Source: Health Products and Food Branch (CA) Revision Year: 2022
Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) of the arylacanoic acid group, with analgesic and anti-inflammatory properties. The mode of action of diclofenac sodium is not fully known, but it is considered to be primarily through its inhibitory effects on prostaglandin synthesis by interfering with the action of prostaglandin synthetase/cyclo-oxygenase, isoforms 1 and 2 (COX-1 and COX-2). It does not act through the pituitary-adrenal axis.
Diclofenac sodium is an NSAID with analgesic and antipyretic properties. Diclofenac inhibits prostaglandin synthesis by interfering with the action of prostaglandin synthetase/ COX-1 and COX-2. This inhibitory effect may partially explain its actions. Diclofenac sodium demonstrated excellent analgesic potential when compared to other NSAIDs. The analgesic potential of the most active metabolite of diclofenac sodium was about 50 times less than the potential of the diclofenac sodium itself.
Although diclofenac sodium does not alter the course of the underlying disease, it has been found to relieve pain, reduce fever, swelling and tenderness, and increase mobility in patients with various rheumatic disorders.
Oral administration: Orally administered diclofenac sodium is rapidly and almost completely absorbed and distributed through the blood to all organs. The plasma concentration shows a linear relationship to the administered dose. After administration of 50 mg of enteric-coated diclofenac sodium, on an empty stomach, the mean peak plasma concentration (CMAX) was reported as approximately 1,500 ng/mL after about 2 h. No accumulation occurs, provided the recommended dosage intervals are observed.
Following a single topical application of PENNSAID (1.0 mL) to a single knee, the mean peak plasma diclofenac sodium concentration (CMAX) in six volunteers was 9.7 ± 4.7 ng/mL after 24 to 48 h (TMAX). The mean total urinary recovery of diclofenac sodium was 3.68%.
Following multiple doses of PENNSAID, 40 drops (one knee) or 80 drops (two knees, four times a day for 84 days, to 20 patients, the mean plasma diclofenac sodium level was 8.95 ± 9.17 ng/mL.
Two additional PK studies had been performed. In an open-label, single-dose pharmacokinetic study, a total of 80 drops of PENNSAID were applied on both knees (40 drops per knee). After a single administration of PENNSAID a maximum diclofenac concentration in plasma of 8.05 ng/mL was reached in about 10 h, and diclofenac remained measurable up to 72 h post-dose in 18 subjects. Mean elimination half-life was 37h (13 subjects).
In an open-label, multiple dose pharmacokinetic study, a total of 80 drops of PENNSAID (40 drops per knee), were applied on both knees over 7 days with the final dose on the morning of Day 8. Additionally, pre-dose samples were collected on Days 6, 7 and 8. Diclofenac reached plasma concentration levels at or near steady state on Day 6. After the last dose of PENNSAID on Day 8, mean plasma Cmax value of diclofenac was 19.4 ng/mL and mean Tmax was 4.0 hrs. The apparent terminal half-life (t½) was 79.0 h.
Diclofenac sodium is extensively bound (99%) to serum albumin. The apparent volume of distribution is 0.12 to 0.17 L/kg.
Diclofenac sodium, regardless of the route of application, once systemically absorbed, undergoes single and multiple hydroxylation followed by o-methylation of the hydroxy metabolites, producing 3', 4', 5- hydroxy, 4'-5-hydroxy and 3'-hydroxy-4'-methoxy derivatives of diclofenac sodium. These phenolic metabolites are largely inactive and, along with the parent compound, are converted mostly to glucuronide conjugates.
Oral administration: Following oral administration, plasma clearance of diclofenac sodium is reported as 263 ± 56 mL/minute. The mean terminal drug half-life in plasma is 1.8 hours. About 60% of the drug and its metabolites are eliminated in the urine and the balance through biliary secretion into the feces. More than 90% of an oral dose is accounted for in elimination products, within 72 hours. About 1% of an oral dose is excreted unchanged in urine.
After topical administration of PENNSAID, the mean total urinary recovery of diclofenac sodium after 120 h was 3.68%. The peak urinary excretion rate was reached by 24 h and was maintained until 48- 72 h.
