Oxaprozin

Limits on what this shows

• Null findings: Non-acidic and COX-2 selective agents did not uncouple [14], which shows structure dependence and means the class result cannot be assumed for each acidic molecule. No oxaprozin null was found either.

Regulatory status

Label [1]: ALT or AST elevations of less than three times the upper limit of normal may occur in up to 15% of NSAID-treated patients (class statement); hepatotoxicity warning. No mitochondrial statement in the label text retrieved.

CLASS EXTRAPOLATION

Mahmud et al., Arthritis Rheum 1996 [14] (Tier C): "conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations"; uncoupling correlated inversely with acidity, and nabumetone, modified flurbiprofen and COX-2 inhibitors did not uncouple. Cohort test: the abstract text retrieved does not name oxaprozin, so whether oxaprozin was among the "conventional NSAIDs" is not determinable; treated as NOT in the cohort. Horie et al., J Pharmacol Exp Ther 1998 [15] (Tier C): 18 acidic NSAIDs in freshly isolated rat hepatocytes; all cytotoxic NSAIDs decreased hepatocellular ATP, attributed to suspected uncoupling; only some of the 18 were named in the excerpt read (including diflunisal, flufenamic, mefenamic and tolfenamic acids, diclofenac, indomethacin, acemetacin and flurbiprofen) and oxaprozin was not among those named. Capped at yellow.

Oxaprozin-specific data

None on mitochondria. Two OpenAlex records for mitochondrial NSAID panels (Moreno-Sanchez 1999 [26]; Nadanaciva 2013 [27]) had no retrievable abstract and do not name oxaprozin among their keywords, so neither is used. Hepatotoxicity case reports exist (Kethu 1999 [28], a 41-year-old woman with biopsy-confirmed icteric hepatitis described as the second documented case) but are clinical outcomes, and no mechanism is stated in the abstract.

Mechanism

Named for the class: protonophoric uncoupling by acidic NSAIDs [14][15]. Absent or unknown for oxaprozin; its glucuronide metabolites are described as without significant pharmacologic activity [1].

Hard Rule 2 check

Liver enzyme elevation and hepatitis are outcomes, not mitochondrial findings.

Counter-evidence held on record

Counter-evidence and confounding Micromolar concentrations in isolated systems are not matched to therapeutic free drug (oxaprozin is about 99% bound), and oxaprozin is absent from the retrieved cohorts. Framing caution Mechanistic context entry. It does not support a CoQ10 or other mitochondrial supplement for oxaprozin; no dose is implied.

Limits on what this shows

• Null and excluded findings: Two NSAID antioxidant papers were opened and excluded because oxaprozin was not tested: Costa 2006 [17] (seven arylpropionic acids, none oxaprozin) and Mouithys-Mickalad 2000 [18] (nimesulide, aceclofenac, diclofenac, indomethacin).

Regulatory status

No oxidative-stress or antioxidant statement in the label text retrieved [1].

Population evidence

None in humans. Costa, Gomes, Lima and Fernandes, Redox Rep 2008 [16] (Tier B, in vitro chemistry, oxaprozin tested; abstract via a listing page summary): "There was a lack of activity for most of the arylpropionic acid derivatives tested, with only naproxen and indoprofen displaying residual activities, as for the oxazole derivative, oxaprozin." Pyrazolones (dipyrone, aminopyrine) were strongest. This is a null for antioxidant activity, not evidence of oxidative stress. Oxaprozin NF-kappaB inhibition (IC50 50 micromol/L) and apoptosis of activated monocytes are described pharmacodynamics [9] and are not redox-marker measurements.

Mechanism

Absent for a pro-oxidant effect of oxaprozin in the retrieved sources; direct singlet oxygen scavenging is minimal [16].

Hard Rule 2 check

Not a nutrient deficiency in any case; this is a context category. The grade reflects a single in vitro Tier B result, not a signal in either direction.

Counter-evidence held on record

Counter-evidence and confounding A cell-free singlet oxygen assay does not reflect in vivo redox status or glutathione, SOD or catalase activity, none of which was measured with oxaprozin. Framing caution Not a reason to take antioxidant supplements. No dose is implied.

Limits on what this shows

• Null and limiting findings: The review states there is no direct evidence linking anemia with low-level blood loss into the bowel [5]. A 15-day randomized trial of oxaprozin 1200 mg once daily (n=49) against diclofenac 50 mg three times daily (n=47) in shoulder periarthritis reported only six mild to moderate adverse events across both groups, with no hemoglobin outcome in the retrieved abstract [11]. The oxaprozin blood loss arm is one study of 10 people for at least 7 days and does not test months or years of treatment.
• At-risk subgroups: Older adults, prior ulcer or GI bleeding, concurrent aspirin (the label lists aspirin as lowering oxaprozin protein binding and adding bleeding risk) or warfarin (synergistic bleeding effect) [1].

