1. Introduction

2. Materials and Methods

3. Results

3.1. Search Strategy

Authors/editorial board members of the following formularies were contacted: Australasian Neonatal Medicines Formulary (ANMF), British National Formulary for Children (BNF for Children), Dutch Pediatric Formulary (DPF, also known as ‘Kinderformularium’), Pediatric and Neonatal Lexi-Drugs (Lexicomp, by Wolters Kluwer®), NeoFax (available through Merative), SwissPedDose and Neonatal Formulary (Oxford University Press). Furthermore, colleagues from Canada, China and Japan shared information about neonatal DI availability in their respective countries, and an internet search led to an online Saudi handbook titled “Neonatal Dosage and Practical Guidelines Handbook 2nd Edition”, whose author was contacted as well. Table 1 summarizes descriptive characteristics of the abovementioned formularies and Figure 1 depicts the geographic points of origin for each formulary/colleague contacted.

Table 1. Descriptive Characteristics of Included Neonatal Formularies.

Table 1. Descriptive Characteristics of Included Neonatal Formularies.

#	Name of Formulary	Publisher	Country of Origin	Language	Format: digital/print	Access: Public/subscription	Edition and Year of Publication (for Print)	URL/ISBN
1	Australasian Neonatal Medicines Formulary (ANMF)	Australasian Neonatal Medicines Formulary (ANMF) consensus group	Australia and New Zealand	English	Digital and print	Public		https://www.anmfonline.org/
2	British National Formulary for Children (BNF for Children)	BMJ, Pharmaceutical Press and RCPCH Publications Ltd	United Kingdom	English	Digital and Print	Public (UK) Subscription (elsewhere)	2022-2023	9780857114297 https://bnfc.nice.org.uk/ (UK only access for the UK health service) Worldwide access is available through a subscription to MedicinesComplete: https://about.medicinescomplete.com/
3	Dutch/German/Austrian and Norwegian Pediatric Formularies (DPF, also known as ‘Kinderformularium’)	Foundation Dutch Knowledge Center Pharmacotherapy for Children and Kinderformularium BV	The Netherlands, Together with Norway, Germany and Austria	Dutch German Norwegian	Digital	Public		https://www.kinderformularium.nl/ www.kinderformularium.de www.koble.info www.kindermedika.at
4	Pediatric and Neonatal Lexi-Drugs (Lexicomp)	Wolters Kluwer®	USA	English (online interface is available in 18 languages)	Digital (web-based and mobile application) and Print	Subscription	2022-2023; 29th Edition	9781591953913 https://online.lexi.com/lco/action/home
5	NeoFax	Merative	USA	English	Digital (web-based and mobile application)	Subscription		https://www.micromedexsolutions.com/home/dispatch/
6	Neonatal Formulary	Oxford University Press	United Kingdom	English	Digital and Print	Full online version requires subscription	8th, 2020	9780198840787 Supplementary material for the print version is freely available at: https://academic.oup.com/book/35484#login-purchase
7	Neonatal Dosage and Practical Guidelines Handbook	Saudi Ministry of Health	Saudi Arabia	English	Print		2nd, 2016	9786038144848 Freely available at the Saudi Ministry of Health website: https://www.moh.gov.sa/HealthAwareness/EducationalContent/BabyHealth/Documents/book.pdf
8	SwissPedDose	Swiss Society of Neonatology	Switzerland	German, French, English, Italian	Digital	Public		https://swisspeddose.ch/

Figure 1. Geographic pinpointing of contacted formularies/colleagues. Purple boxes indicate contacted formularies which responded, boxes in green indicate contacted formularies which did not respond, boxes in red indicate contacted colleagues where no formularies were found. ANMF = Australasian Neonatal Medicines Formulary, BNF for Children = British National Formulary for Children, DPF = Dutch Pediatric Formulary, NNF = Neonatal Formulary (Image source: www.freeworldmaps.net, used with permission in agreement with source’s terms and conditions of use).

Figure 1. Geographic pinpointing of contacted formularies/colleagues. Purple boxes indicate contacted formularies which responded, boxes in green indicate contacted formularies which did not respond, boxes in red indicate contacted colleagues where no formularies were found. ANMF = Australasian Neonatal Medicines Formulary, BNF for Children = British National Formulary for Children, DPF = Dutch Pediatric Formulary, NNF = Neonatal Formulary (Image source: www.freeworldmaps.net, used with permission in agreement with source’s terms and conditions of use).

