Acetaminophen

Acetaminophen is a centrally acting analgesic that produces analgesia by inhibiting prostaglandin production in the brain and spinal cord. It is an effective and inexpensive analgesic with a favorable risk-benefit profile.12 For treatment of mild to moderate pain, acetaminophen should be tried initially at an adequate dose and dur-

ation before considering an NSAID J Acetaminophen is generally considered to be as effective as NSAIDs for mild to moderate joint pain with a superior safety pro-file.16,17

Pot 10 OA

L«MV*Uo«icalcn Cduuton RMI

MMUxM ipt^MbyN l^vyicil Vf^y CW'1«" >Vo/<IIUM

rMponM?

• Cono-rtjnl irmtc Jtont

• Cono-rtjnl irmtc Jtont

IA SfuoxOVO«!

rMpcnM^

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1 -

Conlnu* and men*, far

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FIGURE 58-2. Treatment of osteoarthritis. (COX-2, cyclooxygenase-2; CV, cardiovascular; IA, intra-articular; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; PPI, proton pump inhibitor.)

Table 58-2 Dosing Parameters of Agents Commonly Used to Treat OA

MaxImumDouge

HjdkrtlaB_PoTJ^f Mjd Frcqmmy_jinq/dAyl_

Oui Analgetics

Acetaminophen 325 rogewry 4-6 hams o< 1 6-8 hours 4JOOO

Tiama<Sor 5Û-1ÛÛ mg euety 4-ii hours 100 ( tÙO in rtcJwlyi

ÛQ kö (hflftJQ mL/ftfln SO-HW mg tviry Ii houn 200

Nonselective USAlDs by Chemical Class

(ofantfie <KYt iWtyfcwsf Aspirin snubtt

AOtHCOM

ETodObc

DKlofcrtiK

ihuorofen Naproxen inoljcacul

Metavn COX-2-Se lecdve Agents Ce1«(ïi(ilï Topical Analgesics C ,ifi«ii in c neam QuQJ5^)fa or 0075^ Olclcieiwc iHgel Lower exiremAyJrtrtf UHW extremiiy joints Dielary Supplements Glucosamine suHfjii" Chondro«! in

Cidl, creatinine ctaarancc. "Eerum saltyiate levels should bemonilo<edfai doses greater than igMsy: Total daily dose ofl diclofenac It gel should nol ewceed 32 g lor at after, ted joints.

Acetaminophen should initially be administered on an as-needed basis in doses up to 4 g daily. However, some patients may require scheduled dosing to achieve adequate pain relief. Periodic assessment of pain control should be performed to maintain the lowest effective dose. A common reason for an inadequate response to acetaminophen is failure to use a sufficient dose for an adequate duration. A sufficient trial is defined as up to 4 g daily in divided doses for 4 to 6 weeks.

5M-1JCKM rrg 2-i times daily iOOO-

300-600 mg Iwke daily lJOO

40Q-1jMc mg ooce daily (extended release)

?i mg daily ItJelayed leieasel

100 nwj once dally (extended release)

2S ITIQ 2-3daily 200 7S mg 1-2 times daily (sustained ielease>

400-800 rvtq 3-4 limes daily 3l200

750-500 my twice dji^ Ii00 7SO-ljOWiriflonce duly (controlled release]

775-550 mg Iwicp dally fnaOmmtn scdium) 1 j6S0

ii-li mq once d-iily IJ

100 mgc^ice (telly or 200 mg once daily 200 Apply to affec ted joint every t> Shouts

A g 4 limes daily Ifc g'

500m[|3-iimtsctily()i l.jOC jmjtifKi' [Jjliy 40Û-800 mg 3 (¡mes da:iy with glucosamine

Despite being one of the safest analgesics, important adverse effects attributable to acetaminophen can occur, including hepatic and renal toxicity.18 Total daily doses of 4 g have been associated with significant liver enzyme elevations.19 Doses greater than 4 g are associated with an increased risk of hepatotoxicity. Concomitant use of alcohol may increase this risk; a maximum acetaminophen dose of 2.5 g daily is recommended in patients who consume more than two to three alcoholic beverages per day. Acetaminophen does not appear to exacerbate stable, chronic liver disease; it can be used with caution and vigilant monitoring of liver function in this population.18

20 21

Acetaminophen may worsen kidney function and increase blood pressure. '

Nevertheless, acetaminophen remains the preferred analgesic for mild to moderate pain in patients with hypertension or kidney disease because of the greater risks as-

sociated with NSAID use. Monitoring specifically for these toxicities generally is unnecessary.

