A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Timoptic Side Effects, and Drug Interactions - Timolol Maleate
Timoptic Side Effects, and Drug Interactions - Timolol Maleate
SIDE EFFECTS
Tablets
Timolol maleate is usually well tolerated in properly selected
patients. Most adverse effects have been mild and transient.
In a multicenter (12-week) clinical
trial comparing timolol maleate and placebo
in hypertensive
patients, the following adverse reactions were reported spontaneously
and considered to be causally related to timolol maleate (see TABLE
1).
| TABLE 1 |
| |
Timolol Maleate (n=176) |
Placebo (n=168) |
| |
% |
% |
| Body as a Whole |
|
|
3.4 |
0.6 |
|
|
1.7 |
1.8 |
|
|
0.6 |
|
|
|
0.6 |
|
| Cardiovascular |
|
|
9.1 |
|
|
|
1.1 |
0.6 |
|
|
0.6 |
|
|
|
0.6 |
1.2 |
| Digestive |
|
|
0.6 |
0.6 |
|
|
0.6 |
|
| Skin |
|
|
1.1 |
|
| Nervous System |
|
|
2.3 |
1.2 |
|
|
0.6 |
|
|
|
0.6 |
|
| Psychiatric |
|
|
0.6 |
|
| Respiratory |
|
|
1.7 |
0.6 |
|
|
0.6 |
|
|
|
0.6 |
|
| Special Senses |
|
|
1.1 |
0.6 |
|
|
0.6 |
|
These data are representative of the incidence
of adverse effects that may be observed in properly selected patients
treated with timolol maleate, i.e., excluding patients with
bronchospastic disease, congestive heart failure
or other contraindications to beta
blocker therapy.
In patients with migraine
the incidence of bradycardia
was 5%.
In a coronary artery disease
population studied
in the Norwegian multi-center trial (see CLINICAL
PHARMACOLOGY), the frequency of the principal
adverse reactions and the frequency with which these resulted in
discontinuation of therapy in the timolol and placebo groups were
as shown in TABLE 2.
| TABLE 2 |
| |
Adverse Reaction* |
Withdrawal† |
| |
Timolol |
Placebo |
Timolol |
Placebo |
| |
(n=945) |
(n=939) |
(n=945) |
(n=939) |
| |
% |
% |
% |
% |
| Asthenia or Fatigue |
5 |
1 |
<1 |
<1 |
| Heart Rate <40 beats/minute |
5 |
<1 |
4 |
<1 |
| Cardiac Failure-Nonfatal |
8 |
7 |
3 |
2 |
| Hypotension |
3 |
2 |
3 |
1 |
| Pulmonary Edema-Nonfatal |
2 |
<1 |
<1 |
<1 |
| Claudication |
3 |
3 |
1 |
<1 |
| AV Block¾2nd
or 3rd degree |
<1 |
<1 |
<1 |
<1 |
| Sinoatrial Block |
<1 |
<1 |
<1 |
<1 |
| Cold Hands and Feet |
8 |
<1 |
<1 |
|
| Nausea or Digestive Disorders |
8 |
6 |
1 |
<1 |
| Dizziness |
6 |
4 |
1 |
|
| Bronchial Obstruction |
2 |
<1 |
1 |
<1 |
| * When an adverse reaction
recurred in a patient, it is listed only once. |
| † Only principal
reason for withdrawal in each patient
is listed. These adverse reactions can also occur in patients
treated for hypertension. |
The following additional adverse effects have been reported in clinical
experience with the drug:
Body as a Whole: Extremity pain, decreased exercise
tolerance, weight loss, fever.
Cardiovascular: Cardiac arrest, cardiac
failure, cerebral vascular accident, worsening of angina
pectoris, worsening of arterial insufficiency, Raynaud's phenomenon,
palpitations, vasodilatation.
Digestive: Gastrointestinal pain, hepatomegaly, vomiting,
diarrhea, dyspepsia.
Hematologic: Non-thrombocytopenic purpura.
Endocrine: Hyperglycemia, hypoglycemia.
Skin: Rash, skin
irritation, increased pigmentation, sweating, alopecia.
Musculoskeletal: Arthralgia.
Nervous System: Local weakness, increase in signs
and symptoms of myasthenia
gravis.
Psychiatric: Depression, nightmares, somnolence,
insomnia, nervousness, diminished concentration, hallucinations.
Respiratory: Cough.
Special Senses: Visual disturbances, diplopia, ptosis,
dry eyes.
Urogenital: Impotence, urination
difficulties.
There have been reports of retroperitoneal
fibrosis in patients
receiving timolol maleate and in patients receiving other beta-adrenergic
blocking agents. A causal relationship between this condition
and therapy with beta-adrenergic blocking agents has not been established.