3.4. Comparison of Neonatal Formularies

To complement the above narratives of the six neonatal formularies reviewed here – NeoFax, ANMF, DPF, NNF (print version, 8^th edition), Pediatric and Neonatal Lexi-Drugs and BNF for Children (online version, through MedicinesComplete) – a side-by-side comparison of the formularies is presented in Table 2. This comparison lists the main aspects of the framework and organization of different drug formularies in general, such as the number of available monographs (at the time of writing), listing of references, type of funding etc., as well as aspects that are unique to neonatal drug formularies, such as differentiation in DI between term and preterm neonates, neonatal adverse effects, specific monitoring parameters etc. The table has been constructed based on data provided by formularies’ authors and data gathered from each formulary using a structured data extraction tool [Document S2] for the 10 most commonly used drugs in NICUs in the United States, according to a recent paper by Stark et al. (2022) [9] – ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. The full data extracted for these top 10 drugs can be found in the Supplementary Material [Document S3 and Document S4].

To further illustrate differences and similarities between the examined neonatal formularies, the dosing sections of 3 common drugs in the NICU – caffeine citrate, morphine and gentamicin – were compared and dosing recommendations were subsequently extracted along with directly-related comments (Table 3). To avoid cluttering and excess of information, only dosing recommendations for the main indication of each drug were extracted. An attempt was made to maintain original wording as much as possible on one hand, while formatting all dosing recommendations as uniformly as possible on the other.

Table 2. Content Availability and Organization Comparison Between Neonatal Formularies.

Table 2. Content Availability and Organization Comparison Between Neonatal Formularies.

