CATEGORIES: Arthritis, osteoarthritis; Pain, mild to moderate; Arthritis, rheumatoid; Ankylosing spondylitis; Dysmenorrhea; Inflammation, opthalamic, postoperative; Keratosis, actinic; Pain, ophthalmic; Photophobia, postoperative; Pregnancy Category B; FDA Approved July 1988
Drug Classes: Analgesics, non-narcotic; Nonsteroidal anti-inflammatory drugs; Ophthalmics
BRAND NAMES: Cataflam; Solaraze; Voltaren; Voltaren Ophthalmic; Voltaren-XR
FOREIGN BRAND AVAILABILITY:
Abdiflam (Indonesia);
Abitren (Israel);
Allvoran (Germany);
Almiral (Hong Kong, Malaysia, Singapore, Taiwan);
Almiral SR (Hong Kong, Malaysia);
Alonpin (Japan);
Apo-Diclofenac EC (New Zealand);
Arcanafenac (South Africa);
Arthrifen (Philippines);
Artren (Colombia, Ecuador);
Artrenac (Mexico);
Artrites (Colombia);
Artrites Retard (Colombia);
Berifen (Indonesia);
Berifen Gel (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama);
Betaren (Israel);
Bolabomin (Japan);
Calozan (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama);
Cataflam DD (Ecuador);
Cataflam Drops (Malaysia);
Catanac (Indonesia);
Catas (Korea);
Clo-Far (Mexico);
Clofec (Thailand);
Clonaren (Philippines);
Clonodifen (Mexico);
Cordralan (Peru);
Curinflam (Argentina);
DDL plaster (Korea);
Decrol (Korea);
Depain (Korea);
Diclax (New Zealand);
Diclax SR (New Zealand);
Diclo-Basan (Switzerland);
Diclobene (Austria);
Diclofen (Taiwan, Thailand);
Diclofenac (Colombia);
Diclofen Cremogel (Israel);
Dicloflam (South Africa);
Diclohexal (Australia);
Diclomax (India, Republic of Yemen);
Diclomol (Thailand);
Diclon (Denmark);
Dicloran Gel (South Africa, India);
Dicloren (Taiwan);
Diclosian (Thailand);
Diclotec (Canada);
Diclowal (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama);
Dicsnal (Japan);
Difen (Thailand);
Difena (Taiwan);
Difenac (Japan, South Africa, Thailand);
Dioxaflex (Mexico);
Doflex (India);
Dolaren (Mexico);
Dolflam-Retard (Mexico);
Doloflam (Philippines);
Dolotren (Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama, Taiwan);
Dolotren Gel (Taiwan);
Dosanac (Thailand);
E (Greece);
Ecofenac (Switzerland);
Epifenac (Israel);
Flector (France);
Flexagen (South Africa);
Flogofenac (China);
Flogozan (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama);
Fortfen SR (South Africa);
Freejex (Korea);
Hizemin (Japan);
Inac (Singapore);
Inac gel (Singapore);
Inflamac (Switzerland);
Inflanac (Hong Kong, Malaysia, Thailand);
Jonac Gel (India);
Klotaren (Indonesia);
Lofenac (Thailand);
Lotirac (Korea);
Magluphen (Austria);
Monoflam (Czech Republic, Germany);
Naboal (Japan);
Nac Gel (India);
Naclof (Ecuador, Hong Kong, Korea, Philippines, South Africa, Taiwan, Thailand);
Nacoflar (Indonesia);
Novo-Difenac (Hong Kong);
Novolten (China);
Ofenac (Korea);
Olfen (China, Hong Kong);
Olfen-75 SR (Hong Kong);
Olfen Gel (Singapore, Thailand);
Olfen Roll-On (Israel);
Optanac (Indonesia);
Osteoflam (India);
Painstop (Taiwan);
Panamor (South Africa);
Profenac (Israel);
Relaxyl Gel (India);
Remethan (Germany, Singapore);
Remethan Gel (Taiwan);
Rewodina (Germany, Malaysia, Russia);
Rhewlin (Singapore);
Rhewlin Forte (Singapore);
Rhewlin SR (Singapore);
Rolactin (Korea);
Savismin (Japan);
Soproxen (Thailand);
Staren (Taiwan);
Sting Gel (Singapore);
Tigen Plaster (Korea);
Toraren (Korea);
Tsudohmin (Japan);
Uniren (Singapore);
Valentac (Korea);
Voldic (Israel);
Voldic Emulgel (Israel);
Volero (Korea);
Volfenac (Costa Rica, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama);
Volta (Thailand);
Voltadex Emulgel (Indonesia);
Voltalen (New Zealand);
Voltalen Emulgel (New Zealand);
Voltarene (France);
Voltarene Emulgel (France);
Voltaren Emulgel (Austria, Colombia, Czech Repub
COST OF THERAPY:
|
Voltaren Ophthalmic (diclofenac sodium ophthalmic solution) 0.1% solution is a sterile, topical, nonsteroidal, anti-inflammatory product for ophthalmic use. Diclofenac sodium is designated chemically as 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt, with an empirical formula of C14H10Cl2NO2Na.
Voltaren Ophthalmic is available as a sterile solution which contains diclofenac sodium 0.1% (1 mg/ml). Inactive Ingredients: polyoxyl 35 castor oil, boric acid, tromethamine, sorbic acid (2 mg/ml), edetate disodium (1 mg/ml), and purified water. Diclofenac sodium is a faintly yellow-white to light-beige, slightly hygroscopic crystalline powder. It is freely soluble in methanol, sparingly soluble in water, very slightly soluble in acetonitrile, and insoluble in chloroform and in 0.1 N hydrochloric acid. Its molecular weight is 318.14. Voltaren Ophthalmic 0.1% is an iso-osmotic solution with an osmolality of about 300 mOsmol/1000 g, buffered at approximately pH 7.2. Voltaren Ophthalmic solution has a faint characteristic odor of castor oil.
Pharmacodynamics
Diclofenac sodium is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is thought to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins.
Animal Studies
Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure.
Pharmacokinetics
Results from a bioavailability study established that plasma levels of diclofenac following ocular instillation of 2 drops of diclofenac sodium ophthalmic solution to each eye were below the limit of quantification (10 ng/ml) over a 4 hour period. This study suggests that limited, if any, systemic absorption occurs with diclofenac sodium ophthalmic solution.
