INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
PROTENSIN-M tablets

SCHEDULING STATUS:
S4

PP(10) Zimbabwe Only Reg nr E 78/12.3.5/1137

PROPRIETARY NAME:
(and dosage form)

PROTENSIN-M tablets

COMPOSITION:
Each tablet contains 50 mg hydroflumethiazide and 0,125 mg reserpine.

PHARMACOLOGICAL CLASSIFICATION:
A 7.1.2. - Rauwolfia : Diuretic combinations.

PHARMACOLOGICAL ACTION:
Protensin-M is an anti-hypertensive containing reserpine in combination with a thiazide diuretic. Combination of reserpine with a diuretic allows reduction of the reserpine dose.
Hydroflumethiazide is an oral diuretic. It exerts its effect by inhibiting renal tubular reabsorption, including increased excretion of sodium and chloride and water with concomitant loss of potassium and bicarbonate as well.
The component reserpine probably produces its antihypertensive effects through depletion of tissue stores of catecholamines (adrenalin and noradrenalin) from peripheral sites. The hypotensive effect is mainly due to a reduction in cardiac output and peripheral resistance.
Reserpine is characterized by slow onset of action and sustained effect. Both its cardiovascular and central nervous system depressant effects may persist for up to 6 weeks following withdrawal of the agent. Central nervous system depression is caused by depression of central biogenic amine stores.

INDICATIONS:
Protensin-M is indicated for hypertension, only after careful initial titration, using the individual component agents in this combination separately, and assessment of the patient’s clinical response, to ensure that the doses used in Protensin-M are suitable. (See WARNINGS)

CONTRA-INDICATIONS:
Safety and efficacy in children have not been established.
Protensin-M is contra-indicated in patients with a history of mental depression because of the possibility that it will potentiate depression and increase the possibility of suicide.
Protensin-M is contra-indicated in patients who have previously demonstrated hypersensitivity to its components or those with known hypersensitivity to reserpine or other rauwolfia alkaloids or thiazides. Patients with anuria or oliguria should not be given this medication. The presence of an active peptic ulcer, ulcerative colitis, gallstones, phaeochromocytoma. Parkinson’s disease, epilepsy or depression contra-indicates the use of reserpine. Respiratory distress, cyanosis, anorexia, hypothermia and lethargy have occurred in infants whose mothers have received reserpine prior to delivery. Safety in pregnancy has not been established. Reserpine crosses the placenta and appears in breast milk and therefore SHOULD NOT BE GIVEN TO NURSING MOTHERS.
Thiazide diuretics should not be used in patients with Addison’s disease, acute porphyria, severe renal or hepatic dysfunction (creatinine clearance <30 mL/min).

WARNINGS:
Hydroflumethiazide: Azotemia may be precipitated or increased by hydroflumethiazide. Special caution is necessary in patients with impaired renal function to avoid cumulative or toxic effects.
Since in hepatic cirrhosis, minor alterations of fluid and electrolyte balance may precipitate coma, hydroflumethiazide should be given with caution in cirrhotic patients.
The possibility of sensitivity reactions should be considered in patients with a history of allergy or bronchial asthma.
Hydroflumethiazide potentiates the action of other antihypertensive drugs.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported for sulphonamide derivatives (including thiazides) and reserpine.
Reserpine: May cause mental depression, which may persist for several months.
Protensin-M should be discontinued at the first sign of depression. Depression usually insidiously appears over many weeks or months and may not be attributed to the medicine because of the delay and gradual onset of symptoms. This depression may be severe enough to result in suicide.
An anaesthetist should be aware if a patients undergoing anaesthesia is receiving reserpine treatment, as the effects of thiopentone and other central nervous system depressants may be enhanced by reserpine.
Diabetics: This medicine may raise blood sugar levels.

DOSAGE AND DIRECTIONS FOR USE:
The usual dose of PROTENSIN-M is a half to one tablet once or twice daily, as determined by individual titration with the separate components to meet the requirements of each patient on the basis of clinical response. When the desired blood pressure reduction has been achieved the dose should be reduced to the minimum necessary to maintain a response. The dose of two tablets per day should not be exceeded. A lower dose is recommended in the elderly or severely debilitated patient.
Protensin-M should be taken with meals to reduce gastric irritation.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
If electro-shock therapy is necessary, treatment with Protensin-M should be discontinued at least seven to fourteen days prior to this therapy.

