A study of drug-drug interactions in cancer patients of a south Indian tertiary care teaching hospitalG Kannan1, R Anitha2, Vanitha N Rani1, P Thennarasu1, J Alosh1, J Vasantha1, JR Martin2, MRC Uma1
1 Department of Pharmacy Practice, General Medicine, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India
2 Department of Medical Oncologists, General Medicine, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.85207
Source of Support: None, Conflict of Interest: None
Background : Drug interactions in oncology are of particular importance owing to the narrow therapeutic index and the inherent toxicity of anticancer agents. Interactions with other medications can cause small change in pharmacokinetics or pharmacodynamics of chemotherapeutic agents that could significantly alter their safety and efficacy. Aim : To identify and document the potential drug-drug interactions in prescriptions of patients receiving cancer chemotherapy. Settings and Design : A tertiary care teaching hospital based prospective study. Materials and Methods : Patients admitted in the medical oncology wards with different types of malignancies and receiving cancer chemotherapy during the period of June 2009 to November 2009 were included in the study. A detailed data collection was done in a specially designed proforma with ethical approval and consent of patients and their prescriptions were subjected to drug-drug interaction screening using Drug Interaction Fact Software Version-4 and standard references. Incidence of drug-drug interactions, their types, correlation between age, cancer type, number of drugs prescribed and incidence of drug interactions were analyzed. Statistical Analysis : Logistic regression analysis and Odds ratio were performed to identify the incidence of drug-drug interactions and their correlation with the factors above mentioned. Results : A total of 75 patients (32 males and 43 females; median age 56 years, age range 23-74) were enrolled in the study and their prescriptions were screened. 213 interactions were identified of which, 21 were major, 121 were moderate and 71 were minor. There were 13 (6.1%) clinically significant interactions between anticancer drugs and 14 (6.5%) drug-drug interactions between anticancer drugs and other drugs prescribed for co-morbidities. There was a positive correlation between number of drugs prescribed and drug interactions (P=0.011; OR 0.903). Conclusion : Though there was not any life threatening interactions, the potential interactions were brought to the oncologist purview for ensuring patients safety and to avoid undesirable effects.
Keywords: Cancer chemotherapy, drug interactions, oncology
A drug interaction is defined as the pharmacological or clinical response to the administration or co-exposure of a drug with another substance that modifies the patient's response to the drug.  It is reported that 20-30% of all adverse reactions to drugs are caused by interactions between drugs. This incidence increases among the elderly and patients who take two or more medications. The term 'drug interaction' is most often used to describe drug-drug interactions, but there are various substances and/or factors that can alter the pharmacokinetics and/or pharmacodynamics of medications. These include food,  nutritional supplements,  formulation excipients and environmental factors such as cigarette smoking. 
Drug interactions are frequent in medical practice, and their incidence increases with the number of concurrent medications.  In a study of 205 outpatients seen in an emergency room in Los Angeles, the prevalence of potential drug interactions was 13% in those who received two medications, and 82% in those who were prescribed seven or more drugs.  The elderly are particularly prone to drug interactions, as they are more likely to take between three and seven drugs.  In addition to age, other risk factors for drug interactions are malnutrition, malabsorption, chronic liver disease (including liver metastasis), and impaired renal function. 
Interpatient variability is also an important factor that can influence drug interactions. Important variables are gender, age, genetics and/or co-morbid conditions. These can affect patient responses to treatment and the toxicity profile of the agent. Polypharmacy prevails in many chronic diseases.  Patients with cancer are particularly at risk of drug interactions as they may be taking many different medications as a part of their cancer treatment or for the management of other illnesses. Although the administration of multiple concurrent drugs is likely to increase the risk of undesirable drug interactions, the magnitude of this problem in oncology practice is largely unknown.  This study was conducted with the objective of identifying the incidence of the potential drug-drug interactions, their severity based on various chemotherapy regimens and supportive care medicines in patients on cancer chemotherapy.
