Altace Plus Felodipine 5mg + 5mg Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

Altace Plus Felodipine (felodipine ER/ramipril) is a formulation containing extended-release felodipine, a dihydropyridine calcium channel blocker, along with immediate-release ramipril, an angiotensin converting enzyme (ACE) inhibitor.

Ramipril:

Ramipril is an ACE inhibitor. Following oral administration, ramipril is rapidly hydrolyzed to ramiprilat, its principal active metabolite. ACE catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE activity leads to decreased levels of angiotensin II thereby resulting in decreased vasoconstriction and decreased aldosterone secretion. The latter decrease may result in a small increase in serum potassium (see PRECAUTIONS). Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion result in increases in plasma renin activity.

ACE is identical to kininase II. Thus, ramipril may also block the degradation of the vasodepressor peptide bradykinin, which may contribute to its therapeutic effect.

Felodipine:

The therapeutic effect of the dihydropyridine class of calcium channel blockers is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Felodipine blocks transmembrane influx of calcium through the slow channel without affecting to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues.

Felodipine does not alter total serum calcium. In vitro studies indicate that the effects of felodipine on contractile mechanisms are selective, with greater effects on vascular smooth muscle than on cardiac muscle. Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals.

The effect of felodipine on blood pressure in man is principally a consequence of a dose-related decrease in peripheral vascular resistance, with a modest reflex increase in heart-rate (see Pharmacodynamics).

Pharmacokinetics

Ramipril:

Following oral administration, ramipril is rapidly absorbed with peak plasma concentrations occurring within 1 hour. The extent of absorption of ramipril is 50-60% and is not significantly altered by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.

Following absorption, ramipril is rapidly hydrolyzed in the liver to its active metabolite, ramiprilat, reaching peak plasma concentrations 2-4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat is 56%.

Ramipril is almost completely metabolized to the active metabolite ramiprilat, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites are excreted in the urine, and about 40% are found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

Following a single administration of up to 5 mg of ramipril, plasma concentrations of ramipril and ramiprilat increase in a manner that is greater than proportional to dose; after a single administration of 5 mg to 20 mg of ramipril the plasma concentrations for both are dose-proportional. The non-linear pharmacokinetics observed at the lower doses of ramipril can be explained by the saturable binding of ramiprilat to ACE. At steady-state, the 24-hour AUC for ramiprilat is dose-proportional over the recommended dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44% respectively when 5mg of oral ramipril was compared to 5mg given intravenously.

Plasma concentrations of ramiprilat decline in a triphasic manner. The initial rapid decline, which represents distribution of the drug, has a half life of 2-4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase has a half-life of 9-18 hours, and the terminal elimination phase has a prolonged half-life of > 50 hours. After multiple daily doses of ramipril 5-10 mg, the half-life of ramiprilat concentrations was 13-17 hours, but was considerably prolonged at 2.5 mg (27-36 hours).

After once-daily dosing, steady state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are higher than those seen after the first dose of ramipril especially at low doses (2.5 mg).

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. In patients with creatinine clearance < 40ml/min/1.73m², increases in

C_max and AUC of ramipril and ramiprilat compared to normal subjects were observed following multiple dosing with 5 mg ramipril (see DOSAGE AND ADMINISTRATION).

In patients with impaired liver function, plasma ramipril levels increased about 3-fold, although peak concentrations of ramiprilat in these patients were not different from those seen in patients with normal hepatic function.

A single dose pharmacokinetics study conducted in a limited number of elderly patients indicated that peak ramiprilat levels and the AUC for ramiprilat are higher in older patients (see PRECAUTIONS).

Felodipine:

Felodipine is completely absorbed from the gastrointestinal tract after oral administration. Due to rapid biotransformation of felodipine during its first pass through the portal circulation, the systemic availability is approximately 15% and is independent of the dose in the range of 5-20 mg per day. The plasma protein binding of felodipine is approximately 99%. It is bound predominately to the albumin fraction.

Felodipine is extensively metabolized in the liver, predominantly by cytochrome P-450 CYP 3A4. After 72 hours, approximately 70% of a given dose is excreted as metabolites in the urine and 10% is secreted in the feces. Less than 0.5% of a dose is recovered unchanged in the urine. Six metabolites, which account for 23% of the oral dose, have been identified: none has significant vasodilating activity.

Felodipine has been observed to have a mean blood clearance of 914"355 mL/min in hypertensive patients, 606"245 mL/min in elderly hypertensive patients and 1337"413 mL/min in young healthy volunteers. Its mean terminal half-life was 24.5"7.0 hours in hypertensive patients, 27.5"8.4 hours in elderly hypertensive patients and 14.1"5.6 hours in young healthy volunteers.

The extended release formulation prolongs the absorption phase of felodipine resulting in an increased time to reach peak plasma concentrations (t_max), and a reduced maximum plasma concentration (C_max). The mean t_max ranges from 2.5 to 5 hours. The area under the plasma concentration versus time curve and C_max are linearly related to the dose in the 10 to 40 mg range. Following administration of felodipine to hypertensive patients, mean C_max at steady state is approximately 20% higher after multiple doses than after a single dose. No increase in the AUC is found during multiple dosing. The inter-individual variation in C_max and AUC after repeated dosing is approximately threefold and indicates a need for individualized dosing.

