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PENNSAID
(diclofenac sodium) Topical Solution
WARNING
RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
PENNSAID 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.
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Each 1 gram of solution contains 20 mg of diclofenac sodium. The inactive ingredients: dimethyl sulfoxide USP (DMSO, 45.5% w/w), ethanol, purified water, propylene glycol, and hydroxypropyl cellulose.
PENNSAID is indicated for the treatment of the pain of osteoarthritis of the knee(s).
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS AND PRECAUTIONS].
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 PENNSAID 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, PENNSAID 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 PENNSAID in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.
PENNSAID (diclofenac sodium) topical solution: 2% w/w
PENNSAID (diclofenac sodium) topical solution 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 clear cap. Each pump actuation delivers 20 mg of diclofenac sodium in 1 gram of solution.
NDC Number & Size
112 g bottle ........... NDC # 75987-040-05
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Distributed by: Horizon Pharma USA Inc. Lake Forest, IL 60045. Revised: May 2016
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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.
The data described below reflect exposure to PENNSAID 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 PENNSAID were application site skin reactions. These events were the most common reason for withdrawing from the study.
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%).
Table 1 lists all adverse reactions occurring in > 1% of patients receiving PENNSAID, where the rate in the PENNSAID 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 PENNSAID and More Often than in
Subjects with OA Using Vehicle Control (Pooled)
| Adverse Reaction | PENNSAID 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 |
The safety of PENNSAID 2% is based in part, on prior experience with PENNSAID 1.5%. The data described below reflect exposure to PENNSAID 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 PENNSAID 1.5% were application site skin reactions. These events were the most common reason for withdrawing from the studies.
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 PENNSAID 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%.
In controlled trials, subjects treated with PENNSAID 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 PENNSAID 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 PENNSAID 1.5%, where the rate in the PENNSAID 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 PENNSAID 1.5% Topical Solution
in Placebo and Oral Diclofenac-Controlled Trials
| Treatment Group: | PENNSAID 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) |
In postmarketing surveillance, the following adverse reactions have been reported during post- approval use of PENNSAID 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
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: |
|
| Intervention: | Monitor patients with concomitant use of PENNSAID 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] |
| 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] |
| Intervention: | Concomitant use of PENNSAID and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS]. PENNSAID is not a substitute for low dose aspirin for cardiovascular protection. |
| ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers | |
| Clinical Impact: |
|
| Intervention: |
|
| 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 PENNSAID with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS]. |
| 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 PENNSAID 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 PENNSAID 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 PENNSAID and methotrexate, monitor patients for methotrexate toxicity. |
| Cyclosporine | |
| Clinical Impact: | Concomitant use of PENNSAID and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention: | During concomitant use of PENNSAID 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] Concomitant use of oral NSAIDs with PENNSAID 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 PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. |
| Pemetrexed | |
| Clinical Impact: | Concomitant use of PENNSAID and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention: | During concomitant use of PENNSAID 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. |
Included as part of the PRECAUTIONS section.
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 Gastrointestinal Bleeding, Ulceration, And Perforation].
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
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 PENNSAID in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If PENNSAID is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
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 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
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:
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 - 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.), PENNSAID 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 PENNSAID immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver-related event in patients treated with PENNSAID, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing PENNSAID with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).
NSAIDs, including PENNSAID, 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].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
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].
Avoid the use of PENNSAID in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If PENNSAID is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of PENNSAID in patients with advanced renal disease. The renal effects of PENNSAID may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating PENNSAID. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of PENNSAID [see DRUG INTERACTIONS]. Avoid the use of PENNSAID in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If PENNSAID is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
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.
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 and Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if an anaphylactic reaction occurs.
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, PENNSAID is contraindicated in patients with this form of aspirin sensitivity [see CONTRAINDICATIONS]. When PENNSAID is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
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 PENNSAID at the first appearance of skin rash or any other sign of hypersensitivity. PENNSAID is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS].
Do not apply PENNSAID to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.
Diclofenac may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including PENNSAID, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations].
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 PENNSAID has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including PENNSAID, 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].
The pharmacological activity of PENNSAID in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
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.
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 PENNSAID on skin response to ultraviolet damage in humans are not known.
Avoid contact of PENNSAID 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.
