Latachimo Combination

Latanoprost, timolol (as maleate).

Composition and Description: See Table 1.

Click on icon to see table/diagram/image

Physicochemistry of Active Ingredient: Latanoprost: Latanoprost is colorless to pale yellow and viscous oil. It is very soluble in acetonitrile and N,N-dimethylacetamide, freely soluble in ethanol (99.5), ethyl acetate, isopropanol, methanol, acetone, and octanol. It is practically insoluble in water.
Nonproprietary name: Latanoprost.
Chemical name: (+)-Isopropyl(Z )-7-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.
Molecular formula: C₂₆H₄₀O₅.
Molecular weight: 432.59.
Timolol Maleate: Timolol Maleate occurs as a white to pale yellow-white crystalline powder. It is freely soluble in acetic acid (100), and soluble in water and in ethanol (99.5). It dissolves in 0.1 mol/L hydrochloric acid test solution.
Nonproprietary name: Timolol Maleate.
Chemical name: (2S)-1-[(1,1-Dimethylethyl)amino]-3-(4-morpholin-4-yl-1,2,5-thiadiazol-3-yloxy)propan-2-ol monomaleate.
Molecular formula: C₁₃H₂₄N₄O₃S・C₄H₄O₄.
Molecular weight: 432.49.
Melting point: about 197°C (with decomposition).

Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma and ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues.
Precautions regarding Indications: As a general rule, single-agent therapy should be given priority.

One drop in the affected eye(s) once daily.
Precautions regarding Dosage and Administration: The dosage of this product should not exceed once daily since it has been shown that more frequent administration may decrease the intraocular pressure lowering effect.

This product is contraindicated in the following patients: Patients with active or a history of bronchial asthma, bronchospasm, and severe chronic obstructive pulmonary disease. [Asthmatic attack may be induced or exacerbated by bronchial smooth muscle contractions due to β-receptor blockade.]
Patients with poorly controlled heart failure, sinus bradycardia, and second or third degree atrioventricular block, and cardiogenic shock. [These symptoms may be exacerbated by negative chronotropic/inotropic effects due to β-receptor blockade.]
Patient with known hypersensitivity to latanoprost and timolol maleate or any other component of this product.

Careful Administration: This product should be administered with special caution in the following patients: Patients with right heart failure due to pulmonary hypertension. [These symptoms may be exacerbated by negative chronotropic/inotropic effects due to β-receptor blockade.]
Patients with congestive heart failure. [These symptoms may be exacerbated by negative chronotropic/inotropic effects due to β-receptor blockade.]
Patients with diabetic ketoacidosis or metabolic acidosis. [This product may exacerbate the reduction of the myocardial contractile force due to acidosis.]
Patients with poorly controlled diabetes. [Blood glucose levels should be monitored because this product may mask symptoms of hypoglycemia.]
Aphakic patients, pseudophakic patients with a torn posterior lens capsule. [By administering latanoprost, macular edema, including cystoid macular edema and the decreased visual acuity associated with macular edema, have been reported.]
Patients with intraocular inflammation (iritis/uveitis). [By administering latanoprost, elevated intraocular pressure (IOP) has been reported.]
Patients potentially with latent herpes virus infection. [By administering latanoprost, herpetic keratitis has been reported.]
Pregnant, parturient, nursing women [see Use in Pregnancy & Lactation].
Important Precautions: Because this product is a combination ophthalmic solution containing 50 μg of latanoprost and 6.83 mg of timolol maleate (equivalent to timolol 5 mg) in the 1 mL, adverse reactions to both latanoprost and timolol maleate may occur. Hence, appropriate use of this product should be considered.
It should be noted that this product may be absorbed systemically, and an adverse reaction similar to that caused by systemic administration of β-blockers may occur.
When this product is administered, the iris pigmentation may occur (due to increased melanin content). Before using this product, patients who receive treatment should be well informed of the possibility of the iris pigmentation and the change in iris color. It is reported that pigmentation by administration of latanoprost is expected to increase gradually and stops after discontinuation of treatment. However, the resultant pigmentation is likely to be permanent. In addition, iris color change due to the iris pigmentation may occur. In particular, the treatment of one eye may cause iris color difference between the right and left eyes. The pigmentation of the iris has been reported predominantly in patients with brown-based irises. The change in iris color is mild and may not be detected clinically (see Clinically Significant Adverse Reactions under Adverse Reactions).
Corneal epithelium disorder (superficial punctate keratitis, filamentary keratitis, corneal erosion) may occur during administration of this product. The patients should be adequately instructed to immediately consult a doctor if the subjective symptoms of eye stinging, itching, and eye pain persist.
This product should be administered with special caution in the patients with angle-closure glaucoma due to an insufficient clinical experience.
When switching from miotic to timolol maleate preparation, refractive adjustments may be required due to the disappearance of miotic action. Caution should be exercised when administering this product.
Since blurred vision may temporarily occur after administration of the product, patients should be advised to refrain from operating machinery or driving a car until the symptoms disappear.
Other Precautions: Intravenously administered latanoprost at a dose (2 μg/kg) in monkeys induced increases in transient airway resistance. However, it has been reported that instillation of latanoprost in 11 patients with moderate bronchial asthma at seven times the recommended clinical dose (recommended dose is 1.5 μg/eye) had no effect on lung function.
Use in Children: The safety of this product in pediatric patients has not been established. (No sufficient clinical data.)
Use in the Elderly: Generally elderly patients have declined physiological functions and this product should be administered with caution.

