INFORMATION FOR HEALTH PROFESSIONALS
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Pindolol USP as:
5mg tablet: Circular, white, flat, bevel-edged tablet with a score on one side and embossed NOVO 5 on the other.
10mg tablet: Circular, white, biconvex tablet with a score on one side and embossed NOVO 10 on the other.
15mg tablet: Circular, white, flat, bevel-edged tablet with a score on one side and embossed NOVO 15 on the other.
Pindolol is a beta-adrenergic blocking agent with partial agonist activity (intrinsic sympathomimetic activity - I.S.A.) and is useful in the treatment of hypertension and/or prophylaxis of angina pectoris.
The mechanisms responsible for the antihypertensive effect of pindolol may include:
The mechanism responsible for the antianginal effect of pindolol is a result of a blockade of β-adrenergic receptors, blunting the sympathetic effects on heart rate, systolic blood pressure and the velocity and extent of myocardial contraction. Therefore, pindolol may reduce the oxygen requirements of the heart at any level of effort. However, actions such as increases in left ventricular fibre length, end diastolic pressure and the systolic ejection period may increase the oxygen requirements. When the net effect is beneficial in anginal patients, it is manifested during exercise or stress by delaying the onset of pain and decreasing the incidence and severity of anginal attacks.
A single oral dose of 5mg of pindolol was administered to five healthy volunteers. Antagonism of isoprenaline-induced tachycardia and changes in blood pressure and heart rate were observed 30 minutes after ingestion and persisted for 24 hours.
Ten hypertensive patients received pindolol 20mg to 40mg in divided doses for a period of 16 months. The observed reduction in blood pressure was associated with statistically significant reductions in forearm and total system vascular resistance at rest and during stress testing. Venous tone was significantly reduced during and after exercise. No significant change in cardiac output was reported following prolonged use.
Pindolol decreases the basal rate of myocardial oxygen consumption and blocks increases, which are mediated by increased sympathomimetic nervous system activity.
In some patients, pindolol has been reported to reduce plasma renin activity. However, plasma renin may remain unchanged or may increase following pindolol treatment. There appears to be no significant relationship between pindolol's antihypertensive actions and changes in plasma renin activity.
Oral doses of 15mg, 30mg or 60mg of pindolol were administered to 58 hypertensive patients with normal respiratory function. No significant changes in forced expiratory volume, maximum voluntary ventilation rate, maximum expiratory flow rate or maximum mid-expiratory flow rate were observed.
However, decreased FEV1 has been reported in other studies.
Orally-administered pindolol is rapidly and almost completely absorbed in humans. The bioavailability of an oral dose of pindolol approaches 90% due to the negligible hepatic first pass effect. Maximum plasma concentrations are attained 1.5 to 2 hours after oral administration and the plasma half-life is 3-4 hours. The elimination rate of pindolol is not dose dependent.
Two comparative two-way, single-dose bioavailability studies were performed on VYPEN (pindolol) 15mg tablets and pindolol 15mg tablets ex Sandoz and on VYPEN (pindolol) 5mg tablets and pindolol 5mg tablets ex Sandoz.
The pharmacokinetic plasma data (mean ± standard deviation) calculated for the VYPEN and pindolol tablet formulations are tabulated below:
| VYPEN 1 x 15mg | Pindolol 1 x 15mg | |
|---|---|---|
| AUC (ngh/mL) | 552.32±145.48 (95% CI Westlake ± 16.1%) |
510.80±133.28 |
| Cmax (ng/mL) | 70.65 ± 17.33 (95% CI Westlake ± 17.0%) |
64.27 ± 10.43 |
| Tmax (h) | 1.16 ± 0.54 | 1.34 ± 0.60 |
| t½ (h) | 4.18 ± 0.80 | 3.88 ± 1.23 |
| VYPEN 2 x 5mg | Pindolol 2 x 5mg | |
|---|---|---|
| AUC (ngh/mL) | 220.14±48.59 (95% CI Westlake ± 10.6%) |
225.68±57.01 |
| Cmax (ng/mL) | 37.78 ± 6.11 (95% CI Westlake ± 9.3%) |
37.68 ± 7.73 |
| Tmax (h) | 1.09 ± 0.38 | 1.31 ± 0.44 |
| t½ (h) | 3.03 ± 0.65 | 3.29 ± 0.94 |
Pindolol is partially metabolised in man. Approximately 40 to 50% of an oral
dose is eliminated unchanged in the urine. The principal metabolites of pindolol
are its conjugated glucuronide, and phenolic derivatives of pindolol, which are
conjugated with sulphuric or glucuronic acid.
