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LATANOPROST/TIMOLOL MALEATE
XALACOM
1.0
TRADE NAME OF THE PRODUCT
Xalacom
2.0
DESCRIPTION
Timolol
C13H24 N4O3 S 1/2 H20. 325.43. (1) 2-Propanol, 1-[(1,1-dimethylethyl)amino]-3([4-(4morpholinyl)-1,2,5thiadiazol-3-yl]oxy]-, hemihydrate, (S)-; (2) (S)-1-(tert
Butylamino)-3-[(4-morpholino-1,2,5-=thiadiazol-3-yl)-2-propanol hemihydrate.
CAS 91524-16-2, INN; BAN anti-adrenergic (β -receptor).
Latanoprost
C26H40O5. 432.59 (1) 5-Heptenoic acid, 7-[3,5-dihydroxy-2-(3-hydroxy-5phenylpentyl)cyclopentyl]-1-methylethyl ester, (iR-[1 α(Z),2β(R*), 3α,5α]; (2)
Isopropyl (Z)-7-(IR,2R,3R,5S)-3,5-dihydroxy-2-(3R)-3-hydroxy-5phenylpentyl0[cyclopentyl]-5-heptenoate. CAS-130209-82-4. INN; BAN:
Antiglaucoma agent.
3.0
FORMULATION
Each mL contains:
Latanoprost 50 mcg
Timolol maleate equivalent to 5mg timolol
4.0
CLINICAL PARTICULARS
4.1
Therapeutic indications
Reduction of intraocular pressure (IOP) in patients with open angle
glaucoma or ocular hypertension who are insufficiently responsive to
topical IOP lowering agents.
4.2
Dosage and method of administration
Use in adults (including the elderly):
One drop in the affected eye(s) once daily.
The dosage of latanoprost-timolol maleate should not exceed once daily
since it has been shown that more frequent administration of latanoprost
decreases the intraocular pressure lowering effect.
If one dose is missed treatment should continue with the next dose as
planned.
If more than one topical ophthalmic drug is being used, the drugs should
be administered at least five minutes apart.
Contact lenses should be removed before instillation of the eye drops and
may be reinserted after fifteen minutes. (See section 4.4 Special
Warnings and Special Precautions for Use – General).
When using nasolacrimal occlusion or closing the eyelids for 2 minutes,
the systemic absorption is reduced. This may result in a decrease in
systemic side effects and an increase in local activity.
Use in children:
Safety and effectiveness in children have not been established.
4.3
Contraindications
Latanoprost-timolol maleate (Xalacom) is contraindicated in patients with:
•
•
Reactive airway disease including bronchial asthma, a history of
bronchial asthma or severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome,sino-atrial block, second or
third degree atrioventricular block not controlled with pacemaker,
overt cardiac failure or cardiogenic shock.
•
4.4
Known hypersensitivity to latanoprost, timolol-maleate or any other
component of this product, i.e., benzalkonium chloride, sodium
chloride, sodium dihydrogen phosphate monohydrate, disodium
phosphate anhydrous.
Special warnings and precautions for use
General:
This product contains benzalkonium chloride, which may be absorbed by
contact lenses. (See section 4.2 Dosage and Method of Administration)
Latanoprost:
Latanoprost may gradually increase the brown pigment of the iris. The
eye color change is due to increased melanin content in the stromal
melanocytes of the iris, rather than to an increase in the number of
melanocytes. Typically, the brown pigmentation around the pupil spreads
concentrically towards the periphery of the iris and the entire iris or parts
of the iris become more brownish. The change in iris color is mild in the
majority of cases and may not be detected clinically. The increase in iris
pigmentation in one or both eyes has been documented predominantly in
patients who have mixed-color irides that contain the color brown at
baseline. Neither nevi nor freckles of the iris have been affected by
treatment. No accumulation of pigment in the trabecular meshwork or
elsewhere in the anterior chamber has been observed in clinical trials.
In a clinical trial designed to assess iris pigmentation over five years, there
was no evidence of adverse consequences due to increased pigmentation
even when administration of latanoprost continued. These results are
consistent with post-marketing clinical experience since 1996. In
addition, IOP reduction was similar in patients regardless of the
development of increased iris pigmentation. Therefore, treatment with
latanoprost can be continued in patients who develop increased iris
pigmentation. These patients should be examined regularly and,
depending on the clinical situation, treatment may be stopped.