Pregnant women: This product should be used in pregnant women or women who may be pregnant only if the expected therapeutic benefits outweigh the possible risks associated with treatment. [The safety of this product during pregnancy has not been established. Reproduction studies have been performed in rabbits. In the study of administration during organogenesis in rabbits, increased incidences of abortion and late resorption and reduce in fetal weight were observed when latanoprost was given by intravenous administration at a dose that was approximately 80 times the clinical dose (5 μg/kg/day).]
Nursing mothers: Administration to nursing mothers should be avoided. If the use of this product is unavoidable, the patient should discontinue breastfeeding. [Animal studies (rats, i.v.) have shown that latanoprost and its metabolites are excreted in breast milk. Timolol maleate may be excreted in human breast milk.]
Reference information: In a study in which timolol maleate was orally administered to rats during the period of organogenesis at a dose of 500 mg/kg/day, delayed ossification was observed, and in an oral study in mice at a dose of 1000 mg/kg/day and in rabbits at a dose of 200 mg/kg/day, increased numbers of dead fetuses were observed.

Since studies which could clarify the incidence of adverse reactions have not been conducted, the incidence of adverse reactions associated with the administration of this product is unknown.
Clinically Significant Adverse Reactions (Frequency unknown): Iris pigmentation: Since iris pigmentation may occur, patients should be examined regularly. If iris pigmentation occurs, use of this product may be discontinued according to patient's clinical condition (see Important Precautions under Precautions).
Ocular pemphigoid: Ocular pemphigoid may occur. If symptoms such as conjunctival hyperemia, corneal epithelium disorder, keratoconjunctivitis sicca, conjunctival atrophy, entropion of eyelashes, or eyelid adhesion are observed, administration should be discontinued and appropriate measures should be taken.
Bronchospasm, dyspnoea and respiratory failure: Bronchospasm, dyspnoea and respiratory failure may occur. In the event of such symptoms, treatment should be discontinued and appropriate measures taken.
Cardiac block, cardiac failure, cardiac arrest, cerebral ischemia and cerebrovascular disorder: Heart block, heart failure, cardiac arrest, cerebral ischemia and cerebrovascular disorder may occur. In the event of such symptoms, treatment should be discontinued and appropriate measures taken.
Systemic lupus erythematosus: Systemic lupus erythematosus may occur. In the event of such symptoms, treatment should be discontinued and appropriate measures taken.
Other Adverse Reactions: See Table 2.

Click on icon to see table/diagram/image

Precautions for co-administration: See Table 3.

Click on icon to see table/diagram/image

Precautions Concerning Use: Route of administration: Ophthalmic use only.
Precautions regarding dispensing: Patients should be instructed the following: Be careful not to directly touch the eye with the dropper tip while instillation.
Wipe off the residual eye drop remaining on the eyelids or skin immediately after instillation.
If this product is used with other ophthalmic solution, they should be administered at least 5 minutes apart.
Since this product contains benzalkonium chloride and it may discolor contact lenses, contact lenses should be removed before instillation of the product and may be reinserted after 15 minutes or more.
At the time of administration: Principally, patients should be in a supine position while instillation. Gently pull the lower eyelid down and instill the ophthalmic solution into the conjunctival sac of the affected eye. Close the eye and press gently the lacrimal sac. Leave the eyelids closed and the finger pressing gently for one to five minutes.
Precautions for Handling: The residual solution of the product should not be used four weeks after opening.
Stability study: The long-term stability study (5°C±3°C, 36 months) with final-packaged products confirmed that LATACHIMO COMBINATION OPHTHALMIC SOLUTION remains stable for 3 years under the usual distribution conditions in the market.

Store at 2-8°C with airtight container. Protect from light.
Shelf life: Indicated on the package and label (3 years).
Caution: See Precautions for Handling under Cautions for Usage.

Antiglaucoma Preparations

S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.

P₁S₁S₃