Black Box Warnings Pertinent to Optometrists Len V Koh PhD OD Pacific University College of Optometry, OR

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1 Black Box Warnings Pertinent to Optometrists Len V Koh PhD OD Pacific University College of Optometry, OR The scope of practice for optometrists over the last few decades has expanded significantly. At the moment, most optometric physicians in the United States have the privilege of prescribing not only topical medications, but also non- topical medications. Moreover, many states permit optometrists to perform some forms of ocular injections, while a few states including Oklohoma and Kentucky go even further with limited use of laser for management of ocular disorders. With expanding privilege comes expanding responsibility, optometric physicians must know how to prescribe judiciously and vigilantly because medications are similar to double- edged swords in having not only indicated benefits, but also carry potential adverse effects. This article presents a number of medications within the scope of practice in optometry that carry black box warning of potentially life- threatening adverse reactions. In order to minimize the liability of careless prescribing and its dire consequence, all optometric physicians must be aware of black box warnings prior to the release of a prescription. The majority of medications prescribed by optometrists are in topical formulations, but some ocular manifestations requires non- topical therapy as in cases of deep- tissue infections or systemic causes or when the condition is not responding to topical administration. Although hundreds of oral medications are available in the market, optometrists are working with only a small subset of them. Approximately a dozen of medications with black box warnings are discussed in alphabetical order based on generic names. A representative price is quoted as a rough reference for clinicians when available. Acetaminophen and Codeine Brand Names: Capital and Codeine; Tylenol with Codeine No. 3; Tylenol with Codeine No. 4 Acetaminophen works an analgesic by inhibiting the synthesis of prostaglandins in the central nervous system and peripherally blocking pain impulse generation. Its antipyretic effect comes from inhibition of hypothalamic heat- regulating center. Acetaminophen does not have anti- inflammatory properties. Codeine alters the perception of and response to pain by binding to opiate receptors in the CNS, causing inhibition of ascending pain pathways. It can also suppress coughing by direct central action in the medulla and produce generalized CNS depression. The main use of acetaminophen with codeine in optometric setting is for mild to moderate pain as a result of ocular trauma including corneal abrasion. Doses should be adjusted according to severity of pain and response of the patient. One to two tablets (30-60mg codeine/dose) every 4 hours to a maximum of 12 tablets/24 hours. The maximum dose allowed for acetaminophen is 4000 mg/24 hours. [Black Box Warning]: Acetaminophen may cause severe hepatotoxicity, potentially requiring liver transplant or resulting in death; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day). Risk is increased with alcohol use, pre- existing liver disease, and intake of more than one source of acetaminophen- containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients. Tablets (Acetaminophen- Codeine #2) mg (30): $14.99 Tablets (Acetaminophen- Codeine #3) mg (30): $15.99 Tablets (Acetaminophen- Codeine #4) mg (30): $

2 Acetaminophen and Oxycodone Brandnames: Endocet ; Percocet ; Primlev ; Roxicet ; Roxicet 5/500; Tylox Oxycodone, a narcotic (opiate) analgesics, blocks mu and kappa opiate receptors in the brain to decrease the transmission of pain impulse. Acetaminophen- oxycodone combination can be used to relieve pain secondary to ocular trauma such as lid and conjunctival injury. For mild to moderate pain, mg of oxycodone can be used, whereas severe pain may require mg oxycodone every 4-6 hours. The maximum daily dose of acetaminophen is 4000 mg/day. The black box warning is for acetaminophen as aforementioned. Capsules (Oxycodone- Acetaminophen) mg (20): $15.99 Capsules (Tylox) mg (20): $49.54 Tablets (Endocet) mg (30): $17.99 Tablets (Percocet) mg (20): $94.99 Tablets (Roxicet) mg (20): $12.99 Acetaminophen and Tramadol Brand Names: Ultracet Tramadol is an atypical central- acting analgesic that binds not only to mu- opioid receptors but also inhibits the reuptake of norepinephrine and serotonin dampening the ascending pain pathway. It is thought to have less abuse potential and thus more suitable for patients who have prior history of opioid addiction. Acetaminophen- tramadol combination can also be used for short- term ocular pain relief. Two tablets every 4-6 hours are taken as needed with maximum of 8 tablets/day and the treatment should not exceed 5 days. The black box warning is for hepatoxicity secondary to acetaminophen toxicity as previously covered. Tablets (Tramadol- Acetaminophen) mg (30): $27.99 Tablets (Ultracet) mg (30): $63.99 Acetazolamide Brand Names: Diamox Acetazolamide inhibits carbonic anhydrase reversibly resulting in reduction of hydrogen ion secretion at renal tubule and decrease in production of aqueous humor. It also inhibits carbonic anhydrase in central nervous system to decrease fluid production in the brain. Acetazolamide is one of the medications stocked in an emergency kit for prompt management of acute angle closure and severe papilledema. Initial dose of mg is administered to reduce intraocular pressure in addition to topical hypotensive agents followed by maintenance dose of mg every 4 hours. Acetazolamide can also be used in the treatment of acute and chronic papilledema with dosage of mg twice a day and mg once daily, respectively. Altitudinal sickness has been relieved or resolved by 2

