Solaraze® (diclofenac sodium) Gel, 3%, contains the active ingredient, diclofenac sodium, in a clear, transparent, colorless to slightly yellow gel base. Diclofenac sodium is a white to slightly yellow crystalline powder. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially insol-uble in ether. The chemical name for diclofenac sodium is:

Sodium [o-(2,6-dichloranilino) phenyl] acetate
Diclofenac sodium has a molecular weight of 318.13.

The CAS number is CAS-15307-79-6. The structural formula is represented below:

Solaraze® Gel also contains benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and puri-fied water. 1 g of Solaraze® (diclofenac sodium) Gel contains 30 mg of the active substance, diclofenac sodium.

Last updated on RxList: 7/10/2007

Solaraze® (diclofenac sodium) Gel is indicated for the topical treatment of actinic keratoses (AK). Sun avoidance is indicated during therapy.

Solaraze® Gel is applied to lesion areas twice daily. It is to be smoothed onto the affected skin gently. The amount needed depends upon the size of the lesion site. Assure that enough Solaraze® Gel is applied to adequately cover each lesion. Normally 0.5 g of gel is used on each 5 cm x 5 cm lesion site. The recommended duration of thera-py is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be carefully re-evaluated and management reconsidered.

Available in tubes of 50 g (NDC 10337-803-05) and 100 g (NDC 10337-803-01). Each gram of gel contains 30 mg of diclofenac sodium.

Storage: Store at controlled room temperature 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F). Protect from heat. Avoid freezing.

Manufactured by Patheon Inc., Toronto, Ontario, Canada.
Manufactured for: DOAK DERMATOLOGICS., A SUBSIDIARY OF BRADLEY PHARMACEUTICALS, INC., 383 Route 46 West • Fairfield, NJ 07004, USA
www.doakderm.com
FDA rev date: 6/1/2007

Last updated on RxList: 7/6/2007

Of the 423 patients evaluable for safety in adequate and well-controlled trials, 211 were treated with Solaraze® drug product and 212 were treated with a vehicle gel. Eighty-seven percent (87%) of the Solaraze®-treated patients (183 patients) and 84% of the vehicle-treated patients (178 patients) experienced one or more adverse events (AEs) during the studies. The majority of these reactions were mild to moderate in severity and resolved upon discontinuation of therapy.

Of the 211 patients treated with Solaraze®, 172 (82%) experienced AEs involving skin and the application site compared to 160 (75%) vehicle-treated patients. Application site reactions (ASRs) were the most frequent AEs in both Solaraze®- and vehicle-treated groups. Of note, four reactions, contact dermatitis, rash, dry skin and exfoliation (scaling) were significantly more prevalent in the Solaraze® group than in the vehicle-treated patients.

Eighteen percent of Solaraze®-treated patients and 4% of vehicle-treated patients discontinued from the clinical trials due to adverse events (whether considered related to treatment or not). These discontinuations were main-ly due to skin irritation or related cutaneous adverse reactions.

Table 1 below presents the AEs reported at an incidence of >1% for patients treated with either Solaraze® Gel or vehicle (60- and 90-day treatment groups) during the phase 3 studies.

Skin and Appendages Adverse Events Reported for Solaraze® at less than 1% Incidence in the phase 3 studies: skin hypertrophy, paresthesia, seborrhea, urticaria, application site reactions (skin carcinoma, hyperto-nia, skin hypertrophy lacrimation disorder, maculopapular rash, purpuric rash, vasodilation).

Adverse Reactions Reported for Oral Diclofenac Dosage Form (not topical Solaraze® Gel): *Incidence greater than 1% marked with asterisk.

Body as a Whole: abdominal pain or cramps*, headache*, fluid retention*, abdominal distention*, malaise, swelling of lips and tongue, photosensitivity, anaphylaxis, anaphylactoid reactions, chest pain.

Cardiovascular: hypertension, congestive heart failure, palpitations, flushing, tachycardia, premature ventricular contractions, myocardial infarction, hypotension.

Digestive: diarrhea*, indigestion*, nausea*, constipation*, flatulence*, liver test abnormalities*, PUB*, i.e., peptic ulcer, with or without bleeding and/or perforation, or bleeding without ulcer, vomiting, jaundice, melena, esophageal lesions, aphthous stomatitis, dry mouth and mucous membranes, bloody diarrhea, hepatitis, hepatic necrosis, cirrhosis, hepatorenal syndrome, appetite change, pancreatitis with or without concomitant hepatitis, colitis, intestinal perforation.

