Glakay

Each capsule also contains 15 mg of menatetrenone.
Physicochemistry: Nonproprietary name: Menatetrenone (JAN, INN).
Chemical name: 2-Methyl-3-[(2E, 6E, 10E)-3, 7, 11, 15-tetramethylhexadeca-2, 6, 10, 14-tetraen-l-yl]-1, 4-naphthoquinone.
Molecular formula: C₃₁H₄₀O₂.
Molecular weight: 444.65.
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.
Excipients/Inactive Ingredients: L-aspartic acid, FD&C Yellow No. 6 (Sunset Yellow-FCF), carnauba wax, hydrogenated oil, titanium oxide, gelatin, D-sorbitol solution, concentrated glycerin, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol esters of fatty acid and glyceryl monooleate.

Pharmacotherapeutic Group: Preparation for the treatment of osteoporosis.
Pharmacology: Menatetrenone plays an important role in the formation of γ-carboxyglutamic acid, an amino acid in the bone essential protein osteocalcin, and it is closely involved in bone metabolism. The pharmacological actions of GLAKAY are acceleration of osteogenesis and inhibition of bone resorption. It thus alleviates imbalances in bone tissue metabolism. In clinical trials GLAKAY has demonstrated efficacy in improving bone mass decrease and relief of back pain in patients with osteoporosis. It is administered in small soft capsules that are easy to take.
Mechanism of Action: Acceleration of Osteogenesis: In human osteoblast cultures, calcification was accelerated by administration of menatetrenone at a concentration of 2.25 x 10^-6 mol/L alone or when it was coadministered with 1,25(OH)₂D₃. The osteocalcin level in the cell layers was increased by coadministration with 1,25(OH)₂D₃.
Inhibition of bone resorption: In organ cultures of mouse calvaria, at concentrations of 3 x 10^-6 to 3 x 10^-5 mol/L, menatetrenone inhibited bone resorption induced by IL-1α, PGE₂, PTH and 1,25(OH)₂D₃. In mouse bone marrow cell cultures, at concentrations of 3 x 10^-6 to 1 x 10^-5 mol/L, menatetrenone inhibited the induction of osteoclast release by 1,25(OH)₂D₃.
Effect on serum level of osteocalcin: Menatetrenone was administered to patients with osteoporosis at a dose of 45 mg/day for 2 years. Menatetrenone increased the serum level of osteocalcin and decreased the serum level of Glu-osteocalcin.
Improvement of experimental osteoporosis: Both ovaries of 40-week old rats were resected and they were given low calcium feed for 3 months to produce a state of osteoporosis. Then, menatetrenone was administered orally to the rats at a dose of 30 or 100 mg/kg/day for 6 months. Menatetrenone inhibited reductions in femur splitting strength, bone calcium and hydroxyproline content. When menatetrenone was administered orally at a dose of 3 or 30 mg/kg/day for 6 consecutive months after ovariectomy, reductions in bone splitting strength, calcium and hydroxyproline content in the diaphysis were inhibited.
Both ovaries of 13-week old rats were resected and menatetrenone was administered to them at a dose of 30 mg/kg/day for 8 weeks. Menatetrenone inhibited decrease in connectivity of three dimensional microarchitecture in trabecular bone.
When adrenocortical hormone (10 mg/kg/day of prednisolone at 3 times a week) was administered intramuscularly to rats for 4 weeks, this resulted in reductions in bone splitting strength and bone calcium content. These reductions were inhibited after administering menatetrenone at a dose of 21 mg/kg/day for 4 consecutive weeks.
Clinical Studies: Clinical Efficacy: Efficacy in patients with involutional osteoporosis: In patients with postmenopausal or senile osteoporosis, the efficacy of GLAKAY was as follows: 51.9% (164/316 patients) were rated as "moderately to remarkably improved"; and 84.5% (267/316 patients) were rated as "fairly to remarkably improved"; and it was demonstrated that GLAKAY was effective in maintaining bone mass and reducing pain. The usefulness of GLAKAY was confirmed by a double-blind clinical trial.
In this trial (Phase III comparative study) pain was reduced when GLAKAY was administered alone in 57.2% (87/152 patients) and in 61.1% (66/108 patients) when it was coadministered with analgesics.
Efficacy in patients with secondary osteoporosis: The efficacy of GLAKAY in patients with secondary osteoporosis, including renal osteodystrophia, alcoholic osteopenia and steroidal osteopenia was as follows: 30.9% (17/55 patients) were rated as moderately to remarkably improved", and 60% (33/55 patients) were rated as "fairly to remarkably improved".
Pharmacokinetics: Blood concentration: GLAKAY was administered orally to 9 healthy adult male volunteers at a dose of one capsule (15 mg of menatetrenone) after a meal. The mean plasma menatetrenone concentration began to increase following a time lag of 1 hr after administration and reached a peak at 6 hr after the administration (see Figure 1). Further, GLAKAY was administered orally to six healthy young adults and six elderly persons at one capsule (15 mg of menatetrenone) three times daily after meals for 7 consecutive days in the young adults, C_max and AUC after the final administration were approximately the same as those after the initial administration. In the elderly persons, on the other hand, C_max and AUC determined finally were about 1.3 times and about 1.5 times higher, respectively than those after the initial administration. The plasma concentration determined before the morning dose, stopped increasing on the third day. (See Table 1 and Figure 1.)

