Visken (Xediton Pharmaceuticals) Product Monograph

INDICATIONS

1. a)

   Hypertension

   VISKEN® (pindolol) is indicated for the treatment of mild to moderate hypertension. VISKEN® is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be used alone as an initial agent in those patients in whom, in the judgment of the physician, treatment should be started with a ß-blocker rather than a diuretic.

   The combination of VISKEN® with a diuretic and/or peripheral vasodilator has been found to be compatible and generally more effective than VISKEN® alone. Limited experience with other antihypertensive agents, including methyldopa, has not shown evidence of incompatibility with VISKEN®.

   VISKEN® is not recommended for the emergency treatment of hypertensive crises.

2. b)

   Angina Pectoris

   VISKEN® is indicated for the prophylaxis (prevention) of angina pectoris.

CONTRAINDICATIONS

VISKEN® (pindolol) is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Patients with bronchospasm, including bronchial asthma or severe chronic obstructive pulmonary disease (see PRECAUTIONS)
• Patients with congestive heart failure (see WARNINGS)
• Patients with right ventricular failure secondary to pulmonary hypertension
• Patients with Prinzmetal's Angina (variant angina)
• Patients with sinus bradycardia (<45-50 beats/minute)
• Patients with cardiogenic shock
• Patients with second or third-degree atrioventricular (A-V) block
• Patients with sick sinus syndrome
• Patients with severe peripheral arterial circulatory disturbances
• Patients with untreated pheochromocytoma
• Patients receiving anesthesia with agents which produce myocardial depression, e.g. ether

WARNINGS

1. a)

   Cardiac Failure:

   Special caution should be exercised when administering VISKEN® (pindolol) to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with ß-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating

   cardiac failure. VISKEN® may reduce but does not abolish the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of VISKEN® when the two drugs are used concomitantly. The effects of ß-blockers and digitalis are additive in depressing AV conduction. In patients without a history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalised and/or given a diuretic and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, VISKEN® should be immediately withdrawn.

2. b)

   Abrupt Cessation of Therapy with VISKEN®:

   Patients with angina should be warned against abrupt discontinuation of VISKEN®. 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 ß-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of VISKEN® is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about two weeks and the patient should be observed carefully. The same frequency of administration should be maintained. In situations of greater urgency, VISKEN® therapy should be discontinued stepwise under very close observation.

   If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with VISKEN® be reinstituted promptly, at least temporarily.

3. c) Various skin rashes and conjunctival xerosis have been reported with ß-blockers, including VISKEN®. A severe oculo-muco-cutaneous syndrome, whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis, has occurred with the chronic use of one ß-adrenergic-blocking agent (practolol). This syndrome has not been observed with VISKEN®. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur. A switch to another therapeutic agent might be advisable.
4. d) Sinus bradycardia may occur with the use of VISKEN® due to unopposed vagal activity remaining after blockade of ß₁-adrenergic receptors. However, due to its intrinsic sympathomimetic activity (ISA), VISKEN® causes less bradycardia at rest than some other ß-adrenergic blocking agents. If excessive bradycardia occurs the dosage of VISKEN® should be reduced.
5. e)

   In patients with thyrotoxicosis, possible deleterious effects from long-term use of

   VISKEN® have not been adequately appraised. ß-blockade may mask the clinical signs of continuing hyperthyroidism or complications, and give a false impression of improvement. Therefore, these patients should be carefully monitored for thyroid function. Abrupt withdrawal of VISKEN® may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.

6. f)

   Concomitant use with calcium channel blockers:

   Intravenous verapamil must not be administered to a patient already receiving treatment with VISKEN® due to the associated danger of cardiac arrest.

   Oral calcium channel blockers (verapamil or dilitiazem) should not be given to patients receiving beta-blockers since the depressant effects on myocardial contractility, heart rate and A-V conduction may be additive. However, in exceptional cases when in the opinion of the physician, concomitant use is considered essential; such use should be instituted gradually in a hospital setting, under close medical supervision. If combined therapy is used, close surveillance of vital signs and clinical status should be carried out and the need for continued concomitant treatment periodically assessed.

