Glanatec

Ripasudil hydrochloride hydrate.

Each mL of the ophthalmic solution contains 4.896 mg of ripasudil hydrochloride hydrate equivalent to 4.0 mg of ripasudil.
Each bottle of 5 mL of the ophthalmic solution contains 24.48 mg of ripasudil hydrochloride hydrate equivalent to 20.0 mg of ripasudil.
pH 5.0 to 7.0
Osmotic pressure ratio of approximately 1 (ratio to isotonic sodium chloride solution).
Excipients with known effect: Each mL of the ophthalmic solution contains 0.04 mg of benzalkonium chloride concentrated solution 50.
Excipients/Inactive Ingredients: Anhydrous sodium dihydrogen phosphate, glycerin, sodium hydroxide, benzalkonium chloride concentrated solution 50, purified water.

Pharmacotherapeutic group: Antiglaucoma preparations and miotics.
Pharmacology: Pharmacodynamics: Mechanism of Action: Inhibition of Rho kinase to facilitate aqueous outflow from the conventional outflow pathway via the trabecular meshwork and Schlemm's canal has been suggested as the IOP-lowering mechanism of action by ripasudil.
(1) Ripasudil selectively inhibited human ROCK-1 and ROCK-2, which are isoforms of Rho kinases (in vitro).
(2) After a single instillation of GLANATEC to rabbits, the aqueous outflow rate was significantly increased compared to the group treated with the vehicle.
(3) A single instillation of GLANATEC to rabbits did not affect the volume of uveoscleral outflow or aqueous production.
Pharmacodynamic Effects: After a single instillation of ripasudil hydrochloride hydrate ophthalmic solution at 0.0625% to 0.5% to rabbits and the same solution at 0.1% to 0.4% to monkeys, a concentration-dependent IOP-lowering effect was observed.
Clinical efficacy: Phase 3 Placebo-controlled Double-masked Comparative Study: In Japanese patients with primary open-angle glaucoma or ocular hypertension, placebo or GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily for 8 weeks. Changes in IOP over time and the amount of change in IOP are shown in Figure 1 and Table 1. The study demonstrated a significant IOP-lowering effect in the GLANATEC group compared with the placebo group. (See Figure 1 and Table 1.)

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Phase 3 Combination Study with Latanoprost Ophthalmic Solution: In Japanese patients with primary open-angle glaucoma or ocular hypertension in whom latanoprost ophthalmic solution 0.005% was not adequately effective, placebo or GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily in addition to latanoprost ophthalmic solution 0.005% for 8 weeks. Changes in IOP over time and the amount of change in IOP are shown in Figure 2 and Table 2. (See Figure 2 and Table 2.)

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Phase 3 Combination Study with Timolol Ophthalmic Solution: In Japanese patients with primary open-angle glaucoma or ocular hypertension in whom timolol maleate ophthalmic solution 0.5% was not adequately effective, placebo or GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily in addition to timolol maleate ophthalmic solution 0.5% for 8 weeks. Changes in IOP over time and the amount of change in IOP are shown in Figure 3 and Table 3. The study demonstrated a significant IOP-lowering effect in the GLANATEC group compared with the placebo group. (See Figure 3 and Table 3.)

Click on icon to see table/diagram/image


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Phase 3 Long-term Study: In Japanese patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension, GLANATEC was instilled at 1 drop/eye dose in both eyes twice daily for 52 weeks, either alone or in addition to prostaglandin (PG) analogs, β-blockers, or combination drugs containing them. Changes in IOP over time are shown in Figure 4. The study demonstrated a stable IOP-lowering effect in long-term instillation of GLANATEC and did not show attenuation of the IOP-lowering effect owing to the prolongation of the treatment period, either as monotherapy or in combination therapy. (See Figure 4.)

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Pharmacokinetics: Plasma Concentration and Urinary Excretion: GLANATEC was instilled repeatedly to healthy Japanese male adults at 1 drop/eye dose in both eyes twice daily for 7 days, and the changes of ripasudil and its main metabolite M1 (isoquinoline ring position 1 hydroxylated form) over time in plasma concentrations and their pharmacokinetic parameters are shown in Figure 5 and Table 4. The entry of ripasudil into the systemic circulation and the elimination thereof from the body were rapid. In addition, most of ripasudil and M1 were excreted in the urine by 12 hours after completion of repeated instillation. (See Figure 5 and Table 4.)

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Entry into the Ocular Tissues: After a single dose of GLANATEC (50 μL) was instilled to both eyes of pigmented rabbits, the drug in the cornea and the aqueous humor reached the maximum concentration (68135.4 ng/g and 4126.39 ng/mL, respectively) by 0.25 hour and then was rapidly eliminated. In the lens, the drug reached the maximum concentration (154.37 ng/g) by 0.5 hour and then was slowly eliminated.
After a single dose of ¹⁴C-ripasudil hydrochloride ophthalmic solution 1.0% (50 μL) was instilled to pigmented rabbits, the drug rapidly entered each ocular tissue. In the ocular tissues, a high radioactivity concentration was detected particularly in the iris/ciliary body and the retina/choroid, which are tissues containing melanin. After instillation twice daily for 7 days, the radioactivity concentration in the tissues containing melanin was obviously higher than after the single-dose instillation, and the radioactivity concentration tended to disappear gradually in all tissues.
Toxicology: Preclinical safety data: In the 2.0% (twice daily) group in the 13-week repeated instillation study in rabbits and the 4.0% (4 times daily) group in the 13-week repeated instillation study in dogs, irreversible degeneration of lens fibers with opacification was observed in the suture line of the anterior lens. Such changes in the lens are thought to have been caused by the inhibition of formation of actin stress fibers by the Rho kinase inhibiting effect of GLANATEC, which led to the inhibition of differentiation into the fiber cells of the lens and subsequent extension and migration.

