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TRI-PLEN
TRI-PLEN FORTE

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

TRI-PLEN
TRI-PLEN FORTE
(Tablet)

COMPOSITION:
Each Tri-plen tablet contains: ramipril 2,5 mg and felodipine 2,5 mg
Each Tri-plen Forte tablet contains: ramipril 5 mg and felodipine 5 mg
Contains: Propyl gallate

PHARMACOLOGICAL CLASSIFICATION:
A 7.1 Vasodilators, hypotensive medicines

PHARMACOLOGICAL ACTION:
The calcium antagonist felodipine and the ACE (angiotensin-converting enzyme) -inhibitor ramipril both reduce blood pressure by vasodilatation. Calcium antagonists dilate the arteriolar beds while ACE-inhibitors dilate both arterial and venous beds. Vasodilatation and reduction of blood pressure may lead to activation of the sympathetic nervous system and the renin-angiotensin system. ACE inhibition results in decreased plasma angiotensin II. The onset of the antihypertensive effect of a single dose of Tri-plen or Tri-plen Forte is 1 to 2 hours. The maximum antihypertensive effect occurs within 2 to 4 weeks and is maintained on long-term therapy. The blood pressure reduction is maintained throughout the 24-hour dosage interval.
Felodipine
Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing peripheral vascular resistance via a direct inhibitory action on vascular smooth muscles. Due to the high degree of selectivity for smooth muscle in the arterioles, felodipine in therapeutic doses has no direct effect on cardiac contractility or conduction. The renal vascular resistance is decreased by felodipine. Normal glomerular filtration rate is unchanged. In patients with impaired renal function, glomerular filtration rate may increase. Felodipine possesses a mild natriuretic / diuretic effect.
Ramipril
Ramiprilat, the active metabolite of the prodrug ramipril, is a potent and long-acting ACE (angiotensin-converting enzyme) -inhibitor. In plasma and tissue, ACE catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II and also the breakdown of the vasodilator bradykinin. The vasodilatation induced by the ACE-inhibitor causes a reduction in blood pressure pre-load and after-load. Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in secretion of aldosterone. Ramipril reduces peripheral arterial resistance without major changes in renal plasma flow and glomerular filtration rate. In hypertensive patients, ramipril leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate. The onset of the antihypertensive effect of a single dose of ramipril is 1 to 2 hours, the peak effect occurs at 3 to 6 hours and the duration of action is 24 hours. The maximum antihypertensive effect occurs after 3 to 4 weeks. Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Pharmacokinetics:
Felodipine
The felodipine layer is in an extended-release formulation. Felodipine is completely absorbed from the gastrointestinal tract after oral administration of felodipine ER (extended release), independent of food intake. Due to extensive first pass metabolism the systemic availability of felodipine is approximately 15% in man and is independent of dose in the therapeutic dose range. Plasma concentrations are directly proportional to dose within the therapeutic dose range of 2.5 to 10 mg. The plasma protein binding of felodipine is approximately 99%. It is bound predominantly to the albumin fraction. The average half-life of felodipine in the terminal phase is 25 hours. There is no significant accumulation during long-term treatment. Felodipine is extensively metabolised by the liver and all identified metabolites are haemodynamically inactive. About 70% of a given dose are excreted as metabolites in the urine; the remaining fraction is excreted in the faeces. Less than 0.5% of a dose is recovered unchanged in the urine. Felodipine is a high clearance drug with an average blood clearance of 1200 mL/min. Blood clearance of felodipine is decreased with increasing age. Decreased clearance in elderly patients leads to higher plasma concentration of felodipine. Age only partly explains the inter-individual variation in plasma levels. With the ER formulation, the absorption phase is prolonged. Peak plasma concentrations are reached within 3 to 4 hours after administration of felodipine ER.
Ramipril
The pharmacokinetic parameters of ramiprilat are calculated after intravenous administration of ramipril. Ramipril is metabolised in the liver, and aside from the active metabolite ramiprilat, pharmacologically inactive metabolites have been identified. The formation of active ramiprilat may be decreased in patients with impaired liver function. The metabolites are excreted mainly via the kidneys. The bioavailability of ramiprilat is approximately 28% after oral administration of ramipril. After intravenous administration of 2.5 mg ramipril, approximately 53% of the dose is converted to ramiprilat. A maximum serum concentration of ramiprilat is achieved after 2 to 4 hours. Absorption and bioavailability are not influenced by concomitant intake of food. The protein binding of ramiprilat is approximately 55%. The distribution volume is approximately 500 litres. The effective half-life, after repeated daily dosage of 5 to 10 mg is 13 to 17 hours. Steady-state is achieved after approximately 4 days. Renal clearance is 70 to 100 mL/min and total clearance is approximately 380 mL/min. Impaired renal function delays the elimination of ramiprilat and excretion in the urine is reduced.
Combination product
In Tri-plen and Tri-plen Forte, the pharmacokinetics of ramipril, ramiprilat and felodipine are essentially unaltered compared to the monoproducts, felodipine extended release tablets and ramipril tablets. Felodipine does not influence the ACE inhibition caused by, ramipril. The fixed combination tablets are thus regarded as bio-equivalent to the free combination.

