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Frequently Asked Questions

How can late vitamin K deficiency bleeding (VKDB) in infants be prevented when the 1 mg/0.5 mL vitamin K parenteral preparation is on shortage?

Background

Since 1961, the American Academy of Pediatrics (AAP) has recommended that all newborns receive a single intramuscular (IM) dose of 0.5 to 1 mg vitamin K for the prevention of vitamin K deficiency bleeding (VKDB, formerly known as hemorrhagic disease of the newborn).1 The etiology of vitamin K deficiency in infants is not fully known, but it is likely related to lack of vitamin K transmission through the placenta and lack of hepatic vitamin K stores at birth.2 Signs of VKDB include melena, hematemesis, hematuria, and other overt blood loss, but potentially fatal intracranial hemorrhage can also occur. Early VKDB presents during the first 24 hours of life, classic VKDB within the first week of life, and late VKDB occurs up to 12 weeks after birth. A single IM dose of vitamin K effectively prevents against early, classic, and late VKDB. Therefore, if the 1 mg/0.5 mL vitamin K parenteral preparation is not available, other methods of vitamin K administration to neonates must be considered.

Stability of 0.1 mL syringes

An ampule of vitamin K 10 mg/mL is available in the United States, but there are no data regarding the stability of 1 mg doses (0.1 mL) of this product in a syringe.3-6 According to USP 797, the contents of an opened ampule should not be stored for any time period in the absence of stability and sterility testing.7 Development and appropriate testing of 1 mg unit dose syringes drawn from 10 mg ampules may be an area of future research for compounding or repackaging pharmacies.

Oral vitamin K prophylaxis

Vitamin K is also available in the United States as a 5 mg oral tablet. In Europe and other developed nations, oral vitamin K prophylaxis has been used instead of IM.1 A single dose of oral vitamin K at the time of birth decreases rates of early and classic VKDB, but this strategy does not protect against late VKDB due to the shorter duration of activity of oral vitamin K compared to IM administration. Studies suggest that after a single oral dose, vitamin K levels fall to unsupplemented levels within 2 weeks.8 This disadvantage of oral prophylaxis is the main reason that IM administration remains the standard of care in the U.S.1 In addition, a meta-analysis and a recent Cochrane review both support the continued preference for IM versus oral prophylaxis due to lack of compelling comparative evidence.9,10 However, oral VKDB prophylaxis may be an appropriate option if IM formulations are not available.

Exclusively breastfed infants are at risk for late VKDB since vitamin K is not efficiently transmitted in breastmilk.11 In contrast, infants who receive formula feedings are exposed to vitamin K contained in the formula. Formula-fed infants have been estimated to achieve vitamin K levels 10 times higher than exclusively breastfed infants, which seems to be sufficient to prevent late VKDB unless the patient has other risk factors (see discussion of high-risk patients below).2,8

Continuous oral dosing strategies for exclusively breastfed infants that involve multiple doses given over a period of time to gradually build the infant's body stores have been developed. A variety of continuous oral regimens have been studied, but clinical trials comparing the efficacy and safety of these regimens are lacking. As summarized in the Table, epidemiologic data suggest the lowest prevalence of late VKDB in exclusively breastfed infants with continuous prophylactic regimens lasting for at least 3 months. These include 1 mg orally at birth followed by 25 mcg daily for 13 weeks (as used in the Netherlands), or 2 mg orally at birth followed by 1 mg weekly for 3 months (as used in Denmark).

Table. Incidence of late VKDB with oral vitamin K continuous dosing prophylaxis regimens.11

Country Years studied Oral vitamin K dosing regimen Incidence of late VKDB per 100,000 infants (95% CI)
Netherlandsa 1992-1994 1 mg at birth; 25 mcg daily for 13 weeks 0 (0-0.7)
2005 1 mg at birth; 25 mcg daily for 13 weeks 3.2 (1.2-6.9)
Germany 1993-1994 3 x 1 mg (days 1, 4-10 and 28-42) 1.3 (0.8-2.0)
1995-1998 3 x 2 mg (days 1, 4-10 and 28-42) 0.4 (0.2-0.7)
1997-2000 3 x 2 mg (days 1, 4-10 and 28-42) b 0.8 (0.4-1.4)
1997-2001 3 x 2 mg (days 1, 4-10 and 28-42) c 0.44 (0.2-0.9)
Australia 1993-1994 3 x 1 mg (days 1, 3-5 and 21-28) 1.5 (0.5-3.6)
Denmark 1992-2000 2 mg at birth; 1 mg weekly for 3 months 0 (0-0.9)
Switzerland 1995 2 x 2 mg (days 1 and 4) 1.2 (0-6.5)

a Only exclusively breastfed infants receive prophylaxis in the Netherlands.

b Cremophor-containing injectable formulation administered orally.

c Mixed micellar injection administered orally.

