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Eisai Co., Ltd. 1 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. REQUESTS FOR LITERATURE OR PRODUCT INFORMATION SHOULD BE MADE TO: Customer information Service 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 3