Diclofenac Sodium

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Diclofenac Sodium Prescribing Information

Cardiovascular Thrombotic Events

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
).
Diclofenac sodium extended-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see
CONTRAINDICATIONS
Diclofenac sodium extended-release tablets are 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, PRECAUTIONS; Exacerbation of Asthma Related to Aspirin Sensitivity).
In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular Thrombotic Events).
,

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
).

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
).

Carefully consider the potential benefits and risks of diclofenac sodium extended-release tablets and other treatment options before deciding to use diclofenac sodium extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see

Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).

;

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including diclofenac, can 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. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term therapy is not without risk.

Risk Factors for GI 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 dose 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 sodium extended-release tablets 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 (see PRECAUTIONS; Drug Interactions).

Diclofenac sodium extended-release tablets are indicated:

for relief of the signs and symptoms of osteoarthritis
for relief of the signs and symptoms of rheumatoid arthritis

Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus

Oligohydramnios/Neonatal Renal Impairment

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

For the relief of osteoarthritis, the recommended dosage is 100-mg daily.

For the relief of rheumatoid arthritis, the recommended dosage is 100-mg daily. In the rare patient where diclofenac sodium extended release tablets 100 mg/day is unsatisfactory, the dose may be increased to 100 mg twice a day, if the benefits outweigh the clinical risks of increased side effects.

Different formulations of diclofenac [VOLTAREN
^®(diclofenac sodium enteric-coated tablets); diclofenac sodium extended-release tablets; CATAFLAM
^®(diclofenac potassium immediate-release tablets)] are not necessarily bioequivalent even if the milligram strength is the same.

Diclofenac sodium extended-release tablets are 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

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
;

Anaphylactic Reactions
Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS, WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity).
,

Serious Skin Reactions
NSAIDs, including diclofenac, can cause serious skin adverse events, such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of diclofenac sodium extended-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium extended-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS).
).
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

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
;

Anaphylactic Reactions
Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS, WARNINGS; Exacerbation of Asthma Related to Aspirin Sensitivity).
,

Pregnancy
Risk Summary
Use of NSAIDs, including diclofenac sodium extended-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium extended-release tablets use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium extended-release tablets use at about 30 weeks of gestation and later in pregnancy (see WARNINGS; Fetal Toxicity).
Premature Closure of Fetal Ductus Arteriosus
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
There are no adequate and well-controlled studies of diclofenac sodium extended-release tablets in pregnant women.
Data from observational studies regarding potential embryo-fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.
In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac daily during the period of organogenesis at doses up to approximately 0.5, 0.5, and 1 times, respectively, the maximum recommended human dose (MRHD) of diclofenac sodium extended-release tablets, despite the presence of maternal and fetal toxicity at these doses (see Data).
Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Premature Closure of Fetal Ductus Arteriosus:
Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium extended-release tablets, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity).
Oligohydramnios/Neonatal Renal Impairment:
If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium extended-release tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium extended-release tablets and follow up according to clinical practice (see WARNINGS; Fetal Toxicity).
; Exacerbation of Asthma Related to Aspirin Sensitivity).
In the setting of coronary artery bypass graft (CABG) surgery (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
;

Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 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).
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 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 four years of follow-up.
Avoid the use of diclofenac sodium extended-release tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium extended-release tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
).

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Cardiovascular Thrombotic Events (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
GI Bleeding, Ulceration and Perforation (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
Hepatotoxicity (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
Hypertension (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
Heart Failure and Edema (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
Renal Toxicity and Hyperkalemia (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
Anaphylactic Reactions (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
Serious Skin Reactions (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)
Hematologic Toxicity (see

Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including diclofenac sodium extended-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium extended-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac sodium extended-release tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures, such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium extended-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium extended-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium extended-release tablets if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).
)

See Table 2 for clinically significant drug interactions with diclofenac.

Drugs That Interfere with Hemostasis

Clinical Impact:

Diclofenac and anticoagulants, such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Intervention:

Monitor patients with concomitant use of diclofenac sodium extended-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (ses

Hepatotoxicity

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 5700 patients at some time during diclofenac treatment (ALT [alanine aminotransferase] was not measured in all studies).

In a large, open-label, controlled trial of 3700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1200 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 3700 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 42 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 4 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 sodium extended-release tablets 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 sodium extended-release tablets 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 sodium extended-release tablets, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium extended-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).