INDICATIONS:
Treatment of mild to moderate hypertension in patients whose blood pressure is normalised with individual components in the same doses as the proposed fixed combination.

CONTRA-INDICATIONS:
Tri-plen or Tri-plen Forte must not be used:

-	in patients with hypersensitivity to felodipine, ramipril or any other ACE-inhibitor or any of the excipients of Tri-plen or Tri-plen Forte.
-	in patients with a history of angioneurotic oedema.
-	in patients with haemodynamically relevant bilateral or, in the single kidney, unilateral renal artery stenosis.
-	during pregnancy.
-	by breast-feeding women.
-	in unstable haemodynamic conditions: cardiovascular shock, untreated heart failure, acute myocardial infarction, unstable angina pectoris, and stroke.
-	in patients with AV block II or III.
-	in patients with severely impaired hepatic function.
-	in patients with severely impaired renal function (creatinine clearance less than 20 mL/min) and in patients on dialysis.

Concomitant use of ACE-inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces must be avoided since it may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-flux (e.g. polyacrylonitrile) membranes and low-density lipoprotein apheresis with dextran sulphate.

WARNINGS:
Angio-oedema occurring during treatment with an ACE-inhibitor necessitates immediate discontinuation of the medicine. Angio-oedema may involve the tongue, glottis or larynx and, if so, may necessitate emergency measures.
Angio-oedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be given including, but not necessarily limited to, immediate subcutaneous adrenaline solution 1:1000 (0.3 to 0 5 mL) or slow intravenous adrenaline 1 mg/mL (observe dilution instructions) with control of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Renal function should be monitored, particularly in the initial weeks of treatment with ACE-inhibitors. Caution should be observed in patients with an activated renin-angiotensin system.
Patients with mild to moderately impaired renal function (creatinine clearance 20-60 mL/min) and patients already on diuretic treatment. For dosage see the respective mono-products.
Renovascular hypertension/renal artery stenosis: There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE-inhibitors. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral renal artery stenosis.
There is no experience regarding the administration of Tri-plen and Tri-plen Forte in patients with a recent kidney transplantation. Potassium-sparing diuretics and potassium supplements increase the risk of hyperkalaemia and should, therefore, generally not be given together with Tri-plen and Tri-plen Forte.
Patients with mild to moderately impaired liver function: For dosage refer to the respective mono-products.
Patients with haemodynamically relevant left-ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve, obstructive cardiomyopathy).
In some patients, symptomatic hypotension may be observed after the initial dose, mainly in patients with heart failure (with or without renal insufficiency) treated with high doses of loop diuretics, in hyponatraemia or in reduced renal function. Therefore, Tri-plen and Tri-plen Forte should only be given to such patients after special consideration and after the doses of the individual components have been carefully titrated. Tri-plen and Tri-plen Forte should only be given if the patient is in a stable circulatory condition (refer to Contra-indications). In hypertensive patients without cardiac and renal insufficiency, hypotension may occur especially in patients with decreased blood volume due to diuretic therapy, salt restriction, diarrhoea or vomiting.
Patients who would be at particular risk from an undesirably pronounced reduction in blood pressure (e.g. patients with coronary or cerebrovascular insufficiency) should be treated with ramipril and felodipine in a free combination. If satisfactory and stable blood pressure control is achieved with the doses of ramipril and felodipine included in Tri-plen and Tri-plen Forte, the patient can be switched to this combination. In some cases, felodipine may cause hypotension with tachycardia, which may aggravate angina pectoris.
Concomitant use of ACE-inhibitors and highly permeable dialysis membranes, haemofiltration, LDL apheresis and hyposensitization with the venom of wasps or bees must be avoided, since such use may lead to severe anaphylactoid reactions.
Concomitant treatment with ACE-inhibitors and antidiabetics (insulin and oral antidiabetics) may lead to an enhanced hypoglycaemic effect with the risk of hypoglycaemia. This effect may be most pronounced at the beginning of treatment and in patients with impaired renal function.
Neutropenia/Agranulocytosis: Tri-plen and Tri-plen Forte may cause agranulocytosis and neutropenia. These undesirable effects have also been shown with other ACE-inhibitors, rarely in uncomplicated patients but more frequently in patients with some degree of renal impairment, especially when it is associated with collagen vascular disease (e.g. systemic lupus erythematosus, scleroderma) and therapy with immunosuppressive agents. Monitoring of white blood cell counts should be considered for patients who have collagen vascular disease, especially if the disease is associated with impaired renal function. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE-inhibitor. Should symptoms such as fever, swelling of the lymph nodes, and/or inflammation of the throat occur in the course of therapy with Tri-plen and Tri-plen Forte, the treating physician must be consulted and the white blood picture investigated immediately.
Children, patients with creatinine clearance under 20 mL/min and dialysis-treated patients: No experience is available. Tri-plen and Tri-plen Forte should not be given to these patient groups.
Pregnancy and lactation: Tri-plen or Tri-plen Forte must not be taken during pregnancy or by breast feeding women. Pregnancy must be excluded before initiation of treatment and it must be avoided during therapy with Tri-plen or Tri-plen Forte.

