Solaraze 3%

Available in tubes of 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 1530°C (59-86°F). Protect from heat. Avoid freezing.

Manufactured by: Almirall Hermal GmbH D-21465 Reinbek, Germany. Manufactured for: PharmaDerm, A division of Fougera, Melville, New York 11747. www.pharmaderm.com. www.solaraze.com. Revised: May 2016

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 therapy 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.

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.

Solaraze® (diclofenac sodium) Gel is contraindicated in the following patients:

• In the setting of coronary artery bypass graft (CABG) surgery.

WARNINGS

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 asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs.

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10– 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of Solaraze in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Solaraze is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Heart Failure And Edema

The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)].

Avoid the use of Solaraze in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Solaraze is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

PRECAUTIONS

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, infections, 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.

Information For Patients

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.

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.

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.

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 sodium 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 hairless 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 impairment 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 keratoses 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 differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

SIDE EFFECTS

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 mainly 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.

Table 1: Adverse Events Reported ( > 1% in Any Treatment Group) During Solaraze®Phase 3 Clinical Trials Incidences for 60-Day and 90-Day Treatments

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, hypertonia, 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 multiforme major, angioedema, Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis.

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

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

DRUG INTERACTIONS

Specific interaction studies between Solaraze® Gel and other topical or oral agents were not performed.

Oral Nonsteroidal Anti-Inflammatory Drugs

Although low, there is systemic exposure to diclofenac following labeled use of Solaraze® Gel. Therefore, concomitant administration of Solaraze® Gel with oral NSAIDS or aspirin may result in increased NSAID adverse effects.

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.

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 mainly 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.

Table 1: Adverse Events Reported ( > 1% in Any Treatment Group) During Solaraze®Phase 3 Clinical Trials Incidences for 60-Day and 90-Day Treatments

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, hypertonia, 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 multiforme major, angioedema, Stevens-Johnson syndrome, excess perspiration, exfoliative dermatitis.

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

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

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.

Absorption

When Solaraze® is applied topically, diclofenac is absorbed into the epidermis. In a study in patients with compromised 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 normal 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 AUC0-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.

Comparative bioavailability studies have not been conducted between available diclofenac topical products (gels containing 1 to 3% diclofenac) which have different dosing regimens. A cross-study evaluation of the data indicates that diclofenac is more bioavailable when applied to diseased skin and less bioavailable when applied to intact skin.

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 to 2 hours. Four of the metabolites also have short terminal half-lives of 1 to 3 hours.