Sandoz Bisoprolol Tablets Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Sandoz Bisoprolol Tablets (bisoprolol fumarate) is indicated in the management of patients with mild to moderate hypertension. It is also indicated for the treatment of stable heart failure in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides. It may be used alone or in combination with other antihypertensive agents, particularly thiazide diuretics.

Sandoz Bisoprolol Tablets is not recommended for the emergency treatment of hypertensive crisis.

CONTRAINDICATIONS

Sandoz Bisoprolol (bisoprolol fumarate) is contraindicated in patients with:

• Hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
• acute heart failure, episodes of heart failure decompensation requiring intravenous inotropic therapy, cardiogenic shock;
• second or third degree AV block (without a pacemaker);
• sick sinus syndrome or sinoatrial block;
• bradycardia with less than 60 beats/min before the start of therapy;
• hypotension (systolic blood pressure less than 100 mm Hg);
• severe bronchial asthma or severe chronic obstructive pulmonary disease;
• late stages of peripheral arterial occlusive disease;
• Raynaud's syndrome;
• untreated phaeochromocytoma (see WARNINGS AND PRECAUTIONS);
• metabolic acidosis;
• Due to the presence of lactose in Sandoz Bisoprolol Tablets, use in patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency is also contraindicated (see WARNINGS AND PRECAUTIONS, Sensitivity/Resistance).

WARNINGS AND PRECAUTIONS

General

Allergic Type Reaction: There may be increased difficulty in treating an allergic type reaction in patients on β-blockers. In these patients, the reaction may be more severe due to pharmacologic effects of the β-blockers and the problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other these doses can be associated with excessive alpha-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of a β-agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm or norepinephrine to overcome hypotension.

Risk of Anaphylactic Reaction: While taking β-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Cardiovascular

Cardiac Failure: Special caution should be exercised when administering bisoprolol fumarate to patients with a history of severe heart failure. Safety and effectiveness of bisoprolol doses higher than 10 mg/day in patients with heart failure have not been established. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with β-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. In general, β-blocking agents should be avoided in patients with overt congestive heart failure.

However, in some patients with compensated cardiac failure, it may be necessary to utilize β-blocking agents. In such a situation, they must be used cautiously. Bisoprolol fumarate acts selectively without abolishing the effects of digitalis. However, the positive inotropic effect of digitalis may be reduced by the negative inotropic effect of bisoprolol fumarate when the two drugs are used concomitantly. The effects of β-blockers and digitalis are additive in depressing A-V conduction.

Patients without a history of cardiac failure: In patients without a history of cardiac failure continued depression of the myocardium with β-blockers in some cases lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately and the response observed closely. If cardiac failure continues, bisoprolol fumarate therapy should be immediately withdrawn.

Sinus Bradycardia: Severe sinus bradycardia, resulting from unopposed vagal activity following β-blockade, may occur with the use of bisoprolol fumarate. In such cases, the dosage should be reduced or bisoprolol fumarate discontinued.

Abrupt Cessation of Therapy with Bisoprolol:

Exacerbation of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with β-blockers. Patients, especially those with coronary artery disease, should be warned against discontinuing use of bisoprolol fumarate without a physician’s supervision. Patients with angina and those without overt coronary artery disease should also be warned against abrupt discontinuation of bisoprolol fumarate. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of β-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of bisoprolol fumarate is planned, the dosage should be gradually reduced over a period of about two weeks. The patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, bisoprolol fumarate therapy should be discontinued stepwise and with closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with bisoprolol fumarate be reinstituted promptly, at least temporarily.

Use with caution in the following circumstances:

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase. The initiation and cessation of treatment with bisoprolol necessitates regular monitoring.

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and conditions:

• insulin dependent diabetes mellitus (type 1)
• impaired renal function (serum creatinine ≥ 300 μmol/l)
• impaired liver function
• patients older than 80 years
• restrictive cardiomyopathy
• congenital heart disease
• haemodynamically significant organic valvular disease
• myocardial infarction within 3 months.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I antiarrhythmic drugs and with centrally acting antihypertensive drugs is generally not recommended (see DRUG INTERACTIONS).

Peripheral Vascular Disease: β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Endocrine and Metabolism

Thyrotoxicosis: In patients with thyrotoxicosis, possible deleterious effects from long-term use of bisoprolol fumarate have not been adequately appraised.

β-adrenoceptor blockade may mask clinical signs of hyperthyroidism, such as tachycardia or its complications, and give a false impression of improvement. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or precipitate thyroid storm.

Therefore, in such patients from whom bisoprolol fumarate is to be discontinued, withdrawal should be gradual and the patients monitored closely.

Diabetes Mellitus and Hypoglycaemia: β-blockers may mask some of the manifestations of hypoglycaemia, particularly tachycardia. β-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia in patients with insulin or non-insulin dependent diabetes, especially those with labile diabetes, or with a history of spontaneous hypoglycaemia. Therefore, bisoprolol fumarate should be used with caution in these patients.

Diabetic patients receiving bisoprolol fumarate should be monitored to ensure that diabetes control is maintained. The dose of insulin or oral hypoglycaemic agent may need adjustment.