CI=confidence interval, VKDB=vitamin K deficiency bleeding.

The Danish results were reported in an 8.5-year survey that evaluated the incidence of late VKDB following the standard prophylactic regimen of 2 mg oral vitamin K at birth, followed by 1 mg weekly until month 3 as long as the infants received more than 50% of the diet through breastfeeding. 12 Oral vitamin K dosing was achieved with a multidose dropper bottle vitamin K formulation (Konakion), which was withdrawn from the European market in 2000. A small percentage of patients were given 1 mg IM if they were considered high-risk (gestational age <33 weeks, difficult delivery or asphyxia, and mothers with a history of receiving antiepileptic drugs). About 22% of infants received IM prophylaxis. Among the 507,850 infants born during the survey period, no cases of VKDB were reported.

Two surveys evaluating the efficacy of the continuous dosing regimen used in the Netherlands have been conducted.13,14 The first survey described the incidence of late VKDB from 1992 to 1994 in the Netherlands after administration of 1 mg oral vitamin K at birth followed by 25 mcg daily for 13 weeks in exclusively breastfed infants.13 Infants considered to be "unwell" received vitamin K 1 mg IM instead of the initial oral dose, followed by the same daily dose. Among the 439,000 live births during the study period, 5 cases of late VKDB were reported; 3 cases were attributed to inappropriately managed bile disorders, 1 case occurred in a breastfed infant who received no prophylaxis, and 1 case occurred in a breastfed infant who received incomplete prophylaxis. The second Dutch survey was conducted in 2005; the vitamin K dosing used was the same as the prior survey.14 Six cases of late VKDB were reported in the 187,510 infants born during the study period, all of which occurred in exclusively breastfed infants who were receiving the recommended vitamin K prophylaxis. In 5 cases, VKDB was associated with underlying biliary atresia.

Very little data exist regarding adherence to daily or weekly vitamin K dosing strategies. In the Danish survey described above, parental adherence was good (94%) with weekly oral vitamin K dosing.12 Of note, 71% of infants were still exclusively breastfeeding at month 3 in Denmark, which may have contributed to the overall high adherence rates observed in this survey. Another study of multiple oral dosing regimens reported parental adherence to be 94% to 97%.15 Further data are needed regarding comparative adherence rates between the available oral vitamin K dosing regimens.

Oral prophylaxis and high-risk patients

Data are lacking regarding the most appropriate oral vitamin K dosing strategies in patients with bile disorders and in preterm infants. As illustrated by both Dutch surveys described above, late VKDB has been associated with bile disorders including biliary atresia and cholestasis.13,14 This may be due to inadequate vitamin K absorption caused by lack of bile secretion in this population. It has been suggested that additional oral supplementation should be provided to infants with biliary atresia or cholestasis, but the optimal dose has not been determined. Some authors have recommended a dose of 50 mcg daily to mimic the amount of vitamin K provided by infant formula feedings, but there are no data demonstrating the efficacy of this strategy in patients with liver disease.11,14,16 In contrast, a weekly dose of vitamin K 1 mg orally (following a 2 mg oral dose at birth) as used in Denmark seems to offer similar protection as IM dosing in patients with biliary atresia.11

The other population for which definite oral dosing recommendations are lacking is preterm infants.18 Oral vitamin K prophylaxis is less reliable than IM in preterm infants due to uncertain absorption in this population and lack of data demonstrating efficacy.18 Some investigators have evaluated whether pre-delivery maternal supplementation may be an effective preventative strategy, but a Cochrane review of 7 trials concluded that supplementation of vitamin K in women prior to delivery of preterm infants does not prevent neonatal intraventricular hemorrhage.19 Until further data are available, preterm neonates should continue to receive appropriately dosed IM prophylaxis (0.2 to 0.5 mg). 20

Practical issues related to oral prophylaxis in the United States

An important consideration for the use of oral vitamin K prophylaxis in the United States is the availability of oral dosage forms. The only oral preparation currently available is a 5 mg tablet. A search of several compounding resources revealed only 1 recipe for preparation of an extemporaneous 1 mg/mL vitamin K suspension.21 To prepare the suspension, 5 tablets of vitamin K 5 mg should be mixed with methylcellulose and sorbitol. The resulting suspension must be stored under refrigeration and is only stable for 3 days. The short stability of this preparation would make it impractical to dispense a supply to the patient for daily or weekly dosing and may require that the patient receive the dose from a healthcare provider. In addition, the small volume needed to provide a 25 mcg daily dose from a 1 mg/mL suspension (0.025 mL) would be very difficult to accurately measure.