The bioavailability of felodipine is not influenced by the presence of food in the gastrointestinal tract. However, the peak plasma concentration of felodipine (Cmax) is significantly increased by 1.5 to 2 fold when felodipine is taken after a high fat or high carbohydrate meal versus fasting. Because the effects of felodipine on blood pressure are related to plasma levels, this increase in Cmax may cause a clinically significant fall in blood pressure. Therefore, felodipine should not be administered with meals rich in carbohydrate or fat. However, the absorption characteristics of felodipine are not affected when felodipine is administered with a light meal low in fat and

carbohydrates (i.e. 2 slices of toast with cheese, 150 mL milk with cornflakes, and 150 mL orange juice).

Studies in healthy male volunteers showed significant alterations in the pharmacokinetics of felodipine when felodipine was administered concomitantly with grapefruit juice. Following the administration of a single dose of plain felodipine 5 mg tablets with 200 mL grapefruit juice or 200 mL water AUC and C_max of felodipine increased about threefold as compared to administration with water. When 10 mg felodipine extended release tablets were administered with 250 mL grapefruit juice, felodipine AUC and C_max values doubled as compared to those observed with water. When grapefruit juice was taken for up to 24 hours prior to felodipine administration, a significant pharmacokinetic interaction was observed (see PRECAUTIONS - Interaction with Grapefruit Juice).

Plasma concentrations of felodipine, after a single oral dose and at steady state, increase with age. Mean clearance of felodipine in elderly hypertensives (mean age 74 years) was only 45 percent of that in young volunteers (mean age 26 years). At steady state mean AUC for young patients was 39 percent of that for the elderly patients.

In patients with hepatic disease, the clearance of felodipine was reduced to about 60 percent of that seen in normal young volunteers.

Renal impairment does not alter the plasma concentration profile of felodipine. Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are hemodynamically inactive.

Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.

Ramipril + Felodipine:

With Altace Plus Felodipine, the pharmacokinetics of ramipril, ramiprilat and felodipine are essentially unaltered compared to the individual components.

Pharmacodynamics

Ramipril:

Administration of ramipril to patients with mild to moderate essential hypertension results in a reduction of both supine and standing blood pressure usually with little or no orthostatic change or change in heart rate. Symptomatic postural hypotension is infrequent, although this may occur in patients who are salt-and/or volume depleted (see WARNINGS).

In single-dose studies, doses of 5-20 mg of ramipril lowered blood pressure within 1-2 hours, with peak reductions achieved 3-6 hours after dosing. At recommended doses given once daily, antihypertensive effects have persisted over 24 hours.

The effectiveness of ramipril appears to be similar in the elderly (over 65 years of age) and younger adult patients given the same daily doses.

In studies comparing the same daily dose of ramipril given as a single morning dose or as a twice daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen.

While the mechanism through which ramipril lowers blood pressure appears to result primarily from suppression of the renin-angiotensin-aldosterone system, ramipril has an antihypertensive effect even in patients with low-renin hypertension.

The antihypertensive effect of ACE inhibitors is generally lower in black patients than in non-blacks.

The antihypertensive effect of ramipril and thiazide diuretics used concurrently is greater than that seen with either agent used alone.

Abrupt withdrawal of ramipril has not resulted in a rapid increase in blood pressure.

Felodipine:

The acute hemodynamic effect of felodipine is a reduction in total peripheral resistance which leads to a decrease in blood pressure associated with a modest reflex increase in heart rate. This reflex increase in heart rate frequently occurs during the first week of therapy and generally attenuates over time. Heart rate increases of 5-10 beats per minute may be seen during chronic administration. The effect on the heart rate is inhibited by beta-blocking agents.

Following administration of felodipine a reduction in blood pressure generally occurs within two to five hours.

During chronic administration, substantial blood pressure control lasts for approximately 24 hours; reductions in diastolic blood pressure at trough plasma levels were 40-60 percent of those at peak plasma levels. The antihypertensive effect is dose-dependent and correlates with the plasma concentration of felodipine.

Felodipine in therapeutic doses has no effect on conduction in the conducting system of the heart and no effect on A-V nodal refractoriness. No direct additional effects to those registered after beta-blockade are observed when felodipine is given concomitantly.

Renal vascular resistance is decreased by felodipine while glomerular filtration rate remains unchanged. Mild diuresis, natriuresis and kaliuresis have been observed during the first week of therapy. No significant effects on serum electrolytes have been observed during short and long-term therapy. No general salt and water retention occurs during long-term therapy. In clinical trials, increases in noradrenaline plasma levels have been observed.

Ramipril + Felodipine:

Double-blind clinical studies have shown that the effects of concurrent use of felodipine ER and ramipril are additive with respect to lowering systolic and diastolic blood pressure in mild to moderate hypertensives.

INDICATIONS AND CLINICAL USES

Altace Plus Felodipine (felodipine ER/ramipril) is indicated for the treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate.

Altace Plus Felodipine is not indicated for initial therapy. Patients in whom felodipine ER and ramipril are initiated simultaneously can develop symptomatic hypotension (see WARNINGS B Hypotension).

Patients should be titrated with individual drugs. If the fixed combination represents the dosage determined by this titration, the use of Altace Plus Felodipine may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.

They can be tried as initial agents in those patients in whom diuretics and/or beta blockers are contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

In using ramipril, consideration should be given to the risk of angioedema (see WARNINGS).

The safety and efficacy of ramipril in renovascular hypertension has not been established and therefore its use in this condition is not recommended.

CONTRAINDICATIONS

Altace Plus Felodipine (felodipine ER/ramipril) is contraindicated in:

• patients with known hypersensitivity to felodipine or other dihydropyridines, ramipril or any other ACE inhibitors, or any of the excipients of the formulation;
• patients with a history of angioedema;
• patients with haemodynamically relevant bilateral renal artery stenosis, or unilateral renal artery stenosis in the single kidney.
• patients with hypotensive states.
• women of childbearing potential, in pregnancy, and during lactation. Fetal malformations and adverse effects have been reported in animals

Concomitant use of ACE inhibitors and extracorporeal treatment leading to contact of blood with negatively charged surfaces must be avoided (see PRECAUTIONS, Anaphylactoid reactions during membrane exposure).