Ophthalmologic

Oculomucocutaneous Syndrome: Various skin rashes have been reported with β-blockers, including bisoprolol fumarate. A severe syndrome (oculomucocutaneous syndrome), whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis, has occurred with the chronic use of one β-adrenoceptor blocking agent (practolol). This syndrome has not been observed with bisoprolol fumarate or any other β-adrenoceptor blocking agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.

Peri-Operative Considerations

Anesthesia and Surgery: The necessity or desirability of withdrawing β-blocking agents prior to major surgery is controversial. The impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anaesthesia and surgical procedures. The benefits of continuing a treatment with a β-blocker should be balanced against the risk of withdrawing it in each patient. However, care should be taken when using bisoprolol fumarate with anesthetic agents such as those which may depress the myocardium.

In patients receiving β-blocker therapy, inhalation anaesthetics may enhance the cardio-depressant effect. β -Blockade may have beneficial effects in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the postoperative period. It is currently recommended that maintenance β-blockade be continued peri-operatively.

The anaesthetist must be made aware of β-blockade because of the potential for interactions with other drugs, resulting in severe bradyarrhythmias, attenuation of the reflex tachycardia and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and the increased propensity for vagal-induced bradycardia. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2 mg IV).

Some patients receiving β-adrenoceptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting the heart and maintaining the heart beat has also been reported (see OVERDOSAGE).

Modern inhalational anaesthetic agents are generally well tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were sometimes associated with severe circulatory depression in the presence of β-blockade. If it is thought necessary to withdraw β-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

In emergency surgery, since bisoprolol fumarate is a competitive antagonist at β-adrenoceptor sites, its effects may be reversed, if required, by sufficient doses of such agonists as isoproterenol or noradrenaline.

Phaeochromocytoma:

When a β-blocker is prescribed for a patient known to be suffering from a phaeochromocytoma, an alpha-blocker should be given concomitantly and only after the alpha-blocker has been initiated.

Renal/Hepatic

Impaired Renal or Hepatic Function: Appropriate laboratory tests for monitoring renal, hepatic and hematopoietic function should be performed at regular intervals during long-term treatment. In patients with severe renal disease, haemodynamic changes following β blockade may impair renal function further. β-blockers which are excreted mainly by the kidney may require dose adjustment and safety monitoring in patients with severe renal impairment, including renal failure. Hepatic impairment: may increase the systemic bioavailability of bisoprolol and reduce its total clearance, leading to increased plasma concentrations. Therefore, it should be used with caution in patients with impaired liver function. Use caution in adjusting dose in hepatic and renal impaired patients (See DOSAGE AND ADMINISTRATION).

Respiratory

Bronchospastic Disease: In general, patients with bronchospastic pulmonary disease should not receive β-blockers. However, because bisoprolol fumarate is relative β₁-selective, it may be used cautiously in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since β₁-selectivity is not absolute, the lowest possible dose of bisoprolol fumarate should be employed, and a β₂-agonist (bronchodilator) should be administered concomitantly. The patient should be monitored closely. In patients already on bronchodilators therapy, the dose may have to be increased. Bisoprolol is contraindicated in patients with severe bronchial asthma or severe chronic obstructive lung disease (see

CONTRAINDICATIONS).

Skin

Various rashes have been reported with β‐blocking agents. Cross reactions may occur between β‐blockers, therefore substitutions within the group may not necessarily preclude occurrence of symptoms.

Special Populations

Pregnant Women: Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, β‐adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. If treatment with β‐adrenoceptor blockers is necessary, β₁‐selective adrenoceptor blockers are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and the foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Studies in rats have shown that bisoprolol and/or its metabolites cross the placenta and distribute to the foetus.

Administration of bisoprolol at oral doses of ≥50 mg/kg/day to pregnant rats or ≥12.5 mg/kg/day to pregnant rabbits caused embryofoetal toxicity, resorptions and abortions. The no‐effect dose for embryofoetal toxicity and mortality was 40 mg/kg/day (associated with plasma drug concentrations (AUC) 11 times that expected in humans after 10 mg/kg/day bisoprolol) for rats and 10 mg/kg/day for rabbits (associated with AUC lower than that expected in humans after 10 mg/kg/day doses). No evidence for teratogenic effects of bisoprolol was observed at any dose in rats or rabbits.

Nursing Women: Bisoprolol and/or its metabolites have been found in the milk of lactating rats.

Treatment of rats with bisoprolol at oral doses of 150 mg/kg/day from late gestation and during the lactation period was associated with decreased offspring birth weight and retarded physical development. The no‐effect dose (50 mg/kg) for these effects was associated with an AUC about 14 times greater than that expected in humans.

There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of bisoprolol.

Pediatrics: Safety and effectiveness in children have not been established.

Geriatrics: Bisoprolol fumarate has been used in elderly patients with essential hypertension.

Based on age alone no dosage adjustments are required; however, caution is advised in patients greater than 80 years old since data in this age group is limited. Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose.

Monitoring and Laboratory Tests

Appropriate laboratory tests for monitoring renal, hepatic, and hematopoietic function should be performed at regular intervals during long-term treatment with bisoprolol fumarate.

