Intravitreal Anti-VEGF Treatment for Adults Patients:

Risk Management Recommendations

OMIC is grateful to the ophthalmologists on our Board for their expertise. This specific document reflects the input of the following Board and staff members: Anne M. Menke, RN, PhD; Trexler M. Topping, MD; George Williams, MD, Paul Weber, JD, and Hans Bruhn, MHS.

PURPOSE OF RISK MANAGEMENT RECOMMENDATIONS

OMIC regularly analyzes its claims experience to determine loss prevention measures that our insured ophthalmologists can take to reduce the likelihood of professional liability lawsuits. OMIC policyholders are not required to implement these risk management recommendations. Rather, physicians should use their professional judgment in determining the applicability of a given recommendation to their particular patients and practice situation. These loss prevention documents may refer to clinical care guidelines such as the AmericanAcademy of Ophthalmology’s Preferred Practice Patterns, peer-reviewed articles, or to federal or state laws and regulations. However, our risk management recommendations do not constitute the standard of care nor do they provide legal advice. If legal advice is desired or needed, an attorney should be consulted. Information contained here is not intended to be a modification of the terms and conditions of the OMIC professional and limited office premises liability insurance policy. Please refer to the OMIC policy for these terms and conditions.

Version 9/28/12

Ophthalmologists administer intravitreal anti-VEFG (IVAV) agents for a variety of indications. Sometimes the indication is off-label, sometimes the medication itself has never been approved for any eye indication. This risk management recommendations document presents suggestions to increase patient safety and decrease the likelihood of lawsuits related to these drugs.

PATIENT SELECTION

  • Consider first treating patients with medication approved by the Food and Drug Administration (FDA) for their condition.
  • VisudyneTM(verteporfin), MacugenTM(pegaptanib), LucentisTM(ranibizumab), and EyleaTM(aflibercept) are all approved to treat AMD.
  • LucentisTM(ranibizumab), EyleaTM (aflibercept), and OzurdexTM(dexamethasone) are all approved to treat macular edema following retinal vein occlusion (RVO).
  • LucentisTM(ranibizumab) is approved to treat diabetic macular edema (DME).
  • All other use of anti-VEGF agents is “off-label.”
  • Use of any anti-VEGF drug in the pediatric population is “off-label.”
  • OMIC has risk management recommendations and a sample consent form for the use of anti-VEGF drugs to treat ROP available at
  • Now that other medications have been approved for the treatment of VEGF-mediated diseases, physicians who have been treating their patients with AvastinTM(bevacizumab)wonder if they are required to now switch to these approved drugs. “Off-label” use of an approved medication is a common and legal part of the practice of medicine. OMIC believes that the treating ophthalmologist is in the best position to determine what a particular patient needs, and leaves this decision up to the physician’s judgment. The OMIC website has sample consent forms for these other medications.
  • To determine if patients would benefit from IVAV for AMD, conduct at least an initial fluorescein angiogram and OCT, and evaluate lesion type, location, and size, and presence of subretinal fluid.
  • The prescribing information for intravenous systemic AvastinTM(bevacizumab)contains warnings about gastrointestinal perforations/wound healing complications, hemorrhage, arterial thromboembolic events, hypertension, proteinuria, and congestive heart failure.AvastinTM (bevacizumab)and other anti-VEGF agents have been administered to hundreds of thousands of patients. In addition, clinical trials of approved drugs [LucentisTM(ranibizumab)and EyleaTM(aflibercept)] have shown a low incidence of arterial thromboembolic events (ATEs), defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death, including deaths of unknown cause. All anti-VEGF drugs thus have a potential risk of ATEs. Patients with diabetes had a higher risk of fatal events in LucentisTM (ranibizumab)trials, but the rate of ATEs was low and included causes of death typical of patients with advanced diabetic complications. The relationship between intravitreal use of anti-VEGF agents and ATEs in diabetic patients is not clear.

PREPARATION OF AVASTINTM (BEVACIZUMAB)

  • The medication comes in preservative-free vials intended for intravenous use at a much higher concentration on a single cancer patient. To ensure safe administration, ask a compounding pharmacy to prepare the medication for ophthalmic use, confirm the dose and sterility, identify a syringe suitable for this protein, provide storage and “beyond-use” instructions, and the lot number of the vial.
  • “Credential” the compounding pharmacy to which you send the prescription for intravitreal AvastinTM(bevacizumab). Ask the compounding pharmacy for assurance that it is licensed/registered in the state in which it is dispensing and is complying with USP (United States Pharmacopeia) Chapter 797, which regulates the compounding, transportation, and storage of compounded sterile products (CSP). Be wary of obtaining CSPs from pharmacies that advertise their ability to compound specific drug products such as AvastinTM(bevacizumab), since advertisements of that type are contrary to the “Good Compounding Practices” and the ethical standards of the National Association of State Boards of Pharmacies (