This prospective observational study was carried out in the medical oncology wards of a 1675 bedded, south Indian tertiary care teaching hospital, with the approval of the Institutional ethical committee and informed consent of the patients. Cancer patients admitted for receiving cancer chemotherapy during the period of June to November 2009 were included in the study. Patients' data including demographic details, lab investigations and medications prescribed including anti-cancer drugs, supportive care agents and medications for co-morbid conditions were collected using a special proforma designed for the study. Each patient's drug profile was subjected to the drug-drug interaction screening and the potential interactions were identified and reported to the Oncologist for ensuring patient safety and to avoid undesirable effects. Drug interaction screening was carried out by using Drug interaction facts software version 4 [Table 1]. For more pertinent information standard books like Stockley's Drug Interactions, American Health System Formulary Drug Information, were referred.
Drug interaction fact software version 4
Drug interaction fact software screens potential drug interactions and if one is identified, provides a description of pharmacological mechanisms for the interaction and classifies the interaction by level of severity and scientific evidence as follows:
Logistic regression analysis and Odds Ratio were done to assess the correlation between incidence of drug-drug interactions with age, number of drugs prescribed, associated co-morbid conditions, and type of cancer. The results were tabulated.
A total of 75 patients (32males and 43 females) patients with different types of malignancies receiving cancer chemotherapy were enrolled in the study during the period of June to November 2009. The characteristics of the 75 patients are described in [Table 2]. The median age was 56 years (range, 23- 74), and the most common cancer type was gastrointestinal. A total of 628 drugs were prescribed to 75 patients. Of these, 155 were anti-cancer drugs 430 were cancer therapy related drugs and 43 were medications to treat co-morbid illnesses.
Drug interaction screening tool identified 213 interactions in total, of which, 27 were considered to be potential and required clinical intervention. Of these, 13 interactions were identified between anti-cancer agents [Table 3] and 14 drug-drug interactions were identified between anti cancer drugs and other drug categories prescribed for co-morbidities [Table 4]. Based on the mechanism, 187 (88%) drug interactions were classified as pharmacokinetic, 11 (5%) as pharmacodynamic and 15 (7%) as unknown.
Based on the severity, 21 interactions were major, 121 were moderate and 71 were of minor. The scientific evidence for drug interactions was categorized into 5 types. Of 213 drug interactions identified, 4 (1.88%) interactions were categorized as established, 8 (3.75%) were categorized under probable, 20 (9.39%) were under suspected, 179 (84.04%) were under possible and 1(0.48%) under unlikely [Table 5].
Based on the logistic regression analysis and Odds ratio, a positive correlation was observed between the incidence of drug interactions and number of drugs prescribed (P=0.011, OR 0.903) [Table 6].
A hospital-based study has shown that 4% of cancer-related deaths are associated with drug interactions.  The goal of the present study was to quantify the prevalence of drug-drug interactions in cancer patients receiving chemotherapy.
In this short term prospective study, a total of 75 cancer patients were screened for drug-drug interactions. Of 213 drug-drug interactions identified in 75 patients, 21 were Major, 121 were Moderate and 71 were Minor and almost 15% were supported by good scientific evidence (level of evidence ≤3).
A study done by the team from Princess Margaret Hospital in Toronto, Canada, reported that more than a quarter of cancer patients may be at risk of potentially serious drug interactions, the chemotherapeutic agents were not the primary culprit rather, medications received for co-morbidities and cancer supportive care were more likely to be involved.  In cancer, most of the focus is been on anticancer agents interacting with non-anticancer agents. Though there is some of that type, the majority of interactions are between different classes of non-anticancer agents such as anti-diabetic agents, anti-hypertensive agents, antacids, anti-emetics, corticosteroids, analgesics and antibiotics.
In this study, drug-drug interactions were screened by using the software Facts and comparisons version 4 and this software had been found to have both sensitivity and specificity of 97% in detecting potential drug interactions in a previous study.  Most of the drug-drug interactions identified in this study were pharmacokinetic. A total of 187 interactions were pharmacokinetic in nature.
One of the major pharmacokinetic interactions involved in this study was between cyclophosphamide and doxorubicin. The addition of cyclophosphamide to doxorubicin treatment does not affect exposure to doxorubicin, but may result in an increase in exposure to doxorubicinol, a metabolite. Doxorubicinol only has 5% of the cytotoxic activity of doxorubicin. This pharmacokinetic interaction is not clinically significant and hence dose reduction of any of the agents or avoiding the concomitant use of these two agents is not needed. 