Effect on ability to drive or use machinery

Bisoprolol may cause dizziness or fatigue (see ADVERSE EFFECTS) and, therefore, may adversely affect the patient's ability to drive or use machinery. In a study with coronary heart disease patients bisoprolol did not impair driving performance. However, due to individual variations in reactions to the drug, the ability to drive a vehicle or operate machinery may be impaired. This should be considered particularly at the start of treatment and upon change of medication, as well as in conjunction with alcohol.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In two multi-centre, placebo-controlled clinical trials involving 404 mild-to-moderate hypertensive patients, the most frequently reported adverse reactions (>2%), whether or not drug related, were: arthralgia (2.7%), dizziness (3.5%), headache (10.9%), insomnia (2.5%), diarrhea (3.5%), nausea (2.2%), coughing (2.5%), pharyngitis (2.2%), rhinitis (4.0%), sinusitis (2.2%), URT infection (5.0%), fatigue (8.2%), and peripheral edema (3%).

In total, 187 out of 404 patients (46.3%) reported at least one adverse event. Overall, the events reported were mild to moderate in severity.

Twenty-seven out of 404 patients (6.7%) discontinued therapy due to an adverse event or an intercurrent illness.

The following table (Table 1) presents the adverse experiences, whether or not drug related, reported by >1% of all patients (n=404) enrolled in the two placebo-controlled trials of bisoprolol fumarate given in single daily doses of 2.5 - 40 mg. The adverse drug reactions that appear to be dose related are bradycardia, diarrhea, asthenia, fatigue and sinusitis. As the incidence of bradycardia is 0.5%, it is the only dose related adverse experience not listed below.

(Table 1).

Table 1 - Adverse Experience (>1%): Placebo-Controlled Trials (n=404)

In one long-term, open-label, extension study involving 144 hypertensive patients, the most frequently reported adverse experiences (>2%), whether or not drug related were: arthralgia (4.2%), myalgia (2.1%), muscle cramps (2.1%), dizziness (4.9%), headache (8.3%), earache (2.1%), impotence (2.1%), libido decrease (2.1%), abdominal pain (2.1%), diarrhea (2.8%), bronchitis (2.8%) coughing (4.2%), pharyngitis (4.2%), rhinitis (8.3%), sinusitis (4.9%), URT infection (6.9%), back pain (2.1%), chest pain (2.1%), fatigue (6.9%), fever (2.1%), peripheral edema (3.5%), pain (2.1%) and traumatic injury (2.1%).

The adverse experiences reported were generally mild to moderate in severity. Seventy-nine out of 144 patients (54.9%) reported at least one adverse experience. Out of the total number of patients enrolled, 12 (8.3%) discontinued therapy due to an adverse experience or an intercurrent illness.

The table below, (Table 2) presents the adverse experiences reported by at least 1% of all patients (n=144) enrolled in the long-term, open-label, extension study in which patients received doses of bisoprolol fumarate ranging from 5 to 20 mg daily.

Table 2 - Adverse Experience (>1%): Long-Term, Open-label,

Extension Study (n=144)

The table 3 below shows incidences of adverse events reported from both the placebo and the bisoprolol cohort of the CIBIS II trial. Regardless of causal relationship, all adverse events are included. Each patient is only counted once for each adverse event occurring in at least 1 % of the study population.

Table 3-Adverse Experience CIBIS II trial

AE =Adverse Events

Post-Market Adverse Drug Reactions

The following is a list of spontaneous adverse experience reported with bisoprolol fumarate since its entry into the US market and the markets of some European countries. In these cases, an incidence of causal relationship cannot be accurately determined. The adverse experiences are listed according to body system and are as follows:

CNS (Central Nervous System)

Dizziness, vertigo, headache, paraesthesia, somnolence, decreased concentration/memory, aphasia, insomnia, muscle contractions (involuntary), paresis, sleep disturbances, sleepiness, syncope, tingling sensation, coma, encephalopathy, speech disorder, hallucination, confusion.

Autonomic Nervous System

Dry mouth.

Cardiovascular

Bradycardia, palpitations and other rhythm disturbances, hypotension, dyspnea on exertion, embolism, extrasystoles, atrial fibrillation, left cardiac failure, myocardial infarction, Raynaud-like disorder, hypertension, cardiac failure, circulatory failure, A-V block, cardiac arrest, tachycardia, ventricular fibrillation, arrhythmia.

Skin

Rash, pruritus, alopecia, angioedema, exfoliative dermatitis, hyperpigmentation, psoriaform rash, skin photosensitivity, epidermal necrolysis, erythema multiforme, scleroderma, skin discolouration, urticaria.

Special Senses

Ocular pain/pressure, abnormal lacrimation, taste abnormalities, ageusia, anosmia, conjunctivitis, visual disturbances, reduced tear flow (to be considered if the patient uses lenses).

Endocrine/Metabolic

Hypoglycaemia.

Respiratory

Asthma/bronchospasm, dyspnea, shortness of breath, pulmonary edema, pneumonitis, respiratory insufficiency, allergic rhinitis.

Hematologic

Purpura vasculitis and peripheral ischemia.

Gastrointestinal

Nausea, Vomiting, diarrhea and constipation.

Musculoskeletal

Muscle cramps, twitching/tremor, arthralgia and myalgia.

