Discontinuation of paediatric injectable digoxin: A loss for optimal drug therapy in children

Abstract

In early 2015, the paediatric formulation of injectable digoxin (50 μg/mL) was discontinued in Canada. The only remaining injectable formulation is five times more concentrated. This recent event has major implications for paediatric hospitals all over the country. The use of a more concentrated formulation is of particular concern in low-weight infants because the required volumes of digoxin are almost impossible to draw precisely. Such a situation is problematic because of the narrow therapeutic index of digoxin. There are different ways to deal with this inconvenient situation; however, none is as efficient or safe for infants as the discontinued formulation. The authors believe it remains imperative that patients requiring intravenous digoxin be treated with the safest and most efficient formulation possible, regardless of their age or size.

Paediatric injectable digoxin (50 μg/mL) has recently been discontinued in Canada by its only manufacturer, Sandoz Canada. The last available vials expired February 28, 2015. The only remaining injectable formulation is the regular-strength digoxin (250 μg/mL), which is five times the concentration of the paediatric formulation. This recent event has major implications for pharmacy practice in paediatric hospitals all over the country.

Digoxin is a cardiac glycoside that is used to treat certain types of arrhythmias and heart failure in children. Recent paediatric guidelines are still advocating for its first-line use in supraventricular tachycardias and some cases of postcardiac surgery arrythmias (1,2). Digoxin is considered to be a high-alert medication because of its narrow therapeutic index (3,4). Another potentially hazardous issue is its dosing in micrograms (4). Digoxin intoxication typically causes nonspecific symptoms, such as nausea, vomiting and vision problems – all of which are difficult to assess in young infants – and may cause life-threatening arrhythmias (atrioventricular blockade and bradyarrythmias), which can be extremely difficult to manage (5).

Children, from neonates to teenagers, may receive intravenous digoxin, but the use of the adult formulation of injectable digoxin is of particular concern in low-weight infants such as term and preterm neonates.

To illustrate the serious issues raised by the discontinuation of the paediatric injectable digoxin formulation, we submit a hypothetical case involving a preterm neonate, gestational age 28 weeks, weighing 1 kg. The usual intravenous digitalization dose in preterm neonates, ranging from 15 μg/kg to 25 μg/kg, must be divided into three doses (50%, 25%, 25%) and is followed by a maintenance dose ranging from 4 μg/kg/day to 6 μg/kg/day, divided every 12 h (6).Therefore, if the higher doses were targeted, the required volume of the adult formulation of digoxin for the first few doses would range from 0.012 mL to 0.05 mL. Even smaller volumes (0.008 mL to 0.03 mL) would need to be drawn if the lower doses were deemed necessary. The paediatric formulation allows a more precise and accurate volume draw by being five times more dilute.

This simple case highlights the extremely small volumes resulting from this formulation change. Such small volumes are impossible to draw accurately. A small absolute divergence, such as 0.01 mL, may result in a clinically significant relative error if the intended dose volume is 0.02 mL. A British group evaluated nurses who were required to draw 0.01 mL, 0.02 mL and 0.05 mL of insulin using a 30-unit syringe (7). The average volume drawn was consistently higher than the one intended (+23 %, +12 %, +4 %, respectively). A more recent Canadian study reported that health care professionals asked to calculate, draw and mix a morphine infusion were at a much higher risk for committing a ≥10% error if they had to draw a small volume of 0.06 mL when compared with larger volumes of 0.24 mL and 0.73 mL (60% versus 24%) (8). Moreover, 27% of the participants made ≥2-fold errors with the small volume compared with 1% with larger volumes. Thus, smaller volumes are associated with an increased risk for calculation and drawing errors.

The measurement errors can be explained, in part, by the intrinsic precision error of the syringes, which is equivalent to one-half of the smallest graduation mark. Typically, a 1 mL syringe is graduated every 0.01 mL. Its error is 0.005 mL. If a 0.01 mL dose volume is to be drawn, the relative error would represent 50% of the final volume. Furthermore, standard syringes coupled with a needle usually have a ‘dead space’ that can account for 0.01 mL to 0.05 mL. Small doses are more sensitive to incorrect drawing technique: if the needle was to be changed after measuring the correct amount of medication, it could result in no drug reaching the patient because the dead space would not be filled.

While some measures have been suggested to facilitate the administration of very small volumes (small syringes, small dead volume lines, adequate flush, etc), they can be difficult to standardize within an organization because their use depends on the medication’s volume (9).

Some prescribers were known to order digoxin in millilitres instead of micrograms or milligrams, possibly to avoid potential confusion among these units. This practice is considered to be unsafe and has led to administration errors (10). The change in digoxin concentration increases the risk for fivefold dose errors caused by such practices. Renewed efforts should be committed to enforce the correct prescription of digoxin.

Paediatric injectable digoxin exists elsewhere in the world. We contacted a manufacturer to import an American formulation of 100 μg/mL injectable digoxin via Health Canada’s Special Access Programme. Unfortunately, despite continuous efforts, we were unable to obtain this formulation of digoxin. Because foreign pharmaceutical manufacturers have no legal obligation to sell their drugs in Canada, we have no alternative but to dilute digoxin ourselves.

As-needed compounding of diluted injectable digoxin before administration is possible; however, the reported preparations carry a maximal chemical stability of only 48 h (11). Furthermore, the complexity of the excipients and the required sterility warrants compounding by the hospital pharmacy in a sterile facility with the supervision of a pharmacist. Because injectable digoxin can be needed in cases of medical emergencies, this time-consuming process is unrealistic. To ensure around-the-clock availability of diluted digoxin stock in paediatric critical care units, a daily compounding would be required. This significant addition to the workload of pharmacy dispensaries increases the risk for error. Furthermore, a significant amount of unused diluted digoxin would be wasted in doing so. The issue of the use of small volumes in children due to the lack of paediatric drug formulation is an old one. Thousands of small volumes (< 0.1 mL) of drugs are administered annually in paediatric critical care units (12). The case of digoxin is different because the paediatric formulation was available and its discontinuation directly impacts patient safety. The general use of digoxin has decreased in terms of frequency in the past decade. However, we believe it remains imperative that patients requiring intravenous digoxin be treated with the safest and most efficient formulation possible, regardless of their age or size.

This situation illustrates the numerous challenges and issues arising from a drug becoming unavailable. Such hazardous situations occur more frequently with the increasing number of drug shortages (13,14). In a country where health authorities promote drug research involving children, it is disappointing to recognize that a new battle may need to be waged: a fight to keep paediatric formulations available, especially for high-risk drugs.