Timoriv Overdose

• Overdose of Timoriv in details
• Timoriv warnings
• Timoriv precautions
• Timoriv reviews

What happens if I overdose Timoriv?

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local, or emergency room immediately. Symptoms may include difficult or slowed breathing; fainting; low blood pressure; severe dizziness; very slow heart rate; weakness.

Proper storage of Timoriv:

Store Timoriv at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Timoriv out of the reach of children and away from pets.

Overdose of Timoriv in details

Overdosage has been reported with Timoriv tablets. A 30 year old female ingested 650 mg of Timoriv (maximum recommended daily dose - 60 mg) and experienced second- and third-degree heart block. She recovered without treatment but approximately 2 months later developed irregular heart beat, hypertension, dizziness, tinnitus, faintness, increased pulse rate and borderline first degree heart block.

The oral LD50 of the drug is 1190 and 900 mg/kg in female mice and female rats, respectively.

An in vitro hemodialysis study, using 14C Timoriv added to human plasma or whole blood, showed that Timoriv was readily dialyzed from these fluids; however, a study of patients with renal failure showed that Timoriv did not dialyze readily.

The most common signs and symptoms to be expected with overdosage with a beta-adrenergic receptor blocking agent are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. Therapy with Timoriv should be discontinued and the patient observed closely. The following additional therapeutic measures should be considered:

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(1) Gastric lavage.

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(2) Symptomatic bradycardia: Use atropine sulfate intravenously in a dosage of 0.25 mg to 2 mg to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride should be administered cautiously. In refractory cases the use of a transvenous cardiac pacemaker may be considered.

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(3) Hypotension: Use sympathomimetic pressor drug therapy, such as dopamine, dobutamine or norepinephrine. In refractory cases the use of glucagon hydrochloride has been reported to be useful.

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(4) Bronchospasm: Use isoproterenol hydrochloride. Additional therapy with aminophylline may be considered.

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(5) Acute cardiac failure: Conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases the use of intravenous aminophylline is suggested. This may be followed if necessary by glucagon hydrochloride which has been reported to be useful.

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(6) Heart block (second- or third-degree): Use isoproterenol hydrochloride or a transvenous cardiac pacemaker.

What should I avoid while taking Timoriv?

Timoriv can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Avoid drinking alcohol, which could increase drowsiness and dizziness while you are taking Timoriv.

Timoriv warnings

Cardiac Failure

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 failure. Although beta-blockers should be avoided in overt congestive heart failure, they can be used, if necessary, with caution in patients with a history of failure who are well compensated, usually with digitalis and diuretics. Both digitalis and Timoriv slow AV conduction. If cardiac failure persists, therapy with Timoriv should be withdrawn.

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, patients receiving Timoriv should be digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, Timoriv should be withdrawn.

Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal

Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered Timoriv, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of one to two weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, Timoriv administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue Timoriv therapy abruptly even in patients treated only for hypertension.

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 ‘Timoriv’ IS CONTRAINDICATED, see CONTRAINDICATIONS), SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS, INCLUDING ‘Timoriv’. However, if Timoriv is necessary in such patients, then the drug should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors.

Major Surgery

The necessity or desirability of withdrawal of beta-blocking therapy 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 been subject to 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 blocking agents.

If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or norepinephrine.

Diabetes Mellitus

Timoriv 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.

Thyrotoxicosis

Beta-adrenergic blockade 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-blockade which might precipitate a thyroid storm.

What should I discuss with my healthcare provider before taking Timoriv?

Some medical conditions may interact with Timoriv. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding
• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
• if you have allergies to medicines, foods, or other substances
• if you have heart disease, heart failure, blood flow problems, bronchitis or another lung problem, tumors on your adrenal gland, diabetes mellitus, an overactive thyroid, or you are suffering from an allergic reaction, or you will be having surgery

Some MEDICINES MAY INTERACT with Timoriv. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Indomethacin and derivatives, ibuprofen, naproxen, phenylpropanolamine, sulfinpyrazone, or sulindac because they may decrease Timoriv's effectiveness
• Anticholinesterases (eg, pyridostigmine), cimetidine, diltiazem, disopyramide, flecainide, ketanserin, lithium, mefloquine, mibefradil, nifedipine and derivatives, propafenone, quinidine, reserpine, serotonin reuptake inhibitors (eg, fluoxetine), or verapamil and derivatives because side effects, such as low blood pressure and slowed heart rate, may occur
• Bupivacaine, carbonic anhydrase inhibitors (eg, acetazolamide), cocaine, disopyramide, sympathomimetics (eg, epinephrine), ergot alkaloids (eg, ergotamine), flecainide, insulin, ketanserin, mefloquine, meglitinide antidiabetics (eg, repaglinide), methyldopa, nifedipine and derivatives, quinazolines (eg, imatinib), serotonin reuptake inhibitors (eg, fluoxetine), or verapamil and derivatives because the risk of their side effects may be increased by Timoriv
• Glucagon, meglitinide antidiabetics (eg, repaglinide), phenformin, sympathomimetics (eg, pseudoephedrine, albuterol), or theophyllines (eg, aminophylline) because the their effectiveness may be decreased by Timoriv
• Clonidine because when it is discontinued it may cause rebound high blood pressure

This may not be a complete list of all interactions that may occur. Ask your health care provider if Timoriv may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

Timoriv precautions

General

Impaired Hepatic or Renal Function

Since Timoriv is partially metabolized in the liver and excreted mainly by the kidneys, dosage reductions may be necessary when hepatic and/or renal insufficiency is present.

Dosing in the Presence of Marked Renal Failure

Although the pharmacokinetics of Timoriv are not greatly altered by renal impairment, marked hypotensive responses have been seen in patients with marked renal impairment undergoing dialysis after 20 mg doses. Dosing in such patients should therefore be especially cautious.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timoriv has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

Cerebrovascular Insufficiency

Because of potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow are observed, consideration should be given to discontinuing these agents.

Drug Interactions

Catecholamine-Depleting Drugs

Close observation of the patient is recommended when Timoriv 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.

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.

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.

Quinidine

Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and Timoriv, possibly because quinidine inhibits the metabolism of Timoriv via the P-450 enzyme, CYP2D6.

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 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 Timoriv in rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (250 times1 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 Timoriv 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 Timoriv, the maximum recommended daily human oral dosage, there were no clinically meaningful changes in serum prolactin.

Timoriv 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 Timoriv 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 Timoriv 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. Timoriv should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Timoriv has been detected in human milk.

Because of the potential for serious adverse reactions from Timoriv 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 Timoriv 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 Timoriv 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.

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.

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.

What happens if I miss a dose of Timoriv?

Take the missed dose as soon as you remember. If your next dose is less than 8 hours away, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

References

1. DailyMed. "TIMOLOL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
2. DrugBank. "timolol". http://www.drugbank.ca/drugs/DB00373 (accessed September 17, 2018).
3. MeSH. "Antihypertensive Agents". https://www.ncbi.nlm.nih.gov/mesh/68... (accessed September 17, 2018).

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Information checked by Dr. Sachin Kumar, MD Pharmacology