Pennsaid 2%

Cardiovascular (CV) Thrombotic Events 

• Increased risk of CV events including MI and stroke, which can be fatal. The increase in CV thrombotic risk has been observed most consistently at higher doses.

• Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse CV event in NSAID-treated patients. 

• Increased risk of serious gastrointestinal (GI) events with the concurrent use of aspirin and an NSAID, such as diclofenac.

• Status Post Coronary Artery Bypass Graft (CABG) Surgery: NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

• Post-MI Patients: Avoid use in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. Monitor for signs of cardiac ischemia if Pennsaid is used in patients with a recent MI. 

Gastrointestinal Bleeding, Ulceration, and Perforation

• Serious gastrointestinal adverse events, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, may occur with the use of NSAIDS. These serious adverse events can be fatal and can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

• Risk Factors for GI Bleeding, Ulceration, and Perforation: 

• Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing gastrointestinal bleeding compared with patients with neither of these risk factors.

• Other factors that increase the risk for gastrointestinal 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, and therefore special care should be taken in treating this population. 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 high risk 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 Pennsaid 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.  

Hepatotoxicity

• Measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac. Severe hepatotoxicity may develop without a prodrome of distinguishing symptoms.

• Discontinue immediately 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.).

• Discontinue immediately, and perform a clinical evaluation if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.). 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).

• Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse liver-related event in patients treated with Pennsaid. Use caution with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).

Hypertension

• May lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events.  

• May cause impaired response to angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, thiazide diuretics, or loop diuretics.

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

Heart Failure and Edema

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

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

• Monitor for signs of worsening heart failure if used in patients with severe heart failure.  

Renal Toxicity and Hyperkalemia

• Long-term administration of NSAIDs has increased risk of renal toxicity in patients with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors or ARBs, and the elderly.

• 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. 

• Avoid use in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. Monitor for signs of worsening renal function if used in patients with advanced renal disease. 

• Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment.  

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. Seek emergency help if an anaphylactic reaction occurs.

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. 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. 

• Monitor for changes in the signs and symptoms of asthma when Pennsaid is used in patients with preexisting asthma (without known aspirin sensitivity).  

Serious Skin Reactions

• May cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

• Discontinue 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.

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

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

• Discontinue and evaluate immediately if signs or symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) are present.

Fetal Toxicity

• Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including Pennsaid, in pregnant women at about 30 weeks gestation and later. NSAIDs, including Pennsaid, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

• Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including Pennsaid, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.   

• If NSAID treatment is necessary between about 20 and 30 weeks gestation, limit Pennsaid use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Pennsaid treatment extends beyond 48 hours. Discontinue Pennsaid if oligohydramnios occurs and follow up according to clinical practice.

Hematologic Toxicity

• Monitor hemoglobin or hematocrit if signs or symptoms of anemia develop.  

• NSAIDs, including Pennsaid, may increase the risk of bleeding events. 

• May increase risk of bleeding events with comorbid 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). Monitor for signs of bleeding.

Masking of Inflammation and Fever

• May diminish the utility of diagnostic signs in detecting infections.   

Laboratory Monitoring 

• Consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically due to serious GI bleeding, hepatotoxicity, and renal injury which may occur without warning symptoms or signs. 

Sun Exposure

• Avoid exposure to natural or artificial sunlight on treated knee(s) due to the risk of 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. 

Eye Exposure

• Avoid contact 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.

Oral Nonsteroidal Anti-Inflammatory Drugs

• Do not use combination therapy with Pennsaid and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.