   Verapamil and diltiazem give no protection against the dangers of abrupt beta-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta-blocker. Then the calcium channel blocker may be started with the usual dose.

7. g) Psoriasis: Since beta-blockers may aggravate psoriasis, VISKEN® should only be prescribed after careful consideration of benefits and risks in patients with history of psoriasis.

PRECAUTIONS

1. a) Caution should be exercised in patients prone to non-allergic bronchospasm (e.g. chronic bronchitis, emphysema) since VISKEN® (pindolol) may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of ß-receptors.
2. b)

   VISKEN® should be administered with caution to patients with allergic rhinitis prone to bronchospasm.

   There may be increased difficulty in treating an allergic type reaction in patients on ß-blockers.

   In these patients, the reaction may be more severe due to pharmacologic effects of the ß-blockers and 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 ß-agonists, including parenteral salbutamol or isoproterenol, to overcome bronchospasm and norepinephrine to overcome hypotension.

3. c) VISKEN® should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. ß-adrenergic-blockers may mask the premonitory signs and symptoms (e.g. palpitations, tachycardia, tremor) of acute hypoglycemia whereas sweating is not inhibited. The concurrent use of beta-blockers and antidiabetic medication should always be monitored to confirm that diabetic control is well maintained.
4. d) VISKEN® dosage should be individually adjusted when used concomitantly with other antihypertensive agents. (See DOSAGE AND ADMINISTRATION)
5. e) Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added ß-adrenergic-blocking action of VISKEN® may produce an excessive reduction of sympathetic activity. VISKEN® should not be combined with other ß-blockers.
6. f) Appropriate laboratory tests should be performed at regular intervals during long-term treatment.
7. g)

   The management of patients being treated with ß-blockers and undergoing elective or emergency surgery is controversial. Although ß-adrenergic-receptor-blockade impairs the ability of the heart to respond to ß-adrenergically-mediated reflex stimuli, abrupt discontinuation of therapy with VISKEN® may be followed by severe complications (see WARNINGS).

   Some patients receiving ß-adrenergic-blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in re-starting and maintaining the heart beat has also been reported.

   For these reasons, in patients with angina, undergoing elective surgery, VISKEN® should be withdrawn gradually following the recommendation given under Abrupt Cessation of Therapy (see WARNINGS). According to available evidence, all clinical and physiological effects of ß-blockade are no longer present 48 hours after cessation of medication.

   In emergency surgery, since VISKEN® is a competitive inhibitor of ß-adrenergic-receptor agonists, its effects may be reversed by sufficient doses of such agonists as isoproterenol or levarterenol.

8. h)

   Impaired Renal or Hepatic Function: ß-blocking agents should be used with caution in patients with impaired hepatic or renal function. Poor renal function has only minor effects on VISKEN® clearance, but poor hepatic function may cause blood levels of VISKEN® to increase substantially.

   In patients with severe renal impairment, further impairment of renal function has been only rarely observed during therapy with VISKEN®.

9. i) Anaphylactic reaction: Anaphylactic reactions precipitated by other agents may be particularly severe in patients taking beta-blockers, especially non-selective beta-blockers, and may be resistant to normal doses of adrenaline. Whenever possible, beta-blockers should be avoided in patients who are at increased risk for anaphylaxis.
10. j) Phaeochromocytoma: If patients with phaeochromocytoma are treated with a beta-blocker, an alpha-blocker should always be co-administered. (see CONTRAINDICATIONS)
11. k) Usage in Pregnancy: Since VISKEN® has not been studied in human pregnancy, the drug should not be given to pregnant women. The use of any drug in patients of child-bearing potential requires that the anticipated benefit be weighed against possible hazards. Pindolol crosses the placental barrier.
12. l) Lactating Women: Pindolol passes in small quantities into breast milk.
13. m) Fertility: In rats, VISKEN® (pindolol) did not cause any adverse effects on fertility or reproductive performance at a dose of 10 mg/kg, which is 17-times the human dose. While effects in animals are not always predictive of human effects, at dose levels of 30 mg/kg and greater, female rats were observed to mate less frequently than untreated animals (see TOXICOLOGY).
14. n) Usage in Children: Since there is no experience with VISKEN® in the treatment of pediatric age groups, VISKEN® is not indicated for paediatrics.
15. o) Usage in Geriatric patients: No evidence exists that geriatric patients require different dosages; however these patients should be treated cautiously. An excessive decrease in blood pressure or pulse rate may reduce blood supply to vital organs to inadequate levels.
16. p)

