Dafiro amlodipine/valsartan 10mg/160mg) သွေးတိုးကျဆေး
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Brand: Novartis Spain
သွေးတိုးကျဆေး ဆရာဝန် ညွှန်ကြားချက်ဖြင့်သာသောက်ရန်
Contents
Amlodipine besylate, valsartan.
Description
Amlodipine besylate is 3-ethyl-5-methyl (±)-2-[(2-minoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, mono-benzenesulphonate.
Valsartan is (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}valine.
Excipients/Inactive Ingredients: Microcrystalline cellulose; crospovidone; anhydrous colloidal silica; magnesium stearate; hypromellose, macrogol 4000, talc, titanium dioxide (E171), yellow iron oxide (E172). 10/160 mg tablet also contains red iron oxide (E172).
Valsartan is (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}valine.
Excipients/Inactive Ingredients: Microcrystalline cellulose; crospovidone; anhydrous colloidal silica; magnesium stearate; hypromellose, macrogol 4000, talc, titanium dioxide (E171), yellow iron oxide (E172). 10/160 mg tablet also contains red iron oxide (E172).
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Dafiro combines 2 antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: Amlodipine belongs to the calcium antagonist class and valsartan to the angiotensin II antagonist class of medicines. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Amlodipine: The amlodipine component of Dafiro inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and reduction in blood pressure. 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.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium-channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans even when co-administered with β-blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with β-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.
Valsartan: It is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with cough. In clinical trials where valsartan was compared with an ACE inhibitor (ACEIs), the incidence of dry cough was significantly (P <0.05) lower in patients treated with valsartan than in those treated with an ACEIs (2.6% vs 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACEIs therapy, 19.5% of trial subjects receiving valsartan and 19% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACEIs (P <0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hrs and the peak reduction of blood pressure is achieved within 4-6 hrs. The antihypertensive effect persists over 24 hrs after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
Valsartan has been demonstrated to significantly reduce hospitalizations in patients with chronic heart failure (NYHA class II-IV). The benefits were greatest in patients not receiving either an ACEIs or a β-blocker. Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Clinical Studies: Over 1400 hypertensive patients received Dafiro once daily in 2 placebo-controlled trials. The antihypertensive effect of a single dose of the combination persisted for 24 hrs. Dafiro was studied in 2 placebo-controlled trials in hypertensive patients with a diastolic blood pressure ≥95 mmHg and <110 mmHg. In the 1st study (baseline blood pressure 153/99 mmHg), Dafiro in doses of 5/80 mg, 5/160 mg and 5/320 mg reduced blood pressure 20-23/14-16 mmHg compared to 7/7 mmHg with placebo. In the 2nd study (baseline blood pressure 157/99 mmHg), Dafiro in doses of 10/160 mg and 10/320 mg reduced blood pressure 28/18-19 mmHg compared to 13/9 mmHg with placebo.
A multicenter, randomized, double-blind, active-controlled, parallel-group trial showed normalization of blood pressure (trough sitting diastolic BP <90 mmHg at the end of the trial) in patients not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan 10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53% of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an additional reduction in systolic/diastolic blood pressure of 6/4.8 mmHg and 3.9/2.9 mmHg respectively, compared to patients who remained on valsartan 160 mg only.
A multicenter, randomized, double-blind, active-controlled, parallel-group trial showed normalization of blood pressure (trough sitting diastolic BP <90 mmHg at the end of the trial) in patients not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan 10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53% of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an additional reduction in systolic/diastolic blood pressure of 6/4.8 mmHg and 3.9/2.9 mmHg respectively, compared to patients who remained on valsartan 160 mg only.
A multicenter, randomized, double-blind, active-controlled, parallel-group trial showed normalization of blood pressure (trough sitting diastolic BP <90 mmHg at the end of the trial) in patients not adequately controlled on amlodipine 10 mg in 78% of patients treated with Dafiro 10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of valsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of 2.9/2.1 mmHg compared to patients who remained on amlodipine 10 mg only.
Dafiro was also studied in an active-controlled study of 130 hypertensive patients with diastolic blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood pressure 171/113 mmHg), a Dafiro regimen of 5 mg/160 mg titrated to 10 mg/160 mg reduced sitting blood pressure by 36/29 mmHg as compared to 32/28 mmHg with a regimen of lisinopril/hydrochlorothiazide 10 mg/12.5 mg titrated to 20 mg/12.5 mg.
In other studies, the probability of achieving systolic or diastolic blood pressure control was greater with initial combination therapy than valsartan and amlodipine monotherapy at all levels of baseline blood pressure.
In 2 long-term follow-up studies, the effect of Dafiro was maintained for >1 year. Abrupt withdrawal of Dafiro has not been associated with a rapid increase in blood pressure.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may achieve similar blood pressure control with less edema.
Age, gender and race did not influence the response to Dafiro.
Pharmacokinetics: Linearity: Valsartan and amlodipine exhibit linear pharmacokinetics.
Absorption: Amlodipine: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hrs. Absolute bioavailability has been calculated as between 64-80%. Amlodipine bioavailability is unaffected by food ingestion.
Valsartan: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hrs. Mean absolute bioavailability is 23%. Valsartan shows multiexponential decay kinetics half-life α <1 hr and half-life β about 9 hrs). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 hrs post-dosing plasma valsartan concentrations are similar for the fed and fasted group. This reduction in AUC, however, is not accompanied by a clinically significant reduction in the therapeutic effect and valsartan can therefore be given either with or without food.
