DICLOFENAC SODIUM- diclofenac sodium tablet, delayed release
DICLOFENAC SODIUM- diclofenac sodium tablet
Boehringer Ingelheim Roxane Laboratories
Diclofenac sodium, is a benzene-acetic acid derivative, designated chemically as 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt. The structural formula is:
C14 H10 Cl2 NNaO2 M.W. 318.14
Diclofenac sodium is a faintly yellowish white to light beige, virtually odorless, slightly hygroscopic crystalline powder. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in water and practically insoluble in chloroform and in dilute acid. The n-octanol/water partition coefficient is 13.4 at pH 7.4 and 1545 at pH 5.2. Diclofenac sodium has a dissociation constant (pKa) of 4.0 ± 0.2 at 25°C in water.
Each enteric-coated tablet, for oral administration, contains 25 mg, 50 mg, or 75 mg of diclofenac sodium. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, enteric-coating (black iron oxide, FD&C Blue No. 2, FD&C Red No. 40, FD&C Yellow No. 6, methacrylic acid copolymer, methylparaben, n-butyl alcohol, polysorbate 80, potassium sorbate, propylene glycol, propylparaben, sodium citrate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate, and xanthan gum), lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and stearic acid.
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.
Diclofenac sodium delayed-release tablets are in a pharmaceutic formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH-environment in the duodenum. Its pattern of drug release and absorption is illustrated below:
± 1 SD plasma diclofenac concentrations after a single dose of a 50 mg diclofenac sodium delayed-release tablet (N=38)
When diclofenac sodium delayed-release tablets are administered orally after fasting, diclofenac is completely absorbed from the gastrointestinal tract. Of this, only 50% of the absorbed dose of diclofenac from diclofenac sodium is systemically available, due to first-pass metabolism. Peak plasma levels are achieved in 2 hours in fasting normal volunteers, with a range from 1 to 4 hours. The area-under-the plasma-concentration curve (AUC) is dose-proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.0, 1.5, and 2 µg/mL for 25 mg, 50 mg and 75 mg doses, respectively. It should be noted that the administration of several individual diclofenac sodium 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 50 mg b.i.d., diclofenac did not accumulate in plasma.
When diclofenac sodium is taken with food, there is usually a delay in the onset of absorption of 1 to 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.
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.
A 4-week study, comparing plasma level profiles of diclofenac (diclofenac sodium 50 mg b.i.d.) in younger (26 to 46 years) versus older (66 to 81 years) adults, did not show differences between age groups (10 patients per age group).
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.
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 to 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 to 30% of the dose excreted in the urine and for 10 to 20% of the dose excreted in the bile. Conjugates of three other metabolites together account for 10 to 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.
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 to 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.
Diclofenac sodium 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 was given both in variable (100 to 150 mg/day) and fixed (150 mg/day) dosing schedules on either b.i.d. or t.i.d. dosing regimens. In these trials, diclofenac sodium was found to be comparable to 2400 to 3600 mg/day of aspirin or 500 mg/day of naproxen. Diclofenac was effective when administered as either b.i.d. or t.i.d. dosing regimens.
Diclofenac sodium 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 was given in a fixed (150 or 200 mg/day) dosing schedule as either b.i.d. or t.i.d. dosing regimens. Diclofenac sodium was found to be comparable to 3600 to 4800 mg/day of aspirin, and 2400 mg/day of ibuprofen. Diclofenac sodium was used b.i.d. or t.i.d., administering 150 mg/day in most trials, but 50 mg q.i.d. (200 mg/day) was also studied.
Diclofenac sodium 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 and indomethacin patients were started on 25 mg t.i.d. and were permitted to increase the dose 25 mg per day each week to a maximum dose of 125 mg/day. Diclofenac sodium 75 to 125 mg/day was found to be comparable to indomethacin 75 to 125 mg/day.
G.I. 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 endosopic lesions are primarily seen. A repeat-dose endoscopy study, in patients with rheumatoid arthritis or osteoarthritis treated with diclofenac sodium delayed-release tablets 75 mg b.i.d. (N=101), or naproxen (immediate-release tablets) 500 mg b.i.d. (N=103) for three 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 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 of less than that observed with 3 g of aspirin daily (N=8). In four repeat-dose studies, mean fecal blood loss with 150 mg of diclofenac was also less than that observed with 750 mg of naproxen (N=8 and 6) or 150 mg of indomethacin (N=8 and 6). The clinical significance of these findings is unknown since there is no evidence available to indicate that diclofenac sodium is less likely than other drugs of its class to cause serious gastrointestinal lesions when used in chronic therapy.
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 lbs), 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 maximal 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).
The usual starting dose of diclofenac sodium delayed-release tablets for patients with osteoarthritis, is 100 to 150 mg/day, using a b.i.d. or t.i.d. dosing regimen. In two variable-dose clinical trials in osteoarthritis, of 266 patients started on 100 mg/day, 176 chose to increase the dose to 150 mg/day. Dosages above 150 mg/day have not been studied in patients with osteoarthritis.
The usual starting dose of diclofenac sodium for most patients with rheumatoid arthritis is 150 mg/day, using a b.i.d. or t.i.d. dosing regimen. 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 form the trial due to lack of efficacy than patients receiving 150 mg/day. 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 to 125 mg/day, using a q.i.d. dosing regimen (see DOSAGE AND ADMINISTRATION regarding the 125 mg/day dosage 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.
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