Parameters		Neofax	ANMF	DPF	NNF	Pediatric and Neonatal Lexi-Drugs	BNF for Children
General characteristics	Pediatric and Neonatal formulary or neonatal only	Neonatal only (a parallel module is available for pediatric patients)	Neonatal	Neonatal and pediatric	Neonatal and pediatric (infancy)	Neonatal and pediatric	Neonatal and pediatric
	Number of drug monographs included overall	304 (pediatric: 804)	182	884	265 (covering over 300 unique drugs or drug combinations)	1460 (376 with neonatal dosing)	1031
	Number of monographs with DI for term neonates	304	182	252	N/A	360	218
	Number of monographs with DI for preterm neonates	112	182	73	N/A	336	N/A
	Are references and citations included?	Yes, in-line and collectively under a ‘References’ section	Yes, in-line and collectively under a ‘References’ section	Yes, in-line and collectively under a ‘References’ section	Yes, collectively in the end of the monograph	Yes, in-line and collectively under a ‘References’ section	No
	Is communication between users and authors possible?	Yes	Yes	Yes, contact form “suggestions for improvement” is included in each monograph, delivered to editorial team	Yes (through email to publishers)	Yes, via online customer support	Yes, clinical content enquiries can be made via email
	Peer-reviewed	Yes	Yes	Yes	Yes	Yes	Yes
	Funded by public/not for profit or private/commercial	Commercial	Public/not for profit	Public/not for profit	Commercial	Commercial	Commercial
	Independent from pharmaceutical industry	Yes	Yes	Yes	Yes	Yes	Yes
	Are commercial products listed?	Yes (available formulations and strengths)	Yes	Yes (available formulations and strengths are listed)	Yes	Yes, in Brand Names sections for US, Canada and International (where appropriate)	Yes
Organization	Differentiation between preterm and term patients?	Yes, usually under the ‘Dose’ section	Yes	Yes	Yes	Yes, usually under the ‘Dosing: Neonatal’ section	Yes
	Categories used for preterm age groups (birthweight, PNA, PMA, current weight)	Yes, based on the evidence; usually under the ‘Dose’ section	Where appropriate and indicated	If available from literature: birthweight; PNA; PMA, PCA	Where appropriate and indicated	Where appropriate and indicated; under the ‘Dosing: Neonatal’ section	Where appropriate. Usually based on weight. Corrected gestational age
	Dosing recommendations are differentiated by routes of administration?	Yes	Yes	Yes	Yes	Yes, every dosing recommendation is associated with route(s) of administration	Yes
Dosing Recommendations	Dosing recommendations are differentiated by indication?	Yes	Yes	Yes	Yes	Yes, every dosing recommendation is associated with indication(s)	Yes
	Renal dosage adjustment (if applicable)	Yes, under the ‘Dose’ section	Yes, since 2020	Yes, specific section, including advice on adjustment based on AKI for > 3 months of age. Dose adjustment for neonatal maturation included in neonatal dosing recommendation	Yes	Yes, under the ‘Dosing: Neonatal’ section	Yes
	Hepatic dosage adjustment (if applicable)	Yes, under the ‘Dose’ section	Yes, since 2020	If applicable and available under ‘Warnings and Precautions’ section	Yes	Yes, under the ‘Dosing: Neonatal’ section	Yes
	Other dosage adjustments (if applicable)	Yes, under the ‘Dose’ section (e.g., TH, ECMO)	Yes, since 2020	If available from literature (TDM, ECMO, Hypothermia, obesity, pharmacogenetics)	Yes	Yes, under ‘Dosing: Neonatal’, as Notes at the top	Yes
	Are preparation instructions available?	Yes, under the ‘Special Considerations/ Preparation’ section	Yes	No	Yes	Yes, under the ‘Preparation for Administration: Pediatric’. There is a ‘Extemporaneous Preparations’ section for bulk compounding of oral preparations, plus access to Trissel’s IV Compatibility	Yes
Preparation	Are stability data provided (if applicable)?	Yes, under the ‘Special Considerations/ Preparation’ section	Yes	No	Yes	Yes, in the ‘Storage/Stability’ section, plus access to Trissel’s IV Compatibility	Yes
	Optimal concentration of preparation (if applicable)	Yes, under the ‘Special Considerations/ Preparation’ section	Yes	No	Yes	Yes	Yes
	Maximum concentration of preparation (if applicable)	Yes, under the ‘Special Considerations/ Preparation’ section	Yes	No	No	Yes	Yes
	Is method of administration indicated?	Yes, under the ‘Administration’ section	Yes	Yes, under the ‘Dosages’ section	Yes	Yes, under the ‘Administration: Pediatric’ section	Yes
Administration and Monitoring	Are monitoring advice and parameters available?	Yes, under the ‘Monitoring’ section	Yes	Yes	Yes	Yes, under the ‘Monitoring Parameters’ and ‘Reference Range’ sections	Yes
	If monitoring advice and parameters are indicated, are specific neonatal warnings and precautions mentioned (if applicable)?	Yes	Yes	Yes, if available from literature or clinical expertise	Yes	Yes	Yes
	Drug-drug interactions mentioned?	No; an external drug-drug interactions module is available to Micromedex subscribers	Yes	Yes	Yes	Yes, under the ‘Drug Interactions’ section and in a separate module	Yes
Pharmacological Data	Adverse effects mentioned?	Yes, under the ‘Adverse Effects’ section; frequency is provided where available	Yes	Yes; frequency is provided where available	Yes; a dedicated section is included only in certain monographs	Yes, under the ‘Adverse Reactions’ section; frequency is provided where available	Yes; frequency is provided where available
	If adverse effects are mentioned, are specific neonatal effects mentioned?	Yes	Yes	Yes, If available from literature or clinical expertise	Yes	Yes	Yes
	Are notable excipients mentioned?	Yes, if applicable, under the ‘Contraindications/precautions’ section	Yes, since 2020	Yes (if available from product info, including concentration)	Yes	Yes, under the ‘Dosage Forms: US’ and/or ‘Dosage Forms: Canada’ sections	Yes
	Neonatal Pharmacokinetic data available?	Yes, under the ‘Pharmacology’ section	Yes, wherever available	Yes, if available from literature	Yes	Yes, under the ‘Pharmacokinetics (Adult data unless noted)’ section	Yes, often under the monitoring section
	Transparency on how information is compiled	Yes	Yes	Yes	Yes	Yes	Yes
	Information can be verified by references/source documentation	Yes	Yes	Yes	Yes	Yes	Yes
	Extrapolation from older pediatric age groups or adults based on available data	No (would accept published literature with extrapolated data)	Yes	Yes	N/A	Evidence for dosing provided with inline citations	Yes

AKI = acute kidney Injury, TH = Therapeutic hypothermia, ECMO = extracorporeal membrane oxygenation, PMA = post-menstrual age, PNA = post-natal age, PCA = post-conceptional age, N/A = Not available.