Reproductive

Peyronie’s disease, galactorrhea, mastalgia, still-birth.

General

Fatigue, asthenia, malaise, edema, weight gain, death, scleroderma, overdose effect.

Laboratory Abnormalities

In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding.

Sporadic liver abnormalities have been reported. In two U.S. well-controlled studies versus placebo with bisoprolol fumarate treatment for 4-12 weeks, the incidence of concomitant elevations in SGOT and SGPT of between 1-2 times normal was 3.9% for bisoprolol fumarate compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.

Experience from long-term, uncontrolled studies with bisoprolol fumarate treatment for 6 to 18 months, the incidence of one or more concomitant elevations in SGOT and SGPT of between 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate.

Other laboratory changes include small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreased in WBC and platelets. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate.

As with other β-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term studies converted to a positive titre, although about one-third of these patients subsequently reconverted to a negative titre while on continued therapy.

DRUG INTERACTIONS

General

The clearance of bisoprolol is 'balanced' between renal elimination of the unchanged drug and hepatic metabolism, renal clearance accounting for at least 50% of the dose. The remainder is subject to metabolism primarily by CYP3A4, with a minor contribution from CYP2D6. Bisoprolol plasma concentrations are expected to increase during concurrent administration of CYP3A4 inhibitors by not more than a factor of 2, and decrease during concurrent administration of CYP3A4 inducers. Due to the minor role of CYP2D6 in bisoprolol metabolism, CYP2D6 inhibitors and genetic differences in CYP2D6 activity do not significantly alter bisoprolol plasma concentrations. Bisoprolol may increase the plasma concentrations of other drugs metabolised by CYP3A4 and possibly those metabolised by CYP2D6.

Table 4 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CR= Case Report, CT = Clinical Trial; L = Literature, T = Theoretical

DOSAGE AND ADMINISTRATION

Mild to moderate hypertension

In the treatment of mild to moderate hypertension, Sandoz Bisoprolol Tablets (bisoprolol fumarate) must be individualized to the needs of the patient with gradual dose titration until an optimum response is achieved. The usual initial dose is 2.5 mg to 5 mg once daily either added to a diuretic or alone. If the response to 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily. The usual effective dosage range is 2.5 mg to 20 mg once daily. An appropriate interval for dose titration is 2 weeks.

The maximum recommended dose is 20 mg once daily.

Heart Failure

Titration Phase:

The treatment of stable chronic heart failure with bisoprolol requires a titration phase. The treatment with bisoprolol is to be started with a gradual uptitration according to the following steps:

• 1.25 mg once daily for 1 week. If well tolerated increase to:
• 2.5 mg once daily for a further week. If well tolerated increase to:
• 3.75 mg once daily for a further week. If well tolerated increase to:
• 5 mg once daily for the next 4 weeks. If well tolerated increase to:
• 7.5 mg once daily for the next 4 weeks. If well tolerated increase to:
• 10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Treatment of stable chronic heart failure with bisoprolol is generally a long term treatment.

Patients with renal or hepatic impairment:

In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min) as in other patients, the initial daily dose should be 5 mg. Because of the possibility of accumulation, caution must be used in dose titration. Since limited data suggest that bisoprolol fumarate is not dialysable, drug replacement is not necessary in patients undergoing dialysis.

Treatment modification:

If the maximum recommended dose is not well tolerated, gradual dose reduction may be considered. In case of transient worsening of heart failure, hypotension, or bradycardia, reconsideration of the dosage of the concomitant medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute deterioration of the patient’s condition.

Geriatrics

In the elderly, it is not usually necessary to adjust the dose, unless there is also significant renal or hepatic dysfunction (see PRECAUTIONS).

Children

There is no pediatric experience with bisoprolol fumarate, therefore, its use cannot be recommended for children.

OVERDOSAGE

The most common signs expected with overdosage of β-blockers are bradycardia, hypotension, congestive heart failure, bronchospasm and hypoglycaemia. To date, a few cases of overdose with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered. In general, if overdose occurs, therapy with bisoprolol fumarate should be stopped and supportive, symptomatic treatment should be provided. Patients should be monitored closely. Limited data suggest that bisoprolol fumarate is not dialyzable.

Based on the expected pharmacologic actions and recommendations for other β-blockers, the following general measures should be considered when clinically warranted:

Bradycardia

Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary. Intravenous glucagon has been described to be useful.

Hypotension

IV fluids and vasopressors such as dopamine or norepinephrine should be administered. Monitor blood pressure continuously. Intravenous glucagon may be useful.

Heart Block (second or third degree)

Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.

Congestive Heart Failure

Initiate conventional therapy (i.e. digitalis, diuretics, inotropic agents, vasodilating agents). Glucagon has been reported to be useful.

Bronchospasm

Administer bronchodilator therapy such as isoproterenol or terbutaline (β₂ stimulants) and/or IV aminophylline.

Hypoglycaemia

Administer IV glucose.

Based on the severity of symptoms, management may require intensive support care and facilities for administering cardiac and respiratory support.

It should be remembered that bisoprolol fumarate is a competitive antagonist of isoproterenol and hence large doses of isoproterenol can be expected to reverse many of the effects of excessive doses of bisoprolol fumarate. However, complications of excess isoproterenol should not be overlooked.