Onset of increased iris pigmentation typically occurs within the first year
of treatment, rarely during the second or third year, and has not been seen
after the fourth year of treatment. The rate of progression of iris
pigmentation decreases with time and is stable by five years. The effects
of increased pigmentation beyond five years have not been evaluated.
During clinical trials, the increase in brown iris pigment has not been
shown to progress further upon discontinuation of treatment, but the
resultant color change may be permanent.
Eyelid skin darkening, which may be reversible, has been reported in
association with the use of latanoprost.
Latanoprost may gradually change eyelashes and vellus hair in the treated
eye; these changes include increased length, thickness, pigmentation, and
number of lashes or hairs, and misdirected growth of eyelashes. Eyelash
changes are reversible upon discontinuation of treatment.
The potential for heterochromia exists for patients receiving unilateral
treatment.
Macular edema, including cystoid macular edema, has been reported
during treatment with latanoprost. These reports have mainly occurred in
aphakic patients, in pseudophakic patients with torn posterior lens capsule,
or in patients with known risk factors for macular edema. Caution is
recommended when using latanoprost in these patients.
There is no documented experience with latanoprost-timolol in
inflammatory, neovascular, chronic angle closure glaucoma, in open
angle glaucoma of pseudophakic patients and in pigmentary glaucoma.
Therefore it is recommended that latanoprost-timolol should be used with
caution in these conditions until more experience is obtained.
Latanoprost should be used with caution in patients with a history of
herpetic keratitis, and should be avoided in cases of active herpes simplex
keratitis and in patients with a history of recurrent herpetic keratitis
specifically associated with prostaglandin analogues.
Timolol Maleate:
The same adverse reactions found with systemic administration of betaadrenergic blocking agents may occur with their topical administration.
Patients with a history of severe cardiac disease should be monitored
closely for signs of cardiac failure. The following cardiac and respiratory
reactions may occur after topical application of timolol maleate:
•
aggravation of Prinzmetal’s angina
•
aggravation of peripheral and central circulatory disorders
•
hypotension
•
cardiac failure resulting in death
•
severe respiratory reactions, including fatal bronchospasm in
patients with asthma
•
bradycardia
Due to its negative effect on conduction time, beta-blockers should only
be given with caution to patients with first degree heart block.
Patients with severe peripheral circulatory disturbance/disorders (i.e.
severe forms of Raynaud’s disease or Raynaud’s syndrome) should be
treated with caution.
Timolol maleate should be used with caution, in patients with
mild/moderate chronic obstructive pulmonary disease (COPD) and only if
the potential benefit outweighs the potential risk
A gradual withdrawal of beta-adrenergic blocking agents prior to major
surgery should be considered. Beta-adrenergic blocking agents impair the
ability of the heart to respond to beta-adrenergically mediated reflex
stimuli, which may augment the risk of general anesthesia in surgical
procedures. Protracted severe hypotension during anesthesia and
difficulty restarting and maintaining the heartbeat have been reported.
During surgery, the effects of beta-adrenergic blocking agents may be
reversed by sufficient doses of adrenergic agonists.
Beta-blocking ophthalmological preparations may block systemic betaagonist effects e.g. of adrenaline. The anaesthesiologist should be
informed when the patient is receiving timolol.
Beta-adrenergic blocking agents may increase the hypoglycemic effect of
agents used to treat diabetes, and can mask the signs and symptoms of
hypoglycemia. They should be used with caution in patients with
spontaneous hypoglycemia or diabetes (especially those with labile
diabetes), who are receiving insulin or oral hypoglycemic agents.
Therapy with beta-adrenergic blocking agents may mask certain signs and
symptoms of hyperthyroidism. Abrupt withdrawal of therapy may
precipitate a worsening of this condition.
When treated with beta-adrenergic blocking agents, patients with a history
of atopy or severe anaphylactic reaction to a variety of allergens may be
more reactive to repeated challenge with such allergens. They may be
unresponsive to the usual doses of epinephrine used to treat anaphylactic
reactions.
Timolol maleate has been reported to rarely increase muscle weakness in
some patients with myasthenia gravis or myasthenic symptoms (e.g.
diplopia, ptosis, generalized weakness).
Choroidal detachment after filtration procedures has been reported with
the administration of ocular hypotensive agents.
Ophthalmic beta-blockers may induce dryness of eyes. Patients with
corneal diseases should be treated with caution.
4.5
Interaction with other medicinal products and other forms of
interaction
Specific medicinal product interaction studies have not been performed
with latanoprost-timolol maleate.