Distribution: Amlodipine: Volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins.
Valsartan: The steady-state volume of distribution of valsartan after IV administration is about 17 L indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Amlodipine: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Valsartan: Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (<10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Amlodipine: Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30-50 hrs. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten percent (10%) of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Valsartan: Valsartan shows multiexponential decay kinetics (t½α <1 hr and t½β about 9 hrs). Valsartan is primarily eliminated unchanged in feces (about 83% of dose) and urine (about 13% of dose) mainly as unchanged drug. Following IV administration, plasma clearance of valsartan is about 2 L/hr and its renal clearance is 0.62 L/hr (about 30% of total clearance). The half-life of valsartan is 6 hrs.
Valsartan/Amlodipine: Following oral administration of Dafiro peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6-8 hrs, respectively. The rate and extent of absorption of Dafiro are equivalent to the bioavailability of valsartan and amlodipine when administered as individual tablets.
Special Populations: Elderly: Time to reach peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life.
Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance. Since the 2 components are equally well tolerated in younger and elderly patients, normal dose regimens are recommended (see Dosage & Administration).
Renal Impairment: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. There is no apparent correlation between renal function [measured by creatinine clearance (CrCl)] and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see Dosage & Administration and Precautions).
Hepatic Impairment: Patients with hepatic impairment have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%. On average, in patients with mild to moderate chronic liver disease exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Care should be exercised in patients with liver disease (see Dosage & Administration and Precautions).
Toxicology: Nonclinical Safety Data: Amlodipine: Valsartan: In a variety of preclinical safety studies conducted in several animal species with amlodipine:valsartan, there were no findings that would exclude the use of therapeutic doses of amlodipine:valsartan in humans. Animal studies lasting 13 weeks have been conducted with the combination in rats and marmosets, as well as studies in rats to investigate embryofoetal development toxicity.
In a 13-week oral toxicity study in rats, amlodipine/valsartan-related inflammation of the glandular stomach was observed in males at doses ≥3/48 mg/kg/day. No such effects were observed in female rats at dose ≥3/48 mg/kg/day or in the 13-week marmoset study at any dose, although inflammation of the large intestine was observed in the high-dose marmosets only (no effects at dose ≤5/80 mg/kg/day). The gastrointestinal adverse effects observed in clinical trials with Dafiro were no more frequent with the combination than with the respective monotherapies.
In an oral embryofoetal development study in rats with dose levels of amlodipine:valsartan 5:80 mg/kg/day, amlodipine: valsartan 10:160 mg/kg/day, and amlodipine: valsartan 20:320 mg/kg/day, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. The no-observed-adverse effect level (NOAEL) for embryofoetal effects was amlodipine: valsartan 10:160 mg/kg/day. These doses, are respectively, 4.3 and 2.7 times, the systemic exposure in humans receiving the MRHD (10/320 mg/60 kg).
The combination amlodipine: Valsartan was not tested for mutagenicity, clastogenicity, reproductive performance or carcinogenicity as there was no evidence for any interaction between the 2 compounds.
Amlodipine: Safety data for amlodipine are well established both clinically and nonclinically. No relevant findings were observed in carcinogenicity and mutagenicity studies.
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg/kg/day (8 times the maximum recommended human dose of 10 mg on a mg/m2 basis, based on patient weight of 50 kg).
No evidence of teratogenicity or embryofoetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at dose up to amlodipine 10 mg/kg/day during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
Amlodipine has been tested individually for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.
Valsartan: Valsartan has been tested individually for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.
In a variety of preclinical safety studies conducted in several animal species, there were no findings that would exclude the use of therapeutic doses of valsartan in humans. In preclinical safety studies, high doses of valsartan (200-600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (slightly raised plasma urea, renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance. In embryofetal development studies (segment II) in mice, rats and rabbits, fetotoxicity was observed in association with maternal toxicity in rats at valsartan doses of ≥200 mg/kg/day and in rabbits at doses of ≥10 mg/kg/day. In a peri- and postnatal development toxicity (segment III) study, the offspring of rats given 600 mg/kg during the last trimester and during lactation showed a slightly reduced survival rate and a slight development delay.
Amlodipine: The amlodipine component of Dafiro inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and reduction in blood pressure. 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.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium-channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans even when co-administered with β-blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with β-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.
Valsartan: It is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II, which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with cough. In clinical trials where valsartan was compared with an ACE inhibitor (ACEIs), the incidence of dry cough was significantly (P <0.05) lower in patients treated with valsartan than in those treated with an ACEIs (2.6% vs 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACEIs therapy, 19.5% of trial subjects receiving valsartan and 19% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACEIs (P <0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hrs and the peak reduction of blood pressure is achieved within 4-6 hrs. The antihypertensive effect persists over 24 hrs after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
Valsartan has been demonstrated to significantly reduce hospitalizations in patients with chronic heart failure (NYHA class II-IV). The benefits were greatest in patients not receiving either an ACEIs or a β-blocker. Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Clinical Studies: Over 1400 hypertensive patients received Dafiro once daily in 2 placebo-controlled trials. The antihypertensive effect of a single dose of the combination persisted for 24 hrs. Dafiro was studied in 2 placebo-controlled trials in hypertensive patients with a diastolic blood pressure ≥95 mmHg and <110 mmHg. In the 1st study (baseline blood pressure 153/99 mmHg), Dafiro in doses of 5/80 mg, 5/160 mg and 5/320 mg reduced blood pressure 20-23/14-16 mmHg compared to 7/7 mmHg with placebo. In the 2nd study (baseline blood pressure 157/99 mmHg), Dafiro in doses of 10/160 mg and 10/320 mg reduced blood pressure 28/18-19 mmHg compared to 13/9 mmHg with placebo.
