Comparison of 4-factor VS 3-factor Prothrombin Complex Concentrate (PCC)

Please be noted that currently our PCC, brand Prothrombinex-VF (From National Blood Centre, Malaysia), is 3-factor PCC, which contains very low (non-therapeutic levels) of factor VII.

For each 500 units vial :

Component	Kcentra / Beriplex P/N (Canada)	Prothrombinex-VF (From National Blood Centre, Malaysia)
Factor II	380-800 IU	500 IU
Factor VII	200-500 IU	Low level ( ≤ 500 mg ≈ ≤ 0.01 IU )
Factor IX	400-620 IU	~ 500 IU
Factor X	500-1020 IU	~ 500 IU
Factor V	No info	Low level ( ≤ 500 mg )
Protein C	420-820 IU	No info
Protein S	240-680 IU	No info

*Factor VII = 50,000 units/mg

Dosing Guide

The dose for the same indication may be different by brand. Kindly double check product leaflet

Indication	Kcentra / Beriplex P/N (Canada)	Prothrombinex-VF (From National Blood Centre, Malaysia)
Vitamin K antagonist (VKA) reversal		From product leaflet Initial (Pre-treatment) INR Dose ( IU/kg ) Complete reversal ( 0.9-1.3 ) Partial reversal ( 1.4-2.0 ) 1.5 - 2.5 30 - 2.6 - 3.5 35 25 3.6 - 10.0 50 30 >10.0 50 ** 40 **May not fully correct INR, higher or repeat doses NOT recommended.
Life-threatening hemorrhage associated with warfarin (off-label use)	Initial (Pre-treatment) INR Dose Recommendation Dose suggested Max Dose 2 - <4 25 IU/kg 2500 4 – 6 35 IU/kg 3500 > 6 50 IU/kg 5000 With the correction of vitamin K antagonist-induced impairment of hemostasis in patients who have been treated concomitantly with an appropriate vitamin K dose, repeat dosing with PCC is usually not necessary.	From UptoDate Products contain low or nontherapeutic levels of factor VII component; therefore, additional fresh frozen plasma (FFP) or factor VIIa may be considered When immediate INR reversal is required, concomitant use of 1 to 2 units of FFP should be considered to ensure acute INR reversal. Co-administer vitamin K (phytonadione) 5-10 mg by slow IV infusion; vitamin K may be repeated every 12 hours if INR is persistently elevated. INR Adjusted-dose regimen, weight based <2 20 IU/kg 2-4 30 IU/kg >4 50 IU/kg
Intracranial hemorrhage associated with warfarin (off-label use)	Oral direct factor Xa inhibitor-mediated (api/rivaro-xaban):  50 IU/kg if ICH occurred within 3-5 terminal half-lives of drug exposure or when liver failure co-exists. Direct thrombin inhibitor-mediated (dabigatran [if idarucizumab unavailable], bivalirudin): 50 IU/kg if direct thrombin inhibitor was administered within a period of 3-5 half-lives prior and there is no evidence of renal failure OR there is renal impairment leading to drug exposure beyond 3-5 half-lives.	From UptoDate Four-factor PCC is preferred. Administer with vitamin K IV Fixed-dose regimen, weight based: ·      INR ≥1.4: 50 units/kg; repeat INR within 15 to 60 minutes and serially every 6 to 8 hours for the next 24 to 48 hours. ·      If INR remains ≥1.4 within the first 24 to 48 hours after initial dose, use FFP (alone) for further correction. ·      For initial reversal, it is suggested to administer PCC alone rather than combined with FFP or recombinant factor VIIa
Life-threatening hemorrhage associated with NON-vitamin K antagonist anticoagulation (off-label use)		No recommendation as most studies use 4-factor PCC However, Eikelboom & Merli (2016) 3 suggested (for Rivaro/Api-xaban): PCC Dosage 3-factor 50 IU/kg, may repeat q12h 4-factor 50 IU/kg, one time dose

# From Ref 7

Dosage Guideline of Prothrombinex-VF for Hemophilia B (congenital deficiency of factor IX)

Indication	Desired plasma concentration of factor IX (IU/dL)	Dose (IU/kg)	Frequency of dosing (per day)	Duration of treatment (day)
Minor haemorrhage	20-30	20-30	1	1-2
Moderate-Severe haemorrhage	30-50	30-50	1-2	1-5
Minor surgery *Loading dose *Maintenance	40-60 20-50	40-60 15-40	- 1-2	- 7-10

References:

1.     Product leaflet: Prothrombinex-VF [ CSL Behring (Australia) / National Blood Centre (KL, Malaysia) ]. Revised on 05 March 2015.

