Trastuzumab Biosimilars in the Therapy of Breast Cancer - "Real World" Experiences from four Bavarian University Breast Centres.

Introduction With the introduction of the first trastuzumab biosimilar in the summer of 2018, biosimilar antibodies for breast cancer have found their way into the area of gynaecological oncology. The switch of anti-human epidermal growth factor receptor 2 (HER2) therapy from the reference drug Herceptin ® to a biosimilar has presented challenges to the clinics. In addition to structural and organisational measures, training of employees as well as patient briefing and acceptance were major challenges. The study presented here records - within the context of quality assurance - how the switch to a trastuzumab biosimilar was implemented at four Bavarian university clinics in the Purchasing Association of Bavarian University Pharmacies. Materials/Methods Questionnaires on treatment figures and the switching process were sent to breast centres and pharmacies of four Bavarian university clinics between July and December 2019. The neoadjuvant, adjuvant and metastasised anti-HER2 therapy with trastuzumab with or without pertuzumab was recorded, evaluated and summarised. Results In the anti-HER2-therapy, trastuzumab was used intravenously (i. v.) and subcutaneously. Between July and December 2018, all four clinics in the Purchasing Association switched the i. v. trastuzumab therapy from the reference drug (Herceptin) to a biosimilar (for 2018: Kanjinti ® ). Over 200 patients were treated with trastuzumab i. v. in each of the two half-years of 2018 (before and after the switch). The spectrum of side effects and pCR rates under therapy with the biosimilar were comparable to the experiences made with the reference drug. Three out of four clinics provided training to employees and informed patients by means of a defined information leaflet. Patient acceptance was high. Summary The anti-HER2 therapy could be switched successfully and safely to trastuzumab biosimilars at the Bavarian university hospitals. This may serve as guideline for the further implementation of biosimilars. The structures necessary for this initial switching process have been prepared with trastuzumab as an example.

Cytochrome p450 polymorphisms in geriatric patients: impact on adverse drug reactions--a pilot study.

BACKGROUND AND OBJECTIVE: Up to 23% of the population, depending on their ethnic background, has genetically determined differences in the metabolism of drugs by the cytochrome P450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6. The aim of this survey was to determine the relationship between genetical polymorphisms in these CYP enzymes and adverse drug reactions (ADRs) in geriatric patients. STUDY DESIGN: In a prospective 6-month cohort study of 243 patients in a geriatric rehabilitation ward, mean age 80.2 +/- 7.7 years, ADRs were identified by intensive monitoring by a pharmacoepidemiological team, consisting of pharmacists and physicians. 125 out of these 243 patients were genotyped cross-sectionally for polymorphisms of CYP2C9, CYP2C19 and CYP2D6 by the TaqMan-polymerase chain reaction. The main outcome measures were the prevalence of genetical polymorphisms and the patients' risk for developing an ADR as related to the genotype. RESULTS: Patients received an average of 14.2 drugs during hospitalisation which led to 251 ADRs in the whole cohort and 149 ADRs in the cross-sectional genotyping study. Genotype frequencies of CYP2C9 enzyme were 25.9% (n = 29) intermediate metabolisers (IMs) and 2.7% (n = 3) poor metabolisers (PMs). For the enzyme CYP2C19, 26.8% (n = 33) IMs and 0.8% (n = 1) PMs were detected. For the enzyme CYP2D6, 24.1% (n = 26) IMs and 3.7% (n = 4) PMs were found in the analysed patient population. In total, 61.6% (n = 77) of genotyped patients experienced mutations in at least one of the three cytochrome enzymes. The ADR rate did not differ significantly between patients with genetic mutations and wild-type genotype patients. Moreover, only eight out of 40 ADRs which were associated with drugs metabolised by CYP2C9, CYP2C19 or CYP2D6 were detected in patients with IM genotype and none in patients with PM genotype. CONCLUSION: In this investigation geriatric patients showed a high rate of ADRs. However, no association between the ADR rate and the patients' genotype could be detected, which most likely was a result of the small number of patient samples analysed. Although prophylactic genotyping would have not prevented ADRs in this pilot study, physicians nevertheless have to be aware of potential genetic mutations in patients with polypharmacy.