The rate of urinary excretion of pindolol is highest during the first 8 to 12 hours after dosing, with 80 to 95% of the urinary excretion occurring within the first 24 hours.
In elderly hypertensives with normal renal function, half-life is variable averaging about 7 hours but having values as high as 15 hours. Hypertensive subjects with renal disease have half-lives within the range expected for healthy subjects. A significant decrease (50%) in volume of distribution (VD) is, however, observed in uraemic patients. VD is directly correlated to creatinine clearance.
Renal pindolol clearance is significantly reduced in uraemic patients with a significant reduction in urinary excretion of unchanged pindolol.
Patients with histologically diagnosed cirrhosis of the liver eliminate pindolol more variably and more slowly than healthy subjects. The total body clearance of pindolol may range from about 50mL/min to 300mL/min. Half-life may range from 2.5 hours to 30 hours. Caution is required in such patients if dosage adjustment is considered.
VYPEN (pindolol) is indicated for the treatment of mild to moderate hypertension. It is usually used in combination with other medicines, particularly thiazide diuretics. It may also be administered alone as an initial agent when, in the judgement of the physician, treatment should be initiated with a beta-blocker rather than a diuretic.
The use of pindolol in combination with a diuretic and/or peripheral vasodilator has been found to be compatible and is generally more effective than pindolol alone. Limited experience with other antihypertensive agents, including methyldopa, has not shown evidence of incompatibility with pindolol.
VYPEN is indicated for the prophylaxis of angina pectoris.
VYPEN tablets are usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic, although it may be administered alone (see Indications ).
Dosage must always be adjusted to the individual needs of the patients according to the following guidelines:
VYPEN therapy should be initiated at 10mg daily, with 5mg doses given at breakfast and with the evening meal, and increased to 20mg daily in 2 equal doses after one to two weeks.
If an adequate response is not observed after one to two weeks, the dosage may be increased to 30mg daily with 15mg given with breakfast and 15mg with the evening meal. Doses of 30mg must be given on a t.i.d. schedule.
Patients who show a satisfactory response to doses of 10 to 20mg daily may be maintained on a once daily dosage schedule with the entire dose given in the morning with breakfast.
The maintenance dose usually ranges from 15mg to a maximum of 45mg, which should not be exceeded. However, some patients may be maintained on small doses of VYPEN during long-term therapy.
Dosage must always be adjusted to the individual needs of the patient.
VYPEN tablets should be administered on a three or four times daily dosing regimen in patients with angina. VYPEN therapy should be initiated at 15mg daily, 5mg taken 3 times a day with meals. The dosage may be increased after one to two weeks if an adequate response is not achieved. The maintenance dose is usually between 15mg and a maximum of 40mg per day.
VYPEN tablets are contraindicated in the presence of: sinus bradycardia, second and third degree AV block, right ventricular failure secondary to pulmonary hypertension, congestive heart failure ( see Warnings and Precautions ), cardiogenic shock, anaesthesia with agents which produce myocardial depression (e.g. ether), bronchospasm including bronchial asthma or severe chronic obstructive pulmonary disease ( see Warnings and Precautions ).
Pindolol should be administered with special caution in patients with a history of heart failure. In congestive heart failure, sympathetic stimulation plays a vital role in the support of circulatory function and with beta-blockade there is always the potential hazard of further depression of myocardial contractility, which may precipitate cardiac failure.
Pindolol may reduce the inotropic action of digitalis on the heart muscle, but does not abolish it. However, the negative inotropic action of pindolol may reduce the positive inotropic action of digitalis when the two medicines are used concomitantly.
The effects of beta-blockers and digitalis are additive in the depression of AV conduction. Continued depression of the myocardium over a period of time can in some cases lead to cardiac failure in patients with no history of cardiac failure. Therefore, patients should be fully digitalised and/or given a diuretic at the first sign or symptom of impending cardiac failure and the response should be observed closely. If, despite adequate digitalisation and diuretic therapy, cardiac failure continued, VYPEN should be withdrawn immediately.
