These highlights do not include all the information needed to use DICLOFENAC SODIUM TOPICAL SOLUTION safely and effectively. See full prescribing information for DICLOFENAC SODIUM TOPICAL SOLUTION. DICLOFENAC SODIUM topical solution 2% w/w, for topical use Initial U.S. Approval: 1988

DICLAREAL TOPICAL kit by

Drug Labeling and Warnings

DICLAREAL TOPICAL kit by is a Prescription medication manufactured, distributed, or labeled by FORREAL PHARMACEUTICALS LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

DICLAREAL TOPICAL KIT- diclofenac sodium, capsaicin 
FORREAL PHARMACEUTICALS LLC

Disclaimer: This drug has not been found by FDA to be safe and effective, and this labeling has not been approved by FDA. For further information about unapproved drugs, click here.

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FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

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 Warnings and Precautions (5.1)].
• Diclofenac sodium topical solution is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.2)].

1. INDICATIONS AND USAGE

Diclofenac sodium topical solution is indicated for the treatment of the pain of osteoarthritis of the knee(s).

2. DOSAGE AND ADMINISTRATION

2.1 General Dosing Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.2)].

For relief of the pain of osteoarthritis (OA) of the knee(s), the recommended dose is 40 mg of diclofenac sodium (2 pump actuations) on each painful knee, 2 times a day.

Apply diclofenac sodium topical solution to clean, dry skin.

The pump must be primed before first use. Instruct patients to fully depress the pump mechanism (actuation) 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle should be required.

After the priming procedure, diclofenac sodium topical solution is properly dispensed by completely depressing the pump 2 times to achieve the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and then apply evenly around front, back, and sides of the knee.

Application of diclofenac sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.

2.2 Special Precautions

• Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee.
• Wash and dry hands after use.
• Do not apply diclofenac sodium topical solution to open wounds.
• Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes.
• Do not apply external heat and/or occlusive dressings to treated knees.
• Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry.
• Protect the treated knee(s) from natural and artificial sunlight.
• Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution.
• Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s).
• Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.

3. DOSAGE FORMS AND STRENGTHS

Diclofenac sodium topical solution, USP: 2% w/w

4. CONTRAINDICATIONS

Diclofenac sodium topical solutionis 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 and Precautions (5.7, 5.9)]
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]
• In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]

5. WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

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 (4)].

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 topical solution in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium topical solution is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. 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 NSAID 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 used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac sodium topical solution 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 Drug Interactions (7)].

5.3 Hepatotoxicity

In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

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

Abnormal tests occurred during the first 2 months of therapy with oral 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 NSAID 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 oral 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 topical solution 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 topical solution 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 topical solution, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium topical solution with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).

5.4 Hypertension

NSAIDs, including diclofenac sodium topical solution, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

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

5.5 Heart Failure and Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].

Avoid the use of diclofenac sodium topical solution in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium topical solution is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6 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 topical solution in patients with advanced renal disease. The renal effects of diclofenac sodium topical solution 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 topical solution. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium topical solution [see Drug Interactions (7)]. Avoid the use of diclofenac sodium topical solution in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium topical solution is 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.

5.7 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 (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

5.8 Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium topical solution is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When diclofenac sodium topical solution is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.9 Serious Skin Reactions

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. 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 topical solution at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium topical solution is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

Do not apply diclofenac sodium topical solution to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium topical solution. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium topical solution and evaluate the patient immediately.

5.11 Fetal Toxicity

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including diclofenac sodium topical solution, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium topical solution, 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 topical solution, 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 and 30 weeks gestation, limit diclofenac sodium topical solution use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium topical solution treatment extends beyond 48 hours. Discontinue diclofenac sodium topical solution if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

5.12 Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium topical solution has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac sodium topical solution, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

5.13 Masking of Inflammation and Fever

The pharmacological activity of diclofenac sodium topical solution in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.14 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].

