A life-threatening drug-drug interaction between capecitabine and brivudine in a patient with metastatic breast cancer
Angeliki Tsifi, George Papaxoinis, Panagiotis Diamantopoulos, Marina Mantzourani, Vasiliki Antoniadou, Asimina Halioti & Helen Gogas
To cite this article: Angeliki Tsifi, George Papaxoinis, Panagiotis Diamantopoulos, Marina Mantzourani, Vasiliki Antoniadou, Asimina Halioti & Helen Gogas (2019): A life-threatening drug- drug interaction between capecitabine and brivudine in a patient with metastatic breast cancer, Journal of Chemotherapy, DOI: 10.1080/1120009X.2019.1665875
To link to this article: https://doi.org/10.1080/1120009X.2019.1665875
Published online: 13 Sep 2019.
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Case Report
A life-threatening drug-drug interaction between capecitabine and brivudine in a patient with metastatic breast cancer
Angeliki Tsifi, George Papaxoinis, Panagiotis Diamantopoulos, Marina Mantzourani, Vasiliki Antoniadou, Asimina Halioti, Helen Gogas
First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
In the current report we present the case of a patient experiencing a life-threatening drug-drug interaction involving the concurrent administration of capecitabine and brivudine. A 65- year-old female with metastatic breast cancer was commenced on brivudine for Herpes Zoster, while on capecitabine treatment, by a phys- ician unfamiliar with the potential repercussions of this drug-drug interaction. As a result, she developed skin rash, severe oral mucositis, and severe and prolonged pancytopenia. These side effects were attributed to a serious interaction of capecitabine with brivudine, resulting in inhibition of dihydropyrimidine dehydrogenase. The patient was admitted for supportive care including intravenous hydration, parenteral nutrition, mouth care solutions, fluconazole, antimicrobial therapy, filgrastim, red blood cell and platelet transfusions. She success- fully recovered and was discharged on the 26th day after her admission. Drug-drug interactions can be ser- ious, even life-threatening; thus the physicians should be cautious when prescribing new drugs.
Keywords: Capecitabine, brivudine, drug interactions, dihydropyrimidine dehydrogenase, breast cancer, pancytopenia, mucositis
Introduction
During the last decades we have experienced a tre- mendous progress in preclinical research and a steep increase in the discovery of new drugs that inevitably has led to the hyper-specialization of medical doctors. Thus, the physician should be familiar with complex drug mechanisms of action, while global knowledge of all drug side effects and interactions is impossible. On the other hand, this great evolution in drug discovery has eventually led to an increase in the incidence of drug-related side effects and drug-drug interactions (DDIs). Therefore, the physician should always be extremely cautious when prescribing new medications.
In the current case report, we describe the case of a life-threatening DDI leading to a prolonged hospitalization.
Case report
A 65-year-old female with a history of hypothy- roidism, type 2 diabetes mellitus, and breast cancer,
Correspondence to: George Papaxoinis, First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Ag. Thoma 17, 115 27, Goudi, Greece. Email: [email protected]
for which she had undergone a left modified rad- ical mastectomy followed by adjuvant chemother- apy and radiation therapy, was on systemic chemotherapy with capecitabine monotherapy due to a relapse with metastatic disease. Capecitabine dose was 1000 mg/m2 every 12 h for 14 days fol- lowed by 7 days’ rest, repeated every 21 days. While she was on day 5 of chemotherapy cycle with capecitabine tablets, she was diagnosed by her family doctor with Herpes Zoster and was pre- scribed brivudine tablets 125 mg once daily, which she continued receiving for a total of 7 days. On day 14 of the chemotherapy cycle, she developed a skin rash and severe oral mucositis (NCI CTC
v.4.0 grade 4) thus becoming unable to receive flu-
ids by mouth. As a result, she was admitted to our department for further management (Figure 1).
Additionally, the patient complained of grade 3 diarrhoea and grade 3 weakness, while grade 3 hand and foot syndrome was noticed on clinical examination. A complete blood count (CBC) showed a rapidly deteriorating pancytopenia (Figure 2) with neutropenia becoming grade 4 on day 3 of her admission (day 17 of chemotherapy cycle), thrombocytopenia grade 4 on day 4 (day 18
© 2019 Edizioni Scientifi che per l’Informazione su Farmaci e Terapia
DOI 10.1080/1120009X.2019.1665875 Journal of Chemotherapy 2019 1
Tsifi et al. A life-threatening drug-drug interaction between capecitabine and brivudine
of chemotherapy cycle) and anaemia grade 3 on day 8 of admission (day 22 of chemotherapy cycle). Due to the worsening neutropenia the patient was immediately started on filgrastim 48 I.U. daily sub- cutaneously. Capecitabine was discontinued imme- diately upon her admission and the patient was transfused with red blood cells and platelets. At that time a CBC examination revealed a neutrophil count of 0.2 × 109/L (Normal values 1.5–6.6 × 109/ L), haemoglobin levels of 13.2 g/dl (Normal values 12–16 g/dl) and a platelet count 91 × 109/L (Normal
Figure 1 Oral mucositis grade 4 that lasted more than 14 days.