Nonsteroidal Anti-inflammatory Drugs

Prostaglandins play an important role in the function of several organ systems. These compounds are synthesized via the interaction of two isoforms of the cyclooxygenase enzyme (COX-1 and COX-2) with their substrate, arachidonic acid (Fig. 58-3).

LeukoSiienes

FIGURE 58-3. Synthesis pathway for prostaglandins and leukotrienes. (COX-2, cyclooxygenase enzyme 2; NSAIDs, nonsteroidal anti-inflammatory drugs.) (From DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 1528, Figure 95-6, with permission.)

FIGURE 58-3. Synthesis pathway for prostaglandins and leukotrienes. (COX-2, cyclooxygenase enzyme 2; NSAIDs, nonsteroidal anti-inflammatory drugs.) (From DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008: 1528, Figure 95-6, with permission.)

The COX-1 enzyme is produced normally in various body tissues (e.g., gastric mucosa, kidney, and platelets). Prostaglandins produced by the actions of the COX-1 enzyme in the GI tract preserve the integrity of the GI mucosa by increasing mucus and bicarbonate secretion, maintaining mucosal blood flow, and decreasing gastric acid secretion. COX-1-associated prostaglandins also promote normal platelet activity and function. In the kidney, COX-1-mediated prostaglandins dilate the afferent arteriole, thereby maintaining intraglomerular pressure and glomerular filtration rate when renal blood flow is reduced.

In contrast, the COX-2 enzyme is not produced normally in most tissues, but its production is increased rapidly in the presence of inflammation and local tissue injury. This leads to the synthesis of prostaglandins involved in pain and inflammation. Consequently, blocking the COX-2 enzyme results in analgesic and anti-inflammat-

ory effects. The beneficial effects of NSAIDs in reducing pain, decreasing joint stiffness, and improving function in patients with OA are thought to be due to inhibition of the COX-2 isoenzyme.

Most NSAIDs (e.g., ibuprofen, naproxen, and others) inhibit both COX-1 and COX-2 isoforms. That is, they are nonselective inhibitors of the COX enzyme system. Inhibition of COX-2 is responsible for analgesic effects, whereas inhibition of COX-1 is responsible for the most common adverse effects of NSAIDs. COX-2-selective inhibitors were developed in attempts to preserve the beneficial effects of COX-2 inhibition while avoiding the deleterious effects associated with inhibition of the COX-1 enzyme. This approach has not been entirely successful, as discussed below.

^ NSAIDs are a reasonable alternative when acetaminophen fails to provide an acceptable analgesic response. Some authorities recommend NSAIDs over acetaminophen for patients presenting with severe pain or signs and symptoms of inflammation, but this is a matter of much contention. The rationale for this recommendation is that acetaminophen's central mechanism of action renders it ineffective against

peripheral joint inflammation, and therefore less effective. Consensus guidelines support the use of NSAIDs as an alternative to acetaminophen if clinical features of peripheral inflammation or severe pain are present.14,15 Unfortunately, there is no validated mechanism to identify patients who are more likely to respond to NSAIDs than acetaminophen.

® At equipotent doses, the analgesic and anti-inflammatory activity of all

NSAIDs and aspirin are similar. The selection of a specific NSAID should be based on tolerability, previous response, and cost. Some patients respond to one NSAID better than to another. If an insufficient response is achieved with one NSAID, another agent from the same or a different chemical class should be tried. There is no convincing evidence that changing to an NSAID from a different chemical class is more likely to be effective than selecting another drug from the same chemical class. Pain relief occurs rapidly (within hours), but anti-inflammatory benefits are not realized until after 2 to 3 weeks of continuous therapy. This period is the minimal duration that should be considered an adequate NSAID trial.

