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Eisai Co., Ltd.
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Revised: May 2012 (8th version)
Standard Commodity Classification No. of Japan
87316
- Vitamin K2 syrup -
Kaytwo® Syrup 0.2%
<Menatetrenone preparation>
Storage
KAYTWO should be stored at room temperature.
Expiration date
KAYTWO should be used before the expiration date indicated on the
package or label.
Approval No.
Date of listing in the NHI reimbursement price
Date of initial marketing in Japan
Date of additional indication
Date of latest reexamination
21800AMX10431000
December 2006 (Treatment)
(Limited health insurance applied)
Nov 1984
May 2012
Sep 1990
DESCRIPTION
PRECAUTIONS
1. Composition
Each mL of clear, yellow syrup contains 2 mg of menatetrenone.
This drug also contains sodium benzoate, citric acid hydrate, sesame oil, sodium hydroxide, sorbitan fatty acid esters, D-sorbitol solution, ethyl p-hydroxybenzoate, propylene glycol, polyoxyethylene hydrogenated castor oil 60,
and flavor as inactive ingredients.
1. Important Precautions
The treatment of neonatal bleeding and hypoprothrombinemia applies to neonates such as those with thrombotest
values of 20% or less or hepaplastin test values of 30% or
less.
2. Product description
KAYTWO is a clear, yellow syrup with an orange-like odor.
pH: 3.0 - 5.0
INDICATIONS
Treatment of neonatal hemorrhage and hypoprothrombinemia
Prevention of vitamin K deficiency bleeding in neonates
and infants.
DOSAGE AND ADMINISTRATION
Treatment of neonatal hemorrhage and hypoprothrombinemia
The usual neonate dosage for oral use is 1 mL (2 mg of
menatetrenone), once a day.
The dose may be increased up to 3 mL (6 mg of
menatetrenone) depending on the patient’s symptoms.
Prevention of vitamin K deficiency bleeding in neonates
and infants
The usual initial dosage for oral use, once the neonate is
satisfactorily able to ingest milk, is 1 mL (2 mg of
menatetrenone). This should be followed by a second
1mL dose one week after birth or upon discharge from
the maternity ward, whichever is earlier, and a third 1
mL dose one month after birth.
<Precautions>
Regarding prophylactic treatment for vitamin K deficiency
bleeding in neonates and infants, measures such as continuing administration beyond 1 month after birth should
be considered for neonates and infants in whom vitamin K
deficiency is suspected at the 1-month checkup.
2. Drug Interactions
Precautions for coadministration (KAYTWO should be
administered with care when coadministered with the
following drugs.)
Drugs
Coumarin anticoagulants
(warfarin potassium)
Signs, Symptoms,
and Treatment
Mechanism and
Risk Factors
It should be administered
concomitantly with care.
KAYTWO decreases
the effect of warfarin.
3. Pediatric Use
(1) Administration to low birth weight infants
Safety of KAYTWO in low birth weight infants has not
been established [insufficient clinical experience].
(2) Administration to neonates in the early stages after birth
KAYTWO is a syrup with high osmotic pressure.
This drug should therefore be diluted approximately
10-fold with lukewarm water, or should be administered after the neonate has become able to suckle, when
administered to neonates in the early stages after birth.
4. Precautions concerning Use
Administer KAYTWO orally to neonates and infants after
transferring the drug from the stick-package to a feeding
bottle or spoon, etc (if neonates and infants take this drug
directly from the stick-package, they may be at risk of aspiration or injury to the lips).
5. Other Precautions
Regarding prophylactic treatment for vitamin K deficiency
bleeding in neonates and infants, please refer to the latest
information, such as Japanese guidelines.
PHARMACOKINETICS
The pharmacokinetics of menatetrenone were studied in 6
healthy adult male volunteers after a single oral administration
2
Eisai Co., Ltd.
of 30 mg note). The time to reach peak plasma concentration
(tmax, 3.7 h) and the area under the plasma concentration-time
curve (AUC(0∼∞), 1,463 ng⋅h/mL) were comparable to those
obtained after intramuscular administration of a vitamin K2 injection. Peak plasma concentration (Cmax, 325 ng/mL) was
about 7 times higher than that obtained after intramuscular administration1).
note)
Plasma menatetrenone concentration
KAYTWO Syrup 0.2%: 60 mL (120 mg
)
p.o. (n=3)
note)
KAYTWO Syrup 0.2%: 15 mL (30 mg
)
p.o. (n=3)
Vitamin K2 Injection: 30 mg i.m.
(n=5)
Mean±SE
Changes in plasma menatetrenone concentration after administration of KAYTWO Syrup 0.2% and Vitamin K2 Injection
Note: Single oral doses of 30 mg and 120 mg of menatetrenone
are unapproved.
