Veztenor

Amlodipine besilate, losartan potassium.

Each film-coated tablet contains Amlodipine besilate equivalent to Amlodipine 5 mg and Losartan potassium 50 mg.
Amlodipine inhibits the movement of Ca ions across the cell membrane into vascular smooth muscles and myocytes. Action is greater in the arterial resistant vessels causing peripheral vasodilatation and reduction in afterload. Losartan is an angiotensin II receptor (type AT₁) antagonists antihypertensive which acts by blocking the actions of angiotensin II of renin-angiotensin-aldosterone system. The drug and its active metabolite selectively block the vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively antagonizing the binding of angiotensin II to AT₁ receptors.

Pharmacology: Pharmacokinetics: Losartan: Absorption: 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 is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively.
Distribution: Both losartan and its active metabolite are ≥ 99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres.
Biotransformation: About 14% of an intravenously or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of ¹⁴C-labelled 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.
Elimination: 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-labelled losartan in man, about 35%/43% of radioactivity is recovered in the urine and 58%/50% in the faeces.
Characteristics in patients: In elderly hypertensive patients the plasma concentrations of losartan and its active metabolite do not differ essentially from those found in young hypertensive patients.
In female hypertensive patients the plasma levels of losartan were up to twice as high as in male hypertensive patients, while the plasma levels of the active metabolite did not differ between men and women.
In patients with mild to moderate alcoholic cirrhosis, plasma level of losartan and its active metabolite after oral administration were, respectively, 5 and 1.7 times higher than in young male volunteers.
Plasma concentrations of losartan are not altered in patients with creatinine clearance above 10 mL/min. Compared to patients with normal renal function, the AUC for losartan is about 2 times higher in haemodialysis patients.
The plasma concentrations of the active metabolite are not altered in patients with renal impairment or in haemodialysis patients. Neither losartan nor the active metabolite can be removed by haemodialysis.
Pharmacokinetics in paediatric patients: The pharmacokinetics of losartan have been investigated in 50 hypertensive paediatric patients > 1 month to < 16 years of age following once daily oral administration of approximately 0.54 to 0.77 mg/kg of losartan (mean doses).
The results showed that the active metabolite is formed from losartan in all age groups. The results showed roughly similar pharmacokinetic parameters of losartan following oral administration in infants and toddlers, preschool children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups. When comparing preschool children with adolescents these differences became statistically significant. Exposure in infants/toddlers was comparatively high.
Amlodipine: Absorption, distribution, plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The bioavailability of amlodipine is not affected by food intake.
Biotransformation/elimination: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Use in children: A population PK study has been conducted in 74 hypertensive children aged from 12 months to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.
Use in Elderly: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.
Patients with impaired hepatic function: Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Amlodipine besilate + Losartan potassium (Veztenor) is indicated for the treatment of mild to moderate hypertension in case of inadequate control of monotherapy.

Amlodipine besilate + Losartan potassium (Veztenor) may be administered with or without food. The usual starting dose is one tablet once daily.
Or as directed by the physician.

The most likely manifestation of overdosage could be hypotension and tachycardia; bradycardia could occur from parasympathetic stimulation. If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. The combination cannot be removed by dialysis. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
Limited data are available with regard to overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation. Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Treatment of intoxication: If symptomatic hypotension should occur, supportive treatment should be instituted. Measures are depending on the time of drug intake and kind and severity of symptoms. Stabilisation of the circulatory system should be given priority. After oral intake the administration of a sufficient dose of activated charcoal is indicated. Afterwards, close monitoring of the vital parameters should be performed. Vital parameters should be corrected if necessary. Neither Losartan nor the active metabolite can be removed by haemodialysis. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output.
A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.
Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

This combination is contraindicated in patients who are hypersensitive to any component of this product.
Patients allergic to angiotensin receptor blocker or dihydropyridine Calcium channel antagonist.
Patients with history of angioedema.
Hypersensitivity to the active substance or to any of the excipients.
Losartan is contraindicated in the 2nd and 3rd trimester of pregnancy. Severe hepatic impairment. Losartan should not be administered with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).
Amlodipine is contraindicated in patients with: hypersensitivity to dihydropyridine derivatives, amlodipine or any of the excipients; severe hypotension; shock (including cardiogenic shock); obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis); haemodynamically unstable heart failure after acute myocardial infarction.

Hypotension: Excessive fall of blood pressure can occur with amlodipine in some patients, especially the elderly. In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with losartan. These conditions should be corrected prior to administration of Veztenor.
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. Placebo-controlled trials of amlodipine in patients with New York Heart Association (NYHA) Class III or IV heart failure showed no overall adverse effect on survival or cardiac morbidity. In NYHA Class II/III heart failure patients, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms or left ventricular ejection fraction.
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 renin-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.
In patients whose renal function may depend on the activity of the RAAS (e.g., patients with severe congestive heart failure), losartan treatment has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Also, losartan treatment in patients with unilateral or bilateral renal artery stenosis was associated with increases in serum creatinine or blood urea nitrogen (BUN). In some patients, these effects were reversible upon discontinuation of therapy.
Hepatic Impairment: Caution should be exercised when administering the combination to patients with impaired hepatic function due to increase in the plasma concentration of the combination.
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, Veztenor should be discontinued as soon as possible. Oligohydramnios has also been reported, presumably resulting 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, Veztenor should be discontinued as soon as possible. Oligohydramnios has also been reported, presumably resulting 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.

Diarrhea, dyspepsia, muscle cramp, myalgia, back & leg pain, dizziness, insomnia, nasal congestion, cough, upper respiratory tract infection, sinus disorder, sinusitis, edema, flushing, palpitation, fatigue, headache, somnolence, abdominal pain.

Rifampin: Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite.
Fluconazole: Fluconazole, an inhibitor of P450 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 Veztenor.
Non-Steroidal Anti-Inflammatory Agents (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors: In some patients with compromised renal function who are being treated with NSAIDs, including those that selectively inhibit cyclooxygenase-2 inhibitors (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 Veztenor.

Store at temperatures not exceeding 30°C. Protect from light.

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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