GLANATEC is indicated to decrease elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma as adjunctive therapy in patients who are insufficiently responsive to topical beta-blockers or prostaglandin analogues, or as monotherapy in patients who are intolerant or contraindicated to other intraocular pressure lowering medications.

Posology: Use in adults (aged 20 years or older), including the elderly: Instill one drop into the affected eye(s) twice daily.
Use in paediatric population: Safety in low birth weight infants, newborns, infants, and children has not been established.
Method of Administration: (1) Route of administration: Instillation only.
(2) When dispensing the drug: Instruct patients on the following: 1) In the instillation, the patient should tilt the head backwards, open the affected eye, instill the drug into the conjunctival sac, close the eyelid for 1 to 5 minutes while compressing the lacrimal part, and open the eye.
2) Be careful during the instillation to avoid direct contact of the tip of the container with the eye in order to prevent contamination of the drug.
3) Instill with an interval of at least 5 minutes when using the drug in combination with other ophthalmic solutions.

No overdoses were observed during the development phase of GLANATEC. A topical overdose is not likely to occur or to be associated with toxicity. If overdose with GLANATEC occurs, treatment should be symptomatic and supportive

GLANATEC is contraindicated in patients with history of hypersensitivity to any of the components of GLANATEC (see Description).

Acute primary angle-closure glaucoma: Consider treatments other than drug therapy, such as surgical therapy, when using GLANATEC for acute primary angle-closure glaucoma.
Conjunctival hyperaemia: In clinical studies conducted prior to the time of approval in Japan, conjunctival hyperaemia in association with the use of ripasudil has been reported. The event usually occurs transiently at the time of instillation, but be cautious if it continues. Take any appropriate measures such as discontinuation of treatment if this event occurs.
Conjunctivitis (including conjunctivitis allergic) and blepharitis (including allergic blepharitis): In clinical studies conducted prior to the time of approval in Japan, conjunctivitis (including conjunctivitis allergic) and blepharitis (including allergic blepharitis) have been reported in association with the use of ripasudil. The incidence of conjunctivitis allergic and blepharitis allergic tends to be high in patients with long-term instillation. Take any appropriate measures such as discontinuation of treatment if these events occur.
Other adverse reactions: The adverse reactions listed under Adverse Reactions were observed in clinical studies conducted prior to the time of approval in Japan and may occur. Take any appropriate measures such as discontinuation of treatment if these events occur.
Contact lenses: GLANATEC has not been studied in patients wearing contact lenses. The preservative in GLANATEC, benzalkonium chloride may be adsorbed by the soft contact lens. Patients must be instructed to remove contact lenses prior to the application of GLANATEC and wait at least 15 minutes after instillation of the dose before reinsertion.
Use in children: Safety in low birth weight infants, newborns, infants, and children has not been established (there is no use experience).
Effects on ability to drive and use machines: No findings suggesting that GLANATAC affects the ability to drive or operate machinery or impairment of mental ability were obtained during the development phase of GLANATEC in Japan.

Pregnancy: The safety of GLANATEC has not been established in pregnant women. GLANATEC should be used in pregnant women or possibly pregnant women only when therapeutic benefits are deemed to outweigh potential risks.
Breastfeeding: Animal studies (rats, oral administration) have shown that the drug was extracted in breast milk. Do not instill GLANATEC in breastfeeding women. If use of GLANATEC is unavoidable, breastfeeding should be suspended.
Fertility: No current data.

Summary of the safety profile: In clinical studies conducted by the time of approval in Japan, 500 out of 662 subjects (75.5%) experienced adverse reactions. The main adverse reactions included conjunctival hyperaemia in 457 subjects (69.0%), conjunctivitis (including conjunctivitis allergic) in 71 subjects (10.7%), and blepharitis (including allergic blepharitis) in 68 subjects (10.3%).
Summary of adverse reactions: Adverse reactions and frequencies observed in clinical studies conducted by the time of approval in Japan are listed as follows by body site or by mechanism of onset of events. (See Table 5.)

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Corneal thickness tended to decrease in clinical studies. Decreases in corneal thickness caused by instillation of GLANATEC were reversible.
Postmarketing experience: Following adverse reactions have been reported, but the incidence of events cannot be calculated and are unknown because these events include the events reported as spontaneous reports. (See Table 6.)

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No interaction studies have been performed.

Incompatibilities: Not applicable.

Do not store above 30°C.
Shelf life: 24 months.
Discard four weeks after first opening.

Antiglaucoma Preparations

S01EX07 - ripasudil ; Belongs to the class of other antiglaucoma preparations.

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