Inhibition of the COX-1 isoenzyme is thought to be responsible primarily for the adverse effects of NSAIDs on the gastric mucosa, kidney, and platelets. Direct irritant effects also may contribute to adverse GI events. Minor GI complaints, including nausea, dyspepsia, anorexia, abdominal pain, flatulence, and diarrhea, are reported by 10% to 60% of patients treated with NSAIDs. Asymptomatic gastric and duodenal mucosal ulceration can be detected in 15% to 45% of patients.2 Perforation, gastric outlet obstruction, and GI bleeding are the most severe complications and occur in 1.5% to 4% of patients annually.24

Several risk factors predict a greater likelihood of GI complications in NSAID-treated patients (see Chap. 18). It is not possible to detect high-risk patients based on symptoms alone because there is poor correlation between the presence of symptoms and actual gastroduodenal damage. Patients at high risk for GI complications should be evaluated for the use of a COX-2-selective NSAID or concomitant treatment with a prophylactic gastroprotective agent such as a proton pump inhibitor or misoprostol. However, these strategies do not completely mitigate the risk of GI complications.

NSAIDs can cause renal insufficiency when administered to patients whose renal function depends on prostaglandins. Patients with chronic renal insufficiency or left ventricular dysfunction, the elderly, and those receiving diuretics or drugs that interfere with the renin-angiotensin system are particularly susceptible. Decreased glomerular filtration also may cause hyperkalemia. NSAIDs rarely cause tubuloint-erstitial nephropathy and renal papillary necrosis.

Caution is warranted in pregnant women and women of childbearing age because the risk of bleeding may be increased if the fetus is subjected to the antiplatelet activity of NSAIDs. Ibuprofen and naproxen are rated FDA pregnancy category B in the first and second trimesters. Indomethacin and sulindac have not been rated, whereas celecoxib and etodolac are category C. NSAIDs are contraindicated during the third trimester because they may promote premature closure of the ductus arteriosus in the fetus.

NSAIDs are prone to drug interactions due to high protein binding, detrimental renal effects, and antiplatelet activity. Interactions are encountered frequently with aspirin, warfarin, oral hypoglycemics, antihypertensives, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), ^-blockers, diuretics, and lithium. When an interaction with an NSAID is present, vigilant monitoring is warranted for therapeutic efficacy (e.g., NSAIDs blunt the antihypertensive efficacy of diuretics) and adverse effects (e.g., NSAIDs increase the risk of bleeding in antico-agulated patients).

Selective COX-2 Inhibitors

Elucidation of the activities of individual COX isoforms led to the development of drugs that selectively inhibit the inducible form of the enzyme, COX-2. Thus COX-2 inhibitors were expected to minimize NSAID GI toxicity and antiplatelet effects (see

Fig. 58-3).25 A common misconception is that COX-2 inhibitors are more effective than nonselective NSAIDs in relieving pain and inflammation. In clinical trials, patients experienced similar levels ofpain relief with COX-2 inhibitors and nonselect-ive NSAIDs. This is to be expected since both drug classes inhibit the COX-2 enzyme, which is responsible for producing prostaglandins that result in pain and inflammation.

Celecoxib is the only agent currently marketed in the United States that is considered a true COX-2-selective inhibitor. However, meloxicam, sulindac, and diclofenac also display preferential affinity for the COX-2 isozyme. Celecoxib reduces endoscopically detected GI lesions. However, the clinical importance of this observation has been challenged because many of these lesions are clinically silent and resolve spontaneously. Celecoxib did not reduce the incidence of significant upper GI toxicity compared with NSAIDs in a large clinical trial.26 However, this study allowed patients to take concomitant low-dose aspirin. A post hoc analysis in patients who did not take aspirin revealed celecoxib to be effective in reducing significant upper GI toxicity.

The selective agents rofecoxib (removed from the U.S. market in 2004) and lu-

miracoxib (not currently FDA approved) decrease clinically important events such as

27,28

perforations, ulcers, and bleeding.

The advent of COX-2-selective inhibitors has led to unexpected results. By selectively inhibiting the COX-2 isoform, COX-2-selective NSAIDs may increase the risk of cardiovascular events in certain patients.29 COX-2 is responsible for the production of prostacyclin, a vasodilatory and antiplatelet substance. In contrast, COX-1 controls the production of thromboxane A2, a vasoconstrictor and platelet aggregator. Selective inhibition of COX-2 results in decreased prostacyclin levels in the face of stable thromboxane A2levels. An imbalance in the thromboxane A2: prostacyclin ratio ensues, which creates an environment that favors thrombosis.

