informed [1):<1) 1 (> <1) Application site erythema 6 (> <1) 3 (> <1) Application site paresthesia 5 (> <1) 3 (> <1) Application site dryness 4 (> <1) 3 (> <1) Application site vesicles 3 (> <1) 0 Application site irritation 2 (> <1) 0 Application site papules 1 (> <1) 0 Preferred Term according to MedDRA 9.1. In the placebo-controlled trials, the discontinuation rate due to adverse reactions was 5% for patients treated with VOLTAREN GEL, and 3% for patients in the placebo group. Application site reactions, including application site dermatitis, were the most frequent reason for treatment discontinuation. Long-Term Open-Label Safety Trial: In the open-label, long-term safety study, distribution of adverse reactions was similar to that in the placebo-controlled studies. In this study, where patients were treated for up to 1 year with VOLTAREN GEL up to 32 g per day, application site dermatitis was observed in 11% of patients. Adverse reactions that led to the discontinuation of the study drug were experienced in 12% of patients. The most common adverse reaction that led to discontinuation of the study was application site dermatitis, which was experienced by 6% of patients. Drug Interactions See Table 2 for clinically significant drug interactions with diclofenac. Table 2: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of VOLTAREN GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.11 )]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2 )]. Intervention: Concomitant use of VOLTAREN GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.11 )]. VOLTAREN GEL is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or betablockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of VOLTAREN GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of VOLTAREN GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter . Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VOLTAREN GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6 )]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of VOLTAREN GEL and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VOLTAREN GEL and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of VOLTAREN GEL and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of VOLTAREN GEL and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of VOLTAREN GEL and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2 )]. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is notrecommended. Pemetrexed Clinical Impact: Concomitant use of VOLTAREN GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of VOLTAREN GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation Risk Summary Use of NSAIDs, including VOLTAREN GEL, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VOLTAREN GEL, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of VOLTAREN GEL in pregnant women. Human and animal studies indicate that diclofenac crosses the placenta. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 5, 5, and 10 times, respectively, the maximum recommended topical dose of VOLTAREN GEL, despite the presence of maternal and fetal toxicity at these doses [see Data] . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of VOLTAREN GEL during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Animal data Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose (MRHD) of VOLTAREN GEL based on bioavailability and body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 5 and 10 times the MRHD based on bioavailability and BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (approximately 1 and 2 times the MRHD based on bioavailability and BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Lactation Risk Summary Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for CATAFLAM and any potential adverse effects on the breastfed infant from the CATAFLAM or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including VOLTAREN GEL, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including VOLTAREN GEL, in women who have difficulties conceiving or who are undergoing investigation of infertility. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.13 )]. Of the total number of subjects treated with VOLTAREN GEL in clinical studies, 498 were 65 years of age and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity to the effect of NSAIDs in some older individuals cannot be ruled out. Diclofenac, as with any NSAID, is known to be substantially excreted by the kidney, and the risk of toxic reactions to VOLTAREN GEL may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when using VOLTAREN GEL in the elderly, and it may be useful to monitor renal function. Overdosage Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6 )]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment, contact a poison control center (1-800-222-1222). Diclo Gel with Xrylix Description VOLTAREN GEL (diclofenac sodium topical gel) is a nonsteroidal anti-inflammatory drug (NSAID) for topical use only. The chemical name is 2-[(2,6-dichlorophenyl)amino]benzene acetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C 14 H 10 Cl 2 NNaO 2 , and it has the following chemical structure: It contains the active ingredient, diclofenac sodium, in an opaque, white gel base. Diclofenac sodium is a white to slightly yellow crystalline powder. Diclofenac sodium is a benzeneacetic acid derivative. The inactive ingredients in VOLTAREN GEL include: carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution. Diclo