|
Dorzolamide
DESCRIPTION
TRUSOPT (dorzolamide hydrochloride ophthalmic solution) is
a carbonic anhydrase inhibitor formulated for topical ophthalmic use.
Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-
b]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide
hydrochloride is optically active. The specific rotation is a
25° (C=1, water) = ~ -17°.
405
Its empirical formula is C10H16N2O4S3•HCl
Dorzolamide hydrochloride has a molecular weight of 360.9 and
a melting point of about 264°C. It is a white to off-white, crystalline powder,
which is soluble in water and slightly soluble in methanol and ethanol.
TRUSOPT Sterile Ophthalmic Solution is supplied as a sterile,
isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride.
The pH of the solution is approximately 5.6, and the osmolarity is 260-330 mOsM.
Each mL of TRUSOPT 2% contains 20 mg dorzolamide (22.3 mg of dorzolamide hydrochloride).
Inactive ingredients are hydroxyethyl cellulose, mannitol, sodium citrate
dihydrate, sodium hydroxide (to adjust pH) and water for injection. Benzalkonium
chloride 0.0075% is added as a preservative.
CLINICAL PHARMACOLOGY
Mechanism of Action
Carbonic anhydrase (CA) is an enzyme found in many tissues
of the body including the eye. It catalyzes the reversible reaction involving
the hydration of carbon dioxide and the dehydration of carbonic acid. In humans,
carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic
anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also in
other tissues. Inhibition of carbonic anhydrase in the ciliary processes of
the eye decreases aqueous humor secretion, presumably by slowing the formation
of bicarbonate ions with subsequent reduction in sodium and fluid transport.
The result is a reduction in intraocular pressure (IOP). TRUSOPT Ophthalmic
Solution contains dorzolamide hydrochloride, an inhibitor of human carbonic
anhydrase II. Following topical ocular administration, TRUSOPT reduces elevated
intraocular pressure. Elevated intraocular pressure is a major risk factor in
the pathogenesis of optic nerve damage and glaucomatous visual field loss.
Pharmacokinetics/Pharmacodynamics
When topically applied, dorzolamide reaches the systemic circulation.
To assess the potential for systemic carbonic anhydrase inhibition following
topical administration, drug and metabolite concentrations in RBCs and plasma
and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates
in RBCs during chronic dosing as a result of binding to CA-II. The parent drug
forms a single N-desethyl metabolite, which inhibits CA-II less potently than
the parent drug but also inhibits CA-I. The metabolite also accumulates in RBCs
where it binds primarily to CA-I. Plasma concentrations of dorzolamide and metabolite
are generally below the assay limit of quantitation (15 nM). Dorzolamide binds
moderately to plasma proteins (approximately 33%). Dorzolamide is primarily
excreted unchanged in the urine; the metabolite also is excreted in urine. After
dosing is stopped, dorzolamide washes out of RBCs nonlinearly, resulting in
a rapid decline of drug concentration initially, followed by a slower elimination
phase with a half-life of about four months.
To simulate the systemic exposure after long-term topical ocular
administration, dorzolamide was given orally to eight healthy subjects for up
to 20 weeks. The oral dose of 2 mg b.i.d. closely approximates the amount of
drug delivered by topical ocular administration of TRUSOPT 2% t.i.d. Steady
state was reached within 8 weeks. The inhibition of CA-II and total carbonic
anhydrase activities was below the degree of inhibition anticipated to be necessary
for a pharmacological effect on renal function and respiration in healthy individuals.
Clinical Studies
The efficacy of TRUSOPT was demonstrated in clinical studies
in the treatment of elevated intraocular pressure in patients with glaucoma
or ocular hypertension (baseline IOP 23 mmHg). The IOP-lowering effect of TRUSOPT
was approximately 3 to 5 mmHg throughout the day and this was consistent in
clinical studies of up to one year duration.
The efficacy of TRUSOPT when dosed less frequently than three
times a day (alone or in combination with other products) has not been established.
In a one year clinical study, the effect of TRUSOPT 2% t.i.d.
on the corneal endothelium was compared to that of betaxolol ophthalmic solution
b.i.d. and timolol maleate ophthalmic solution 0.5% b.i.d. There were no statistically
significant differences between groups in corneal endothelial cell counts or
in corneal thickness measurements. There was a mean loss of approximately 4%
in the endothelial cell counts for each group over the one year period.
INDICATIONS AND USAGE
TRUSOPT Ophthalmic Solution is indicated in the treatment of
elevated intraocular pressure in patients with ocular hypertension or open-angle
glaucoma.
DOSAGE AND ADMINISTRATION
The dose is one drop of TRUSOPT Ophthalmic Solution in the
affected eye(s) three times daily. TRUSOPT may be used concomitantly with other
topical ophthalmic drug products to lower intraocular pressure. If more than
one topical ophthalmic drug is being used, the drugs should be administered
at least ten minutes apart.
HOW SUPPLIED
TRUSOPT Ophthalmic Solution is a slightly opalescent, nearly
colorless, slightly viscous solution.
No. 3519 — TRUSOPT Ophthalmic Solution 2% is supplied in OCUMETER®*
PLUS container, a white, opaque, plastic ophthalmic dispenser with a controlled
drop tip as follows: NDC 0006-3519-35, 5 mL
NDC 0006-3519-36, 10 mL.
Storage
Store TRUSOPT Ophthalmic Solution at 15-30°C (59-86°F). Protect
from light.
