Infla-eze

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During clinical development, 913 patients were exposed to VOLTAREN ® GEL in randomized, double-blind, multicenter, vehicle-controlled, parallel-group studies in osteoarthritis of the superficial joints of the extremities. Of these, 513 patients received VOLTAREN ® GEL for osteoarthritis of the knee and 400 were treated for osteoarthritis of the hand. Additionally, 583 patients were exposed to VOLTAREN ® GEL in an uncontrolled, open-label, long-term safety trial in osteoarthritis of the knee. Of these, 355 patients were treated for osteoarthritis of 1 knee and 228 were treated for osteoarthritis of both knees. Duration of exposure ranged from 8 to 12 weeks for the placebo-controlled studies, and up to 12 months for the open-label safety trial.

Short-Term Placebo-Controlled Trials:

Adverse reactions observed in at least 1% of patients treated with VOLTAREN ® GEL: Non-serious adverse reactions that were reported during the short-term placebo-controlled studies comparing VOLTAREN ® GEL and placebo (vehicle gel) over study periods of 8 to 12 weeks (16 g per day), were application site reactions. These were the only adverse reactions that occurred in > 1% of treated patients with a greater frequency in the VOLTAREN ® GEL group (7%) than the placebo group (2%).

Table 1 lists the types of application site reactions reported. Application site dermatitis was the most frequent type of application site reaction and was reported by 4% of patients treated with VOLTAREN ® GEL, compared to 1% of placebo patients.

†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.

Aspirin

When diclofenac is administered with aspirin, the binding of diclofenac to protein is reduced, although the clearance of free diclofenac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.

Anticoagulants

The effects of anticoagulants such as warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

ACE-Inhibitors

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Diuretics

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. The response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure [see Warnings and Precautions (5.6)], as well as to assure diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs, including diclofenac, and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs, including diclofenac, are administered concomitantly with methotrexate.

Cyclosporine

Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore concomitant therapy with diclofenac may increase cyclosporine’s nephrotoxicity. Caution should be used when diclofenac is administered concomitantly with cyclosporine.

Oral Nonsteroidal Anti-inflammatory Drugs

Specific interaction studies of VOLTAREN ® GEL and oral NSAIDs were not performed. Also, the clinical trials of VOLTAREN ® GEL prohibited concomitant use of oral NSAIDS. There is systemic exposure to diclofenac following normal use of Voltaren® Gel, up to 6% of the systemic levels of a single oral dose of diclofenac sodium. [see Clinical Pharmacology (12.3)]Therefore, concomitant administration of VOLTAREN ® GEL with oral NSAIDs or aspirin may result in increased adverse NSAID effects.

Topical Treatments

Concomitant use of VOLTAREN ® GEL with other topical products, including topical medications, sunscreens, lotions, moisturizers, and cosmetics, on the same skin site has not been tested and should be avoided because of the potential to alter local tolerability and absorption.

There has been no experience of overdose with VOLTAREN ® GEL.

No events of accidental ingestion have been reported with VOLTAREN ® GEL. Effects similar to those observed after an overdose of diclofenac tablets can be expected if substantial amounts of VOLTAREN ® GEL are ingested. Symptoms following acute oral NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur after an overdose.

In the event of oral ingestion resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. Forced diuresis may theoretically be beneficial because the drug is excreted in the urine. The effect of dialysis or hemoperfusion in the elimination of diclofenac (99% protein-bound) remains unproven. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac. Supportive and symptomatic treatment should be given for complications such as renal failure, convulsions, gastrointestinal irritation, and respiratory depression.

For additional information about overdose treatment, call a Poison Control Center (1-800-222-1222).

VOLTAREN ® GEL (diclofenac sodium topical gel) is a nonsteroidal anti-inflammatory drug (NSAID) for topical use only. 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 benzene–acetic acid derivative. The chemical name is 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C 14H 10Cl 2NNaO 2. It has the following structural formula:

VOLTAREN ® GEL also contains carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution.

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.

* 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 for pain in the CMC-1 joint, and baseline as a covariate, and the treatment-by-CMC-1 indicator interaction. Difference is weighted by size of CMC-1 strata

Advise the patient to read the FDA-approved patient labeling (NSAIDs Medication Guide and Instructions for Use) prior to using VOLTAREN ® GEL.

Inform patients of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy

Cardiovascular Effects

VOLTAREN ® GEL, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Advise patients of the importance of this follow-up [see Warnings and Precautions (5.1)].

Gastrointestinal Effects

VOLTAREN ® GEL, like other NSAIDs, can cause GI discomfort and, rarely, more serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding. Instruct patients to ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.2)].

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flulike” symptoms). If these occur, patients should be instructed to stop therapy with VOLTAREN ® GEL and seek immediate medical therapy [see Warnings and Precautions (5.3)].

Adverse Skin Reactions

VOLTAREN ® GEL, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching. Instruct patients to ask for medical advice when observing any indicative signs or symptoms [see Warnings and Precautions (5.8)].

Advise patients to stop VOLTAREN ® GEL immediately if they develop any type of rash and contact their physicians as soon as possible.

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.

Weight Gain and Edema

Instruct patients to report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with VOLTAREN ® GEL [see Warnings and Precautions (5.5)].

Anaphylactoid Reactions

Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see Warnings and Precautions (5.7)].

Effects During Pregnancy

In late pregnancy, as with other NSAIDs, VOLTAREN ® GEL should be avoided because it will cause premature closure of the ductus arteriosus [see Warnings and Precautions (5.9)].

Eye Exposure

Instruct patients to avoid contact of VOLTAREN ® GEL with the eyes and mucosa, although not studied, should be avoided. Patients should be advised that if eye contact occurs, they should immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

Proper Application

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.

Comments or Questions?

Call toll-free 1-888-526-5449

Marketed by:

Alvix Laboratories, LLC

6601 Sunplex Drive

Ocean Springs, MS 39564

Manufactured by:

Novartis Pharma Produktions GmbH
Wehr, Germany for

Sandoz Inc., Princeton, NJ 08540

Revised: November 2014