5.15 Sun Exposure

Instruct patients to avoid exposure to natural or artificial sunlight on treated knee(s) because studies in animals indicated topical diclofenac treatment resulted in an earlier onset of ultraviolet light-induced skin tumors. The potential effects of diclofenac sodium topical solution on skin response to ultraviolet damage in humans are not known.

5.16 Eye Exposure

Avoid contact of diclofenac sodium topical solution with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

5.17 Oral Nonsteroidal Anti-Inflammatory Drugs

Concomitant use of oral NSAIDs with diclofenac sodium topical solution 1.5% resulted in a higher rate of rectal hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Therefore, do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.

6. ADVERSE REACTIONS

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

• Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
• GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Heart Failure and Edema [see Warnings and Precautions (5.5)]
• Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
• Anaphylactic Reactions [see Warnings and Precautions (5.7)]
• Serious Skin Reactions [see Warnings and Precautions (5.9)]
• Hematologic Toxicity [see Warnings and Precautions (5.12)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Diclofenac Sodium Topical Solution

The data described below reflect exposure to diclofenac sodium topical solution of 130 patients treated for 4 weeks (mean duration of 28 days) in one Phase 2 controlled trial. This population’s mean age was approximately 60 years, 85% of patients were Caucasian, 65% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution were application site skin reactions. These events were the most common reason for withdrawing from the study.

Application Site Reactions:

In this controlled trial, application site reactions were characterized by one or more of the following: dryness (22%), exfoliation (7%), erythema (4%), pruritus (2%), pain (2%), induration (2%), rash (2%), and scabbing (<1%).

Other Common Adverse Reactions:

Table 1 lists all adverse reactions occurring in >1% of patients receiving diclofenac sodium topical solution, where the rate in the diclofenac sodium topical solution group exceeded vehicle, from a controlled study conducted in patients with osteoarthritis.

Table 1: Incidence of Adverse Reactions Occurring in >1% of Subjects with Osteoarthritis Using Diclofenac Sodium Topical Solution and More Often than in Subjects with OA Using Vehicle Control (Pooled)

Adverse Reaction	Diclofenac Sodium Topical Solution  N=130 n (%)	Vehicle Control N=129 n (%)
Urinary tract infection	4 (3%)	1 (<1%)
Application site induration	2 (2%)	1 (<1%)
Contusion	2 (2%)	1 (<1%)
Sinus congestion	2 (2%)	1 (<1%)
Nausea	2 (2%)	0

Diclofenac Sodium Topical Solution 1.5%

The safety of diclofenac sodium topical solution 2% is based in part, on prior experience with diclofenac sodium topical solution 1.5%. The data described below reflect exposure to diclofenac sodium topical solution 1.5% of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasian, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution 1.5% were application site skin reactions. These events were the most common reason for withdrawing from the studies.

Application Site Reactions:

In controlled trials, application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of diclofenac sodium topical solution 1.5% and oral diclofenac. In the open-label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%.

Other Common Adverse Reactions:

In controlled trials, subjects treated with diclofenac sodium topical solution 1.5% experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 2). The combination of diclofenac sodium topical solution 1.5% and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases.

Table 2 lists all adverse reactions occurring in ≥1% of patients receiving diclofenac sodium topical solution 1.5%, where the rate in the diclofenac sodium topical solution 1.5% group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence.

Table 2: Adverse Reactions Occurring in ≥1% of Patients Treated with Diclofenac Sodium 1.5% Topical Solution in Placebo and Oral Diclofenac-Controlled Trials