Following topical application, DMSO is absorbed and generally distributed throughout the body tissues and fluids. DMSO is detectable in serum after 5 minutes. The peak serum concentration occurs in 4-6 h. DMSO is metabolized by oxidation to dimethyl sulfone or by reduction to dimethyl sulfide. Dimethyl sulfoxide and dimethyl sulfone are excreted in the urine and feces. Dimethyl sulfide is a volatile gas that is eliminated through the breath and skin and is responsible for the garlic-like odour sometimes noticed by patients. Trace amounts persist in serum for more than 2 weeks after a single intra vesical instillation. No residual accumulation of DMSO has occurred in patients who have received treatment for protracted periods of time. Following multiple doses of PENNSAID, 40 drops (one knee) or 80 drops (two knees) q.i.d. for up to 84 days, the mean plasma diclofenac sodium level was 8.95 ± 9.17 ng/mL. The mean whole blood level of (DMSO) was 647.8 ± 659.3 ng/mL, in 18 patients, up to 6 h following the last application.
Two additional Pharmacokinetic studies have been performed. In an open-label, single-dose pharmacokinetic study, a total of 80 drops of PENNSAID were applied on both knees (40 drops per knee). After a single administration of PENNSAID, maximum DMSO concentration in plasma of 0.48 μg/mL was reached in about 8 h, and DMSO remained measurable up to 24 h post-dose in 18 subjects. Mean elimination half-life was 8.4 h (9 subjects).
In an open-label, multiple dose pharmacokinetic study, a total of 80 drops of PENNSAID (40 drops per knee), were applied on both knees over 7 days with the final dose on the morning of Day 8. DMSO reached plasma concentration levels at or near steady state on Day 6. Following the last dose of PENNSAID on Day 8, mean Cmax value of DMSO was 1.2 μg/mL and mean Tmax value was 3.8 h. The mean apparent terminal half-life (t½) was 43 hrs. Dimethyl sulfone (DMSO2) reached plasma concentration levels at or near steady state on Day 6. Following the last dose of PENNSAID on Day 8, Cmax values of DMSO2 were 18.0 μg/mL and mean Tmax value was 9.4 h.
No microbiological information is required for this drug product.
Diclofenac sodium:
| Species | Route of Administration | LD50 mg/kg |
| Mouse | p.o. | 389 |
| i.v. | 133 | |
| Rat | p.o. | 173 |
| i.v. | 106 | |
| Guinea pig | p.o. | 1110 |
| i.v. | 127 | |
| Rabbit | p.o. | 194 |
Symptoms included bradycardia and convulsions. The most frequent autopsy findings in animals that died were gastric irritation, perforation and their sequelae.
Dimethyl sulfoxide (DMSO):
The dermal LD50 of DMSO is approximately 40,000 mg/kg in mice and rats. The oral and intravenous LD50 values are >2,500 mg/kg in laboratory animals (mouse, rat, cat, dog and monkey).
There was no evidence of significant change in serum creatinine levels, and no histological changes, with DMSO treatment. There was no additional nephrotoxicity in rats with dichromate-induced renal failure that were given DMSO compared to those that were given only the dichromate.
Diclofenac sodium:
Diclofenac sodium given orally to male and female rats, in doses of 0.25, 1.0 and 2.0 mg/kg/day, from 59 weeks (high-dose groups) to 98 weeks (low- and intermediate-dose groups) resulted in high, doserelated mortality caused by severe ulceration of the gastrointestinal tract, with perforated ulcers leading to peritonitis and its sequelae. Hematological patterns showing neutrophilic leucocytosis and anemia were seen in the high- and intermediate-dose groups, particularly females at weeks 52 and 98. Females tended to develop enlarged adrenals and eventually experienced depressed glucose and elevated alkaline phosphatase levels. No increase in tumour incidence was observed in the drugtreated groups as compared to the control group.
Diclofenac sodium, given orally once daily to baboons (Papio spp.), at dose levels of 0, 5, 15 (reduced to 10 on day 254) and 50 (reduced to 30 on day 38) mg/kg/day, for up to 52 weeks, caused ulceration of the gastrointestinal tract, constipation and occasional diarrhea. In all groups receiving diclofenac, there was a dose-related fall in serum albumin level. In the recovery groups (controlled, low and intermediate), no intestinal lesions were present.
Dimethyl sulfoxide (DMSO):
Sixty percent (60 ) or 100 DMSO was applied dermally to the shaved back of dogs and monkeys at doses of 3,300 to 33,000 mg/kg/week for 6 months. Initially, the skin became transiently reddened and warm, particularly with 100% DMSO. With continued application, erythema, desquamation and focal skin lesions occurred at three weeks and lasted for the duration of treatment. No other changes were observed.