Teratogenic Effects

Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3 and 4.6 mg/kg/day felodipine (from 0.4 to 4 times the maximum recommended human dose on a mg/m² basis) showed digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. The frequency and severity of the changes appeared dose-related and were noted even at the lowest dose. These changes have been shown to occur with other members of the dihydropyridine class. Similar fetal abnormalities were not observed in rats given felodipine.

In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was observed but an abnormal position of the distal phalanges was noted in about 40 percent of the fetuses.

Non-teratogenic Effects

In a study on fertility and general reproductive performance in rats, prolongation of parturition with difficult labour and an increased frequency of fetal and early postnatal deaths were observed in groups treated with felodipine doses of 9.6 mg/kg/day and above.

Significant enlargement of the mammary glands in excess of the normal enlargement for pregnant rabbits was found with felodipine doses greater than or equal to 1.2 mg/kg/day. This effect occurred only in pregnant rabbits and regressed during lactation. Similar changes in the mammary glands were not observed in rats or monkeys.

WARNINGS

Serious Warnings and Precautions

When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, Altace Plus Felodipine should be discontinued as soon as possible.

Angioedema

Angioedema-Head and Neck

Angioedema has been reported in patients with ACE inhibitors, including ramipril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, Altace Plus Felodipine (felodipine ER/ramipril) should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not

limited to 0.3 to 0.5 ml of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS).

Angioedema – Intestinal

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases facial angioedema also occurred. The intestinal angioedema symptoms resolved after stopping the ACE inhibitor.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).

Angioedema, including laryngeal edema, may occur especially following the first dose of Altace Plus Felodipine.

Congestive Heart Failure

The safety and efficacy of the felodipine component in Altace Plus Felodipine has not been established in patients with heart failure. Caution should, therefore, be exercised when using Altace Plus Felodipine in hypertensive patients with compromised ventricular function, particularly in combination with a beta-blocker. Acute hemodynamic studies in a small number of patients with New York Heart Association Class II or III heart failure with felodipine have not demonstrated negative inotropic effects.

Hypotension, Myocardial Ischemia

Altace Plus Felodipine may, occasionally, precipitate symptomatic hypotension and rarely syncope. It may lead to reflex tachycardia which, particularly in patients with severe obstructive coronary artery disease, may result in myocardial ischemia. Careful monitoring of blood pressure during the initial administration and titration of felodipine is recommended.

Care should be taken to avoid hypotension especially in patients with a history of cerebrovascular insufficiency, and in those taking medications known to lower blood pressure.

Symptomatic hypotension occurs usually after the first or second dose or when the dose is increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, vomiting, in other situations in which a significant activation of the renin-angiotensin system is to be anticipated such as in patients with severe, and particularly with malignant hypertension, in patients with haemodynamically relevant left-ventricular outflow impediment (e.g., stenosis of the aortic valve) or in patients with haemodynamically relevant renal artery stenosis.

In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident (see ADVERSE REACTIONS). Because of the potential fall in blood pressure in these patients, therapy with

Altace Plus Felodipine should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of Altace Plus Felodipine is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has been associated with oligouria, and/or progressive azotemia, and rarely, with acute renal failure and/or death.

Generally, it is recommended that dehydration, hypovolaemia or salt depletion be corrected before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed against the risk of volume overload). When these conditions have become clinically relevant, treatment with Altace Plus Felodipine must only be started or continued if appropriate steps are taken concurrently to prevent an excessive fall in blood pressure and deterioration of renal function.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response may not be a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion in hypertensive patients. However, lower doses of Altace Plus Felodipine and/or reduced concomitant diuretic therapy should be considered.

Beta-Blocker Withdrawal

Altace Plus Felodipine gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blockers.

Outflow Obstruction

Altace Plus Felodipine should be used with caution in the presence of fixed left ventricular outflow obstruction.

Dermatologic Lesion

Along with leucocytoclastic vasculitis, other dermatologic events have been observed. These include rash and flush. All cases of dermatologic lesions should be carefully diagnosed and monitored.

Neutropenia/agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Rare cases of agranulocytosis, neutropenia or leukopenia have been reported in which a causal relationship to ramipril cannot be excluded. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease (see PRECAUTIONS – Monitoring and Laboratory Tests).

Pregnant Women

See CONTRAINDICATIONS

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, Altace Plus Felodipine should be discontinued as soon as possible.

Pregnancy must be excluded before starting treatment. Pregnancy must be avoided in cases where treatment with Altace Plus Felodipine is required. If the patient intends to become pregnant, treatment with Altace Plus Felodipine must be discontinued.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

Animal Data: No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. The doses used were: 10, 100, or 1000 mg/kg in rats (2500 times maximum human dose), 0.4, 1.0, or 2.5 mg/kg in rabbits (6.25 times maximum human dose), and 5, 50, 500 mg/kg in cynomolgus monkeys (1250 times maximum human dose). In rats, the highest dose caused reduced food intake in the dams, with consequent reduced birth weights of the pups and weight development during lactation period. In rabbits, maternal effects were mortalities (high and middle dose) and reduced body weight. In monkeys, maternal effects were mortalities (high and middle dose), vomiting, and reduced weight gain.

Nursing Women

The presence of concentrations of ACE inhibitor have been reported in human milk. The use of Altace Plus Felodipine is contraindicated during breast-feeding.

