Novartis, which markets Lucentis in Europe, argue that Avastin has not been shown to be safe in treating diseases of the eye.

Following release of the CATT results in April, the companies said Lucentis is the most appropriate treatment for wet-AMD and Avastin is associated with a greater risk of systemic adverse events. The companies funded a Johns Hopkins study of Medicare claims data showing a higher risk of mortality and hemorrhagic cerebrovascular accident in patients injected with Avastin compared to Lucentis.

The Adverse Reactions section of Avastin's labeling includes reports of eye disorders from unapproved use of the drug in treating various ocular conditions. These adverse events include endophthalmitis and intraocular inflammation.

In CATT, monthly Avastin injections were associated with twice the number of reported cases of endophthalmitis compared to monthly Lucentis injections, although the overall rates were low (0.7% for the monthly Lucentis group, and 1.4% for the monthly Avastin group). There were no reports of endophthalmitis among subjects receiving either Lucentis or Avastin on an as-needed basis, and there was one report of pseudoendophthalmitis with monthly Lucentis injection.

Focusing On Aseptic Conditions

FDA's alert to health care providers suggests the agency is focusing its investigation of the Florida cases on sterility issues in the repackaging process.

"Health care professionals should be aware that repackaging sterile drugs without proper aseptic technique can compromise product sterility, potentially putting the patient at risk for microbial infections," FDA's alert states. "Health care professionals should ensure that drug products are obtained from appropriate, reliable sources and properly administered."

The Ophthalmic Mutual Insurance Company, which is affiliated with the American Academy of Ophthalmology, has risk management recommendations for intravitreal use of Avastin. They state that proper aseptic technique should be used during the preparation and administration of the injection, and that compounding pharmacies should be accredited and comply with the USP standards for compounding, transportation and storage of sterile products.

In the CATT trial, commercially acquired Avastin was repackaged in glass vials in an aseptic filling facility, according to the study manuscript published in the New England Journal of Medicine.

When asked for comment on the adverse event reports in Florida and Tennessee, Genentech said it does not support or promote the off-label use of intravitreal Avastin and the drug is not manufactured for or been proven safe for use in the eye.

"Avastin is not available as single-use vials for injection into the eye, so intravitreal Avastin is compounded in smaller doses for use in an ocular setting, which is associated with further uncertainty due to the risk of contamination and subsequent infection/inflammation following the compounding procedures," the company said.

- Sue Sutter (s.sutter@elsevier.com)

Avastin-Related Eye Infections Could Bring FDA Pressure On Compounding Pharmacies

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