Postoperative Anti-Inflammatory Effects
In two double-masked, controlled, efficacy studies of postoperative inflammation, a total of 206 cataract patients were treated with diclofenac sodium ophthalmic solution and 103 patients were treated with vehicle placebo. Diclofenac sodium ophthalmic solution was favored over vehicle placebo over a 2 week period for the clinical assessments of inflammation as measured by anterior chamber cells and flare. In double-masked, controlled studies of corneal refractive surgery [radial keratotomy (RK) and laser photorefractive keratectomy (PRK)] patients were treated with diclofenac sodium ophthalmic solution and/or vehicle placebo. The efficacy of diclofenac sodium ophthalmic solution given before and shortly after surgery was favored over vehicle placebo during the 6 hour period following surgery for the clinical assessments of pain and photophobia. Patients were permitted to use a hydrogel soft contact lens with diclofenac sodium ophthalmic solution for up to 3 days after PRK.
Diclofenac sodium ophthalmic solution is indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction and for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery.
Non-FDA Approved Indications
Unlabeled uses of diclofenac ophthalmic solution have included noninfected inflammatory conditions such as chronic conjunctivitis, keratoconjunctivitis, trauma, and to inhibit miosis during cataract surgery.
Diclofenac sodium ophthalmic solution is contraindicated in patients who are hypersensitive to any component of the medication.
The refractive stability of patients undergoing corneal refractive procedures and treated with diclofenac has not been established. Patients should be monitored for a year following use in this setting. With some nonsteroidal anti-inflammatory drugs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery. There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.
General
It is recommended that diclofenac sodium ophthalmic solution, like other NSAIDs, be used with caution in surgical patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time. Diclofenac may slow or delay healing. Results from clinical studies indicate that diclofenac sodium ophthalmic solution has no significant effect upon ocular pressure; however, elevations in intraocular pressure may occur following cataract surgery.
Information for the Patient
Except for the use of a bandage hydrogel soft contact lens during the first 3 days following refractive surgery, diclofenac sodium ophthalmic solution should not be used by patients currently wearing soft contact lenses due to adverse events that have occurred in other circumstances.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity studies in rats given diclofenac in oral doses up to 2 mg/kg/day (approximately the human oral dose) revealed no significant increases in tumor incidence. There was a slight increase in benign rat mammary fibroadenomas in mid-dose females (high-dose females had excessive mortality) but the increase was not significant for this common rat tumor. A 2 year carcinogenicity study conducted in mice employing oral diclofenac up to 2 mg/kg/day did not reveal any oncogenic potential. Diclofenac did not show mutagenic potential in various mutagenicity studies including the Ames test. Diclofenac administered to male and female rats at 4 mg/kg/day did not affect fertility.
Pregnancy
Teratogenic Effects, Pregnancy Category C
Reproduction studies performed in mice at oral doses up to 5000 times (20 mg/kg/day) and in rats and rabbits at oral doses up to 2500 times (10 mg/kg/day) the human topical dose have revealed no evidence of teratogenicity due to diclofenac despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. 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 be used during pregnancy only if clearly needed.
Nonteratogenic Effects
Because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), the use of diclofenac sodium ophthalmic solution during late pregnancy should be avoided.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Ocular
Transient burning and stinging were reported in approximately 15% of patients across studies with the use of diclofenac sodium ophthalmic solution. In cataract surgery studies, keratitis was reported in up to 28% of patients receiving diclofenac sodium ophthalmic solution, although in many of these cases keratitis was initially noted prior to the initiation of treatment. Elevated intraocular pressure following cataract surgery was reported in approximately 15% of patients undergoing cataract surgery. Lacrimation complaints were reported in approximately 30% of case studies undergoing incisional refractive surgery. The following adverse reactions were reported in approximately 5% or less of the patients: abnormal vision, acute elevated IOP, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal opacity, corneal lesions, discharge, eyelid swelling, injection, iritis, irritation, itching, lacrimation disorder, and ocular allergy.
Systemic
The following adverse reactions were reported in 3% or less of the patients: Abdominal pain, asthenia, chills, dizziness, facial edema, fever, headache, insomnia, nausea, pain, rhinitis, viral infection, and vomiting.
Overdosage will not ordinarily cause acute problems. If diclofenac sodium ophthalmic solution is accidentally ingested, fluids should be taken to dilute the medication.
Cataract Surgery
One drop of diclofenac sodium ophthalmic solution should be applied to the affected eye, 4 times daily beginning 24 hours after cataract surgery and continuing throughout the first 2 weeks of the postoperative period.
Corneal Refractive Surgery
One or two drops of diclofenac sodium ophthalmic solution should be applied to the operative eye within the hour prior to corneal refractive surgery. Within 15 minutes after surgery, 1 or 2 drops should be applied to the operative eye and continued 4 times daily for up to 3 days.
Voltaren Ophthalmic 0.1% (1 mg/ml) sterile solution is supplied in dropper-tip, plastic, squeeze bottles containing 2.5 or 5 ml.
Storage
Store between 15-30°C (59-86°F). Protect from light.
Dispense in original, unopened container only.
Diclofenac, as the sodium or potassium salt, is a benzeneacetic acid derivative, designated chemically as 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium or monopotassium salt.
Diclofenac, as the sodium or potassium salt, is a faintly yellowish white to light beige, virtually odorless, slightly hygroscopic crystalline powder. Molecular weights of the sodium and potassium salts are 318.14 and 334.25, respectively. It is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water while diclofenac potassium is soluble in water. The n-octanol/water partition coefficient is, for both diclofenac salts, 13.4 at pH 7.4 and 1545 at pH 5.2. Both salts have a single dissociation constant (pKa) of 4.0± 0.2 at 25°C in water.
Diclofenac Potassium
Diclofenac potassium is available as Cataflam Immediate-Release Tablets of 50 mg for oral administration.
Cataflam Inactive Ingredients: Calcium phosphate, colloidal silicon dioxide, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, starch, sucrose, talc, titanium dioxide.
Diclofenac Sodium
Diclofenac sodium is available as Voltaren Delayed-Release (enteric-coated) Tablets of 25, 50, and 75 mg for oral administration, and Voltaren-XR Extended-Release Tablets of 100 mg.
