Diclofenac Potassium (Page 6 of 8)

10 OVERDOSAGE

Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and, coma have occurred, but were rare [see Warnings and Precautions ( 5.1, 5.2, 5.4, 5.6)] .
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1-800-222-1222).
Anaphylactic reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

11 DESCRIPTION

Diclofenac potassium for oral solution is a nonsteroidal anti-inflammatory drug, available as a buffered soluble powder, designed to be mixed with water prior to oral administration. Diclofenac potassium for oral solution is a white to off-white, buffered, flavored powder for oral solution packaged in individual unit dose packets.
The chemical name is potassium [o-(2,6-dichloroanilino) phenyl] acetate. The molecular mass is 334.24 g/mole. Its molecular formula is C 14 H 10 Cl 2 NKO 2 , and it has the following structure.

diclofenacosstructure

The inactive ingredients in diclofenac potassium for oral solution include: flavoring agent (peppermint), glyceryl behenate, mannitol, sucralose and tribasic sodium phosphate anhydrous.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Diclofenac potassium has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of diclofenac potassium, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics

Absorption
Diclofenac is 100% absorbed after oral administration compared to intravenous administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. In fasting volunteers, measurable plasma levels were observed within 5 minutes of dosing with diclofenac potassium. Peak plasma levels were achieved at approximately 0.25 hour in fasting normal volunteers, with a range of 0.17 to 0.67 hours. High fat food had no significant effect on the extent of diclofenac absorption, but there was a reduction in peak plasma levels of approximately 70% after a high fat meal. Decreased C max may be associated to decreased effectiveness.
Distribution
The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg.
Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15 to 105 mcg/mL) achieved with recommended doses.
Elimination
Metabolism
Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4’hydroxy-, 5-hydroxy-, 3’-hydroxy-, 4’,5-dihydroxy-and 3’-hydroxy-4’-methoxy diclofenac. The major diclofenac metabolite, 4’-hydroxydiclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy diclofenac is primarily mediated by CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3’-hydroxy-diclofenac. In patients with renal impairment, peak concentrations of metabolites 4’-hydroxyand 5-hydroxydiclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.
Excretion
Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.
Specific Populations
Race: There are no pharmacokinetic differences due to race.
Hepatic Impairment: The liver metabolizes almost 100% of diclofenac; there is insufficient information available to support dosing recommendations for diclofenac potassium in patients with hepatic insufficiency [see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.6)] .
Renal Impairment: In patients with renal impairment (inulin clearance 60 to 90, 30 to 60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions ( 5.6) and Use in Specific Populations ( 8.7)] .
Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions ( 7)] .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis , Mutagenesis ,Impairment Of Fertility

Carcinogenesis
Long term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (less than the recommended human dose [RHD] of 50 mg/day on a body surface area [mg/m 2 ] basis) 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/m 2 /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 (less than the RHD on a mg/m 2 basis) in males and 1 m/kg/day (less than the RHD on a mg/m 2 basis) in females did not reveal any oncogenic potential.
Mutagenesis
Diclofenac sodium was not genotoxic in in vitro (reverse mutation in bacteria [Ames], mouse lymphoma tk) or in in vivo (including dominant lethal and male germinal epithelial chromosomal aberration in Chinese hamster) assays.
Impairment of Fertility
Diclofenac sodium administered to male and female rats at 4 mg/kg/day (less than the RHD on a mg/m 2 basis) did not affect fertility.

14 CLINICAL STUDIES

The efficacy of diclofenac potassium in the acute treatment of migraine headache was demonstrated in two randomized, double-blind, placebo-controlled trials.
Patients enrolled in these two trials were predominantly female (85%) and white (86%), with a mean age of 40 years (range: 18 to 65). Patients were instructed to treat a migraine of moderate to severe pain with 1 dose of study medication. Patients evaluated their headache pain 2 hours later. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated. In addition, the proportion of patients who were “sustained pain free”, defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours post-dose without a return of mild, moderate, or severe pain and no use of rescue medication for 24 hours post-dose, was also evaluated. In these studies, the percentage of patients achieving pain freedom 2 hours after treatment and sustained pain freedom from 2 to 24 hours post-dose was significantly greater in patients who received diclofenac potassium compared with those who received placebo (see Table 3). The percentage of patients achieving pain relief 2 hours after treatment (defined as a reduction in headache severity from moderate or severe pain to mild or no pain) was also significantly greater in patients who received diclofenac potassium compared with those who received placebo (see Table 3). Table 3: Percentage of Patients with 2-Hour Pain Freedom, Sustained Pain Freedom 2 to 24 Hours, and 2-Hour Pain Relief Following Treatment

Study 1 Diclofenac potassium for oral solution (n=265) Placebo (n=257)
2-Hour Pain Free 24% 13%
2-24h Sustained Pain Free 22% 10%
2-Hour Pain Relief 48% 27%
Study 2 Diclofenac potassium for oral solution (n=343) Placebo (n=347)
2-Hour Pain Free 25% 10%
2-24h Sustained Pain Free 19% 7%
2-Hour Pain Relief 65% 41%

The estimated probability of achieving migraine headache pain freedom within 2 hours following treatment with diclofenac potassium is shown in Figure 1. Figure 1: Percentage of Patients with Initial Headache Pain Freedom within 2 Hours

diclofenacossfig1
(click image for full-size original)

There was a decreased incidence of nausea, photophobia and phonophobia following administration of diclofenac potassium, compared to placebo. The efficacy and safety of diclofenac potassium was unaffected by age or gender of the patient.

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