Ординатура / Офтальмология / Английские материалы / Risk Prevention in Ophthalmology_Kraushar_2008

intramuscular use, to treat age-related macular degeneration, diabetic macular edema, and retinal vein occlusion; glaucoma surgeons use 5-fluorouracil (5-FU) and mitomycin-C (MMC) for glaucoma surgery; and comprehensive ophthalmologists use MMC to prevent the recurrence of pterygia following excision, cornea surgeons use glue on the cornea. Once a drug is approved for use, individual physicians for any indication may prescribe it without violating federal law. The FDA considers such prescribing the “practice of medicine” and has chosen not to regulate such practices.17

Off-label use of a drug is sometimes the standard of care. What is important is that we have to make sure we are doing what the standard of care dictates. Physicians should consider if there are published peer-reviewed articles supporting the use of the new treatment and whether the treatment is being used by a reasonable number of other practitioners with the same level of training.

Ophthalmologists should discuss all options with patients and be clear if the recommendation is an off-label use; and they should document the deci- sion-making process and the informed consent discussion that led to using a drug off label. Ophthalmologists should also heed the drug’s history of adverse events and advise and monitor patients accordingly. Doctors who want to proceed should have the patient sign a consent form. A number of off-label consent forms are posted on the website of the Ophthalmic Mutual Insurance Company (www.omic.com), including forms for Avastin, MMC when used in glaucoma and refractive surgery, and off-label photorefractive keratectomy.18

What Are the Requirements When Using Investigational Drugs?

Two types of investigational new drugs (INDs) were formally recognized, those with commercial applicability or marketing potential (commercial INDs) and those designed to meet the needs of individual investigators (noncommercial INDs).

The first method of obtaining an IND is to enroll the patient in an ongoing clinical trial by the drug’s sponsor, usually as part of a commercial IND. The other method to obtain a nonapproved drug is to enroll a patient under a “treatment” or “compassionate use” protocol (the vast majority of noncommercial INDs). The FDA clearly prefers incorporation of patients into an ongoing sponsored program.17

Patients enrolled in a commercial investigation of a new drug adhere to the protocol of the study that is approved by a local institutional review board. Patients are carefully monitored for effects and side effects of the drug during and often beyond the duration of the study. Informed consent from the patient is an integral part of the IND process. Failure to meet FDA requirements with experimental or investigational drugs may constitute strong evidence in support of a negligence action in the event of any proximate injury to the patient.

Is it Legal to Prescribe Marijuana?

Marijuana is listed as a schedule I controlled substances. Schedule I drugs are substances that have a high potential for abuse, no currently accepted medical use in treatment in the United States, and lack accepted information on the safety of their use, even under medical supervision. However, marijuana has many supporters who firmly believe in its medicinal value. One of the medicinal values in ophthalmology is intraocular pressure reduction in glaucoma.

Some states, such as California, have enacted laws allowing patients with legitimate medical need as certified by a physician the right to possess or grow marijuana. These state laws, however, do not change the fact that marijuana is a schedule I drug under federal law. The laws also do not allow marijuana to be dispensed by pharmacists. States that authorize medical marijuana place patients who wish to possess and use the drug in a conflict of law position. Although the laws allow a qualified patient to legally possess or grow marijuana, they do not define how much medical marijuana a patient may legally possess, resulting in some patients being arrested by the state for growing too many plants.

Obtaining the drug or the plants creates additional problems because many patients cannot grow their own. In response, cannabis buyer cooperatives were created for the purpose of manufacturing and distributing marijuana to the patients. The U.S. Justice Department challenged the legality of one of these cooperatives, ultimately leading to a U.S. Supreme Court decision that the cooperative violated the Controlled Substances Act by manufacturing and distributing marijuana.19

How to Prescribe for Special Patient Groups

Women with Childbearing Potential and Pregnant Women

During pregnancy, any drug that is absorbed systemically can affect both the pregnant woman and the fetus. Therefore, the clinician must consider the adverse effects of the drug itself as well as its potential for teratogenicity.

Medications are categorized by the FDA according to the potential risk to the fetus into five categories:

Category A: Controlled studies with pregnant women have failed to demonstrate a risk to the fetus in the first trimester, and there was no evidence of risk in later trimesters. The possibility of fetal harm appears remote.

Category B: Animal reproduction studies either have not demonstrated a fetal risk but there are no controlled studies with pregnant women or have shown an adverse effect that was not confirmed in controlled studies with women in the first trimester and there was no evidence of a risk in later trimesters.

Category C: Animal studies have revealed adverse effects on the fetus (teratogenic, embryocidal, or other) and there are no controlled studies in women, or

studies with women and animals are not available. Drugs should be given only if the potential benefits justify the potential risk to the fetus.