Aspirin

Clinical Impact:

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see

Gastrointestinal Bleeding, Ulceration, and Perforation

Risk Factors for GI Bleeding, Ulceration, and Perforation

Strategies to Minimize the GI Risks in NSAID-treated patients

Use the lowest effective dose 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 sodium extended-release tablets 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 (see PRECAUTIONS; Drug Interactions).

Intervention:

Concomitant use of diclofenac sodium extended-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see

Hepatotoxicity

Diclofenac sodium extended-release tablets are not a substitute for low dose aspirin for cardiovascular protection.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers

Clinical Impact:

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

Intervention:

During concomitant use of Diclofenac sodium extended-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of Diclofenac sodium extended-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function

(see

Renal Toxicity and Hyperkalemia
Renal Toxicity
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 sodium extended-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium extended-release tablets may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium extended-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium extended-release tablets (see PRECAUTIONS; Drug Interactions).Avoid the use of diclofenac sodium extended-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium extended-release tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
)

.
When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics

Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of Diclofenac sodium extended-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy, including antihypertensive effects

(see

Renal Toxicity and Hyperkalemia

Renal Toxicity

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 sodium extended-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium extended-release tablets may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium extended-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium extended-release tablets (see PRECAUTIONS; Drug Interactions).Avoid the use of diclofenac sodium extended-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium extended-release tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

)

Digoxin

Clinical Impact:

The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

Intervention:

During concomitant use of Diclofenac sodium extended-release tablets and digoxin, monitor serum digoxin levels.

Lithium

Clinical Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of Diclofenac sodium extended-release tablets and lithium, monitor patients for signs of lithium toxicity.

Methotrexate

Clinical Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

Intervention:

During concomitant use of Diclofenac sodium extended-release tablets and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine

Clinical Impact:

Concomitant use of Diclofenac sodium extended-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.

Intervention:

During concomitant use of Diclofenac sodium extended-release tablets and cyclosporine, monitor patients for signs of worsening renal function.

NSAIDs and Salicylates

Clinical Impact:

Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy

(see

Gastrointestinal Bleeding, Ulceration, and Perforation

Risk Factors for GI Bleeding, Ulceration, and Perforation

Strategies to Minimize the GI Risks in NSAID-treated patients

Use the lowest effective dose 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 sodium extended-release tablets 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 (see PRECAUTIONS; Drug Interactions).

)

Intervention:

The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.

Pemetrexed

Clinical Impact:

Concomitant use of Diclofenac sodium extended-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).

Intervention:

During concomitant use of Diclofenac sodium extended-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of pemetrexed.

In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following pemetrexed administration.

CYP2C9 Inhibitors or Inducers

Clinical Impact:

Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Coadministration of diclofenac with CYP2C9 inhibitors (e.g., voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac.

Intervention:

A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers

(see

CLINICAL PHARMACOLOGY

Mechanism of Action

Diclofenac sodium extended-release tablets have analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of diclofenac sodium extended-release 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

Pharmacokinetics

Absorption

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 (see Table 1). When diclofenac sodium extended-release tablets are taken with food, there is a delay of 1 to 2 hours in the T_maxand a 2-fold increase in C_maxvalues. The extent of absorption of diclofenac, however, is not significantly affected by food intake.

Table 1. Pharmacokinetic Parameters for Diclofenac
PK Parameter	Normal Healthy Adults (18 to 48 years)
PK Parameter	Mean	Coefficient of Variation (%)
Absolute bioavailability (%) [N = 7]	55	40
T_max(hr) [N = 12]	5.3	28
Oral clearance (CL/F; mL/min) [N = 12]	895	56
Renal clearance (% unchanged drug in urine) [N = 7]	< 1	-
Apparent volume of distribution (V/F; L/kg) [N = 56]	1.4	58
Terminal half-life (hr) [N = 56]	2.3	48

Distribution

The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 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.

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'-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.

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.

Special Populations

Pediatric

: The pharmacokinetics of diclofenac sodium extended-release tablets has not been investigated in pediatric patients.

Race

: Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment

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

Renal Impairment

: 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 60 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.

Drug Interaction Studies

Voriconazole

: When coadministered with voriconazole (inhibitor of CYP2C9, 2C19, and 3A4 enzyme), the C_maxand AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS; Drug Interactions).

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 PRECAUTIONS; Drug Interactions).

)

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