Nintedanib

oral tyrosine kinase inhibitor, antifibrotic

Also sold as Ofev.

Analyze another medication Medication directory

Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Nintedanib has almost no classical depletion machinery. It is cleared by the gut and bile (93.4% fecal, 0.65% renal), is broken down mainly by esterases with only a minor CYP3A4 role, is a P-gp substrate with 4.7% oral bioavailability, and its label does not describe CYP induction or inhibition by the drug or any vitamin or mineral interaction [1][2]. Its real nutrient-relevant signal is gastrointestinal: diarrhea in 62% vs 18% of patients, nausea 24% vs 7%, decreased appetite 11% vs 5% and weight decrease 10% vs 3% [1][6]. The EU label adds that serious diarrhea has led to dehydration and electrolyte disturbances [3]. That is a loss-through-diarrhea disturbance, never an instruction to raise intake, and no retrieved study measured potassium, sodium or magnesium in nintedanib users.

oral tyrosine kinase inhibitor, antifibrotic · ATC L01EX09 (WHO ATC/DDD Index [4]) · also sold as Ofev · reviewed 2026-10-08. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Nintedanib in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe: Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Potassium, sodium and magnesium: loss through diarrhea, label caution, no measured analyte

Yellow — Low

See study details

Nintedanib causes diarrhea in most treated patients, and the EU label warns that serious diarrhea has led to dehydration and electrolyte disturbances, but no retrieved trial or cohort reports a measured potassium, sodium or magnesium value in nintedanib users.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow

Limits on what this shows

Null findings: Hyponatremia: none of 29 nintedanib starters vs 3 of 52 pirfenidone starters (single centre, retrospective) [15]. Pirfenidone-associated SIADH should not be transferred to nintedanib. No serum potassium or magnesium data were found for nintedanib.
At-risk subgroups: Patients with persistent moderate or severe diarrhea; older patients; patients on diuretics or other agents that lower potassium or magnesium; patients with reduced oral intake.

Direction

Disturbance or loss secondary to gastrointestinal fluid loss (depletion by diarrhea). Not a dietary deficiency and not a renal effect.

Regulatory status

EU SmPC section 4.4: "Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported in the post-marketing"; dehydration is listed as uncommon in IPF (section 4.8) [3]. The US label (revision 5/2025) mentions hydration only as diarrhea management ("Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide)") and does not mention electrolytes, dehydration or anemia in the sections read [1][2]. Both read through summarizing fetches.

Population evidence

INPULSIS pooled safety [6] (n=638 nintedanib, 423 placebo, 52 weeks): diarrhea 62.4% vs 18.4%; of those with diarrhea, severe 5.3% vs 2.6%, median duration 138.5 vs 7.0 days; antidiarrheal use 55.3% vs 25.6%; discontinuation for diarrhea 4.4% vs 0.2%; dose reduction for diarrhea 10.7% (text) or 14.3% (Table 4), an unreconciled discrepancy in the paper. Label: diarrhea 62% vs 18% [1]. INPULSIS-1 and -2 separately [5]: 61.5% vs 18.6% and 63.2% vs 18.3%. INBUILD [11] (n=332 vs 331): diarrhoea 136.4 vs 23.0 per 100 patient-years. Single-centre interview study, 79 ILD patients on nintedanib [9]: 47 had diarrhea within 3 months, 31 of them with watery stool. None of [6], [9], [11] reports sodium, potassium, magnesium or dehydration as a result.

Mechanism

Present: increased stool volume and frequency, with reported nausea (24.5% vs 6.6%) and vomiting (11.6% vs 2.6%) [6]. The cause of the diarrhea is not established in the sources opened.

Missing for orange

A report naming the analyte (for example potassium) and giving measured values in nintedanib-treated patients with and without diarrhea. Near-orange candidate: the EU label is a Tier A statement, but it names no analyte, gives no frequency and no measurements.

Counter-evidence held on record

Counter-evidence and confounding Diarrhea is also common on placebo (18.4%) and in advanced lung disease. Hydration status and electrolytes were not reported in the sources opened, so the size of any electrolyte effect is unknown. Framing caution This is a loss-through-diarrhea disturbance, not a signal to increase potassium, magnesium or sodium intake. Correction belongs to a prescriber guided by labs. Do not recommend electrolyte supplements from this entry.

