Included as part of the PRECAUTIONS section.
Potentiation Of Respiratory Reactions Including Asthma
COSOPT contains timolol maleate, a beta-adrenergic
blocking agent; and although administered topically, is absorbed systemically.
Therefore, the same types of adverse reactions that are attributable to
systemic administration of beta-adrenergic blocking agents may occur with
topical administration. For example, severe respiratory reactions, including
death due to bronchospasm in patients with asthma, and rarely death in
association with cardiac failure, have been reported following systemic or
ophthalmic administration of timolol maleate [see CONTRAINDICATIONS and PATIENT INFORMATION].
Sympathetic stimulation may be essential for support of
the circulation in individuals with diminished myocardial contractility, and
its inhibition by beta-adrenergic receptor blockade may precipitate more severe
In patients without a history of cardiac failure
continued depression of the myocardium with beta-blocking agents over a period
of time can, in some cases, lead to cardiac failure. At the first sign or
symptom of cardiac failure, COSOPT should be discontinued [see
CONTRAINDICATIONS and PATIENT INFORMATION].
COSOPT contains dorzolamide, a sulfonamide; and although
administered topically, it is absorbed systemically. Therefore, the same types
of adverse reactions that are attributable to sulfonamides may occur with
topical administration of COSOPT. Fatalities have occurred, although rarely,
due to severe reactions to sulfonamides including Stevens-Johnson syndrome,
toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis,
aplastic anemia, and other blood dyscrasias. Sensitization may recur when a
sulfonamide is readministered irrespective of the route of administration. If
signs of serious reactions or hypersensitivity occur, discontinue the use of
this preparation [see CONTRAINDICATIONS and PATIENT INFORMATION].
Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease
(e.g., chronic bronchitis, emphysema) of mild or moderate severity,
bronchospastic disease, or a history of bronchospastic disease (other than
bronchial asthma or a history of bronchial asthma, in which COSOPT is
contraindicated) should, in general, not receive beta-blocking agents,
including COSOPT [see CONTRAINDICATIONS and PATIENT INFORMATION].
Increased Reactivity To Allergens
While taking beta-blockers, patients with a history of
atopy or a history of severe anaphylactic reactions to a variety of allergens
may be more reactive to repeated accidental, diagnostic, or therapeutic
challenge with such allergens. Such patients may be unresponsive to the usual
doses of epinephrine used to treat anaphylactic reactions.
Potentiation Of Muscle Weakness
Beta-adrenergic blockade has been reported to potentiate
muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia,
ptosis, and generalized weakness). Timolol has been reported rarely to increase
muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.
Masking Of Hypoglycemic Symptoms In Patients With Diabetes
Beta-adrenergic blocking agents should be administered
with caution in patients subject to spontaneous hypoglycemia or to diabetic
patients (especially those with labile diabetes) who are receiving insulin or
oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the
signs and symptoms of acute hypoglycemia.
Masking Of Thyrotoxicosis
Beta-adrenergic blocking agents may mask certain clinical
signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing
thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of
beta-adrenergic blocking agents that might precipitate a thyroid storm.
Renal And Hepatic Impairment
Dorzolamide has not been studied in patients with severe
renal impairment (CrCl < 30 mL/min). Because dorzolamide and its metabolite
are excreted predominantly by the kidney, COSOPT is not recommended in such
Dorzolamide has not been studied in patients with hepatic
impairment and should therefore be used with caution in such patients.
Impairment Of Beta-Adrenergically Mediated Reflexes
The necessity or desirability of withdrawal of
beta-adrenergic blocking agents prior to major surgery is controversial.
Beta-adrenergic receptor blockade impairs the ability of the heart to respond
to beta-adrenergically mediated reflex stimuli. This may augment the risk of
general anesthesia in surgical procedures. Some patients receiving
beta-adrenergic receptor blocking agents have experienced protracted severe hypotension
during anesthesia. Difficulty in restarting and maintaining the heartbeat has
also been reported. For these reasons, in patients undergoing elective surgery,
some authorities recommend gradual withdrawal of beta-adrenergic receptor
If necessary during surgery, the effects of
beta-adrenergic blocking agents may be reversed by sufficient doses of
Carbonic anhydrase activity has been observed in both the
cytoplasm and around the plasma membranes of the corneal endothelium. There is
an increased potential for developing corneal edema in patients with low
endothelial cell counts. Caution should be used when prescribing COSOPT to this
group of patients.