ACTION AND CLINICAL PHARMACOLOGY

Sandoz Bisoprolol Tablets (bisoprolol fumarate) is a synthetic β₁-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range. This preferential effect is not absolute, however, and at higher doses bisoprolol may also inhibit β₂-adrenoceptors, located chiefly in the bronchial and vascular musculature.

Mechanism of Action

The mechanism of action of its antihypertensive effects has not been completely established. Factors which may be involved include:

• Antagonism of β-adrenoceptors to decreased cardiac output.
• Inhibition of renin release by the kidneys.
• Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.

In normal volunteers, bisoprolol fumarate therapy resulted in a reduction of exercise and isoproterenol-induced tachycardia. The maximal effect occurred with 1-4 hours post-dosing. Effects persisted for 24 hours at doses equal to or greater than 5 mg.

Electrophysiology studies in man have demonstrated that bisoprolol fumarate significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and with rapid atrial stimulation, prolongs AV nodal conduction.

Bisoprolol fumarate is well absorbed following oral administration. The absolute bioavailability after a 10 mg dose is greater than 80%. Absorption is not affected by the presence of food. The first pass metabolism of bisoprolol fumarate is less than 20%.

Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within

2-4 hours of dosing with 5 to 20 mg and mean peak values range from 16 ng/mL at 5 mg to

70 ng/mL at 20 mg. Once daily dosing with bisoprolol fumarate results in less than two fold intersubject variation in peak plasma levels. The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients in part because of decreased renal function in that population. Steady-state is attained within 5 days with once-daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the first order kinetics and once-daily dosing. Plasma concentrations are proportional to administered dose in the range of 5 to 20 mg. Pharmacokinetic characteristics of the 2 enantiomers are similar.

Bisoprolol fumarate is eliminated equally by renal and non renal pathways with about 50% of the dose appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. Bisoprolol fumarate is not metabolized by cytochrome P450 2D6 (debrisoquin hydroxylase).

In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately three-fold compared to healthy subjects.

In patients with liver cirrhosis, the rate of elimination of bisoprolol fumarate is more variable and significantly slower than that in healthy subjects, with plasma half-life ranges from 8.3 to 21.7 hours.

Pharmacodynamics

The most prominent effect of bisoprolol fumarate is the negative chronotropic effect, resulting in a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.

STORAGE AND STABILITY

Sandoz Bisoprolol Tablets (bisoprolol fumarate) tablets should be stored between 15 and 25ºC. No other special storage conditions are necessary.

DOSAGE FORMS, COMPOSITION AND PACKAGING

1.25 mg: Each white, film-coated, round tablet with embossment “BIS 1,25” on one side and plain on the other side contain 1.25 mg of bisoprolol fumarate. Available in bottles of 100 tablets.

Nonmedicinal ingredients: Calcium hydrogen phosphate, colloidal anhydrous silica, croscarmellose sodium, hypromellose, lactose monohydrate, macrogol (polyethylene glycol), maize starch (pregelatinised), magnesium stearate, microcrystalline cellulose and titanium dioxide.

2.5 mg: Each white, film-coated, round, scored and divisible into two parts tablet with embossment “BIS 2,5” on one side and plain on the other side contains 2.5 mg of bisoprolol fumarate. Available in bottles of 100 tablets.

Nonmedicinal ingredients: Calcium hydrogen phosphate, colloidal anhydrous silica, croscarmellose sodium, hypromellose, lactose monohydrate, macrogol (polyethylene glycol), maize starch (pregelatinised), magnesium stearate, microcrystalline cellulose and titanium dioxide.

5 mg: Each yellow, film-coated, round, scored and divisible into two parts tablet with debossment “B 5” on the other side contains 5 mg of bisoprolol fumarate. Available in bottles of 100 tablets.

Nonmedicinal ingredients: Calcium hydrogen phosphate, colloidal anhydrous silica, croscarmellose sodium, hypromellose, lactose monohydrate, macrogol (polyethylene glycol), maize starch (pregelatinised), magnesium stearate, microcrystalline cellulose, titanium dioxide and yellow ferric oxide.

10 mg: Each apricot-coloured, film-coated, round, scored and divisible into two parts tablet with debossment “B 10” on the other side contains 10 mg of bisoprolol fumarate. Available in bottles of 100 tablets.

Nonmedicinal ingredients: Calcium hydrogen phosphate, colloidal anhydrous silica, croscarmellose sodium, hypromellose, lactose monohydrate, macrogol (polyethylene glycol), maize starch (pregelatinised), magnesium stearate, microcrystalline cellulose, red ferric oxide, titanium dioxide and yellow ferric oxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: bisoprolol fumarate

Chemical name: (2RS)-1-[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]propan-2-ol fumarate

Structural formula:

O N CH3 O O CH3 CH3 CH3 H H OH OH OH O O 1/2

Molecular formula: (C₁₈ H₃₁NO₄ )_{2 ·} C₄H₄O₄

Molecular weight: 766.96 g/mol

Description: White crystalline powder

pH values: pH of a 1% solution: 6.0 and 7.0

pKa: The pKa value for bisoprolol fumarate free base is 9.5 by potentiometric titration. The pKa values for fumaric acid are 3.03 and 4.44

Melting point: 100 - 103ºC by the capillary method.

