Losartan K, amlodipine besilate.
Pharmacology: Pharmacodynamics: Losartan: Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (eg, vascular smooth muscle, adrenal gland). Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor.
Amlodipine: Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine 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. 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: Losartan: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 (CYP450) enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed.
Following oral and IV administration of 14C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite.
In vitro studies indicate that CYP450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (<1% of the dose compared to 14% of the dose in normal subjects) was seen in about 1% of individuals studied. The terminal half-life (t½) of losartan is about 2 hrs and of the metabolite is about 6-9 hrs.
The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.
Following oral administration, losartan is well-absorbed (based on absorption of radiolabeled losartan) and undergoes substantial metabolism; the systemic bioavailability of Losartan is approximately 33%. About 14% of an orally administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hr and in 3-4 hrs, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the area under the curve (AUC) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its peak plasma concentration (Cmax), but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).
Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an IV dose of 14C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.
Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma-free fractions of 1.3% and 0.2%, respectively.
Plasma protein-binding is constant over the concentration range achieved with recommended doses.
Amlodipine: After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 hrs and 12 hrs. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food. 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. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients.
Elimination from the plasma is biphasic with a terminal elimination t½ of about 30-50 hrs. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing.
The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.
Renal Impairment: Patients with renal failure may, therefore, receive the usual initial dose.
Hepatic Impairment and Elderly: Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in the AUC of approximately 40-60% and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Treatment of mild to moderate hypertension. It is also indicated in hypertension not responding to monotherapy with calcium antagonists or angiotensin II receptor antagonists.
Usual Initial Dose: 1 tablet daily.
If blood pressure control is inadequate after a week or 2, the dose may be increased. The dosage, however, should be individualized. It may also be substituted for the titrated doses of the individual components.
Symptoms: Losartan: Hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation, LD50=1,000 mg/kg (orally in rat).
Amlodipine: Gross overdosage could result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to an including shock with fatal outcome have been reported.
Hypersensitivity to losartan potassium, amlodipine besilate or to any of the component of Amlife.
Hypotension: Excessive fall of blood pressure can occur with amlodipine in some patients, especially the elderly. In patients who are intravascularly volume-depleted (eg, those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with losartan. These conditions should be corrected prior to administration of this combination of losartan and amlodipine.
Aggravation of Angina: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy, or at the time of dosage increase.
Congestive Heart Failure: In general, calcium channel blockers should be used with caution in patients with heart failure.
Electrolyte Imbalance: Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed.
Renal Impairment: The combination should be used with caution in patients with severe renal disease. As a consequence of inhibiting the rennin-angiotensin-aldosterone system (RAAS), changes in renal function have been reported in susceptible individuals treated with losartan; in some patients, these changes in renal function were reversible upon discontinuation of therapy.
Hepatic Impairment: Caution should be exercised when administering losartan plus amlodipine to patients with impaired hepatic function due to increase in the plasma concentration of the combination.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles and operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.
Use in pregnancy: Drugs that act directly on the RAAS can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, this combination of losartan and amlodipine should be discontinued as soon as possible. Oligohydramnios has also been reported, presumably reporting from decreased fetal renal function.
Use in lactation: It is not known whether losartan or amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing may be discontinued while the combination is administered.
Use in children: Safety and effectiveness in pediatric patients have not been established.
Use in pregnancy:
Drugs that act directly on the RAAS can cause fetal and neonatal
morbidity and death when administered to pregnant women. When pregnancy
is detected, this combination of losartan and amlodipine should be
discontinued as soon as possible. Oligohydramnios has also been
reported, presumably reporting from decreased fetal renal function.
Use in lactation: It is not known whether losartan or
amlodipine is excreted in human milk. In the absence of this
information, it is recommended that nursing may be discontinued while
the combination is administered.
Losartan plus amlodipine is well tolerated. Adverse effects include nausea, headache, dizziness, abdominal pain, fatigue, flushing, palpitation and asthenia.
Rifampin: Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite.
Fluconazole: Fluconazole, an inhibitor of CYP450 2C9, decreased active metabolite concentration and increased losartan concentration.
Agents That Increase Serum Potassium: As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium.
Lithium: Losartan reduces lithium excretion; hence, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with this combination.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 (COX-2) Inhibitors: In some patients with compromised renal function who are being treated with NSAIDs, including those that selectively inhibit COX-2 inhibitors, the co-administration of losartan may result in a further deterioration of renal function. These effects are usually reversible. Reports suggest that NSAIDs, including selective COX-2 inhibitors, may diminish the antihypertensive effect of losartan. This interaction should be given consideration in patients taking NSAIDs, including selective COX-2 inhibitors, concomitantly with this combination of losartan and amlodipine.
Store at temperatures not exceeding 30°C. Protect from light.
Shelf-Life: 24 months.
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.
50 mg/5 mg FC tab 30's. 100 mg/5 mg FC tab 30's. 100 mg/10 mg FC tab 30's.