3 acetazolamide at mg/day in divided doses every 8-12 hours with optional addition of dexamethasone. [Black Box Warning] Rare fatalities have occurred because of severe reactions to sulfonamides, including Stevens- Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, and aplastic anemia and other blood dyscrasias. Caution is advised for patients receiving concomitant high- dose aspirin and acetazolamide because anorexia, tachypnea, lethargy, coma, and death have been reported. Extra caution is needed when it comes to an emergency medication like acetazolamide because in emergency setting, there is increased chance that the drug is administered in rush without proper questioning of prior history of sulfa allergy. Tablets (AcetaZOLAMIDE) 125 mg (90): $45.99 Tablets (Acetazolamide) 250 mg (60): $47.99 FLUOROQUINOLONES CIPROFLOXACIN (Cipro), MOXIFLOXACIN (Avelox), NORFLOXACIN (Noroxin), OFLOXACIN (Floxin) Flouroquinolones are a group of broad- spectrum antibiotics that kill susceptible strains of bacteria by inhibiting bacterial DNA gyrase or topoisomerase II which are important enzymes in unwinding bacterial DNA for replication and transcription. Ciprofloxacin is one of the most prescribed oral antibiotics for genitourinary and other infections. In eye care setting, topical fluoroquinolones are preferred by many optometrists as first- line treatment of ocular infections including bacterial conjunctivitis and keratitis, but oral fluoroquinolones such as ciprofloxacin can be prescribed for soft tissue infection such as preseptal cellulitis in patient who has prior allergic reaction to penicillins and cephalosporins. Recommended Dosage for Adults Ciprofloxacin mg every 12 hours Moxi floxacin 400 mg every 24 hours Norfloxacin 400 mg every 12 hours (maximum: 800 mg/day) Ofloxacin mg every 12 hours [Black Box Warning # 1]: There have been reports of tendon inflammation and/or rupture with quinolone antibiotics; the risk may be increased with concurrent corticosteroids, organ transplant recipients, and in patients >60 years of age. Rupture of the Achilles tendon is most frequent, but other tendon sites including rotator cuff and biceps have also been reported. Discontinuation is recommended at first sign of tendon inflammation or pain. [Black Box Warning # 2]: Flouroquinolones may exacerbate muscle weakness related to myasthenia gravis. Cases of severe exacerbations, including the need for ventilatory support and deaths have been reported, so avoid use of fluoroquinolones in patients with myasthenia gravis. Ibuprofen Brand Names: Advil [OTC], Motrin IB [OTC] Ibuprofen is a member of the NonSteroidal AntiInflammatory Drugs (NSAIDs) which reversibly inhibits cyclooxygenase- 1 and 2 (COX- 1 and 2) enzymes resulting in decreased formation of prostaglandins and 3

4 thromboxane. It has antipyretic, analgesic, and anti- inflammatory properties, thus it is used most often as an over- the- counter (OTC) medication for mild to moderate pain and fever. A dosage of mg every 4-6 hours is used for pain and fever with a maximum daily OTC dose <1200 mg. Under physician supervision, the maximum daily dose is 2400 mg. For inflammatory disease, higher dosage of mg is required with a maximum dose of 3200 mg. In optometry, ibuprofen may be recommended to patients with mild ocular pain or headache. [Black Box Warning #1]: NSAIDs are associated with an increased risk of adverse cardiovascular thrombotic events, including fatal myocardial infection and stroke. Risk may be increased with duration of use or pre- existing cardiovascular risk factors or disease. Careful evaluation of individual cardiovascular risk profiles is necessary prior to prescribing. Ibuprofen is contraindicated in patients with heart failure and peripheral edema. [Black Box Warning #2]: NSAIDs may increase risk of gastrointestinal (GI) irritation, inflammation, ulceration, bleeding, and perforation. These events can be fatal and may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of ethanol, the elderly or debilitated patients. A clinical pearl with NSAIDs is generally to use the lowest effective dose for the shortest duration of time to reduce risk of adverse events. A concomitant use of a proton pump inhibitor like omeprazole is recommended for patients with increased risk of GI complications. Tablets (Advil) 200 mg (100): $20.63 Tablets (Ibuprofen) 200 mg (500): $16.99 Tablets (Ibuprofen) 400 mg (30): $11.99 Itraconazole Brand Name: Sporanox Itraconazole interferes with cytochrome P450 activity and inhibits ergosterol synthesis in fungal cell membrane. It can be prescribed occasionally by optometrists for treatment of fungal keratitis while the patient is referring to a corneal specialist for further management. The usual dosage for adults is mg/day with doses >200 mg/day given in 2 divided doses. [Black Box Warning #1]: Negative inotropic effects have been observed following intravenous administration. Discontinue or reassess use if signs or symptoms of heart failure (HF) occur during treatment. CHF has been reported, particularly in patients receiving a total daily oral dose of 400 mg; and in patients with risk factors for HF such as COPD, renal failure, edematous disorders, ischemic or valvular disease. [Black Box Warning #2]: Serious cardiovascular adverse events including, QT prolongation, ventricular tachycardia, torsade de pointes, cardiac arrest and/or sudden death have been observed due to itraconazole- induced increased serum concentrations of the following: Cisapride, dofetilide, ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine), felodipine, levomethadyl, lovastatin, methadone, midazolam (oral), nisoldipine, pimozide, simvastatin, quinidine, or triazolam; concurrent use of these drugs are contraindicated. Capsules (Itraconazole) 100 mg (30): $ Capsules (Sporanox) 100 mg (30): $

