DICLOFENAC SODIUM- diclofenac sodium gel
Amneal Pharmaceuticals of New York LLC
FOR DERMATOLOGIC USE ONLY. NOT FOR OPHTHALMIC USE.
WARNING: RISK OF SERIOUS CARDIOVASCULAR EVENTS
Cardiovascular Thrombotic Events
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
Diclofenac Sodium Gel, 3% is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
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 insoluble 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:
Diclofenac Sodium Gel, 3% also contains benzyl alcohol, hydroxyethyl cellulose, methoxypolyethylene glycol 350, PEG-60 hydrogenated castor oil, and purified water.
1 g of Diclofenac Sodium Gel, 3% contains 30 mg of the active substance, diclofenac sodium.
The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown. The contribution to efficacy of individual components of the vehicle has not been established.
When diclofenac sodium gel, 3% 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 diclofenac sodium gel, 3% 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 diclofenac sodium gel, 3% 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 diclofenac sodium gel, 3% in three adequate and well-controlled clinical trials was assayed for diclofenac levels. Each patient was administered 0.5 g of diclofenac sodium gel, 3% 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 diclofenac sodium gel, 3% is much lower than that occurring after oral daily dosing of diclofenac sodium.
No information is available on the absorption of diclofenac when diclofenac sodium gel, 3% is used under occlusion.
Diclofenac binds tightly to serum albumin. The volume of distribution of diclofenac following oral administration is approximately 550 mL/kg.
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.
Diclofenac Sodium Gel, 3% is indicated for the topical treatment of actinic keratoses (AK). Sun avoidance is indicated during therapy.
Clinical trials were conducted involving a total of 427 patients (213 treated with diclofenac sodium gel, 3% and 214 with a gel vehicle). 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 problems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (masoprocol, 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 diclofenac sodium gel, 3% ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medication. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. Patients were instructed to apply a small amount of diclofenac sodium gel, 3% (approximately 0.5 g) onto the affected 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 primary efficacy variable. No long-term patient follow-ups, after the 30-day assessments, were performed for the detection of recurrence.
|Diclofenac Sodium Gel, 3%||Vehicle||p-value|
|Study 1 90 days treatment||27/58 (47%)||11/59 (19%)||<0.001|
|Study 2 90 days treatment||18/53 (34%)||10/55 (18%)||0.061|
|Study 3 60 days treatment||15/48 (31%)||5/49 (10%)||0.021|
|30 days treatment||7/49 (14%)||2/49 (4%)||0.221|
|Scalp||Forehead||Face||Arm/Forearm||Back of Hand|
|Study 1 90 days treatment|
|Diclofenac Sodium Gel, 3%||1/4 (25%)||17/30 (57%)||9/17 (53%)||4/12 (33%)||6/16 (38%)|
|Vehicle||3/9 (33%)||8/24 (33%)||5/17 (29%)||4/12 (33%)||0/14 (0)|
|Study 2 90 days treatment|
|Diclofenac Sodium Gel, 3%||2/6 (33%)||9/19 (47%)||4/5 (80%)||5/8 (63%)||1/17 (6%)|
|Vehicle||0/4 (0)||6/22 (27%)||2/8 (25%)||0/5 (0)||3/16 (19%)|
|Study 3 60 days treatment|
|Diclofenac Sodium Gel, 3%||3/7 (43%)||13/31 (42%)||10/19 (53%)||0/1 (0)||2/8 (25%)|
|Vehicle||0/6 (0)||5/36 (14%)||2/13 (15%)||0/2 (0)||1/9 (11%)|
|30 days treatment|
|Diclofenac Sodium Gel, 3%||2/5 (40%)||4/29 (14%)||3/14 (21%)||0/0 (0)||0/9 (0)|
|Vehicle||0/5 (0)||2/29 (7%)||2/18 (11%)||0/1 (0)||1/9 (11%)|
|All data combined|
|Diclofenac Sodium Gel, 3%||8/22 (36%)||43/109 (39%)||26/55 (47%)||9/21 (43%)||9/50 (18%)|
|Vehicle||3/24 (13%)||21/111 (19%)||11/56 (20%)||4/20 (20%)||5/48 (10%)|
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