HYDROFLUMETHIAZIDE
Side-effects
Electrolyte imbalances including: hypokalaemia, hyponatraemia, hypomagnesaemia, hypocalcaemia and hypochloraemic alkalosis.
Gastrointestinal System: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhoea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, hyperglycaemia and glycosuria.
Central Nervous System: dizziness, vertigo, paraesthesiae, headache and xanthopsia.
Haematologic: leukopoenia, agranulocytosis, aplastic and haemolytic anaemia, neonatal and adult thrombocytopoenia.
Dermatologic/Hypersensitivity: purpura, photosensitivity, rash, urticaria and necrotizing angiitis (vasculitis) (cutaneous vasculitis), toxic epidermal necrolysis, lupus erythematosus .
Cardiovascular: orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.
Miscellaneous: muscle spasm, weakness, restlessness, fever, impotence, respiratory distress including pneumonitis, pulmonary oedema and anaphylactic reactions.

Special precautions with Hydroflumethiazide
Interference with adequate electrolyte intake will contribute to hypokalaemia. Digitalis therapy may exaggerate metabolic effects of hypokalaemia especially with reference to myocardial activity. If dietary salt is unduly restricted, especially during hot weather in severely oedematous patients with congestive failure or renal disease, a low salt syndrome may complicate therapy with hydroflumethiazide.
Hydroflumethiazide may increase the responsiveness to tubocurarine. The antihypertensive effect of the drug may be enhanced in the post-sympathectomy patient. Hydroflumethiazide decreases arterial responsiveness to noradrenalin, necessitating due care in surgical patients. It is recommended that hydroflumethiazide be discontinued 48 hours before elective surgery.
Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates or narcotics.
Pathological changes in the parathyroid glands with hypercalcaemia and hypophosphataemia have been observed in patients on prolonged hydroflumethiazide therapy.
Caution is necessary in patients with hyperuricaemia or a history of gout, since gout may be precipitated.
Hydroflumethiazide may decrease serum protein-bound iodine with signs of thyroid disturbance.
Hydroflumethiazide may cause hyperglycaemia and glycosuria in diabetics and other susceptible patients.

Interactions with Hydroflumethiazide
Antihypertensive medications, especially diazoxide, or preanaesthetic and anaesthetic agents or skeletal muscle relaxants; effects may be potentiated when used concurrently with hydroflumethiazide; dosage adjustments may be necessary.
Amphotericin B, corticosteroids, corticotropin (ACTH) or carbenoxolone; concurrent use with hydroflumethiazide may intensify electrolyte imbalance, particularly hypokalaemia.
Cardiac glycosides: Concurrent use with hydroflumethiazide may enhance the possibility of digitalis toxicity with hypokalaemia.
Cholestyramine and cholestipol: May inhibit gastrointestinal absorption of the hydroflumethiazide; administration 1 hour before or 4 hours after cholestyramine is recommended.
Hypoglycaemics: Hydroflumethiazide may raise blood glucose levels; for adult-onset diabetics, dosage adjustment of hypoglycaemic medications may be necessary during and after hydroflumethiazide therapy; insulin requirements may be increased, decreased, or unchanged.
Lithium salts: Concurrent use with hydroflumethiazide is not recommended, as it may provoke lithium toxicity because of reduced renal clearance.
Methenamine: Effectiveness may be decreased when used concurrently with hydroflumethiazide because of alkalinization of the urine.
Nonsteroidal anti-inflammatory agents In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of hydroflumethiazide.

Laboratory Test Interactions with Hydroflumethiazide

•	Blood and urine glucose levels (usually only in patients with a predisposition to glucose intolerance)
•	Serum bilirubin levels (by displacement from albumin binding)
•	Serum calcium levels (hydroflumethiazide should be discontinued before parathyroid function tests are carried out)
•	Serum uric acid levels (may be increased)
•	Serum magnesium, potassium, and sodium levels (may be decreased; serum magnesium levels may increase in uremic patients)
•	Serum protein-bound iodine (PBI) levels (may be decreased)

RESERPINE
Side effects
Gastrointestinal System: anorexia, nausea, increased intestinal motility, diarrhoea, abdominal cramps, dryness of the mouth, vomiting. At higher doses, increased gastric acid secretion and increased salivation may occur.
Central Nervous System: depression, excessive sedation, nightmares, headaches, dizziness, blurred vision, syncope, impotence or decreased libido, nervousness, paradoxical anxiety, dull sensorium, deafness, glaucoma, uveitis, optic atrophy, Parkinsonian-like syndrome, miosis, increased appetite, inability to concentrate, lethargy, breast engorgement and galactorrhoea, gynecomastia and increased prolactin levels.
Haematological: epistaxis, purpura due to thrombocytopoenia.
Dermatological: conjunctival infection, flushing of the skin, pruritus, rash.
Cardiovascular: bradycardia, dyspnoea, angina pectoris and other direct cardiac effects (eg. premature ventricular contractions, sodium and fluid retention, congestive failure).
Miscellaneous: nasal congestion, oedema, weight gain, muscular aches, enhanced susceptibility to colds, dysuria, non-puerperal lactation.
Withdrawal of reserpine or reduction of the dose causes reversal of many of the side effects although mental disorders may persist for weeks after the cessation of treatment.
Special precautions with Reserpine
Since reserpine may increase gastric secretion and motility, it should be used cautiously in patients with a history of peptic ulcer or other gastrointestinal disorders. This compound may precipitate biliary colic in patients with gallstones, or bronchial asthma in susceptible persons.
Reserpine should be used with caution in debilitated patients or in patients with cardiac arrhythmias, myocardial infarction, severe cardiac damage and epilepsy.
Anxiety or depression, as well as psychosis may develop during reserpine therapy. If depression is present when therapy is begun it may be aggravated. PROTENSIN-M should be discontinued at the first, sign of depression.
EXTREME CAUTION SHOULD BE USED IN TREATING PATIENTS WITH A HISTORY OF MENTAL DEPRESSION, AND THE POSSIBILITY OF SUICIDE SHOULD BE KEPT IN MIND.
Caution should be exercised when treating hypertensive patients with renal insufficiency, since they adjust poorly to lowered blood pressure levels.

