Challenges of dispensing costly tablets with short shelf-life.

Afatinib, trametinib and regorafenib are three costly oral oncology drugs with a short shelf-life after the original container has been opened. Their short shelf-lives are due to degradation on exposure to moisture. Therefore, manufacturers recommend them to be dispensed in the original packaging with the desiccant. However, the prescribed quantities do not always match the quantities in the original packaging, usually because of dose modifications for toxicities. This leads to potentially significant drug wastage and financial losses. We describe some potential approaches to this issue.

Novel agents improve survival of transplant patients with multiple myeloma including those with high-risk disease defined by early relapse (<12 months).

The treatment of multiple myeloma (MM) has changed with the advent of thalidomide, bortezomib, and lenalidomide, the so-called novel agents (NAs). Given the complexity of MM therapy in the NA era we pursued a population based study to assess for improvements in survival as well as to characterize the relevance of early relapse (within 12 months) and the International Staging System in this clinical setting. We reviewed our experience with 460 patients with MM treated with autologous stem cell transplant (ASCT) between 1988 and 2008, of whom 306 had relapsed. The cohort was divided into two groups based upon relapse pre-2004 and relapse during/after 2004 (2004+), which correlated to availability of bortezomib and lenalidomide. Improvements in both overall survival (OS) (median 32.0 months vs. 71.8 months; p < 0.001) and post-relapse survival (PRS) (median 15.2 months vs. 42.8 months; p < 0.001) correlated with the NA era. Exposure to NAs conferred a better PRS (median 35.7 months vs. 9.1 months; p < 0.001). Although all patients had improvements in survival, those who relapsed late continued to do better. Lastly, in the NA era, the ISS remains an important prognostic tool in relapse, but only in the late relapsing cohort.

Evaluation of osmolality and pH of various concentrations of methotrexate, cytarabine, and thiotepa prepared in normal saline, sterile water for injection, and lactated Ringer's solution for intrathecal administration.

BACKGROUND: Neurotoxicity of intrathecal (IT) chemotherapy has been variously attributed to the preservatives, volume, osmolality, and pH of the preparations. There has been little evaluation of how different drug concentrations or diluents can affect the osmolality and pH of the final solution. We conducted a three-part study: survey of cancer centers regarding the drug concentrations and diluent used in preparing IT chemotherapy; review of the literature on common practice of preparing IT chemotherapy; evaluation of the pH and osmolality of commonly used chemotherapy preparations for IT. METHOD: We surveyed selected cancer centers to provide information on their standard volume, drug concentrations, and choice of diluents. MEDLINE was searched for clinical reports using the MeSH terms of 'cytarabine,' 'methotrexate,' or 'thiotepa' with the subheading 'Cerebrospinal fluid' and combined with 'intrathecal' in all database fields. Data retrieved included the choice of diluent, volume, and/or drug concentration. We evaluated the pH and osmolality of methotrexate (1, 2, 5, and 10 mg/mL), cytarabine (2, 5, 10, and 25 mg/mL), and thiotepa (1, 2, and 5 mg/mL) in normal saline, sterile water for injection (SWFI), and lactated Ringer's solution. RESULTS: Nine centers were surveyed (seven in Canada, one in Australia, one in United Kingdom). Most centers used 5 mL of preservative-free normal saline, irrespective of the drug or drug concentration used. Forty-four reports in the literature were reviewed. Most reported 5 mL of preservative-free normal saline. Most information on drug concentrations was provided for methotrexate, with an average concentration of about 1-2.5 mg/ mL. Cytarabine 0.4-20 mg/mL and thiotepa 1 mg/mL were also reported. In our in vitro evaluation, there was a trend of increased pH associated with increasing concentration of methotrexate and cytarabine. There was no apparent impact of thiotepa concentration on the pH values of the final preparations, irrespective of the diluent used. Except for cytarabine 10 and 25 mg/mL, all the tested solutions have pH within 10% of the physiologic range of CSF. There was a concentration-dependent change in osmolality with methotrexate and cytarabine preparations. Osmolality was increased with increased concentrations in all except methotrexate mixed in SWFI and thiotepa mixed in normal saline and lactated Ringer's solution. Except for some thiotepa solutions, all the tested solutions have osmolality within 10% of the physiologic range of CSF. CONCLUSIONS: There is limited published literature on the potential impact of diluent and drug concentration on the pH and osmolality of IT chemotherapy preparation. Most cancer centers conventionally prepare IT chemotherapy with 5 mL of preservative diluent normal saline, irrespective of the specific drug or dose used. The conventional practice means that most methotrexate preparations are likely to have comparable pH and osmolality to CSF. In contrast, cytarabine preparations may show significantly higher pH than the CSF, while thiotepa preparations generally have lower osmolality than the CSF.