Weight loss and decreased appetite: an outcome entry, no nutrient measured

Yellow — Low

See study details

Nintedanib reduces appetite and body weight more than placebo, which can lower overall energy and protein intake, but weight loss is an outcome, not a deficiency of any named nutrient, and no study retrieved measured a nutrient.

Full detail and limits

Limits on what this shows

Null findings: In [7] efficacy was not lost with weight loss: annual FVC decline difference vs placebo was 209.6 mL (95% CI 135.7-283.6) in the more-than-5% weight-loss group and 78.5 mL (40.1-116.9) in the 5% or less group (interaction p=0.0008). Serum albumin and micronutrients were not reported in [8].
At-risk subgroups: Lower baseline BMI (under 25 kg/m2 in 307 of 1,061 patients in [7]); patients switched from pirfenidone with prior anorexia [8].

Direction

Reduced intake (mechanism class H) producing an outcome. No nutrient direction can be assigned (Hard Rule 2).

Regulatory status

US label Table 1 (IPF): weight decreased 10% vs 3%; decreased appetite 11% vs 5%; nausea 24% vs 7%; vomiting 12% vs 3% [1][2]. EU SmPC: weight decreased common, decreased appetite common in IPF [3].

Population evidence

INPULSIS pooled [6]: weight decreased 9.7% vs 3.5%; weight loss led to discontinuation in 0.9% (6) vs 0.2% (1); decreased appetite 10.7% vs 5.7%. Post-hoc INPULSIS analysis [7] (n=1,061): mean annual weight change -3.3 kg on nintedanib vs -1.5 kg on placebo; more than 5% weight loss over 52 weeks in 241 (37.8%) vs 85 (20.1%); reasons for loss were not known to the authors. INBUILD [11]: weight decrease 12.4 vs 3.9 per 100 patient-years; decreased appetite 14.0 vs 5.1. Retrospective switch study [8] (30 switched from pirfenidone, 64 pirfenidone-naive, nintedanib 150 mg twice daily): nintedanib anorexia 14/30 (46.7%) vs 14/64 (21.9%), p=0.028; lower BMI predicted early discontinuation, OR 0.487 (95% CI 0.280-0.849). FAERS/JADER disproportionality [14]: weight decreased ROR 5.19 (95% CI 4.97-5.41, 2,153 cases); decreased appetite ROR 6.46 (6.20-6.74, 2,268 cases); exploratory, no causality.

Mechanism

Present through intake: nausea, vomiting, diarrhea and anorexia [6][8]. Metabolic or absorptive mechanisms were not described.

Counter-evidence held on record

Counter-evidence and confounding Placebo-arm patients also lose weight (-1.5 kg/year, 20.1% lose more than 5%) and more than 5% loss in the placebo arm tracked faster FVC decline [7], so weight loss partly reflects the disease. The abstract and text of [7] disagree on one placebo value (BMI 30 or more: -104.5 vs -175.7 mL/year). Framing caution Report as a reduced-intake and weight outcome to monitor, not as a deficiency of protein, calories or any vitamin or mineral. No supplement is recommended from this entry.

Skeletal muscle mass (sarcopenia): indication-linked context in IPF cohorts

Yellow — Low

See study details

Low erector spinae muscle area predicts death in IPF, but the cohorts either excluded nintedanib or did not stratify by drug, so no effect of nintedanib on muscle mass is shown.

Full detail and limits

Limits on what this shows

Null findings: No study located measuring change in muscle mass on nintedanib versus an untreated comparator.

Direction

Outcome and disease marker. No nutrient measured. Weight and appetite effects of nintedanib (previous entries) could plausibly add to a pre-existing deficit, but no source tested this.

Regulatory status

Not addressed in the labels read.

