Drug Interactions between methotrexate and Opdivo
This report displays the potential drug interactions for the following 2 drugs:
- methotrexate
- Opdivo (nivolumab)
Interactions between your drugs
methotrexate nivolumab
Applies to: methotrexate and Opdivo (nivolumab)
MONITOR: Although immune checkpoint inhibitors (ICI) such as programmed cell death-1 (PD-1), programmed death ligand-1 inhibitors (PD-L1), and anti-CTLA-4 monoclonal antibodies may be indicated for use in combination in with other immunosuppressive agents, their pharmacodynamic effects and efficacy may be affected by corticosteroids and immunosuppressants. The mechanism of this interaction is related to the immunosuppressive effects of corticosteroids and other immunosuppressants, particularly their inhibition of T-cell activation, which may reduce the efficacy of immune checkpoint inhibitors that rely on a strong immune response to target tumor cells. Additionally, immune-related adverse events (irAEs) from ICIs may indicate a stronger immune response and improved tumor outcomes and treating them with immunosuppressive agents could therefore reduce immune activity and the efficacy of ICIs. For instance, data from the Dutch Melanoma Treatment Registry (DTMR) showed that patients with advanced melanoma who experienced severe ICI toxicity had a longer median overall survival (OS) (23 months vs. 15 months), but those needing anti-TNF therapy for steroid-refractory toxicity had worse outcomes (17 months vs. 27 months with steroids alone). In a study of patients with advanced NSCLC (n=640), oral or intravenous corticosteroid use (>/= 10 mg prednisone equivalent per day) at the time of or within 30 days of starting PD-1/PD-L1 blockade with either pembrolizumab, nivolumab, atezolizumab, or durvalumab (n=90) was associated with decreased response and overall poorer outcomes, compared to those who received and discontinued corticosteroid treatment prior to commencing PD-1/PD-L1 therapy. Further, an international multicenter cohort study in melanoma patients who developed irAEs with ICI therapy found that higher peak doses of corticosteroids, but not cumulative doses, were associated with worse survival, though the impact of second-line immunosuppressants remains unclear. A prospective observational study using data from a German multicenter skin cancer registry (ADOREG) evaluated patients with unresectable advanced melanoma who received immunosuppressive therapy (IST) (e.g., methylprednisolone, prednisolone, dexamethasone, infliximab, interferon, methotrexate) within 60 days before or within 30 days after the start of an ICI. The initiation of IST before, but not after the start of ICI, was associated with worse progression free survival in patients without brain metastasis, and worse OS in patients with brain metastasis. However, based on available literature, it is difficult to determine whether these effects are due to corticosteroid and/or immunosuppressant use or if they reflect subgroups of patients in studies with poorer prognoses.
MANAGEMENT: Caution and closer monitoring for reduced efficacy of immune checkpoint inhibitors (ICI) is advised if corticosteroids and/or other immunosuppressants are used concurrently. Based on available literature, the use of immunosuppressants and/or systemic corticosteroids (>=10 mg prednisone equivalent/day) should be avoided at the time of, or within 30 to 60 days of starting therapy with an ICI if clinically possible. Corticosteroids and/or immunosuppressants can generally be safely used for the treatment of immune-mediated reactions after starting an ICI. Some manufacturers advise that corticosteroids may be used as premedication when the ICI is used in combination with chemotherapy, as antiemetic prophylaxis, and/or to alleviate chemotherapy-related adverse effects. Individual product labeling for the ICI in question should be consulted for specific recommendations.