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Effect of meal: GLAKAY was administered orally to 3 healthy adult male volunteers at a dose of one capsule (15 mg of menatetrenone) after one night of fasting or within 30 min of breakfast, and the plasma menatetrenone concentration was determined. When GLAKAY was administered orally after one night of fasting, the absorption was found to be lower than that after breakfast (see Figure 2).
Eighteen healthy adult male volunteers were divided into 3 groups of 5 subjects each, and GLAKAY was administered orally to them at a dose of one capsule (15 mg of menatetrenone) within 30 mins of giving them a meal containing one of 3 different amounts of fat (fat content: 8.8 g, 20.0 g or 34.9 g) in accordance with a cross over design. When the plasma menatetrenone was greater according to the fat content of the meal, GLAKAY was administered orally to 12 of eighteen healthy adult male volunteers at a dose of one capsule (15 mg of menatetrenone) within 30 mins of giving them a meal containing a large amount of fat (53.8 g). When the plasma menatetrenone concentration was determined, it was found that its absorption (AUC) was similar to that for a meal with a fat content of 34.9 g but the maximum plasma concentration (C_max) in the volunteers receiving the meal containing 34.9 g of fat content was greater than the group receiving the meal with a fat content of 53.8 g (see Figure 3 and Tables 2 to 4).

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Improvement of bone mass decrease and relief of back pain in patients with osteoporosis.

The usual adult dosage for oral use is 45 mg of menatetrenone daily in three divided doses after meals.

Patients on warfarin potassium therapy (see Interactions).

GLAKAY should be administered to patients who have been diagnosed as having osteoporosis and have a decrease in bone mass and pain in accordance with the criteria prepared by the General Study Group on Prevention and Treatment of Senile Osteoporosis (general criteria based on whether it is or not) of the Ministry of Health and Welfare (MHW) of Japan, etc.
Rash, redness, pruritus or other sympotoms may occur.
In the event of such symptoms, treatment should be discontinued.
Use in Children: The safety in children has not been established (no clinical experience).
Use in the Elderly: As GLAKAY is usually administered to the elderly for a long period of time, their condition should be carefully observed during administration.

The safety of GLAKAY in pregnant women or nursing mothers has not been established (no clinical experience).

Adverse reactions were reported in 302 of 6,321 patients (4.78%), (at the end of the reexamination period). (See Table 5.)

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Contraindications for Co-Administration (GLAKAY should not be coadministered with the following drugs.) See Table 6.

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Precautions concerning Use: Caution in administration: GLAKAY should be taken after meals because its absorption is decreased when administered to patients with an empty stomach.
The absorption of GLAKAY decreases if a meal has a low fat content, since menatotrenone is lipophilic. (See Pharmacology: Pharmacokinetics under Actions.)
Caution in handling over drug: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug from the package prior to use. (It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, causing perforation and resulting in serious complications such as mediastinitis).

GLAKAY should be stored at room temperature not exceeding 25°C.
PTP packages should be protected from high temperature and moisture after opening aluminum bag. (Softening, discolor and adhesion to the inside of press-through package may occur to capsule shells.)
Since the active ingredient, menatetrenone is unstable in light, this product should be protected from light.

Agents Affecting Bone Metabolism

M05BX08 - menatetrenone ; Belongs to the class of other drugs affecting bone structure and mineralization. Used in the treatment of bone diseases.

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