Interactions with Reserpine
Alcohol or CNS depressants; concurrent use may enhance the effects of the CNS depressant or the reserpine.
Antihypertensives, other or diuretics: antihypertensive effects may be potentiated when used concurrently with reserpine; although some combinations are frequently used for therapeutic advantage, when used concurrently , dosage adjustments may be necessary.
Beta-blockers: concurrent administration with beta-blockers may result in additive and possible excessive beta-adrenergic blockage.
Digitalis glycosides or quinidine: concurrent use may result in cardiac arrhythmias.
Levodopa: since reserpine may cause dopamine depletion and parkinsonism effects, concurrent use is not recommended.
Methotrimeprazine: concurrent use may result in additive hypotension.
Monoamine oxidase (MAO) inhibitors: reserpine should be given with caution to patients receiving monoamine oxidase inhibitors. Concurrent use with reserpine may result in moderate to sudden and severe hypertension, hyperpyrexia which can reach crisis levels and excitation.
Sympathomimetics, indirect-acting amines such as amphetamines, adrenaline, methylphenidate, phenylpropanolamine, pseudoephedrine, tyramine: reserpine inhibits the action of indirect-acting sympathomimetics by depleting catecholamine stores.
Direct-acting amines such as epinephrine, isoproterenol, norepinephrine (levarterenol, metaraminol and phenylephrine: reserpine may prolong the action of direct-acting sympathomimetics. Patients taking reserpine are sensitive to the effects of adrenaline and other directly-acting sympathomimetics.
Tricyclic antidepressants: concurrent use may decrease the hypotensive effects.
Non-steroidal anti-inflammatories: concurrent use may reduce the action of reserpine.

Laboratory Test Interactions with Reserpine
Reserpine may affect the following:

•	Urinary steroid calorimetric determinations (falsely low because reserpine slightly decreases absorbance).
•	Serum prolactin levels (may be increased).
•	Urinary catecholamine excretion.
•	Urinary vanillymandelic acid (VMA) excretion (chronic or parenteral administration of reserpine results in an overall decrease).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Signs and symptoms
Hydroflumethiazide: Diuresis, lethargy progressing to coma with minimal cardio-respiratory depression, gastrointestinal irritation, hypermotility, elevated blood urea nitrogen and serum electrolyte changes.
Reserpine: Impairment of consciousness ranging from drowsiness to coma, flushing, conjunctival injection, miosis, hypotension, hypothermia, respiratory depression, bradycardia, diarrhoea.
Treatment
Induce emesis or use gastric lavage followed by activated charcoal to empty stomach. Treat hypotension by volume expansion, if possible. If a vasopressor is needed, use phenylephrine, levarterenol, metaraminol or norepinephrine. Treat significant bradycardia with vagal blocking agents, along with other appropriate measures.
Monitor serum electrolytes and renal function and institute supportive measures as required. Treat gastrointestinal effects symptomatically. Observe patient for at least 72 hours.

IDENTIFICATION:
Light green to green, round biconvex compressed tablets about 8,7 mm in diameter scored on one side and impressed MJ on the other.

PRESENTATION:
Bottles containing 100 tablets.

STORAGE INSTRUCTIONS:
Store in cool, dry place at room temperature not exceeding 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REFERENCE NUMBER:
H648 (Wet/Act 101/1965)

NAME AND BUSINESS ADDRESS OF APPLICANT:
Bristol-Myers Squibb (Pty) Ltd
47 Van Buuren Road,
BEDFORDVIEW, 2008

DATA OF PUBLICATION OF THIS PACKAGE INSERT:
September 1977

        SP206/1

Updated on this site: February 2002
Current: April 2005
Source: Community Pharmacy
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