Patients with angina should be warned against abrupt discontinuation of VYPEN. Severe exacerbation of angina and myocardial infarction or ventricular arrhythmias have been reported in patients with angina pectoris following the abrupt discontinuation of beta-blocker therapy. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of angina pectoris.
Therefore, when discontinuation of pindolol is planned in patients with angina pectoris, the dosage should be reduced gradually over a period of approximately two weeks and the patients should be carefully observed. The frequency of administration should not be altered. In situations of greater urgency, pindolol therapy should be discontinued in a stepwise manner, and the patient should be observed more closely. If angina markedly worsens or if acute coronary insufficiency develops, prompt reinstitution of VYPEN therapy is recommended, at least temporarily.
Various skin rashes and conjunctival xerosis have been reported with beta-blocking agents, including pindolol. Oculomucocutaneous syndrome, a severe syndrome characterised by conjunctivitis sicca and psoriasiform rashes, otitis media and sclerosing serositis, has occurred with the chronic use of the beta-adrenergic blocking agent practolol. Although this syndrome has not been observed with pindolol or any other beta-blocker, physicians should be aware of the possibility of such reactions and if they develop, pindolol treatment should be discontinued.
Due to the unopposed vagal activity, which remains after beta-adrenergic-receptor blockade, sinus bradycardia may occur with the use of pindolol.
However, pindolol causes less bradycardia at rest than some other beta-adrenergic blocking agents due to its intrinsic sympathomimetic activity. The dosage of pindolol should be reduced if excessive bradycardia develops.
The possible deleterious effects of long-term use of pindolol have not been adequately assessed in patients with thyrotoxicosis. Beta-blockade may mask the clinical signs of continuing hyperthyroidism or complications, thereby giving a false impression of improvement. Abrupt withdrawal of pindolol may therefore be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
Pindolol may block bronchodilation by endogenous and exogenous catecholamine stimulation of beta-receptors. Therefore, caution should be exercised in patients prone to non-allergic bronchospasm (such as chronic bronchitis and emphysema).
Pindolol should be administered with caution to patients with rhinitis prone to bronchospasm.
Beta-adrenergic-blocking agents may mask the premonitory signs and symptoms of acute hypoglycaemia. VYPEN should, therefore, be administered with caution to patients who are subject to spontaneous hypoglycaemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents.
There may be increased difficulty in treating an allergic type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacologic effects of the beta-blockers and problems with fluid changes.
Adrenaline 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 adrenaline may be needed to overcome the bronchospasm, while on the other hand, 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 adrenaline include vigorous supportive care such as fluids and the use of beta-agonists including parenteral salbutamol or isoprenaline to overcome bronchospasm and noradrenaline to overcome hypotension.
When VYPEN is used concomitantly with other antihypertensive agents, the dosage should be individualised ( see Dosage and Administration ).
Beta-blocking agents should be used with caution in patients with impaired hepatic or renal function. Poor renal function has only minor effects on pindolol clearance but poor hepatic function may cause blood levels of pindolol to increase substantially.
During long-term treatment, appropriate laboratory tests should be performed at regular intervals.
In patients undergoing elective or emergency surgery: the management of patients being treated with beta-blocking agents and undergoing elective or emergency surgery is controversial. Although beta-blockers impair the heart's ability to respond to beta-adrenergically-mediated reflex stimuli, severe complications may follow the abrupt discontinuation of pindolol therapy.
Some patients receiving beta-blockers have been subjected to protracted severe hypotension during anaesthesia. There have also been reports of difficulty restarting and maintaining the heartbeat. Therefore, in anginal patients undergoing elective surgery, pindolol therapy should be withdrawn gradually according to the recommendation given under Abrupt Cessation of Therapy. According to available evidence, all of the clinical and physiological effects of beta-blockade are no longer present 48 hours after cessation of medication.
Pindolol is a competitive inhibitor of beta-adrenergic-receptor agonists. Its effects may therefore be reversed by sufficient doses of agonists such as isoprenaline or noradrenaline during emergency surgery.
Pindolol should not be administered to pregnant women since this medicine has not been studied in human pregnancy. The use of any medicine in women of child-bearing potential requires that the anticipated benefit be weighed against the possible hazards.
