Variation in captopril formulations in pharmacies across Canada

Abstract

Captopril, an angiotensin-converting enzyme inhibitor used to manage congestive heart failure in the paediatric population, has limited data on efficacy and safety. Its variety of liquid formulations dispensed by different pharmacies poses a challenge in optimizing captopril dosing in patients. Fourteen tertiary paediatric centre pharmacies across Canada were contacted to decipher the type of captopril formulation they dispense, their recipe and the stability of each formulation. Of the 14 centres surveyed, four dispensed solid tablets, two dispensed either solid tablets or liquid formulations, and eight dispensed extemporaneously prepared liquid formulations. There was also great variety in the solutions used to prepare the liquid formulations. The bioequivalence of these preparations has not been studied. As a result, physicians cannot be certain about the effective dose of captopril. Uniformity is recommended among paediatric pharmacies in Canada when preparing medications such as captopril. Proper testing of the stability and bioequivalence of medications is recommended.

Captopril is an angiotensin-converting enzyme inhibitor commonly prescribed for managing heart failure in paediatric patients (1–4). Although believed to be clinically effective in paediatric patients, captopril has not been tested in this population. The data relevant to drug efficacy and safety are based on trials involving adults with acquired heart disease. Hence, the dosing of captopril and its potential toxicity are in question. The only licensed form of captopril is the tablet form; however, many children are unable to swallow tablets (5–8). As a result, there are various formulations prescribed to paediatric patients by different pharmacies. The effect of these formulations on drug absorption, optimal drug dosing and drug toxicity have not been studied. The known side effects of captopril, which may be potentiated by improper dosing, include renal impairment, lowering of blood pressure, oxygen desaturation and chorea (9,10).

At our institution (McMaster Children’s Hospital, Hamilton, Ontario), patients are prescribed captopril tablets. Parents are responsible for dissolving these tablets in water before every dose. This is a recent change from a formulation used in the past. The community pharmacies in the Hamilton region continue to prepare various formulations of captopril. This observation came to light when we were reflecting on interpatient variability in optimizing the captopril dose, along with the inconvenience for patients and their families. We became aware of this fact when we were seeing a five-month old patient discharged from The Hospital for Sick Children (Toronto, Ontario). The patient was originally taking a liquid formulation, but then had to switch to the tablet form (to be crushed and dissolved in water) after transfer of care to our institution. This caused frustration and confusion for the parents, who had been accustomed to one regimen for some time. An article published in the United Kingdom (11) highlighted the potential dangers of using varying liquid formulations that are frequently not licensed. Another survey published in the United Kingdom (12) specifically showed the diversity of captopril formulations used across the country, and its potential effects on drug dosing and toxicity. We decided to perform a survey of the tertiary paediatric centres across Canada to investigate how they dispensed captopril for paediatric patients with heart failure.

METHODS

A total of 14 tertiary paediatric centres across Canada were identified (Table 1). A telephone survey was conducted with a clinical pharmacist responsible for paediatric services, a drug information pharmacist or a compounding pharmacist. The survey aimed to obtain information about the type of captopril formulation they dispensed, their recipe and its stability. The questionnaire is presented below:

1. Do you dispense tablets for parents to dissolve or a liquid formulation?

2. If liquid, do you prepare your own formulation?

3. What is the recipe of your formulation?

4. How long is your formulation stable for and under what conditions?

TABLE 1.

Tertiary paediatric centres across Canada

Institution	City	Province
Janeway Children’s Health and Rehabilitation Centre	St John’s	Newfoundland and Labrador
IWK Health Centre	Halifax	Nova Scotia
Sainte-Justine UHC	Montreal	Quebec
Montreal Children’s Hospital	Montreal	Quebec
Children’s Hospital of Eastern Ontario	Ottawa	Ontario
Kingston General Hospital	Kingston	Ontario
The Hospital for Sick Children	Toronto	Ontario
McMaster Children’s Hospital	Hamilton	Ontario
Children’s Hospital of Western Ontario	London	Ontario
Children’s Hospital of Winnipeg	Winnipeg	Manitoba
Royal University Hospital	Saskatoon	Saskatchewan
Alberta Children’s Hospital	Calgary	Alberta
Stollery Children’s Hospital	Edmonton	Alberta
British Columbia Children’s Hospital	Vancouver	British Columbia

RESULTS

From the survey of 14 centres, significant variability was found in the type of captopril formulations used (Figure 1). Four centres were only dispensing solid tablets to crush and dissolve before each dose. Two centres – the Children’s Hospital of Western Ontario (London, Ontario) and the Stollery Children’s Hospital (Edmonton, Alberta) – provided a choice between solid tablets and a liquid formulation. The remaining eight centres were only dispensing extemporaneously prepared liquid formulations (Table 2).

