C Stability of sildenafil (Revatio dilutions in dextrose 5% · injectable drugs, 15th edn....

A. F. Y. Al HadithyA. L. de GoedeM. EckhardtL. HanffB. C. P. Koch

Stability of sildenafil (Revatio�)dilutions in dextrose 5%

Accepted: 21 August 2011Published online: 27 September 2011� Copyright jointly held by Springer andESICM 2011

This comment refers to the article availableat: doi:10.1007/s00134-010-2065-4.

Dear Editor,With great interest we read the paper ofFraisse et al. [1] in which the authorsdocument the intravenous (i.v.) use ofsildenafil in paediatric patients withcongenital heart disease and pulmonaryhypertension. The findings of theauthors are important, since the com-mercially available sildenafil solutionfor injection (Revatio� 0.8 mg/ml,50 ml) is only licensed for administra-tion as a bolus injection and unwantedexcessive hypotensive effects mayoccur after administration of a bolusdose. Recently, we administered silde-nafil intravenously to two paediatricpatients at the Erasmus MC SophiaChildren’s Hospital. One of the children(girl, age 4.5 years, 17 kg) was treatedwith sildenafil orally for 16 days (3 mg/kg daily) and subsequently with silde-nafil i.v. bolus injections for 27 days(0.5–1.0 mg/kg three times daily).Bolus sildenafil injections resulted inreductions in arterial systolic and dia-stolic pressures of approximately 20%.The second child (boy, neonate, age23 days, 3.0 kg) received one bolussildenafil i.v. dose of 0.2 mg/kg, afterwhich arterial systolic and diastolicpressures dropped also by approxi-mately 20%. Thereafter, a sildenafilcontinuous infusion was started with a

loading dose of 0.4 mg/kg in 3 h andmaintenance dose of 1.9 mg/kg dailyfor 5 days in total. During the continu-ous i.v. infusion, no marked fluctuationsin arterial systolic and diastolic pres-sures were observed.

As described by Fraisse et al. [1],maintenance infusions of sildenafilmay have clear advantages. However,in order to correctly administer con-tinuous i.v. (maintenance) infusions ofsildenafil to paediatric patients, thecommercially available product mayfrequently require dilution prior toadministration. The current authorizedversion of the summary of productcharacteristics of Revatio�, and majorhandbooks such as those by Trissel [2]and Bing [3], as well as other pharma-ceutical literature sources, do notprovide information on how sildenafildilutions for continuous i.v. adminis-tration should be prepared and stored.Also Fraisse et al. [1] did not explicitlystate how the maintenance infusionshould be prepared and stored.

To address this issue, we studied thestability of two Revatio� dilutions(0.067 and 0.667 mg/ml) in dextrose5%, which is the diluent of choice inmost neonatal and paediatric intensivecare units. Both dilutions were stored in50-ml Luer-LokTM polypropylenesyringes (BD Plastipak, Spain) atambient room temperature (20–25�C)and at 37�C (laboratory incubator) for24 h and 7 days. Thereafter, and afterperforming a system suitability test andthe preparation of two three-pointaqueous calibration curves (concentra-tion ranges are 0.04–0.08 and0.4–0.8 mg/ml), we determined theconcentration of sildenafil in both dilu-tions using a validated HPLC method(C18 ODS-3 5-lm column, 50:50 v/vacetonitrile/ammonium acetate 10 mMmobile phase, detection at 292 nm;Shimadzu LC20 diode array detectorand HPLC system), and the coefficientsof variation for repeatability, reproduc-ibility and accuracy were found to be0.1, 1.7 and 1.8%, respectively. Thesystem suitability test complied with the

general requirements of the UnitedStates Pharmacopeia [tailing andcapacity (k0) factors were about 0.97and 3.3, respectively]. The calibrationcurves exhibited satisfactory correla-tion coefficient and goodness-of-fitvalues (both C0.999).

Measurement of the sildenafilconcentrations in both dilutions at theend of the incubation periods (1 and7 days) suggested no marked degra-dation at either temperature (roomtemperature or 37�C), since all of theconcentrations measured were higherthan 95.4% (percent of nominal con-centration at t = 0 h) and since thepeak-purity index was 1.000 in all ofthe measurements, indicating theabsence of degradation products.

Our findings therefore suggest thatRevatio� dilutions in dextrose 5% inthe range 0.067–0.667 mg/ml arechemically stable for up to 1 week atroom temperature (and hence clini-cally usable provided that antisepticconditions are strictly applied duringcompounding). Our findings thusprovide the pharmaceutical basis toenable administration of diluted sil-denafil as a maintenance infusion topaediatric patients.

References

1. Fraisse A, Butrous G, Taylor MB, OakesM, Dilleen M, Wessel DL (2011)Intravenous sildenafil for postoperativepulmonary hypertension in children withcongenital heart disease. Intensive CareMed 37:502–509

2. Trissel LA (2009) Handbook oninjectable drugs, 15th edn. AmericanSociety of Health-System Pharmacists,Bethesda

3. Bing CM (2009) Extended stability forparenteral drugs, 4th edn. AmericanSociety of Health-System Pharmacists,Bethesda

A. F. Y. Al Hadithy ()) � A. L. de Goede �M. Eckhardt � L. Hanff � B. C. P. KochHospital Pharmacy, Erasmus MedicalCenter, Rotterdam, The Netherlandse-mail: a.alhadithy@erasmusmc.nl

Intensive Care Med (2011) 37:1899DOI 10.1007/s00134-011-2356-4 CORRESPONDENCE