As a consequence, COX-2-selective inhibitors may offer enhanced GI safety but compromised cardiovascular safety. Increased cardiovascular risk associated with COX-2 inhibitors is likely multifactorial in nature and may be attributable primarily to selectivity, dosage, and potency of selective agents. This relationship can be explained in part by the mechanism of theses drugs—greater inhibition of COX-2 results in a larger decrease in prostacyclin relative to thromboxane A2 (favoring thrombosis) but also less GI ulceration because of the greater preservation of mucosal protective factors. Other mechanisms for increasing cardiovascular risk have been proposed for various agents.30

Concomitant use of low-dose aspirin mitigates some of the increased cardiovascu-

lar risk but also obliterates the GI safety of COX-2 selectivity. Patients treated with a COX-2-selective agent plus aspirin experience GI complications at a rate commensurate with that of patients given traditional nonselective agents. Use of less selective agents (e.g., meloxicam) to avoid cardiovascular concerns with COX-2 inhibitors may not be justified because neither GI nor cardiovascular safety is optimized. In patients at risk for cardiovascular disease, a nonselective NSAID plus a proton pump inhibitor is a reasonable option (Table 58-3). Naproxen appears to have the least cardiovascular risk of the nonselective NSAIDs and should generally be considered first.16

Table 58-3 Treatment Options Based on CV and

High CV Risk

Low CV Risk

High GI Risk

PIS-NSAI'P* ptUS

COX-2 Of

PPl or misoprostoE

N5-N5AID I

gastroprotection

Low GI Risk

NS-NSAIC^

NS-NSAID

COX-2, selective cyclooxygenase-2 inhibitor; CV, cardiovascular; NS-NSAID, nonselective nonsteroidal anti-jnf|arrimaiory drLig; PPIr proton pump inhibitor,

^Naproxen may be considered initially due to potentially lower CV risk compared with other MS-NSAIDs,

The COX-2 enzyme is also produced normally in the kidney; thus COX-2 inhibitors exert renal effects similar to those of conventional NSAIDs. Both drug classes may increase sodium reabsorption and fluid retention and can provoke renal insuffi ciency and hyperkalemia. COX-2 inhibitors should be used with caution in patients with heart failure or hypertension.

COX-2 inhibitors are susceptible to the same drug interactions as nonselective agents. However, the interaction with warfarin is less pronounced because platelet function is affected to a lesser degree.

Glucosamine and Chondroitin

Glucosamine is believed to function as a "chondroprotective" agent, stimulating the cartilage matrix and protecting against oxidative chemical damage. Chondroitin is administered often in conjunction with glucosamine. It is thought to inhibit degradat-ive enzymes and serve as a substrate for the production of proteoglycans. Numerous clinical trials have evaluated the efficacy of these substances for the treatment of OA. However, results vary widely and the quality of several of these studies has been questioned. Of the two available glucosamine salts, glucosamine hydrochloride has consistently demonstrated poor efficacy, whereas glucosamine sulfate may provide benefit.31 In the context of such limitations, glucosamine and chondroitin reduce pain

31 32

and improve mobility by 20% to 35%. ' They also may slow disease progression by decreasing the rate of cartilage destruction, although the clinical impact of this 9 33

effect is not clear. Glucosamine is not effective for treating acute pain; beneficial effects often mature over a period of weeks. Because these agents are loosely regulated in the United States as dietary supplements, product standards are inconsistent, and the constituents are not validated by any regulatory agency.

In the landmark GAIT trial conducted by the National Institutes of Health (NIH), glucosamine, chondroitin, and their combination were no more effective than placebo in decreasing pain symptoms in patients with knee OA after 24 weeks.34 Celecoxib was significantly more effective than placebo. In the subgroup of patients with moderate to severe OA pain, the combination of glucosamine and chondroitin appeared to have a moderate effect, although this subgroup analysis must be interpreted with caution. Analysis of radiologic changes after 2 years of treatment showed no significant

benefit of glucosamine, chondroitin sulfate, or the combination over placebo.