Treatment Group:	Diclofenac Sodium Topical Solution 1.5% N=911	Topical Placebo; N=332
Adverse Reaction	N (%)	N (%)
Dry Skin (Application Site)	292 (32)	17 (5)
Contact Dermatitis (Application Site)	83 (9)	6 (2)
Dyspepsia	72 (8)	13 (4)
Abdominal Pain	54 (6)	10 (3)
Flatulence	35 (4)	1 (<1)
Pruritus (Application Site)	34 (4)	7 (2)
Diarrhea	33 (4)	7 (2)
Nausea	33 (4)	3 (1)
Pharyngitis	40 (4)	13 (4)
Constipation	29 (3)	1 (<1)
Edema	26 (3)	0
Rash (Non-Application Site)	25 (3)	5 (2)
Infection	25 (3)	8 (2)
Ecchymosis	19 (2)	1 (<1)
Dry Skin (Non-Application Site)	19 (2)	1 (<1)
Contact Dermatitis, vesicles (Application Site)	18 (2)	0
Paresthesia (Non-Application Site)	14 (2)	3 (<1)
Accidental Injury	22 (2)	7 (2)
Pruritus (Non-Application Site)	15 (2)	2 (<1)
Sinusitis	10 (1)	2 (<1)
Halitosis	11 (1)	1 (<1)
Application Site Reaction (not otherwise specified)	11 (1)	3 (<1)

6.2 Postmarketing Experience

In postmarketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium topical solution 1.5%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: abdominal pain, accidental injury, allergic reactions, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, neck rigidity, pain

Cardiovascular: palpitation, cardiovascular disorder

Gastrointestinal: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, lip swelling, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis, swollen tongue

Metabolic and Nutritional: creatinine increased

Musculoskeletal: leg cramps, myalgia

Nervous: depression, dizziness, drowsiness, lethargy, paresthesia at application site

Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis, throat swelling

Skin and Appendages: At the Application Site: rash, skin burning sensation;

Other Skin and Appendages Adverse Reactions: eczema, skin discoloration, urticaria

Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion

Vascular: blood pressure increased, hypertension

7. DRUG INTERACTIONS

See Table 3 for clinically significant drug interactions with diclofenac.

Table 3: 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 increased the 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 topical solution 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 [see Warnings and Precautions (5.12)]
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 Warnings and Precautions (5.2)]
Intervention:	Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)].; Diclofenac sodium topical solution is 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, co-administration 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 topical solution 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 topical solution 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 Warnings and Precautions (5.6)]. 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 topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
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 topical solution 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 topical solution 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 topical solution and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium topical solution 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 Warnings and Precautions (5.2)]; Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.; Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium topical solution 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 topical solution 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 two days before, the day of, and two 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 five days before, the day of, and two days following pemetrexed administration.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Use of NSAIDs, including diclofenac sodium topical solution, 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 topical solution use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium topical solution use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including diclofenac sodium topical solution, 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.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations were observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0.6, 0.6, and 1.3 times, respectively, the maximum recommended human dose (MRHD) of 162 mg diclofenac sodium via diclofenac sodium topical solution, despite the presence of maternal and fetal toxicity at these doses [see Data]. Based on 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 the Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium topical solution, can cause premature closure of the fetal ductus arteriosus (see Data).

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 topical solution treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium topical solution and follow up according to clinical practice (see Data).

Labor or Delivery          

There are no studies on the effects of diclofenac sodium topical solution during labor or delivery. In animal studies, NSAIDs, including diclofenac inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal data

Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce malformations despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.6 times the maximum recommended human dose [MRHD] of diclofenac sodium topical solution, 162 mg diclofenac sodium/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.6 and 1.3-times, respectively, the MRHD based on BSA comparison). Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in diclofenac sodium topical solution) are equivocal as to potential teratogenicity.

In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.12 and 0.24 times the MRHD, respectively, based on BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats.

In published studies, diclofenac administration to pregnant rats prolonged gestation and produced liver toxicity and neuronal loss in offspring (1 mg/kg, IP; 0.06 times the MRHD based on BSA comparison), impaired nephrogenesis in the kidney (3.6 mg/kg, IP; 0.2 times the MRHD based on BSA comparison), and caused adverse effects on the developing testes (6.1 mg/kg, oral; 0.4 times the MRHD based on BSA comparison).