Specific rotation: Bisoprolol fumarate is a racemic mixture of S (-) and R (+) enantiomers. In assay of bulk material, the specific rotation was zero, within the error of measurement.

Partition coefficient: 0.129

Solubilities: Bisoprolol fumarate is soluble in Water and Methanol.

CLINICAL TRIALS

Comparative Bioavailability Study

A comparative, randomized, single-dose, 2-way crossover bioavailability study comparing a new formulation of Sandoz Bisoprolol 10 mg tablets to a previously approved formulation of Sandoz Bisoprolol 10 mg tablets in 25 healthy adult male and female subjects under fasting conditions was conducted. The summary of results from the comparative bioavailability study carried out by Sandoz Canada Inc. is presented in the following table:

Table 5 - Summary Table of the Comparative Bioavailability Data

* Sandoz Bisoprolol (bisoprolol fumarate) 10 mg tablets (Sandoz Canada Inc.) (new formulation) Sandoz Canada Inc., Canada, (Sandoz Bisoprolol) 1 x 10 mg

† Sandoz Bisoprolol (bisoprolol fumarate) 10 mg tablets (Sandoz Canada Inc.) were purchased in Canada (previously approved formulation) Sandoz Canada Inc., Canada (Sandoz Bisoprolol Tablet), 1 x 10 mg tablet.

^§ Expressed as the arithmetic mean (CV%) only

In total 2,647 ambulatory patients with chronic heart failure were included in the CIBIS II trial in accordance with the following inclusion/exclusion criteria:

Inclusion criteria: CHF of at least three months duration (stable for at least 6 weeks).

Exclusion criteria: Resting heart rate <60 beats/min; supine systolic BP <100 mmHg; myocardial infarction or unstable angina within the preceding 3 months; percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) within the preceding 6 months; atrioventricular block of second degree or greater without a functioning pacemaker, haemodynamically significant organic valvular disease; obstructive or restrictive cardiomyopathy.

Patient demographics: 83% (n = 2202) of patients were in NYHA class III and 17% (n = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction ≤ 35%, based on echocardiography).

Results: Total mortality was reduced from 17.3% to 11.8% (absolute reduction 5.5%; relative reduction 34% [95% confidence interval 19‐46%]). A decrease in sudden death (3.6% vs. 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol, hospital admissions due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed. Hospitalizations due to hypotension and acute decompensation were lower in the bisoprolol group compared to the placebo group (0%, 0.3% and 6.74%).

DETAILED PHARMACOLOGY

Human Pharmacology

β₁-selectivity of bisoprolol fumarate has been demonstrated in both animal and human studies. No effects at therapeutic doses on β₂-adrenoceptor density have been observed. Pulmonary function studies have been conducted in volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD) utilizing pulmonary function testing. Bisoprolol fumarate doses ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airway resistance (AWR) and decreases in forced expiratory volume (FEV₁) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increase in AWR also noted with the other cardioselective β-blockers. The changes induced by β-blockade with all agents were reversed by bronchodilator therapy.

Pharmacodynamics

Bisoprolol is a β₁-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilising activity. It only shows very low affinity to the β₂-receptor of the smooth muscles of bronchi and vessels as well as to the β₂-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and β₂-mediated metabolic effects. Its β₁-selectivity extends beyond the therapeutic dose range. However, its β₁-selectivity is not absolute and at doses greater than the maximum recommended of 10 mg, bisoprolol may also inhibit β₂-adrenoreceptors.

The haemodynamic effects of bisoprolol are those that can be expected from β-adrenoceptor blockade. Besides the negative chronotropic effect resulting in a reduction in resting and exercise heart rate there is, as shown in acute studies with intravenous administration, a fall in resting and exercise cardiac output with only little change in stroke volume, and a small increase in right atrial pressure at rest or during exercise. The decrease in cardiac output correlates with the heart rate reduction, and the observed increases in total peripheral resistance and pulmonary arterial resistance after acute administration are considered to be due to reflex autonomic changes resulting from the negative chronotropic and slight negative inotropic effects.

Acute intravenous administration of 10 mg bisoprolol to hypertensive patients reduced glomerular filtration rate (GFR), renal blood flow (RBF) and plasma renin activity (PRA) whereas the renal vascular resistance was reduced after short-term treatment (10 mg bisoprolol taken orally for 4 weeks) with no significant changes in RBF, GFR or PRA. Adrenaline (epinephrine) and noradrenalin (norepinephrine) levels also remained unaffected after the 4-week treatment in hypertensive patients.

Bisoprolol shows the same pattern of cardiac electrophysiologic effects as other β-adrenoceptor blocking agents. It acts on those parts of the conduction system that are influenced by the sympathetic nervous system. In electrophysiological studies it reduced heart rate, prolonged sinoatrial (SA) and atrioventricular (AV) nodal conduction, and prolonged the refractory periods of the SA and AV node. There was no statistically significant effect on atrial effective refractory period in patients with a history of syncope or cardiac arrhythmias. However, in patients with coronary artery disease, there was a small significant increase in right atrial effective and functional refractory periods. Right ventricular effective refractory period was temporarily prolonged during a study in patients with coronary artery disease, but the clinical relevance of the small increase is uncertain. RR and PR intervals were increased and QTc intervals reduced but all parameters remained within normal limits after bisoprolol.