Figure 1).

Different captopril formulations dispensed by pharmacies across Canada. Ora-Sweet/Ora-Plus Blend, Paddock Laboratories Inc, USA

TABLE 2.

Types of captopril formulations dispensed by the surveyed pharmacies

City	Institution	Formulation	Solution
Hamilton	McMaster Children’s Hospital	Solid	Water
Kingston	Kingston General Hospital	Liquid	Distilled water
Ottawa	Children’s Hospital of Eastern Ontario	Solid	Tap water
Montreal	Sainte-Justine UHC	Liquid	Simple syrup
Montreal	Montreal Children’s Hospital	Liquid	Ora-Sweet/Ora-Plus Blend
St John’s	Janeway Children’s Health and Rehabilitation Centre	Liquid	Simple syrup
London	Children’s Hospital of Western Ontario	Solid	Water
		Liquid	Ora-Sweet/Ora-Plus Blend
Winnipeg	Children’s Hospital of Winnipeg	Liquid	Water and ascorbic acid
Calgary	Alberta Children’s Hospital	Liquid	Simple syrup
Edmonton	Stollery Children’s Hospital	Solid	Water
		Liquid	Simple syrup
Saskatoon	Royal University Hospital	Liquid	Simple syrup
Vancouver	British Columbia Children’s Hospital	Liquid	Simple syrup
Toronto	The Hospital for Sick Children	Solid	Water
Halifax	IWK Health Centre	Solid	Water

See Table 1 for the province that each hospital is located in. Ora-Sweet/Ora-Plus Blend, Paddock Laboratories Inc, USA

The stability of the various liquid formulations has been studied. Two separate studies (13,14) found that the captopril formulation made with distilled, purified water was more stable than formulations made with other diluents such as sucrose syrup, methylcellulose or sodium ascorbate. Another study by Lye et al (15) found that captopril formulations had greater stability in distilled water compared with tap water, undiluted syrup compared with diluted syrup and formulations containing EDTA compared with those that did not. Overall, a suspension using simple syrup was found to confer the greatest stability (30 days at 5°C) (15). There are, however, no studies measuring the difference in the absorption of captopril with different diluents.

DISCUSSION

Captopril is dispensed in a variety of forms – such as the licensed tablet form to dissolve and unlicensed liquid formulations – in the different tertiary paediatric centre pharmacies across Canada. The liquid formulations have yet to be studied for their bioequivalence. As a result, physicians and patients continue to struggle with dosing adjustments.

When the licensed form of captopril (ie, tablets) is dispensed by pharmacies, it is difficult to ensure that patients are receiving an adequate amount of medication. To completely dissolve the tablet, it must be mixed in water for almost 10 min. It is difficult and inconvenient for parents to administer the medication in this form.

We urge all health care professionals, including paediatricians, subspecialists and pharmacists, to recognize the issues associated with drug formulations and the potential impact on patient safety. We recommend that health care professionals involved in the care of children come together and discuss these issues relating to captopril and other medications, and come to a consensus for an optimal liquid formulation. This formulation should then be studied not only for its stability but also its bioequivalence. If such uniformity were established among the tertiary centres, it would then be transferred to community pharmacies. An excellent example of such an approach is highlighted in the establishment of The Hospital for Sick Children’s formula for preparing a propranolol suspension. Although its absorption and safety have not been tested, the recipe is used uniformly in all of the tertiary centres except the IWK Health Centre (Halifax, Nova Scotia) and Janeway Children’s Health and Rehabilitation Centre (St John’s, Newfoundland and Labrador). Also, the community pharmacies surveyed in Hamilton (Walmart, Dell and West End pharmacies) were all using the same recipe to prepare a propranolol suspension.

The dosing, stability and safety of a medication such as captopril are very important because it is commonly prescribed to paediatric patients. We believe that the present study has highlighted the diversity that exists in the various dispensing forms and demonstrated that steps need to be taken to bring uniformity to formulations so that patient safety and convenience are increased. It may be helpful for a group of paediatric health care professionals across the nation to work together in an effort to solve this important issue of drug formulation.