PRECAUTIONS

Due to the additive actions of an ACE inhibitor with a calcium-channel blocker, concomitant therapy of felodipine and ramipril may result in hypotension. In controlled studies, hypotension was observed in 0.1% of uncomplicated hypertensive patients. Dizziness occurred more frequently than placebo (see ADVERSE EVENTS).

Renal Impairment

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk; therefore, discontinuation of diuretic therapy may be required.

Use of Altace Plus Felodipine (felodipine ER/ramipril) should include appropriate assessment of renal function.

Altace Plus Felodipine should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses (see DOSAGE AND ADMINISTRATION). Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency.

Anaphylactoid reactions during membrane exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (i.e. polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Anaphylactoid reactions during LDL apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Anaphylactoid reactions during desensitisation

There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

Hyperkalemia and Potassium-Sparing Diuretics

Elevated serum potassium (greater than 5.7 mEq/l) was observed in approximately 1% of hypertensive patients in clinical trials with ramipril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy in any hypertensive patient. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (see PRECAUTIONS - Drug Interactions).

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, ramipril blocks 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 repletion.

Aortic Stenosis

There is concern on theoretical grounds, that patients with aortic stenosis might be a particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Patients with Impaired Liver Function

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors in patients with or without pre-existing liver abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported with Altace Plus Felodipine (see ADVERSE REACTIONS). Should the patient receiving Altace Plus Felodipine experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigations be carried out. Discontinuation of Altace Plus Felodipine should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. In patients with impaired liver function, response to the treatment with ramipril may be either increased or reduced. In addition, in patients in whom severe liver cirrhosis with oedema and/or ascites is present, the renin-angiotensin system may be significantly activated. Ramipril should be used with particular caution in patients with pre-existing liver abnormalities.

Altace Plus Felodipine should be used with caution in patients with pre-existing liver abnormalities. In such patients baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Rarely, ACE inhibitors, including ramipril, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Patients with impaired liver function may have elevated plasma concentrations of felodipine and, therefore, may require lower doses of Altace Plus Felodipine (see ACTION AND CLINICAL PHARMACOLOGY – Pharmacokinetics, Felodipine). These patients should have their blood pressure monitored closely during initial administration and after dosage adjustment of Altace Plus Felodipine. A dosage of 10 mg felodipine daily should not be exceeded (see DOSAGE AND ADMINISTRATION – Felodipine, Use in Patients with Impaired Liver Function).

Pediatric Use

The safety and effectiveness of Altace Plus Felodipine in children have not been established; therefore use in this age group is not recommended.

Patient Alertness

Some undesirable effects (e.g. some symptoms of a reduction in blood pressure such as lightheadedness, dizziness, syncope) may be accompanied by an impairment of the ability to concentrate and react. This may constitute a risk in situations where these abilities are of special importance, e.g., when driving a car or operating machinery (see ADVERSE REACTIONS).

Use in Elderly

Although clinical experience with Altace Plus Felodipine has not identified differences in response between the elderly (> 65 years) and younger patients, greater sensitivity of some older individuals cannot be ruled out. Patients over 65 years of age may have elevated plasma concentrations of felodipine and, therefore, may require lower doses of Altace Plus Felodipine (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). These patients should have their blood pressure monitored closely during initial administration and after dosage adjustment of felodipine. A dosage of 10 mg felodipine daily should not be exceeded (see DOSAGE AND ADMINISTRATION- Felodipine, Use in the elderly).

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of ramipril, has been reported. Such possibility should be considered as part of the differential diagnosis of cough.

Gingival Hyperplasia

Felodipine can induce gingival enlargement in patients with pronounced gingivitis and periodontitis. However, such changes may be reversed by measures of good oral hygiene and mechanical debridement of the teeth.

Peripheral Edema

Mild to moderate peripheral edema was the most common adverse event in the clinical trials investigating felodipine effects. The incidence of peripheral edema was dose-dependent. Frequency of peripheral edema ranged from about 10 percent in patients under 50 years of age taking 5 mg felodipine daily to about 30 percent in those over 60 years taking 20 mg felodipine daily. This adverse effect generally occurs within 2-3 weeks of the initiation of treatment. Care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

Monitoring and Laboratory Tests

Hematological monitoring

Periodic monitoring of white blood cell counts should be considered to permit detection of a possible leukopenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma) or those treated with other drugs that can cause changes in the blood picture (see Drug Interactions – Allopurinol, Immunosuppressants, Corticosteroids, Procainamide, Cytostatics and other substances that may change the blood picture).

Renal function monitoring

Use of ramipril should include appropriate assessment of renal function, particularly in the initial weeks treatment with an ACE inhibitor. Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency. Particularly careful monitoring is required in patients with:

• heart failure
• renovascular disease, including patients with haemodynamically relevant unilateral renal artery stenosis. In the latter patient group, even a small increase in serum creatinine may be indicative of unilateral loss of renal function.
• impairment of renal function
• kidney transplant

Electrolyte monitoring

It is recommended that serum potassium be monitored regularly. More frequent monitoring of serum potassium is necessary in patients with impaired renal function.

Interaction with Grapefruit Juice

Published data show that through inhibition of cytochrome P-450, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of dihydropyridine calcium channel blockers. In view of the absolute bioavailability of felodipine, the potential for a significant increase in pharmacodynamic effects exists (see ACTION AND CLINICAL PHARMACOLOGY B Pharmacokinetics). Therefore, the consumption of grapefruit juice prior to and during treatment with Altace Plus Felodipine should be avoided.