References (29)
- Arbour KC, Mezquita L, Long N, et al. (2018) "Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer." J Clin Oncol, 36, p. 2872-2878
- (2020) "Product Information. Novoeight (antihemophilic factor)." Novo Nordisk Pharmaceuticals Inc
- Horvat TZ, Adel NG, Dand TO, et al. (2015) "Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center." J Clin Oncol, 33, p. 3193-8
- Jove M, Vilarino N, Nadal E (2019) "Impact of baseline steroids on efficacy of programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) blockade in patients with advanced non-small cell lung cancer." Transl Lung Cancer Res, 8, S364-8
- Scott SC, Pennell NA (2018) "Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab." J Thorac Oncol, 13, p. 1771-5
- Fuca G, Galli G, Poggi M, et al. (2019) "Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors." ESMO Open, 4, e000457
- (2022) "Product Information. Imfinzi (durvalumab)." AstraZeneca Pty Ltd
- (2023) "Product Information. Yervoy (ipilimumab)." Bristol-Myers Squibb, SUPPL-129
- (2021) "Product Information. Yervoy (ipilimumab)." Bristol-Myers Squibb Australia Pty Ltd, V15.0
- (2022) "Product Information. Yervoy (ipilimumab)." Bristol-Myers Squibb Pharmaceuticals Ltd
- (2023) "Product Information. Libtayo (cemiplimab)." Regeneron Pharmaceuticals Inc, SUPPL-16
- (2023) "Product Information. Libtayo (cemiplimab)." Sanofi-Aventis Australia Pty Ltd, lib-ccdsv7-piv4-05ju
- (2023) "Product Information. Libtayo (cemiplimab)." Sanofi
- (2023) "Product Information. Tecentriq (atezolizumab)." Genentech, SUPPL-51
- (2023) "Product Information. Imfinzi (durvalumab)." Astra-Zeneca Pharmaceuticals, SUPPL-42
- (2023) "Product Information. Opdualag (nivolumab-relatlimab)." (Obsolete) Bristol-Myers Squibb Australia Pty Ltd, 2
- (2022) "Product Information. Opdualag (nivolumab-relatlimab)." Bristol-Myers Squibb
- (2024) "Product Information. Keytruda (pembrolizumab)." Merck Sharp & Dohme LLC, SUPPL-160
- (2024) "Product Information. Keytruda (pembrolizumab)." Merck Sharp & Dohme (Australia) Pty Ltd
- (2024) "Product Information. Keytruda (pembrolizumab)." Merck Sharp & Dohme (UK) Ltd
- (2024) "Product Information. Tecentriq (atezolizumab)." Roche Products Pty Ltd
- (2024) "Product Information. Tecentriq Hybreza (atezolizumab-hyaluronidase)." Genentech
- Kochanek C, Gilde C, Zimmer L, et al (2024) Effects of an immunosuppressive therapy on the efficacy of immune checkpoint inhibition in metastatic melanoma - An analysis of the prospective skin cancer registry ADOREG https://www.sciencedirect.com/science/article/pii/S0959804923008109#:~:text=Immuno
- Verheijden RJ, Burgers FH, Janssen J, et al (2024) Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma https://www.ejcancer.com/article/S0959-8049(24)00828-1/fulltext#:~:text=Recent%20studies%20indicate%20an%20association,secon
- Verheijden RJ, May AM, Black CU, et al. (2024) Association of anti-TNF with decreased survival in steroid refractory ipilimumab and anti-PD1-treated patients in the dutch melanoma treatment registry https://pubmed.ncbi.nlm.nih.gov/31988197/
- (2024) "Product Information. Tecentriq (atezolizumab)." Roche Products Ltd
- (2024) "Product Information. Imfinzi (durvalumab)." AstraZeneca UK Ltd
- Kostine M, Mauric E, Tison A, et al. (2021) "Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events." Eur J Cancer, 157, p. 474-84
- BeiGene AUS (2025) Australian product information Tevimbra (tislelizumab (rch)) https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent=&id=CP-2024-PI-02006-1&d=20250108172310101&d=20250108172310101.&d=20250130172310101
Drug and food interactions
methotrexate food
Applies to: methotrexate
MONITOR: Limited data suggest that consumption of greater than 180 mg/day of caffeine may interfere with the efficacy of methotrexate (MTX) in patients with rheumatoid arthritis. The exact mechanism of interaction is unknown but may be related to the antagonistic effect of caffeine on adenosine receptors, as anti-inflammatory properties of MTX is thought to result from the accumulation of adenosine. In a study of 39 patients treated with MTX 7.5 mg/week (without folate supplementation) for 3 months, patients with high caffeine intake (more than 180 mg/day) experienced significantly less improvement in morning stiffness and joint pain from baseline than patients with low caffeine intake (less than 120 mg/day). There were no significant differences between the responses of patients with moderate caffeine intake (120 to 180 mg/day) and those of the other 2 groups. In an interview of 91 patients treated with MTX, 26% of patients who discontinued the drug were regular coffee drinkers compared to only 2% of those still receiving the drug. Because treatment failure was the reason for MTX discontinuation in 80% of patients who discontinued, the investigators suggested that caffeine may have interfered with MTX efficacy.