Since pindolol is secreted in human milk, nursing should not be undertaken by mothers receiving pindolol.
There is no data available on the use of pindolol in paediatric patients.
A common finding among the various pindolol animal studies was the occurrence of tissue and/or urinary pigmentation. Three distinct pigment types were detected; a pindolol-derived indigoid urinary pigment, a lipid-derived tissue pigment and a pindolol-derived tissue pigment.
Human autopsy and liver biopsy specimens obtained from patients who had been given therapeutic doses of pindolol for 8 to 28 weeks failed to reveal microscopic evidence of the deposition of pindolol-derived pigments. Pindolol-derived urinary pigment was not detected in specimens obtained from patients who were given therapeutic doses of pindolol for 1 year.
A literature survey of 24,393 patients treated with pindolol revealed that the most frequently reported adverse reactions were: dizziness, headache, fatigue, nausea, gastrointestinal disorders, vivid dreams, hypotension, weakness and vertigo.
Adverse reactions grouped by system are as follows:
Cardiovascular: Congestive heart failure and severe bradycardia ( see Warnings and Precautions ) may occur. Syncope, postural hypotension, lengthening of PR interval, second degree AV block, palpitations, oedema, tachycardia, chest pains, Raynaud's phenomenon, claudication, hot flushes and, very rarely, arrhythmia and coronary insufficiency.
Nervous System: Fatigue, lassitude, unusual dreams, nightmares, insomnia, sleep disturbances, dizziness, depression, headache, nervousness, irritability, hallucinations, lightheadedness, vertigo, drowsiness, tinnitus, anxiety, lethargy, weakness, parasthesia, hyperhidrosis. Aggressiveness, motor disorders and confusion have been reported rarely.
Gastrointestinal System: Nausea and vomiting, indigestion, abdominal discomfort, dry mouth or nose, diarrhoea, loose stools, constipation, flatulence, mesenteric arterial thrombosis, ischaemic colitis.
Musculoskeletal: Muscle or leg cramps, joint or muscle pain, cold extremities, tremor.
Respiratory: Dyspnoea, wheezing, bronchospasm.
Allergic/Dermatologic: ( see Warnings and Precautions ) Exanthema, sweating, pruritis, psoriasiform rash, erythematous rash, fever, sore throat.
Ophthalmic: Blurred vision, gritty eyes.
Haematologic: Agranulocytosis, thrombocytopenic, and non-thrombocytopenic purpura.
Miscellaneous: Weight gain, appetite stimulation.
Clinical Laboratory: Elevation in alkaline phosphatase, SGOT and SGPT, LDH and serum uric acid. Rarely, reductions in bilirubin are observed.
The added beta-adrenergic-blocking action of pindolol may produce an excessive reduction of sympathetic activity in patients receiving catecholamine-depleting medicines, such as reserpine or guanethidine. These patients should, therefore, be monitored closely. VYPEN should not be used in combination with other beta-blockers.
Pindolol may also counteract the effect of beta-receptor agonists being used for the treatment of asthma.
The bioavailability of pindolol is not significantly effected by co-administration of food, hydralazine, hydrochlorothiazide or aspirin. Pindolol has no effect on warfarin activity or the clinical effectiveness of digoxin although small transient decreases in plasma digoxin concentrations have been noted.
Congestive heart failure, bradycardia, hypotension, bronchospasm and hypoglycaemia are the most common signs to be expected with beta-adrenergic-blocking agent overdose.
In all cases of overdosage, pindolol treatment should be discontinued and the patient should be observed closely. In addition, the following therapeutic measures are suggested if required:
Large doses of isoprenaline can be expected to reverse many of the effects of excessive doses of pindolol since pindolol is a competitive antagonist of isoprenaline. However, the complications of excessive isoprenaline should not be overlooked.
Protect from light and moisture. Keep out of reach of children. Store below 30°C.
Prescription Medicine.
All potencies: 100 tablets.
Pindolol is 1-(Indol-4-yloxy)-3-(isopropyl amino)-2-propanol. Its molecular formula and weight are C14H20N2O2 and 248.3 respectively.
Douglas Pharmaceuticals Ltd
PO Box 45-027
AUCKLAND 8
Ph: (09) 835-0660
Fax: (09) 835-0665
8 September 1999