Hemic and Lymphatic: hemoglobin decrease, leukopenia, thrombocytopenia, eosinophilia, hemolytic anemia, aplastic anemia, agranulocytosis, purpura, allergic purpura, bruising.

Metabolic and Nutritional Disorders: azotemia, hypoglycemia, weight loss.

Nervous System: dizziness*, insomnia, drowsiness, depression, diplopia, anxiety, irritability, aseptic meningitis, convulsions, paresthesia, memory disturbance, nightmares, tremor, tic, abnormal coordination, disorientation, psychotic reaction.

Respiratory: epistaxis, asthma, laryngeal edema, dyspnea, hyperventilation, edema of pharynx.

Skin and Appendages: rash*, pruritus*, alopecia, urticaria, eczema, dermatitis, bullous eruption, erythema mul-tiforme major, angioedema, Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis.

Special Senses: tinnitus*, blurred vision, taste disorder, reversible and irreversible hearing loss, scotoma, vitre-ous floaters, night blindness, amblyopia.

Urogenital: nephrotic syndrome, proteinuria, oliguria, interstitial nephritis, papillary necrosis, acute renal failure, urinary frequency, nocturia, hematuria, impotence, vaginal bleeding.

Although the systemic absorption of Solaraze® is low, concomitant oral administration of other NSAIDs such as aspirin at anti-inflammatory/analgesic doses should be minimized.

Last updated on RxList: 7/6/2007

As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to diclofenac. Diclofenac sodium should be given with caution to patients with the aspirin triad. The triad typically occurs in asth-matic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bron-chospasm after taking aspirin or other NSAIDs.

General

Solaraze® (diclofenac sodium) Gel should be used with caution in patients with active gastrointestinal ulceration or bleeding and severe renal or hepatic impairments. Solaraze® should not be applied to open skin wounds, infec-tions, or exfoliative dermatitis. It should not be allowed to come in contact with the eyes.

The safety of the concomitant use of sunscreens, cosmetics or other topical medications and Solaraze® is unknown.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There did not appear to be any increase in drug-related neoplasms following daily topical applications of diclofenac sodium gel for 2 years at concentrations up to 0.035% diclofenac sodium and 2.5% hyaluronate sodi-um in albino mice. (Note: Solaraze® contains 3% diclofenac sodium.) When administered orally for 2 years, diclofenac showed no evidence of carcinogenic potential in rats given diclofenac sodium at up to 2 mg/kg/day (3 times the estimated systemic human exposure*), or in mice given diclofenac sodium at up to 0.3 mg/kg/day in males and 1 mg/kg/day in females (25% and 83%, respectively, of the estimated systemic human exposure).

A photococarcinogenicity study with up to 0.035% diclofenac in the Solaraze® vehicle gel was conducted in hair-less mice at topical doses up to 2.8 mg/kg/day. Median tumor onset was earlier in the 0.035% group (Solaraze® contains 3% diclofenac sodium).

Diclofenac was not genotoxic in in vitro point mutation assays in mammalian mouse lymphoma cells and Ames microbial test systems, or when tested in mammalian in vivo assays including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. It was also negative in the transformation assay utilizing BALB/3T3 mouse embryo cells.

Fertility studies have not been conducted with Solaraze® Gel. Diclofenac sodium showed no evidence of impair-ment of fertility after oral treatment with 4 mg/kg/day (7 times the estimated systemic human exposure) in male or female rats.

* Based on body surface area and assuming 10% bioavailability following topical application of 2 g Solaraze® Gel per day (1 mg/kg diclofenac sodium).

Pregnancy:

Teratogenic Effects: Pregnancy category B

The safety of Solaraze® (diclofenac sodium) Gel has not been established during pregnancy. However, reproductive studies performed with diclofenac sodium alone at oral doses up to 20 mg/kg/day (15 times the estimated systemic human exposure*) in mice, 10 mg/kg/day (15 times the estimated systemic human exposure) in rats, and 10 mg/kg/day (30 times the estimated systemic human exposure) in rabbits have revealed no evidence of teratogenicity despite the induction of maternal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.

* Based on body surface area and assuming 10% bioavailability following topical application of 2 g Solaraze® Gel per day (1 mg/kg diclofenac sodium).

Diclofenac has been shown to cross the placental barrier in mice and rats. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless the benefits to the mother justify the potential risk to the fetus. Because of the risk to the fetus resulting in premature closure of the ductus arteriosus, diclofenac should be avoided in late pregnancy.

Labor and Delivery

The effects of diclofenac on labor and delivery in pregnant women are unknown. Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use of diclofenac during late pregnancy should be avoided and, as with other nonsteroidal anti-inflammatory drugs, it is possible that diclofenac may inhibit uterine contractions and delay parturition.