8.2 Lactation

Risk Summary

Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac and any potential adverse effects on the breastfed infant from the diclofenac or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac sodium topical solution, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium topical solution, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Males

Published studies in adult male rodents report that diclofenac, at clinically relevant doses, can produce adverse effects on male reproductive tissues. The impact of these findings on male fertility is not clear [See Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

Of the 911 patients treated with diclofenac sodium topical solution 1.5% in seven controlled, Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with diclofenac sodium topical solution 1.5% in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to diclofenac sodium topical solution 1.5% for this elderly population.

10. OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in diclofenac sodium topical solution. Consider activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment, contact a poison control center (1-800-222-1222).

11 DESCRIPTION

Diclofenac sodium 2% topical solution, contains diclofenac sodium, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug, and is available as a clear, colorless to faintly pink or orange solution for topical application. The chemical name is 2[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2, and it has the following chemical structure.

Each 1 gram of solution contains 20 mg of diclofenac sodium USP. The inactive ingredients: dimethyl sulfoxide (DMSO, 45.5% w/w), ethanol 96%, hydroxypropyl cellulose, propylene glycol and purified water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

The mechanism of action of diclofenac sodium topical solution, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics

Absorption:

After administration of diclofenac sodium topical solution (40 mg/knee every 12 h; total daily diclofenac exposure: 80 mg/knee) for 7.5 days, the mean (SD) AUC0-12 and mean (SD) Cmax were 77.27 (49.89) ngh/mL and 12.16 (7.66) ng/mL, respectively, on Day 1; and 204.58 (111.02) ngh/mL and 25.24 (12.95) ng/mL, respectively, at steady state on Day 8. After administration of diclofenac sodium 1.5% topical solution (19.3 mg/knee every 6 h; total daily diclofenac exposure 77.2 mg/knee), the mean (SD) AUC0-12 and mean (SD) Cmax were 27.46 (23.97) ngh/mL and 2.30 (2.02) ng/mL, respectively, on Day 1; and 141.49 (92.47) ngh/mL and 17.04 (11.28) ng/mL, respectively, at steady state on Day 8.

The pharmacokinetics and effect of diclofenac sodium topical solution were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of diclofenac sodium topical solution under these conditions is not recommended.

Distribution:

Diclofenac is more than 99% bound to human serum proteins, primarily to albumin.

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. Acylglucuronidation 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.

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.

Specific Populations:

Pediatric: The pharmacokinetics of diclofenac sodium topical solution has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been studied.

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day approximately 0.85 and 1.7 times, respectively, the maximum recommended human topical dose of diclofenac sodium topical solution (based on apparent bioavailability and body surface area comparison).

In a dermal carcinogenicity study conducted in albino mice, daily topical applications of diclofenac sodium for two years at concentrations up to 0.035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) did not increase neoplasm incidence.

In a photococarcinogenicity study conducted in hairless mice, topical application of diclofenac sodium at doses up to 0.035% diclofenac sodium (a 57-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) resulted in an earlier median time of onset of tumors.

Mutagenesis

Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal aberration assay of bone marrow cells.

Impairment of Fertility

Fertility studies have not been conducted with diclofenac sodium topical solution. Diclofenac sodium administered to male and female rats at doses up to 4 mg/kg/day (approximately 3.4 times the MRHD of diclofenac sodium topical solution based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies conducted in rats found no effect of dermally applied DMSO on fertility, reproductive performance, or offspring performance.

However, published studies report that treatment of adult male rats with diclofenac by the oral route at 10 mg/kg (0.6 times the MRHD) for 14 days and at 0.25 mg/kg (0.01 times the MRHD) for 30 days produced adverse effects on male reproductive hormones and testes.

13.2 Animal Toxicology and/or Pharmacology

Ocular Effects

No adverse effects were observed using indirect ophthalmoscopy after multiple-daily dermal application to rats for 26 weeks and minipigs for 52 weeks of DMSO at twice the concentration found in diclofenac sodium topical solution. Published studies of dermal or oral administration of DMSO to rabbits, dogs and pigs described refractive changes of lens curvature and cortical fibers indicative of myopic changes and/or incidences of lens opacity or discoloration when evaluated using slit-lamp biomicroscopy examination, although no ocular abnormalities were observed in rhesus monkeys during daily oral or dermal treatment with DMSO for 9 to 18 months.