values 140–440 × 109/L). She also underwent an upper gastrointestinal endoscopy, which revealed that she had developed a grade 4 oral, pharyngeal, and oesophageal mucositis and candidiasis and as a result she was additionally put on parenteral nutrition, on mouth care solutions, intravenous proton pump inhibitors (PPIs), and fluconazole. During the following days, she had a fever of
38.1 C. After blood and urine cultures were obtained, the patient was commenced on intraven- ous piperacillin-tazobactam, amikacin, and vanco- mycin. The blood cultures yielded Aeromonas hydrophila and Escherichia coli, both susceptible to piperacillin-tazobactam, thus vancomycin and amikacin were discontinued. The patient eventually became afebrile on day 10 of hospitalization but was still in need of multiple red blood cell and platelet transfusions and daily administration of fil- grastim, because of persistent severe thrombocyto- penia and agranulocytosis, with her platelet count
below 10 × 109/L, her neutrophil count remaining undetectable and her haemoglobin levels below
8.0 g/dL. On day 13 of her admission, the patient demonstrated signs of a lower respiratory infection and the fever recurred. The patient was commenced on aztreonam and amikacin intravenously based on the results of a sputum culture positive for Klebsiella pneumoniae and a skin-lesion culture positive for Pseudomonas aeruginosa. All blood cultures were negative. After two weeks of hospital- ization the patient’s white cell and platelet counts gradually begun to recover, the filgrastim injections and parenteral nutrition were discontinued and the patient was carefully started on an oral diet. After the completion of a 14-day antimicrobial treatment and of a 21-day fluconazole treatment the patient was successfully discharged on day 26 of admission.
Figure 2 Diagram describing the evolution of blood neutrophil, platelet and haemoglobin levels during hospital admission of the patient.
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Tsifi et al. A life-threatening drug-drug interaction between capecitabine and brivudine
Discussion
DDIs are sometimes severe and may be even fatal, if overlooked.1 The physician in charge should be careful of DDIs when prescribing a new drug. This seems to be the case with capecitabine and its ser- ious interaction with soribudine and its analogues, such as brivudine, resulting in maximizing the adverse effects of capecitabine due to the inhibition of dihydropyrimidine dehydrogenase and occasion- ally having a fatal outcome.2,3
Capecitabine is an effective antimetabolite that is currently approved for colorectal and breast can- cer.4,5 It is an orally administered fluoropyrimidine carbamate activated by thymidine phosphorylase.6 After its oral administration, it is fully absorbed by the intestinal membrane and it is converted in the liver into 5΄ -deoxy-5-flourocytidine (5΄ -DFCR) by carboxylesterase.6 It is then converted into 5΄deoxy- 5-flourouridine (5΄ -DFUR) by cytidine deaminase, an enzyme that can be found in most tissues, espe- cially in healthy liver tissue and human tumour tis- sues.6 Finally, 5΄ -DFUR is converted into 5- Fluorouracil (5-FU) by thymidine phosphorylase, which is also an enzyme found in great concentra- tions in healthy liver tissue and human tumours.6 Thus, 5FU is used as a potent anticancer drug, respecting the healthy tissues and mainly, targeting tumour tissues.6,7 5-FU is subsequently catabolized by dihydropyrimidine dehydrogenase (DPD) and other enzymes into inactive metabolites, or anabol- ized by thymidine phosphorylase and thymidine kin- ase into cytotoxic molecules.3–6
The adverse effects of capecitabine are usually
well tolerable and can be efficiently managed by dose reduction.7 They include diarrhoea, stomatitis, nausea, vomiting, abdominal pain and hand-foot syndrome, while they are associated with a lower incidence of myelotoxicity compared to infusional 5-FU.6,7
In 1993, the new oral antiviral drug sorivudine [1-beta-D-arabinofuranosyl-(E) -5-(2-bromoviny- l)uracil] was approved by the Japanese government. As a result of its use in patients with cancer and Herpes Zoster eighteen people died after exhibiting severe myelotoxicity and gastrointestinal haemor- rhage.8 The combination of the two drugs resulted in an extremely dangerous interaction, because sor- ivudine’s metabolite 5-bromovinyluracil was shown to inhibit DPD and as a result the catabolism of 5- FU, thus leading to toxic levels of 5-FU and exces- sive toxicity.8
Brivudine [(E)-5-(2-bromovinyl)-2΄-deoxyuridine]
is a thimydine nucleoside analogue with activity against Varicella-Zoster virus.9,10 After its phos- phorylation it interacts with the viral DNA
polymerase and inhibits the replication of the virus.10 Similarly to its predecessor, brivudine is also implicated in DDI’s with 5-FU, an interaction that is explicitly mentioned in the drug’s label.7,11 Nevertheless, it was given to our patient and as a consequence, the toxic effects of orally adminis- tered capecitabine were intensified by the simultan- eous administration of a drug that inhibits DPD.