The effect on intraocular pressure or the known effects of systemic betablockade may be potentiated when latanoprost-timolol maleate is given to
patients already receiving an oral beta-adrenergic blocking agent, and the
use of two or more topical beta-adrenergic blocking agents is not
recommended.
There have been reports of paradoxical elevations in IOP following the
concomitant ophthalmic administration of two prostaglandin analogs.
Therefore, the use of two or more prostaglandins, prostaglandin analogs,
or prostaglandin derivatives is not recommended.
Mydriasis has occasionally been reported when timolol maleate was given
with epinephrine.
The potential exists for additive effects resulting in systemic hypotension
and/or marked bradycardia when timolol maleate is administered with:
•
calcium channel blockers
•
catecholamine-depleting drugs or beta-adrenergic blocking agents
•
antiarrythmics (including amiodarone)
•
digitalis glycosides
•
guanethidine
Potentiated systemic beta blockade (e.g., decreased heart rate,
depression) has been reported during combined treatment with
CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and
timolol.
Beta-adrenergic blocking agents may increase the hypoglycemic effect of
agents used to treat diabetes. (See section 4.4 Special Warnings and
Special Precautions for Use – Timolol Maleate).
4.6
Fertility, pregnancy and lactation
Fertility:
Latanoprost has not been found to have any effect on male or female fertility
in animal studies. Reproduction and fertility studies of timolol maleate 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. (See section 5.3 Preclinical
Safety Data – Impairment of Fertility - Latanoprost and Timolol
Maleate)
Pregnancy
There are no adequate and well controlled studies in pregnant women.
Latanoprost-timolol maleate should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. (See section 5.3
Preclinical Safety Data – Latanoprost and Timolol Maleate).
Lactation
Latanoprost and its metabolites may pass into breast milk. Timolol
maleate has been detected in human milk following oral and ocular drug
administration. Because of the potential for serious adverse reactions 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.
4.7
Effects on ability to drive and use machines
Instillation of eye drops may cause transient blurring of vision. Until this has
resolved, patients should not drive or use machines.
4.8
Undesirable effects
Latanoprost-Timolol Maleate:
Clinical Trials:
Adverse events observed in ≥1% of the patients treated with latanoprosttimolol maleate in three controlled, phase three clinical trials (6 month, 6
month, and 12 month, respectively) were:
Ocular:
Eye Disorders: Abnormal vision, blepharitis cataract, conjunctival
disorder, conjunctivitis, corneal disorder, errors of refraction, eye
hyperemia, eye irritation, eye pain, increased iris pigmentation, keratitis,
photophobia, and vision field defect.
Systemic:
Infections and Infestations: Infection, sinusitis, and upper respiratory tract
infection.
Metabolism and Nutrition Disorders: Diabetes mellitus,
hypercholesterolemia.
Psychiatric Disorders: Depression.
Nervous System Disorders: Headache
Vascular Disorders: Hypertension.
Skin and Subcutaneous Tissue Disorders: Hypertrichosis, rash, and skin
disorder.
Musculoskeletal and Connective Tissue Disorders: Arthritis
Other significant adverse events that have been reported with the
individual components of latanoprost-timolol maleate are listed below.
Latanoprost:
Clinical Trials:
The following events were considered drug related:
Eye Disorders: Eye irritation (burning, grittiness, itching, stinging and
foreign body sensation), transient punctuate epithelial erosions, and eyelid
edema
Skin and Subcutaneous Tissue Disorders: Skin rash
Post Marketing Surveillance:
The following additional events have been reported:
Nervous System Disorders: Dizziness
Eye Disorders: Corneal edema and erosions, eyelash and vellus hair
changes (increased length, thickness, pigmentation, and number),
iritis/uveitis, macular edema, including cystoid macular edema,
misdirected eyelashes sometimes resulting in eye irritation; vision blurred,
photophobia, periorbital and lid changes resulting in deepening of the
eyelid sulcus. (See section 4.4 Special Warnings and Special
Precautions for Use – Latanoprost).
Respiratory, Thoracic and Mediastinal Disorders: Asthma, asthma
aggravation, acute asthma attacks, and dyspnea.
Skin and Subcutaneous Tissue Disorders: Darkening of the palpebral skin
of the eyelids and localized skin reaction on the eyelids.
Musculoskeletal and Connective Tissue Disorders: Muscle /joint pain.
General Disorders and Administration Site Conditions: Non-specific chest
pain.