Should women become pregnant while receiving an ACE-inhibitor, the treatment must be stopped promptly and switched to a different medicine. Should women contemplate pregnancy, the doctor should consider alternative medication.

ACE-inhibitors pass through the placenta and can be presumed to cause disturbances in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth-mass can occur.
Infants exposed to ACE-inhibitors in utero are to be closely monitored for hypotension, oliguria and hyperkalaemia. If oliguria is present or developing, support of blood pressure and renal perfusion may be necessary.

DOSAGE AND DIRECTIONS FOR USE:
The tablets should be swallowed whole with a sufficient amount of liquid. The tablets must not be divided, crushed or chewed.
Adults, including elderly: One tablet Tri-plen or Tri-plen Forte once daily. The maximum dose is one tablet Tri-plen Forte once daily.
Patients with impaired liver function: See sections Contra-indications, Warnings and Special Precautions for use.
Patients with impaired renal function or patients already on diuretic treatment: See sections Contra-indications, Warnings and Special Precautions for use.
Children: No experience is available. Tri-plen and Tri-plen Forte should not be given to children.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Ramipril
The most frequently reported side-effects are nausea, dizziness and headache. A dry cough has been reported.
Cardiovascular system
Hypotension may occur after the initial dose of ramipril as well as after increasing the dose of ramipril. Symptomatic hypotension (i.e. headache, tiredness, palpitations, tinnitus) accompanied by dizziness, nausea and a feeling of weakness can be observed in salt/volume depleted patients such as those treated with diuretics or patients on dialysis as well as in patients with severe congestive heart failure. Syncope has been observed. In patients with concomitant congestive heart failure with or without renal insufficiency, excessive hypotension has been observed and may be associated with oliguria or azotemia. In these patients therapy should be started under close medical supervision, and at a reduced starting dose.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of physiological saline.
Renal function
Treatment with ramipril may impair renal function.
Patients with renal insufficiency may require reduced or less frequent doses of ramipril and their renal function should be closely monitored. There is a risk of impairment of renal function particularly in patients with congestive heart failure or renovascular disease (bilateral renal artery stenosis or unilateral renal artery stenosis in the single kidney), in patients with pre-existing impairment of renal function as well as in kidney transplant patients.
Some patients with no apparent pre-existing renal disease may develop increases in blood urea, proteinuria and serum creatinine when ramipril is given. In patients with renal insufficiency there is a risk of hyperkalaemia.
Decrease in serum sodium can also occur.
Liver function
As ramipril is a prodrug metabolised in the liver to its active moiety, particular caution and close monitoring should be applied in patients with liver impairment. The metabolism of the parent compound and therefore the formation of the bioactive metabolite ramiprilat may be decelerated resulting in markedly elevated plasma levels of the parent-compound due to the diminished activity of esterases in the liver.
Surgery/anaesthesia
In patients undergoing surgery or during anaesthesia with agents producing hypotension, ramipril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism it can be corrected by volume expansion.
Neutropenia and proteinuria
Regular monitoring of white blood cell counts and protein levels in urine should be performed in patients with collagen vascular disease, such as lupus erythematosus and systemic sclerosis, in particular where associated with impaired renal function and concomitant therapy with drugs like corticosteroids and antimetabolites.
Hyperkalaemia
Elevated serum potassium may occur in hypertensive patients.
Risk factors for the development of hyperkalaemia include renal insufficiency and the concomitant use of agents to treat hypokalaemia as well as potassium sparing diuretics.
Gastrointestinal tract
Gastrointestinal disorders, e.g. nausea, diarrhoea or gastric pain may occur but these reactions are often transient. Taste disturbances may occur.
Angioneurotic oedema
Angioneurotic oedema may occur during therapy with ACE-inhibitors including ramipril. If laryngeal stridor or angio-oedema of the face, tongue or glottis occurs, treatment with ramipril must be discontinued and appropriate therapy instituted immediately.
Allergic reactions
Hypersensitivity reactions accompanied by pruritus, rash and sometimes fever may occur, but may resolve spontaneously after withdrawal of ramipril.
Laboratory values
Increases in blood urea and serum creatinine may occur, particularly in patients with renal insufficiency or in patients pre-treated with a diuretic. Elevation of serum potassium may occur, since ramipril decreases aldosterone secretion.
Potassium sparing diuretics such as spironolactone, amiloride, triamterene or potassium supplements should therefore be avoided.
Increases in liver enzymes and/or bilirubin.
Changes in blood picture - decrease in haemoglobin; leukopenia and thrombocytopenia