DMSO administered in large doses to dogs, rabbits and pigs (particularly by the oral route) caused changes in the refractive index of the lens, with progressive myopia in the nucleus and an increase in hyperopia in the lens cortex. Chemical analysis indicated a reduction of the usual concentrations of soluble protein, urea, glutathione, uric and amino acid in the lens of affected eyes. The most sensitive animal was the rabbit, where the no observed effect level (NOEL) was 500 mg/kg/day. The lenticular changes seen in pigs after 27 weeks of topical DMSO at 2.7-4.5 g/kg doses were reversible. Two months after cessation of treatment, lens alterations regressed. However, following 5 g/day oral DMSO to dogs, lesions persisted after 8 months. No change to the lens of monkeys was detected at oral doses up to 5 g/kg/day for 100 days. The doses required to produce ocular changes in animals are far in excess of those that have been used clinically in humans.
Careful examination of patients who had received treatment with DMSO, 30 gm/day for 3-19 months revealed no adverse effects on the eye. In another study, 84 patients treated with DMSO, (average dose of’18.5 mL of 90% DMSO; average duration of 2.5 months) were examined ophthalmoscopically; no toxicity to the eye was observed. These exposures are orders of magnitude higher than the recommended dosage of PENNSAID.
Daily oral administration to rats of 50% DMSO, 5.0 g/kg for 45 days, caused slight weight loss. Microscopic examination of the liver showed necrosis of the liver cells (degenerative modifications of the hepatocytes) with inflammation and irritation of the portal spaces. However, orally administered doses of 2.0 g/kg affected neither weight gain nor growth of the 5 weeks old young animal. Histopathological examination showed no abnormality. In a study by Smith et al. (1967) of rats receiving daily oral DMSO doses of 1.0, 3.0 and 10 g/kg for 59 consecutive days, no grossly adverse effects were observed.
Smith et al. (1967) observed the response of three dogs to repeated oral doses of 2.5-10 g/kg DMSO, for 14 to 35 days. Halitosis, vomiting and ocular changes were observed. One dog that died had liver degeneration and hemorrhagic gastroenteropathy.
Rhesus monkeys, receiving 2-3 g/kg of DMSO intravenously, once daily for nine days, showed no evidence of damage to the liver, kidneys or eyes. Feinman and co-workers administered DMSO orally to monkeys for five consecutive days, at doses up to 4.0 g/kg, and reported no markedly adverse effects.
Carcinogenicity of DMSO in animals has not been determined.
PENNSAID was examined in three mutagenicity studies.
In the Salmonella typhimurim reverse mutation assay (Ames test), no mutagenic effect was observed for PENNSAID tested up to 5000 μg/plate in any of the test strains in the two experiments with or without metabolic activation.
PENNSAID showed no clastogenic activity in human peripheral lymphocyte cultures at concentrations up to 5000 µg/mL, under either metabolic activation or non-activation conditions.
In the in vivo mouse micronucleus assay, PENNSAID-treated animals at the maximum tolerated dose of 12 mL/kg showed no significant increase in micronucleus frequency compared to negative control, whereas the known clastogenic agent cyclophosphamide induced large and statistically significant increases in micronucleus frequency.
Mutagenicity studies were carried out in vitro in bacteria and in mammalian cells, with and without microsomal activation. In vivo studies were also performed. Diclofenac sodium was not mutagenic in any of these test systems.
DMSO was studied with the Ames test and was found to be non-mutagenic.
Doses of 2 or 4 mg/kg/day were given orally to male and female rats with no noticeable effect on fertility. Dosing was carried out during pre-mating, mating, gestation and lactation periods. At the higher dose, prolonged gestation and dystocia were observed. Embryo toxicity (low birth weight, failure to survive) was observed at both doses, but it was minimal at 2 mg/kg/day. Post-natal survival and growth of pups from drug-treated females were comparable to those of controls, except for slightly retarded growth at the higher dose.
Teratology studies in mice and rats, at oral doses of 2, 3, 10, and 20 mg/kg/day, showed no teratogenic effects on fetuses. At the higher doses, pronounced gastrointestinal effects were observed in the dams and a marked toxic effect noted in fetuses (reduced birth weights and increased fetal death).
Pregnant rabbits, treated with an oral dose of 5 or 10 mg/animal/day throughout the gestation period, showed a dose-dependent increase in resorption rate, diminished fetus weight, and abnormal skeletal findings. Definite embryo toxicity was observed at the highest dose although there was no evidence to suggest teratogenicity.
Studies show that for induction of a teratogenic effect in mammals, very high doses (2,500-10,000mg/kg) of DMSO must be administered systemically, not topically.
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