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Drug Interactions between penicillamine and tremelimumab

This report displays the potential drug interactions for the following 2 drugs:

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Moderate

penicillAMINE tremelimumab

Applies to: penicillamine and tremelimumab

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)
  1. 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
  2. (2020) "Product Information. Novoeight (antihemophilic factor)." Novo Nordisk Pharmaceuticals Inc
  3. 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
  4. 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
  5. 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
  6. 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
  7. (2022) "Product Information. Imfinzi (durvalumab)." AstraZeneca Pty Ltd
  8. (2023) "Product Information. Yervoy (ipilimumab)." Bristol-Myers Squibb, SUPPL-129
  9. (2021) "Product Information. Yervoy (ipilimumab)." Bristol-Myers Squibb Australia Pty Ltd, V15.0
  10. (2022) "Product Information. Yervoy (ipilimumab)." Bristol-Myers Squibb Pharmaceuticals Ltd
  11. (2023) "Product Information. Libtayo (cemiplimab)." Regeneron Pharmaceuticals Inc, SUPPL-16
  12. (2023) "Product Information. Libtayo (cemiplimab)." Sanofi-Aventis Australia Pty Ltd, lib-ccdsv7-piv4-05ju
  13. (2023) "Product Information. Libtayo (cemiplimab)." Sanofi
  14. (2023) "Product Information. Tecentriq (atezolizumab)." Genentech, SUPPL-51
  15. (2023) "Product Information. Imfinzi (durvalumab)." Astra-Zeneca Pharmaceuticals, SUPPL-42
  16. (2023) "Product Information. Opdualag (nivolumab-relatlimab)." Bristol-Myers Squibb Australia Pty Ltd, 2
  17. (2022) "Product Information. Opdualag (nivolumab-relatlimab)." Bristol-Myers Squibb
  18. (2024) "Product Information. Keytruda (pembrolizumab)." Merck Sharp & Dohme LLC, SUPPL-160
  19. (2024) "Product Information. Keytruda (pembrolizumab)." Merck Sharp & Dohme (Australia) Pty Ltd
  20. (2024) "Product Information. Keytruda (pembrolizumab)." Merck Sharp & Dohme (UK) Ltd
  21. (2024) "Product Information. Tecentriq (atezolizumab)." Roche Products Pty Ltd
  22. (2024) "Product Information. Tecentriq Hybreza (atezolizumab-hyaluronidase)." Genentech
  23. 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
  24. 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
  25. 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/
  26. (2024) "Product Information. Tecentriq (atezolizumab)." Roche Products Ltd
  27. (2024) "Product Information. Imfinzi (durvalumab)." AstraZeneca UK Ltd
  28. 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
  29. 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

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Drug and food interactions

Moderate

penicillAMINE food

Applies to: penicillamine

ADJUST DOSING INTERVAL: Food may interfere with the gastrointestinal absorption of penicillamine. In a study of six healthy volunteers, administration of penicillamine (500 mg) following a standard breakfast reduced the mean peak plasma concentrations of penicillamine by 48% compared to administration in the fasting state.

MANAGEMENT: Penicillamine should be administered on an empty stomach, at least one hour before or two hours after meals, and at least one hour apart from any other drug, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract.

References (2)
  1. Osman MA, Patel RB, Schuna A, Sundstrom WR, Welling PG (1983) "Reduction in oral penicillamine absorption by food, antacid and ferrous sulfate." Clin Pharmacol Ther, 33, p. 465-70
  2. (2001) "Product Information. Cuprimine (penicillamine)." Merck & Co., Inc

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Moderate

penicillAMINE food

Applies to: penicillamine

ADJUST DOSING INTERVAL: Oral administration of aluminum, copper, iron, zinc, magnesium, and possibly other minerals such as calcium may decrease the gastrointestinal absorption of penicillamine, and vice versa. The proposed mechanism involves chelation of penicillamine to polyvalent cations, which leads to formation of a nonabsorbable complex. In a study of six healthy volunteers, administration of penicillamine (500 mg) following a single dose of ferrous sulfate (300 mg) or antacid (Maalox Plus 30 mL) reduced the mean peak plasma concentration of penicillamine by 65% and 34%, respectively, compared to administration in the fasting state. In addition to chelation, some investigators suggest that antacids may also reduce penicillamine bioavailability by increasing gastric pH, which favors the oxidation of penicillamine to its poorly absorbed disulfide form. These changes could result in diminished therapeutic effects of penicillamine.

MANAGEMENT: Mineral supplements or other products containing polyvalent cations (e.g., antacids or preparations containing antacids such as didanosine buffered tablets or pediatric oral solution) should be administered at least two hours before or two hours after the penicillamine dose. In addition, pharmacologic response to penicillamine should be monitored more closely whenever these products are added to or withdrawn from therapy, and the penicillamine dosage adjusted as necessary. When penicillamine is coadministered with Suprep Bowel Prep (magnesium/potassium/sodium sulfates), the manufacturer recommends administering penicillamine at least 2 hours before and not less than 6 hours after Suprep Bowel Prep to avoid chelation with magnesium.

References (8)
  1. Osman MA, Patel RB, Schuna A, Sundstrom WR, Welling PG (1983) "Reduction in oral penicillamine absorption by food, antacid and ferrous sulfate." Clin Pharmacol Ther, 33, p. 465-70
  2. Harkness JA, Blake DR (1982) "Penicillamine nephropathy and iron." Lancet, 2, p. 1368-9
  3. Netter P, Bannwarth B, Pere P, Nicolas A (1987) "Clinical pharmacokinetics of D-penicillamine." Clin Pharmacokinet, 13, p. 317-33
  4. Joyce DA (1989) "D-penicillamine pharmacokinetics and pharmacodynamics in man." Pharmacol Ther, 42, p. 405-27
  5. (2001) "Product Information. Cuprimine (penicillamine)." Merck & Co., Inc
  6. Haagsma CJ (1998) "Clinically important drug interactions with disease-modifying antirheumatic drugs." Drugs Aging, 13, p. 281-9
  7. Lyle WH (1976) "Penicillamine and iron." Lancet, 2, p. 420
  8. (2010) "Product Information. Suprep Bowel Prep Kit (magnesium/potassium/sodium sulfates)." Braintree Laboratories

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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.


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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor 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.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.