Voltaren Inactive Ingredients: Hydroxypropyl methylcellulose, iron oxide, lactose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, povidone, propylene glycol, sodium hydroxide, sodium starch glycolate, talc, titanium dioxide, D&C yellow no. 10 aluminum lake (25 mg tablet only), FD&C blue no. 1 aluminum lake (50 mg tablet only).
Voltaren-XR Inactive Ingredients: Cetyl alcohol, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, polyethylene glycol, polysorbate, povidone, silicon dioxide, sucrose, talc, titanium dioxide.
Pharmacodynamics
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac has shown anti-inflammatory, analgesic, and antipyretic activity. As with other NSAIDs, its mode of action is not known; its ability to inhibit prostaglandin synthesis, however, may be involved in its anti-inflammatory activity, as well as contribute to its efficacy in relieving pain related to inflammation and primary dysmenorrhea. With regard to its analgesic effect, diclofenac is not a narcotic.
Pharmacokinetics
Diclofenac potassium immediate-release tablets, diclofenac sodium delayed-release tablets, and diclofenac sodium extended-release tablets, contain the same therapeutic moiety, diclofenac. They differ in the cationic portion of the salt (see DESCRIPTION), as well as in their release characteristics. Diclofenac potassium immediate-release tablets are formulated to release diclofenac in the stomach. Diclofenac sodium delayed-release (enteric-coated) tablets are in a pharmaceutical formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH-environment of the duodenum. Conversely, diclofenac sodium extended-release tablets are formulated to release drug over a prolonged period. The primary pharmacokinetic difference between the three products is in the pattern of drug release and absorption, as described below and shown in TABLE 1.
|
||||||||||||||||||||||||
For this reason, separate sections are provided below to describe the different absorption profiles of diclofenac potassium immediate-release tablets, diclofenac sodium delayed-release tablets, and diclofenac sodium extended-release tablets.
Absorption
Under fasting condition, diclofenac is completely absorbed from the gastrointestinal tract. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available.
Diclofenac Potassium Immediate-Release Tablets
In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with diclofenac potassium immediate-release tablets. Peak plasma levels are achieved in approximately 1 hour in fasting normal volunteers, with a range from 0.33-2 hours.
The extent of diclofenac absorption is not significantly affected when diclofenac potassium immediate-release tablets is taken with food. However, the rate of absorption is reduced by food, as indicated by a delay in Tmax and decrease in Cmax values by approximately 30%. After repeated oral administration of diclofenac potassium immediate-release tablets 50 mg tid no accumulation of diclofenac in plasma occurred.
Diclofenac Sodium Delayed-Release Tablets
Peak plasma levels are achieved in 2 hours in fasting normal volunteers, with a range from 1-4 hours. The area under the plasma concentration curve (AUC) is dose-proportional within the range of 25-150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.0, 1.5, and 2.0 μg/ml for 25, 50, and 75 mg doses, respectively. It should be noted that the administration of several individual diclofenac sodium delayed-release tablets may not yield equivalent results in peak concentration as the administration of one tablet of a higher strength. This is probably due to the staggered gastric emptying of tablets into the duodenum. After repeated oral administration of diclofenac sodium delayed-release 50 mg bid, diclofenac did not accumulate in plasma.
When diclofenac sodium delayed-release is taken with food, there is usually a delay in the onset of absorption of 1-4.5 hours, with delays as long as 10 hours in some patients, and a reduction in peak plasma levels of approximately 40%. The extent of absorption of diclofenac, however, is not significantly affected by food intake.
Diclofenac Sodium Extended-Release Tablets
The extent of diclofenac absorption from the extended-release tablet is not significantly affected when the drug is taken with food, however, food significantly altered the absorption pattern as indicated by a delay of 1-2 hours in Tmax and a 2-fold increase in Cmax values. The plasma profile of the extended-release tablet, under fasting conditions, was characterized by multiple peaks and high intersubject variability in blood profiles. In contrast, the plasma profile for the extended-release tablets under fed conditions showed a more consistent absorption pattern with a single peak usually occurring between 5 and 6 hours after the meal.
Distribution
Plasma concentrations of diclofenac decline from peak levels in a biexponential fashion, with the terminal phase having a half-life of approximately 2 hours. Clearance and volume of distribution are about 350 ml/min and 550 ml/kg, respectively. More than 99% of diclofenac is reversibly bound to human plasma albumin.
As with other NSAIDs, diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.
Metabolism and Elimination
Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile.
Conjugates of unchanged diclofenac account for 5-10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20-30% of the dose excreted in the urine and for 10-20% of the dose excreted in the bile. Conjugates of three other metabolites together account for 10-20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life 80 hours) accounts for only 1.4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity.
Special Populations
A 4 week study, comparing plasma level profiles of diclofenac (diclofenac sodium delayed-release 50 mg bid) in younger (26-46 years) versus older (66-81 years) adults, did not show differences between age groups (10 patients per age group).
Geriatric Population
An 8 day study, comparing the kinetics of diclofenac (100 mg diclofenac sodium extended-release tablets qd) in osteoarthritis patients older than 65 years versus younger than 65 years showed no significant differences between the two groups with respect to peak plasma levels, time to peak levels, or AUC.
Patients With Renal and/or Hepatic Impairment
To date, no differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal (50 mg intravenously) or hepatic impairment (100 mg oral solution). In patients with renal impairment (n=5, creatinine clearance 3-42 ml/min), AUC values and elimination rates were comparable to those in healthy subjects. In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubins, n=10), diclofenac concentrations and urinary elimination values were comparable to those in healthy subjects.
Individualization of Dosage
Diclofenac, like other NSAIDs, shows interindividual differences in both pharmacokinetics and clinical response (pharmacodynamics). Consequently, the recommended strategy for initiating therapy is to use a starting dose likely to be effective for the majority of patients and to adjust dosage thereafter based on observation of diclofenac's beneficial and adverse effects.
In patients weighing less than 60 kg (132 lb), or where the severity of the disease, concomitant medication, or other diseases warrant, the maximum recommended total daily dose of diclofenac should be reduced. Experience with other NSAIDs has shown that starting therapy with maximum doses in patients at increased risk due to renal or hepatic disease, low body weight (<60 kg), advanced age, a known ulcer diathesis, or known sensitivity to NSAID effects, is likely to increase frequency of adverse reactions and is not recommended (see PRECAUTIONS).