PREVENTING AND MANAGING COMPLICATIONS FROM IVAV

  • Increased intraocular pressure
  • Monitor patients for elevations in intraocular pressure (IOP).
  • Check IOP with tonometry on all patients prior to the intravitreal injection. Document the results.
  • Check the eye after the procedure by one of these techniques and document the results:
  • Check optic nerve perfusion immediately after the injection OR
  • Check IOP 30 minutes after the injection using tonometry.
  • Endophthalmitis
  • FDA-approved labels for both LucentisTM(ranibizumab)and EyleaTM(aflibercept)state that the “intravitreal injection should be administered under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape, and a sterile eye speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide should be given prior to the injection.”
  • Two recent articles on endophthalmitis associated with intravitreal injection indicated that antisepsis, especially with povidone-iodine, is quite effective, but that the use of prophylactic antibiotics is ineffective, costly, and leads to increased resistance.[1],[2]Both question the need forantibiotics. The articles also reviewed the need for a mask, citing studies that show that use of a mask or abstaining from talking during the injection are helpful.Neither felt there was adequate evidence to mandate use of a mask. Recommendations include:
  • Minimize talking by the physician, assistants, and patients during the procedure.
  • Use appropriate aseptic technique, including a lid speculum and povidone-iodine.
  • Verify that the compounding pharmacy maintains strict compliance with USP chapter 797 mandates.
  • Use your judgment on whether or not to prescribe prophylactic antibiotics, and what steps are needed to prevent infection.
  • Monitor patients for symptoms suggestive of endophthalmitis.
  • Instruct patients to contact you immediately if the eye becomes red, sensitive to light, painful, or develops a change in vision. Consider giving these instructions in writing.
  • If the contralateral eye needs treatment on the same day, use a new syringe, sterile field, gloves, drape, eyelid speculum, and injection needle.

INFORMED CONSENT DISCUSSION AND DOCUMENTATION

  • Arterial thromboembolic events (ATEs)
  • Inform patients who will receive AvastinTM (bevacizumab) of the warnings and complications associated with intravenous systemic use in patients with colorectal cancer (see above). Patients should be warned of these potential complications, but told that patients who experienced them had metastatic colon and lung cancer, and were given 400 times the dose at more frequent intervals in a way that spread the drug throughout their bodies. The results of clinical trials of intravitreal anti-VEGF drugs and reports of long-term “off-label” use indicate that the risk of systemic complications is low.
  • All patients receiving IVAV should be told that whenever a medication is used in a large number of patients, a small number of coincidental life-threatening problems may occur that have no relationship to the treatment. Patients may also experience these events as the result of diseases such as diabetes. Indeed, diabetic patients should be told that the risk of fatal events appears to be higher in diabetic patients, but further research is needed to confirm this.
  • “Off-label” status
  • AvastinTM(bevacizumab)is not approved for intravitreal injection or for the treatment of any eye condition. Patients should be informed that use in the eye is “off-label.” The sample consent form addresses this.
  • Inform patients that there are anti-VEGF drugs that have been approved for intravitreal injection to treat AMD, and that one, LucentisTM(ranibizumab)has been approved for macular edema following retinal vein occlusion and diabetic macular edema.
  • Patients receiving any of the approved drugs for an indication that is not approved should be informed that the drug has not been approved for their indication. Sample off-label language is available in the AvastinTM (bevacizumab) consent form at
  • Treatment of both eyes on the same day
  • Document your decision-making process in the medical record.
  • Inform the patient of the possibility of vision-threatening complications in both eyes.
  • Explain the measures you will take to reduce the risk of infection (i.e., you will use a new syringe, sterile field, gloves, drape, eyelid speculum, and injection needle).
  • Ensure that the patient has a ride home before administering the injections.
  • Consent for ongoing treatment
  • In general, informed consent may be considered to have ongoing force and effect until 1) the patient revokes the consent or 2) circumstances (i.e., the patient’s medical or ocular condition) change so as to materially affect the nature of the procedure or the risk/benefit ratio. This means that unless either of these situations materialize, you need only obtain the patient’s informed consent once.
  • Discontinue treatment or obtain and document informed consent again if the patient’s medical or ocular condition changes to the point that the risk/benefit ratio is affected
  • Documentation
  • Document the decision-making process that led to choosing the particular drug as the treatment for the patient. Note results of earlier attempts at treatment and the results of diagnostic tests.
  • Evaluate and document the continued need, effectiveness, and safety of the medication prior to each injection.
  • Note the dose, lot number of the vial, any reactions to the injection and how they were handled, and the discharge and follow-up instructions.

RISK MANAGEMENT ASSISTANCE

OMIC policyholders may obtain confidential risk management help by contacting OMIC’s Risk Management Hotline at 800.562-6642, option 4.

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[1]Wykoff CC, Flynn HW, and Rosenfeld PJ. Prophylaxis for Endophthalmitis Following Intravitreal Injection: Antisepsis and Antibiotics. American Journal of Ophthalmology. November 2011: 717-719.

[2]Schimel AM, Flynn HW. Infection: The Evolving Role of Antibiotics. Review of Ophthalmology. August 2012, 56-59.