Fenoprofen Calcium: Package Insert and Label Information (Page 2 of 4)

5.10 Premature Closure of Fetal Ductus Arteriosus

Fenoprofen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including FENOPROFEN CALCIUM, USP, in pregnant women starting at 30 weeks of gestation (third trimester) [ see Use in Specific Populations ( 8.1) ].

5.11 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 FENOPROFEN CALCIUM, USP has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including FENOPROFEN CALCIUM, USP, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, 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) ].

5.12 Masking of Inflammation and Fever

The pharmacological activity of FENOPROFEN CALCIUM, USP in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.13 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) ].

5.14 Ocular Effects

Studies to date have not shown changes in the eyes attributable to the administration of FENOPROFEN CALCIUM, USP. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking FENOPROFEN CALCIUM, USP.

5.15 Central Nervous System Effects

Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking FENOPROFEN CALCIUM, USP.

5.16 Impact on Hearing

Since the safety of FENOPROFEN CALCIUM, USP has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with FENOPROFEN CALCIUM, USP.

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 ( 5.11) ]

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.

During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies.

Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials

Digestive System — During clinical trials with FENOPROFEN CALCIUM, USP, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving FENOPROFEN CALCIUM, USP as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% FENOPROFEN CALCIUM, USP vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarketing studies.

Nervous System — The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. FENOPROFEN CALCIUM, USP was discontinued in less than 0.5% of patients because of these side effects during premarketing studies.

Skin and Appendages — Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. FENOPROFEN CALCIUM, USP was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies.

Special Senses — Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. FENOPROFEN CALCIUM, USP was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies.

Cardiovascular — Palpitations (2.5% vs. 0.4%). FENOPROFEN CALCIUM, USP was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies.

Miscellaneous — Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%), and nasopharyngitis (1.2% vs. none).

Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials

Digestive System —Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool. Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis.

Cardiovascular —Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia.

Genitourinary Tract —Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and papillary necrosis.

Hypersensitivity —Angioedema (angioneurotic edema).

Hematologic —Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia.

Nervous System —Depression, disorientation, seizures, and trigeminal neuralgia.

Special Senses —Burning tongue, diplopia, and optic neuritis.

Skin and Appendages —Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia.

Miscellaneous —Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia, and fever.

7. DRUG INTERACTIONS

See Table 1 for clinically significant drug interactions with fenoprofen.

Table 1: Clinically Significant Drug Interactions with Fenoprofen
Drugs That Interfere with Hemostasis
Clinical Impact:
  • Fenoprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of fenoprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
  • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention: Monitor patients with concomitant use of FENOPROFEN CALCIUM, USP 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 ( 5.11) ].
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 FENOPROFEN CALCIUM, USP and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11) ].

FENOPROFEN CALCIUM, USP 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 FENOPROFEN CALCIUM, USP and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
  • During concomitant use of FENOPROFEN CALCIUM, USP 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 FENOPROFEN CALCIUM, USP 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 fenoprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of FENOPROFEN CALCIUM, USP 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 FENOPROFEN CALCIUM, USP 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 FENOPROFEN CALCIUM, USP and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of FENOPROFEN CALCIUM, USP and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of FENOPROFEN CALCIUM, USP and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact: Concomitant use of fenoprofen 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) ].
Intervention: The concomitant use of fenoprofen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact: Concomitant use of FENOPROFEN CALCIUM, USP and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:

During concomitant use of FENOPROFEN CALCIUM, USP 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.

Phenobarbital
Clinical Impact: Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease in the plasma half-life of fenoprofen.
Intervention: When phenobarbital is added to or withdrawn from treatment, dosage adjustment of FENOPROFEN CALCIUM, USP may be required.
Hydantoins, sulfonamides, or sulfonylureas
Clinical Impact: In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their binding sites other drugs that are also albumin bound, and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced.
Intervention: Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs.

Drug/Laboratory Test Interactions

Amerlex-M kit assay values of total and free triiodothyronine in patients receiving FENOPROFEN CALCIUM, USP have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroid-stimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are not affected. Thus, results of the Amerlex-M kit assay should be interpreted with caution in these patients.

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