14 CLINICAL STUDIES

14.1 Study in Osteoarthritis of the Knee

Diclofenac Sodium Topical Solution

The use of diclofenac sodium topical solution for the treatment of pain of osteoarthritis of the knee was evaluated in a single double-blind controlled trial conducted in the US, involving patients treated with diclofenac sodium topical solution at a dose of 2 pumps twice a day for 4 weeks. Diclofenac sodium topical solution was compared to topical vehicle, applied directly to the study knee. In this trial, patients treated with diclofenac sodium topical solution experienced a greater reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale compared to patients treated with vehicle. Numerical results of the WOMAC pain subscale are summarized in Table 4.

Table 4: Change in Treatment Outcomes after 4 Weeks of Treatment with Diclofenac Sodium Topical Solution

* WOMAC pain subscale is based on the sum of pain scores for five items using a 5-point Likert scale.
Efficacy Variable	Treatment
	Diclofenac Sodium Topical Solution; N=130	Vehicle Control; N=129
WOMAC Pain Subscale*
Baseline	12.4	12.6
Mean Change from Baseline	-4.5	-3.6

16 HOW SUPPLIED/STORAGE AND HANDLING

Diclofenac Sodium Topical Solution, USP 2% w/w, is supplied as a clear, colorless to faintly pink or orange solution containing 20 mg of diclofenac sodium per gram of solution, in a white polypropylene-dose pump bottle with a cap. Each pump actuation delivers 20 mg of diclofenac sodium in 1 gram of solution.

112 g bottle                 NDC: 81877-645-12

Storage

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium topical solution and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulceration and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].

Hepatotoxicity

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). If these occur, instruct patients to stop diclofenac sodium topical solution and seek immediate medical therapy [see Warnings and Precautions (5.3)].

Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].

Serious Skin Reactions, including DRESS

Advise patients to stop using diclofenac sodium topical solution immediately if they develop any type of rash or fever and contact their health care provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium topical solution, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]

Fetal Toxicity

Inform pregnant women to avoid use of diclofenac sodium topical solution and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.11)]. If treatment with diclofenac sodium topical solution is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of diclofenac sodium topical solution with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use of NSAIDs and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium topical solution until they talk to their healthcare provider [see Drug Interactions (7)].

Eye Exposure

Instruct patients to avoid contact of diclofenac sodium topical solution with the eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

Prevention of Secondary Exposure

Instruct patients to avoid skin-to-skin contact between other people and the knee(s) to which diclofenac sodium topical solution was applied until the knee(s) is completely dry.

Special Application Instructions

Instruct patients not to apply diclofenac sodium topical solution to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and reduce tolerability of the drug.

Instruct patients to wait until the area treated with diclofenac sodium topical solution is completely dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication.

Instruct patients to minimize or avoid exposure of treated knee(s) to natural or artificial sunlight.

Manufactured for:
Forreal Pharmaceuticals LLC, Royal Oak, MI 48067
Questions? 877-367-3250

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

NSAIDs can cause serious side effects, including:

• Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase:
  • with increasing doses of NSAIDs
  • with longer use of NSAIDs

Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

• Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:
  • anytime during use
  • without warning symptoms
  • that may cause death

The risk of getting an ulcer or bleeding increases with:

• past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
• taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
• increasing doses of NSAIDs
• longer use of NSAIDs
• smoking
• drinking alcohol
• older age
• poor health
• advanced liver disease
• bleeding problems

NSAIDs should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are NSAIDs?

NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.

Who should not take NSAIDs?

Do not take NSAIDS:

• if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
• right before or after heart bypass surgery.

Before taking NSAIDs, tell your health care provider about all of your medical conditions, including if you:

• have liver or kidney problems
• have high blood pressure
• have asthma
• are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy.
• are breastfeeding or plan to breast feed.