By: Laboratories Merck Sharp & Dohme-Chibret
63963 Clermont-Ferrand Cedex 9, France Issued
Updated June 19, 2004
SIDE EFFECTS
Controlled clinical trials
The most frequent adverse events associated with TRUSOPT were
ocular burning, stinging, or discomfort immediately following ocular administration
(approximately one-third of patients). Approximately one-quarter of patients
noted a bitter taste following administration. Superficial punctate keratitis
occurred in 10-15% of patients and signs and symptoms of ocular allergic reaction
in approximately 10%. Events occurring in approximately 1-5% of patients were
conjunctivitis and lid reactions (see PRECAUTIONS,
General), blurred vision, eye redness, tearing, dryness, and photophobia.
Other ocular events and systemic events were reported infrequently, including
headache, nausea, asthenia/fatigue; and, rarely, skin rashes, urolithiasis,
and iridocyclitis.
In a 3-month, double-masked, active-treatment-controlled, multicenter
study in pediatric patients, the adverse experience profile of TRUSOPT was comparable
to that seen in adult patients.
Clinical practice
The following adverse events have occurred either at low incidence
(<1%) during clinical trials or have been reported during the use of TRUSOPT
in clinical practice where these events were reported voluntarily from a population
of unknown size and frequency of occurrence cannot be determined precisely.
They have been chosen for inclusion based on factors such as seriousness, frequency
of reporting, possible causal connection to TRUSOPT, or a combination of these
factors: signs and symptoms of systemic allergic reactions including angioedema,
bronchospasm, pruritus, and urticaria; dizziness, paresthesia; ocular pain,
transient myopia, choroidal detachment following filtration surgery, eyelid
crusting; dyspnea; contact dermatitis, epistaxis, dry mouth and throat irritation.
DRUG INTERACTIONS
Although acid-base and electrolyte disturbances were not reported
in the clinical trials with TRUSOPT, these disturbances have been reported with
oral carbonic anhydrase inhibitors and have, in some instances, resulted in
drug interactions (e.g., toxicity associated with high-dose salicylate therapy).
Therefore, the potential for such drug interactions should be considered in
patients receiving TRUSOPT.
WARNINGS
TRUSOPT 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 with
TRUSOPT. 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.
PRECAUTIONS
General
The management of patients with acute angle-closure glaucoma
requires therapeutic interventions in addition to ocular hypotensive agents.
TRUSOPT has not been studied in patients with acute angle-closure glaucoma.
TRUSOPT has not been studied in patients with severe renal
impairment (CrCl <30 mL/min). Because TRUSOPT and its metabolite are excreted
predominantly by the kidney, TRUSOPT is not recommended in such patients.
TRUSOPT has not been studied in patients with hepatic impairment
and should therefore be used with caution in such patients.
In clinical studies, local ocular adverse effects, primarily
conjunctivitis and lid reactions, were reported with chronic administration
of TRUSOPT. Many of these reactions had the clinical appearance and course of
an allergic-type reaction that resolved upon discontinuation of drug therapy.
If such reactions are observed, TRUSOPT should be discontinued and the patient
evaluated before considering restarting the drug. (See ADVERSE
REACTIONS.)
There is a potential for an additive effect on the known systemic
effects of carbonic anhydrase inhibition in patients receiving an oral carbonic
anhydrase inhibitor and TRUSOPT. The concomitant administration of TRUSOPT and
oral carbonic anhydrase inhibitors is not recommended.
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.
Choroidal detachment has been reported with administration
of aqueous suppressant therapy (e.g., dorzolamide) after filtration procedures.
INFORMATION FOR PATIENTS
TRUSOPT 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. Patients
should be advised that if serious or unusual reactions or signs of hypersensitivity
occur, they should discontinue the use of the product (see WARNINGS).
Patients should be advised that if they develop any ocular reactions, particularly
conjunctivitis and lid reactions, they should discontinue use and seek their
physician's advice.
Patients should be instructed to avoid allowing the tip of
the dispensing container to contact the eye or surrounding structures.
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.
Patients also should 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 ten minutes apart.
Patients should be advised that TRUSOPT 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 TRUSOPT administration.
nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use
Safety and IOP-lowering effects of TRUSOPT have
been demonstrated in pediatric patients in a 3-month, multi-center, double masked,
active-treatment-controlled trial.
Geriatric Use
No overall differences in safety or effectiveness
have been observed between elderly and younger patients.
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 salts.
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.
The following tests for mutagenic potential
were negative: (1) in vivo (mouse) cytogenetic assay; (2) in vitro
chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and
(5) Ames test.
In reproduction studies of dorzolamide hydrochloride
in rats, there were no adverse effects on the reproductive capacity of males
or females at doses up to 188 or 94 times, respectively, the recommended human
ophthalmic dose.
Pregnancy
Teratogenic Effects. Pregnancy Category C. Developmental
toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of
2.5 mg/kg/day (31 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 1.0 mg/kg/day (13 times the
recommended human ophthalmic dose). There are no adequate and well-controlled
studies in pregnant women. TRUSOPT should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers
In a study of dorzolamide hydrochloride in lactating
rats, decreases in body weight gain of 5 to 7% in offspring at an oral dose
of 7.5 mg/kg/day (94 times the recommended human ophthalmic dose) were seen
during lactation. A slight delay in postnatal development (incisor eruption,
vaginal canalization and eye openings), secondary to lower fetal body weight,
was noted.
It is not known whether this drug is excreted
in human milk. Because many drugs are excreted in human milk and because of
the potential for serious adverse reactions in nursing infants from TRUSOPT,
a decision should be made whether to discontinue
|
