Cardea

Each film-coated tablet contains: Losartan potassium, BP 50 mg, Amlodipine (as besilate), BP 5 mg.

Pharmacotherapeutic group: Is a combination of an angiotensin II receptor (type AT1) antagonist and a calcium channel blocker.
Pharmacology: Pharmacodynamics: Mechanism of action: Combines two agents with complementary mechanisms of action to improve blood pressure control in hypertensive patients: losartan potassium, an angiotensin II receptor blocker (ARB), and amlodipine, a calcium channel blocker (CCB). Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Losartan: Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system, and a major determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland, kidneys, and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation. A second angiotensin II receptor has been identified as the AT2 receptor subtype, but it plays no known role in cardiovascular homeostasis.
Losartan is a potent, synthetic, orally active compound. Based on binding and pharmacological bioassays, it binds selectively to the AT1 receptor. In vitro and in vivo, both losartan and its pharmacologically active carboxylic acid metabolite (E-3174) block all physiologically relevant actions of angiotensin II, regardless of the source or route of synthesis. In contrast to some peptide antagonists of angiotensin II, losartan has no agonist effects.
Amlodipine: Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.
Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Pharmacokinetics: Absorption: Losartan: Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. There was no clinically significant effect on the plasma concentration profile of losartan when the drug was administered with a standardized meal.
Amlodipine: After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Distribution: Losartan: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Amlodipine: Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients.
Metabolism: Losartan: About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labeled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.
In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.
Amlodipine: Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination: Losartan: Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the feces. Following an intravenous dose of 14C-labeled losartan in man, about 43% of radioactivity is recovered in the urine and 50% in the feces.
Amlodipine: Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

This is used for the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled on either monotherapy.

The recommended dose is one tablet per day.
It can be administered with or without food. It is recommended to take tablet with water.
It can be administered with other antihypertensive agents.
Losartan is an effective treatment of hypertension in daily doses of 50 mg to 100 mg, while amlodipine is effective in doses of 5 mg to 10 mg as monotherapy. The maximum recommended dose of Amlodipine and Losartan Potassium tablet is 5 mg/100 mg.
A patient whose blood pressure is not adequately controlled with losartan alone or amlodipine alone may be switched to combination therapy.
Amlodipine and Losartan Potassium tablet 5 mg/50 mg may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or losartan 50 mg alone.
A patient co-administered with losartan and amlodipine may be switched to (fixed dose combination containing same dose of each ingredient) for compliance improvement.
Use in patients with renal impairment: No dosage adjustment is necessary in patients with mild renal impairment (i.e. creatinine clearance 20-50 mL/min). For patients with moderate to severe renal impairment (i.e. creatinine clearance <20 mL/min) or patients on dialysis, administration of Amlodipine and Losartan Potassium tablet is not recommended.
Use in patients with intravascular volume depletion: For patients with intravascular volume-depletion (e.g. those treated with high-dose diuretics), a starting dose of 25 mg losartan once daily should be considered. Since a 25 mg dose of losartan is not available with Amlodipine and Losartan Potassium tablet, this dose should be achieved with losartan monotherapy.
Use in patients with hepatic impairment: In cases where a lower dose of losartan (i.e. 25 mg once daily) is required for patients with a history of hepatic impairment, administration of Amlodipine and Losartan Potassium tablet is not recommended.
Use in the Elderly: Because of decreased clearance in the elderly, amlodipine therapy should usually be initiated at 2.5 mg daily. Since a 2.5 mg dose of amlodipine is not available with Amlodipine and Losartan Potassium tablet, this dose should be achieved with amlodipine monotherapy.
Use in patients ≤18 years of age: Since safety and efficacy of Amlodipine and Losartan Potassium tablet in children ≤18 years of age has not been established, administration of Amlodipine and Losartan Potassium tablet is not recommended.

Losartan: Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor the active metabolite can be removed by hemodialysis.
Amlodipine: Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m² basis) caused a marked peripheral vasodilation and hypotension.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Amlodipine and Losartan Potassium tablet is contraindicated in patients who are hypersensitive to any component of this product.
Amlodipine and Losartan Potassium tablet should not be administered with Aliskiren in patients with diabetes.