A multicenter, randomized, double-blind, active-controlled, parallel-group trial showed normalization of blood pressure (trough sitting diastolic BP <90 mmHg at the end of the trial) in patients not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan 10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53% of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an additional reduction in systolic/diastolic blood pressure of 6/4.8 mmHg and 3.9/2.9 mmHg respectively, compared to patients who remained on valsartan 160 mg only.
A multicenter, randomized, double-blind, active-controlled, parallel-group trial showed normalization of blood pressure (trough sitting diastolic BP <90 mmHg at the end of the trial) in patients not adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan 10 mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53% of patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an additional reduction in systolic/diastolic blood pressure of 6/4.8 mmHg and 3.9/2.9 mmHg respectively, compared to patients who remained on valsartan 160 mg only.
A multicenter, randomized, double-blind, active-controlled, parallel-group trial showed normalization of blood pressure (trough sitting diastolic BP <90 mmHg at the end of the trial) in patients not adequately controlled on amlodipine 10 mg in 78% of patients treated with Dafiro 10 mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of valsartan 160 mg produced an additional reduction in systolic/diastolic blood pressure of 2.9/2.1 mmHg compared to patients who remained on amlodipine 10 mg only.
Dafiro was also studied in an active-controlled study of 130 hypertensive patients with diastolic blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood pressure 171/113 mmHg), a Dafiro regimen of 5 mg/160 mg titrated to 10 mg/160 mg reduced sitting blood pressure by 36/29 mmHg as compared to 32/28 mmHg with a regimen of lisinopril/hydrochlorothiazide 10 mg/12.5 mg titrated to 20 mg/12.5 mg.
In other studies, the probability of achieving systolic or diastolic blood pressure control was greater with initial combination therapy than valsartan and amlodipine monotherapy at all levels of baseline blood pressure.
In 2 long-term follow-up studies, the effect of Dafiro was maintained for >1 year. Abrupt withdrawal of Dafiro has not been associated with a rapid increase in blood pressure.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may achieve similar blood pressure control with less edema.
Age, gender and race did not influence the response to Dafiro.
Pharmacokinetics: Linearity: Valsartan and amlodipine exhibit linear pharmacokinetics.
Absorption: Amlodipine: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hrs. Absolute bioavailability has been calculated as between 64-80%. Amlodipine bioavailability is unaffected by food ingestion.
Valsartan: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hrs. Mean absolute bioavailability is 23%. Valsartan shows multiexponential decay kinetics half-life α <1 hr and half-life β about 9 hrs). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 hrs post-dosing plasma valsartan concentrations are similar for the fed and fasted group. This reduction in AUC, however, is not accompanied by a clinically significant reduction in the therapeutic effect and valsartan can therefore be given either with or without food.
Distribution: Amlodipine: Volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins.
Valsartan: The steady-state volume of distribution of valsartan after IV administration is about 17 L indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Amlodipine: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Valsartan: Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (<10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Amlodipine: Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30-50 hrs. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten percent (10%) of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Valsartan: Valsartan shows multiexponential decay kinetics (t½α <1 hr and t½β about 9 hrs). Valsartan is primarily eliminated unchanged in feces (about 83% of dose) and urine (about 13% of dose) mainly as unchanged drug. Following IV administration, plasma clearance of valsartan is about 2 L/hr and its renal clearance is 0.62 L/hr (about 30% of total clearance). The half-life of valsartan is 6 hrs.
Valsartan/Amlodipine: Following oral administration of Dafiro peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6-8 hrs, respectively. The rate and extent of absorption of Dafiro are equivalent to the bioavailability of valsartan and amlodipine when administered as individual tablets.
Special Populations: Elderly: Time to reach peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life.
Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance. Since the 2 components are equally well tolerated in younger and elderly patients, normal dose regimens are recommended (see Dosage & Administration).
Renal Impairment: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. There is no apparent correlation between renal function [measured by creatinine clearance (CrCl)] and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see Dosage & Administration and Precautions).
Hepatic Impairment: Patients with hepatic impairment have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%. On average, in patients with mild to moderate chronic liver disease exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Care should be exercised in patients with liver disease (see Dosage & Administration and Precautions).
Toxicology: Nonclinical Safety Data: Amlodipine: Valsartan: In a variety of preclinical safety studies conducted in several animal species with amlodipine:valsartan, there were no findings that would exclude the use of therapeutic doses of amlodipine:valsartan in humans. Animal studies lasting 13 weeks have been conducted with the combination in rats and marmosets, as well as studies in rats to investigate embryofoetal development toxicity.