Osteoarthritis/RheumatoidArthritis/Ankylosing Spondylitis
The usual starting dose of diclofenac potassium immediate-release tablets or diclofenac sodium delayed-release for patients with osteoarthritis, is 100-150 mg/day, using a bid or tid dosing regimen. For patients with osteoarthritis, the usual starting dose of diclofenac sodium extended-release tablets is 100 mg qd. In two variable-dose clinical trials in osteoarthritis using diclofenac sodium delayed-release tablets, of 266 patients started on 100 mg/day, 176 chose to increase the dose to 150 mg/day. Dosages above 200 mg/day have not been studied in patients with osteoarthritis.
For most patients with rheumatoid arthritis, the usual starting dose of diclofenac potassium immediate-release tablets or diclofenac sodium delayed-release tablets is 150 mg/day, using a bid or tid dosing regimen. The usual starting dose of diclofenac sodium extended-release tablets is 100 mg qd. Patients requiring more relief of pain and inflammation may increase the dose to 200 mg/day. In clinical trials, patients receiving 200 mg/day were less likely to drop from the trial due to lack of efficacy than patients receiving 150 mg/day as diclofenac sodium delayed-release tablets or 100 mg/day as diclofenac sodium extended-release tablets. Dosages above 225 mg/day are not recommended in patients with rheumatoid arthritis because of increased risk of adverse events.
The recommended dose of diclofenac sodium delayed-release tablets for patients with ankylosing spondylitis is 100-125 mg/day, using a qid dosing regimen (see DOSAGE AND ADMINISTRATION regarding the 125 mg/day dosing regimen). In a variable-dose clinical trial, of 132 patients started on 75 mg/day, 122 chose to increase the dose to 125 mg/day. Dosages above 125 mg/day have not been studied in patients with ankylosing spondylitis.
Analgesia/Primary Dysmenorrhea
Because of earlier absorption of diclofenac from diclofenac potassium immediate-release tablets, it is the formulation indicated for management of pain and primary dysmenorrhea when prompt onset of pain relief is desired. The results of clinical trials suggest an initial diclofenac potassium immediate-release tablets dose of 50 mg for pain or for primary dysmenorrhea, followed by doses of 50 mg every 8 hours, as needed. With experience, some patients with recurring pain, such as dysmenorrhea, may find that an initial dose of 100 mg of diclofenac potassium immediate-release tablets, followed by 50 mg doses, will provide better relief. After the first day, when the maximum recommended dose may be 200 mg, the total daily dose should generally not exceed 150 mg.
Diclofenac Potassium Immediate-Release Tablets in Analgesia/Primary Dysmenorrhea
The analgesic efficacy of diclofenac potassium immediate-release tablets was demonstrated in trials of patients with postoperative pain (following gynecologic, oral, and orthopedic surgery), osteoarthritis of the knee, and primary dysmenorrhea. The effectiveness of diclofenac potassium immediate-release tablets in studies of pain or primary dysmenorrhea showed that onset of analgesia began, in some patients, as soon as 30 minutes, and relief of pain lasted as long as 8 hours, following single 50 or 100 mg doses. Duration of pain relief was judged by the time at which approximately half of the patients needed remedication. The onset and duration of pain relief for either the 50 or 100 mg dose was essentially the same, whether patients had moderate or severe pain at baseline.
Diclofenac potassium immediate-release tablets was studied in single-dose and multiple-dose pain trials. The pain models in single-dose studies were post-dental extraction and post-gynecologic surgery: the efficacy of the 50 mg dose (n=258) and the 100 mg dose (n=255) was comparable to aspirin 650 mg in onset of pain relief, but generally provided a longer duration of analgesia than aspirin. The pain models for multiple-dose trials were post-orthopedic surgery pain as well as pain associated with primary dysmenorrhea: the efficacy of the 50 mg dose (n=101) and the 100 mg dose (n=442), followed by 50 mg every 8 hours, was comparable to naproxen sodium 550 mg followed by 275 mg every 8 hours. In one study of chronic pain, in patients with osteoarthritis (n=196), diclofenac potassium immediate-release tablets 50 mg tid was comparable in efficacy to ibuprofen 800 mg tid and diclofenac sodium delayed-release tablets 50 mg tid.
Diclofenac Sodium Delayed-Release Tablets in Osteoarthritis
Diclofenac sodium delayed-release tablet was evaluated for the management of the signs and symptoms of osteoarthritis of the hip or knee in a total of 633 patients treated for up to 3 months in placebo- and active-controlled clinical trials against aspirin (n=449), and naproxen (n=92). Diclofenac sodium delayed-release tablet was given both in variable (100-150 mg/day) and fixed (150 mg/day) dosing schedules in either bid or tid dosing regimens. In these trials, diclofenac sodium delayed-release tablet was found to be comparable to 2400-3600 mg/day of aspirin or 500 mg/day of naproxen. Diclofenac sodium delayed-release tablet was effective when administered as either bid or tid dosing regimens.
Diclofenac Sodium Delayed-Release Tablets in Rheumatoid Arthritis
Diclofenac sodium delayed-release tablet was evaluated for managing the signs and symptoms of rheumatoid arthritis in a total of 468 patients treated for up to 3 months in placebo- and active-controlled clinical trials against aspirin (n=290), and ibuprofen (n=74). Diclofenac sodium delayed-release tablet was given in a fixed (150 or 200 mg/day) dosing schedule as either bid or tid dosing regimens. Diclofenac sodium delayed-release tablet was found to be comparable to 3600-4800 mg/day of aspirin, and 2400 mg/day of ibuprofen. Diclofenac sodium delayed-release tablet was used bid or tid, administering 150 mg/day in most trials, but 50 mg qid (200 mg/day) was also studied.
Diclofenac Sodium Delayed-Release Tablets in Ankylosing Spondylitis
Diclofenac sodium delayed-release tablet was evaluated for the management of the signs and symptoms of ankylosing spondylitis in a total of 132 patients in one active-controlled clinical trial against indomethacin (n=130). Both diclofenac sodium delayed-release and indomethacin patients were started on 25 mg tid and were permitted to increase the dose 25 mg/day each week to a maximum dose of 125 mg/day. Diclofenac sodium delayed-release tablet 75-125 mg/day was found to be comparable to indomethacin 75-125 mg/day.