Out of the 6 examined neonatal formularies, 3 have a specific focus on neonatology neonatal-specific (ANMF, NeoFax and NNF), whereas the other 3 provide pediatric DI as well. Pediatric and Neonatal Lexi-Drugs has the largest number of monographs overall (1,460), followed by BNF for Children (1,031), DPF (884), NeoFax (304, neonatal only), NNF (265) and ANMF (182). The number of neonatal-specific monographs was not obtainable from all formularies, but they range between slightly less than 200 and over 350 neonatal-specific monographs.

Almost all formularies provide specific references for DI, both in-line and collectively in a designated section of the monograph. References are usually from primary literature and/or product information (SmPC). Only BNF for Children does not provide references, but does offer a direct link to the British SmPC in the Electronic Medicines Compendium (emc), on which at least some of the DI is based (of note, the emc is a freely available resource for DI on medicines licensed for use in the UK, unrelated to BNF for Children). All formularies have been found to be peer-reviewed as part of their validation process, and all are independent from the pharmaceutical industry. Commercial products are listed in all formularies, with each formulary listing some or all of the commercial products available in the country/region it targets.

With regard to organization of information, all formularies differentiate between preterm and term infants, and use conventional and accepted neonatal terminology to differentiate between neonatal subpopulations, as age and birthweight are usually a good indication of the level of maturation of the patient, from which physiological status (e.g., hepatic and renal function, lung and gastrointestinal maturity etc.) – which affects PK parameters and therefore expected level of response to drug therapy – is derived.

Additionally, all formularies denote specifically the route of administration appropriate for each dosing recommendation, and all provide hepatic and renal dosage adjustments as appropriate, as well as other types of dosage adjustments required by altered physiological status (e.g., therapeutic hypothermia, ECMO).

Regarding the drug preparation aspect, all formularies beside DPF offer specific information and guidance on how to best prepare the drug, ranging from manufacturer’s instructions to extemporaneous preparations derived from primary literature. However, some formularies provide more data than others regarding preparation information. Thus, as mentioned, DPF does not provide preparation data at all, while ANMF monographs published since 2020 do provide optimal and maximal concentrations where applicable (notably, no such information was identified for the 10 studied drugs [Document S3 and S4]), and NNF sometimes provides optimal concentrations but no maximal concentrations for any of the 10 drugs studied.

All formularies provide information on the method of administration, i.e., duration of infusion, distance from feeding etc. and all formularies provide monitoring advice, usually in a dedicated section, which details monitoring parameters, suggested timetables and desired plasma levels where appropriate.

All formularies provide drug interactions information and adverse effects in dedicated sections (NNF monographs are inconsistent regarding the inclusion of such section), save for NeoFax, which does not include a drug interactions section within each monograph (a drug interactions module is available separately to Micromedex subscribers). All formularies save for ANMF also provide frequencies of adverse effects where available, either in percentages or categorically.

All formularies mention notable excipients with potential effects on neonates. PK data is also provided in all formularies, although not in the same manner: NeoFax, ANMF and NNF provide only neonatal PK data where available, DPF provides PK data in older children, if available, as a comparison for neonatal data, and Pediatric and Neonatal Lexi-Drugs provides neonatal and pediatric PK data where available, and where unavailable, adult PK data is provided.

Table 3. Comparison of Dosing Recommendations for Caffeine Citrate, Morphine and Gentamicin.

Table 3. Comparison of Dosing Recommendations for Caffeine Citrate, Morphine and Gentamicin.