Pharmacokinetics

Absorption: Bisoprolol is almost completely (>90%) absorbed from the gastrointestinal tract and, because of its small first pass metabolism of about 10%-15%, has an absolute bioavailability of about 85-90% after oral administration. The bioavailability is not affected by food. The drug shows linear kinetics and the plasma concentrations are proportional to the administered dose over the dose range 5 to 20 mg. Peak plasma concentrations occur within 2-3 hours.

Distribution: Bisoprolol is extensively distributed. The volume of distribution is 3.5 L/kg. Binding to plasma proteins is approximately 35%; uptake into human blood cells was not observed.

Metabolism: In humans, only oxidative metabolic pathways have been detected with no subsequent conjugation. All metabolites, being very polar, are renally eliminated. The major metabolites in human plasma and urine were found to be without pharmacological activity. In vitro data from studies in human liver microsomes show that bisoprolol is primarily metabolized via CYP3A4 (~95%) with CYP2D6 having only a minor role. The minor contribution of CYP2D6 to the metabolism of bisoprolol observed in vitro is consistent with the in vivo data in extensive and restricted debrisoquine metabolisers, which showed no difference between the two groups of metabolisers. Bisoprolol is a racemate consisting of the R and S enantiomers. The intrinsic clearance by human recombinant CYP3A4 appears to be non-stereoselective while the metabolism by CYP2D6 is stereoselective (R/S =1.50).

Elimination: The clearance of bisoprolol is 'balanced' between renal elimination of the unchanged drug (~50%) and hepatic metabolism (~50%) to metabolites which are also renally excreted. The total clearance of the drug is 15.6 ± 3.2 L/h with renal clearance being 9.6 ± 1.6 L/h. In a study with

₁₄C-labelled bisoprolol the total urinary and fecal excretion was 90 ± 2.7% and 1.4 ± 0.1% of the dose, respectively (mean ± SEM recoveries of the total dose within 168 hours). Bisoprolol has an elimination half-life of 10-12 hours.

Renal Impairment: Since the clearance of bisoprolol is balanced between renal elimination of the unchanged drug (~50%) and hepatic metabolism (~50%), the plasma accumulation factor of bisoprolol in patients with either complete renal or hepatic impairment should not exceed 2. In a study in patients with a mean creatinine clearance of 28 mL/min the plasma accumulation factor was less than 2, and it has been shown that as the creatinine clearance falls the AUC increases as does the t_1/2 and Cmax. According to these studies in patients with renal impairment no dosage adjustment is normally required up to the maximum dose of 10 mg bisoprolol.

Hepatic Impairment: There were no clinically relevant differences in the pharmacokinetics of bisoprolol between patients with normal or impaired hepatic function. Thus, dose reduction is not required in patients with mild or moderate liver disease. Renal function should be monitored in patients with severe liver disease, since renal impairment may develop and require dose reduction up to the maximum dose of 10 mg bisoprolol.

Chronic Cardiac Failure: In a small sub study of the CIBIS II study in patients with CHF (NYHA III) on 10 mg bisoprolol, the steady state AUC was greater, the T_1/2 longer (17 ± 5 hours) and the clearance lower than in healthy volunteers, the values being similar to those observed in patients with renal impairment. Bisoprolol pharmacokinetics in patients with CHF and concomitant impaired liver and/or renal function have not been studied, however dose reduction may be required in such patients.

Elderly: Some pharmacokinetic parameters (t_1/2, AUC, Cmax) have been found to be greater in the elderly compared to younger adults which appears to be due to a reduction in renal clearance in the elderly. However, the pharmacokinetic differences between younger adults and the elderly are unlikely to be clinically significant, and based on age alone no dosage adjustments are required.

Following oral administration of Sandoz Bisoprolol 5 mg to healthy subjects under fasting conditions, a mean peak plasma concentration (C_max) of Bisoprolol of approximately 21.6 ng/mL was achieved within approximately 1.6 hours (T_max).

TOXICOLOGY

Toxicology studies in animals have established that bisoprolol fumarate has a wide margin of safety. In multiple-dose studies in the rat and dog, findings were related to pharmacologic effects and/or were class effects known to occur with other β-blockers and thus were not specific to bisoprolol fumarate. In the rat, at high multiples of human therapeutic doses, increased serum triglycerides, focal myocardial necrosis, increased heart weight/size, and pulmonary phospholipidosis were observed. In the dog, the tolerance threshold for bisoprolol fumarate was determined by its pharmacologic actions (i.e., hypotension) which resulted in lethality. Increases in serum triglycerides and hepatocyte inclusion bodies were also seen in dogs.