Tell your health care provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking new medicine without talking to your health care provider first.

What are the possible side effects of NSAIDs?

NSAIDs can cause serious side effects, including:

See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?”

• new or worse high blood pressure
• heart failure
• liver problems including liver failure
• kidney problems including kidney failure
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting and dizziness.

Get emergency help right away if you get any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop taking your NSAID and call your health care provider right away if you get any of the following symptoms:

• nausea
• more tired or weaker than usual
• diarrhea
• itching
• your skin or eyes look yellow
• indigestion or stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms, legs, hands, and feet

If you take too much of your NSAID, call your health care provider or get medical help right away.

These are not all the possible side effects of NSAIDs. For more information, ask your health care provider or pharmacist about NSAIDs.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about NSAIDs

• Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your health care provider before using over-the-counter NSAIDs for more than 10 days.

General information about the safe and effective use of NSAIDs

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk with your health care provider. You can ask your pharmacist or health care provider for information about NSAIDs that is written for health professionals.

For more information, contact Forreal Pharmaceuticals LLC at 877-367-3250

This Medication Guide has been approved by the U.S. Food and Drug Administration. 

Instructions for Use

Diclofenac Sodium (dye kloe' fen ak soe' dee um) Topical Solution, USP 2%

Read the Medication Guide that comes with diclofenac sodium topical solution first. Be sure that you read, understand and follow these Instructions for Use before you use diclofenac sodium topical solution for the first time.

Important: For use on the skin only (topical). Do not get diclofenac sodium topical solution in your eyes, nose or mouth.

Before you use diclofenac sodium topical solution:

• Apply diclofenac sodium topical solution exactly as your healthcare provider tells you. Talk with your   healthcare provider or pharmacist if you are not sure.
• Only use diclofenac sodium topical solution to treat pain from osteoarthritis in your knee or knees.
• Apply diclofenac sodium topical solution on clean, dry skin that does not have any cuts, infections or rashes.
• Use diclofenac sodium topical solution two times a day on your knee or knees as prescribed.
• If you get diclofenac sodium topical solution in your eyes, rinse your eyes right away with water or saline. Call your healthcare provider if your eyes are irritated for more than one hour.

Diclofenac sodium topical solution comes in a pump bottle from your healthcare provider.

If you are using a diclofenac sodium topical solution pump bottle follow the steps below:

Before you use diclofenac sodium topical solution pump bottle for the first time, you will need to prime the pump. To prime the pump, remove the cap (See Figure A) and fully press the top of the pump all the way down 4 times while holding the bottle in an upright position (See Figure B). Dispense this portion of the medicine into a tissue or paper towel and throw it away in a trash can. The pump is now ready to use. You should not need to prime the pump again.

Steps for using diclofenac sodium topical solution pump bottle:

Step 1: Wash your hands with soap and water before applying diclofenac sodium topical solution.

Step 2: Remove the bottle cap and press the pump head down firmly and fully to dispense diclofenac sodium topical solution into the palm of your hand. Release the pump head and then press the pump head down firmly and fully a second time. When you use your diclofenac sodium topical solution pump bottle, you can hold the bottle at an angle. Put 2 pumps of diclofenac sodium topical solution on your hand (See Figure C).

Step 3: Apply diclofenac sodium topical solution evenly around the front, back, and sides of your knee. Diclofenac sodium topical solution should be applied without massaging the knee (See Figures D and E).

Step 4: Repeat Steps 2 and 3 for your other knee if your healthcare provider has prescribed diclofenac sodium topical solution for both knees.

Step 5: Wash your hands with soap and water right away after applying diclofenac sodium topical solution.

Step 6: Replace the cap on the bottle and store in an upright position.

After you use diclofenac sodium topical solution:

Do not:

• cover your knee with clothing until your knee is completely dry.
• put sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medicines on your knee until it is completely dry.
• take a shower or a bath for at least 30 minutes after you put diclofenac sodium topical solution on your knee(s).
• use heating pads or cover the treated area with bandages where you have applied diclofenac sodium topical solution.
• exercise following application of diclofenac sodium topical solution.
• use sunlamp and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in the sunlight.