Drug Name	ANMF	BNF for Children	DPF	Pediatric and Neonatal Lexi-Drugs	NeoFax	NNF
Caffeine citrate Indication: Apnea of Prematurity	Caffeine citrate: Route: IV, Oral LD: 20 mg/kg MD: 10 mg/kg (range 5−20 mg/kg) daily Post-op apnoea (single dose): 10 mg/kg Caffeine Base: Route: IV, Oral LD: 10 mg/kg MD: 5 mg/kg (range 2.5−10 mg/kg) daily Post-op apnoea (single dose): 5 mg/kg Comments: ● Maintenance dose may be increased or decreased as per the clinical need.	Caffeine citrate: Neonate: Route: IV, Oral LD: 20 mg/kg MD: 5 mg/kg once daily, started 24 hours after the loading dose Comments: ● Dose equivalence and conversion: Caffeine citrate 2 mg ≡ caffeine base 1 mg ● MD above 20 mg/kg/day can be considered if therapeutic efficacy is not achieved	GA < 37 weeks Caffeine citrate: Route: IV, Oral LD: 20 mg/kg/day MD: 5-10 mg/kg/day Caffeine base: Route: IV, Oral LD: 10 mg/kg MD: 2.5-5 mg/kg/day Comments: ● The injection solution can be administered orally.	Manufacturer’s labeling: Preterm neonates: Route: IV LD: 20 mg/kg caffeine citrate as a one-time dose Route: IV, Oral MD: 5 mg/kg/dose caffeine citrate once daily, beginning 24 hours after loading dose Alternate dosing: GA < 32 weeks: Route: IV LD: 20-40 mg/kg caffeine citrate Route: IV, Oral MD: 5-20 mg/kg/dose caffeine citrate once daily starting 24 hours after the loading dose Comments: ● loading doses as high as 80 mg/kg of caffeine citrate have been reported, but should be utilized with caution. ● Dose expressed as caffeine citrate; caffeine base is ½ the dose of the caffeine citrate	FDA-Approved Dosage: Route: IV, Oral LD: 20-25 mg/kg of caffeine citrate IV over 30 minutes or orally. Route: IV, Oral MD: 5-10 mg/kg/dose of caffeine citrate IV slow push or orally every 24 hours Off-label Dosage: GA 22-28 weeks: Route: IV LD: Median, 20 mg/kg IV (range, 19-23 mg/kg) Route: IV, Oral MD: Median, 8 mg/kg/day (range 5-10 mg/kg/day) Comments: ● May consider an additional loading dose and higher maintenance doses if able to monitor serum concentrations.	Route: IV, Oral LD: 20-25 mg/kg of caffeine citrate IV or orally. MD: 5 mg/kg IV or orally once every 24 hours Comments: ● As the baby matures it may be necessary to increase the dose of caffeine citrate by an additional 1 mg/kg every one to two weeks to ensure that the minimal caffeine concentrations (15-20 mg/L) that are recommended for treatment of apnoea or prematurity are maintained. ● Drug equivalence: There is 1 mg of caffeine base in 2 mg of caffeine citrate.
Morphine Indication: analgesia	Route: PO Starting dose: 50–200 microgram/kg every 3–6 hours. Route: IV bolus 50 mcg/kg (maximum recommended 100 mcg/kg) every 4 hours. Route: continuous IV infusion Range: 5-40 mcg/kg/hour: Ventilated infants or after surgery: ● PNA 0-7 days: Starting dose: 10 mcg/kg/hour Range: 5-40 mcg/kg/hour ● PNA 8-30 days: Starting dose: 15 mcg/kg/hour Range: 5-40 mcg/kg/hour ● PNA 31-90 days: Starting dose: 20 mcg/kg/hour Range: 5-40 mcg/kg/hour Comments: Infants after cardiovascular surgery may need a lower starting dose and be titrated to clinical response.	Route: SC Dose: Initially 100 micrograms/kg every 6 hours, adjusted according to response. Route: IV Dose: 50 micrograms/kg every 6 hours, adjusted according to response, dose to be administered over at least 5 minutes, alternatively (by intravenous injection) initially 50 micrograms/kg, dose to be administered over at least 5 minutes, followed by (by continuous intravenous infusion) 5–20 micrograms/kg/hour, adjusted according to response.	Route: PO Term Neonates Dose: 0.3-0.6 mg/kg/day in 6 doses. Route: Rectal Dose: 0.6–1.2 mg/kg/day in 6 doses. Route: IV Premature neonates Gestational age < 37 weeks and term neonates: Starting dose: 50-100 mcg/kg/dose over 60 minutes MD: 3-20 mcg/kg/hour, as continuous infusion. Administer under supervision. If the effect is insufficient, the hourly dose can be given as a bolus injection, increasing gradually.	Route: PO Dose: 0.05-0.1 mg/kg/dose every 4 to 8 hours as needed. Route: IM, IV (preferred), SC: Initial: 0.05-0.1 mg/kg/dose every 4 to 8 hours as needed Comment: use lowest effective dose and titrate carefully as clinically indicated. Route: continuous IV infusion: Preterm and term neonates: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully based on patient response and considering benefits and risk of additional opiate exposure Comments: ● Continuous IV infusion: use caution if patient at risk of hypotension; some experts recommend not using in neonates with GA <27 weeks.	