T2000-19
`89008901
`
`Cataflam®
`diclofenac potassium
`Immediate-Release Tablets
`
`Voltaren®
`diclofenac sodium
`Delayed-Release (enteric-coated) Tablets
`
`Voltaren®-XR
`diclofenac sodium
`Extended-Release Tablets
`
`Rx only
`
`Prescribing Information
`
`DESCRIPTION
`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. The structural formula is shown in Figure 1.
`
`R = K: Cataflam®, diclofenac potassium
`R = Na: Voltaren® or Voltaren®-XR, diclofenac sodium
`
`Figure 1
`
`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.
`
`LUPIN EX. 1006
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
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`

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`Page 2
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`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 is available as VOLTAREN Delayed-Release (enteric-coated)
`Tablets of 25 mg, 50 mg, 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.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacodynamics
`Diclofenac, the anion in Cataflam, Voltaren, and Voltaren-XR, 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
`Cataflam Immediate-Release Tablets, Voltaren Delayed-Release Tablets, and Voltaren-XR
`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.
`Cataflam Immediate-Release Tablets are formulated to release diclofenac in the stomach.
`Voltaren 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, Voltaren-XR 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.
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`Table 1
`Mean (% CV) Pharmacokinetics of Diclofenac Following
`Single Oral Doses of CATAFLAM, VOLTAREN Delayed-Release,
`and VOLTAREN-XR
`
`Drug
`
`Cataflam
`
`Voltaren
`
`Voltaren-XR
`
`
`Dose
`(mg)
`
` 50
`
` 50
`
`100
`
`AUC
`(ng•hr/mL)
`
`Cmax
`(ng/mL)
`
` Tmax
`(hr)
`
`1309
`(21.7%)
`
`1429
`(38.4%)
`
`2079
`(33.7%)
`
`1312
`(44.1%)
`
`1417
`(22.4%)
`
`417
`(40.7%)
`
`1.00
`(74.6%)
`
`2.22
`(49.8%)
`
`5.25
`(28.3%)
`
`For this reason, separate sections are provided below to describe the different
`absorption profiles of Cataflam Immediate-Release Tablets, Voltaren Delayed-Release Tablets,
`and Voltaren-XR 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.
`Cataflam Immediate-Release Tablets: In some fasting volunteers, measurable plasma levels
`are observed within 10 minutes of dosing with Cataflam. Peak plasma levels are achieved in
`approximately 1 hour in fasting normal volunteers, with a range from 0.33 to 2 hours.
`The extent of diclofenac absorption is not significantly affected when Cataflam 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
`Cataflam 50 mg t.i.d. no accumulation of diclofenac in plasma occurred.
`Voltaren Delayed-Release Tablets: 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 2.0 µg/mL for 25-mg, 50-mg,
`and 75-mg doses, respectively. It should be noted that the administration of several individual
`Voltaren 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 Voltaren 50 mg b.i.d., diclofenac did
`not accumulate in plasma.
`When Voltaren 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
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`plasma levels of approximately 40%. The extent of absorption of diclofenac, however, is not
`significantly affected by food intake.
`Voltaren-XR 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 to 2 hours in Tmax
`and a two-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 (Voltaren 50 mg b.i.d.) 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
`Voltaren-XR q.d.) 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.
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`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 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.
`
`Clinical Studies
`Cataflam Immediate-Release Tablets in Analgesia/Primary Dysmenorrhea: The analgesic
`efficacy of Cataflam 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 Cataflam 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-mg 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-mg or 100-mg dose was essentially the same,
`whether patients had moderate or severe pain at baseline.
`Cataflam 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), Cataflam 50 mg t.i.d. was comparable in efficacy to ibuprofen 800 mg t.i.d. and
`Voltaren Delayed-Release Tablets 50 mg t.i.d.
`Voltaren Delayed-Release Tablets in Osteoarthritis: Voltaren 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). Voltaren was given both in variable (100-150 mg/day)
`and fixed (150 mg/day) dosing schedules in either b.i.d. or t.i.d. dosing regimens. In these
`trials, Voltaren was found to be comparable to 2400 to 3600 mg/day of aspirin or 500 mg/day
`of naproxen. Voltaren was effective when administered as either b.i.d. or t.i.d. dosing
`regimens.
`Voltaren Delayed-Release Tablets in Rheumatoid Arthritis: Voltaren 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). Voltaren was given in a fixed (150 or 200 mg/day) dosing schedule as either
`b.i.d. or t.i.d. dosing regimens. Voltaren was found to be comparable to 3600 to 4800 mg/day
`of aspirin, and 2400 mg/day of ibuprofen. Voltaren 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.
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`Voltaren Delayed-Release Tablets in Ankylosing Spondylitis: Voltaren 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 Voltaren and
`indomethacin patients were started on 25 mg t.i.d. and were permitted to increase the dose
`25 mg/day each week to a maximum dose of 125 mg/day. Voltaren 75-125 mg/day was found
`to be comparable to indomethacin 75-125 mg/day.
`Voltaren-XR Extended-Release Tablets in Osteoarthritis: The use of Voltaren-XR 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, Voltaren-XR Tablets at doses of 100 mg q.d.