Category D: There is positive evidence of human fetal risk, but the benefits from use by pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Category X: Studies with animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug by pregnant women clearly outweighs any possible benefit. The drug is contraindicated for women who are or may become pregnant.

Because it is almost impossible to ethically conduct controlled studies with pregnant women to evaluate the risk of a drug to the fetus, hardly any drugs that are used clinically are in category A. Most of the ophthalmic drugs are in either category B or C. A drug in category B is not necessarily safer than one in category C with regard to teratogenicity, because animal studies are often not applicable to human beings. Certainly, drugs in categories D and X should be avoided as much as possible.

It is well known that systemic absorption of certain topical ophthalmic drugs by mucosa membrane can achieve therapeutic levels. Ophthalmologists should fully discuss the unknown risk of toxicity to the fetus with pregnant women or women with childbearing potential. This is particularly important for those ophthalmic illnesses that require chronic therapy, such as glaucoma. In addition to the possible teratogenic potential, the pharmacologic effects from systemic absorption of ophthalmic drugs on the fetus prior to delivery and the neonate after delivery should be considered. For instance, topical β-blocker usage before delivery may decrease the fetus’ heart rate, and topical pilocarpine usage before delivery may cause hyperthermia, hyperemia, diaphoresis, restlessness, or and seizures in the newborn. This symptom complex may be mistaken for neonatal meningitis and cause needless therapy.20

Particular caution is necessary and the risk/benefit ratio must be considered whenever drug treatment is contemplated for a pregnant woman. All routine nonessentialophthalmicmedicationsshouldbeavoidedduringpregnancy.Ophthalmologists are encouraged to refer to the National Registry of Drug-Induced Ocular Side Effects for updated information regarding the side effects of ophthalmic medications for pregnant or lactating women.

Nursing Women

The potential toxicity of drugs and chemicals that are excreted in breast milk may be difficult to detect. Virtually all investigations of milk secretion and synthesis have been carried out in animals, and there are considerable differences in the compositions of milk of different species. Drug excretion into milk may be accomplished by binding to the proteins or to the surfaces of the milk fat globules. With few exceptions, all drugs that are present in the maternal circulation are transferred

into milk. Unless studies on the nursing infant’s blood or urine are performed, there is no way of determining the actual amount of drug being absorbed by the infant from the milk.21 In one study, the timolol level (5.6 ng/mL) in the breast milk of a nursing mother on topical timolol therapy was six times higher than in the plasma (0.93 ng/ml).22

Nursing women who require chronic ophthalmic drugs should be counseled on the potential risks of excretion of drugs in milk and on the potential toxicity to infants. Alternatives including avoiding breast milk should be discussed.

Pediatric Populations

Infants and children have increased potential for ocular and systemic drug-induced adverse reactions for several reasons. (1) They may receive an excessive dose owing to the difficulty in instilling drops, particularly if they are uncooperative;

(2) administration of a drug may be continued by a parent or nurse who does not recognize early signs of drug toxicity; (3) differences exist between children and adults in their physiologic responses to the same drug; (4) drug absorption through the conjunctival epithelium and skin may be more rapid in infants; (5) metabolic enzyme systems are immature, especially in neonates, and may prolong the halflives of drugs; and (6) the dosage relative to blood volume, body weight, and surface area is greater for infants and children (blood in adults dilutes an absorbed drug 20 times more than in neonates).20

Ophthalmologists should be aware and cautious of some commonly used topical ophthalmic drugs that may have potent and dangerous systemic adverse reactions in pediatric populations. The list includes but is not limited to the following:

1.The systemic hypertension and cardiotoxic effects of the higher concentrations (10%, 2.5%) of phenylephrine (Neo-Synephrine) are especially dangerous in the infant with intracranial bleeding or with a left-to-right shunt.

2.Infants, blond children, children with spastic paralysis or brain damage, and children with Down’s syndrome have an increased susceptibility to anticholinergic (parasympatholytic) drugs, such as atropine, homatropine, scopolamine, and cyclopentolate.

3.Serious ocular and systemic adverse effects of corticosteroids instilled in the eye in high doses or on a long-term basis can occur in the pediatric age group. These effects include secondary open-angle glaucoma, posterior subcapsular cataracts, Cushing’s syndrome with adrenal suppression, and decreased resistance to bacterial, viral, and fungal infections. The potential danger of ocular side effects is magnified in children because it is often difficult to measure intraocular pressure accurately and to monitor lenticular changes.

4.Serious allergic reactions of some topical antibiotics, some leading to death, have been reported. Such reactions include irreversible bone marrow suppression with chloramphenicol, Stevens-Johnson syndrome, and aplastic anemia with sulfonamide.