Population evidence

Nakano 2020 [16]: single-centre retrospective, 144 enrolled and 119 with repeat CT; 28 patients received pirfenidone and none received nintedanib; relative decline in erector spinae area over about 6 months predicted mortality, adjusted HR 1.039 (95% CI 1.007-1.071, p=0.015); 59 of 119 died. Suzuki 2021 [17]: 208 antifibrotic-treated IPF patients from two centres (nintedanib about 21% in one centre and 43.1% in the other, pirfenidone the rest; the centre percentages as read do not sum to 100%), CT at antifibrotic initiation; lower erector spinae area was an independent mortality predictor, continuous HR 0.957 (0.930-0.986), sex-specific dichotomised HR 1.899 (1.141-3.249). Single time point; no analysis by drug; no longitudinal change on nintedanib.

Class cohort test

Not class extrapolation. [16] excluded nintedanib, so it is Tier C for this drug and describes the disease only. [17] included nintedanib users but pooled them with pirfenidone, so no nintedanib-specific effect can be separated.

Counter-evidence held on record

Counter-evidence and confounding In [17] the CT was taken at antifibrotic start, so low muscle mass preceded the drug (confounding by indication presumed, Hard Rule 6). Age, inactivity, hypoxemia and inflammation are competing explanations. Framing caution Context for monitoring weight and strength in nintedanib users. Not a nintedanib-caused muscle or protein deficiency.

Food effect, grapefruit and P-gp/CYP3A4 modulators: nutrient-to-drug direction, a timing matter

Yellow — Low

See study details

Food raises nintedanib exposure by about 20% and delays absorption, and P-gp/CYP3A4 modulators change exposure markedly; this runs from the diet or co-medication to the drug, so it is a timing and exposure interaction, not a depletion.

Full detail and limits

Direction

Nutrient or co-medication affects the drug (Hard Rule 4). Not a drug effect on a nutrient.

Regulatory status

Food increased exposure by about 20%, median tmax 2.00 h fasted vs 3.98 h fed; absolute bioavailability 4.7% [2]; EU SmPC states exposure increased approximately 20% with food [3]. Ketoconazole raised AUC 1.61-fold and Cmax 1.83-fold; rifampicin reduced AUC to 50.3% and Cmax to 60.3%; the label advises avoiding inducers such as carbamazepine, phenytoin and St John's wort [2]. Interaction text via summarizing fetch.

Circulating claim

A consumer page (Tier D) says grapefruit and Seville orange juice can raise nintedanib levels and to take nintedanib with food [24]. The label sections read do not name grapefruit; the instruction to take with food was seen only on the consumer page and is not confirmed in the label text read. No study of nintedanib with grapefruit was located.

Mechanism

Present: P-gp substrate, minor CYP3A4 pathway (about 5% of metabolism in vitro vs about 25% ester cleavage) [2]. Grapefruit inhibition of intestinal CYP3A4 and P-gp is established pharmacology generally, but its effect on nintedanib is untested in sources opened.

Separation interval

None documented. Consistent dosing relative to meals is the practical issue; no mineral or vitamin separation interval appears in the label sections read.

Counter-evidence held on record

Counter-evidence and confounding Grapefruit magnitude is unknown; the quantified interactions are ketoconazole and rifampicin only. Framing caution A timing and exposure note for a pharmacist. Not a depletion finding and not a dosing recommendation.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden: CLASS EXTRAPOLATION from other kinase inhibitors, nintedanib not in the cohort

Yellow — Low

See study details

Three other kinase inhibitors impaired respiratory chain activity and membrane potential in liver cells, and nintedanib has a labeled liver-enzyme signal, but nintedanib was not tested and no nintedanib mitochondrial study was found.

Full detail and limits

Limits on what this shows

Null findings: No nintedanib mitochondrial toxicity, oxygen consumption or membrane potential study was retrieved.

Direction

Excess toxicity burden (not a nutrient deficiency). Drug toxicity is not a nutrient deficiency (Hard Rule 2); listed because the category is mandatory.

CLASS EXTRAPOLATION

Paech 2018 [22], HepG2 cells and isolated mouse liver mitochondria: ponatinib, regorafenib and sorafenib reduced respiratory chain complex activity, lowered mitochondrial membrane potential and increased mitochondrial ROS. Nintedanib was not among them; this drug was NOT in the cohort test (read through a database summary page, not the paper). Capped at yellow.