Diclofenac Sodium Extended-Release Tablets in Osteoarthritis
The use of diclofenac sodium extended-release tablets in controlling the signs and symptoms of osteoarthritis was assessed in two double-blind, controlled trials in which 742 patients participated and 517 patients were treated for 3 months. In one active- and placebo-controlled study, diclofenac sodium extended-release tablets at doses of 100 mg qd were comparable to diclofenac sodium delayed-release tablets 50 mg bid in patients whose osteoarthritis symptoms were stabilized after 2 weeks of treatment with diclofenac sodium delayed-release tablets 75 mg bid. In another study, diclofenac sodium extended-release tablets at doses of 100 mg qd and 100 mg bid were compared to diclofenac sodium delayed-release tablets 50 mg qid. Diclofenac sodium extended-release tablets 100 mg bid were comparable to diclofenac sodium delayed-release tablets 50 mg qid. With the diclofenac sodium extended-release tablets formulation, although there was a trend toward greater efficacy at doses of 200 mg daily than 100 mg daily, there was also an increase in side effects when 200 mg of diclofenac sodium extended-release tablets were administered to patients with osteoarthritis.
Diclofenac Sodium Extended-Release Tablets in Rheumatoid Arthritis
The use of diclofenac sodium extended-release tablets in controlling the signs and symptoms of rheumatoid arthritis was assessed in two double-blind, controlled trials in which 704 patients participated and 441 patients were treated for 3 months. In one active- and placebo-controlled study, diclofenac sodium extended-release tablets 100 mg qd were comparable to diclofenac sodium delayed-release tablets 50 mg bid in patients whose rheumatoid arthritis symptoms were stabilized after 2 weeks' treatment of diclofenac sodium delayed-release tablets 75 mg bid. In another study, diclofenac sodium extended-release tablets at doses of 100 mg qd and 100 mg bid were compared to diclofenac sodium delayed-release tablets 50 mg qid; diclofenac sodium extended-release tablets 100 mg bid were comparable to diclofenac sodium delayed-release tablets 50 mg qid. There was a trend toward greater efficacy with doses of 200 mg daily as compared to 100 mg daily of diclofenac sodium extended-release tablets. There was also an increase in side effects when 200 mg of diclofenac sodium extended-release tablets were administered to patients with rheumatoid arthritis.
Special Studies
(The clinical significance of the findings outlined below is unknown.)
GI Blood Loss/Endoscopy Data
GI blood loss and endoscopy studies were performed with diclofenac sodium delayed-release (enteric-coated) tablets that, unlike immediate-release tablets, do not dissolve in the stomach where the endoscopic lesions are primarily seen; diclofenac potassium immediate-release tablets have not been similarly studied. A repeat-dose endoscopy study, in patients with rheumatoid arthritis or osteoarthritis treated with diclofenac sodium delayed-release tablets 75 mg bid (n=101), or naproxen (immediate-release tablets) 500 mg bid (n=103) for 3 months, resulted in a significantly smaller number of patients with an increase in endoscopy score from baseline and a significantly lower mean endoscopy score after treatment in the diclofenac sodium-treated patients. Two repeat-dose endoscopic studies, in normal volunteers showed that daily doses of diclofenac sodium delayed-release tablets 75 or 100 mg (n=6 and n=14, respectively) for 1 week caused fewer gastric lesions, and those that did occur had lower scores than those observed following daily 500 mg doses of naproxen (immediate-release tablets). In healthy subjects, the daily administration of 150 mg of diclofenac sodium (n=8) for 3 weeks resulted in a mean fecal blood loss less than that observed with 3.0 g of aspirin daily (n=8). In four repeat-dose studies, mean fecal blood loss with 150 mg of diclofenac sodium delayed-release tablets was also less than that observed with 750 mg of naproxen (n=8 and n=6) or 150 mg of indomethacin (n=8 and n=6).
Diclofenac potassium immediate-release tablets and diclofenac sodium delayed-release tablets are indicated for the acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis. Diclofenac sodium extended-release tablets are indicated for chronic therapy of osteoarthritis and rheumatoid arthritis. In addition, diclofenac potassium immediate-release tablets and diclofenac sodium delayed-release tablets are indicated for the treatment of ankylosing spondylitis. Only diclofenac potassium immediate-release tablets is indicated for the management of pain and primary dysmenorrhea, when prompt pain relief is desired, because it is formulated to provide earlier plasma concentrations of diclofenac (see CLINICAL PHARMACOLOGY, Pharmacokinetics and CLINICAL STUDIES).
Non-FDA Approved Indications
While not FDA approved indications, diclofenac has also been used in the management of pain and nonrheumatic inflammatory conditions.
Diclofenac in all oral formulations is contraindicated in patients with known hypersensitivity to diclofenac and diclofenac-containing products. Diclofenac should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to diclofenac have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, General, Pre-Existing Asthma).
Gastrointestinal Effects
Peptic ulceration and gastrointestinal bleeding have been reported in patients receiving diclofenac. Physicians and patients should therefore remain alert for ulceration and bleeding in patients treated chronically with diclofenac even in the absence of previous GI tract symptoms. It is recommended that patients be maintained on the lowest dose of diclofenac possible, consistent with achieving a satisfactory therapeutic response.
Risk of GI Ulcerations, Bleeding, and Perforation With NSAID Therapy
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients for 3-6 months, and in about 2-4% of patients treated for 1 year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.
Hepatic Effects
Elevations of one or more liver tests may occur during diclofenac therapy. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [=the Upper Limit of the Normal range]), or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the hepatic enzymes, ALT (SGPT) is the one recommended for the monitoring of liver injury.
In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5700 patients at some time during diclofenac sodium delayed-release tablet treatment. In a large, open, controlled trial, meaningful elevations of ALT and/or AST occurred in about 4% of 3700 patients treated for 2-6 months, including marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (>8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Transaminase elevations were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis (see ADVERSE REACTIONS).
