Prescription Drug Information: Fenoprofen Calcium (Page 3 of 5)

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.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Use of NSAIDs, including FENOPROFEN CALCIUM, USP, during the third trimester of pregnancy increases the risk of 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).

There are no adequate and well-controlled studies of FENOPROFEN CALCIUM, USP 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.

In animal reproduction studies, embryo-fetal lethality and skeletal abnormalities were noted in offspring of pregnant rabbits following oral administration of fenoprofen during organogenesis at 0.6 times the maximum human daily dose of 3200 mg/day. However, there were no major malformations noted following oral administration of fenoprofen calcium to pregnant rats and rabbits during organogenesis at exposures up to 0.3 and 0.6 times the maximum human daily dose of 3200 mg/day.

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 fenoprofen, resulted in increased pre- and post-implantation loss.

Clinical Considerations
Labor or Delivery
There are no studies on the effects of FENOPROFEN CALCIUM, USP during labor or delivery. In animal studies, NSAIDS, including fenoprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data
Human Data
There are no adequate and well-controlled studies of FENOPROFEN CALCIUM, USP 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.

Animal data
Pregnant rats were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.15 times and 0.3 times the maximum human daily dose (MHDD) of 3200 mg/day based on body surface area comparison) during the period of organogenesis. No major malformations were noted and there was no evidence of maternal toxicity at these doses, however, the exposures were below the exposures that will occur in humans.
Pregnant rabbits were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.3 times and 0.6 times the MHDD of 3200 mg/day based on body surface area comparison) during the period of organogenesis. Maternal toxicity (mortality) was noted in the high dose animals. Although no major malformations were noted, there was an increased incidence of embryo-fetal lethality and skeletal abnormalities were present at 0.6 times the MHDD.
Pregnant rats were treated from Gestation Day 14 through Post-Natal Day 20 with oral doses of fenoprofen of 6.25, 12.5, 25, 50, or 100 mg/kg (0.02, 0.04, 0.08, 0.15, or 0.3 times the MDD of 3200 mg/day based on body surface area comparison). All doses produced significant toxicity, including vaginal bleeding, prolonged parturition, increased stillbirths, and maternal deaths.
Pregnant rats were treated from Gestation Day 6 through Gestation Day 19 and Post Partum Day 1 to 20 (excluding parturition) with an oral dose of fenoprofen of 100 mg/kg (0.3 times the MDD of 3200 mg/day based on body surface area comparison) demonstrated only a small increase in the incidence of impaired parturition despite the presence of maternal toxicity (gastrointestinal ulceration and renal toxicity).

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