Incorrect dilution of ready-to-use concentrates of gemcitabine that contain ethanol can result in higher than recommended alcohol concentrations in the final infusion solution, leading to local adverse effects and intoxication.
Gemcitabine (dFdC, 2’,2’-difluorodeoxycytidine) is a pyrimidine antimetabolite and is a prodrug. Its cytotoxic effect stems from the inhibition of DNA synthesis. It received a marketing authorisation in 1995 for the treatment of a wide range of solid tumours, including non-small cell lung cancer, breast cancer, pancreatic cancer, epithelial ovarian cancer and bladder cancer.(1)
In 2011, the Dutch Pharmacovigilance Centre Lareb received 31 reports of adverse events (AEs) following use of gemcitabine concentrate solution for infusion from five Dutch hospitals.(2) After injection, patients mentioned infusion-related reactions, including pain at the site of injection, diagnosed as thrombophlebitis. Patients also reported drowsiness, dizziness, tingling or a burning sensation. According to the healthcare workers, these side-effects had not been observed previously. After multidisciplinary evaluation of these AEs, a clear time relationship with the introduction of new ready- to-use (RTU) gemcitabine concentrates for infusion was demonstrated. These AEs did not occur with gemcitabine powder solutions for injection.(2,3)
To date, only two reports have been published on this subject.(2,3) As far as the authors are aware, these AEs have only been reported in The Netherlands. Remarkably, all reports were related to the use of gemcitabine RTU concentrate from a single manufacturer.
RTU concentrates have been introduced to reduce the risk of microbiological contamination or preparation errors during the parenteral drug preparation of solutions for infusion. An important limitation of RTU concentrates for infusion is the limited volume available to dissolve the active pharmaceutical ingredient (API); solubility of the API can therefore be a problem. This problem is usually solved by pH adjustment.The pH of the solution is controlled by either the salt form of the drug (hydrochloric acid) or using a buffer (for example, sodium phosphate or sodium acetate). When pH adjustment alone is insufficient to achieve the desired concentration, a combination of an aqueous solution and a water soluble organic solvent (such as ethanol, propylene glycol or macrogol) is often used in parenteral formulations.(4) Many formulations using co-solvents such as these are marketed using high concentrations of organic solvent and are usually (but not always) diluted before injection. Limitations of using co-solvents in parenteral solutions include side-effects, for example, pain, inflammation and haemolysis upon injection.
Ethanol (ethyl alcohol or alcohol) is a commonly used excipient in oral and parenteral pharmaceutical formulations worldwide. Ethanol is added to parenteral formulations to enhance or maintain active pharmaceutical ingredient solubility and as an antimicrobial agent.(4) Ethanol in parenteral formulations can cause side-effects. The central nervous system, the cardiovascular system and the lungs are most affected by ethanol. The most common local side-effects of ethanol are pain at the site of injection and haemolysis.(5) To reduce the risk of these side effects it is recommended that formulations containing ethanol are injected slowly.
Gemcitabine RTU concentrates registered in Europe are listed in Table 1. Six preparations contain ethanol and one product contains three co-solvents (macrogol, propylene glycol and ethanol). There are four gemcitabine RTU concentrates registered that contain no ethanol.
Regarding the RTU concentrate formulations containing ethanol, the ethanol concentration is approximately 400mg/ml. According to the summary of product characteristics, it is recommended that the total quantity of the gemcitabine 40mg/ml concentrate for solution for infusion should be diluted into at least 500ml of sterile sodium chloride 0.9% solution and administered over 30 minutes.(1) From the report of Lareb, it appears that the preparation was not executed according to the manufacturers’s recommendations in some cases. The gemcitabine RTU concentrate was diluted in 100–500ml, which resulted in a higher ethanol concentration and local AEs. The reported dizziness and drunkenness could be the result of the ethanol used in the RTU formulation.(2,3) To demonstrate this hypothesis, two typical cases receiving gemcitabine in a 30-minute infusion are evaluated below.