Drug Interactions

As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via the CYP 3A4 isoenzyme. Coadministration of felodipine with other drugs which follow the same route of biotransformation may result in altered bioavailability of felodipine or these drugs. Dosages of similarly metabolized drugs particularly those of low therapeutic ratio, especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered felodipine to maintain optimum therapeutic blood levels.

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, warfarin. An increase in the plasma levels of

felodipine may be expected.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin. A decrease in the plasma levels of felodipine may be expected.

Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, terfenadine, theophylline.

Concomitant Diuretic Therapy: Due principally to the ramipril component, patients concomitantly taking Altace Plus Felodipine and diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of hypotensive effects after the first dose of ramipril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If it is not possible to discontinue the diuretic, the starting dose of ramipril should be reduced and the patient should be closely observed for several hours following the initial dose and until blood pressure has stabilized (see WARNINGS and DOSAGE AND ADMINISTRATION). Regular monitoring of serum sodium is recommended in patients undergoing concurrent diuretic therapy.

Other substances with antihypertensive potential (e.g. nitrates): Potentiation of the antihypertensive effect is to be anticipated.

Vasopressor sympathomimetics: These may reduce the antihypertensive effect of Altace Plus Felodipine. Particularly close blood pressure monitoring is recommended.

Agents Increasing Serum Potassium: Since ramipril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium, since they may lead to a significant increase in serum potassium. Salt substitutes which contain potassium should also be used with caution (see also Nonsteroidal Anti-inflamatory Agents and acetylsalicylic acid).

Agents Causing Renin Release: The antihypertensive effect of ramipril is augmented by antihypertensive agents that cause renin release (i.e. diuretics).

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be further increased.

Antacids: In one open-label, randomized, cross-over single dose study in 24 male subjects, it was determined that the bioavailability of ramipril and the pharmacokinetic profile of ramiprilat were not affected by concomitant administration of the antacid, magnesium and aluminum hydroxides.

Warfarin: The co-administration of ramipril with warfarin did not alter the anticoagulant effects.

Acenocoumarol: In a multi-dose, double-blind, placebo-controlled, pharmacodynamic interaction study with 14 patients with mild hypertension administered both ramipril and therapeutic doses of acenocoumarol, blood pressure, thrombotest time and coagulation factors were not significantly changed.

Heparin: rise in serum potassium concentration possible.

Nonsteroidal Anti-inflammatory Agents and acetylsalicylic acid: The antihypertensive effects of ACE inhibitors may be reduced with concomitant administration of nonsteroidal anti-inflammatory agents (e.g. indomethacin). Concomitant treatment of ACE inhibitors and nonsteroidal anti-inflammatory drugs may lead to an increased risk of worsening of renal function and an increase in serum potassium (see also Agents Increasing Serum Potassium).

Cimetidine: In healthy volunteers, pharmacokinetic studies showed an approximately 50 percent increase in the area under the felodipine plasma concentration time curve (AUC) as well as the C_max of felodipine when given concomitantly with cimetidine. It is anticipated that a clinically significant interaction may occur in some hypertensive patients. Therefore it is recommended that low doses of felodipine, and therefore Altace Plus Felodipine, be used when given concomitantly with cimetidine.

Erythromycin: Concomitant treatment with erythromycin has been shown to cause an increase in felodipine plasma levels.

Phenytoin, Carbamazepine and Phenobarbitol: In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (phenytoin, carbamazepine, phenobarbital) than in healthy volunteers. The mean area under the felodipine plasma concentration-time curve was also reduced in epileptic patients to approximately 6% of that observed in healthy volunteers. Since a clinically significant interaction may be anticipated, alternative antihypertensive therapy should be considered in these patients.

Alcohol: increased vasodilatation. Alcohol may enhance the hemodynamic effects of Altace Plus Felodipine.

Salt: Increased dietary salt intake may attenuate the antihypertensive effect of Altace Plus Felodipine.

Beta-Adrenoceptor Blocking Agents: A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and C_max of metoprolol, however, were increased approximately 31 and 36 percent, respectively. In controlled clinical trials, however, beta-blockers including metoprolol were concurrently administered with felodipine and were well tolerated.

Tacrolimus: Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.

Digoxin: When concomitantly administered with felodipine as conventional tablets the peak plasma concentration of digoxin was significantly increased. With the extended release formulation of felodipine there was no significant change in peak plasma levels or AUC of digoxin. In one open-label study in 12 subjects, administered multiple doses of both ramipril and digoxin, no changes were found in serum levels of ramipril, ramiprilat, and digoxin.

Antidiabetic agents (e.g. insulin, metfomin, sulfonylurea derivates): ACE inhibitors may reduce insulin resistance. In isolated cases, such reduction may lead to hypoglycaemic reactions in patients concomitantly treated with antidiabetics. Particularly close blood glucose monitoring is, therefore, recommended in the initial phase of co-administration.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood picture: increased likelihood of haematological reactions.

ADVERSE REACTIONS

The combination of ramipril and felodipine ER in a 1:1 ratio has been evaluated in 763 hypertensive patients in short-term double-blind trials and 278 patients during long term studies for 1 year. The most frequent clinical adverse experiences were headache (8.4%), increased cough (5.9%), vasodilatation (3.0%), bronchitis (2.9%) and dizziness (2.6%).