Acute Toxicity

The acute toxicity of bisoprolol fumarate was studied in mice, rats, and dogs. Tables 6A and 6B below summarize the results of the studies performed:

Table 6A - Acute Toxicity - Bisoprolol Fumarate Alone

Table 6B - Acute Toxicity - Bisoprolol Fumarate/HCTZ

(1:2.5 Combination)

Clinical signs in mice and rats were reduced spontaneous activity, prone position, and dyspnea. In mice, convulsions and tremor were also observed. Dogs were more sensitive to bisoprolol fumarate than rodents. Clinical signs in dogs were staggering, salivation, vomiting, prone or lateral position, dyspnea, convulsions, and tonic spasms. In all three species, clinical signs were seen soon after dosing and subsided rapidly in animals that survived. Delayed effects were not observed.

LD₅₀'s of the S (-)-enantiomer in mice and rats were similar to or greater than LD₅₀'s for bisoprolol fumarate (racemate).

Clinical signs in mice and rats were reduced spontaneous activity, twitching, prone position, trembling, dyspnea, and piloerection. In both species, clinical signs were seen soon after dosing. Clinical signs subsided rapidly in mice that survived, but were seen up to day 6 in rats that survived. There was no potentiation of the acute toxicity of bisoprolol fumarate when it was given in combination with hydrochlorothiazide in mice or rats.

Multiple Dose Toxicity

The toxicity of bisoprolol fumarate was studied using daily oral doses in rats for 6 weeks, and 3, 6, and 12 months, and in dogs for 1, 6 and 12 months.

A 1-month daily IV dosing study was conducted in rats and dogs. The toxicity of bisoprolol fumarate in combination with hydrochlorothiazide was studied in each species using daily oral dosing for 6 months.

The results of the studies performed are displayed in table 6A and 6B below.

Myocardial Necrosis

A listing of the myocardial necrosis studies performed can be found in tables 7A and 7B. Minimal focal myocardial necrosis and/or fibrosis, accompanied by varying amounts of inflammatory infiltrates were seen in myocardial sections of both control and treated male (but not female) animals in the 6-month study of bisoprolol fumarate in combination with hydrochlorothiazide. In general, the focal myocardial changes in control and treated rats did not differ in morphology, severity, or location in the myocardium. Group incidence rates appeared to be higher in the active treatment groups than in the controls.

Cardioactive drugs, as a pharmacologic class, are known to produce myocardial changes in rats (Van Vleet and Ferrans, 1986) and minimal focal myocardial necrosis and/or fibrosis is commonly seen in untreated male rats (Boorman, 1981; Greaves and Faccini, 1984). Results of the two 3-month rat studies indicated the following: (1) High multiples of human therapeutic doses of bisoprolol fumarate, metoprolol, and hydrochlorothiazide alone and in combination increased the group incidence of focal myocardial necrosis/fibrosis in male rats. (2) When bisoprolol fumarate was given in combination with hydrochlorothiazide, the group incidence of focal myocardial necrosis/fibrosis appeared slightly higher than when each agent was given alone. (3) Myocardial changes described have the same morphology and severity in control and drug-treated groups.

Table 7A - Subacute and Chronic Toxicity: Bisoprolol Fumarate Alone

Table 7A - Subacute and Chronic Toxicity: Bisoprolol Fumarate Alone (continued)

Table 7B - Subacute and Chronic Toxicity: Bisoprolol Fumarate and HCTZ in a 1:25 Ratio

1. (a) regarding myocardial necrosis please see Table 8A and 8B
2. (b)

   cardiovascular collapse due to impulse formation and conduction disturbances

   Table 8A

   Myocardial Necrosis in Studies with Bisoprolol Fumarate and

   Bisoprolol/ Hydrochlorothiazide (1:2.5) Combination in Male Rats

Table 8B

Myocardial Necrosis in 3-Month Studies with Bisoprolol fumarate

Metoprolol and Hydrochlorothiazide in Male Rats

In conclusion, bisoprolol fumarate and metoprolol, alone or in combination with hydrochlorothiazide, and hydrochlorothiazide alone are associated with an increased incidence of minimal myocardial changes in male rats given high multiples of human therapeutic doses. These myocardial changes are not severe and the effect is species- and sex-specific. The myocardial changes discussed above are most likely a class effect, probably due to the exaggerated pharmacologic actions of these drugs at high doses. Metoprolol has been marketed and used clinically for more than 10 years, hydrochlorothiazide for more than 20 years, and fixed combinations of metoprolol and hydrochlorothiazide for several years. Therefore, the myocardial findings in these studies are not considered to indicate any potential risk for man.

Carcinogenicity

Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 123 mg/kg/day. On a body-weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based on a 50 kg individual); on a body-surface-area-basis, these doses are 59 times (mice) and 64 times (rats) the MRHD.

Teratology and Reproduction

In reproductive toxicology studies in rats, bisoprolol fumarate had no effect on fertility or general reproductive performance. Bisoprolol fumarate, like other β-blockers, caused maternal and embryotoxic effects at high doses, but was not teratogenic in either rats or rabbits. In a perinatal and postnatal study in rats, maternal toxic effects and reduced birth weight were observed at the high dose, but no other effects on reproductive performance were seen.

Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body-weight-basis and 26 times the MRHD on the basis of body-surface area. The maternotoxicity occurred at 375 times the MRHD on a body-weight basis and

77 times the MRHD on the basis of body-surface area. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body-weight and body-surface-area, respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.

Mutagenicity

The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.