Drug-specific context

ALT and/or AST at or above 3 times ULN: 5.0% (32) vs 0.7% (3) in pooled INPULSIS [6]; 14.2% (47/332) vs 1.8% (6/331) in INBUILD, with any hepatic adverse event in 26.2% vs 7.3% [12]; no case met the ALT/AST 3x ULN plus bilirubin 2x ULN combination on nintedanib [12]. Label: hepatic injury including fatal cases postmarketing, mostly in the first three months [1]. These are hepatotoxicity outcomes; no mitochondrial mechanism for nintedanib was shown.

Mechanism

Plausible by class, unverified for nintedanib.

Counter-evidence held on record

Counter-evidence and confounding Different drugs, hepatoma cells and concentrations of unknown relevance. Liver injury has multiple mechanisms. Framing caution Do not read as evidence that nintedanib damages mitochondria. It is a class-level hypothesis.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress: reverse direction, small human before-and-after study plus a mouse model

Yellow — Low

See study details

The only human data show whole-blood reduced glutathione rising during nintedanib treatment, and mouse data show lower ROS and MDA, so nintedanib does not appear to raise oxidative stress; evidence is small and uncontrolled.

Full detail and limits

Limits on what this shows

Null findings: Most other markers (taurine, TBARS, Kyn/Trp, protein-bound thiols) moved only as non-significant trends in the nintedanib arm [18]. Class opposite signal: sorafenib, regorafenib and ponatinib raised mitochondrial ROS in HepG2 cells [22]; nintedanib was not tested there.

Direction

Reverse (protective or neutral). Not a depletion.

Population evidence

Fois 2020 [18]: 18 IPF patients (8 on nintedanib 300 mg/day, 10 on pirfenidone) vs 18 matched healthy controls, 24 weeks, before-and-after design. Nintedanib group: blood reduced glutathione 486 +/- 70 to 723 +/- 194 umol/L (p=0.006); asymmetric dimethylarginine 0.501 +/- 0.094 to 0.468 +/- 0.071 umol/L (p=0.024); TBARS trend -18% (not significant); no change in FEV1, FVC or DLCO. Baseline GSH in IPF was reported lower than in controls (457 vs 880 umol/L, from a database abstract summary). No placebo arm.

Animal evidence

Pan 2023 [19]: bleomycin mouse model (n=12 per group), nintedanib 30, 60, 120 mg/kg/day by gavage; reported lower ROS and MDA and higher SOD and GSH-Px, dose-dependent; numeric values were not available in the text read (figures not seen).

Mechanism

Antifibrotic and anti-inflammatory action reducing redox stress in a fibrosis model, per [19]; not shown in humans beyond the GSH change.

Counter-evidence held on record

Counter-evidence and confounding Eight nintedanib patients, no comparator group, mild disease and a 24-week window leave room for regression to the mean and disease-course effects. Mouse results are bleomycin-specific. Framing caution A reverse-direction finding. Do not present it as a recommendation to use antioxidant supplements, and do not present it as proof that nintedanib is antioxidant in humans.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Iron: possible loss through gastrointestinal bleeding, iron never measured

Yellow — Low

See study details

Nintedanib carries a labeled bleeding risk and a case report documents severe anemia from gastric antral vascular ectasia, which would drain iron, but no retrieved study measured ferritin, transferrin saturation or serum iron in nintedanib users.

Full detail and limits

Limits on what this shows

Null findings: Serious bleeding equal across arms in pooled INPULSIS [6]. No study located comparing ferritin or hemoglobin between nintedanib and placebo.
At-risk subgroups: Patients on anticoagulants, antiplatelets or NSAIDs; known bleeding risk; prior GI lesions (the label cautions on diverticular disease, recent abdominal surgery, corticosteroids and NSAIDs for perforation) [1].

Direction

Depletion secondary to blood loss, if bleeding occurs. Anemia is not iron deficiency (Hard Rule 2); iron status was not reported anywhere in the sources opened.