Adverse events that occurred have been previously reported for felodipine or ramipril as monotherapy for the treatment of hypertension. In clinical trials with the combination of felodipine and ramipril, peripheral edema and vasodilatation occurred at a lower incidence than with felodipine monotherapy (Table 1). The most common adverse events occurring in ≥ 1% of patients on combination therapy are shown in the following table:

Table 1. Incidence (%) of adverse events on monotherapy vs combination therapy

FR = felodipine ER + ramipril combination therapy

1 This column includes patients receiving felodipine ER 2.5 mg (n=213), 5 mg (n=233) or 10 mg (n=40). 2 This column includes patients receiving ramipril 2.5 mg (n=255), 5 mg (n=289) or 10 mg (n=41). 3 This column includes only felodipine ER + ramipril combinations administered in a 1:1 dosage ratio.

During clinical trials serious adverse event occurred on study medication in 30 of 2198 patients (1.4%). The following serious adverse events were observed in 13 of 680 (1.9%) patients treated with the 2.5/2.5 mg dosage strength: myocardial infarction (2 patients), gastroenteritis, influenza, epistaxis, colon carcinoma, cerebrovascular accident (2 patients), hemiplegia, retinal disorder, hydronephrosis, abdominal pain (2 patients), carcinoma, blurred vision, dizziness, heaviness in extremities, minor stroke, surgery (2 patients), accidental injury (2 patients), arthralgia, sinus bradycardia, joint disorder, angina pectoris, shock, sweating, and vomiting. The following serious adverse events were observed in 5 of 429 (2.0%) patients treated with the 5.0/5.0 mg dosage strength: colon carcinoma, gastroenteritis, pulmonary embolism, abdominal pain (2 patients), and malignant cerebral tumor.

Of the 680 patients treated with the 2.5/2.5 mg dosage strength, 27 patients (4.0%) discontinued due to adverse events. Of the 429 patients treated with the 5.0/5.0 mg dosage strength, 15 patients (3.5%) discontinued due to adverse events.

Treatment-emergent clinical adverse events that occurred with an incidence of <1% but in at least two patients in double-blind and long term safety trials (1 year) are listed below by body system:

Body as a Whole: fever, pain, pain in extremity, surgery, carcinoma, face edema, neck pain.

Cardiovascular System: arrhythmia, extrasystoles, tachycardia, T inverted, angina pectoris, ECG abnormal, myocardial infarction, chest pain, migraine, postural hypotension, peripheral vascular disorder, cerebrovascular accident.

Digestive System: periodontal abscess, colitis, constipation, anorexia, dyspepsia, eructation, flatulence, gastroenteritis, gastrointestinal disorder, gastrointestinal pain, vomiting, liver fatty deposit, sore throat, enteritis, gastritis.

Endocrine System: diabetes mellitus.

Metabolic and Nutritional Disorders: gout, edema.

Musculo-skeletal System: arthralgia, arthritis, arthrosis, joint disorder, muscle cramps, myalgia.

Nervous System: dry mouth, hot flashes, sweating increased, sleep disorders, abnormal dreams, anxiety, depression, insomnia, nervousness, somnolence, hypesthesia, libido decreased, paresthesia.

Respiratory System: bronchospasm, dyspnea, respiratory disorder, sputum increased, laryngitis, pneumonia, pharyngitis, rhinitis, epistaxis, sinusitis.

Skin and Appendages: rash, eczema, urticaria, pruritis, skin disorder,

Special Senses: tinnitus, otitis media, conjunctivitis, eye disorder, abnormal vision, blurred vision.

Urogenital System: dysuria, increased urinary frequency, cystitis, urinary tract infection, polyuria, pyelonephritis.

Laboratory findings:

Hemoglobin and hematocrit: Trend analyses of long-term therapy indicated decreases in hemoglobin. Reductions in hemoglobin and hematocrit have been reported with the use of ACE inhibitors but are rarely of clinical importance.

Hyperkalemia: (see PRECAUTIONS)

Others: It is known that ACE inhibitors can cause elevations of liver enzymes and/or bilirubin in isolated cases. This has also been observed with Altace Plus Felodipine.

In addition to those reported above, other adverse experiences have been previously reported with the individual components felodipine and ramipril.

Felodipine -component Adverse Reaction:

The following adverse events may occur in connection with felodipine treatment:

Body as a whole: peripheral edema, asthenia, chest pain, facial edema, flu-like illness, fever.

Cardiovascular: palpitations, warm sensation/flushing, tachycardia, premature beats, postural hypertension, bradycardia.

Gastrointestinal: nausea, dyspepsia, constipation, abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation, cholestatic hepatitis, gingival hyperplasia, gingivitis, salivary gland enlargement.

Metabolic: ALT (SGPT) increased.

Musculoskeletal: arthralgia, muscle cramps, myalgia.

Nervous/Psychiatric: headache, dizziness, paraesthesia, insomnia, depression, anxiety disorders, irritability, nervousness, somnolescence, decrease in libido, tremor, confusion.

Respiratory: upper respiratory infection, cough, dyspnea, epistaxis.

Dermatologic: rash, pruritus, erythema multiforme, erythema nodosum, leucocytoclastic vasculitis, urticaria, photosensitivity reactions.

Special Senses: visual disturbances.

Urogenital: impotence/sexual dysfunction, urinary frequency, urinary urgency, dysuria, polyuria.

Serious adverse events reported from controlled clinical trials and during marketing experience (incidence <0.5%) were myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia, and anemia.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty. Furthermore, isolated cases of extrasystoles, arthralgia, myalgia, parasthesiae, hypersensitivity reactions (such as urticaria), elevations of liver enzymes, confusion and insomnia have been reported, but it has not been possible to establish a definite connection with felodipine.

Laboratory Tests: For the following laboratory values statistically significant decreases were observed: bilirubin, red blood count, hemoglobin, and urate. Statistically significant increases were found in erythrocyte sedimentation rate and thrombocyte count. In isolated cases, there were increased liver enzymes. None of these changes were considered to be of clinical significance.