MANAGEMENT: Until further information is available, the potential for interaction should be considered in patients who consume substantial amounts of caffeine and caffeine-containing foods and are prescribed methotrexate for rheumatoid arthritis. It may be appropriate to limit caffeine intake if an interaction is suspected in cases of treatment failure.
References (1)
- Nesher G, Mates M, Zevin S (2003) "Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis." Arthritis Rheum, 48, p. 571-572
methotrexate food
Applies to: methotrexate
GENERALLY AVOID: Coadministration of methotrexate with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Methotrexate, especially at higher dosages or during prolonged treatment, has been associated with severe hepatotoxicity including acute hepatitis, chronic fibrosis, cirrhosis, and fatal liver failure.
MANAGEMENT: The risk of hepatic injury should be considered when methotrexate is used with other potentially hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Baseline and periodic monitoring of hepatic function is recommended, while liver biopsy may be warranted during long-term use of methotrexate. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, pale stools, and jaundice.
References (3)
- (2002) "Product Information. Methotrexate (methotrexate)." Lederle Laboratories
- Cerner Multum, Inc. "UK Summary of Product Characteristics."
- (2023) "Product Information. Methotrexate (methotrexate)." Hospira Inc
methotrexate food
Applies to: methotrexate
MONITOR: Limited data suggest that consumption of greater than 180 mg/day of caffeine may interfere with the efficacy of methotrexate (MTX) in patients with rheumatoid arthritis. The exact mechanism of interaction is unknown but may be related to the antagonistic effect of caffeine on adenosine receptors, as anti-inflammatory properties of MTX is thought to result from the accumulation of adenosine. In a study of 39 patients treated with MTX 7.5 mg/week (without folate supplementation) for 3 months, patients with high caffeine intake (more than 180 mg/day) experienced significantly less improvement in morning stiffness and joint pain from baseline than patients with low caffeine intake (less than 120 mg/day). There were no significant differences between the responses of patients with moderate caffeine intake (120 to 180 mg/day) and those of the other 2 groups. In an interview of 91 patients treated with MTX, 26% of patients who discontinued the drug were regular coffee drinkers compared to only 2% of those still receiving the drug. Because treatment failure was the reason for MTX discontinuation in 80% of patients who discontinued, the investigators suggested that caffeine may have interfered with MTX efficacy.
MANAGEMENT: Until further information is available, the potential for interaction should be considered in patients who consume substantial amounts of caffeine and caffeine-containing foods and are prescribed methotrexate for rheumatoid arthritis. It may be appropriate to limit caffeine intake if an interaction is suspected in cases of treatment failure.
References (1)
- Nesher G, Mates M, Zevin S (2003) "Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis." Arthritis Rheum, 48, p. 571-572
Therapeutic duplication warnings
No warnings were found for your selected drugs.
Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.
See also
Drug Interaction Classification
Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit. | |
Moderately clinically significant. Usually avoid combinations; use it only under special circumstances. | |
Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan. | |
No interaction information available. |
Further information
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