Severe reactions, including
fatalities, have occurred during and immediately after INTRAVENOUS injection
of phytonadione, even when precautions have been taken to dilute the phytonadione
and to avoid rapid infusion. Severe reactions, including fatalities, have
also been reported following INTRAMUSCULAR administration. Typically these
severe reactions have resembled hypersensitivity or anaphylaxis, including
shock and cardiac and/or respiratory arrest. Some patients have exhibited
these severe reactions on receiving phytonadione for the first time. Therefore
the INTRAVENOUS and INTRAMUSCULAR routes should be restricted to those situations
where the subcutaneous route is not feasible and the serious risk involved
is considered justified.
Phytonadione is a vitamin, which is a clear, yellow to amber,
viscous, odorless or nearly odorless liquid. It is insoluble in water, soluble
in chloroform and slightly soluble in ethanol. It has a molecular weight of
Phytonadione is 2-methyl-3-phytyl-1, 4-naphthoquinone.
Its empirical formula is C31H46O2 and its
structural formula is:
Vitamin K1 Injection
(Phytonadione Injectable Emulsion, USP) is a yellow, sterile, nonpyrogenic
aqueous dispersion available for injection by the intravenous, intramuscular
and subcutaneous routes. Each milliliter contains phytonadione 2 or 10 mg,
polyoxyethylated fatty acid derivative 70 mg, dextrose, hydrous 37.5 mg in
water for injection; benzyl alcohol 9 mg added as preservative. May contain
hydrochloric acid for pH adjustment. pH is 6.3 (5.0 to 7.0). Phytonadione
is oxygen sensitive.
Vitamin K1 Injection (Phytonadione Injectable
Emulsion, USP) aqueous dispersion of vitamin K1 for parenteral
injection, possesses the same type and degree of activity as does naturally-occurring
vitamin K, which is necessary for the production via the liver of active prothrombin
(factor II), proconvertin (factor VII), plasma thromboplastin component (factor
IX), and Stuart factor (factor X). The prothrombin test is sensitive to the
levels of three of these four factors−II, VII, and X. Vitamin K is
an essential cofactor for a microsomal enzyme that catalyzes the post-translational
carboxylation of multiple, specific, peptide-bound glutamic acid residues
in inactive hepatic precursors of factors II, VII, IX, and X. The resulting
gamma-carboxy-glutamic acid residues convert the precursors into active coagulation
factors that are subsequently secreted by liver cells into the blood.
is readily absorbed following intramuscular administration. After absorption,
phytonadione is initially concentrated in the liver, but the concentration
declines rapidly. Very little vitamin K accumulates in tissues. Little is
known about the metabolic fate of vitamin K. Almost no free unmetabolized
vitamin K appears in bile or urine.
In normal animals
and humans, phytonadione is virtually devoid of pharmacodynamic activity.
However, in animals and humans deficient in vitamin K, the pharmacological
action of vitamin K is related to its normal physiological function, that
is, to promote the hepatic biosynthesis of vitamin K dependent clotting factors.
action of the aqueous dispersion, when administered intravenously, is generally
detectable within an hour or two and hemorrhage is usually controlled within
3 to 6 hours. A normal prothrombin level may often be obtained in 12 to 14
In the prophylaxis and treatment of hemorrhagic
disease of the newborn, phytonadione has demonstrated a greater margin of
safety than that of the water-soluble vitamin K analogues.
INDICATIONS AND USAGE
Vitamin K1 Injection (Phytonadione Injectable
Emulsion, USP) is indicated in the following coagulation disorders which are
due to faulty formation of factors II, VII, IX and X when caused by vitamin
K deficiency or interference with vitamin K activity.