How should I store diclofenac sodium topical solution?

• Store diclofenac sodium topical solution at room temperature between 68°F to 77°F (20°C to 25°C).

Keep diclofenac sodium topical solution and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Forreal Pharmaceuticals LLC, Royal Oak, MI 48067
Questions? 877-367-3250

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL

NDC: 81877-645-12
Rx ONLY

DICLAREAL

Topical Kit

Rx Only

For External
Use Only

Diclofenac Sodium Topical Solution 2%
(112 grams — 1 Bottle)

Capsaicin Cream 0.025%
(60 gram — 1 Tube)

Usual Dosage: See package insert for dosage and full prescribing information.

Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room
Temperature].

Keep this and all medication out of reach of children.

Forreal Pharmaceuticals LLC
YOUR SOLUTION TO BETTER HEALTHCARE

DICLAREAL TOPICAL KIT 
diclofenac sodium, capsaicin kit

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 81877-645(NDC: 81877-640)

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 81877-645-12	1 in 1 KIT	10/12/2023	06/07/2024

Quantity of Parts
Part #	Package Quantity	Total Product Quantity
Part 1	1 BOTTLE	112 g
Part 2	1 TUBE	60 g

Part 1 of 2

DICLOFENAC SODIUM 
diclofenac sodium solution

Product Information
Item Code (Source)	NDC: 13107-269
Route of Administration	TOPICAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
DICLOFENAC SODIUM (UNII: QTG126297Q) (DICLOFENAC - UNII:144O8QL0L1)	DICLOFENAC SODIUM	20 mg  in 1 g

Inactive Ingredients
Ingredient Name	Strength
DIMETHYL SULFOXIDE (UNII: YOW8V9698H)
ALCOHOL (UNII: 3K9958V90M)
HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
WATER (UNII: 059QF0KO0R)

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 13107-269-47	1 in 1 CARTON
1		112 g in 1 BOTTLE; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA213040	10/12/2023	06/07/2024

Part 2 of 2

RUGBY CAPSAICIN  EXTERNAL ANALGESIC
capsaicin cream

Product Information
Item Code (Source)	NDC: 0536-2525
Route of Administration	TOPICAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Capsaicin (UNII: S07O44R1ZM) (Capsaicin - UNII:S07O44R1ZM)	Capsaicin	0.25 mg  in 1 g

Inactive Ingredients
Ingredient Name	Strength
CARBOMER COPOLYMER TYPE A (ALLYL PENTAERYTHRITOL CROSSLINKED) (UNII: 71DD5V995L)
Cetyl Acetate (UNII: 4Q43814HXS)
Methylparaben (UNII: A2I8C7HI9T)
PPG-20 Methyl Glucose Ether Distearate (UNII: 0057334FAB)
Propylene Glycol (UNII: 6DC9Q167V3)
Propylparaben (UNII: Z8IX2SC1OH)
Steareth-100 (UNII: 4OH5W9UM87)
Stearic Acid (UNII: 4ELV7Z65AP)
Stearyl Alcohol (UNII: 2KR89I4H1Y)
Trolamine (UNII: 9O3K93S3TK)
Water (UNII: 059QF0KO0R)

Product Characteristics
Color	WHITE	Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0536-2525-25	1 in 1 CARTON
1		60 g in 1 TUBE; Type 0: Not a Combination Product

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
OTC Monograph Drug	M014	10/12/2023	06/07/2024

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		10/12/2023	06/07/2024

Labeler - FORREAL PHARMACEUTICALS LLC (118029197)

Revised: 6/2024

Document Id: 271c14e4-60be-4638-994a-672ef3ff8ba8

34391-3

Set id: 11fe93a7-2c2f-4fdd-8324-760761fb3563

Version: 2

Effective Time: 20240618