Route: IV, IM, SC Dose: 0.05-0.2 mg/kg per dose. Repeat as required (usually every 4 hours). Route: IV continuous infusion LD: 0.1 mg/kg MD: 0.01 mg/kg/hour Comment: postoperatively may be increased further to 20 mcg/kg/hour.	Short term pain relief: Route: PO Dose: 200 mcg/kg Route: SC, IV (preferred) Dose: 100 mcg/kg Comments: ● Rapid intravenous administration does not cause hypotension but may cause respiratory depression. ● A further 50 mcg/kg/dose can usually be given after 6 hours without making ventilator support necessary. Severe or sustained pain: Route: IV LD: 200 mcg/kg MD: 20 mcg/kg/hour Comments: ● Provide ventilatory support. ● While this [dosage regimen] will usually control even severe pain in the first 2 months of life, providing a plasma morphine level of 120-160 ng/mL, treatment has to be individualized. ● Staff needs discretion to give further 20 mcg/kg bolus up to once every 4 hours to control any ‘break-through’ pain.
Gentamicin Indication: gentamicin-susceptible infection, neonatal sepsis	Route: IV, IM (only if IV access is not available) Dose: 5 mg/kg Dosing interval depends on GA: ● < 30+0 weeks: 48 hourly ● 30+0 – 34+6 weeks: 36 hourly ● ≥ 35+0 weeks: 24 hourly ● Concurrent cyclo-oxygenase inhibitors (indomethacin or ibuprofen): Extend dosing interval by 12 hours ● Therapeutic hypothermia: 36 hourly Comments: ● Subsequent dosing interval is based on gentamicin concentration at 22 hours after the administration of the second dose (table provided)	Route: slow IV injection or IV infusion Dose: 5 mg/kg Dosing interval depends on age: ● Up to 7 days: every 36 hours, to be given in an extended interval dose regimen. ● 7-28 days: every 24 hours, to be given in an extended interval dose regimen. * Note: BNF for Children provides more information on gentamicin concentrations and dose adjustment in the ‘Monitoring Requirements’ section.	Route: IV Dose: ● GA < 32 weeks and PNA 0-7 days: 5 mg/kg/48 hours ● GA 32-37 weeks and PNA 0-7 days: 5 mg/kg/36 hours ● Preterms, PNA 1-4 weeks: 4 mg/kg/day ● Term neonates: 4 mg/kg/day ● Therapeutic hypothermia: GA ≥ 36 weeks and PNA 0-1 days: 5 mg/kg/36 hours Comments: ● Dose should be adjusted according to plasma levels ● It is recommended to determine plasma levels before the second dose of gentamicin ● Empiric use does not necessitate plasma levels determination	Route: IV, IM Dose: ● GA < 30 weeks and PNA ≤ 14 days: 5 mg/kg/dose every 48 hours ● GA < 30 weeks and PNA ≥ 15 days: 5 mg/kg/dose every 36 hours ● GA 30-34 weeks and PNA ≤ 10 days: 5 mg/kg/dose every 36 hours ● GA 30-34 weeks and PNA 11-60 days: 5 mg/kg/dose every 24 hours ● GA ≥ 35 weeks and PNA ≤ 7 days: 4 mg/kg/dose every 24 hours ● GA ≥ 35 weeks and PNA 8-60 days: 5 mg/kg/dose every 24 hours Comments: ● Determination of dosing interval requires consideration of multiple factors including concomitant medications (e.g., ibuprofen, indomethacin), history of birth depression, birth hypoxia/asphyxia, and presence of cyanotic congenital heart disease. ● Dosage should be individualized based upon serum concentration monitoring. ● Higher doses and different dosing intervals may be required to achieve target concentrations if MIC ≥1 mg/L	Route: IV Dose: ● PMA ≤ 29 weeks and PNA 0-7 days: 5 mg/kg/48 hours ● PMA ≤ 29 weeks and PNA 8-28 days: 4 mg/kg/36 hours ● PMA ≤ 29 weeks and PNA ≥ 29 days: 4.5 mg/kg/24 hours ● PMA 30-34 and PNA 0-7 days: 4.5 mg/kg/36 hours ● PMA 30-34 and PNA ≥ 8 days: 4 mg/kg/24 hours ● PMA ≥ 35 weeks: 4 mg/kg/24 hours Comments: ● Renal function and drug elimination are most strongly correlated with PMA ● PMA is the primary determinant of dosing interval, with Postnatal Age as the secondary qualifier.	Route: IV, IM Dose: 5 mg/kg when GA < 44 weeks, thereafter 7 mg/kg Dosing interval: ● < 30 weeks: every 48 hours ● 30–36 weeks: every 36 hours ● Term infants: every 36 hours in the first week of life, thereafter every 24 hours Comments: ● Extend the dosing interval if the renal function is poor. ● It may be helpful to measure the level 24 hours after the first dose is given. ● Individualized treatment: a strategy to individualize treatment in very immature infants (≤ 28 weeks gestation) may be followed by measuring the serum gentamicin level 22 hours after a single dose of 5 mg/kg. The timing to the next dose is then calculated according to the level (table provided).