Nursing Mothers

Because of the potential for serious adverse reactions in nursing infants from diclofenac sodium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Actinic keratosis is not a condition seen within the pediatric population. Solaraze® should not be used by children.

Geriatric Use

Of the 211 subjects treated with Solaraze® in controlled clinical studies, 143 subjects were 65 and over. Of those 143 subjects, 55 subjects were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differ-ences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Last updated on RxList: 7/6/2007

Due to the low systemic absorption of topically-applied Solaraze® Gel, overdosage is unlikely. There have been no reports of ingestion of Solaraze®. 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.

Solaraze® (diclofenac sodium) Gel is contraindicated in patients with a known hypersensitivity to diclofenac, benzyl alcohol, polyethylene glycol monomethyl ether 350 and/or hyaluronate sodium.

Last updated on RxList: 7/6/2007

The mechanism of action of diclofenac sodium in the treatment of actinic keratosis (AK) is unknown. The contribution to efficacy of individual components of the vehicle has not been established.

Pharmacokinetics

Absorption

When Solaraze® is applied topically, diclofenac is absorbed into the epidermis. In a study in patients with com-promised skin (mainly atopic dermatitis and other dermatitic conditions) of the hands, arms or face, approximately 10% of the applied dose (2 grams of 3% gel over 100 cm²) of diclofenac was absorbed systemically in both nor-mal and compromised epidermis after seven days, with four times daily applications.

After topical application of 2 g Solaraze® three times daily for six days to the calf of the leg in healthy subjects, diclofenac could be detected in plasma. Mean bioavailability parameters were AUC_0-t 9±19 ng•hr/mL (mean±SD) with a Cmax of 4±5 ng/mL and a Tmax of 4.5±8 hours. In comparison, a single oral 75 mg dose of diclofenac (Voltaren™) produced an AUC of 1600 ng.hr/mL. Therefore, the systemic bioavailability after topical application of Solaraze® is lower than after oral dosing.

Blood drawn at the end of treatment from 60 patients with AK lesions treated with Solaraze® in three adequate and well-controlled clinical trials was assayed for diclofenac levels. Each patient was administered 0.5 g of Solaraze® Gel twice a day for up to 105 days. There were up to three 5 cm X 5 cm treatment sites per patient on the face, forehead, hands, forearm, and scalp. Serum concentrations of diclofenac were, on average, at or below 20 ng/mL. These data indicate that systemic absorption of diclofenac in patients treated topically with Solaraze® is much lower than that occurring after oral daily dosing of diclofenac sodium.

No information is available on the absorption of diclofenac when Solaraze® is used under occlusion.

Distribution

Diclofenac binds tightly to serum albumin. The volume of distribution of diclofenac following oral administration is approximately 550 mL/kg.

Metabolism

Biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much smaller extent than diclofenac. Metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. The small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise.

Elimination

Diclofenac and its metabolites are excreted mainly in the urine after oral dosing. Systemic clearance of diclofenac from plasma is 263±56 mL/min (mean±SD). The terminal plasma half-life is 1-2 hours. Four of the metabolites also have short terminal half-lives of 1-3 hours.

CLINICAL STUDIES

Clinical trials were conducted involving a total of 427 patients (213 treated with Solaraze® and 214 with a gel vehi-cle). Each patient had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm X 5 cm regions: scalp, forehead, face, forearm and hand. Up to three major body areas were studied in any patient. All patients were 18 years of age or older (male and female) with no clinically significant medical prob-lems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (maso-procol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel, 50% glycolic acid peel) and hyaluronan-containing cosmetics. Patients were excluded from participation for reasons of known or suspected hypersensitivity to any Solaraze® ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflamma-tory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medica-tion. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not per-mitted. Patients were instructed to apply a small amount of Solaraze® Gel (approximately 0.5 g) onto the affect-ed skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all patients were instructed to avoid sun exposure. Complete clearing of the AK lesions 30 days after completion of treatment was the pri-mary efficacy variable. No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence.

Last updated on RxList: 7/6/2007

In clinical studies, localized dermal side effects such as contact dermatitis, exfoliation, dry skin and rash were found in patients treated with Solaraze® at a higher incidence than in those with placebo.

Patients should understand the importance of monitoring and follow-up evaluation, the signs and symptoms of dermal adverse reactions, and the possibility of irritant or allergic contact dermatitis. If severe dermal reactions occur, treatment with Solaraze® may be interrupted until the condition subsides. Exposure to sunlight and the use of sunlamps should be avoided.

Safety and efficacy of the use of Solaraze® together with other dermal products, including cosmetics, sunscreens, and other topical medications on the area being treated, have not been studied.