    Because dizziness or fatigue may occur during initiation of treatment with

    ß-adrenoreceptor blocking drugs, patients driving vehicles or operating machinery should exercise caution until they have determined their individual response to treatment.

ADVERSE REACTIONS

Cardiovascular

Congestive heart failure (see WARNINGS), severe bradycardia (see WARNINGS), may occur. Syncope, lightheadedness, and postural hypotension. Lengthening of PR interval, second degree AV block, palpitation, chest pains, cold extremities, Raynaud's phenomenon, claudication, hot flushes. Very rarely arrhythmia, coronary insufficiency.

Central Nervous System

Insomnia, nightmares, vivid dreams, fatigue, drowsiness, weakness, dizziness, vertigo, tinnitus, headache, mental depression, nervousness. The following adverse reactions have been reported rarely: aggressiveness, motor disorders, confusion.

Gastrointestinal

Diarrhea, constipation, flatulence, heartburn, nausea and vomiting, abdominal pain and dry mouth.

Respiratory

Shortness of breath and/or dyspnea, wheezing, bronchospasm.

Allergic, Dermatological (see WARNINGS)

Exanthema, sweating, pruritis, psoriasiform rash.

Eyes

Itching, burning, grittiness, dryness.

Miscellaneous

Muscle cramps, appetite stimulation, weight gain, urinary frequency.

Clinical Laboratory

On rare occasions, changes in the following parameters were noted: elevated transaminases, alkaline phosphatase, LDH, serum uric acid; reduced bilirubin.

Post- Market Adverse Drug Reactions

The following adverse drug reactions are, in most cases, mild and transient in nature and necessity for interruption of VISKEN® therapy is rarely observed (see WARNINGS and PRECAUTIONS).

These adverse drug reactions (table 1) have been derived from post-marketing experience with VISKEN®. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Table 1 Adverse drug reactions (frequency not known)

Psychiatric disorders

Sleep disorders, depression, hallucinations

Nervous system disorders

Tremor, dizziness, headache

Cardiac disorders

Bradycardia, conduction disorder, cardiac failure

Vascular disorders

Hypotension, symptoms of peripheral vascular disorders (peripheral coldness), Raynaud’s-like symptoms

Respiratory, thoracic and mediastinal disorders

Bronchospasm, dyspnea

Gastrointestinal disorders

Gastrointestinal disorders (nausea, vomiting, abdominal pain and diarrhea) Skin and subcutaneous tissue disorders

Skin reaction, hyperhidrosis, worsening of psoriasis

Musculoskeletal and connective tissue disorders

Muscle cramps

General disorders and administration site conditions

Fatigue

DRUG INTERACTIONS

Table 2 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

SYMPTOMS AND TREATMENT OF OVERDOSAGE

An overdosage of beta-blocker may lead to pronounced bradycardia, hypotension, cardiac failure, cardiogenic shock, conduction abnormalities, cardiac arrest, dyspnea, bronchospasm, vomiting, hypoglycemia, depressed levels of consciousness, generalized convulsions, coma and death. In rare circumstances, overdose of beta-blockers with intrinsic sympathomimetic activity (ISA), like VISKEN®, may present with tachycardia and hypertension. Concomitant ingestion of alcohol, antihypertensives, antidepressants, or antiarrhythmic may aggravate the signs and symptoms of overdose.