Potential Adverse Effects: In
addition, a variety of adverse effects not observed in clinical
trials with timolol maleate, but reported with other beta-adrenergic
blocking agents, should
be considered potential adverse effects of timolol maleate:
Nervous System: Reversible mental
depression progressing
to catatonia; an acute
reversible syndrome
characterized by disorientation for time
and place, short-term memory loss, emotional lability, slightly
clouded sensorium, and decreased performance
on neuropsychometrics.
Cardiovascular: Intensification of AV block
(see CONTRAINDICATIONS).
Digestive: Mesenteric arterial
thrombosis, ischemic colitis.
Hematologic: Agranulocytosis, thrombocytopenic purpura.
Allergic: Erythematous rash, fever
combined with aching and sore
throat, laryngospasm
with respiratory distress.
Miscellaneous: Peyronie's disease.
There have been reports of a syndrome
comprising psoriasiform
skin rash, conjunctivitis
sicca, otitis, and sclerosing
serositis attributed
to the beta-adrenergic receptor
blocking agent, practolol.
This syndrome has not
been reported with timolol maleate.
Clinical Laboratory Test Findings: Clinically important
changes in standard
laboratory parameters were rarely associated with the administration
of timolol maleate. Slight increases in blood
urea nitrogen, serum potassium,
uric acid, and triglycerides,
and slight decreases in hemoglobin, hematocrit
and HDL cholesterol
occurred, but were not progressive or associated with clinical
manifestations. Increases in liver
function tests have been reported.
Ophthalmic Solutions and Ophthalmic Gel Forming Solution
The most frequently reported adverse experiences have been burning
and stinging upon instillation
(approximately 1 in 8 patients).
The following additional adverse experiences have been reported
less frequently with ocular
administration
of this or other timolol maleate formulations.
Body as a Whole: Headache (not in ophthalmic
gel forming solution), asthenia/fatigue,
chest pain.
Cardiovascular: Bradycardia, arrhythmia, hypotension,
(hypertension for the ophthalmic
gel forming solution) syncope,
heart block, cerebral
vascular accident,
cerebral ischemia, cardiac
failure, worsening of angina
pectoris, palpitation, cardiac
arrest, pulmonary edema, edema, claudication, Raynaud's phenomenon,
and cold hands and feet.
Digestive: Nausea, diarrhea, dyspepsia, anorexia,
and dry mouth.
Immunologic: Systemic lupus
erythematosus.
Nervous System/Psychiatric: Dizziness (not in ophthalmic
gel forming solution), increase in signs and symptoms of myasthenia
gravis, paresthesia, somnolence, insomnia, nightmares, behavioral
changes and psychic disturbances including depression, confusion,
hallucinations, anxiety, disorientation, nervousness, and memory
loss.
Skin: Alopecia and psoriasiform
rash or exacerbation
of psoriasis.
Hypersensitivity: Signs and symptoms of allergic
reactions, including angioedema, urticaria, and localized
and generalized rash.
Respiratory: Bronchospasm (predominantly in patients
with pre-existing bronchospastic disease), respiratory failure,
dyspnea, nasal congestion, cough, and upper respiratory infections
(not in ophthalmic gel forming solution).
Endocrine: Masked symptoms of hypoglycemia
in diabetic patients (see WARNINGS).
Special Senses: Signs and symptoms of ocular
irritation including conjunctivitis
(not in ophthalmic
gel forming solution), blepharitis,
keratitis, [ocular pain, discharge
(e.g., crusting), foreign body sensation, itching and tearing
(not in ophthalmic
gel forming solution)],
and dry eyes; ptosis; decreased corneal sensitivity; cystoid
macular edema; visual disturbances including refractive
changes and diplopia; pseudopemphigoid; choroidal detachment
following filtration
surgery (see PRECAUTIONS, General),
and tinnitus.
Urogenital: Retroperitoneal fibrosis, decreased libido,
impotence, and Peyronie's disease.
The following additional adverse effects have been reported in
clinical experience with ORAL timolol maleate or other ORAL beta-blocking
agents, and may be considered potential
effects of ophthalmic
timolol maleate:
Allergic: Erythematous rash, fever
combined with aching and sore
throat, laryngospasm
with respiratory distress.
Body as a Whole: Extremity pain, decreased exercise
tolerance, weight loss.
Cardiovascular: Worsening of arterial
insufficiency, vasodilatation.
Digestive: Gastrointestinal pain, hepatomegaly, vomiting,
mesenteric arterial
thrombosis, ischemic colitis.
Hematologic: Nonthrombocytopenic purpura, thrombocytopenic
purpura, agranulocytosis.
Endocrine: Hyperglycemia, hypoglycemia.
Skin: Pruritus, skin
irritation, increased pigmentation, sweating.
Musculoskeletal: Arthralgia.