Concomitant use of oral NSAIDs with PENNSAID 1.5% resulted in a higher rate of rectal hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Therefore, do not use combination therapy with PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
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 PENNSAID and periodically during the course of ongoing therapy.
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].
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].
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 PENNSAID and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS].
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].
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 and WARNINGS AND PRECAUTIONS].
Advise patients to stop PENNSAID immediately if they develop any type of rash and contact their health care provider as soon as possible [see WARNINGS AND PRECAUTIONS].
Advise females of reproductive potential who desire pregnancy that NSAIDs, including PENNSAID, may be associated with a reversible delay in ovulation [see Use in Specific Populations]
Inform pregnant women to avoid use of PENNSAID 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 and Use In Specific Populations].
Inform patients that the concomitant use of PENNSAID 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 and DRUG INTERACTIONS]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Inform patients not to use low-dose aspirin concomitantly with PENNSAID until they talk to their healthcare provider [see DRUG INTERACTIONS].
Instruct patients to avoid contact of PENNSAID 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.
Instruct patients to avoid skin-to-skin contact between other people and the knee(s) to which PENNSAID was applied until the knee(s) is completely dry.
Instruct patients not to apply PENNSAID 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 PENNSAID 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.
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 PENNSAID (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 PENNSAID) 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 PENNSAID) resulted in an earlier median time of onset of tumors.
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.
Fertility studies have not been conducted with PENNSAID. Diclofenac sodium administered to male and female rats at doses up to 4 mg/kg/day (approximately 3.4 times the MRHD of PENNSAID 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.
Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation
Use of NSAIDs, including PENNSAID, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including PENNSAID, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of PENNSAID in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in PENNSAID) are equivocal as to potential teratogenicity. In animal reproduction studies, no evidence of teratogenicity was 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 PENNSAID, 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.
Labor or Delivery
There are no studies on the effects of PENNSAID during labor or delivery. In animal studies, NSAIDs, including diclofenac inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Animal data
Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity 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 PENNSAID, 162 mg/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 PENNSAID) are equivocal as to potential teratogenicity. In rats, maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.
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 CATAFLAM and any potential adverse effects on the breastfed infant from the CATAFLAM or from the underlying maternal condition.
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).
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including PENNSAID, 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 PENNSAID, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Safety and effectiveness in pediatric patients have not been established.
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].
Of the 911 patients treated with PENNSAID 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 PENNSAID 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 PENNSAID 1.5% for this elderly population.
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].
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 PENNSAID. 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).
PENNSAID is contraindicated in the following patients:
Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of PENNSAID, 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.
After administration of PENNSAID 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) ng•h/mL and 12.16 (7.66) ng/mL, respectively, on Day 1; and 204.58 (111.02) ng•h/mL and 25.24 (12.95) ng/mL, respectively, at steady state on Day 8. After administration of PENNSAID 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) ng•h/mL and 2.30 (2.02) ng/mL, respectively, on Day 1; and 141.49 (92.47) ng•h/mL and 17.04 (11.28) ng/mL, respectively, at steady state on Day 8.
The pharmacokinetics and effect of PENNSAID were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of PENNSAID under these conditions is not recommended.
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.
Metabolism
Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5hydroxy-, 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'-hydroxydiclofenac.
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.
Pediatric: The pharmacokinetics of PENNSAID has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been studied.
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].
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 PENNSAID. 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.
The use of PENNSAID 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 PENNSAID at a dose of 2 pumps twice a day for 4 weeks. PENNSAID was compared to topical vehicle, applied directly to the study knee. In this trial, patients treated with PENNSAID 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 PENNSAID
| Efficacy Variable | Treatment | |
| PENNSAID N=130 |
Vehicle Control N=129 |
|
| WOMAC Pain Subscale* | ||
| Baseline | 12.4 | 12.6 |
| Mean Change from Baseline | -4.5 | -3.6 |
| * WOMAC pain subscale is based on the sum of pain scores for five items using a 5-point Likert scale. | ||
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:
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.
The risk of getting an ulcer or bleeding increases with:
NSAIDs should only be used:
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:
Before taking NSAIDs, tell your health care provider about all of your medical conditions, including if you:
Tell your health care provider about all of the medicines you take, including prescription or overthe-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)?”
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:
Stop taking your NSAID and call your health care provider right away if you get any of the following symptoms:
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-FDA1088.
Other information about NSAIDs
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.