K1 Injection is indicated in:
anticoagulant-induced prothrombin deficiency caused by coumarin
or indanedione derivatives;
prophylaxis and therapy of hemorrhagic disease of the newborn;
hypoprothrombinemia due to antibacterial therapy;
hypoprothrombinemia secondary to factors limiting absorption
or synthesis of vitamin K, e.g., obstructive jaundice, biliary fistula, sprue,
ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis
of the pancreas, and regional enteritis;
other drug-induced hypoprothrombinemia where it is definitely
shown that the result is due to interference with vitamin K metabolism, e.g.,
Hypersensitivity to any component of this medication.
Benzyl alcohol as a preservative in Bacteriostatic Sodium
Chloride Injection has been associated with toxicity in newborns. Data are
unavailable on the toxicity of other preservatives in this age group. There
is no evidence to suggest that the small amount of benzyl alcohol contained
in Vitamin K1 Injection (Phytonadione Injectable Emulsion, USP),
when used as recommended, is associated with toxicity.
immediate coagulant effect should not be expected after administration of
phytonadione. It takes a minimum of 1 to 2 hours for measurable improvement
in the prothrombin time. Whole blood or component therapy may also be necessary
if bleeding is severe.
Phytonadione will not counteract
the anticoagulant action of heparin.
When vitamin K1 is
used to correct excessive anticoagulant-induced hypoprothrombinemia, anticoagulant
therapy still being indicated, the patient is again faced with the clotting
hazards existing prior to starting the anticoagulant therapy. Phytonadione
is not a clotting agent, but overzealous therapy with vitamin K1 may
restore conditions which originally permitted thromboembolic phenomena. Dosage
should be kept as low as possible, and prothrombin time should be checked
regularly as clinical conditions indicate.
large doses of vitamin K are not warranted in liver disease if the response
to initial use of the vitamin is unsatisfactory. Failure to respond to vitamin
K may indicate that the condition being treated is inherently unresponsive
to vitamin K.
Benzyl alcohol has been reported to be
associated with a fatal “Gasping Syndrome” in premature infants.
This product contains aluminum that may be toxic. Aluminum may reach toxic
levels with prolonged parenteral administration if kidney function is impaired.
Premature neonates are particularly at risk because their kidneys are immature,
and they required large amounts of calcium and phosphate solutions, which
Research indicates that patients with
impaired kidney function, including premature neonates, who receive parenteral
levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at
levels associated with central nervous system and bone toxicity. Tissue loading
may occur at even lower rates of administration.
Temporary resistance to prothrombin-depressing anticoagulants
may result, especially when larger doses of phytonadione are used. If relatively
large doses have been employed, it may be necessary when reinstituting anticoagulant
therapy to use somewhat larger doses of the prothrombin- depressing anticoagulant,
or to use one which acts on a different principle, such as heparin sodium.
Prothrombin time should be checked regularly as
clinical conditions indicate.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies of carcinogenicity, mutagenesis or impairment of
fertility have not been conducted with Vitamin K1 Injection (Phytonadione
Injectable Emulsion, USP).
Pregnancy Category C: Animal reproduction studies have not
been conducted with Vitamin K1 Injection. It is also not known
whether Vitamin K1 Injection can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Vitamin K1 Injection
should be given to a pregnant woman only if clearly needed.
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised
when Vitamin K1 Injection is administered to a nursing woman.
Hemolysis, jaundice, and hyperbilirubinemia in neonates,
particularly those that are premature, may be related to the dose of Vitamin
K1 Injection. Therefore, the recommended dose should not be exceeded
(see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
Deaths have occurred after intravenous and intramuscular
administration. (See Box Warning.)
sensations” and “peculiar” sensations of taste have been
observed, as well as rare instances of dizziness, rapid and weak pulse, profuse
sweating, brief hypotension, dyspnea, and cyanosis.
swelling, and tenderness at the injection site may occur.
possibility of allergic sensitivity including an anaphylactoid reaction, should
be kept in mind.
Infrequently, usually after repeated
injection, erythematous, indurated, pruritic plaques have occurred; rarely,
these have progressed to scleroderma-like lesions that have persisted for
long periods. In other cases, these lesions have resembled erythema perstans.
has been observed in the newborn following administration of phytonadione.