Stability issues of parenteral chemotherapy drugs.

The pharmacist often needs to have all the information required to prepare and to assign an expiry date for parenteral products of antineoplastic agents. The pharmaceutical manufacturers usually provide data on how to prepare their products and the associated physicochemical stability. Standard reference texts also provide additional summary information of other primary data. However, it is not uncommon to find knowledge gaps in this area. Hence, additional extrapolation and consensus on interpretation is often needed to address issues not covered by data from the pharmaceutical manufacturers, standard reference texts, or official guidelines. Some of the key issues have been identified in our recent development of a chemotherapy preparation and stability chart. These include use of data from different brands, expiry date of original vial and final products, risk of contamination, infusion volume and stability, multi-day home-use products, syringe preparations, and products to be used immediately. Potential approaches to address these common issues are described in this article.

Interaction between mercaptopurine and milk.

Mercaptopurine is a purine analog used for acute lymphoblatic leukemia and chronic myelogenous leukemias. Since it is inactivated by xanthine oxidase (XO), concurrent intake of substances containing XO may potentially reduce bioavailability of mercaptopurine. Cow's milk is known to contain a high level of XO. In vitro and in vivo data suggest that concurrent intake of cow's milk may reduce the bioavailability of mercaptopurine. This interaction may be clinically significant. Therefore most patients should try to separate the timing of taking mercaptopurine and drinking milk.

Evaluation of predictive formulae for glomerular filtration rate for carboplatin dosing in gynecological malignancies.

OBJECTIVES: Carboplatin dosing is usually based on glomerular filtration rate (GFR). The Cockcroft-Gault and the Modified Diet in Renal Disease (MDRD) Study formulae are based on serum creatinine to estimate GFR when measured GFR is impractical. The MDRD formula has been shown to be more accurate in non-cancer patients with chronic renal disease. We compared the accuracy of these formulae for dosing carboplatin in patients with gynecological cancers. METHODS: Patient data were collected retrospectively at the Vancouver Centre of the British Columbia Cancer Agency, Canada. GFR estimated by formula was compared to measured GFR. Dose derived from estimated GFR was compared to dose derived from measured GFR. Bias (percentage error) and precision (absolute percentage error) were compared with two-sided paired t-test. RESULTS: A total of 96 patients were evaluable: median age 60 years, weight 62 kg, height 159 cm, baseline serum creatinine 71 micromol/l, GFR 91 ml/min. Both formulae had limited precision with a small bias for estimated GFR and dosing. Eight-five percent of patients would have received a significantly different dose if estimated GFR from any formula was used. The MDRD formula was more precise than the Cockcroft-Gault formula. CONCLUSIONS: The MDRD formula seems to be more accurate than the Cockcroft-Gault formula in this population. However, both have limited precision and measured GFR should be preferred for carboplatin dosing.

Leaching of diethylhexyl phthalate from polyvinyl chloride materials into etoposide intravenous solutions.

Etoposide intravenous solution is associated with leaching of diethylhexyl phthalate (DEHP) from bags and tubings made from polyvinyl chloride (PVC). Recent evidence suggests that this may be more substantial than previously found. Since DEHP is potentially hepatotoxic and carcinogenic, it is preferable to prepare and administer etoposide bags and tubings made from non-PVC materials.