5.More pronounced systemic effects from topical antiglaucoma medications occur

in pediatric patients, such as the systemic bronchopulmonary toxic effects of topical β-blockers in neonates and infants and the central nervous system depressive effects of selective α2-agonists.

Phenylephrine 1% in combination with cyclopentolate 0.2% (Cyclomydril) can be safely given to all infants for mydriasis or cycloplegia. For cycloplegia in pediatric patients past early infancy and in darkly pigmented children, the 0.5% or 1% concentration can be used. Tropicamide (Mydriacyl) 0.5% or 1% eye drops combined with phenylephrine 2.5% eye drops also produce wide pupillary dilation for indirect ophthalmoscopy in infants and children.20

How to Reduce the Risk of Delivering Drugs Via a Needle to the Eye

Drug delivery by needle in ophthalmic care includes peribulbar and retrobulbar injections of anesthesia, absolute alcohol, and major tranquilizers such as chlorpromazine; subtenon or subconjunctival injections of steroids, antibiotics, and antimetabolites; and intraocular or intravitreous injections of steroids, antibiotics, and newer medications such as anti–vascular endothelial growth factor. Because few drugs that are given subconjunctival or intraocularly are specifically FDA approved, and injection of medications into or around the eye with a needle carries significant risks, it is important for ophthalmologists to be especially vigilant to maintain clear communication with the patients, adhere to the off-label use requirement, be familiar with the current standard of care, and document appropriately.

When reasonably confident that patients would benefit from a drug, ophthalmologists should discuss all options, the nature of off-label use, the current standard of practice of the proposed therapy, and the possible complications of the therapy. The common risks of direct drug delivery with a needle into the eye are bleeding, retinal detachment, and infection. An additional risk of injecting a steroid intraocularly is increased intraocular pressure. For an injection around the eye, such as retrobulbar or peribulbar injection and subconjunctival or subtenon injection, perforation or penetration of the globe may be the most alarming complication with serious outcomes that often lead to litigation.23

Ophthalmologists should take the time to review the proper technique for administration of mediation by needle around the eye or ask a colleague who is experienced in the procedure for supervision initially. In addition, one should also be aware of the clinical signs and symptoms to recognize a complication quickly and manage the patient’s injury promptly and properly. Signs and symptoms of complications include severe pain, sudden loss of vision, floaters, sudden increase in intraocular pressure, shallowing of the anterior chamber, vitreous hemorrhage, poor red reflex, hypotony, and a poking-through sensation. When a complication occurs, the ophthalmologist should maintain good rapport with the patient, keeping him or

her fully informed of all aspects of the clinical situation, and obtain necessary and appropriate consultations. Appropriate risk management officers should be notified and early contact made with the insurance carrier.23

Do Not Forget that Some Patients Have Poor Eye Sight

The following medical error reported anonymously on the Mortality and Morbidity Rounds on the Web (Web M&M) of the Agency for Healthcare Research and Quality (AHRQ), an online journal and forum on patient safety and health care quality, highlighted the importance of the physician’s awareness of the patient’s visual limitation in the compliance of medical therapy24:

An elderly man developed a deep vein thrombosis during his hospital stay. At discharge, he was to receive enoxaparin (Lovenox) for self-administration at home in addition to other medications. Before leaving the hospital, he was given written information sheets regarding his medications and received counseling from a nurse and a pharmacist.

Several days after discharge, the patient called the primary care triage nurse and stated that he had been discharged with a bag of medications and some injections, but that he could not administer them because he could not read the instructions. After retrieving his chart, the triage nurse noted that the patient was blind and, upon questioning, also learned that he lived alone.

Although the patient of this story was not receiving an ophthalmic therapy, any ophthalmic practice certainly has a number of patients who have very limited vision or are legally blind and experience similar difficulties in using their medications. Ophthalmologists need to identify any factors that might impede the patient’s compliance with therapy. It might involve a proactive and respectful discussion of their ability to perform self-care tasks, perform manual tasks independently, and read, understand, and follow written instructions. Ophthalmologists should also involve the caregiver of the patient in providing therapy. Alternative therapies need to be considered for patients who cannot adhere to a medical therapy.

How Does Compliance of Drug Use Legally Affect

One’s Practice?

Noncompliance could lead to an undeserved liability claim against the ophthalmologist. Sometimes when medical malpractice claims arise, the role of noncompliance in causing the injury or poor result may not be fully appreciated by those evaluating the claim. Thus, identifying noncompliant patients becomes extremely important for purposes of risk management.