Regulatory status

US label: bleeding events 10% (nintedanib) vs 7% (placebo) in IPF studies; "Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk"; GI perforation under 1% vs none; thrombocytopenia listed in postmarketing reactions [1][2]. EU SmPC lists bleeding as common [3]. Hemoglobin and iron are not safety parameters in the sections read.

Population evidence

INPULSIS pooled [6]: any bleeding 10.3% vs 7.8%; epistaxis 4.1% vs 3.1%; serious bleeding 1.3% (8) vs 1.4% (6), so serious bleeding did not differ between arms. Case report [13]: a 76-year-old woman, more than 2 years of nintedanib 150 mg twice daily, melena and hemoglobin 4.0 g/dL, gastric antral vascular ectasia treated with argon plasma coagulation; melena resolved and hemoglobin stabilized after nintedanib was stopped; iron indices not reported in the text read. FAERS/JADER [14]: haematochezia ROR 4.46 (95% CI 4.03-4.93, 389 cases).

Mechanism

Present (bleeding, label). The mechanism of the bleeding tendency is not stated in the label text read; a vascular-pathway basis is plausible pharmacology but was not verified from an opened source.

Missing for orange

Ferritin, transferrin saturation or hemoglobin measured in nintedanib users in a cohort or trial, plus a second independent cohort.

Counter-evidence held on record

Counter-evidence and confounding One case report and a spontaneous-report signal cannot establish frequency. Older age, aspirin, anticoagulants and lesion type are competing explanations in the case. Framing caution This is a bleeding-recognition prompt, not an iron-deficiency claim. Iron supplementation is not recommended from this entry; unexplained anemia needs a bleeding work-up first.

Copper

Not graded — disclosed evidence gap

See study details

No evidence was found that nintedanib raises or lowers copper, and no circulating claim about nintedanib and copper was found.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

Why no grade: Dual condition met: no Tier B or C evidence supports even a yellow grade, and no circulating consumer claim about nintedanib and copper was found to rebut. This is a disclosed gap, not a finding of safety. Genuine gap on the evidence reached; the database-search portion is tooling-limited and should be re-checked when access is restored.

What was searched

Web search "nintedanib copper OR ceruloplasmin OR cuproptosis OR copper lung fibrosis". Results were cuproptosis and copper-in-fibrosis papers on the disease (not opened) and a narrative review of magnesium, zinc and copper in lung fibrosis [23], which was opened. That review describes a raised copper/zinc ratio and a pro-fibrotic role for copper in IPF and reports no drug effect of nintedanib on copper levels; it cites no nintedanib copper measurement, and it is a narrative review without drug-level stratification (Tier C at most, no nintedanib data).

Channel outcomes

DailyMed label and EU SmPC: no copper content. PubMed listing, Europe PMC, OpenAlex and Crossref searches returned 429 and were not repeated; PMC article pages returned reCAPTCHA; further web search budget was exhausted. Mixed result: no hit on open web search plus tooling-limited access to bibliographic databases.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk: animal data in colitis only, no human microbiome measurement

Yellow — Low

See study details

Nintedanib shifted gut bacteria in a mouse colitis model, but no human microbiome study of nintedanib was found even though diarrhea affects about 6 in 10 patients.

Full detail, limits and 1 references

Limits on what this shows

Null findings: Fibrosis itself changes the gut microbiota: in bleomycin mice without nintedanib, Firmicutes and Lactobacillus fell and Enterobacteriales rose [25]. This is a confounder for any nintedanib microbiome result in IPF patients.

Direction

Unclear. In the one animal study nintedanib was reported as restoring a disturbed profile (reverse), not depleting it.

Animal evidence

Li 2022 [20] (located through editorial [21]): DSS-colitis mice, nintedanib 50 and 100 mg/kg by gavage on days 1-7 (50 mice in five groups, n=5 per group in figure legends). 16S sequencing compared control, DSS and nintedanib 100 mg/kg: DSS reduced Lachnospiraceae, Rikenellaceae and Oscillospira; nintedanib vs DSS reduced Sutterella and S24-7 and increased Bacteroides, Bilophila and Parabacteroides. No alpha-diversity statistics, no healthy-animal nintedanib group in the microbiome comparison.