Ramipril-component Adverse Reactions

The following adverse events may occur in connection with ramipril treatment:

Body as a whole: peripheral edema, asthenia, rash, anaphylactoid reactions, angioneurotic edema.

Cardiovascular: symptomatic hypotension, postural hypotension, flushing, syncope, angina pectoris, arrhythmia, chest pain, palpitations, myocardial infarction, tachycardia, vascular stenosis, cerebrovascular disorders (including ischaemic stroke), disturbed orthostatic regulation, exacerbation of perfusion disturbances due to vascular stenoses.

Respiratory: increased cough, nasal congestion, sinusitis, bronchitis, bronchospasm (including aggravated asthma).

CNS: anxiety, amnesia, confusion, convulsions, depression, dizziness, fatigue, impaired hearing, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, polyneuritis, sleep disturbances, somnolence, tinnitus, tremor, vertigo, vision disturbances (including blurred vision), burning sensation (mainly to skin of face and extremities), smell disturbances, impaired psychomotor skills (impaired reactions), attention disturbances , disorders of balance, lightheadness , restlessness, precipitation or intensification of Raynaud’s phenomenon.

Dermatologic: apparent hypersensitivity reactions (with manifestations of urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, erythema multiforms, pemphigus, Stevens-Johnson syndrome. Angioedema with fatal outcome (may be/become life-threatening, rarely severe courses can cause fatal obstruction).

In addition, the following cutaneous or mucosal reactions may occur: maculopapular rash, maculo-papular exanthema, psoriasiform exanthema, erythroderma/exfoliative dermatitis, exacerbation of psoriasis, lichenoid exanthema, pemphigoid exanthema and enanthema, reversible alopecia, and toxic epidermal necrolysis or onycholysis.

Gastrointestinal: hepatic failure, cholestatic jaundice, hepatitis (cases of fatal outcome have been very exceptionally reported), abdominal pain (sometimes with enzyme changes suggesting pancreatitis), upper abdominal pain, pancreatitis (cases of fatal outcome have been very exceptionally), increased levels of pancreatic enzymes, decreased appetite, anorexia, constipation, diarrhea, dry mouth, glossitis, aphtous stomatitis, gastritis, intestinal angioedema, digestive disturbances, dyspepsia, dysphagia, gastroenteritis, nausea, increased salivation, taste disturbance, vomiting, abdominal discomfort. In isolated cases liver damage (including acute liver failure) may occur.

Rarely, ACE inhibitors, including ramipril, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.

Renal: impaired renal function, oliguria, and acute renal failure. Increases in blood urea nitrogen (BUN) and serum creatinine. Rarely, a deterioration of pre-existing proteinuria may develop (though ACE inhibitors usually reduce proteinuria) or an increase in urinary output (in connection with an improvement in cardiac performance).

Haematologic: agranulocytosis, leucopenia, eosinophilia, thrombocytopenia, pancytopaenia, bone marrow depression and hemolytic anemia.

Other: arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, transient erectile impotence, increased sweating, malaise, myalgia, weight gain, conjunctivitis, muscle cramps, reduced libido, loss of taste, depressed mood, gynaecomastia.

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA (antinuclear antibody), elevated ESR, eosinophilia and leucocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur.

Clinical laboratory test findings: increased creatinine; increases in blood urea nitrogen (BUN); decreases in red blood cell count, hemoglobin or hematocrit; hyponatraemia; elevations of liver enzymes, serum bilirubin, uric acid, blood glucose; proteinuria and significant increases in serum potassium.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

For the management of a suspected drug overdose, contact your regional Poison Control Centre.

To date there have been no reports of overdosage with Altace Plus Felodipine (felodipine/ramipril) in humans. Given the absence of practical experience with overdosage, the following is a synopsis of experiences gained with the individual components.

Ramipril:

Symptoms:

Limited data are available regarding overdosage of ramipril in humans. Two cases of overdosage have been reported.

Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure.

Management:

In the case of an overdosage with ramipril, the most likely clinical manifestation would be symptoms attributable to severe hypotension, which would normally be treated by intravenous volume expansion with normal saline. It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

Primary detoxification by, for example, gastric lavage, administration of adsorbents, sodium sulfate; (if possible during the first 30 minutes). In the event of hypotension administration of α1-adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which is usually available only in scattered research laboratories, must be considered in addition to volume and salt substitution.

No experience is available concerning the efficacy of forced diuresis, alteration in urine pH, haemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or haemofiltration is nevertheless considered, see also “PRECAUTIONS, Anaphylactoid reactions during membrane exposure” section.

Felodipine:

Symptoms:

Overdosage can cause excessive peripheral vasodilation with marked hypotension and possibly bradycardia.

Management:

In the case of known overdosage, activated charcoal may be used. If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. The intravenous administration of fluids may be used to treat hypotension. Plasma volume may be increased by infusion of a plasma volume expander. When accompanied by bradycardia, atropine 0.5-1 mg should be administered intravenously. Sympathomimetic drugs predominantly affecting the α1-adrenoceptor may be given if the above-mentioned measures are considered insufficient. Removal of felodipine from the circulation by hemodialysis has not been established.

DOSAGE AND ADMINISTRATION

Dosage must be individualized. A fixed combination is not recommended for initial therapy. The dose of Altace Plus Felodipine (felodipine/ramipril) should be determined by titration to the individual components. Altace Plus Felodipine tablets must not be divided, crushed or chewed. The tablets should not be administered with a meal rich in carbohydrates or fat (see ACTION AND CLINICAL PHARMACOLOGY- Pharmacokinetics).

