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?
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
Oral vitamin K dosing regimen
Incidence of late VKDB per 100,000 infants (95% CI)
1 mg at birth; 25 mcg daily for 13 weeks
1 mg at birth; 25 mcg daily for 13 weeks
3 x 1 mg (days 1, 4-10 and 28-42)
3 x 2 mg (days 1, 4-10 and 28-42)
3 x 2 mg (days 1, 4-10 and 28-42) b
3 x 2 mg (days 1, 4-10 and 28-42) c
3 x 1 mg (days 1, 3-5 and 21-28)
2 mg at birth; 1 mg weekly for 3 months
2 x 2 mg (days 1 and 4)
Only exclusively breastfed infants receive prophylaxis in the Netherlands.
Cremophor-containing injectable formulation administered orally.
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
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
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
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:
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.
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