Timolol Maleate (Page 3 of 4)

Risk of 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 anaphylactic reactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2 year study of timolol maleate in rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (250 times 1 the maximum recommended human dose). Similar differences were not observed in rats administered doses equivalent to approximately 20 or 80 times1 the maximum recommended human dose.

In a lifetime study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinoma in female mice at 500 mg/kg/day (approximately 400 times1 the maximum recommended human dose), but not at a 5 or 50 mg/kg/day. In a subsequent study in female mice, in which postmortem examinations were limited to uterus and lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin that occurred in female mice administered 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 which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended daily human oral dosage, there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when elevated 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 three additional strains. In the assays with tester strain TA100, no consistent dose-response relationship was observed, nor did the ratio of test to control revertants reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 125 times1 the maximum recommended human dose.


1
Based on patient weight of 50 kg.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Teratogenicity studies with timolol in mice, rats and rabbits at doses up to 50 mg/kg/day (approximately 40 times1 the maximum recommended daily human dose) showed 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 (approximately 830 times1 the maximum recommended daily human 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 approximately 40 times1 the maximum recommended daily human dose, in this case without apparent maternotoxicity. There are no adequate and well controlled studies in pregnant women. Timolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Timolol maleate has been detected in human milk.

Because of the potential for serious adverse reactions from timolol 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of timolol for the treatment of hypertension or migraine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In a clinical study of timolol in patients who had survived the acute phase of a myocardial infarction, approximately 350 patients (37%) were 65 to 75 years of age. Safety and efficacy were not different between these patients and younger patients (see CLINICAL PHARMACOLOGY: Pharmacodynamics).

Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See PRECAUTIONS: Impaired Hepatic or Renal Function and Dosing in the Presence of Marked Renal Failure.)

The results from 5 single- and/or multiple-dose PK studies comparing the impact of age on the PK of hydrochlorothiazide, when given in combination with other antihypertensive drugs, were consistent. They indicated a mean median increase in Cmax and AUC of 38% and 99% respectively, in elderly relative to younger subjects.

ADVERSE REACTIONS

Timolol maleate tablets are usually well tolerated in properly selected patients. Most adverse effects have been mild and transient.

In a multi-center (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:

Timolol Maleate
(n=176)
%
Placebo
(n=168)
%

BODY AS A WHOLE

fatigue/tiredness

3.4

0.6

headache

1.7

1.8

chest pain

0.6

0

asthenia

0.6

0

CARDIOVASCULAR

bradycardia

9.1

0

arrhythmia

1.1

0.6

syncope

0.6

0

edema

0.6

1.2

DIGESTIVE

dyspepsia

0.6

0.6

nausea

0.6

0

SKIN

pruritus

1.1

0

NERVOUS SYSTEM

dizziness

2.3

1.2

vertigo

0.6

0

paresthesia

0.6

0

PSYCHIATRIC

decreased libido

0.6

0

RESPIRATORY

dyspnea

1.7

0.6

bronchial spasm

0.6

0

rales

0.6

0

SPECIAL SENSES

eye irritation

1.1

0.6

tinnitus

0.6

0

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 percent.

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:

Adverse Reaction * Withdrawal
Timolol
(n=945)
%
Placebo
(n=939)
%
Timolol
(n=945)
%
Placebo
(n=939)
%
*
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.

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 Block 2nd or 3rd Degree

<1

<1

<1

<1

Sinoatrial Block

<1

<1

<1

<1

Cold Hands and Feet

8

<1

<1

0

Nausea or Digestive Disorders

8

6

1

<1

Dizziness

6

4

1

0

Bronchial Obstruction

2

<1

1

<1

The following additional adverse effects have been reported in clinical experience with the drug: Body as a Whole: anaphylaxis, 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: nonthrombocytopenic 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.

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