Infections and Infestations: Not known: herpetic keratitis
Timolol Maleate (Ocular Administration):
Immune System Disorders: Signs and symptoms of systemic allergic
reactions including anaphylaxis, angioedema, urticaria, pruritus and
localized and generalized rash.
Metabolism and Nutrition Disorders: Anorexia, masked symptoms of
hypoglycemia in diabetic patients (See section 4.4 Special Warnings and
Special Precautions for Use – Timolol Maleate).
Psychiatric Disorders: Behavioral changes and psychic disturbances
including, confusion, hallucinations, anxiety, disorientation, nervousness,
and memory loss; decreased libido; insomnia; depression and nightmares.
Nervous System Disorders: Cerebral ischemia, cerebral vascular accident,
dizziness, increase in signs and symptoms of myasthemia gravis (See
section 4.4 Special Warnings and Special Precautions for Use –
Timolol Maleate), paresthesia, somnolence, headache and syncope.
Eye Disorders; Cystoid macular edema; decreased corneal sensitivity;
signs and symptoms of ocular irritation (e.g., burning, stinging, itching,
tearing, redness), blepharitis, keratitis, vision blurred, dry eyes, corneal
erosion, choroidal detachment following filtration surgery (See section 4.4
Special Warnings and Special Precautions for Use – Timolol Maleate);
ptosis; and visual disturbances including refractive changes and diplopia.
Ear and Labyrinth Disorders: Tinnitus
Cardiac Disorders: Arrhythmia, bradycardia, atrioventricular block,
congestive heart failure, cardiac arrest, cardiac failure, heart block,
palpitation and worsening of angina pectoris (See section 4.4 Special
Warnings and Special Precautions for Use – Timolol Maleate).
Vascular Disorders: Claudication, cold hands and feet, hypotension, and
Raynaud’s phenomenon.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm
(predominatly in patients with pre-existing bronchospastic disease. (See
section 4.4 Special Warnings and Special Precautions for Use –
Timolol Maleate), cough, dyspnea, nasal congestion, pulmonary edema,
and respiratory failure.
Gastrointestinal Disorders: Diarrhea, dry mouth, dysgeusia, dyspepsia,
nausea, vomiting, abdominal pain and retroperitoneal fibrosis.
Skin and Subcutaneous Tissue Disorders: Alopecia, pseudopemphigoid,
skin rash and psoriasiform rash or exacerbation of psoriasis.
Musculoskeletal and Connective Tissue Disorders: Systemic lupus
erythematosus and myalgia.
Reproductive System and Breast Disorders: Decreased libido, impotence,
sexual dysfunction and Peyronie’s disease.
General Disorders and Administration Site Conditions: Asthenia/fatigue,
chest pain, and edema.
4.9
Overdosage
If overdosage with latanoprost-timolol occurs, treatment should be
symptomatic.
Information concerning overdose with the individual components is
provided below:
Latanoprost
Apart from ocular irritation and conjunctival hyperemia, no other ocular
adverse effects areknown if latanoprost is overdosed.
If latanoprost is accidentally ingested the following information may be
useful. One 2.5 mL bottle contains 125 micrograms latanoprost. More
than 90% is extensively metabolized during the first pass through the liver.
Intravenous infusion of 3 mcg/kg in healthy volunteers induced no
symptoms but a dose of 5.5 – 10 mcg/kg caused nausea, abdominal pain,
dizziness, fatigue, hot flushes and sweating. In patients with moderate
bronchial asthma, bronchoconstriction was not induced by latanoprost
when applied topically on the eys in a dose of seven times the clinical dose
of latanoprost. (See section 5.3 Preclinical Safety Data –
Latanoprost:Systemic/Ocular Effects)
Timolol Maleate
There have been reports of inadvertent overdosage with timolol-maleate
ophthalmic solution resulting in systemic effects similar to those seen with
systemic beta-adrenergic blocking agents such as dizziness, headache,
shortness of breath, bradycardia, bronchospasm, and cardiac arrest. (See
section 4.8 Undesirable Effects-Timolol Maleate (Ocular
Administration)
An in vitro hemodialysis study demonstrated that timolol was readily
dialyzed from human plasma or whole blood.
A study with renal failure patients demonstrated that timolol was not
readily dialyzed.
5.0
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Mechanism of Action
Product consists of two components: latanoprost and timolol maleate.