Regulatory status

Label (Daypro, revised 11/2024) [1]: NSAIDs cause an increased risk of serious GI adverse events including bleeding, ulceration and perforation. Anemia: "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 signs or symptoms of anemia occur, monitor hemoglobin or hematocrit. Long-term NSAID treatment: consider periodic CBC and chemistry profile because serious GI bleeding, hepatotoxicity and renal injury can occur without warning signs. Anemia and increased bleeding time are listed among reactions with incidence above 1% in 2253 trial patients on 1200 to 1800 mg/day (summarizer wording; the frequency table was not retrieved). The label text retrieved does not mention iron, vitamins or minerals [1].

Population evidence

Moore, Derry and McQuay 2008 [5] (Tier A, systematic review of randomized trials using autologous chromium-51 labelled erythrocytes, oxaprozin in the cohort): Table 2 lists oxaprozin as 1 study arm, 10 participants, weighted mean fecal blood loss 2.30 mL/day, against 0.76 mL/day in 172 placebo-arm participants and 0.46 mL/day at the start of trials (950 participants). On the same table naproxen is 1.98, ibuprofen 2.03 and piroxicam 1.89 mL/day, and aspirin above 1800 mg/day 5.01 mL/day. The review notes about 5% of NSAID takers lose 5 mL/day or more and 1% lose 10 mL/day or more (pooled for all NSAIDs, not oxaprozin alone). Included trials were randomized, had a placebo arm, and gave the drug for at least 7 days [5]; a reconstructed abstract describes the participants as primarily healthy young men. The oxaprozin dose, duration and original trial citation were not retrievable (the Rainsford review [12] lists a reference titled "Gastrointestinal blood loss of oxaprozin and aspirin with placebo control", title only, not opened). This is a bleeding measurement, not an iron measurement.

Mechanism

Proposed, class-level: COX-1 and COX-2 inhibition (label mechanism statement [1]) with mucosal injury and occult bleeding. The label names blood loss, fluid retention and an incompletely described effect on erythropoiesis as possible anemia causes [1]. No oxaprozin study of ferritin, iron absorption or iron turnover was retrieved.

Hard Rule 2 and 6 checks

GI bleeding and anemia are clinical outcomes, not iron deficiency; deficiency needs measured iron indices. Confounding by indication is presumed (rheumatic disease, aspirin or anticoagulant co-use, age). Direction is loss through bleeding, a toxicity route, not an absorption defect. The SOS observational meta-analysis of individual NSAIDs and upper GI complications [24] was opened at abstract level and does not name oxaprozin, so none of its relative risks apply here. Circulating claim: a PeaceHealth page states "NSAIDs cause gastrointestinal (GI) irritation, bleeding, and iron loss" on its oxaprozin page with no citation (Tier D) [31].

Counter-evidence held on record

Counter-evidence and confounding Average controlled blood loss in the oxaprozin arm is a few mL/day, from a single small arm, and etodolac on the same table (0.55 mL/day) sits near the placebo range, showing wide drug-to-drug spread. No cohort compared ferritin before and after starting oxaprozin. Framing caution This is a toxicity pathway (blood loss), not a dietary or absorption deficiency. New iron deficiency or dark stools on oxaprozin calls for evaluating the bleeding source and the prescription, not an iron supplement by default. No iron dose is recommended here.

Limits on what this shows

• Null findings: No copper, ceruloplasmin or serum copper measurement in oxaprozin users was found.

Regulatory status

No copper statement in the label text retrieved [1].

Population evidence

Bozic et al., Chem Pharm Bull 2012 [22] (Tier B, synthetic inorganic chemistry, oxaprozin as ligand; listing page summary): transition metal complexes of oxaprozin with Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) were synthesized and tested for antiproliferative activity; the Ni complex was most active against HCT-116 cells. This shows chemical ability to bind copper, not an effect on body copper. A Rainsford review of oxaprozin [12] mentions zinc and copper ions in the context of albumin binding (summarizer-level, abstract and reference text only), which would be a metal-affecting-drug direction (Hard Rule 4) if confirmed.

Mechanism

Named: carboxylate coordination to Cu(II) in vitro [22]. No physiological mechanism.

Counter-evidence held on record

Counter-evidence and confounding Rheumatic disease alters serum copper independently of treatment (confounding by indication). Framing caution No copper supplement is implied. Entry is graded separately from Iron and Zinc.

Limits on what this shows

• Null findings: The ketorolac effect occurred without mucosal damage or delayed transit [19]. No oxaprozin fecal 16S or metagenomic study was found.

Regulatory status

No microbiome statement in the label text retrieved [1]. The label states biliary excretion of unchanged drug is minor and enterohepatic recycling is insignificant [1], so exposure of the lower gut to parent drug by that route is limited; diarrhea and constipation are listed adverse reactions.