This has occurred rarely and primarily with doses above those recommended.
(See PRECAUTIONS, Pediatric Use.)
The intravenous LD50 of Vitamin K1 Injection
(Phytonadione Injectable Emulsion, USP) in the mouse is 41.5 and 52 mL/kg
for the 0.2% and 1% concentrations, respectively.
DOSAGE AND ADMINISTRATION
Whenever possible, Vitamin K1 Injection (Phytonadione
Injectable Emulsion, USP) should be given by the subcutaneous route. (See
Box Warning.) When intravenous administration is considered unavoidable, the
drug should be injected very slowly, not exceeding 1 mg per minute.
from light at all times.
Parenteral drug products should
be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit.
Vitamin K1 Injection
may be diluted with 0.9% Sodium Chloride Injection, 5% Dextrose Injection,
or 5% Dextrose and Sodium Chloride Injection. Benzyl alcohol as a preservative
has been associated with toxicity in newborns. Therefore,all of the above diluents should be preservative-free (see WARNINGS). Other diluents should not be used. When dilutions
are indicated, administration should be started immediately after mixture
with the diluent, and unused portions of the dilution should be discarded,
as well as unused contents of the ampul.
of Hemorrhagic Disease of the Newborn
American Academy of Pediatrics recommends that vitamin K1 be given
to the newborn. A single intramuscular dose of Vitamin K1 Injection
0.5 to 1 mg within one hour of birth is recommended.
Treatment of Hemorrhagic Disease of the Newborn
administration of vitamin K1 should not replace proper laboratory
evaluation of the coagulation mechanism. A prompt response (shortening of
the prothrombin time in 2 to 4 hours) following administration of vitamin
K1 is usually diagnostic of hemorrhagic disease of the newborn,
and failure to respond indicates another diagnosis or coagulation disorder.
K1 Injection 1 mg should be given either subcutaneously or intramuscularly.
Higher doses may be necessary if the mother has been receiving oral anticoagulants.
blood or component therapy may be indicated if bleeding is excessive. This
therapy, however, does not correct the underlying disorder and Vitamin K1 Injection
should be given concurrently.
Prothrombin Deficiency in Adults
excessively prolonged prothrombin time caused by oral anticoagulant therapy—2.5
to 10 mg or up to 25 mg initially is recommended. In rare instances 50
mg may be required. Frequency and amount of subsequent doses should be determined
by prothrombin time response or clinical condition (see WARNINGS). If in 6
to 8 hours after parenteral administration the prothrombin time has not been
shortened satisfactorily, the dose should be repeated.
of Dosage Guidelines (See circular text for details)
of the Newborn
0.5 to 1 mg IM within 1 hour of birth
1 mg SC or IM
(Higher doses may be necessary if the
mother has been receiving oral
2.5 mg to 10 mg or
up to 25 mg
(caused by coumarin or
(rarely 50 mg)
2.5 mg to 25 mg or
Due to other causes
more (rarely up to
Salicylates or other drugs;
Factors limiting absorption
In the event of shock or excessive blood loss, the use
of whole blood or component therapy is indicated.
Hypoprothrombinemia Due to Other Causes in Adults
dosage of 2.5 to 25 mg or more (rarely up to 50 mg) is recommended, the amount
and route of administration depending upon the severity of the condition and
If possible, discontinuation or reduction
of the dosage of drugs interfering with coagulation mechanisms (such as salicylates;
antibiotics) is suggested as an alternative to administering concurrent Vitamin
K1 Injection. The severity of the coagulation disorder should determine
whether the immediate administration of Vitamin K1 Injection is
required in addition to discontinuation or reduction of interfering drugs.
Vitamin K1 Injection (Phytonadione Injectable
Emulsion, USP) is supplied in a package of 25 as follows:
1 mL Ampul
1 mL Ampul
Store at 20 to 25°C (68 to 77°F). [See USP Controlled
from light. Keep ampuls in tray until time of use.