These two components decrease elevated intraocular pressure (IOP) by
different mechanisms of action and the combined effect results in
additional IOP reduction compared to either compound administered
alone.
Latanoprost
The active substance of latanoprost, a prostaglandin F2alpha analogue, is a
selective prostanoid FP receptor agonist that reduces the IOP by increasing
the outflow of aqueous humour, primarily through the uveoscleral route
and also through the trabecular meshwork.
Clinical trials have shown that latanoprost has no significant effect on the
production of aqueous humour. Latanoprost has not been found to have
any effect on the blood-aqueous barrier
.
Latanoprost has not induced fluorescein leakage in the posterior segment
of pseudophalic human eyes during short term treatment.
Latanoprost in clinical doses has not been found to have any significant
pharmacological effects on the cardiovascular or respiratory system.
Timolol Maleate
Timolol maleate is a beta-1 and beta-2 (non-selective) adrenergic receptor
blocking agent that does not have significant intrinsic sympathomimetic,
direct myocardial depressant, or local anesthetic (membrane-stabilizing)
activity.
Beta-adrenergic receptor blockade reduces cardiac output in both healthy
subjects and patients with heart disease. In patients with severe
impairment of myocardial function, beta-adrenergic receptor blockade
may inhibit the stimulatory effect of the sympathetic nervous system
necessary to maintain adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles results
in increased airway resistance from unopposed parasympathetic activity.
Such an effect in patients with asthma or other bronchospastic conditions
is potentially dangerous (See section 4.3 Contraindications and section
4.4 Special Warnings and Special Precautions for Use – Timolol
Maleate).
Timolol maleate ophthalmic solution, when applied topically on the eye,
has the action of reducing elevated as well as normal intraocular pressure,
whether or not accompanied by glaucoma. Elevated intraocular pressure
is a major risk factor in the pathogenesis of glaucomatous visual field loss.
The higher the level of intraocular pressure, the greater the likelihood of
glaucomatous visual field loss and optic nerve damage.
The precise mechanism of the ocular hypotensive action of timolol
maleate is not clearly established at this time. Tonography and
fluorophotometry studies in man suggest that its predominant action may
be related to reduced aqueous formation. However, in some studies a
slight increase in outflow facility was also observed.
Clinical Effects:
In dose finding studies, latanoprost-timolol maleate produced significantly
greater decreases in mean diurnal IOP compared to latanoprost and timolol
maleate administered once daily as monotherapy. In two well controlled,
double masked six-month clinical studies the IOP reducing effect of
latanoprost-timolol maleate was compared with latanoprost and timolol
maleate monotherapy in patients with an IOP of at least 25 mm Hg or
greater. Following a 2 to 4 week run-in with timolol maleate (mean
decrease in IOP from enrollment of 5 mm Hg), additional decreases in
mean diurnal IOP of 3.1, 2.0 and 0.6 mm Hg were observed after 6 months
of treatment with latanoprost-timolol maleate and latanoprost and timolol
maleate (twice daily), respectively. The IOP lowering effect of
latanoprost-timolol maleate was maintained in a 6 month open label
extension of these studies.
Onset of action of latanoprost-timolol maleate is within one hour and
maximal effect occurs within six to eight hours. Adequate IOP reducing
effect has been shown to be present up to 24 hours post dosage after
multiple treatments.
5.2
Pharmacokinetic properties
Latanoprost-Timolol Maleate:
No pharmacokinetic interactions between latanoprost and timolol maleate
were observed, although there was an approximate two-fold increased
concentration of the acid of latanoprost in aqueous humour 1 to 4 hours after
administration of latanoprost-timolol maleate compared to monotherapy.
Latanoprost:
Absorption:
Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is
hydrolyzed to the acid form to become biologically active. Studies in man
indicate that the peak concentration in the aqueous humor is reached about two
hours after topical administration.
Distribution:
The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost
can be measured in aqueous humor during the first four hours, and in plasma
only during the first hour after local administration.
Metabolism:
Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea
to the biologically active acid. The active acid of latanoprost reaching the
systemic circulation is primarily metabolized by the liver to the 1,2-dinor and
1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
Excretion:
The elimination of the acid of latanoprost from human plasma is rapid (t1/2 =17
min) after both intravenous and topical administration. Systemic clearance is
approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are
mainly eliminated via the kidneys. Approximately 88% and 98% of the
administered dose is recovered in the urine after topical and intravenous dosing,
respectively.