Poor compliance may reflect a suboptimum patient–physician relationship. In analyzing malpractice claims against ophthalmologists who suffered indemnifications of at least $250,000, Kraushar and Robb7 reported that 43% of claims of alleged

malpractice occurred within 1 month of the initial physician–patient encounter and 17% occurred at the initial encounter. The lack of time for development of patient–physician rapport is a major risk factor of litigation.7

How Can the Ophthalmologist Improve a Patient’s Compliance with Drug Therapy?

It has been reported that having a good understanding of disease improved patients’ regimen compliance by up to 10 times.25 Much research effort has been initiated by major ophthalmic organizations, including the American Glaucoma Society, to identify barriers to drug compliance and solutions to improve it. Some suggestions to improve compliance include the following:

1.Ask open-ended questions about the treatment regimen to reveal whether the patient is using the medication properly. For example, ask “How often do you use the timolol eye drop?” instead of “Are you using the timolol eye drop?”

2.Identify the reasons of noncompliance. Some of the reasons include difficulty in administration of the medication, intolerance of the medication, lack of understanding of the purpose for using the medication, inability to afford it, or belief that the inconvenience or side effects of a medication outweigh its benefits.

3.Provide patients with medication instructions or fact sheets. Patient Medication Fact Sheets for many common drugs, including β-blocker eye drops, oral corticosteroids, topical corticosteroids, long-acting miotic eye drops, miotic eye drops and gel, steroid eye drops, and ointment, can be ordered from the United States Pharmacopeial Convention (USPC) by writing to 12601 Twinbrook Parkway, Rockville, MD 20852, or by calling 800-227-8772.

4.Keep medical regimens, especially in chronic therapy, simple. For instance, maximize the monotherapy in glaucoma medical management or switch to another medication instead of adding more medication, use medications that require less frequent dosing, and avoid medications that had an immediate intolerable side effect upon instillation.

Ophthalmologists should document such a communication with a patient to secure compliance with treatment, as well as any refusal or delay in treatment that is caused by a patient.

How Can Ophthalmologists Provide Patient Counseling

Regarding Medications?

In a study of glucocorticoid therapy, the PIAA Medication Error Study found that after “incorrect dose” “communication failure between physician and patient” was the most common error.2 With the increased availability of in the public media and especially on the Internet, many patients are well informed about the potential for drugs applied to the eye to affect a wide variety of body functions. Moreover, pharmacists are

by consistently acting in a timely and appropriate manner in the best interest of the patients, ophthalmologists will continue to enjoy the rewarding patient–physician relationship and to do no harm.

References

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2.Brick DC. Medication errors result in costly claims for ophthalmologists. Surv Ophthalmol 1995;40:232–236.

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4.Miller JW. Using a drug before the risks and benefits are known from a phase 3 clinical trial. Arch Ophthalmol 2004;124:1029–1031.

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6.Bettman JW. Seven hundred medicolegal cases in ophthalmology. Ophthalmology 1990;97: 1379–1384.

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10.Bettman JW, Monica ML. Nonmedical issues in claims against ophthalmologist. OMIC publication archives. Digest, Winter 1994. Available at: http://www.omic.com/resources/risk_ man/deskref/medicaloffice/general/8.cfm.

11.Abood RR. Pharmacy Practice and the Law, 4th ed. Boston: Jones and Bartlett Publishers; 2005:101–144.

12.Cantor LB. Ophthalmic generic drug approval process: implications for efficacy and safety. J Glaucoma 1997;6:344–349.

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14.Weir RE, Zaidi FH, Charteris DG, Bunce C, Soltani, Lovering AM. Variability in the content of Indian generic ciprofloxacin eye drops. Br J Ophthalmol 2005;89:1094–1096.

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16.Demorest BD. Minimize the risks of patient co-management. OMIC publication archives. Digest, Spring 1995. Available at: http://www.omic.com/resources/risk_man/desref/comanagement/1.cfm.

17.Lee PP, Yang JC. The nonapproved use of medications. Ophthalmology 1991;98:1071–1074.

18.Craven ER, Moran EC. Medical implications of using off-label drugs and devices. OMIC publication archives. Digest, Winter, 1996. Available at: http://www.omic.com/resources/ risk_man/deskred/clinical/28.cfm.

19.Abood RR. Pharmacy Practice and the Law, 4th ed. Boston: Jones and Bartlett Publishers; 2005:145–183.

20.Apt L, Gaffney WL. Toxic effects of topical eye medications in infants and children. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology. Philadelphia: Lippincott Williams & Wilkins; 2002;43:133342–133752.

21.Samples JR, Meyer SM. Use of ophthalmic medications in pregnant and nursing women. Am J Ophthalmol 1988;106:616–623.