CLINICAL STUDIES
Clinical efficacy
1. In a double-blind clinical trial, the usefulness of KAYTWO
has been demonstrated in 148 neonates with hypoprothrombinemia (Thrombotest value, 20% or less).
Rate of
effectiveness (%)
Moderately to
highly effective
Fairly to highly
effective
6 mg group
63%
91%
2 mg group
59%
84%
Placebo group
26%
43%
Treatment group
KAYTWO (vitamin K2) treatment groups showed significantly superior results compared to the placebo group. Adverse reactions, such as hyperbilirubinemia were not observed2).
2. KAYTWO (vitamin K2) was administered orally to neonates with hemorrhage (hematemesis, melena, and umbilical hemorrhage) at a dose of 2 mg. Hemorrhagic symptoms
resolved after a single dose in 10 of 13 neonates. Hemostasis was achieved with an additional 2 mg dose in 2 of the
remaining 3 neonates, and with an additional 6 mg dose in
the remaining neonate. Thrombotest and hepaplastintest
values also improved significantly after administration of
KAYTWO3).
PHARMACOLOGY
1. Mechanisms of action
Vitamin K2 (hereinafter referred to as K2) is involved in the
carboxylation reaction which converts glutamic acid residues into physiologically active γ-carboxyglutamic acid in
the biosynthesis process of blood coagulation factors (prothrombin, VII, IX and X).
K2 physiologically causes hemostatic effects by accelerating the synthesis of normal prothrombin, etc. in the liver
and activating the body’s hemostatic mechanisms4).
2. Improvement of hypoprothrombinemia
(1) In 5 healthy adult male volunteers in whom hypoprothrombinemia had been induced by oral administration of warfarin potassium 40 mg, recovery of decreased coagulability was compared after a single oral
administration of vitamin K1 (hereinafter referred to as
K1) 30 mg or K2 30 mg note), using a cross-over design.
The K2 treatment group demonstrated more rapid recovery of prothrombin time (%) than the K1 treatment
group 5).
(2) Male rabbits in which hypoprothrombinemia had been
induced using warfarin potassium (an anticoagulant
drug) were treated with oral K1 or K2 at doses of 1 or 2
mg/kg. K2 improved hypoprothrombinemia more rapidly than K1 6).
3. Hemostatic effect
In the K1 treatment group of mice, 50% of deaths due to
hemorrhage caused by 10-day repeated administration of
dicumarol (an anticoagulant drug) at 50 mg/kg/day were
prevented by coadministration of oral K1 at 5 mg/kg/day. In
the K2 treatment group of mice, however, coadministration
of oral K2 at 5 mg/kg/day prevented all (100%) such
deaths7).
PHYSICOCHEMISTRY
Nonproprietary name: Menatetrenone (JAN, INN)
Chemical name:
2-Methyl-3-[(2E, 6E, 10E)-3, 7, 11, 15tetramethylhexadeca-2, 6, 10, 14tetraen -1-yl]-1,4-naphthoquinone
Molecular formula: C31H40O2
Molecular weight: 444.65
Structural formula:
Description:
Menatetrenone occurs as yellow, crystals, crystalline powder, waxy mass or oily material. It is very soluble in hexane, soluble in ethanol (99.5), sparingly soluble in
2-propanol, slightly soluble in methanol, and practically
insoluble in water.
It decomposes and the color becomes more intense by light.
Melting point: about 37°C
PACKAGING
KAYTWO Syrup 0.2% (1 mL): 50 packets
Eisai Co., Ltd.
NOTES ON INSURANCE BENEFITS
When this drug is used for the “Prevention of vitamin K deficiency bleeding in neonates and infants”, treatment is not covered by health insurance.
REFERENCES
1) Morishita N. et al.: Clin. Report, 15, 2081, 1981.
2) Maki M. et al.: J. Clin. Exp. Med., 120, 222, 1982.
3) Ukita M. et al.: Obstetr. Gynecol, 51, 1367, 1984.
4) Stenflo J. et al.: Proc. Natl. Acad. Sci. U. S. A., 71, 2730,
1974.
5) Moriguchi H. et al.: J. New Remed. Clin., 30, 1687,
1981.
6) Tajima T. et al.: Folia Pharmacol. Japon., 67, 412, 1971.
7) Tajima T. et al.: ibid., 67, 406, 1971.
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INFORMATION SHOULD BE MADE TO:
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FreeDial: 0120-419-497
Eisai Co., Ltd.
Manufactured and marketed by:
Sannova Co., Ltd.
3038-2, Serada-cho, Ota-shi, Gunma, 370-0426
Marketed by:
Eisai Co., Ltd.
6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088
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