Human evidence

None on microbiome. Diarrhea in 62.4% (nintedanib) vs 18.4% (placebo) [6]. Two Japanese retrospective diarrhea studies [9][10] report predictors and stool form and no microbiome data. A fecal microbiota transplantation trial for nintedanib-induced diarrhea is registered (NCT05755308) [26]; the record could not be read and is listed only as not opened.

Counter-evidence held on record

Counter-evidence and confounding The colitis model does not test nintedanib in a healthy gut or in IPF. Indication-linked and diarrhea-linked changes cannot be separated in the evidence found. Framing caution Not a statement that nintedanib disrupts the microbiome. It is an acknowledged unknown.

ClinicalTrials.gov NCT05755308: Faecal microbiota transplantation to ameliorate nintedanib-induced diarrhea in patients with idiopathic pulmonary fibrosis. — Registry record. Title seen in a search result only; the page returned no study content.Not opened. Cited as existence of a registered trial only.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization: bleeding-related anemia, case-level only

Yellow — Low

See study details

The only hemoglobin value tied to nintedanib in the sources opened is a single case of bleeding-related anemia; no study measured hemoglobin, hematocrit or red-cell mass in nintedanib users against a comparator.

Full detail and limits

Limits on what this shows

Null findings: No anemia or hemoglobin comparison was found in INPULSIS pooled safety [6], the INBUILD frequent adverse event table [11] or the hepatic table [12]; the INBUILD table lists only events above 10 per 100 patient-years, so absence there is not informative.
At-risk subgroups: Same as Iron: bleeding risk, antithrombotic co-therapy.

Direction

Reduced red-cell mass through blood loss in rare cases. Not a drug effect on hemoglobin synthesis, and not the lung disease: hypoxemia from IPF itself is a disease effect and is excluded (Hard Rule 2).

Regulatory status

Anemia and hemoglobin are not discussed as safety findings in the US label sections read [1][2] or in EU section 4.4 [3]. Bleeding is labeled (10% vs 7%) [1].

Population evidence

Case report [13]: hemoglobin 4.0 g/dL at presentation with melena after more than 2 years of nintedanib, stabilized after discontinuation. Pooled INPULSIS [6] reports bleeding rates but no anemia or hemoglobin data.

Mechanism

Indirect only, through the bleeding events described under Iron.

Counter-evidence held on record

Counter-evidence and confounding This entry and the Iron entry rest on the same case and the same labeled bleeding risk (see Overlap map). It is one line of evidence, not two. Framing caution A case-level observation. It is not a finding that nintedanib lowers oxygen-carrying capacity in general.

ATP production: CLASS EXTRAPOLATION from other kinase inhibitors, nintedanib not in the cohort

Yellow — Low

See study details

Other kinase inhibitors lowered cellular ATP in galactose-grown liver cells at concentrations below those causing cell death; nintedanib was not tested and no nintedanib ATP measurement was found.

Full detail and limits

Limits on what this shows

Null findings: None located.

Direction

Reduced cellular ATP in vitro (class). No human relevance shown.

CLASS EXTRAPOLATION

Paech 2018 [22]: ponatinib, regorafenib and sorafenib depleted cellular ATP at concentrations lower than those causing cytotoxicity in galactose-cultured HepG2 cells. Nintedanib was NOT in the cohort. Same source as Mitochondrial burden, counted once (Overlap map). Capped at yellow.

Population evidence

None for nintedanib: no human ATP, lactate-to-pyruvate, or muscle energetics study was retrieved.

Counter-evidence held on record

Counter-evidence and confounding In vitro, other drugs, single cell type. Fatigue or low energy in IPF patients is largely disease-driven and is not evidence for this entry. Framing caution A class-level hypothesis only. No claim of energy depletion by nintedanib is supported.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