CLASS EXTRAPOLATION

Hutka et al., Front Pharmacol 2021 [19] (Tier C, rat): low-dose ketorolac for four weeks caused dysbiosis (loss of Firmicutes families, more Enterobacteriaceae) and altered bile acids without mucosal damage. Cohort test: only ketorolac was dosed; oxaprozin NOT in the cohort. Makivuokko et al., Br J Nutr 2010 [20] (Tier C, human intestinal microbiota in NSAID users): the abstract refers to NSAID users generically and does not name oxaprozin, so oxaprozin cannot be confirmed in the cohort and it is treated as NOT in the cohort; the abstract was read through a summarizing fetch and its findings are not relied on. Capped at yellow.

Population evidence

None for oxaprozin. Maier et al., Nature 2018 [21], screened more than 1,000 marketed drugs against 40 gut bacterial strains; the main text read does not name oxaprozin (the supplementary table was not opened), so it is context only and supports no statement here.

Mechanism

Named in rats for ketorolac: altered small-intestinal microbiota and bile acid composition [19]. Unknown for oxaprozin.

Counter-evidence held on record

Counter-evidence and confounding One rat model of a different NSAID, and human NSAID-user comparisons confounded by age, disease and co-medication such as acid suppressants. Framing caution Mechanistic and context entry. It does not support a probiotic, fiber or antibiotic decision; persistent diarrhea or black stools on oxaprozin belong with the prescriber.

Limits on what this shows

• Null findings: No arterial oxygenation, red-cell oxygen affinity or hemoglobin series with oxaprozin was found. The 15-day diclofenac comparison trial reported only six mild to moderate adverse events in 96 patients [11].

Regulatory status

Label [1]: anemia statement and hemoglobin or hematocrit monitoring as above; postmarketing hematologic events include aplastic anemia, hemolytic anemia, thrombocytopenia, pancytopenia, purpura, agranulocytosis and hematuria (summarizer wording of Section 6.2).

Population evidence

None measuring oxygen delivery. The only oxaprozin-specific hematologic measurement retrieved is the chromium-labelled fecal blood loss arm (2.30 mL/day, 10 participants) [5], covered in the Iron entry. No oxaprozin case report of hemolysis or methemoglobinemia was retrieved: searches for oxaprozin with hemolytic anemia, aplastic anemia, methemoglobinemia, erythrocytes and hemoglobin oxidation returned no oxaprozin paper (see Ungraded section for channels).

Mechanism

Three routes in the label and general pharmacology, none shown to lower oxygen delivery at therapeutic dosing: blood loss anemia (Iron entry), fluid retention (dilutional fall in hemoglobin concentration, label wording), and rare immune or marrow reactions listed postmarketing [1].

Hard Rule 2 check

Anemia is an outcome, not a nutrient deficiency, and a drug reaction is an adverse event, not an oxygen-delivery deficiency. Oxaprozin has no intended hemodynamic oxygen-demand effect to clarify. This entry is a context and monitoring flag only. The label basis is Tier A for the existence of the warning, not for any measured oxygen-delivery change, so the entry stays yellow.

Counter-evidence held on record

Counter-evidence and confounding Postmarketing reports have no denominator, and the label lists three possible anemia causes that are not oxygen-delivery mechanisms. Framing caution Do not read this as an oxygen-carrying deficiency that supplements can fix. Unexplained fatigue, pallor, jaundice or dark urine on oxaprozin is a prescriber question; no iron, folate or antioxidant supplement is implied.

Limits on what this shows

• Null findings: Non-acidic agents and COX-2 inhibitors did not uncouple [14]. No oxaprozin ATP null was found.

Regulatory status

No ATP or energy-metabolism statement in the label text retrieved [1].

CLASS EXTRAPOLATION

Horie 1998 [15] (Tier C): "All of the cytotoxic NSAIDs and diphenylamine extensively decreased hepatocellular ATP content" in isolated rat hepatocytes, attributed to suspected uncoupling of oxidative phosphorylation (excerpt read; 18 NSAIDs studied, oxaprozin not among those named in the excerpt). Mahmud 1996 [14] reports stimulated mitochondrial respiration (the uncoupling signature) for conventional NSAIDs. Cohort test: oxaprozin not confirmed in either; treated as NOT in the cohort. Capped at yellow.

Population evidence

None in humans or animals for oxaprozin.

Mechanism

Class-level uncoupling; unknown for oxaprozin.

Hard Rule 7 note

Entered separately from Mitochondrial burden and Oxygen delivery/utilization; it shares sources with Mitochondrial burden (see Overlap map).

Counter-evidence held on record

Counter-evidence and confounding Hepatocyte ATP loss was linked to cytotoxic doses in vitro; nothing links it to ATP shortage in patients on oxaprozin. Framing caution Not an indication of low energy in people taking oxaprozin and not a reason for any supplement. No dose is implied.