`were comparable to Voltaren Delayed-Release Tablets 50 mg b.i.d. in patients whose
`osteoarthritis symptoms were stabilized after 2 weeks of treatment with Voltaren Delayed-
`Release Tablets 75 mg b.i.d. In another study, Voltaren-XR Tablets at doses of 100 mg q.d.
`and 100 mg b.i.d. were compared to Voltaren Delayed-Release Tablets 50 mg q.i.d. Voltaren-
`XR Tablets 100 mg b.i.d. were comparable to Voltaren Delayed-Release Tablets 50 mg q.i.d.
`With the Voltaren-XR Tablet 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 Voltaren-XR Tablets were administered to patients with osteoarthritis.
`Voltaren-XR Extended-Release Tablets in Rheumatoid Arthritis: The use of Voltaren-XR
`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, Voltaren-XR Tablets 100 mg q.d.
`were comparable to Voltaren Delayed-Release Tablets 50 mg b.i.d. in patients whose
`rheumatoid arthritis symptoms were stabilized after 2 weeks’ treatment of Voltaren Delayed-
`Release Tablets 75 mg b.i.d. In another study, Voltaren-XR Tablets at doses of 100 mg q.d.
`and 100 mg b.i.d. were compared to Voltaren Delayed-Release Tablets 50 mg q.i.d.; Voltaren-
`XR Tablets 100 mg b.i.d. were comparable to Voltaren Delayed-Release Tablets 50 mg q.i.d.
`There was a trend toward greater efficacy with doses of 200 mg daily as compared to 100 mg
`daily of Voltaren-XR Tablets. There was also an increase in side effects when 200 mg of
`Voltaren-XR Tablets were administered to patients with rheumatoid arthritis.
`Special Studies (The clinical significance of the findings outlined below is unknown.)
`G.I. Blood Loss/Endoscopy Data: G.I. blood loss and endoscopy studies were performed
`with Voltaren Delayed-Release (enteric-coated) Tablets that, unlike Immediate-Release
`Tablets, do not dissolve in the stomach where the endoscopic lesions are primarily seen;
`Cataflam Immediate-Release Tablets have not been similarly studied. A repeat-dose endoscopy
`study, in patients with rheumatoid arthritis or osteoarthritis treated with Voltaren Delayed-
`Release Tablets 75 mg b.i.d. (N=101), or naproxen (immediate-release tablets) 500 mg b.i.d.
`(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 Voltaren-treated patients. Two repeat-dose endoscopic studies, in normal volunteers
`showed that daily doses of Voltaren 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 Voltaren (N=8) for 3 weeks
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`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 Voltaren 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).
`
`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 Cataflam, Voltaren, or Voltaren-XR 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
`Cataflam Immediate-Release Tablets or Voltaren Delayed-Release
`for patients with
`osteoarthritis, is 100 to 150 mg/day, using a b.i.d. or t.i.d. dosing regimen. For patients with
`osteoarthritis, the usual starting dose of Voltaren-XR Extended-Release Tablets is 100 mg q.d.
`In two variable-dose clinical trials in osteoarthritis using Voltaren 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 Cataflam
`Immediate-Release Tablets or Voltaren Delayed-Release Tablets is 150 mg/day, using a b.i.d.
`or t.i.d. dosing regimen. The usual starting dose of Voltaren-XR Extended-Release Tablets is
`100 mg q.d. 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 Voltaren Delayed-Release
`Tablets or 100 mg/day as Voltaren-XR 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 Voltaren 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 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
`Cataflam 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 Cataflam dose of 50 mg for pain or for primary dysmenorrhea, followed
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`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 Cataflam, 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.
`
`INDICATIONS AND USAGE
`Cataflam Immediate-Release Tablets and Voltaren Delayed-Release Tablets are indicated for
`the acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid
`arthritis. Voltaren-XR Extended-Release Tablets are indicated for chronic therapy of
`osteoarthritis and rheumatoid arthritis. In addition, Cataflam Immediate-Release Tablets and
`Voltaren Delayed-Release Tablets are indicated for the treatment of ankylosing spondylitis.
`Only Cataflam 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).
`
`CONTRAINDICATIONS
`Diclofenac in all formulations, Cataflam, Voltaren, and Voltaren-XR, 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–Preexisting Asthma).
`
`WARNINGS
`
`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 G.I. 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 G.I. 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 G.I. tract symptoms.
`In patients observed in clinical trials of several months to 2 years’ duration, symptomatic upper
`G.I. 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 G.I. toxicity and what steps to take if they
`occur.
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`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 G.I. 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 G.I. 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 G.I. 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 Voltaren 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 U.S. 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 two months of therapy. Based on these experiences,
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`transaminases should be monitored within 4 to 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–Preexisting 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–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 Labor and Delivery).
`
`PRECAUTIONS
`
`General
`Cataflam Immediate-Release Tablets, Voltaren Delayed-Release Tablets, and Voltaren-XR
`Extended-Release Tablets 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.
`
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`Hematologic Effects: Anemia is sometimes seen in patients receiving diclofenac or other
`NSAIDs. This may be due to fluid retention, G.I. 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.
`Preexisting 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 nons