In addition to enzyme elevations seen in clinical trials, postmarketing surveillance has found rare cases of severe hepatic reactions, including liver necrosis, jaundice, and fulminant fatal hepatitis with and without jaundice. Some of these rare reported cases underwent liver transplantation.
Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. In the largest US trial (open-label) that involved 3700 patients monitored first at 8 weeks and 1200 patients monitored again at 24 weeks, almost all meaningful elevations in transaminases were detected before patients became symptomatic. In 42 of the 51 patients in all trials who developed marked transaminase elevations, abnormal tests occurred during the first 2 months of therapy with diclofenac. Postmarketing experience has shown severe hepatic reactions can occur at any time during treatment with diclofenac. Cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy. Based on these experiences, transaminases should be monitored within 4-8 weeks after initiating treatment with diclofenac (see PRECAUTIONS, Laboratory Tests). As with other NSAIDs, if abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), diclofenac should be discontinued immediately.
To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms), and the appropriate action patients should take if these signs and symptoms appear.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to diclofenac. Diclofenac should not be given 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 nonsteroidal anti-inflammatory drugs. Fatal reactions have been reported in such patients (see CONTRAINDICATIONS, and PRECAUTIONS, General, Pre-Existing Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Advanced Renal Disease
In cases with advanced kidney disease, treatment with diclofenac, as with other NSAIDs, should only be initiated with close monitoring of the patient's kidney functions (see PRECAUTIONS, General, Renal Effects).
Pregnancy
In late pregnancy, diclofenac should, as with other NSAIDs, be avoided because it will cause premature closure of the ductus arteriosus (see PRECAUTIONS, Pregnancy, Teratogenic Effects, Pregnancy Category B, and PRECAUTIONS, Labor and Delivery).
General
Diclofenac oral formulations should not be used concomitantly with other diclofenac-containing products since they also circulate in plasma as the diclofenac anion.
Fluid Retention and Edema
Fluid retention and edema have been observed in some patients taking diclofenac. Therefore, as with other NSAIDs, diclofenac should be used with caution in patients with a history of cardiac decompensation, hypertension, or other conditions predisposing to fluid retention.
Hematologic Effects
Anemia is sometimes seen in patients receiving diclofenac or other NSAIDs. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis.
Renal Effects
As a class, NSAIDs have been associated with renal papillary necrosis and other abnormal renal pathology in long-term administration to animals. In oral diclofenac studies in animals, some evidence of renal toxicity was noted. Isolated incidents of papillary necrosis were observed in a few animals at high doses (20-120 mg/kg) in several baboon subacute studies. In patients treated with diclofenac, rare cases of interstitial nephritis and papillary necrosis have been reported (see ADVERSE REACTIONS).
A second form of renal toxicity, generally associated with NSAIDs, is seen in patients with conditions leading to a reduction in renal blood flow or blood volume, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in a reduction of renal blood flow, which may precipitate overt renal failure. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
Cases of significant renal failure in patients receiving diclofenac have been reported from marketing experience, but were not observed in over 4000 patients in clinical trials during which serum creatinine and BUN values were followed serially. There were only 11 patients (0.3%) whose serum creatinine and concurrent serum BUN values were greater than 2.0 mg/dl and 40 mg/dl, respectively, while on diclofenac (mean rise in the 11 patients: creatinine 2.3 mg/dl and BUN 28.4 mg/dl).
Since diclofenac metabolites are eliminated primarily by the kidneys, patients with significantly impaired renal function should be more closely monitored than subjects with normal renal function.
Porphyria
The use of diclofenac in patients with hepatic porphyria should be avoided. To date, 1 patient has been described in whom diclofenac probably triggered a clinical attack of porphyria. The postulated mechanism, demonstrated in rats, for causing such attacks by diclofenac, as well as some other NSAIDs, is through stimulation of the porphyrin precursor delta-aminolevulinic acid (ALA).
Aseptic Meningitis
As with other NSAIDs, aseptic meningitis with fever and coma has been observed on rare occasions in patients on diclofenac therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on diclofenac, the possibility of its being related to diclofenac should be considered.
Pre-Existing Asthma
About 10% of patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diclofenac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma.
Other Precautions
The pharmacologic activity of diclofenac may reduce fever and inflammation, thus diminishing their utility as diagnostic signs in detecting underlying conditions.
In order to avoid exacerbation of manifestations of adrenal insufficiency, patients who have been on prolonged corticosteroid treatment should have their therapy tapered slowly rather than discontinued abruptly when diclofenac is added to the treatment program.
Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving diclofenac, the drug should be discontinued and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.
Information for the Patient
Diclofenac, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, and more rarely, liver toxicity (see WARNINGS, Hepatic Effects), which may result in hospitalization and even fatal outcomes.
NSAIDs are often essential agents in the management of arthritis and have a major role in the management of pain, but they also may be commonly employed for conditions that are less serious.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.
Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects, Risk of GI Ulcerations, Bleeding, and Perforation With NSAID Therapy). If diclofenac is used chronically, patients should also be instructed to report any signs and symptoms that might be due to hepatotoxicity of diclofenac; these symptoms may become evident between visits when periodic liver laboratory tests are performed (see WARNINGS, Hepatic Effects, and Laboratory Tests).
Laboratory Tests
Hepatic Effects
Transaminases and other hepatic enzymes should be monitored in patients treated with NSAIDs. For patients on diclofenac therapy, it is recommended that a determination be made within 4 weeks of initiating therapy and at intervals thereafter. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and abnormal liver tests are detected, persist or worsen, diclofenac should be discontinued immediately.
Hematologic Effects
Patients on long-term treatment with NSAIDs, including diclofenac, should have their hemoglobin or hematocrit checked periodically for signs or symptoms of anemia. Appropriate measures should be taken in case such signs of anemia occur.
Protein Binding
In vitro, diclofenac interferes minimally or not at all with the protein binding of salicylic acid (20% decrease in binding), tolbutamide, prednisolone (10% decrease in binding), or warfarin. Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence in vitro on the protein binding of diclofenac in human serum.
