CATAFENAC

Diclofenac potassium tablets, USP are a benzeneacetic acid derivative.

Diclofenac potassium tablets

USP, 50 mg are available as orange, film-coated tablets for oral administration.

The chemical name is 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monopotassium salt.

The structural formula is

C 14 H 10 Cl 2 KNO 2 M.W. 334.24 g/mol Diclofenac potassium, USP is a faintly yellowish white to light beige, virtually odorless, slightly hygroscopic crystalline powder.

It is freely soluble in methanol, soluble in ethanol and water, and practically insoluble in chloroform and in dilute acid.

The n-octanol/water partition coefficient is 13.4 at pH 7.4 and at pH 5.2.

It has a single dissociation constant (pKa) of 4.0 ± 0.2 at 25°C in water.

Each tablet, for oral administration, contains 50 mg of diclofenac potassium.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, FD&C Blue No.

Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 4000, povidone, sodium starch glycolate, titanium dioxide, and tricalcium phosphate.

Carefully consider the potential benefits and risks of diclofenac potassium tablets and other treatment options before deciding to use diclofenac potassium tablets.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals See WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation.

Diclofenac potassium tablets are indicated: for treatment of primary dysmenorrhea for relief of mild to moderate pain for relief of the signs and symptoms of osteoarthritis for relief of the signs and symptoms of rheumatoid arthritis.

Lactation Asthma Female likely to be pregnant Pregnancy, first 5 months (of) Digestive haemorrhage, history Heart failure Hepatic impairment Renal impairment Inflammatory bowel disease, history (de) Newborn exposed in utero to the medicine Patients treated by extended application Elderly Allergic field Extended treatment Gastroduodenal ulcer, history (d).

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of diclofenac potassium tablets, 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.

Diclofenac is 100% absorbed after oral administration compared to intravenous (IV) administration as measured by urine recovery.

However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available.

In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with diclofenac potassium tablets.

Peak plasma levels are achieved approximately 1 hour in fasting normal volunteers, with a range of 0.33 to 2 hours.

Food has no significant effect on the extent of diclofenac absorption.

However, there is usually a delay in the onset of absorption and a reduction in peak plasma levels of approximately 30%.

Table 1.

Pharmacokinetic Parameters for Diclofenac PK Parameter Normal Healthy Adults (20 to 52 years) Mean Coefficient of Variation (%) Absolute bioavailability (%) [N = 7] 55 40 T max (hr) [N = 65] 1.0 76 Oral clearance (CL/F; mL/min) [N = 61] 622 21 Renal clearance (% unchanged drug in urine) [N = 7] < 1 — Apparent volume of distribution (V/F; L/kg) [N = 61] 1.3 33 Terminal half-life (hr) [N = 48] 1.9 29 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.

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.

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'-hydroxy-diclofenac, has very weak pharmacologic activity.

The formation of 4’-hydroxy-diclofenac is primarily mediated by CYP2C9.

Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion.

Acyl glucuronidation mediated by

UGT2B7 and oxidation mediated by CYP2C8 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 dysfunction, peak concentrations of metabolites 4'-hydroxy.

• and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

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.

The pharmacokinetics of diclofenac has not been investigated in pediatric patients.

Pharmacokinetic differences due to race have not been identified.

Hepatic metabolism accounts for almost 100% of diclofenac elimination, so patients with hepatic disease may require reduced doses of diclofenac potassium tablets compared to patients with normal hepatic function.

Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency.

No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment.

In patients with renal impairment (inulin clearance to 90, 30 to 60, and less than 30 mL/min; N = 6 in each group), area under the curve (AUC) values and elimination rate were comparable to those in healthy subjects.

When coadministered with voriconazole (inhibitor of CYP2C9, 2C19, and 3A4 enzyme), the C max and AUC of diclofenac increased by 114% and 78%, respectively.

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 for clinically significant drug interactions of NSAIDs with aspirin.

Mechanism of action

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) derived from phenylacetic acid in the arylcarboxylic acid group.

It has the following properties: analgesic, antipyretic, anti-inflammatory activity and short-term inhibition of platelet function.

All of these properties are related to inhibition of prostaglandin synthesis.