In contrast, a European study (the GUIDE trial) that compared a prescription gluc-osamine product with acetaminophen and placebo in patients with knee OA found that glucosamine performed better versus placebo than did acetaminophen.36

Interpretation of these results is challenging given the inconsistencies in study design, differences in end points applied, preparations of glucosamine tested (gluc-

osamine hydrochloride versus sulfate), and the comparator agents (celecoxib versus acetaminophen). Based on the available data, it appears that glucosamine and chon-droitin may be effective for some patients with OA of the knee.

The use of glucosamine (derived from crab, lobster or shrimp shells) and/or chon-

droitin (derived from cattle or shark cartilage) may warrant caution in patients with

shellfish allergies, but preliminary evidence suggests little drug-allergy interaction. Additionally, glucosamine may alter cellular glucose uptake, thus elevating blood glucose levels in diabetic patients. A randomized, placebo-controlled trial of 38 diabetic participants failed to detect any significant alteration in hemoglobin Aic levels after 3 months of glucosamine/chondroitin therapy; however, a relatively short study

period and low number of participants may account for these negative findings. Blood glucose levels in diabetic patients should be monitored closely after glucosa-mine initiation or dosage adjustments. Given the favorable safety profile of glucosa-mine and chondroitin, it is reasonable to present these agents as a treatment option to patients with symptomatic knee OA in the absence of contraindicating factors.

Intra-articular Therapy

© Intra-articular injection ofcorticosteroids or hyaluronan represents an alternative to oral agents for the treatment ofjoint pain3 These modalities usually are reserved for patients unresponsive to other treatments because of the relative invasiveness of intra-articular injections compared with oral drugs, the small risk of infection, and the cost of the procedure.

Hyaluronan (or Hyaluronic Acid)

The mechanism of action of hyaluronan is not fully understood. Healthy cartilage and synovial fluid are replete with hyaluronic acid, a viscous substance believed to facilitate lubrication and shock absorbency under varying conditions of load bearing. Patients with OA demonstrate an absolute and functional decline in hyaluronic acid; thus exogenous administration is referred to as viscosupplementation. In responders, the benefit of hyaluronan administration persists for periods that exceed its residence time in the synovium, suggesting that benefits beyond viscoelasticity are involved. Inhibition of inflammatory mediators and cartilage degradation, stimulation of the cartilage matrix, neuroprotective actions, and the ability of hyaluronan to induce its own synthesis may account in part for the benefit.

Pain and joint function have been evaluated frequently in clinical trials administering hyaluronan to patients with OA. Results are conflicting, with some suggesting dramatic improvements and others indicating no effect. In one controlled trial, hy-aluronan injections relieved pain to a similar extent as oral NSAIDs.40 Hyaluronan provides greater pain relief for a longer time than intra-articular corticosteroids, but corticosteroids work more rapidly.40

Several formulations of hyaluronan are available for the treatment of knee pain in patients with OA who are unresponsive to other measures. Administration typically consists of weekly injections for 3 to 5 weeks and is well tolerated, although some patients may report local reactions. Rarely, postinjection flares and anaphylaxis have been reported. Intra-articular injection is associated with a low risk of infection (approximately 1 joint in 50,000 injections). Patients should be counseled to minimize activity and stress on the joint for several days after each injection.

Corticosteroids

Use of systemic corticosteroids is discouraged in patients with OA. However, in a subset of patients with an inflammatory component or knee effusion involving one or two joints, intra-articular corticosteroids can be useful as monotherapy or as an adjunct to analgesics. The affected joint can be aspirated and subsequently injected with a corticosteroid. The aspirate should be examined for the presence of crystalline formation and infection. A single joint should not be injected more than three to five times per year.

The crystalline nature of corticosteroid suspensions can provoke a postinjection flare in some patients. The ensuing flare mimics the flare of arthritis and inflammation that accompanies infection. Cold compresses and analgesics are recommended to treat symptoms in affected patients.

Tramadol

Use of opioid analgesics may be warranted when pain is unresponsive to other pharmacologic agents or when such agents are contraindicated. Tramadol is a centrally acting synthetic opioid oral analgesic that also weakly inhibits the reuptake of serotonin and norepinephrine. It is effective for treatment of moderate pain but is devoid of anti-inflammatory activity. There is a low potential for abuse compared with conventional opioid analgesics, and tramadol is not scheduled as a controlled substance in the United States.