Drug/Laboratory Test Interactions
Effect on Blood Coagulation
Diclofenac increases platelet aggregation time but does not affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, or factors V and VII to XII. Statistically significant changes in prothrombin and partial thromboplastin times have been reported in normal volunteers. The mean changes were observed to be less than 1 second in both instances, however, and are unlikely to be clinically important. Diclofenac is a prostaglandin synthetase inhibitor, however, and all drugs that inhibit prostaglandin synthesis interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (or 12 mg/m2/day, approximately the human dose) have revealed no significant increases in tumor incidence. There was a slight increase in benign mammary fibroadenomas in mid-dose-treated (0.5 mg/kg/day or 3 mg/m2/day) female rats (high-dose females had excessive mortality), but the increase was not significant for this common rat tumor. A 2 year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m2/day) in males and 1 mg/kg/day (3 mg/m2/day) in females did not reveal any oncogenic potential. Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. Diclofenac sodium administered to male and female rats at 4 mg/kg/day (24 mg/m2/day) did not affect fertility.
Pregnancy, Teratogenic Effects, Pregnancy Category B
Reproduction studies have been performed in mice given diclofenac sodium (up to 20 mg/kg/day or 60 mg/m2/day) and in rats and rabbits given diclofenac sodium (up to 10 mg/kg/day or 60 mg/m2/day for rats, and 80 mg/m2/day for rabbits), and have revealed no evidence of teratogenicity despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. 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 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, 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
Safety and effectiveness of diclofenac in pediatric patients have not been established.
Geriatric Use
Of the more than 6000 patients treated with diclofenac in US trials, 31% were older than 65 years of age. No overall difference was observed between efficacy, adverse event, or pharmacokinetic profiles of older and younger patients. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients.
Adverse reaction information is derived from blinded, controlled, and open-label clinical trials, as well as worldwide marketing experience. In the description below, rates of more common events represent clinical study results; rarer events are derived principally from marketing experience and publications, and accurate rate estimates are generally not possible.
In 718 patients treated for shorter periods, i.e., 2 weeks or less, with diclofenac potassium immediate-release tablets, adverse reactions were reported one-half to one-tenth as frequently as by patients treated for longer periods. In a 6 month, double-blind trial comparing diclofenac potassium immediate-release tablets (n=196) versus diclofenac sodium delayed-release tablets (n=197) versus ibuprofen (n=197), adverse reactions were similar in nature and frequency. In controlled clinical trials, the incidence of adverse reactions for diclofenac sodium delayed-release tablets and diclofenac sodium extended-release tablets at comparable doses were similar.
The incidence of common adverse reactions (greater than 1%) is based upon controlled clinical trials in 1543 patients treated up to 13 weeks with diclofenac sodium delayed-release tablets. By far the most common adverse effects were gastrointestinal symptoms, most of them minor, occurring in about 20%, and leading to discontinuation in about 3%, of patients. Peptic ulcer or GI bleeding occurred in clinical trials in 0.6% (95% confidence interval: 0.2-1%) of approximately 1800 patients during their first 3 months of diclofenac treatment and in 1.6% (95% confidence interval: 0.8-2.4%) of approximately 800 patients followed for 1 year.
Gastrointestinal symptoms were followed in frequency by central nervous system side effects such as headache (7%) and dizziness (3%).
Meaningful (exceeding 3 times the Upper Limit of Normal) elevations of ALT (SGPT) or AST (SGOT) occurred at an overall rate of approximately 2% during the first 2 months of diclofenac sodium delayed-release treatment. Unlike aspirin-related elevations, which occur more frequently in patients with rheumatoid arthritis, these elevations were more frequently observed in patients with osteoarthritis (2.6%) than in patients with rheumatoid arthritis (0.7%). Marked elevations (exceeding 8 times the ULN) were seen in 1% of patients treated for 2-6 months (see WARNINGS, Hepatic Effects).
The Following Adverse Reactions Were Reported in Patients Treated With Diclofenac:
Incidence Greater Than 1% — Causal Relationship Probable:
(All derived from clinical trials.)
*Incidence, 3-9% (incidence of unmarked reactions is 1-3%).
Incidence Less Than 1% — Causal Relationship Probable:
(Adverse reactions reported only in worldwide marketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized.)
Incidence Less Than 1% — Causal Relationship Unknown:
(The following reactions have been reported in patients taking diclofenac under circumstances that do not permit a clear attribution of the reaction to diclofenac. These reactions are being included as alerting information to physicians. Adverse reactions reported only in worldwide marketing experience or in the literature, not seen in clinical trials, are considered rare and are italicized.)
Worldwide reports of overdosage with diclofenac cover 66 cases. In approximately one-half of these reports of overdosage, concomitant medications were also taken. The highest dose of diclofenac was 5.0 g in a 17-year-old male who suffered loss of consciousness, increased intracranial pressure, aspiration pneumonitis, and died 2 days after overdose. The next highest doses of diclofenac were 4.0 g and 3.75 g. The 24-year-old female who took 4.0 g and the 28- and 42-year-old females, each of whom took 3.75 g, did not develop any clinically significant signs or symptoms. However, there was a report of a 17-year-old female who experienced vomiting and drowsiness after an overdose of 2.37 g of diclofenac.
Animal LD50 values show a wide range of susceptibilities to acute overdosage, with primates being more resistant to acute toxicity than rodents (LD50 in mg/kg-rats, 55; dogs, 500; monkeys, 3200).
In case of acute overdosage, 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: see CLINICAL PHARMACOLOGY) remains unproven. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac.
Diclofenac may be administered as 50 mg diclofenac potassium immediate-release tablets, as 25, 50, and 75 mg diclofenac sodium delayed-release tablets, or as 100 mg diclofenac sodium extended-release tablets. Diclofenac potassium immediate-release tablets is the formulation indicated for management of acute pain and primary dysmenorrhea when prompt onset of pain relief is desired because of earlier absorption of diclofenac. For the same reason, diclofenac sodium extended-release tablets are not indicated for the management of acute painful conditions and should be used as chronic therapy in patients with osteoarthritis and rheumatoid arthritis.
The dosage of diclofenac should be individualized to the lowest effective dose to minimize adverse effects (see CLINICAL PHARMACOLOGY, Individualization of Dosage).
Osteoarthritis
The recommended dosage is 100-150 mg/day: Diclofenac potassium immediate-release tablets or diclofenac sodium delayed-release 50 mg bid or tid; or diclofenac sodium delayed-release 75 mg bid. The recommended dosage for chronic therapy with diclofenac sodium extended-release is 100 mg qd. Dosages of diclofenac sodium extended-release tablets of 200 mg daily are not recommended for patients with osteoarthritis. Dosages above 200 mg/day have not been studied in patients with osteoarthritis.