There have been reports of bacterial keratitis associated
with the use of multiple-dose containers of topical ophthalmic products. These
containers had been inadvertently contaminated by patients who, in most cases,
had a concurrent corneal disease or a disruption of the ocular epithelial
surface [see PATIENT INFORMATION].
Patient Counseling Information
See FDA-Approved Patient Labeling (PATIENT INFORMATION).
Potential For Exacerbation Of Asthma And COPD
COSOPT may cause severe worsening of asthma and COPD
symptoms including death due to bronchospasm. Advise patients with bronchial
asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary
disease not to take this product. [see CONTRAINDICATIONS].
Potential Of Cardiovascular Effects
COSOPT may cause worsening of cardiac symptoms. Advise
patients with sinus bradycardia, second or third degree atrioventricular block,
or cardiac failure not to take this product. [see CONTRAINDICATIONS].
COSOPT contains dorzolamide (which is a sulfonamide) and,
although administered topically, is absorbed systemically. Therefore the same
types of adverse reactions that are attributable to sulfonamides may occur with
topical administration, including severe skin reactions. Advise patients that
if serious or unusual reactions or signs of hypersensitivity occur, they should
discontinue the use of the product and seek their physician's advice. [see
WARNINGS AND PRECAUTIONS].
Handling Ophthalmic Solutions
Instruct patients 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
Intercurrent Ocular Conditions
Advise patients 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.
Concomitant Topical Ocular Therapy
If more than one topical ophthalmic drug is being used,
the drugs should be administered at least five minutes apart.
Contact Lens Use
Advise patients that COSOPT 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 administration of COSOPT.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a two-year study of dorzolamide hydrochloride
administered orally to male and female Sprague-Dawley rats, urinary bladder
papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day
(250 times the recommended human ophthalmic dose). Papillomas were not seen in
rats given oral doses equivalent to approximately 12 times the recommended
human ophthalmic dose. No treatment-related tumors were seen in a 21-month
study in female and male mice given oral doses up to 75 mg/kg/day (~900 times the
recommended human ophthalmic dose).
The increased incidence of urinary bladder papillomas
seen in the high-dose male rats is a class-effect of carbonic anhydrase
inhibitors in rats. Rats are particularly prone to developing papillomas in
response to foreign bodies, compounds causing crystalluria, and diverse sodium
No changes in bladder urothelium were seen in dogs given
oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the
recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4
mg/kg/day (~5 times the recommended human ophthalmic dose) for one year.
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 of timolol maleate 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.
The following tests for mutagenic potential were negative
for dorzolamide: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal
aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames
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 with either
timolol maleate or dorzolamide hydrochloride demonstrated no adverse effect on
male or female fertility at doses up to approximately 100 times the systemic
exposure following the maximum recommended human ophthalmic dose.
Use In Specific Populations
Pregnancy Category C. Developmental toxicity
studies with dorzolamide hydrochloride in rabbits at oral doses of ≥2.5
mg/kg/day (37 times the recommended human ophthalmic dose) revealed
malformations of the vertebral bodies. These malformations occurred at doses
that caused metabolic acidosis with decreased body weight gain in dams and
decreased fetal weights. No treatment-related malformations were seen at 1
mg/kg/day (15 times the recommended human ophthalmic dose).
Teratogenicity studies with timolol in mice, rats, and
rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure
following the maximum recommended human ophthalmic dose) demonstrated no
evidence of fetal malformations. Although delayed fetal ossification was
observed at this dose in rats, there were no adverse effects on postnatal
development of offspring. Doses of 1,000 mg/kg/day (142,000 times the systemic
exposure following the maximum recommended human ophthalmic dose) were
maternotoxic in mice and resulted in an increased number of fetal resorptions.
Increased fetal resorptions were also seen in rabbits at
doses of 14,000 times the systemic exposure following the maximum recommended
human ophthalmic dose, in this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in
pregnant women. COSOPT should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
It is not known whether dorzolamide is excreted in human
milk. Timolol maleate has been detected in human milk following oral and
ophthalmic drug administration. Because of the potential for serious adverse
reactions from COSOPT in nursing infants, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.
The safety and effectiveness of dorzolamide hydrochloride
ophthalmic solution and timolol maleate ophthalmic solution have been
established when administered individually in pediatric patients aged 2 years
and older. Use of these drug products in these children is supported by
evidence from adequate and well-controlled studies in children and adults.
Safety and efficacy in pediatric patients below the age of 2 years have not
No overall differences in safety or effectiveness have
been observed between elderly and younger patients.