Once the patient has been successfully titrated with the individual components as described below, Altace Plus Felodipine may be substituted if the titrated dose and dosing schedule can be achieved by the fixed combination (see INDICATIONS AND CLINICAL USE and WARNINGS, Hypotension).

Altace Plus Felodipine is available in doses of 2.5/2.5 mg and 5.0/5.0 mg (felodipine ER/ramipril).

Felodipine: For felodipine monotherapy, the usual recommended initial dose is 5 mg once daily. Depending on the patient’s response, the dosage should be adjusted accordingly. Dose adjustment, if necessary, should be done at intervals of not less than two weeks. The maintenance dose range is 2.5 to 10 mg once daily.

In clinical trials, doses above 10 mg daily showed an increased blood pressure response but a disproportionately higher incidence of peripheral edema and other vasodilatory adverse events.

Modification of the recommended dosage is not usually required in patients with renal impairment.

Use in the Elderly: Patients over 65 years may develop elevated plasma concentrations of felodipine. A starting dose no higher than 2.5 mg once daily is recommended. A dosage of 10 mg daily should not be exceeded (see PRECAUTIONS, Use in Elderly).

Use in Patients with Impaired Liver Function: Patients with impaired liver function may develop elevated plasma concentrations of felodipine. A starting dose no higher than 2.5 mg once daily is recommended. A dosage of 10 mg daily should not be exceeded (see PRECAUTIONS - Patients with Impaired Liver Function).

Ramipril: Dosage of ramipril must be individualized. Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with ramipril may need to be adjusted.

Monotherapy: The recommended initial dosage of ramipril in patients not on diuretics is 2.5mg once daily. Dosage should be adjusted according to blood pressure response, generally, at intervals of at least two weeks. The usual dose range is 2.5 to 10mg once daily. A daily dose of 20mg should not be exceeded.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not controlled with ramipril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of ramipril.

Concomitant Diuretic Therapy: Symptomatic hypotension occasionally may occur following the initial dose of ramipril and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with ramipril to reduce the likelihood of hypotension (see WARNINGS). If the diuretic cannot be discontinued, an initial dose of 1.25 mg ramipril should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of ramipril should subsequently be titrated (as described above) to the optimal response.

Use in renal impairment: For patients with a creatinine clearance below 40ml/min/1.73m² (serum creatinine above 2.5 mg/dL), the recommended initial dose is 1.25 mg ramipril once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5mg. In patients with severe renal impairment (creatinine clearance below 10ml/min/1.73m²) the maximum total daily dose of 2.5 mg should not be exceeded.

PHARMACEUTICAL INFORMATION

Drug Substances

Proper Name: extended-release felodipine + ramipril

Structural Formula:

OC₂H₅

H -N O CH₃

O=

N

HOOC

Molecular Formula:

felodipine: C₁₈H₁₉Cl₂NO₄ ramipril: C₂₃H₃₂N₂O₅

Molecular Weight:

felodipine: 384.26 ramipril: 416.52

Chemical Name:

felodipine: 3,5-pyridinecarboxylic acid, 4-(2,3-dichorophenyl)-1,4-dihydro

2,6-dimethyl-, ethyl methyl ester

ramipril: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid

Description: Felodipine is a slightly yellowish, crystalline powder with a melting point of 142°C to 145°C. It is not hygroscopic. It is soluble in acetone, dichloromethane, ethanol, heptane, methanol, 2-propanolol, n-octanol, and practically insoluble in water.

Ramipril is a white to off-white crystalline powder with a melting point of 105^o C ^to 112^o C. Slightly soluble in water, and freely soluble in ethanol

Cl

Cl

H

H₃COOC COOC₂H₅

H₃C N CH₃

H

and methanol.

Composition

ALTACE Plus Felodipine 2.5 mg + 2.5 mg tablets contain extended-release felodipine 2.5 mg and ramipril 2.5 mg. Non-medicinal ingredients are: hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide, lactose anhydrous, maize starch, microcrystalline cellulose, paraffin, polyethylene glycol, polyoxyl 40 hydrogenated castor oil, propyl gallate, sodium aluminium silicate, sodium stearyl fumarate, titanium dioxide.

ALTACE Plus Felodipine 5 mg + 5 mg tablets contain extended-release felodipine 5 mg and ramipril 5 mg. Non-medicinal ingredients are: hydroxypropylcellulose, hydroxypropylmethylcellulose, iron oxide, lactose anhydrous, maize starch, microcrystalline cellulose, paraffin, polyethylene glycol, polyoxyl 40 hydrogenated castor oil, propyl gallate, sodium aluminium silicate, sodium stearyl fumarate, titanium dioxide.

Stability and Storage Recommendations

Store ALTACE Plus Felodipine tablets between 15 ^o C to 30^o C and protect from moisture.

AVAILABILITY OF DOSAGE FORMS

ALTACE Plus Felodipine is supplied as circular, biconvex, film-coated, two-layered tablets with felodipine in an extended-release gel matrix formulation in one layer and rapidly dissolving ramipril in the other layer.

Altace Plus Felodipine 2.5 mg + 2.5 mg tablet: Film-coated, apricot, circular, two-layered, biconvex tablet engraved on one side and 2.5 mg on the other and containing 2.5 mg extended release felodipine and 2.5 mg ramipril.

Altace Plus Felodipine 5 mg + 5 mg tablet: Film-coated, reddish-brown, circular, two-layered, biconvex tablet engraved on one side and 5 mg on the other and containing 5 mg extended release felodipine and 5 mg ramipril.

Each tablet strength is available in blister packages of 30 tablets and in polyethylene bottles of 100, 300, or 500 tablets.