Nervous System/Psychiatric: Vertigo, local
weakness, diminished concentration, reversible
mental depression
progressing to catatonia, an acute reversible
syndrome characterized
by disorientation
for time and place, emotional
lability, slightly clouded sensorium, and decreased performance
on neuropsychometrics.
Respiratory: Rales, bronchial
obstruction.
Urogenital: Urination difficulties.
Ophthalmic Gel Forming Solution
In clinical trials,
transient blurred
vision upon instillation
of the drop was reported in approximately one in three patients
(lasting from 30 seconds to 5 minutes). Less than 1% of patients
discontinued from the studies due to blurred vision. The frequency
of patients reporting burning and stinging upon instillation
was comparable between timolol maleate ophthalmic gel forming solution
and timolol maleate ophthalmic
solution (approximately
one in eight patients).
Adverse experiences reported in 1-5% of patients were:
Ocular: Pain, conjunctivitis, discharge
(e.g., crusting), foreign body sensation, itching and tearing.
Systemic: Headache, dizziness, and upper respiratory
infections.
DRUG INTERACTIONS
Catecholamine-depleting Drugs: Close observation
of the patient is recommended when timolol maleate is administered
to patients receiving catecholamine-depleting drugs such as reserpine,
because of possible additive effects and the production
of hypotension and/or
marked bradycardia, which may produce vertigo, syncope, or postural
hypotension.
Quinidine: Potentiated systemic
beta-blockade (e.g., decreased heart
rate) has been reported during combined treatment
with quinidine and timolol, possibly because quinidine inhibits
the metabolism of timolol via
the P-450 enzyme, CYP2D6.
Tablets
Calcium Antagonists: Literature reports suggest that
oral calcium antagonists may be used in combination with beta-adrenergic
blocking agents when heart
function is normal,
but should be avoided in patients with impaired cardiac
function. Hypotension, AV conduction
disturbances, and left
ventricular failure
have been reported in some patients receiving beta-adrenergic blocking
agents when an oral calcium
antagonist was added
to the treatment regimen.
Hypotension was more likely to occur if the calcium antagonist were
a dihydropyridine derivative, (e.g., nifedipine) while left
ventricular failure
and AV conduction
disturbances were more likely to occur with either verapamil or
diltiazem.
Intravenous calcium
antagonists should be used with caution in patients receiving beta-adrenergic
blocking agents.
Digitalis and Either Diltiazem or Verapamil: The
concomitant use of beta-adrenergic blocking
agents with digitalis
and either diltiazem or verapamil may have additive
effects in prolonging AV conduction
time.
Clonidine: Beta adrenergic
blocking agents may
exacerbate the rebound
hypertension which
can follow the withdrawal
of clonidine. If the two drugs are coadministered, the beta
adrenergic blocking
agent should be withdrawn several days before the gradual withdrawal
of clonidine. If replacing clonidine by beta-blocker therapy, the
introduction of beta adrenergic blocking
agents should be delayed for several days after clonidine administration
has stopped.
Risk from Anaphylactic Reaction: While taking beta-blockers,
patients with a history of atopy or a history of severe anaphylactic
reaction 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 anaphylactoid reactions.
Non-steroidal Anti-inflammatory Drugs: Blunting of
the antihypertensive effect
of beta-adrenoceptor blocking
agents by non-steroidal anti-inflammatory drugs has been reported.
When using these agents concomitantly, patients should be observed
carefully to confirm that the desired therapeutic effect has been
obtained.
Ophthalmic Solutions: Although timolol maleate used
alone has little or no effect
on pupil size, mydriasis
resulting from concomitant therapy with timolol maleate and epinephrine
has been reported occasionally.
Ophthalmic Solutions and Ophthalmic Gel Forming Solution
Beta-adrenergic Blocking Agents: Patients who are
receiving a beta-adrenergic blocking
agent orally and timolol
maleate should be observed for potential
additive effects of
beta-blockade, both systemic
and on intraocular pressure. The concomitant
use of two topical beta-adrenergic
blocking agents is
not recommended.
Calcium Antagonists: Caution should be used in the
coadministration of beta-adrenergic blocking
agents, such as timolol maleate, and oral
or intravenous calcium
antagonists because of possible atrioventricular
conduction disturbances, left
ventricular failure,
and hypotension. In patients
with impaired cardiac
function, coadministration
should be avoided.
Digitalis and Calcium Antagonists: (Not for preservative-free
ophthalmic solution.) The concomitant
use of beta-adrenergic blocking agents with digitalis
and calcium antagonists
may have additive effects
in prolonging atrioventricular
conduction time.
Injectable Epinephrine: (See PRECAUTIONS,
General, Anaphylaxis.)
Additional Information for Preservative-Free Ophthalmic Solution:
Although timolol maleate used alone has little or no effect
on pupil size, mydriasis
resulting from concomitant
therapy with timolol maleate and epinephrine has been reported occasionally.
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