Amlodipine and Losartan Potassium tablet: Hypotension: In patients who are intravascularly volume-depleted (e.g., those treated with high-dose diuretics) or with severe aortic stenosis, symptomatic hypotension may occur. Intravascular volume depletion should be corrected prior to administration of Amlodipine and Losartan Potassium tablet, or a lower starting dose should be used. Because of the gradual onset of action, acute hypotension is unlikely.
Losartan: Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Amlodipine and Losartan Potassium tablet as soon as possible.
Hypersensitivity: Angioedema.
Electrolyte/Fluid Imbalance: Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with losartan as compared to the placebo group; however, few patients discontinued therapy due to hyperkalaemia. Concomitant use of other drugs that may increase serum potassium may lead to hyperkalaemia.
Amlodipine: Increased Angina or Myocardial Infarction: Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.
Use in Patients with Heart Failure: In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of non-ischaemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Effects on Ability to Drive and Use Machines: No studies of the effects of Amlodipine and Losartan Potassium tablet on the ability to drive and operate machines have been performed. However, certain side effects that have been reported with Amlodipine and Losartan Potassium tablet may affect some patients' ability to drive or operate machinery. Individual responses to Amlodipine and Losartan Potassium tablet may vary.
Liver function impairment: Amlodipine and Losartan Potassium tablet: Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose of losartan should be considered for patients with a history of hepatic impairment. Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t_1/2) is 56 hours in patients with impaired hepatic function, titrate slowly when administering amlodipine to patients with severe hepatic impairment.
Renal Function Impairment: Losartan: As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported in susceptible individuals; these changes in renal function may be reversible upon discontinuation of therapy. Other drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with losartan; these changes in renal function may be reversible upon discontinuation of therapy.
Use in Children: Since safety and efficacy of Amlodipine and Losartan Potassium tablet in children ≤18 years of age has not been established, administration of Amlodipine and Losartan Potassium tablet is not recommended.
Neonates with a history of in utero exposure to Amlodipine and Losartan Potassium tablet: If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Use in the Elderly: In clinical studies, there was no age-related difference in the efficacy or safety profile of losartan. Because of decreased clearance of amlodipine in the elderly, with a resulting increase of AUC of approximately 40-60% amlodipine therapy should usually be initiated at 2.5 mg daily. Since a 2.5 mg dose of amlodipine is not available with Amlodipine and Losartan Potassium tablet, this dose should be achieved with amlodipine monotherapy.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue Amlodipine and Losartan Potassium tablet as soon as possible.
Although there is no experience with the use of Amlodipine and Losartan Potassium tablet in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin-angiotensin system, begins in the second trimester; thus, risk to the fetus increases if Amlodipine and Losartan Potassium tablet is administered during the second or third trimesters of pregnancy.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Amlodipine and Losartan Potassium tablet as soon as possible.
These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Amlodipine and Losartan Potassium tablet, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to CARDEA for hypotension, oliguria, and hyperkalemia.
There are no adequate and well-controlled studies of amlodipine in pregnant women. The safety of amlodipine in pregnant women has not been established. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at the dose 50 times the maximum recommended human dose.

Losartan: Blood and lymphatic system disorders: Uncommon: Anaemia, Henoch-Schönlein purpura, ecchymosis, haemolysis.
Immune system disorders: Rare: Anaphylactic reactions, angioedema, urticaria.
Metabolism and nutrition disorders: Uncommon: Anorexia, gout.
Psychiatric disorders: Common: Insomnia.
Uncommon: Anxiety, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorder, somnolence, memory impairment.
Nervous system disorders: Common: Headache, dizziness.
Uncommon: Nervousness, paraesthesia, peripheral neuropathy, tremor, migraine, syncope.
Eye disorders: Uncommon: Blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity.
Ear and labyrinth disorders: Uncommon: Vertigo, tinnitus.
Cardiac disorders: Uncommon: Hypotension, orthostatic hypotension, sternalgia, angina pectoris, grade II-AV block, cerebrovascular event, myocardial infarction, and palpitation, arrhythmias (atrial fibrillations, sinus bradycardia, tachycardia, ventricular tachycardia, and ventricular fibrillation).
Vascular disorders: Uncommon: Vasculitis.
Respiratory, thoracic and mediastinal disorders: Uncommon: Decreased libido, impotence.
General disorders and administration site conditions: Common: Asthenia, fatigue, chest pain.
Uncommon: Facial oedema.
Amlodipine: The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship.
Cardiovascular: Arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.
Central and Peripheral Nervous System: Hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
Gastrointestinal: Anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
General: Allergic reaction, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
Musculoskeletal System: Arthralgia, arthrosis, muscle cramps, myalgia.
Psychiatric: Sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
Respiratory System: Dyspnea, epistaxis.
Skin and Appendages: Angioedema, erythema multiforme, pruritus, rash, rash erythematous, rash maculo-papular.
Special Senses: Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
Urinary System: Micturition frequency, micturition disorder, nocturia.
Autonomic Nervous System: Dry mouth, sweating increased.
Metabolic and Nutritional: Hyperglycemia, thirst.
Haematopoietic: Leukopenia, purpura, thrombocytopenia.

Losartan: In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Amlodipine and Losartan Potassium tablet and other agents that affect the RAAS. Do not co-administer aliskiren with Amlodipine and Losartan Potassium tablet in patients with diabetes. Avoid use of aliskiren with Amlodipine and Losartan Potassium tablet in patients with renal impairment (GFR <60 mL/min).
Amlodipine: In Vitro Data: In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit Juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Magnesium and Aluminum Hydroxide Antacid: Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (Alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Store at temperatures not exceeding 30°C.

Angiotensin II Antagonists / Calcium Antagonists

C09DB06 - losartan and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.

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