If overdosage occurs, in all cases therapy with VISKEN® (pindolol) should be discontinued and the patient observed closely. If required, the following therapeutic measures are suggested:

1. 1. Bradycardia: atropine or another anticholinergic drug.
2. 2. Heart block (second or third degree): isoproterenol or transvenous cardiac pacemaker.
3. 3. Congestive heart failure: conventional therapy.
4. 4. Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful in addition to atropine and digitalis (see PRECAUTIONS concerning the use of epinephrine).
5. 5. Bronchospasm: aminophylline or isoproterenol.
6. 6. Hypoglycemia: intravenous glucose.

It should be remembered that VISKEN® 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 VISKEN®. However, the complications of excess isoproterenol should not be overlooked.

DOSAGE AND ADMINISTRATION

1. a)

   Hypertension

   VISKEN® (pindolol) is usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic but may be used alone (see INDICATIONS).

   VISKEN® should be taken with meals.

   The dosage of VISKEN® must always be adjusted to the individual requirements of the patients in accordance with the following guidelines:

   VISKEN® therapy should be initiated with doses of 5 mg in the morning with breakfast and 5 mg with the evening meal. If an adequate response is not achieved after one to two weeks, the dose should be increased to 10 mg twice a day.

   If after one to two additional weeks an adequate response is not observed, dosage may be increased to 15 mg twice a day (30 mg/day).

   Doses greater than 30 mg daily must be given on a t.i.d. schedule.

   Patients who show a satisfactory response to VISKEN® at daily doses of 10 to 20 mg may be maintained by giving the required total dose once daily in the morning with breakfast.

   The usual maintenance dose is within the range of 15 to 45 mg daily which should not be exceeded. However, during long-term therapy, some patients may be maintained on smaller doses of VISKEN®.

2. b)

   Angina Pectoris

   The dosage of VISKEN® must always be adjusted to the individual requirements of the patient.

   In angina, VISKEN® should be administered on a three or four times per day dosing regimen. VISKEN® therapy should be initiated with doses of 5 mg three times a day taken with meals. If after one to two weeks an adequate response is not observed, dosage may be increased. The usual maintenance dose is 15 mg up to the maximum of 40 mg per day.

   Special populations:

   Patients with impaired renal function/ hepatic function

   Patients with impaired renal or hepatic function may usually be treated with normal doses. Only in severe cases may a reduction of the daily dose be necessary (see PHARMACOLOGY – Special Populations).

   Pediatric patients

   Since the efficacy and safety of VISKEN® has not been established in children, VISKEN® is not indicated for paediatrics.

   Geriatric patients

   No evidence exists that geriatric patients require different dosages; however these patients should be treated cautiously. (see PRECAUTIONS and PHARMACOLOGY – Special Populations)

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: pindolol

Chemical Name: 4-(2-hydroxy-3-isopropylaminopropoxy)-indole

Structural Formula:

NH O NH

OH

CH₃

CH₃ *

Molecular Formula: C₁₄H₂₀N₂O₂

Molecular Weight: 248.3

Description: It is a white, odourless powder soluble in methanol and acetic acid.

DOSAGE FORMS, COMPOSITION AND PACKAGING

VISKEN 5 mg tablets: Each whitish, compressed tablet, 7 mm in diameter, slope faced, bisected with "LB" embossed on one side and flat faced, beveled edge with "VISKEN 5" embossed on reverse side, contains: pindolol 5 mg. Bottles of 100.

VISKEN 10 mg tablets: Each whitish, compressed tablet, 8 mm in diameter, slope faced, bisected on one side and flat faced, beveled edge with "VISKEN 10" embossed on reverse side, contains: pindolol 10 mg. Bottles of 100.

Non-medicinal Ingredients

microcrystalline, pregelatinized starch, magnesium stearate, silica colloidal anhydrous.

STORAGE AND STABILITY

Store at 15-30°C. Protect from light.

