Istalol (Page 3 of 3)

12.3 Pharmacokinetics

In a study of plasma drug concentration in 12 healthy subjects, the systemic exposure to timolol was determined following twice daily administration of ISTALOL (exaggerated regimen) for eight days. With ISTALOL, mean plasma concentrations of timolol were 0.68 ng/mL and 0.88 ng/mL two hours after the first dose and the dose on the eighth day, respectively.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.

In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day, (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests, the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.

14 CLINICAL STUDIES

In a controlled, double-masked, parallel study in 332 patients with untreated intraocular pressures of 22 mm Hg or greater, ISTALOL 0.5% administered once daily (AM) was equivalent to timolol maleate ophthalmic solution 0.5% administered twice daily. In both groups, mean intraocular pressure decreased from 25 mm Hg at baseline to 18 mm Hg at peak and 19 mm Hg at trough. ISTALOL was generally well tolerated, and 3% of patients had treatment discontinued for adverse events judged related to treatment. There was a slight decrease in cardiovascular function consistent with known systemic absorption of β-adrenoceptor antagonists.

16 HOW SUPPLIED/STORAGE AND HANDLING

ISTALOL (timolol maleate ophthalmic solution) 0.5% is supplied in white LDPE bottles with 15 mm PP yellow caps and 15 mm LLDPE white dropper tips as follows:
NDC 24208-004-03 5 mL in 10 mL container
NDC 24208-004-01 2.5 mL in 7.5 mL container

Storage:
Store at 15ºC to 25ºC (59ºF to 77ºF).

17 PATIENT COUNSELING INFORMATION

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product [see Contraindications (4.1, 4.2)].

Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions (5.8)].

Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

Patients should be advised that ISTALOL contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following ISTALOL administration.

Distributed by:
Bausch & Lomb Americas Inc.
Bridgewater, NJ 08807 USA

Manufactured by:
Bausch & Lomb Incorporated
Tampa, FL 33637 USA

Under License from:
Senju Pharmaceutical Co., Ltd.
Osaka, Japan 541-0046
ISTALOL is a trademark of Bausch & Lomb Incorporated or its affiliates.
© 2022 Bausch & Lomb Incorporated or its affiliates

9733101 (Folded) 9733201 (Flat)

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

carton5ml
(click image for full-size original)

NDC 24208-004-03

Rx only

Istalol®
(timolol maleate
ophthalmic solution)
0.5%

For Topical Ophthalmic Use

5mL

Sterile

BAUSCH + LOMB

Once Daily

9542004AB44207

ISTALOL timolol maleate solution/ drops
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:24208-004
Route of Administration OPHTHALMIC DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TIMOLOL MALEATE (TIMOLOL ANHYDROUS) TIMOLOL ANHYDROUS 5 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
BENZALKONIUM CHLORIDE 0.05 mg in 1 mL
SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE
POTASSIUM SORBATE
SODIUM CHLORIDE
SODIUM HYDROXIDE
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:24208-004-03 1 BOTTLE, DROPPER in 1 CARTON contains a BOTTLE, DROPPER
1 5 mL in 1 BOTTLE, DROPPER This package is contained within the CARTON (24208-004-03)
2 NDC:24208-004-01 1 BOTTLE, DROPPER in 1 CARTON contains a BOTTLE, DROPPER
2 2.5 mL in 1 BOTTLE, DROPPER This package is contained within the CARTON (24208-004-01)
3 NDC:24208-004-02 1 BOTTLE, DROPPER in 1 CARTON contains a BOTTLE, DROPPER
3 2.5 mL in 1 BOTTLE, DROPPER This package is contained within the CARTON (24208-004-02)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021516 08/02/2004
Labeler — Bausch & Lomb Incorporated (196603781)
Establishment
Name Address ID/FEI Operations
Bausch & Lomb, Incorporated 079587625 MANUFACTURE (24208-004)

Revised: 03/2022 Bausch & Lomb Incorporated

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