Tramadol is a reasonable option for patients with contraindications to NSAIDs or failure to respond to other oral therapies. For the treatment of hip or knee OA, tramadol is as effective as NSAIDs. The addition of tramadol to NSAIDs or acetaminophen may augment the analgesic effects of a failing regimen, thereby securing sufficient pain relief in some patients. Moreover, concomitant tramadol may permit the use of lower NSAID doses.

Dizziness, vertigo, nausea, vomiting, constipation, and lethargy are all relatively common adverse events. These effects are more pronounced for several days after initiation and following upward dose titration. Seizures have been reported rarely; the risk is dose-related and appears to increase with concomitant use of antidepressants, such as tricyclic antidepressants or selective serotonin reuptake inhibitors. Tramadol should be avoided in patients receiving monoamine oxidase (MAO) inhibitors because tramadol inhibits the uptake of norepinephrine and serotonin.

Other Opioid Analgesics

Opioids decrease pain, improve sleep patterns, and increase functioning in patients with OA who are unresponsive to nonpharmacologic therapy and nonnarcotic analgesics. Use of opioid analgesics for nonmalignant pain is becoming more acceptable. Emerging evidence suggests that patients can achieve satisfactory analgesia by using nonescalating doses of opioids with a minimal risk of addiction.41 Opioid analgesics should be reserved for patients who experience moderate to severe pain and do not respond to or are not candidates for other pharmacologic and nonpharmacologic 42

strategies. Opioids also may be useful in patients with conditions that preclude the use of NSAIDs, such as renal failure, heart failure, or anticoagulation.

Opioid analgesics should be initiated at low doses in combination with acetaminophen or an NSAID when possible. Combining opioids with other analgesics reduces the opioid requirement, thereby minimizing adverse events. Conservative initial doses are warranted, with the dose titrated to adequate response with minimal side effects.

Oxycodone is the most extensively studied of the opioids recommended for OA. However, other agents such as morphine, hydromorphone, methadone, and transdermal fentanyl are also effective.43 The American Pain Society (APS) recommends against using codeine and propoxyphene for OA because of the high incidence of adverse effects and limited analgesic effectiveness.

If opioid therapy is considered, there should be an initial comprehensive medical history and physical examination, firm documentation that nonopioid therapy has failed, clearly defined treatment goals, an understanding between the provider and the patient of the true benefits and risks of long-term opioids, use of a single provider and pharmacy whenever possible, and comprehensive follow-up.

Topical Analgesics

Topical analgesics sometimes are used for mild pain or as an adjunct to systemic therapy. There are limited data to support the use of salicylate-containing rubefacients (e.g., methyl salicylate and trolamine salicylate) or other counterirritants (e.g., menthol, camphor, and methyl nicotinate) in OA.44 See for more informa tion on these products when used for musculoskeletal disorders.

Capsaicin achieves pain relief by depleting substance P from sensory neurons in the spine, thereby decreasing pain transmission. Capsaicin is not effective for acute pain; up to 2 weeks may be necessary before pain relief is appreciated. Most patients experience a local burning sensation at the site of application. The discomfort usually does not result in discontinuation and often abates within the first week. Patients should be cautioned not to allow capsaicin to come into contact with eyes or mucous membranes and to wash their hands after each application.

Topical NSAID preparations are effective for treating OA involving the superficial joints of the hands, wrists, elbows, knees, ankles, or feet. Administration via a topical vehicle targets the joints involved and decreases systemic exposure. This may be an attractive option for patients at risk of developing adverse events from oral NSAIDs.

Diclofenac sodium topical gel 1% (Voltaren Gel) is available in the United States; its approval was based on two clinical trials that found decreased pain and improved joint function in patients with hand or knee OA.45,46 Systemic absorption of topical diclofenac sodium is ~17 times lower than that seen with oral diclofenac. Thus, GI, cardiovascular and renal adverse effects would not be expected with proper administration. The most common adverse effects include application site dermatitis, pruritus, and phototoxicity.

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