A 52-year-old male patient, diagnosed with undifferentiated large cell carcinoma, (body surface 1.79 m2, weight 63kg), received gemcitabine treatment (300mg/m2) with a total dose of 537mg. The total amount of ethanol received is 5293mg, which will be administered in 30 minutes. The calculated blood alcohol concentration (BAC) will be 88.6mg/l at the end of the infusion. This concentration is presumed to be safe or unlikely to produce an effect.(6)
A 72-year-old male patient diagnosed with non-small lung cell carcinoma, (body surface 2.09m2, weight 91kg) is treated with gemcitabine (1125mg/m2) over so minutes with a total dose of 2353mg. Total ethanol of 23,226mg will be administered, resulting in a BAC of 413mg/l. This is comparable to the consumption of one and a half alcoholic drinks in the 30-minute period.
Travelling home by car in this case may give rise to problems as driving under influence (that is, BAC >200mg/l) is an offense in most European countries.(7)
Although both cases are presumed to be safe or unlikely to produce an effect,6 each patient might experience the effects of the ethanol to a differing degree. For example, if the patient abstains from alcohol or lacks alcohol dehydrogenase, which would lead to difficulties in metabolism, a greater effect might be felt than for a patient who regularly partakes of alcohol. It should also be mentioned that the alcohol is administered directly into the bloodstream.
The Pharmacovigilance Working Party concluded that the AEs reported for gemcitabine concentrate resulted from the insufficient dilution of the concentrate, which led to a higher concentration of alcohol in the final solution.3 They indicated that the product information for gemcitabine should be updated to emphasise the need to dilute the concentrate correctly before infusion, and the marketing authorisation holder should be asked to monitor reports of AEs suggestive of reconstitution errors. Based on the cases presented, the authors believe that a warning for potential effects on driving ability should also be included. Currently, gemcitabine RTU concentrates without ethanol are available on the market.(1) In the case of volume-sparing infusion therapy, low/ethanol-free concentrates or powder for solution for infusion should be administered. Moreover, these AEs emphasise the need for a good implementation strategy when a new product is introduced in the hospital.
- Ethanol-containing parenteral formulations can cause local adverse reactions.
- Ethanol-containing parenteral formulations can cause intoxication.
- Incorrect dilution of ready-to-use concentrates of gemcitabine that contain ethanol can cause a higher than recommended alcohol concentration in the final solution.
- In the case of volume sparing infusion therapy, low/ethanol-free concentrates or powder for solution for infusion should be administered.
- These adverse reactions emphasise the need for a good implementation strategy when a new product is introduced in the hospital.
- Summary of Product Characteristics. Gemcitabine (various manufacturers). http://cbg-meb.nl (accessed 1 September 2012).
- Lareb. Netherlands Pharmacovigilance Centre. Eekeren R van Infusiegerelateerde bijwerkingen bij gemcitabineconcentraat door aanwezigheid van alcohol. Geneesmiddelenbulletin 2011;45(10):117-8.
- European Medicines Agency. Pharmacovigilance Working Party (phVWP);June 2011 plenary meeting. www.ema.europa.eu/docs/en_GB/document_library/Report/2011/06/WC500108098.pdf (accessed 1 September 2012).
- Strickley RG et al. Solubilizing excipients in oral and injectable formulations. Pharmaceutical Res 2004;21(2):201–30.
- Yalkowsky SH et al. Formulation-related problems associated with intravenous drug delivery. J Pharmaceutical Sci 1998;87(7):787-96.
- The International Council on Alcohol, Drugs & Traffic Safety. www.icadts.nl/reports/medicinaldrugs1.pdf (accessed 1 September 2012).
- European Alcohol Policy Alliance. Drinking and driving in Europe: A eurocare report to the European Union. www.eurocare.org/resources/policy_issues/road_safety (accessed 1 September 2012).