Timolol Maleate:
The maximum concentration of timolol maleate in the aqueous humor is
reached about one hour after topical administration of eye drops. Part of the
dose is absorbed systemically and a maximum plasma concentration of 1
ng/ml is reached 10 to 20 minutes after topical administration of one eye drop
to each eye once daily (300 micrograms/day). The half-life of timolol maleate
in plasma is about six hours. Timolol maleate is extensively metabolized in
the liver. The metabolites are excreted in the urine together with some
unchanged timolol maleate.
5.3
Preclinical safety data
The ocular and systemic safety profile of the individual components is well
established. No adverse ocular or systemic effects were seen in rabbits treated
topically with the fixed combination or with concomitantly administered
latanoprost and timolol ophthalmic solutions. Safety pharmacology,
genotoxicity and carcinogenicity studies with each of the components
revealed no special hazards for humans. Latanoprost did not affect corneal
wound healing in the rabbit eye, whereas timolol inhibited the process in the
rabbit and the monkey eye when administered more frequently than once a
day.
Latanoprost:
Systemic/Ocular Effects:
The ocular as well as systemic toxicity of latanoprost has been investigated in
several animal species. Generally, latanoprost is well tolerated with a safety
margin between clinical ocular dose and systemic toxicity of at least 1000 times.
High doses of latanoprost, approximately 100 times the clinical dose/kg body
weight, administered intravenously to unanesthetized monkeys have been shown
to increase the respiration rate probably reflecting bronchoconstriction of short
duration. In monkeys, latanoprost has been infused intravenously in doses of up
to 500 mcg/kg without major effects on the cardiovascular system. In animal
studies, latanoprost has not been found to have sensitizing properties.
In the eye, no toxic effects have been detected with doses of up to 100
micrograms/eye/day in rabbits or monkeys (clinical dose is approximately 1.5
micrograms/eye/day). Latanoprost has no or negligible effects on the intraocular
blood circulation when used at the clinical dose and studied in monkeys.
In chronic ocular toxicity studies, administration of latanoprost 6
micrograms/eye/day has also been shown to induce increased palpebral fissure.
This effect is reversible and occurs at doses above the clinical dose level. The
effect has not been seen in humans.
Carcinogenesis:
Carcinogenicity studies in mice and rats were negative.
Mutagenesis:
Latanoprost was found negative in reverse mutation tests in bacteria, gene
mutation in mouse lymphoma and mouse micronucleus test. Chromosome
aberrations were observed in vitro with human lymphocytes. Similar effects
were observed with prostaglandin F2α, a naturally occurring prostaglandin, and
indicates that this is a class effect
Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis
in rats were negative and indicate that latanoprost does not have mutagenic
potency.
Impairment of Fertility:
Latanoprost has not been found to have any effect on male or female fertility in
animal studies. In the embryotoxicity study in rats, no embryotoxicity was
observed at intravenous doses (5, 50 and 250 micrograms/kg/day) of
latanoprost. However, latanoprost induced embryolethal effects in rabbits at
doses of 5 micrograms/kg/day and above. Latanoprost has been shown to
cause embryofetal toxicity in rabbits characterized by increased incidences of
late resorption and abortion and reduced fetal weight when given in
intravenous doses approximately 100 times the human dose.
Teratogenesis:
No teratogenic potential has been detected.
Timolol Maleate:
Carcinogenesis:
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 postmortem 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 maleate 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.
Mutagenesis:
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 maleate
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.
Impairment of Fertility:
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.
Teratogenesis:
Teratogenicity studies with timolol maleate 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 1000 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.
6.0
PHARMACEUTICAL PARTICULARS
6.1
Shelf life
Please see outer package for the expiry date of the product.
6.2
Storage
Store unopened bottle(s) under refrigeration at 2° – 8°C (36°F to 46°F).
After first opening the container,store at or below 25° (77°F) and use
within four weeks.
. Protect from light.
6.3
Availability
Xalacom 50 mcg/5 mg per 5 mL Ophthalmic Solution: Clear and
colorless solution free of visible particulates. Each bottle contains 2.5 mL
eye drop solution corresponding to approximately 80 drops.
CAUTION: Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without
prescription.
Manufactured by: Pharmacia NV/SA, Puurs, Belgium
Imported by: Pfizer, Inc.
23rd Floor, Ayala Life-FGU Center
6811 Ayala Avenue
Makati City, Philippines
Reference No.: CDS ver 3.0
Reference Date: November 2011
Revision No.: 2
Revision Date: 21 November 2011
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