Felodipine
Dizziness, flushing, headache, fatigue, hypotension and peripheral oedema may occur. Gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain and mental depression have also been reported.
A paradoxical increase in ischaemic chest pain may occur at the start of treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness.
There have been reports of rashes, fever and abnormalities in liver function due to hypersensitivity reactions. Gingival hyperplasia has been reported but is often reversible on drug withdrawal.

Interaction with other medicaments and other forms of interaction:
Non recommended associations:
Potassium salts, potassium-retaining diuretics: Since ACE-inhibitors may cause a rise in serum potassium, concurrent use of Tri-plen or Tri-plen Forte and potassium-retaining diuretics (e.g. spironolactone, amiloride, triamterene) or potassium salts requires close monitoring of serum potassium.
Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux (e.g. poly-acrylonitrile) membranes and low-density lipoprotein apheresis with dextran sulphate: Risk of severe anaphylactoid reactions, refer to Contra-indications.
Precautions for concomitant use:
Antihypertensive agents or other substances with blood pressure-lowering potential (e.g. diuretics, antipsychotics, and narcotics): Potentiation of the hypotensive effect of Tri-plen or Tri-plen Forte is to be expected. Concerning diuretics refer to dosage and warnings.
Sympathomimetics: These may reduce the antihypertensive effect of Tri-plen or Tri-plen Forte. Close blood pressure monitoring is recommended.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood picture: Increased likelihood of haematological reactions due to ramipril.
Lithium: Excretion of lithium may be reduced by ACE-inhibitors leading to lithium toxicity. Lithium levels must, therefore be monitored.
Take into account:
Enzyme inhibitors of the cytochrome P450 enzyme system (e.g. rifampicin, cimetidine, erythromycin, and certain flavonoids present in for instance grapefruit juice):Increase in the plasma levels of felodipine may be expected.
Enzyme inducers of the cytochrome P450 enzyme system (e.g. phenytoin, carbamazepine, and barbiturates):Decrease in the plasma levels of felodipine may be expected.
Non-steroidal anti-inflammatory drugs: Attenuation of the effect of ramipril is to be expected. Furthermore, concomitant administration of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening renal function and increase in serum potassium.
Antidiabetic agents: Potentiation of sensitivity to insulin, sulphonylureas, and metformin by ACE-inhibitors is possible and this may lead to an increased risk of hypoglycaemic reactions.
Alcohol: Increased vasodilatation.
Food: The absorption of felodipine and ramipril is not influenced by food intake.
Salt: Increased dietary salt intake may attenuate the anti-hypertensive effects of Tri-plen and Tri-plen Forte.
Desensitization therapy: Increased likelihood and greater severity of anaphylactic and anaphylactoid reactions due to ACE inhibition.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Overdosage may cause excessive peripheral vasodilatation with marked hypotension, bradycardia, shock, electrolyte disturbances and renal failure.
Management:
Primary detoxification by, for example, gastric lavage, administration of adsorbents and/or sodium sulphate (if possible during the first 30 minutes). In case of hypotension, administration of alpha₁-adrenergic agonists and angiotensin II must be considered in addition to volume and salt substitution.

IDENTIFICATION:
Tri-plen: An apricot, circular, biconvex, film coated tablet engraved H/OD on one side and 2.5 on the other side. The core is of double-layer type with white to off-white and yellow layers.
Tri-plen Forte: A reddish-brown, circular, biconvex, film coated tablet engraved H/OE on one side and 5 on the other side. The core is of double layer type with white to off-white and yellow layers.

PRESENTATION:
Tri-plen and Tri-plen Forte: Blisters containing 30 tablets.

STORAGE INSTRUCTIONS:
Store below 25°C. Protect from light
Keep out of reach of children

REGISTRATION NUMBERS:
Tri-plen Tablets:        31/7.1/0677
Tri-plen Forte Tablets:        31/7.1/0678

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Aventis Pharma (Pty) Ltd
2 Bond Street, Midrand, 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
3 September 1999

        143889

Updated on this site: August 2003
Source: Community Pharmacy
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