LD = loading dose, MD = maintenance dose, GA = gestational age, PNA = postnatal age, PMA = postmenstrual age (equals to GA + PNA), mcg = microgram, ng = nanogram, SC = subcutaneous.

Dosing recommendations for caffeine, morphine and gentamicin illustrate some similarities and differences between the formularies.

Caffeine usually appears in commercial products as caffeine citrate. All formularies indicate dosing both for caffeine citrate and caffeine base as well as the proportion between them (2:1), and always clearly indicate if the recommended dosing is for the citrate salt or the base compound. Regarding the dosing recommendations themselves, they are fairly consistent across formularies: all formularies mention the need for a loading dose (LD), usually 20 mg/kg of caffeine citrate, although some formularies (NeoFax, NNF) allow for LD of up to 25 mg/kg. Additionally, both Pediatric and Neonatal Lexi-Drugs and NNF provide information for even higher LD (up to 80 mg/kg), and Pediatric and Neonatal Lexi-Drugs states that such dosage should be used with caution, detailing adverse effects observed under such dosage, while NNF mentions such LD not for treatment of apnea of prematurity but for facilitating extubation in neonates born under 30 weeks of gestation. Maintenance doses (MD) range between 5 and 10 mg/kg/day of caffeine citrate across formularies. ANMF, BNF for Children, NeoFax and NNF also recommend adjusting MD based on clinical need. All formularies provide both routes of administration (IV, oral), while BNF for Children, DPF and NNF state explicitly that the injection solution may be administered orally (oral preparations of caffeine, either commercial or extemporaneous, are widely available). Only Pediatric and Neonatal Lexi-Drugs and NeoFax address premature neonates explicitly with specific age-based dosage recommendations.

Morphine may be given to neonatal patients through several routes of administration. All formularies indicate the oral and IV route, which are the most common routes. However, subcutaneous injection is also possible according to BNF for Children, Pediatric and Neonatal Lexi-Drugs, NeoFax and NNF, whereas IM injection is mentioned only by Pediatric and Neonatal Lexi-Drugs and NeoFax, and dosing recommendations for the rectal route are only available on DPF. All formularies suggest IV dosing via a bolus LD followed by continuous infusion MD with similar dosage recommendations, with all but ANMF explicitly stating that doses should be individualized/given as needed.

Dosing recommendations vary according to route of administration, but are overall fairly comparable across formularies. Specific, age-based recommendations for preterm infants are available on ANMF, DPF and Pediatric and Neonatal Lexi-Drugs.

Gentamicin is an antibiotic in common use in neonatal units, mainly for its efficacy in empiric treatment of suspected neonatal sepsis. It is usually given through the IV route, although IM injections are also possible (albeit less preferred). All formularies except DPF state that IM injections are possible (with reservations), where it should be noted that BNF for Children and NeoFax do not provide this information in the neonatal dosing section, but in other sections of the monograph.

Dosing recommendations for gentamicin are largely similar across formularies, as are the dosing intervals, which are affected by the age of the infant, since it has rather good correlation with the degree of renal function, because gentamicin is eliminated mostly renally. The age categories for determining optimal dosing interval slightly differ between formularies, with NeoFax and Pediatric and Neonatal Lexi-Drugs suggesting 6 age categories and on the other end BNF for Children suggests only two age groups. All formularies beside BNF for Children address in the neonatal dosing section the need for therapeutic drug monitoring during treatment with gentamicin. BNF for Children does address this issue, not in the neonatal dosing section but in the ‘monitoring parameters’ section.

4. Discussion

5. Conclusions

References

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