The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients.

BACKGROUND AND OBJECTIVE: Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients. PATIENTS AND METHODS: An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nuremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information. RESULTS: A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs. CONCLUSION: This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.

Identification of adverse drug reactions in geriatric inpatients using a computerised drug database.

INTRODUCTION AND OBJECTIVE: Geriatric patients with multiple comorbidities are at high risk of experiencing an adverse drug reaction (ADR) during hospitalisation. The aim of the study was to compare the rate of ADRs as predicted by a computerised pharmacological database to the actual rate determined by direct observation in a sample of geriatric patients. STUDY DESIGN: During a 4-month period, geriatric patients were monitored using prospective observation. Patients were intensively screened for ADRs by a pharmacoepidemiological team (PET), consisting of two pharmacists and a physician. Actual ADRs detected by the PET were compared with those predicted by a computerised drug database. Furthermore, the set of actual ADRs, which resulted from drug-drug interactions (DDIs), were contrasted with potential DDIs signalled by the database. The main outcome measures were the incidence of actual ADRs. For the detection rate of the database we focused on frequent ADRs (>1% according to product information and database) and all DDIs indicated automatically by the database. RESULTS: 163 patients (121 female), mean age 79.8 +/- 7.1 years (range 60-98), were included in the study which was conducted on a geriatric rehabilitation hospital ward. The mean duration of hospitalisation was 24.3 +/- 8.4 days. Elderly patients received an average of 14.0 drugs (range 2-35) during their hospital stay. Of all patients, 60.7% experienced at least one ADR. The PET detected a total of 153 ADRs, with a mean of 0.9 ADRs per patient (range 0-5). The computerised drug database predicted an average of 309 potential ADRs for each patient; however, only 21 ADRs per patient were of high frequency. In 48% of ADR-positive patients (defined by PET) at least one of these frequent ADRs occurred.DDIs were detected by the PET in 14.7% of patients. Our database indicated a mean of 12 potential DDIs per patient. In 14 out of 24 DDI-positive patients, at least one signal indicated a real DDI. The database sensitivity was consequently 58.3%. CONCLUSION: In geriatric patients the incidence of ADRs is high. Computerised drug databases are a useful tool for detecting and avoiding ADRs. Our software, however, also produced a large number of signals that did not relate to actual ADRs found by the PET. The sheer number of these 'false' signals shows the need for refinement and optimisation of databases for daily clinical use.

Lack of awareness of community-acquired adverse drug reactions upon hospital admission : dimensions and consequences of a dilemma.

OBJECTIVE: Adverse drug reactions (ADRs) are a well-known cause of hospital admission. Nevertheless a quantitative estimate of the preventability of and physicians' awareness of these reactions is lacking. STUDY DESIGN AND METHODS: Using intensive bedside and computer-assisted drug surveillance methods a 13-month prospective pharmacoepidemiological survey was carried out on patients admitted to two medical wards of the Erlangen-Nuremberg University Hospital in Erlangen, Germany. This study aimed to define the incidence of preventable and unavoidable ADRs. In addition we investigated the awareness of the physicians to ADRs at the time of admission and the rate of contraindicated pre-admission prescriptions. RESULTS: In 78 (8.5%) of 915 (10.9%) admissions a total of 102 (42 preventable) community-acquired ADRs were detected on admission. In 45 (3.8%) of the admissions ADRs led directly to hospitalisation. 56.9% of the ADRs were not recognised by the attending physician on admission. Marked correlation was found between the awareness of ADRs and their probability and severity scores (r = 0.85 and r = 0.94, respectively; p < 0.05). The most frequently detected ADRs were due to direct toxicity and secondary pharmacological effects. Idiosyncratic reactions were often missed and 18.6% of all drugs prescribed prior to admission were contraindicated. Leading the list were diuretics, analgesics/NSAIDs and antipsychotics/sedatives. CONCLUSIONS: Awareness of existing ADRs on hospital admission and appropriate prescribing prior to hospital admission require attention. Early detection of ADRs on hospital admission can be achieved by the use of computer support systems. Many ADRs could be prevented by adhering to indications and contraindications.