Shortage information

According to the American Society of Health-System Pharmacists drug shortage website, vitamin K injection by Hospira is currently on shortage due to manufacturing delays.22 At the time of this writing (November 8, 2011), Hospira expects more supply to be available by mid-December 2011. Amphastar may also have 1 mg prefilled syringes available depending on nationwide supply and demand. Clinicians are urged to regularly check the following website for the most current availability information: www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=852

Recommendations

There is no definitive consensus on the best oral vitamin K regimen to prevent late VKDB but it is clear that more than a single dose is needed, especially in breastfed infants. Continuous oral prophylaxis with weekly doses of 1 mg or daily doses of 25 mcg for 3 months appear to be the most effective strategies based on European epidemiologic data; however, the limited oral dosage forms available in the United States may prevent widespread use of oral prophylaxis. Infants who are primarily or exclusively formula-fed may not need long-term oral prophylaxis but it may be prudent to recommend at the discretion of the physician. The decision of how to most effectively and practically provide vitamin K prophylaxis for late VKDB when the 1 mg/0.5 mL parenteral preparation is not available should be made in consultation with neonatologists and pharmacists, and consider all relevant patient- and institution-specific factors.

References

1. American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. Pediatrics. 2003;112(1 Pt 1):191-192.

2. Tandoi F, Mosca F, Agosti M. Vitamin K prophylaxis: leaving the old route for the new one? Acta Paediatrica. 2005;94(Suppl 449):125-128.

3. Trissel LA. Handbook on Injectable Drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011.

4. Catania PN. King Guide to Parenteral Admixtures. Napa, CA: King Guide Publications, Inc.; 2007.

5. Bing CM. Extended Stability for Parenteral Drugs. 4th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2009.

6. Gahart BL, Nazareno AR. 2011 Intravenous Medications. 27th ed. St. Louis, MO: Mosby, Inc.; 2011.

7. United States Pharmacopoeia-National Formulary. USP-34, NF-29. Rockville, MD: United States Pharmacopeial Convention; 2010.

8. Sutor AH, von Kries R, Cornelissen EAM, McNinch AQ, Andrew M. Vitamin K deficiency bleeding (VKDB) in infancy. Thromb Haemost. 1999;81(3):456-461.

9. Brousson MA, Klein MC. Controversies surrounding the administration of vitamin K to newborns: a review. CMAJ. 1996;154(3):307-315.

10. Puckett RM, Offringa M. Prophylactic vitamin K for vitamin K deficiency bleeding in neonates. Cochrane Database Syst Rev. 2000;(4):CD002776.

11. Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev. 2009;23(2):49-59.

12. Hansen KN, Minousis M, Ebbesen F. Weekly oral vitamin K prophylaxis in Denmark. Acta Paediatr. 2003;92(7):802-805.

13. Cornelissen M, von Kries R, Loughnan P, Schubiger G. Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K. Eur J Pediatr. 1997;156(2):126-130.

14. Ijland MM, Pereira RR, Cornelissen EA. Incidence of late vitamin K deficiency bleeding in newborns in the Netherlands in 2005: evaluation of the current guideline. Eur J Pediatr. 2008;167:165-9.

15. Doran O, Austin NC, Taylor BJ. Vitamin K administration in neonates: survey of compliance with recommended practices in the Dunedin area. N Z Med J. 1995;108(1006):337-339.

16. van Hasselt PM, de Koning TJ, Kvist N, et al. Prevention of vitamin K deficiency bleeding in breastfed infants: lessons from the Dutch and Danish biliary atresia registries. Pediatrics. 2008;121(4):e857-e863.

17. van Winckel M, de Bruyne R, van de Velde S, van Biervliet S. Vitamin K, an update for the paediatrician. Eur J Pediatr. 2009;168(2):127-134.

18. Clarke P. Vitamin K prophylaxis for preterm infants. Early Hum Dev. 2010;86(Suppl 1):17-20.

19. Crowther CA, Crosby DD, Henderson-Smart DJ. Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database Syst Rev. 2010;(1):CD000229.

20. Takemoto CK, Hodding JH, Kraus DM. Pediatric and Neonatal Dosage Handbook. 18th ed. Hudson, OH: Lexi-Comp; 2011.

21. Nahata MC, Pai VB, Hipple TF. Pediatric Drug Formulations. 5th ed. Cincinnati, OH: Harvey Whitney Books Company; 2004.

22. American Society of Health-System Pharmacists. Current Drug Shortages. http://www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=852. Accessed November 7, 2011.