2.     UptoDate: Drug information: Prothrombin complex concentrate, 4-factor, unactivated, from human plasma

3.     UptoDate: Drug information: Prothrombin complex concentrate, 3-factor, unactivated, from human plasma

4.     Eikelboom J. & Merli G.M. Bleeding with direct oral anticoagulants vs warfarin: clinical experience. American Journal of Emergency Medicine 34 (2016) 3–8. Accessed online at: https://www.ajemjournal.com/article/S0735-6757(16)30647-7/pdf

5.     Dabi A. & Koutrouvelis A.P. Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications. Critical Care Research and Practice, vol. 2018, Article ID 4907164, 11 pages, 2018. Accessed online at: https://www.hindawi.com/journals/ccrp/2018/4907164/#B51

6.     Steiner T et al. Anticoagulant-Associated Intracranial Hemorrhage in the Era of Reversal Agents. Stroke. 2017;48:1432-1437. DOI: 10.1161/STROKEAHA.116.013343. Accessed online at: https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.116.013343

7.     Tomaselli GF et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;Dec 1:[Epub ahead of print]. Accessed online at: http://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.1085?_ga=2.153937912.1348582126.1564395594-1295211746.1554257012

8.     Tomaselli GF et al. SUMMARY OF 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;Dec 1:[Epub ahead of print]. Accessed online at: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2017/11/29/17/23/2017-acc-expert-consensus-of-bleeding-on-oacs

Updated by J.C.K. Ho on 29/07/2019

Oral Salbutamol and Acute Exacerbation of Airway Obstruction

The management principles of asthma are well established and the subject of numerous readily available clinical practice guidelines. First-line symptomatic treatment is short-acting, inhaled ß2-agonists (SABAs), such as salbutamol or terbutaline.2In Australia, salbutamol is available in various forms, including pressurised, metered-dose inhalers, nebuliser solution, intravenous solution and a syrup for oral administration.3

Most current guidelines recommend the use of salbutamol by metered-dose inhaler via a spacer in the treatment of mild, moderate and severe acute asthma. Nebulised salbutamol is indicated in critical, life-threatening presentations.2

Outcomes for children with acute asthma in the community or hospital setting are no worse for salbutamol delivered via a spacer than nebulised salbutamol. In fact, outcomes for salbutamol delivered via a spacer are favourable in terms of limiting time in the emergency department and minimising side effects.4 Spacers are now widely used in the community. They are inexpensive, portable and easy to maintain.

There is minimal evidence to support the use of oral salbutamol for the management of asthma in developed countries. The practice is specifically – and increasingly strongly – discouraged in a number of guidelines (Box 1). Additionally, there is no evidence for any benefit in bronchiolitis5 or acute cough.6

Box 1. Specific reference to oral ß-agonist administration in recent asthma guidelines

Australia, 200613	‘Oral therapy with SABAs is discouraged in all age groups due to a slower onset of action and the higher incidence of behavioural side effects and sleep disturbance. It may have a limited role in the treatment of children under 2–3 years of age with mild occasional asthma.’
Australia, 20142	‘Oral short-acting ß2 agonists are associated with adverse effects and should not be used in any age group.’
New Zealand, 200514	‘Oral ß2-agonists for treatment of asthma symptoms should be discouraged in all age groups because the onset of action is slow (30–60 minutes), they are relatively ineffective, and the incidence of behavioural side-effects and sleep disturbance is relatively high.’
Malaysia, 201415	‘Routine oral bronchodilator use is discouraged due to its narrow therapeutic index and erratic gastrointestinal absorption resulting in variable and inconsistent efficacy.’
Global Initiative for Asthma (GINA), 201416	‘Oral bronchodilator therapy is not recommended due to its slower onset of action and higher rate of side-effects compared with inhaled SABA.’
Singapore, 200817	‘Inhaled bronchodilators are preferred as they have quicker onset of action and fewer side effects than oral or IV administration.’ ‘Oral therapy is seldom required as most children are able to use inhaler therapy with the appropriate spacer device.’
British Thoracic Society/Scottish Intercollegiate Guidelines Network, 201418	‘Oral ß2 agonists are not recommended for acute asthma in infants.’

Oral salbutamol preparations lead to a slower bronchodilator response than inhaled salbutamol.9 They also pose the risk of unintentional ingestion by young children. Although most ingestions are benign, potential complications include hypokalaemia, hypoglycaemia, restlessness and tachycardia.10

Despite recommendations against the use of oral bronchodilators in developed countries, the World Health Organization (WHO) has been reluctant to delete oral salbutamol from its list of essential medicines.11 Reasons for continued use – particularly in resource-poor settings – include:

• non-availability and relatively high cost of inhaled dosage forms
• ease of use of oral medication
• improved compliance9
• perceived social stigma of using inhalers
• lack of time and resources to enable patient education regarding inhaler technique.12

In Malaysia:

1. Formulari Ubat Kementerian Kesihatan Malaysia stated that:

Generic Name	Cate-gory	Indication(s)	Dosage
Salbutamol 2 mg Tablet	B	Asthma and other conditions associated with reversible airways obstruction	CHILD 2 - 6 years : 1 - 2 mg 3 - 4 times daily, 6 - 12 years : 2 mg 3 - 4 times daily. CHILD over 12 years and ADULT : 2 - 4 mg 3 - 4 times daily
Salbutamol 2 mg/5 ml Syrup	B		CHILD 2 - 6 years : 1 - 2 mg 3 - 4 times daily, 6 - 12 years : 2 mg 3 -4 times daily

2. Paediatric Protocols for Malaysian Hospitals (4th Edition) stated that oral salbutamol has no role  during acute asthma attack, acute bronchiolitis and croup.

For any usage of medication outside the FUKKM indication and Malaysia Paediatric Protocols recommendation (e.g. below two years old), the responsibility lies solely on the prescriber.

References:

* https://www.racgp.org.au/afp/2016/april/it-is-time-to-stop-prescribing-oral-salbutamol/

* FUKKM [online]: Accessed on 15 July 2019