PHARMACOLOGY

Effects on the Cardiovascular System

Pindolol, in the non-anesthetized dog, produced a 70% inhibition of tachycardia and changes in blood pressure induced by isoproterenol at doses of 0.05 mg/kg i.v. and 2 mg/kg i.v. respectively. Complete antagonism was observed following pindolol at doses of 0.1 to 5 mg/kg i.v. In the anesthetized dog, 0.2 to 2.0 mg/kg i.v. produced dose dependent decreases in blood pressure; heart rate changes were unrelated to dose and were reduced by 12% after a dose of 0.2 mg/kg i.v. and 4% after i.v. injection of 2 mg/kg.

In the anesthetized dog, 0.2 to 1 mg/kg i.a. antagonized the vasodilation induced by isoproterenol, whereas transient 25 to 40% reductions in vascular resistance were observed after intra-arterial doses of 50 and 200 mg/kg. Intravenous doses of 2 mg/kg of pindolol elicited peripheral vasodilation and an associated reduction in total peripheral resistance.

In vivo studies on the guinea pig atrium showed that pindolol produced dose dependent antagonism of epinephrine-induced positive inotropy and chronotropy.

In five healthy volunteers given a single oral dose of 10 mg of pindolol, antagonism of isoproterenol-induced tachycardia and changes in blood pressure and heart rate were observed 30 minutes after ingestion and persisted for 24 hours.

In ten hypertensive patients receiving pindolol for 16 months in divided doses of 20 to 40 mg, blood pressure reduction was associated with statistically significant reduction in forearm and total systemic vascular resistance at rest and during stress testing. Venous tone was significantly reduced during and after exercise. No significant change was reported in cardiac output following prolonged use (see ACTIONS).

Pindolol has little membrane stabilizing activity being approximately 1/12 that of quinidine in prolonging the relative refractory period of cardiac cells in the isolated guinea pig atrium. A concentration of up to 5% pindolol was devoid of local anesthetic effects when applied to the cornea of the eye.

Pindolol possesses partial agonist (intrinsic sympathomimetic) activity. Long-lasting increases in myocardial activity manifested by positive chronotropic actions were observed following i.v. infusions of pindolol at doses of 0.16 mcg/kg to 2.5 mg/kg in the reserpinized, adrenalectomized and vagotomized cat.

Pindolol decreases the basal rate of myocardial oxygen consumption and blocks increases mediated by increased sympathetic nervous system activity.

Pindolol has antiarrhythmic activity. At doses of 8 mg/kg in the anesthetized dog, pindolol increased the dose of ouabain required to produce ventricular arrhythmia. In guinea pigs and dogs, it delayed the onset of ouabain-induced ventricular arrhythmia and in the dog produced reversion to sinus rhythm.

Pindolol has been reported to reduce plasma renin activity in some patients. However, plasma renin may remain unchanged or increase following treatment. There does not appear to be any significant relationship between the antihypertensive activity of pindolol and changes in plasma renin activity.

Effects on Pulmonary Function

In a study of 58 hypertensive patients with normal respiratory function who received oral doses of 15, 30, or 60 mg of pindolol, no significant changes were observed in forced expiratory volume (FEV), maximum voluntary ventilation rate, maximum expiratory flow rate and maximum mid-expiratory flow rate.

Decreased FEV₁ has, however, been reported in other studies.

Other Effects

Electroencephalographic changes, following oral doses of 5 and 10 mg in healthy volunteers, consisted of theta and fast beta and decreases in alpha activity. In rats given 5.2 mg/kg s.c., pindolol blocked tetrabenzine-induced ptosis but not catalepsy. In mice at doses of 1 to 30 mg/kg i.v., pindolol antagonized reserpine-induced hypothermia.

Special populations

Geriatrics

The elderly population may show higher plasma concentrations of pindolol as a combined result of a decreased metabolism of the drug in elderly population, a decreased hepatic blood flow and a decreased renal elimination.

Pregnancy

The elimination half-life of pindolol does not differ significantly between pregnant and non-pregnant patients. (see PRECAUTIONS).

Transplacental distribution of pindolol is not stereoselective. Pregnancy may alter the pharmacokinetic disposition of pindolol, suggesting an increase in the distribution volume and total clearance.