• Pruritus (Common)
• Skin Erythema (Common)
• Eczema (Common)
• Dermatitis (Common)
• Desquamation at the application site (Uncommon)
• Rash (Common)
• Dry skin (Uncommon)
• Pustulous eruption (Very rare)
• Purpura (Very rare)
• Skin ulcer (Very rare)
• Photosensitivity (Very rare)
• Bully dermatosis (Rare)
• Urticaria
• Contact dermatitis Burning sensation at the application site Ulceration at the application site (Very rare)
• Systemic effects Hypersensitivity (Very rare)
• Angioedema (Very rare)
• Digestive disorder
• Asthma crisis (Very rare)
• Renal disorder.

Symptoms following acute

NSAID overdosages 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; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia.

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 in patients with a large overdose (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.

Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.

Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

The relative increase in serious

CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.

Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.

The increase in

CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms.

Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events See WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation.

Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

NSAIDs are contraindicated in the setting of CABG See CONTRAINDICATIONS.

Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment.

In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.

Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up.

Avoid the use of diclofenac in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If diclofenac is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal.

These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic.

GI ulcers, gross bleeding or perforation caused by NSAIDs occurred in approximately 1% of patients treated for to 6 months, and in about 2% to 4% of patients treated for one year.

However, even short-term therapy is not without risk.

Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors.

Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status.

Most postmarketing reports of fatal

GI events occurred in elderly or debilitated patients.

Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients Use the lowest effective dosage for the shortest possible duration.

Avoid administration of more than one

NSAID at a time.

Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding.

For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.

Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

If a serious

GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac until a serious GI adverse event is ruled out.

In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.

In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the upper limit of normal [ULN]) of aspartate aminotransferase (AST) (also known as SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (alanine aminotransferase [ALT] was not measured in all studies).

In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks.

Meaningful elevations of

ALT and/or AST occurred in about 4% of patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients.

In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs.

Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic.

Abnormal tests occurred during the first 2 months of therapy with diclofenac in of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac.

Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure.

Some of these reported cases resulted in fatalities or liver transplantation.

In a

European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury.

In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and 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.

Based on clinical trial data and postmarketing experiences, transaminases should be monitored within to 8 weeks after initiating treatment with diclofenac.

However, severe hepatic reactions can occur at any time during treatment with diclofenac.

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, abdominal pain, diarrhea, dark urine, etc)., diclofenac should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms).

If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc)., discontinue diclofenac immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac, use the lowest effective dose for the shortest duration possible.

Exercise caution when prescribing diclofenac with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).

NSAIDs, including diclofenac potassium tablets, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events.

Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately 2-fold increase in hospitalization for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.

Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs.

Use of diclofenac may blunt the

CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) .

Avoid the use of diclofenac in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

If diclofenac is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.

In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly.

Discontinuation of

NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of diclofenac in patients with advanced renal disease.

The renal effects of diclofenac may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients.

Diclofenac is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product See WARNINGS; Anaphylactic Reactions, Serious Skin Reactions.

History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.

Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients See WARNINGS; Anaphylactic Reactions, Exacerbation of Asthma Related to Aspirin Sensitivity.

In the setting of coronary artery bypass graft (CABG) surgery.

Carefully consider the potential benefits and risks of diclofenac potassium immediate-release tablets and other treatment options before deciding to use diclofenac potassium tablets.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals See WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation.

After observing the response to initial therapy with diclofenac potassium tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.

For treatment of pain or primary dysmenorrhea the recommended dosage is 50 mg three times a day. With experience, physicians may find that in some patients an initial dose of 100 mg of diclofenac potassium tablets, followed by 50-mg doses, will provide better relief.

For the relief of osteoarthritis the recommended dosage is to 150 mg/day in divided doses, 50 mg twice a day or three times a day. For the relief of rheumatoid arthritis the recommended dosage is to 200 mg/day in divided doses, 50 mg three times a day or four times a day. Different formulations of diclofenac [VOLTAREN ® (diclofenac sodium enteric-coated tablets); Voltaren ® -XR (diclofenac sodium extended-release tablets); diclofenac potassium tablets] are not necessarily bioequivalent even if the milligram strength is the same.

Diclofenac potassium tablets

USP, 50 mg are available as orange, round, biconvex, film-coated tablets debossed with the numbers “93” and “948” on one face of the tablet and plain on the other.

Bottles of 21 (NDC 43063-848-21) Bottles of 30 (NDC 43063-848-30) Store at 20° to 25°C (68° to 77°F) .

Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

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