Last updated on RxList: 7/6/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DICLOFENAC 3% - TOPICAL

(dye-KLO-fen-ack)

COMMON BRAND NAME(S): Solaraze

USES: This medication is used to treat a certain skin condition (actinic keratoses). Diclofenac is known as a nonsteroidal anti-inflammatory drug (NSAID).

HOW TO USE: Use this medication on the skin only. Gently apply enough medication to cover the affected skin well, usually 2 times daily or as directed by your doctor. This medication is usually applied for 60 to 90 days. Wash your hands after using, unless you are using this medication to treat the hands.

Do not apply the medication in or around the eyes, open skin wounds, or infected/scraped/burned skin. If you do get the medication in those areas, flush with plenty of water.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same times each day.

Tell your doctor if your condition persists or worsens. It may take up to 30 days after finishing the medication for the skin to completely heal.

SIDE EFFECTS: Rash, scaling, dry skin, or itching may occur at application site. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: eye redness/itching, stomach/abdominal pain, headache, shortness of breath, muscle pain, swelling at application site.

Tell your doctor immediately if any of these rare but very serious side effects occur: dark urine, yellowing eyes/skin, change in the amount of urine, easy bruising/bleeding, unexplained stiff neck, signs of infection (e.g., fever, persistent sore throat), persistent/severe headache, swelling hands/feet, sudden/unexplained weight gain, vision changes, hearing changes (e.g., ringing in the ears), mental/mood changes (e.g., depression), fast/pounding heartbeat, fainting.

Other medications similar to this medication may infrequently cause serious bleeding from the stomach or intestines. Also, related drugs rarely have caused blood clots to form, resulting in heart attacks and strokes. If you notice any of the following rare but very serious side effects, stop using this medication and seek immediate medical attention: black/bloody stools, persistent stomach/abdominal pain, vomit that looks like coffee grounds, chest pain, sudden vision changes, weakness on one side of the body, slurred speech.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using diclofenac, tell your doctor or pharmacist if you are allergic to it; or to other ingredients in this product such as benzyl alcohol; or to aspirin or other NSAIDs (e.g., ibuprofen, naproxen, celecoxib); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: aspirin-sensitive asthma (a history of worsening breathing with runny/stuffy nose after taking aspirin or other NSAIDs), recent heart bypass surgery (CABG).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, stomach/intestine problems (e.g., bleeding, ulcers), heart disease (e.g., heart failure, history of heart attack), high blood pressure, stroke, swelling (edema, water retention), poorly controlled diabetes, a severe loss of body water (dehydration), blood disorders (e.g., anemia, bleeding/clotting problems), asthma, growths in the nose (nasal polyps).

Before having surgery, tell your doctor or dentist that you are using this medication.

This medicine may cause stomach bleeding. Daily use of alcohol and tobacco may increase your risk for stomach bleeding, especially when combined with this medicine. Limit alcohol and stop smoking. Consult your doctor or pharmacist for more information.

Your condition may get worse when exposed to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Wear protective clothing when outdoors. Ask your doctor whether you should use sunscreen along with this medication.

Older adults may be more sensitive to the side effects of this drug, especially stomach/intestinal bleeding and kidney effects.

During the first 6 months of pregnancy, this medication should be used only when clearly needed. It is not recommended for use during the last 3 months of pregnancy due to possible harm to the unborn baby and problems with normal labor/delivery. Discuss the risks and benefits with your doctor.

Based on information from related drugs, this medication may pass into breast milk. Though there have been no reports of harm to nursing infants, consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anti-platelet drugs (e.g., clopidogrel), "blood thinners" (e.g., warfarin, heparin, enoxaparin), cidofovir, corticosteroids (e.g., prednisone), cyclosporine, desmopressin, digoxin, high blood pressure medications (e.g., ACE inhibitors such as lisinopril, beta blockers such as atenolol), lithium, methotrexate, pemetrexed, probenecid, other products applied to skin on the treated area, SSRI antidepressants (e.g., fluoxetine, sertraline), tenofovir, "water pills" (diuretics such as hydrochlorothiazide, furosemide, triamterene).

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (NSAIDs such as aspirin, ibuprofen, or naproxen) that are similar to this drug and, if taken together, may increase your risk for side effects. Low-dose aspirin should be continued if prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention (usually at dosages of 81-325 milligrams per day). Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: This medication may be harmful if swallowed. If overdose or swallowing is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose/swallowing may include: seizures, severe stomach pain, change in the amount of urine, slow/shallow breathing.

NOTES: Do not share this medication with others.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from heat. Do not freeze. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.