Zinc (and magnesium) as add-ons needed with nintedanib
Where it comes from: A 2025 narrative review of magnesium, zinc and copper in lung fibrosis, which states that "the association of zinc and magnesium with pirfenidone and nintedanib could be beneficial" and that no adverse effects of the combination have been reported [23].
Why it fails: The review cites no measurement of zinc or magnesium in nintedanib users and no trial of the combination; its supporting evidence is general IPF and bleomycin-model work, not nintedanib depletion. A potential benefit of an add-on is not a depletion finding. For zinc, no nintedanib mechanism, label statement or study was found (no Tier A, B or C support for this drug). For magnesium, the only plausible route is diarrheal loss, graded yellow above without measurements.
Hyponatremia with nintedanib (SIADH, transferred from pirfenidone)
Where it comes from: Not found as a nintedanib claim; recorded because pirfenidone, the other IPF antifibrotic, has a published SIADH signal and the two drugs are often discussed together [15].
Why it fails: In the one retrospective series that compared them, 0 of 29 nintedanib starters developed hyponatremia vs 3 of 52 on pirfenidone [15]. No label, trial or case report in the sources opened links nintedanib to hyponatremia. Small series; absence is not proof. Listed as a pre-emptive rebuttal, not a traced circulating claim.

How the body handles this medication

Metabolism and enzymes: Hydrolytic ester cleavage by esterases is the prevalent pathway, forming BIBF 1202, which is glucuronidated. CYP3A4 is the predominant CYP enzyme but a minor route (about 5% vs about 25% ester cleavage in vitro). Induction or inhibition of CYP enzymes by nintedanib is not described in the label text read.[2] sec 12.3; [3] sec 5.2
Elimination: Fecal and biliary excretion 93.4% of dose; renal excretion 0.65%. Hepatic impairment raises exposure: AUC 2.2-fold (Child-Pugh A) and 7.6-fold (Child-Pugh B); not recommended in moderate or severe impairment; severe not studied.[1][2]
Absorption and transporters: Absolute bioavailability 4.7% (100 mg). Absorption and bioavailability are reduced by transporter effects and substantial first-pass metabolism; P-gp substrate.[1][2][3]
Food effect: Food raised exposure by about 20% and delayed absorption (median tmax 2.00 h fasted vs 3.98 h fed). Instruction to take with food seen only on a consumer page, not in the label text read.[2][3][24]
Interactions: Ketoconazole (P-gp/CYP3A4 inhibitor): AUC 1.61-fold, Cmax 1.83-fold. Rifampicin (inducer): AUC 50.3%, Cmax 60.3% of baseline; avoid carbamazepine, phenytoin, St John's wort. No vitamin, mineral or antacid interaction appears in the label text read.[2] sec 7
Renal handling of water and electrolytes: No effect on renal tubular handling is described. The relevant route to fluid and electrolyte loss is the gut: serious diarrhea leading to dehydration and electrolyte disturbances (EU), and bleeding events 10% vs 7% (US).[1][3]

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

Labs / persistent diarrhea
Hydration, creatinine and electrolytes
If diarrhea is moderate to severe or lasts beyond a few days despite loperamide, a basic metabolic panel (potassium, sodium, creatinine) and magnesium is reasonable, especially with diuretics. The label directs early hydration and antidiarrheal treatment, dose reduction or stopping if diarrhea persists [1][2]. A monitoring prompt based on the EU label caution [3], not a measured-deficiency finding. Do not self-supplement.
Weight / appetite
Weight trend and intake
Track body weight from the start; in INPULSIS 37.8% of nintedanib patients lost more than 5% in 52 weeks [7]. Early dietitian input is reasonable when appetite falls or weight drops. Low BMI predicted early discontinuation in one series [8].
Labs / liver
Liver enzymes and bilirubin
ALT/AST at or above 3 times ULN occurred in 5.0% vs 0.7% (INPULSIS pooled) [6] and 14.2% vs 1.8% (INBUILD) [12]; most events appear in the first three months [1]. Exposure rises 2.2-fold (Child-Pugh A) and 7.6-fold (Child-Pugh B) in hepatic impairment; the label does not recommend use in moderate or severe impairment [2]. Specific testing schedule per the current label.
Bleeding / CBC
Hemoglobin if bleeding
Black or bloody stool, new unexplained anemia or fatigue warrants a CBC and evaluation for GI bleeding before attributing anything to iron status [13]. Take extra care with anticoagulants, antiplatelets and NSAIDs; the label advises weighing bleeding risk [1].
Timing / interactions
Meals, grapefruit and inducers
Keep timing relative to meals consistent, since food raises exposure about 20% [2]. A consumer source advises avoiding grapefruit [24]; the label names P-gp/CYP3A4 inhibitors (ketoconazole, erythromycin) and advises avoiding inducers such as carbamazepine, phenytoin and St John's wort [2]. No mineral or vitamin separation interval is documented.
Special populations
Pregnancy, renal and hepatic status
The US label carries an embryo-fetal toxicity warning (section 5.4 per the summary read) [1]. Renal excretion is only 0.65% of a dose [2], so kidney function matters mainly through dehydration. Pediatric use was not reviewed here.