In a 13-week oral toxicity study in rats, amlodipine/valsartan-related inflammation of the glandular stomach was observed in males at doses ≥3/48 mg/kg/day. No such effects were observed in female rats at dose ≥3/48 mg/kg/day or in the 13-week marmoset study at any dose, although inflammation of the large intestine was observed in the high-dose marmosets only (no effects at dose ≤5/80 mg/kg/day). The gastrointestinal adverse effects observed in clinical trials with Dafiro were no more frequent with the combination than with the respective monotherapies.
In an oral embryofoetal development study in rats with dose levels of amlodipine:valsartan 5:80 mg/kg/day, amlodipine: valsartan 10:160 mg/kg/day, and amlodipine: valsartan 20:320 mg/kg/day, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. The no-observed-adverse effect level (NOAEL) for embryofoetal effects was amlodipine: valsartan 10:160 mg/kg/day. These doses, are respectively, 4.3 and 2.7 times, the systemic exposure in humans receiving the MRHD (10/320 mg/60 kg).
The combination amlodipine: Valsartan was not tested for mutagenicity, clastogenicity, reproductive performance or carcinogenicity as there was no evidence for any interaction between the 2 compounds.
Amlodipine: Safety data for amlodipine are well established both clinically and nonclinically. No relevant findings were observed in carcinogenicity and mutagenicity studies.
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg/kg/day (8 times the maximum recommended human dose of 10 mg on a mg/m2 basis, based on patient weight of 50 kg).
No evidence of teratogenicity or embryofoetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at dose up to amlodipine 10 mg/kg/day during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
Amlodipine has been tested individually for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.
Valsartan: Valsartan has been tested individually for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.
In a variety of preclinical safety studies conducted in several animal species, there were no findings that would exclude the use of therapeutic doses of valsartan in humans. In preclinical safety studies, high doses of valsartan (200-600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (slightly raised plasma urea, renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance. In embryofetal development studies (segment II) in mice, rats and rabbits, fetotoxicity was observed in association with maternal toxicity in rats at valsartan doses of ≥200 mg/kg/day and in rabbits at doses of ≥10 mg/kg/day. In a peri- and postnatal development toxicity (segment III) study, the offspring of rats given 600 mg/kg during the last trimester and during lactation showed a slightly reduced survival rate and a slight development delay.
Indications/Uses
Treatment of essential hypertension.
As initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of Dafiro as initial therapy for hypertension should be based on an assessment of potential benefits and risks.
As initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of Dafiro as initial therapy for hypertension should be based on an assessment of potential benefits and risks.
Dosage/Direction for Use
A patient whose blood pressure is not adequately controlled on monotherapy may be switched to combination therapy with Dafiro. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered. Recommended Dose: 1 tab/day.
For convenience, patients receiving valsartan and amlodipine from separate tablets may be switched to Dafiro containing the same component doses.
Initial Therapy: Usual Starting Dose: 5/80 mg once daily. The dosage can be increased after 1-2 weeks of therapy to a maximum of one 10/320 mg once daily as needed to control blood pressure. Dafiro is not recommended as initial therapy in patients with intravascular volume depletion (see Precautions).
Maximum Dose: 10/320 mg.
Both amlodipine and valsartan monotherapy can be taken with or without food. It is recommended to take Dafiro with some water.
Elderly: Since both components of the combination are equally well tolerated when used at similar doses in elderly (≥65 years) or younger patients, no dose adjustment of the starting dose is required (see Pharmacology under Actions).
Children (<18 years): Dafiro is not recommended for use in patients <18 years due to a lack of data on safety and efficacy.
Renal and Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment but caution should be exercised when administering Dafiro to patients with hepatic impairment or biliary obstructive disorders due to amlodipine and valsartan (see Pharmacology under Actions and Precautions).
For convenience, patients receiving valsartan and amlodipine from separate tablets may be switched to Dafiro containing the same component doses.
Initial Therapy: Usual Starting Dose: 5/80 mg once daily. The dosage can be increased after 1-2 weeks of therapy to a maximum of one 10/320 mg once daily as needed to control blood pressure. Dafiro is not recommended as initial therapy in patients with intravascular volume depletion (see Precautions).
Maximum Dose: 10/320 mg.
Both amlodipine and valsartan monotherapy can be taken with or without food. It is recommended to take Dafiro with some water.
Elderly: Since both components of the combination are equally well tolerated when used at similar doses in elderly (≥65 years) or younger patients, no dose adjustment of the starting dose is required (see Pharmacology under Actions).
Children (<18 years): Dafiro is not recommended for use in patients <18 years due to a lack of data on safety and efficacy.
Renal and Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment but caution should be exercised when administering Dafiro to patients with hepatic impairment or biliary obstructive disorders due to amlodipine and valsartan (see Pharmacology under Actions and Precautions).
Overdosage
There is no experience of overdose with Dafiro yet. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Overdosage with amlodipine may result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, 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.
If the ingestion is recent, induction of vomiting or gastric lavage may be considered.
Administration of activated charcoal to healthy volunteers immediately or up to 2 hrs after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.
Both valsartan and amlodipine are unlikely to be removed by hemodialysis.
Overdosage with amlodipine may result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, 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.
If the ingestion is recent, induction of vomiting or gastric lavage may be considered.
Administration of activated charcoal to healthy volunteers immediately or up to 2 hrs after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.
Both valsartan and amlodipine are unlikely to be removed by hemodialysis.
Contraindications
Hypersensitivity to amlodipine, valsartan or to any of the excipients of Dafiro. Concomitant use of angiotensin receptor antagonists (ARBs)- including valsartan-or of ACEIs with aliskiren in patients with type 2 diabetes (see Interactions).
Use in Pregnancy: Due to the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. Administration of ACEIs (a specific class of drugs acting on the renin-angiotensin-aldosterone system, RAAS) to pregnant women during the 2nd and 3rd trimesters has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, 1st trimester use of ACEIs has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have inadvertently taken valsartan.
There are no adequate clinical data with amlodipine in pregnant women. Animal studies with amlodipine have shown reproductive toxicity at dose 8 times the maximum recommended dose of 10 mg (see Toxicology: Nonclinical Safety Data under Actions).
Women of Childbearing Potential: As for any drug that also acts directly on the RAAS, Dafiro must not be used during pregnancy (see Contraindications) or in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Dafiro must be discontinued as soon as possible.
Use in Pregnancy: Due to the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. Administration of ACEIs (a specific class of drugs acting on the renin-angiotensin-aldosterone system, RAAS) to pregnant women during the 2nd and 3rd trimesters has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, 1st trimester use of ACEIs has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have inadvertently taken valsartan.
There are no adequate clinical data with amlodipine in pregnant women. Animal studies with amlodipine have shown reproductive toxicity at dose 8 times the maximum recommended dose of 10 mg (see Toxicology: Nonclinical Safety Data under Actions).
Women of Childbearing Potential: As for any drug that also acts directly on the RAAS, Dafiro must not be used during pregnancy (see Contraindications) or in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Dafiro must be discontinued as soon as possible.
Special Precautions
Sodium- and/or Volume Depletion: Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Dafiro in placebo-controlled studies. In patients with an activated renin-angiotensin system (RAS) (eg, volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving ARBs, symptomatic hypotension may occur. Correction of this condition prior to administration of Dafiro or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Dafiro, the patient should be placed in the supine position and if necessary, given an IV infusion of normal saline. Treatment can be continued once blood pressure has been stabilized.
Hyperkalaemia: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other drugs that may increase potassium levels (heparin, others) should be used with caution and with frequent monitoring of potassium.
Renal Artery Stenosis: Dafiro should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis, stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.
Renal Impairment: No data is available for severe cases (CrCl <10 mL/min) and caution is therefore advised. No dosage adjustment of Dafiro is required for patients with mild to moderate renal impairment. The use of ARBs, including valsartan, or of ACEIs with aliskiren should be avoided in patients with severe renal impairment (GFR <30 mL/min) (see Interactions).
Kidney Transplantation: To date, there is no experience of the safe use of Dafiro in patients who have had a recent kidney transplantation.
Hepatic Impairment: Valsartan is mostly eliminated unchanged via the bile, whereas, amlodipine is extensively metabolized by the liver. Particular caution should be exercised when administering Dafiro to patients with hepatic impairment or biliary obstructive disorders (see Pharmacology under Actions).
Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACEIs. Dafiro should be immediately discontinued in patients who develop angioedema and Dafiro should not be re-administered.
Heart Failure/Post-Myocardial Infarction: In general, calcium-channel blockers, including amlodipine, should be used with caution in patients with serious congestive heart failure [New York Heart Association (NYHA) functional class 3-4]. In patients whose renal function may depend on the activity of the renin-angiotensin aldosterone system (eg, patients with severe congestive heart failure), treatment with ACEIs or angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
Acute 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.
Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy: As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.
Dual Blockade of RAS: Caution is required while co-administering ARBs, including valsartan; with other agents blocking the RAS eg, ACEIs or aliskiren (see section Interactions).
Impairment of Fertility: There is no information on the effects of amlodipine or valsartan on human fertility. Studies in rats did not show any effects of amlodipine or valsartan on fertility (see Toxicology: Nonclinical Safety Data under Actions).
Use in lactation: It is not known whether valsartan and/or amlodipine are excreted in human milk. Valsartan was excreted in the milk of lactating rats. It is therefore not advisable for women who are breastfeeding to use Dafiro.
If hypotension occurs with Dafiro, the patient should be placed in the supine position and if necessary, given an IV infusion of normal saline. Treatment can be continued once blood pressure has been stabilized.
Hyperkalaemia: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other drugs that may increase potassium levels (heparin, others) should be used with caution and with frequent monitoring of potassium.
Renal Artery Stenosis: Dafiro should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis, stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.
Renal Impairment: No data is available for severe cases (CrCl <10 mL/min) and caution is therefore advised. No dosage adjustment of Dafiro is required for patients with mild to moderate renal impairment. The use of ARBs, including valsartan, or of ACEIs with aliskiren should be avoided in patients with severe renal impairment (GFR <30 mL/min) (see Interactions).
Kidney Transplantation: To date, there is no experience of the safe use of Dafiro in patients who have had a recent kidney transplantation.
Hepatic Impairment: Valsartan is mostly eliminated unchanged via the bile, whereas, amlodipine is extensively metabolized by the liver. Particular caution should be exercised when administering Dafiro to patients with hepatic impairment or biliary obstructive disorders (see Pharmacology under Actions).
Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACEIs. Dafiro should be immediately discontinued in patients who develop angioedema and Dafiro should not be re-administered.
Heart Failure/Post-Myocardial Infarction: In general, calcium-channel blockers, including amlodipine, should be used with caution in patients with serious congestive heart failure [New York Heart Association (NYHA) functional class 3-4]. In patients whose renal function may depend on the activity of the renin-angiotensin aldosterone system (eg, patients with severe congestive heart failure), treatment with ACEIs or angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
Acute 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.
Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy: As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.
Dual Blockade of RAS: Caution is required while co-administering ARBs, including valsartan; with other agents blocking the RAS eg, ACEIs or aliskiren (see section Interactions).
Impairment of Fertility: There is no information on the effects of amlodipine or valsartan on human fertility. Studies in rats did not show any effects of amlodipine or valsartan on fertility (see Toxicology: Nonclinical Safety Data under Actions).
Use in lactation: It is not known whether valsartan and/or amlodipine are excreted in human milk. Valsartan was excreted in the milk of lactating rats. It is therefore not advisable for women who are breastfeeding to use Dafiro.
Use In Pregnancy & Lactation
Use in Pregnancy: Due to the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. Administration of ACEIs (a specific class of drugs acting on the renin-angiotensin-aldosterone system, RAAS) to pregnant women during the 2nd and 3rd trimesters has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, 1st trimester use of ACEIs has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have inadvertently taken valsartan.
There are no adequate clinical data with amlodipine in pregnant women. Animal studies with amlodipine have shown reproductive toxicity at dose 8 times the maximum recommended dose of 10 mg (see Toxicology: Nonclinical Safety Data under Actions).
Women of Childbearing Potential: As for any drug that also acts directly on the RAAS, Dafiro must not be used during pregnancy (see Contraindications) or in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Dafiro must be discontinued as soon as possible.
Use in Lactation: It is not known whether valsartan and/or amlodipine are excreted in human milk. Valsartan was excreted in the milk of lactating rats. It is therefore not advisable for women who are breastfeeding to use Dafiro.
There are no adequate clinical data with amlodipine in pregnant women. Animal studies with amlodipine have shown reproductive toxicity at dose 8 times the maximum recommended dose of 10 mg (see Toxicology: Nonclinical Safety Data under Actions).
Women of Childbearing Potential: As for any drug that also acts directly on the RAAS, Dafiro must not be used during pregnancy (see Contraindications) or in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Dafiro must be discontinued as soon as possible.
Use in Lactation: It is not known whether valsartan and/or amlodipine are excreted in human milk. Valsartan was excreted in the milk of lactating rats. It is therefore not advisable for women who are breastfeeding to use Dafiro.
Adverse Reactions
The safety of Dafiro has been evaluated in 5 controlled clinical studies with 5175 patients, 2613 of whom received valsartan in combination with amlodipine.
Adverse drug reactions are ranked under heading of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000) including isolated reports.
Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Infections and Infestations: Common: Nasopharyngitis, influenza.
Immune System Disorders: Rare: Hypersensitivity.
Eye Disorders: Rare: Visual disturbance.
Psychiatric Disorders: Rare: Anxiety.
Nervous System Disorders: Common: Headache. Uncommon: Dizziness, somnolence, postural dizziness, paresthesia.
Ear and Labyrinth Disorders: Uncommon: Vertigo. Rare: Tinnitus. Cardiac Disorders: Uncommon: Tachycardia, palpitations. Rare: Syncope.
Vascular Disorders: Uncommon: Orthostatic hypotension. Rare: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Cough, pharyngolaryngeal pain.
Gastrointestinal Disorders: Uncommon: Diarrhea, nausea, abdominal pain, constipation, dry mouth.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rash, erythema. Rare: Hyperhidrosis, exanthema, pruritus.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Joint swelling, back pain, arthralgia. Rare: Muscle spasm, sensation of heaviness.
Renal and Urinary Disorders: Rare: Pollakiuria, polyuria.
Reproductive System and Breast Disorders: Rare: Erectile dysfunction.
General Disorders and Administration Site Conditions: Common: Edema, pitting edema, facial edema, peripheral edema, fatigue, flushing, asthenia, hot flush.
Additional Information on the Combination: In double-blind, active- or placebo-controlled completed clinical trials, the incidence of peripheral edema was statistically lower in patients treated with the combination (5.8%) than in patients treated with amlodipine monotherapy (9%).
Laboratory Evaluation: Very few hypertensive patients treated with valsartan/amlodipine showed notable changes in laboratory test results from baseline. There was a slightly higher incidence of notably increased blood urea nitrogen (BUN) in the amlodipine/valsartan (5.5%) and valsartan monotherapy (5.5%) groups as compared to the placebo group (4.5%).
Additional Information on Individual Components: Adverse reactions previously reported with 1 of the individual components may occur with Dafiro even if not observed in clinical trials.
Amlodipine: Other additional adverse experiences reported with amlodipine monotherapy, irrespective of their causal association with Dafiro were as follows: Eye Disorders: Uncommon: Diplopia.
Blood and Lymphatic System Disorders: Very Rare: Thrombocytopenia, leucocytopenia.
Immune System Disorders: Very Rare: Allergic reactions.
Metabolism and Nutritional Disorders: Very Rare: Hyperglycemia. Psychiatric Disorders: Uncommon: Insomnia, mood changes.
Nervous System Disorders: Uncommon: Tremor, hypoesthesia, dysgeusia. Very Rare: Peripheral neuropathy, hypertonia.
Cardiac Disorders: Very Rare: Arrhythmia, bradycardia, atrial fibrillation, ventricular tachycardia, myocardial infarction.
Vascular Disorders: Very Rare: Vasculitis.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnea, rhinitis.
Gastrointestinal Disorders: Uncommon: Vomiting, dyspepsia. Very Rare: Pancreatitis, gastritis, gingival hyperplasia.
Hepatobiliary Disorders: Very Rare: Hepatitis, jaundice.
Skin and Subcutaneous Tissue Disorders: Uncommon: Alopecia, purpura, skin discoloration, photosensitivity. Very Rare: Angioedema, urticaria, erythema multiforme, Stevens-Johnson syndrome.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Myalgia.
Renal and Urinary Disorders: Uncommon: Micturition disorder, nocturia.
Reproductive System and Breast Disorders: Uncommon: Gynecomastia.
General Disorders and administration Site Conditions: Uncommon: Pain, malaise, chest pain.
Investigations: Uncommon: Decreased and increased weight. Very Rare: Increased hepatic enzyme (mostly consistent with cholestasis). Because amlodipine clinical trials were conducted under widely varying conditions, adverse experience rates observed in the clinical trials of Dafiro cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Valsartan: Other adverse drug reactions reported in clinical studies, post-marketing experience and laboratory findings in hypertension indication are presented according to system organ class. For all the adverse drug reactions reported from post-marketing experience and laboratory findings, it is not possible to apply any adverse drug reaction frequency, and therefore, they are mentioned with a "not known" frequency.
Adverse drug reactions with valsartan monotherapy: Blood and Lymphatic System Disorders: Decreased in hemoglobin and hematocrit, neutropenia, thrombocytopenia. Immune System Disorders: Not Known: Hypersensitivity including serum sickness.
Metabolism and Nutrition Disorders: Not Known: Increase of serum potassium.
Vascular Disorders: Not Known: Vasculitis.
Hepatobiliary Disorders: Not Known: Elevation of liver function values including serum bilirubin.
Skin and Subcutaneous Tissue Disorders: Not Known: Angioedema.
Musculoskelatal and Connective Tissue Disorders: Not Known: Myalgia.
Renal and Urinary Disorders: Not Known: Renal failure and impairment, elevation of serum creatinine.
The following events have also been observed during clinical trials in hypertensive patients irrespective of their causal association with Dafiro: Insomnia, decreased libido, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Adverse drug reactions are ranked under heading of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000) including isolated reports.
Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Infections and Infestations: Common: Nasopharyngitis, influenza.
Immune System Disorders: Rare: Hypersensitivity.
Eye Disorders: Rare: Visual disturbance.
Psychiatric Disorders: Rare: Anxiety.
Nervous System Disorders: Common: Headache. Uncommon: Dizziness, somnolence, postural dizziness, paresthesia.
Ear and Labyrinth Disorders: Uncommon: Vertigo. Rare: Tinnitus. Cardiac Disorders: Uncommon: Tachycardia, palpitations. Rare: Syncope.
Vascular Disorders: Uncommon: Orthostatic hypotension. Rare: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Cough, pharyngolaryngeal pain.
Gastrointestinal Disorders: Uncommon: Diarrhea, nausea, abdominal pain, constipation, dry mouth.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rash, erythema. Rare: Hyperhidrosis, exanthema, pruritus.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Joint swelling, back pain, arthralgia. Rare: Muscle spasm, sensation of heaviness.
Renal and Urinary Disorders: Rare: Pollakiuria, polyuria.
Reproductive System and Breast Disorders: Rare: Erectile dysfunction.
General Disorders and Administration Site Conditions: Common: Edema, pitting edema, facial edema, peripheral edema, fatigue, flushing, asthenia, hot flush.
Additional Information on the Combination: In double-blind, active- or placebo-controlled completed clinical trials, the incidence of peripheral edema was statistically lower in patients treated with the combination (5.8%) than in patients treated with amlodipine monotherapy (9%).
Laboratory Evaluation: Very few hypertensive patients treated with valsartan/amlodipine showed notable changes in laboratory test results from baseline. There was a slightly higher incidence of notably increased blood urea nitrogen (BUN) in the amlodipine/valsartan (5.5%) and valsartan monotherapy (5.5%) groups as compared to the placebo group (4.5%).
Additional Information on Individual Components: Adverse reactions previously reported with 1 of the individual components may occur with Dafiro even if not observed in clinical trials.
Amlodipine: Other additional adverse experiences reported with amlodipine monotherapy, irrespective of their causal association with Dafiro were as follows: Eye Disorders: Uncommon: Diplopia.
Blood and Lymphatic System Disorders: Very Rare: Thrombocytopenia, leucocytopenia.
Immune System Disorders: Very Rare: Allergic reactions.
Metabolism and Nutritional Disorders: Very Rare: Hyperglycemia. Psychiatric Disorders: Uncommon: Insomnia, mood changes.
Nervous System Disorders: Uncommon: Tremor, hypoesthesia, dysgeusia. Very Rare: Peripheral neuropathy, hypertonia.
Cardiac Disorders: Very Rare: Arrhythmia, bradycardia, atrial fibrillation, ventricular tachycardia, myocardial infarction.
Vascular Disorders: Very Rare: Vasculitis.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnea, rhinitis.
Gastrointestinal Disorders: Uncommon: Vomiting, dyspepsia. Very Rare: Pancreatitis, gastritis, gingival hyperplasia.
Hepatobiliary Disorders: Very Rare: Hepatitis, jaundice.
Skin and Subcutaneous Tissue Disorders: Uncommon: Alopecia, purpura, skin discoloration, photosensitivity. Very Rare: Angioedema, urticaria, erythema multiforme, Stevens-Johnson syndrome.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Myalgia.
Renal and Urinary Disorders: Uncommon: Micturition disorder, nocturia.
Reproductive System and Breast Disorders: Uncommon: Gynecomastia.
General Disorders and administration Site Conditions: Uncommon: Pain, malaise, chest pain.
Investigations: Uncommon: Decreased and increased weight. Very Rare: Increased hepatic enzyme (mostly consistent with cholestasis). Because amlodipine clinical trials were conducted under widely varying conditions, adverse experience rates observed in the clinical trials of Dafiro cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Valsartan: Other adverse drug reactions reported in clinical studies, post-marketing experience and laboratory findings in hypertension indication are presented according to system organ class. For all the adverse drug reactions reported from post-marketing experience and laboratory findings, it is not possible to apply any adverse drug reaction frequency, and therefore, they are mentioned with a "not known" frequency.
Adverse drug reactions with valsartan monotherapy: Blood and Lymphatic System Disorders: Decreased in hemoglobin and hematocrit, neutropenia, thrombocytopenia. Immune System Disorders: Not Known: Hypersensitivity including serum sickness.
Metabolism and Nutrition Disorders: Not Known: Increase of serum potassium.
Vascular Disorders: Not Known: Vasculitis.
Hepatobiliary Disorders: Not Known: Elevation of liver function values including serum bilirubin.
Skin and Subcutaneous Tissue Disorders: Not Known: Angioedema.
Musculoskelatal and Connective Tissue Disorders: Not Known: Myalgia.
Renal and Urinary Disorders: Not Known: Renal failure and impairment, elevation of serum creatinine.
The following events have also been observed during clinical trials in hypertensive patients irrespective of their causal association with Dafiro: Insomnia, decreased libido, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
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Drug Interactions
Amlodipine: Simvastatin: Co-administration of multiple doses of amlodipine 10 mg with simvastatin 80 mg resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.
CYP3A4 Inhibitors: Co-administration of a daily dose of diltiazem 180 mg with amlodipine 5 mg in elderly hypertensive patients resulted in a 1.6-fold increase in amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Caution should therefore be exercised when co-administering amlodipine with CYP3A4 inhibitors.
CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers.
In monotherapy, amlodipine has been safely administered with thiazide diuretics, β-blockers, ACEIs, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, Maalox (aluminum hydroxide gel, magnesium hydroxide and simethicone), cimetidine, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic drugs.
Valsartan: Dual Blockade of the Renin-Angiotensin System (RAS) with ARBs, ACEIs or Aliskiren: The concomitant use of ARBs with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalemia and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on Dafiro and other agents that affect the RAS (see Precautions).
The concomitant use of ARBs or ACEIs with aliskiren should be avoided in patients with severe renal impairment (GFR<30 mL/min) (see Precautions) and contraindicated in type 2 diabetes (see Contraindications).
Potassium: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, others) requires caution and frequent monitoring of potassium levels.
Nonsteroidal Anti-Inflammatory Agents (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (Cox-2 Inhibitors): When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy) or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increase risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifyng the treatment in patients on valsartan who are taking NSAIDs concomitantly.
Transporters: The results from an in vitro study in human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: Cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Incompatibilities: Not applicable.
CYP3A4 Inhibitors: Co-administration of a daily dose of diltiazem 180 mg with amlodipine 5 mg in elderly hypertensive patients resulted in a 1.6-fold increase in amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Caution should therefore be exercised when co-administering amlodipine with CYP3A4 inhibitors.
CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers.
In monotherapy, amlodipine has been safely administered with thiazide diuretics, β-blockers, ACEIs, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, Maalox (aluminum hydroxide gel, magnesium hydroxide and simethicone), cimetidine, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and oral hypoglycemic drugs.
Valsartan: Dual Blockade of the Renin-Angiotensin System (RAS) with ARBs, ACEIs or Aliskiren: The concomitant use of ARBs with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalemia and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on Dafiro and other agents that affect the RAS (see Precautions).
The concomitant use of ARBs or ACEIs with aliskiren should be avoided in patients with severe renal impairment (GFR<30 mL/min) (see Precautions) and contraindicated in type 2 diabetes (see Contraindications).
Potassium: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, others) requires caution and frequent monitoring of potassium levels.
Nonsteroidal Anti-Inflammatory Agents (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (Cox-2 Inhibitors): When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy) or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increase risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifyng the treatment in patients on valsartan who are taking NSAIDs concomitantly.
Transporters: The results from an in vitro study in human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: Cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Incompatibilities: Not applicable.
Storage
Do not store above 30°C. Protect from moisture.
MIMS Class
ATC Classification
C09DB01 - valsartan and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.
Presentation/Packing
FC tab 5/160 mg (dark yellow, oval, imprinted with "NVR" on one side and "ECE" on the other side) x 28's. 10/160 mg (light yellow, oval, imprinted with "NVR" on one side and "UIC" on the other side) x 28's.
Dafiro amlodipine/valsartan 10mg/160mg) သွေးတိုးကျဆေး
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