Rheumatoid Arthritis
The recommended dosage is 100-200 mg/day: Diclofenac potassium immediate-release tablets or diclofenac sodium delayed-release 50 mg tid or qid; or diclofenac sodium delayed-release 75 mg bid. The recommended dosage for chronic therapy with diclofenac sodium extended-release is 100 mg qd. In the rare patient where diclofenac sodium extended-release 100 mg/day is unsatisfactory, the dose may be increased to 100 mg bid if the benefits outweigh the clinical risks. Dosages above 225 mg/day are not recommended in patients with rheumatoid arthritis.
Ankylosing Spondylitis
The recommended dosage is 100-125 mg/day: Diclofenac sodium delayed-release 25 mg qid with an extra 25 mg dose at bedtime if necessary. Dosages above 125 mg/day have not been studied in patients with ankylosing spondylitis.
Analgesia and Primary Dysmenorrhea
The recommended starting dose of diclofenac potassium immediate-release tablets is 50 mg tid. With experience, physicians may find that in some patients an initial dose of 100 mg of diclofenac potassium immediate-release tablets, followed by 50 mg doses, will provide better relief. After the first day, when the maximum recommended dose may be 200 mg, the total daily dose should generally not exceed 150 mg.
Cataflam Tablets
50 mg: Light brown, round, biconvex (imprinted "CATAFLAM" on one side and "50" on the other side).
Voltaren Delayed-Release Tablets
25 mg: Yellow, biconvex, triangular-shaped (imprinted "VOLTAREN 25" on one side).
50 mg: Light brown, biconvex, triangular-shaped (imprinted "VOLTAREN 50" on one side).
75 mg: Light pink, biconvex, triangular-shaped (imprinted "VOLTAREN 75" on one side).
Voltaren-XR Extended-Release Tablets
100 mg: Light pink, coated, round, biconvex with beveled edges (imprinted "Voltaren-XR" on one side and "100" on the other side).
Storage
Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container.
Solaraze 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.
Solaraze also contains benzyl alcohol, hyaluronate sodium, polyethylene glycol monomethyl ether, and purified water.
1 g of Solaraze gel contains 30 mg of the active substance, diclofenac sodium.
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 diclofenac sodium gel 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 7 days, with 4 times daily applications.
After topical application of 2 g diclofenac sodium gel 3 times daily for 6 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·h/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 sodium delayed-release tablet produced an AUC of 1600 ng·h/ml. Therefore, the systemic bioavailability after topical application of diclofenac sodium gel is lower than after oral dosing.
Blood drawn at the end of treatment from 60 patients with AK lesions treated with diclofenac sodium gel in three adequate and well-controlled clinical trials were assayed for diclofenac levels. Each patient was administered 0.5 g of diclofenac sodium gel twice a day for up to 105 days. There were up to three 5 cm × 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 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 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 trials were conducted involving a total of 427 patients (213 treated with diclofenac sodium gel and 214 with 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 × 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 ingredient, pregnancy, allergies to aspirin or other nonsteriodal antiinflammatory 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 were not permitted. Patients were instructed to apply a small amount of diclofenac sodium gel (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 is indicated for the topical treatment of actinic keratoses (AK). Sun avoidance is indicated during therapy.
Diclofenac sodium gel is contraindicated in patients with a known hypersensitivity to diclofenac, benzyl alcohol, polyethylene glycol monomethyl ether 350 and/or hyaluronate sodium.
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.
General
Diclofenac sodium gel should be used with caution in patients with active gastrointestinal ulceration or bleeding and severe renal or hepatic impairments. Diclofenac sodium gel 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 diclofenac sodium gel is unknown.
Information for the Patient
In clinical studies, localized dermal side effects such as contact dermatitis, exfoliation, dry skin, and rash were found In patients treated with diclofenac sodium gel 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 diclofenac sodium gel 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 diclofenac sodium gel together with other dermal products, including cosmetics, sunscreens, and other topical medications on the area being treated have not been studied.
Carcinogenesis, Mutagenesis, and 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: Diclofenac sodium gel 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 diclofenac sodium 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 (diclofenac sodium gel 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 diclofenac sodium 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 diclofenac sodium gel per day (1 mg/kg diclofenac sodium).
Pregnancy, Teratogenic Effects, Pregnancy Category B
The safety of 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 diclofenac sodium 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 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. Diclofenac sodium gel should not be used by children.
Geriatric Use
Of the 211 subjects treated with diclofenac sodium gel 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.
Although the systemic absorption of diclofenac sodium gel is low, concomitant oral administration of other NSAIDs such as aspirin at anti-inflammatory/analgesic doses should be minimized.
Of the 423 patients evaluable for safety in adequate and well-controlled trials, 211 were treated with diclofenac sodium gel drug product and 212 were treated with vehicle gel. Eighty-seven percent (87%) of the diclofenac sodium gel 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 diclofenac sodium gel, 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 diclofenac sodium gel and vehicle treated groups. Of note, four reactions, contact dermatitis, rash, dry skin, and exfoliation (scaling) were significantly more prevalent in the diclofenac sodium gel group than in the vehicle treated patients.
Eighteen percent (18%) of diclofenac sodium gel-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 4A and TABLE 4B below presents the AEs reported at an incidence of >1% for patients treated with either diclofenac sodium gel or vehicle (60-and 90 day treatment groups) during the Phase 3 studies.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skin and appendages adverse events reported for diclofenac sodium gel 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 diclofenac sodium gel)
*Incidence greater than 1% marked with asterisk.
Due to the low systemic absorption of topically applied diclofenac sodium gel, overdosage is unlikely. There have been no reports of ingestion of diclofenac sodium gel. 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.
Diclofenac sodium 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 diclofenac sodium gel is applied to adequately cover each lesion. Normally 0.5 g of gel is used on each 5 cm× 5 cm lesion site. The recommended duration of therapy is from 60-90 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 gel is available in tubes of 25 and 50 g. Each gram of gel contains 30 mg of diclofenac sodium.
Storage: Store at controlled room temperatures: 15-30°C (59-86°F) Protect from heat. Avoid freezing.