Overlap map, to prevent double counting

Mitochondrial burden
Shares evidence with: ATP production
Note: One source: Paech 2018 [22] (ponatinib, regorafenib, sorafenib in HepG2). Same class extrapolation, nintedanib not in the cohort. Counted as one line of evidence, not two.
Iron
Shares evidence with: Oxygen delivery/utilization
Note: One case report [13] and the same labeled bleeding risk [1][3]. The anemia in the case is the oxygen-delivery observation; the blood loss is the iron mechanism. One underlying event, not two confirmations.
Potassium, sodium and magnesium
Shares evidence with: Weight loss and decreased appetite
Note: Both rest on the same gastrointestinal adverse events (diarrhea, nausea, vomiting) from INPULSIS [6] and the label [1]. The weight outcome and the possible electrolyte loss are downstream of one mechanism.
Weight loss and decreased appetite
Shares evidence with: Skeletal muscle mass
Note: Jouneau 2020 [7] and the muscle cohorts [16][17] describe the same disease-linked wasting phenomenon from different angles. No shared dataset, but the muscle entry is context for the weight entry, not independent evidence of a drug effect.
Oxidative stress
Shares evidence with: Mitochondrial burden
Note: No shared evidence. The ROS increase seen with other kinase inhibitors in [22] is cited in the oxidative stress entry only as a contrast; it is not used to grade that entry. Sources [18][19] are used for oxidative stress only.
Mitochondrial burden
Shares evidence with: Hepatic enzyme elevation (outcome, no entry)
Note: Liver enzyme data [6][12] provide context for the class hypothesis. Hepatotoxicity is a drug toxicity outcome and is not graded as a nutrient entry.
Gut microbiome risk
Shares evidence with: Potassium, sodium and magnesium
Note: No shared evidence. Both mention diarrhea [6]; the microbiome entry relies on [20] and [25], the electrolyte entry on [3][6][9][15].

All references used above

Nintedanib

Findings for this medication

What the research found

Potassium, sodium and magnesium: loss through diarrhea, label caution, no measured analyte

Weight loss and decreased appetite: an outcome entry, no nutrient measured

Skeletal muscle mass (sarcopenia): indication-linked context in IPF cohorts

Food effect, grapefruit and P-gp/CYP3A4 modulators: nutrient-to-drug direction, a timing matter

The five body-system areas

⚡Mitochondrial Burden

Mitochondrial burden: CLASS EXTRAPOLATION from other kinase inhibitors, nintedanib not in the cohort

💥Oxidative Stress

Oxidative stress: reverse direction, small human before-and-after study plus a mouse model

⚖️Copper and Iron Balance

Iron: possible loss through gastrointestinal bleeding, iron never measured

Copper

🌿Gut Microbiome Risk

Gut microbiome risk: animal data in colitis only, no human microbiome measurement

💨Oxygen and ATP Output

Oxygen delivery/utilization: bleeding-related anemia, case-level only

ATP production: CLASS EXTRAPOLATION from other kinase inhibitors, nintedanib not in the cohort

Claims checked and not supported

Zinc (and magnesium) as add-ons needed with nintedanib

Hyponatremia with nintedanib (SIADH, transferred from pirfenidone)

How the body handles this medication

What the research says is worth watching

Overlap map, to prevent double counting

Mitochondrial Burden

Oxidative Stress

Copper and Iron Balance

Gut Microbiome Risk

Oxygen and ATP Output