Patients with hepatic / renal impairment

Patients with impaired renal or hepatic function may usually be treated with normal doses. Only in severe cases may a reduction of the daily dose be necessary. The plasma half-life of pindolol is increased up to 11.5 hours, depending on severity, in patient with renal impairment and is increased up to 30 hours, depending on severity, in patients with liver cirrhosis.

TOXICOLOGY

1. a) Acute Toxicity

1. b) Subacute

1. c) Chronic Toxicity

1. d)

   Disposition of Pigment

   Oral administration of pindolol to rats at a dose of 200 mg/kg/day for 26 weeks resulted in the deposition of a melanin-like pigment in the liver, spleen, adrenal gland and subcutaneous tissue. Partial disappearance of this pigment from Kupffer cells in the liver occurred within four weeks following discontinuation of pindolol.

   In dogs given oral doses of 5, 15, and 45 mg/kg/day for 26 weeks, dose related increases in hepatocyte lipid content were observed.

   However, despite the pigment deposition and increased lipid content, all tests done for hepatic, splenic and adrenal function were normal. The significance of pigment and lipid changes is unknown.

2. e)

   Teratology and Reproduction Studies

   1. i)

      Teratology

      The parameters studied in the rat and rabbit teratology studies were the following: total number of pregnancies, implantations, viable fetuses, dead fetuses, total prenatal deaths, abnormal fetuses in % of living fetuses.

      Rat:

      Doses of 30 and 100 mg/kg were administered orally to groups of 20 pregnant rats (Sandoz Closed Strain) on days 7-16 of gestation. Treatment with pindolol did not adversely affect any of the parameters studied.

      Rabbit:

      Doses of 8, 23 and 80 mg/kg were administered orally to groups of respectively, 13, 16 and 15 pregnant rabbits (Swiss Hare Strain) on days 6-18 of gestation. None of the parameters studied was significantly affected.

ii) Reproduction

Rat: Doses of 10, 30 and 100 mg/kg were administered orally to groups of 15 male (Sandoz Closed Strain) and 30 female (Carworth Wistar CFE Strain) rats. Males were treated for 70 days prior to and during the mating period. The females were treated for up to 15 days prior to mating, during mating, and throughout the gestation and lactation period to 21 days postpartum, with an interim sacrifice at Day 13 of gestation.

Spermatogenesis and fertility were reduced at doses of 30 but not 100 mg/kg/day. Tubular atrophy in the testes was found in male rats treated with doses of 30 and 100 mg/kg/day.

There was significantly greater mortality in the offspring of females treated with 100 mg/kg/day in the first four-day postpartum period and in pups of females receiving 30 mg/kg/day during the 4 to 21-day postpartum interval. This increased mortality may be consequence of deficits in maternal rearing behaviour, inhibition of lactation or the presence of the drug in maternal milk.

1. f)

   Carcinogenicity Studies

   Mouse: Pindolol was administered to 50 male and 50 female mice (Sandoz OFI Strain) at dietary levels of approximately 124 mg/kg/day for 82 weeks, with an equal number of mice serving as controls. The incidence of nodules and masses observed at necropsy were comparable in the treated and control groups. This strain of mice was previously shown to be susceptible to chemical carcinogenesis.

   Rat: Pindolol was administered to 50 male and 50 female rats (Sandoz OFA Strain) at a mean dose of 50 mg/kg/day for 83 weeks. A similar group of 100 rats served as a control. Mortality and incidence of tumor were comparable in the treated and untreated groups. This strain of rat was previously shown to be susceptible to chemically (2AAF) induced carcinogenesis.

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    DATA ON FILE

32. 32.

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32.A Loew D. Investigations on neuropharmacological effects of LB-46. Sandoz Limited,

Basle, Switzerland, 20.1.70, see above.

32.B Saameli K. Pharmacological properties of a new ß-receptor blocking agent, LB-46.

Sandoz Limited, Basle, Switzerland, 30.1.69, see above.