Gel with Xrylix - Clinical Pharmacology Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of VOLTAREN GEL, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Pharmacokinetics The pharmacokinetics of VOLTAREN GEL were assessed in healthy volunteers following repeated applications during 7 days of VOLTAREN GEL to 1 knee (4 x 4 g per day) or to 2 knees and 2 hands (4 x 12 g per day) versus the recommended oral dose of diclofenac sodium for the treatment of osteoarthritis (3 x 50 mg per day). A summary of the pharmacokinetic parameters is presented in Table 2. Table 3. Pharmacokinetic Parameters and Comparison of VOLTAREN GEL to Oral Diclofenac Sodium Tablets After Repeated Administration Treatment C max (ng/mL) Mean SD % of Oral (CI) T max (hr) Median Range AUC 0-24 (ng h/mL) Mean SD % of Oral (CI) VOLTAREN GEL 4 x 4 g per day (=160 mg diclofenac sodium per day) 15 7.3 0.6% (0.5-0.7) 14 (0-24) 233 128 5.8% (5-6.7) VOLTAREN GEL 4 x 12 g per day (=480 mg diclofenac sodium per day) 53.8 32 2.2% (1.9-2.6) 10 (0-24) 807 478 19.7% (17-22.8) Diclofenac sodium tablets, orally 3 x 50 mg per day (=150 mg diclofenac sodium per day) 2270 778 100% 6.5 (1-14) 3890 1710 100% C max = maximum plasma concentration, t max =time of C max . AUC 0-24 =area under the concentration time curve. SD=standard deviation. CI=confidence interval. Systemic exposure (area under the concentration-time curve) and maximum plasma concentrations of diclofenac are significantly lower with VOLTAREN GEL than with comparable oral treatment of diclofenac sodium. Systemic exposure with recommended use of VOLTAREN GEL (4 x 4 g per day applied to 1 knee) is on average 17 times lower than with oral treatment. (Basis: treatment with VOLTAREN GEL of 1 knee, 4 times a day versus 50 mg, 3 times a day of oral diclofenac tablets.) The amount of diclofenac sodium that is systemically absorbed from VOLTAREN GEL is on average 6% of the systemic exposure from an oral form of diclofenac sodium. The average peak plasma concentration with recommended use of VOLTAREN GEL (4 x 4 g per day applied to 1 knee) is 158 times lower than with the oral treatment. The pharmacokinetics of VOLTAREN GEL has been tested under conditions of moderate heat (application of a heat patch for 15 minutes prior to gel application) and of moderate exercise (first gel application followed by a 20-minute treadmill exercise). No clinically relevant differences of systemic absorption and of tolerability were found between applications of VOLTAREN GEL (4 x 4 g per day on 1 knee) with and under the conditions tested. However, the pharmacokinetics of VOLTAREN GEL were not tested under the condition of heat application following gel application. Therefore, concurrent use of VOLTAREN GEL and heat is not recommended. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions ( 7 )]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years at doses up to 2 mg/kg/day (approximately 0.5 and 1 times, respectively, the maximum recommended human topical dose of VOLTAREN GEL based on bioavailability and body surface area (BSA) comparison) resulted in no significant increases in tumor incidence. In a dermal carcinogenicity study conducted in albino mice, daily topical applications of a diclofenac sodium gel product for two years at concentrations up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in VOLTAREN GEL) did not increase neoplasm incidence. In a photococarcinogenicity study conducted in hairless mice, topical application of a diclofenac sodium gel product at doses up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in VOLTAREN GEL) resulted in an earlier median time of onset of tumors. Mutagenesis Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro , and in vivo rat chromosomal aberration assay of bone marrow cells. Impairment of Fertility Diclofenac did not affect male or female fertility in rats at doses up to 4 mg/kg/day (approximately 2 times than the maximum human topical dose of VOLTAREN GEL based on bioavailability and BSA comparison). Clinical Studies Pivotal Studies in Osteoarthritis of the Superficial Joints of the Extremities Study 1 evaluated the efficacy of VOLTAREN GEL for the treatment of osteoarthritis of the knee in a 12-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial. VOLTAREN GEL was administered at a dose of 4 g, 4 times daily, on 1 knee (16 g per day). Pain as assessed by the patients at Week 12 using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) Pain Subindex was lower in the VOLTAREN GEL group than the placebo group. Study 2 evaluated the efficacy of VOLTAREN GEL for the treatment of osteoarthritis in subjects with osteoarthritis of the hand in an 8-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group study. VOLTAREN GEL was administered at a dose of 2 g per hand, 4 times daily, on both hands (16 g per day). Pain in the target hand as assessed by the patients at Weeks 4 and 6 on a visual analog scale from 0 to 100 was lower in the VOLTAREN GEL group than the placebo group. Table 4. Efficacy outcomes of VOLTAREN GEL in Studies 1 and 2 VOLTAREN GEL Placebo (Vehicle) Adjusted Difference (Placebo - VOLTAREN GEL ) Study 1 (Knee) WOMAC Pain * # at Week 12 Sample Size 127 119 Mean Outcome 28 37 = 7 95% Confidence Interval (1, 12) Study 2 (Hand) Pain Intensity # at Week 4 Sample Size 198 187 Mean Outcome 43 50 = 7 95% Confidence Interval (2, 12) Study 2 (Hand) Pain Intensity # at Week 6 Sample Size 198 187 Mean Outcome 40 47 = 7 95% Confidence Interval (1, 13) * WOMAC = Western Ontario McMaster Osteoarthritis Index. # Scale from 0 (best) to 100 (worst). Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment and center and baseline covariate. Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment, center, indicator of pain in the CMC-1 joint, and baseline as a covariate, and the treatment-by-CMC-1 strata. How Supplied/Storage and Handling VOLTAREN GEL (diclofenac sodium topical gel, 1%) is available in tubes containing 100 grams of the topical gel in each tube. Each tube contains diclofenac sodium in a gel base (10 mg of diclofenac sodium per gram of gel or 1%). 100 grams tube NDC 63481-684-47 3 Pack (3 Tubes containing 100 g each) ..NDC 63481-684-03 5 Pack (5 Tubes containing 100 g each) ..NDC 63481-684-05 Storage Store at room temperature 20 C to 25 C (68 F to 77 F) [See USP Controlled Room Temperature]. Keep from freezing. Store the dosing card with your VOLTAREN GEL Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with VOLTAREN GEL and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions ( 5.1 )]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions ( 5.2 )]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, instruct patients to stop VOLTAREN GEL and seek immediate medical therapy [see Warnings and Precautions ( 5.3 )]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions ( 5.5 )]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions ( 5.7 )]. Serious Skin Reactions Advise patients to stop VOLTAREN GEL immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions ( 5.9 )]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including VOLTAREN GEL, may be associated with a reversible delay in ovulation [see Use in Specific Populations ( 8.3 )] Fetal Toxicity Inform pregnant women to avoid use of VOLTAREN GEL and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 )]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of VOLTAREN GEL with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 )]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with VOLTAREN GEL until they talk to their healthcare provider [see Drug Interactions ( 7 )]. Eye Exposure Instruct patients to avoid contact of VOLTAREN GEL with the eyes and mucosa, although not studied, should be avoided. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour [see Warnings and Precautions ( 5.15 )]. Special Application Instructions Instruct patients how to use the dosing card to measure the proper dose of VOLTAREN GEL to apply. If the patient loses their dosing card, instruct them that they can call 1-800-398-5876 to request a replacement dosing card or ask their pharmacist for a new dosing card. Instruct patients how to correctly measure the 2.25 inches (2 g) dose or 4.5 inches (4 g) dose while waiting for a replacement dosing card [see Dosage and Administration ( 2.2 )]. Instruct patients not to apply VOLTAREN GEL to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug. Instruct patients to avoid concomitant use of VOLTAREN GEL with other topical products, including sunscreens, cosmetics, lotions, moisturizers, and insect repellants. Concomitant use may result in skin reactions or change the absorption of VOLTAREN GEL. Instruct patients to minimize or avoid exposure of treated areas to natural or artificial sunlight [see Warnings and Precautions ( 5.14 ) and Dosage and Administration ( 2.4 )]. Comments or Questions? Call toll-free 1-800-398-5876 Marketed by: Endo Pharmaceuticals Inc. Malvern, PA 19355 Manufactured by: Novartis Pharma Produktions GmbH, Wehr, Germany for Sandoz Inc., Princeton, NJ 08540 Revised: April 2016 Medication Guide Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a coronary artery bypass graft (CABG). Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called corticosteroids , anticoagulants , SSRIs , or SNRIs o increasing doses of NSAIDs o older age o longer use of NSAID o poor health o smoking o advanced liver problems o drinking alcohol o bleeding problems NSAIDs should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain Who should not take NSAIDs? Do not take NSAIDs : if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs right before or after heart bypass surgery Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy. Are breastfeeding or plan to breast feed Tell your healthcare provider all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you have any of the following symptoms: shortness of breath or trouble breathing slurred speech chest pain swelling of the face or throat weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea vomit blood more tired or weaker than usual there is blood in your bowel movement or it is black and sticky like tar diarrhea itching unusual weight gain your skin or eyes look yellow skin rash or blisters with fever indigestion or stomach pain swelling of the arms, legs, hands and feet flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General Information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. This Medication Guide has been approved by the U.S. Food and Drug Administration. Marketed by: Endo Pharmaceuticals Inc., Malvern, PA 19355 Manufactured by: Novartis Pharma Produktions GmbH, Wehr, Germany for Sandoz Inc., Princeton, NJ 08540 Revised: April 2016 Instructions for Use VOLTAREN GEL (diclofenac sodium) Important: Use the dosing card that is in you need to be
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