Pharmacodynamic interactions were reported to an extent of 5.16% in this study. Interaction between furosemide and amikacin was a major interaction of this type as it produces ototoxicity in patients by its additive effects. Interaction between cisplatin and docetaxel increases the risk of peripheral neuropathy during concurrent use of two agents and in some cases; the neuropathy may progress or become irreversible despite discontinuation of the medications.Patients on concurrent therapy with cisplatin and docetaxel should be monitored closely for symptoms of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. A similar effect is observed on co administration of paclitaxel and vincristine. Since the development of peripheral neuropathy may be dose-related, the recommended dosages should generally not be exceeded. Consideration should be given to dosage reductions or immediate discontinuation of these medications in patients who develop peripheral neuropathy to limit further damage. If necessary, therapy should generally be reinstituted only after resolution of neuropathy symptoms or return of symptoms to baseline status. In some cases, reduced dosages may be required. 
Coadministration of methotrexate with other agents known to induce hepatotoxicity may potentiate the risk of liver injury and is generally not recommended unless the potential benefit outweighs the risk. Patients prescribed with methotrexate in combination with other potentially hepatotoxic agents like cytarabine, paracetamol, prednisolone should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity. Baseline and regular monitoring of hepatic function is also recommended.
Drug interactions in cancer chemotherapy are of particular importance owing to the narrow therapeutic index and the inherent toxicity of anticancer agents. Interactions of cancer chemotherapeutic agents with other medications can cause small changes in the pharmacokinetics or pharmacodynamics of a chemotherapy agent that could significantly alter its efficacy or toxicity. A drug interaction has a significant impact on the clinical use of the interacting drugs when the plasma concentrations of these drugs are strongly correlated with both systemic toxicity and, in some cases, antitumor activity. It is only through prospective, preclinical and early clinical evaluation that these clinically significant drug interactions can be identified and the information used to provide better therapy for cancer patients. ,
According to the software some of the drug interactions were classified as unknown (without an exact mechanism). In this study 15 interactions were unknown. Interaction between 5-flurouracil and folinic acid (leucovorin) belongs to this category. 5-flurouracil induces its anticancer activity in part, by inhibiting thymidylate synthase through formation of a ternary complex between 5-flurouracil-thymidylate synthase and reduced folates. Many tumor cells have been found to have relatively low levels of reduced folates, thereby influencing the efficiency of thymidylate synthase inhibition by 5-flurouracil. Administration of folinic acid prior to 5-flurouracil therapy is now commonly used as a mechanism to optimize the use of this anticancer therapy for the treatment of colorectal, breast and head/neck carcinomas. 
Based on the onset of drug-drug interactions, majority of the interactions were delayed in nature. Interaction between insulin and dexamethasone, methotrexate and paracetamol were some examples of rapid onset. 20 patients with co-morbid conditions were screened for interactions. Most common co-morbid conditions were diabetes and hypertension. 67 interactions were identified in these patients of which, 11 interactions were between anti-diabetic or anti-hypertensive agents and supportive care drugs like steroids, anti-emetics, anti-histamines, analgesics and antacids.
When considering the risk of drug related problems, age is an important factor. Studies indicate that there is an increased incidence of adverse drug reactions in young, geriatric and elderly patients. Most elderly patients have at least one co-morbid illness and this leads to prescribing more number of drugs. In accordance with previous studies, the incidence of drug-drug interactions with number of drugs prescribed was statistically significant in this study indicating that increasing number of medications was a risk factor for potential drug interactions in our population. ,
This study is limited by the fact that it was performed in a single institution; thus, its external validity is unknown. Another limitation of this study is that, because of its high sensitivity, the screening software was capable of detecting the majority of drug interactions, including those supported by lower levels of evidence and those for which the clinical consequences are not severe.
This study was conducted to identify the incidence of drug-drug interactions, its frequency and severity in cancer patients. From this study, it was observed that potential drug interactions were frequent in chemotherapy and many were clinically important. These interactions seemed to be more likely to occur in patients who stay longer and who receive a higher number of medications. Development of alert guidelines and computer-based screening would help physicians to recognize and prevent potentially dangerous drug interactions.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]