The early diagnosis of capecitabine and brivu- dine interaction may be difficult in cancer patients. The physician can be misled by the early symptoms of the patient or even misinterpret the severity of the threat that this interaction constitutes for the patient’s life. An accurate acquisition of recent medical history before the addition of the new regi- men by the physician in charge should be sufficient for the acceleration of the diagnostic process.
Treatment and management
Once the diagnosis of capecitabine and brivudine interaction was made, the patient was urgently admitted due to the anticipated maximization of capecitabine’s toxicity and the likelihood of a fatal outcome at two to four weeks from the onset of symptoms as described in various case reports.2,3 As already mentioned above, parenteral nutrition and antifungal treatment was commenced, and the patient received blood and platelet transfusions and filgrastim subcutaneously. Her neutropenic fever was controlled with broad spectrum antibiotics as were the hospital acquired infections. Contrary to most of the cases presented in the literature that were associated with fatal results, the patient recov- ered successfully from the toxicity and was dis- charged and referred to her oncologist.2,3
However, side effects may persist for a long time
or cause irreversible disability and thus these patients frequently need continuous supportive care.7 Therefore, for the prevention of serious or even life-threatening DDIs strict protocols should be implemented aiming at effectively control the drug prescription process. This could be achieved with the collaboration of both doctors and phar- macists. The type of drug that is being adminis- tered and what should be avoided- for example food- should be adequately explained to the patient. Also, the establishment of up-to-date elec- tronic files containing disease and medication his- tory would greatly contribute to the prevention of prescription errors and DDIs. Finally, simple meas- ures such as wrist bands worn by patients while on specific treatments and indicating which drugs should be avoided could further decrease unfortu- nate DDI-related incidents.
After all, adverse effects precipitated by DDIs
can be immense in terms of morbidity and
Journal of Chemotherapy 2019 3
Tsifi et al. A life-threatening drug-drug interaction between capecitabine and brivudine
mortality.1 In the European Union it is believed that they are responsible for 5% of hospital admis- sions and for 197.000 of deaths annually.12 Fortunately, to our knowledge there is only a small number of fatal cases involving a capecitabine- bri- vudine interaction, most of which occurred despite the warning labels on the medication package.2 Specifically, in our case the wrong treatment of choice for Herpes Zoster was selected. Since the patient was already on capecitabine, another anti- viral regimen such as acyclovir should have been considered.7 As an alternative, if the patient is already receiving brivudine, a minimum of four weeks should transpire until the patient is able to receive capecitabine.7 Ideally, DPD enzyme activity should be measured before the initiation of any treatment with fluoropyrimidines in order to fur- ther decrease the probability of enhancement of their adverse effects.7–9
Finally, it should be noted that uridine triacetate
was recently approved as an antidote in cases of fluoropyrimidine overdosage or associated severe/ life-threatening toxicity.13 It is an acetylated pro- drug of uracil that acts as a uridine replacement therapy. More specifically, uridine triacetate is an orally administered agent that is converted to uri- dine by deacetylases. This leads to increased uri- dine levels, which compete the cytotoxic effect of 5- FU. The drawback of this agent is that its activity is proven only when administered within 72 hours from fluoropyrimidine administration.14 Therefore, its use was not indicated in the present case.
Conclusions
In this report we present the case of a life-threaten- ing DDI in a patient with breast cancer, who recovered successfully after long-lasting hospitaliza- tion. The message of this report is that the treating physician should be careful when prescribing new drugs and check interactions with those currently administered. The collaboration between physicians and pharmacists, as well as the presence of elec- tronic patient files and the use of special advisory wrist bands are important measures in order to prevent prescription errors and eventually DDIs.
Disclosure statement
The authors declare no conflict of interest related to the study.
Notes on contributors
Angeliki Tsifi MD is a consultant internist with special interest in critical care.
George Papaxoinis MD, PhD is a consultant med- ical oncologist.
Panagiotis Diamantopoulos MD, PhD is a consultant internist with special interest in hemato-oncology.
Marina Mantzourani MD, PhD is an associate professor in internal medicine.
Vasiliki Antoniadou MD is a cardiology registrar.
Asimina Halioti MD is an internal medi- cine registrar.
Helen Gogas MD, PhD is a professor in medical oncology, head of the First Department of Medicine of the National and Kapodistrean University of Athens, with special interest in mel- anoma and breast cancer.
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