5 Ketoconazole Ketaconazole is another systemic antifungal medication that alters the permeability of the cell wall by blocking fungal cytochrome P450 and inhibiting biosynthesis of triglycerides and phospholipids by fungi. It also can be used urgently by optometrists for treatment of fungal keratitis while the patient is waiting to see a corneal specialist for further management. A daily dose of mg is recommended. [Black Box Warning #1]: Ketoconazole has been associated with hepatotoxicity, including some fatalities. Thus special caution is needed in patients with pre- existing hepatic impairment and liver function monitoring is warranted. [Black Box Warning #2]: Concomitant use with cisapride is contraindicated due to the occurrence of ventricular arrhythmias. Tablets (Ketoconazole) 200 mg (14): $30.99 Lindane Brand names: GBH Shampoo, Kwell Lindane is an antiparasitic agent used to kill mites that attach themselves to the skin (scabies) and lice on the head or pubic area (crabs). It is directly absorbed by parasites and ova and stimulates the nervous system resulting in seizures and death of parasitic arthropods. Lindane is included in this article because it may be used by some optometrists to treat young patients with lice infestation. The lotion form is for treatment of scabies by applying a thin layer on skin from the neck to the toes for 8-12 hours. Then the lotion is removed completely with bathe. For head and crab lice, Lindane shampoo, approximately 30 ml, is applied and massaged into dry hair with subsequent addition of small quantities of water to form lather for 4 minutes. The hair is rinsed thoroughly and combed with a fine- tooth comb to remove residual nits. [Black Box Warning]: Lindane may be associated with severe neurologic toxicities. It is absolutely contraindicated in premature infants and uncontrolled seizure disorders. Seizures and death have been reported with use in infants, small children, patients <50 kg, or patients with a history of seizures. [Black Box Warning]: Lindane is not considered a drug of first choice; use only in patients who have failed first- line treatments, or in patients who cannot tolerate permethrin or crotamiton agent. A lindane medication use guide must be given to all patients along with instructions for proper use. Patients should be informed that itching may occur following successful killing of lice and re- treatment may not be indicated. Lindane is developed for external use only, so avoid contact with face, eyes, mucous membranes, and urethral meatus. An FDA- approved patient medication guide is available with the product information and must be dispensed with Lindane. Lindane lotion Lindane shampoo 5

6 Pimecrolimus Brand name: Elidel Pimecrolimus is an immunosuppressant drug acting as an inhibitor of calcineurin, which is essential for production of proinflammatory cytokines such as interleukin- 2, interleukin- 4 and interferon gamma. Thus it prevents release of inflammatory cytokines and has been shown to prevent the release of allergic mediators from mast cells. Pimecrolimus is often used by dermatologists for treatment of atopic dermatitis and sometimes by optometrists for contact dermatitis around the lids in patients who are steroid responders. A thin layer is applied gently and completely onto affected area twice a day. [Black Box Warning #1]: Topical calcineurin inhibitors have been associated with rare cases of lymphoma and skin malignancy; avoid use on malignant or premalignant skin conditions, for instance cutaneous T- cell lymphoma. Pimecrolimus should be used for short- term and intermittent treatment using the minimum amount necessary for the control of symptoms; application should be limited to involved areas. Limit sun and ultraviolet light exposure. [Black Box Warning #2]: The use of pimecrolimus in children <2 years of age is not recommended, particularly since the effect on immune system development is unknown. Cream (Elidel) 1% (60): $ Tacrolimus Brand name: Protopic Tacrolimus prevents T- lymphocyte activation via similar mechanism as pimecrolimus by inhibiting calcineurin phosphatase activity. It is also used by optometrists for contact dermatitis in patients who are steroid responders. A thin layer is applied to affected area twice a day. The black box warning is for rare cases of malignancy as previously mentioned for pimecrolimus. The lower 0.03% ointment is recommended for children ages 2-15 and use in children <2 is contraindicated. Ointment (Protopic) 0.03% (30): $ Ointment (Protopic) 0.1% (30): $ In summary, the scope of optometry has expanded over the years and so is optometric armamentarium. Optometric physicians must know and be responsible for what is prescribed to patients for management of ocular disorders. Fortunately, the number of drugs that optometrists have privilege to prescribe is much less as compared to for example, an internist, nevertheless within this subset of medications, there are some that warrants more attention as presented in this article because they carry potentially life- threatening adverse reactions, thus are warned by the FDA with black boxes. One final take home message for all prescribers is to establish a good habit of perusing manufacturer s label or online resources of any unfamiliar drug prior to the release of a prescription. Happy prescribing! References: