Favotan

Amlodipine camsylate, losartan potassium.

Each tablet contains: FAVOTAN (5/50 MG TABLET): Amlodipine Camsylate 7.84 mg (5 mg as Amlodipine) and Losartan Potassium 50.00 mg.
FAVOTAN (5/100 MG TABLET): Amlodipine Camsylate 7.84 mg (5 mg as Amlodipine) and Losartan Potassium 100.00 mg.

Pharmacotherapeutic group: Angiotensin II antagonists, plain (losartan), combinations with dihydropyridine derivatives (amlodipine). ATC code: C09DB06.
Pharmacology: Pharmacodynamics: Amlodipine: The amlodipine component of FAVOTAN 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 in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.
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, hemodynamic 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 beta-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 beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
Losartan: Losartan is a synthetic oral angiotensin - II receptor (type AT₁) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin/angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT₁ receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation.
Losartan selectively blocks the AT₁ receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite EXP-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.
Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is no potentiation of undesirable bradykinin-mediated effects.
During administration of losartan, removal of the angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, PRA and angiotensin II values fell within three days to the baseline values. Both losartan and its principal active metabolite have a far greater affinity for the AT₁-receptor than for the AT₂-receptor. The active metabolite is 10-40 times more active than losartan on a weight for weight basis.
Amlodipine/Losartan: Hypertension studies: The proposed indication for FAVOTAN 5/50 mg and 5/100 mg tablets is the treatment of essential hypertension in patients whose blood pressure is not adequately controlled on amlodipine or losartan monotherapy.
The clinical development programme for FAVOTAN included the following studies where the main efficacy objective was to demonstrate increased blood pressure lowering by the combination treatment over each component administered as monotherapy: HM-ALOS-201: Phase II efficacy and safety study in hypertensive patients. Four combinations of amlodipine camsylate/losartan 5/50 mg, 5/100 mg, 10/50 mg, 10/100 mg compared to amlodipine camsylate 5 mg, 10 mg and losartan 50 mg, 100 mg.
HM-ALOS-301: Phase III efficacy and safety study in patients with hypertension unresponsive to 5 mg amlodipine. Comparison of amlodipine camsylate/losartan 5/50 mg with amlodipine camsylate 10 mg monotherapy.
HM-ALOS-302: Phase III efficacy and safety study in patients with hypertension unresponsive to 100 mg losartan. Comparison of amlodipine camsylate/losartan 5/100 mg with losartan 100 mg monotherapy.
Blood pressure reductions and responder rates at Week 8 are summarised for studies HM-ALOS-201, HM-ALOS-301, and HM-ALOS-302. The same primary efficacy variable (reduction from baseline in sitDBP) and secondary efficacy variables (reductions in sitDBP at 4 weeks, sitSBP and responder rates at 4 and 8 weeks) were used in all studies.
The Phase II efficacy study (HM-ALOS-201) evaluated 4 combinations of amlodipine camsylate/losartan (5/50 mg, 5/100 mg, 10/50 mg and 10/100 mg in comparison with each monotherapy (amlodipine 5 mg or 10 mg, losartan 50 mg or 100 mg) in a double blind factorial design trial. After 8 weeks of treatment, clinically and statistically superior hypotensive effects on sitDBP were achieved with the combinations 5/50 mg, 5/100 mg and 10/50 mg and on sitSBP with the combinations 5/50 mg and 5/100 mg compared to the respective monotherapies. The reductions in sitDBP at 8 weeks were also significantly greater in the 10/100 mg combination group compared to losartan 100 mg monotherapy but not to amlodipine 10 mg monotherapy.
The two Phase III studies for assessment of efficacy of the combination products were of similar design. In the first study (HM-ALOS-301), the combination amlodipine camsylate/losartan 5/50 mg was compared to amlodipine camsylate 10 mg monotherapy and in the second study (HM-ALOS-302) amlodipine camsylate/losartan 5/100 mg was compared to losartan 100 mg monotherapy.
In study HM-ALOS-301 the combination of amlodipine camsylate/losartan 5/50 mg was statistically non-inferior to amlodipine camsylate 10 mg in reducing sitDBP after 8 weeks of treatment in patients unresponsive to 5 mg amlodipine. Clinically relevant reductions of 8.85 mmHg and 9.37 mmHg respectively were obtained. Although, there were no statistically significant differences between treatments for the secondary endpoints, at the end of the study clinically meaningful reductions in sitSBP of 12.22 mmHg and 13.38 mmHg and response rates of 89.13% and 87.91% were achieved in the 5/50 mg combination group and amlodipine 10 mg monotherapy groups respectively.
In study HM-ALOS-302 the combination of amlodipine camsylate/losartan 5/100 mg was statistically superior to losartan 100 mg in reducing sitDBP after 8 weeks of treatment in patients unresponsive to 100 mg losartan. A mean reduction in sitDBP of 11.69 mmHg was achieved with the combination compared to a mean reduction of 3.17 mmHg achieved with losartan 100 mg monotherapy. There were also significant differences in favour of the combination for the secondary efficacy parameters. At the end of the study reductions in sitSBP of 13.37 mmHg and 3.39 mmHg and response rates of 90% and 66.67% were achieved in the 5/100 mg combination group and losartan 100 mg monotherapy groups respectively.
The clinical development program for the FAVOTAN combination products fulfilled the efficacy objective with regard to mean reductions in sitting blood pressure. Over a range of doses used clinically for each monotherapy, the combination of amlodipine camsylate with losartan produced clinically relevant reductions in blood pressure which, at the doses of 5/50 mg, 5/100 mg and 10/50 mg, were significantly greater than those achieved with either monotherapy. In patients whose blood pressure was not optimally controlled with amlodipine 10 mg monotherapy, equivalent blood pressure lowering was obtained with the combination amlodipine 5 mg and losartan 50 mg. In patients whose blood pressure was inadequately controlled on losartan 100 mg monotherapy, an additional blood pressure lowering effect was achieved by combination.
Pharmacokinetics: Amlodipine: Absorption: After intake of therapeutic doses, amlodipine is well absorbed and the maximum plasma concentration is obtained after 6-12 hours. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. Food does not affect the absorption of amlodipine.
Biotransformation/elimination: Plasma half-life is about 30-40 hours and a stable concentration is achieved in 7-8 days. Distribution volume is up to 21 l/kg. Plasma protein binding is high (98%). Plasma elimination is 7 ml/min/kg. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine. Amlodipine half-life will be extended for patients with impaired hepatic function.
A comparison of the pharmacokinetics of amlodipine camsylate with the reference product Norvasc (amlodipine besylate Pfizer Korea) administered as a single oral dose of 5 mg (amlodipine base) showed similar absorption profiles. Mean peak plasma levels of 3.6 and 3.7 ng/ml were attained at means of 6.9 and 7.3 hours after Norvasc and amlodipine camsylate respectively and mean elimination half-lives were 42.2 and 39.3 hours respectively. These values are consistent with prescribing information for Norvasc. Bioequivalence of Hanmi's amlodipine camsylate 5 mg formulation to Norvasc 5 mg was demonstrated.
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 tablets 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 1% 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 poly-exponentially, 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 excretions contribute to the elimination of losartan and its metabolites. Following an oral dose/intravenous administration 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 alcohol-induced hepatic cirrhosis, the plasma levels 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 a creatinine clearance above 10 ml/minute. 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.
Combination: In the studies comparing co-administration and combined administration of amlodipine camsylate and losartan, pharmacokinetic parameters were similar for amlodipine, losartan and the active metabolite EXP-3174 following co- or combined administration of 5/50 mg and 5/100 mg doses. As the therapeutic activity of losartan is largely attributable to the active metabolite, it is considered that the fixed dose combination will be therapeutically equivalent to co-administered amlodipine 5 mg together with losartan 50 mg or 100 mg.
Three Phase 1 clinical trials have been conducted with the amlodipine camsylate/losartan combination drugs to date: HM-ALOS-101, HM-ALOS-103 and HM-ALOS-104.
The HM-ALOS-101 study, conducted to evaluate the possible pharmacokinetic interactions between amlodipine camsylate and losartan potassium after repeated administration alone or in combination, concluded that there was no interaction between amlodipine and losartan when administered in combination compared with being administered alone.
The HM-ALOS-103 and HM-ALOS-104 studies were conducted to evaluate the pharmacokinetic equivalence between single administration of two combination therapies (amlodipine camsylate 5mg/losartan 50mg and amlodipine camsylate 5mg/losartan 100mg, respectively) and co-administration of each single agent. All parameters, area under the plasma concentration/time curve at time t (AUC_t), area under the plasma concentration/time curve at infinity (AUC_∞), and the maximum plasma concentration (C_max) except C_max of losartan 50mg were equivalent between the combination and co-administration groups.
Toxicology: No toxicology study has been conducted with this drug. Non-clinical data with amlodipine and losartan is as follows: Amlodipine: Carcinogenesis: Rats and mice treated with amlodipine in diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day. For rats, the highest dose was, on a mg/m² basis, about twice the maximum recommended human dose (*,based on 50 kg body weight of patient).
Mutagenesis: Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or on chromosome level.
Impairment of Fertility: There was no effect on the fertility of rats treated with amlodipine (64 days for male and 14 days for female prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times* the maximum recommended human dose of 10 mg/day on a mg/m² basis).
*In an assumption that patients weight is 50 kg.
Losartan: Carcinogenesis: Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160- and 90-times (rats) and 30- and 15-times (mice) the exposure of a 50 kg human given 100 mg per day.
Mutagenesis: Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.
Impairment of Fertility: Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea, implantation, and live fetuses at C-section. At 100 mg/kg/day has only shown a decrease in the number of corpora lutea. The relationship of these findings to the drug is uncertain because there was no effect at these dosage levels on implantation, post-implantation loss rate, or live animals at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in human at the maximum recommended human daily dosage (100 mg).

This product is indicated for essential hypertension patients whose blood pressure is not adequately controlled on amlodipine or losartan monotherapy.

The recommended dose of this product is one tablet per day. This product can be taken with or without food. Take this drug with water. It is recommended to take this drug at the same time each day (e.g. every morning).
Dose titration with individual components (i.e. amlodipine and losartan) is recommended before taking this drug. When monotherapy for individual components fails to control a patient's blood pressure, however, direct change to this drug may be considered in cases as follows: 5/50 mg tab: For patients whose blood pressure is not adequately controlled with amlodipine 5 mg or losartan 50 mg alone.
5/100 mg: For patients whose blood pressure is not adequately controlled with amlodipine 5 mg or losartan 100 mg alone.
For convenience, patients receiving losartan and amlodipine from separate tablets/capsules may be switched to this product containing the same individual components.
Renal impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (e.g. creatinine clearance: 20-50 mL/min). This product is not recommended for use in patients with moderate or severe renal impairment (e.g. creatinine clearance: <20 mL/min) and dialysis patients.
Patients with intravascular volume-depletion: This product is not recommended for patients with intravascular volume depletion (e.g. patients under treatment with high dose of diuretics). (Please note Warnings.)
Patients with hepatic impairment: Among patients with anamnesis of hepatic impairments, this product is not recommended for whom require the reduction of losartan (e.g. 25 mg, once daily).
Elderly patients: This product is not recommended for initial treatment for elderly patients with the age of 75 or more because the recommended initial dose of losartan is 25 mg, once daily.
Pediatric patients: This product is not recommended for patients under the age of 18 due to the lack of data on safety and efficacy for them.
Children and Pediatric Use: This drug is not recommended for pediatric patients under the age of 18 due to the lack of data on safety and efficacy for them.
Geriatric Use: This product is not recommended for initial treatment for elderly patients with the age of 75 or more because the recommended initial dose of losartan is 25 mg, once daily.
Effect on Clinical Test: Pulse rate and laboratory test conducted alter 8 weeks of amlodipine/losartan treatment have shown delayed pulse when comparing to baseline, without clinical significance. Elevations in serum creatinine and hepatic enzyme have been observed in some patients, but the symptoms didn't require the monitor of specific clinical test data.

OVERDOSE AND TREATMENT: No overdose regarding this drug has been reported. Amlodipine or losartan overdose cases are as follows: Amlodipine: Overdose with amlodipine may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. In addition, fatal consequences that led to shock state or caused shock have been observed because of marked and potentially prolonged systemic hypotension that lasted for a long time. The administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10 mg has significantly decreased amlodipine absorption. Gastric lavage may be helpful in some cases. Clinically severe hypotension due to the overdose of this drug calls for active cardiovascular support, including frequent monitoring of cardiac and respiratory function and ensuring sufficient fluid volume like blood and urine output by pulling the limbs on a place higher than the body. 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. Amlodipine is unlikely to be removed by hemodialysis because it is highly combined with protein.
Losartan: Significant lethality was observed in mice and rats alter the administration of 1,000 mg/kg/single dose and 2,000 mg/kg/single dose, respectively. (About 44 and 170 times the maximum recommended human dose on a mg/m² basis.) Few data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan nor its active metabolite can be removed by hemodialysis.

Patients with hypersensitivity to the active substances or to dihydropyridine derivatives.
Pregnant women, women with childbearing potential or nursing mothers (see Use in Pregnancy & Lactation).
Patients with severe hepatic impairment.
Patients with severe aortic valvular stenosis.
Patient with shock.

Fetal/Neonatal Morbidity and Mortality: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and even death when they are administered to pregnant women. Several dozen cases have been reported in the world literature in among patients who were taking ACE (angiotensin converting enzyme) inhibitors. When pregnancy is confirmed, therefore, discontinue the drug immediately.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal 11mb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of FAVOTAN as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, FAVOTAN should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of In utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Losartan has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation.
Patients with Intravascular Volume Depletion: For losartan, patients with intravascular volume depletion (e.g. those treated with diuretics), hypotension may occur after the initiation of therapy with this product.
Therefore, these conditions should be treated before administering the product. For patients who require losartan 25 mg once daily, this product is not recommended for use because it does not contain 25 mg of losartan. (See Dosage & Administration.)

Administration with Special Precautions: Patients with intravascular volume depletion (e.g. patients who are taking diuretic drug); Patients under stringent salt-restriction; Mild to severe renal impairment patients (e.g. creatinine clearance <20 mL/min) or dialysis patients; Hyperkalemia patients.
General Precautions: Slight blood pressure lowering effect remains after the discontinuation of amlodipine because the half-life of its blood concentration is long. Therefore, use caution to determine dose and dosing interval, and monitor patients' condition when administering other blood pressure depressant after discontinuing amlodipine.
Hypersensitivity: angioedema (refer to Adverse Reactions).
Patients with Impaired Hepatic Function: Because significantly increased plasma concentrations of losartan in cirrhotic patients has been reported, this drug is not recommended for patients with impaired liver function if a lower dose should be considered in these patients.
Patients with Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported. These changes in renal function were reversible upon the discontinuation of the therapy. For patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with losartan. Some studies have reported that ACE inhibitors have increased blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis. Similar symptoms have been reported with losartan, but these symptoms were reversible upon the discontinuation of the drug.
Hyperkalemia (serum potassium >5.5 mmol/L) has occurred among 1.5% of patients with losartan monotherapy, but the discontinuation of losartan was not necessary. Concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium, or other agents which may lead to increase in potassium level (e.g. heparin, food or beverages containing high potassium amount such as 100% orange juice) should be carefully considered (especially for elderly patients or patients with impaired renal function) for administration. Serum potassium level should also be monitored with caution.
Losartan may lead to transient hypotension accompanying shock, apsychia, and dyspnea. In that case, therefore, discontinue administration and provide the patient with appropriate treatment. In particular, doctors need to fully monitor the condition of patients as follows: Patients required 25 mg losartan per day should not receive the drug because this drug does not contain 25 mg of losartan; Patients with intravascular volume depletion (e.g. patients getting diuretic treatment); Patients under stringent salt-restriction; Mild to severe renal impairment patients (e.g. creatinine clearance: <20 mL/min) or patients undergoing dialysis.
Effects on the Ability to Drive and Use Machines: Dizziness may occur due to blood pressure lowering effect. So, patients should not operate machines, which may cause risk while taking this drug (e.g., driving or activities in high altitude).

Pregnant women: The safety of amlodipine for pregnant women has not been established. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at the dose 50 times the maximum recommended human dose. The potential risk of losartan for fetus should not be excluded considering the mechanism of action of Angiotensin II inhibitors. Animal studies have shown that losartan has caused damage and death to fetus and newborn babies. This appears to be attributed to impacts on the renin angiotensin-aldosterone system. For human fetus, kidney perfusion due to the development of renin angiotensin-aldosterone system becomes active from the second trimester of pregnancy. So, the administration of this drug during the second and third trimester of pregnancy increases risk to fetus. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy may cause injury or even death to fetus. Therefore, pregnant women must not receive this drug and immediately discontinue the drug once pregnancy is confirmed.
Nursing Mother: While it is not known whether amlodipine and/or losartan are/is excreted in human milk, significant levels of amlodipine and/or losartan active metabolite were shown to be present in animal milk. Therefore, nursing mothers should not receive this drug.

The safety of FAVOTAN has been evaluated in three controlled clinical studies with 646 patients with essential hypertension, 325 of whom received amlodipine/losartan in combination during weeks (Trial 201, 301 and 302). Adverse reactions have been ranked under headings of frequency using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000). (See Table 1.)

Click on icon to see table/diagram/image

Additional Safety Information from single active ingredient: Adverse drug reactions previously reported with individual components (amlodipine or losartan) may occur while taking the drug, even if not observed in clinical trials of this product.
Amlodipine: In general, treatment with amlodipine was well-tolerated. In placebo-controlled clinical trials with hypertension patients and/or angina pectoris patients, most frequently reported adverse events which are not included as previously mentioned are as follows: General system: fatigue.
Cardiovascular system: oedema.
Gastrointestinal system: abdominal pain.
No abnormal findings on laboratory test with clinical significance in the clinical trials associated with amlodipine were reported.
Following adverse events were reported with relatively low frequency during the post-marketing period: Autonomic Nervous System: mouth dryness, hyperhidrosis.
General: asthenia, back pain, malaise, pain, weight gain, weight decrease.
Cardiovascular: hypotension, syncope.
Central and Peripheral Nervous system: hypertonia, hyperesthesia/paresthesia, neuropathy peripheral, tremor.
Endocrine system: gynecomastia.
Gastrointestinal: change in bowel habit, gastritis, gingival hyperplasia, pancreatitis, vomiting.
Metabolic and Nutritional: hyperglycemia.
Musculoskeletal System: arthralgia, muscle cramps, myalgia.
Hemopoietic: purpura, thrombocytopenia.
Psychiatric: impotence, insomnia, dysthymic disorder.
Respiratory System: cough, dyspnea, rhinitis.
Skin and Appendages: alopecia, dyschromia, urticaria.
Special senses: dysgeusia, tinnitus.
Urinary System: micturition frequency, micturition disorder, nocturia.
Vascular system: vasculitis.
Vision: vision disorder.
Leukocytes/R.E.S: neutropenia.
Allergic reactions including pruritus, rash, angioedema, pleomorphism, erythema, hepatitis, jaundice, and hepatic enzymes elevations have been rarely reported, and most of them were related to cholestasis. For some cases, severe enough to require hospitalization have been reported in association with the use of amlodipine. The relationship of most of the events with amlodipine, however, is not certain.
Like other calcium channel inhibitors, adverse reactions as follows have been rarely reported. Whether they came from underlying disease or medication, however, could not be determined: myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation), and chest pain.
Other reactions as follows have been reported from the use of amlodipine: Cardiovascular system: decreased blood pressure, sinoatrial block or atrioventricular block can sometimes occur, abdominal discomfort may be rarely observed.
Gastrointestinal system: epigastric pain, diarrhea, loose stool, and constipation may sometimes occur.
Skin: erythralgia, maculopapular rash may rarely occur.
Others: sometimes pisometacarpeum, burning sensation, glucose tolerance disorder, weakness.
Losartan: The following adverse events were also reported at a rate of 1% or greater in patients treated with losartan under clinical trial with losartan monotherapy for adult patients with essential hypertension: muscle cramp, back pain, melosalgia, nasal congestion, upper respiratory infection, sinusitis, diarrhea, cough, sinus disorder, pharyngitis, myalgia, insomnia, fatigue, edema, swelling, and abdominal pain. A patient with known hypersensitivity to aspirin and penicillin, when treated with losartan, was withdrawn from study due to angioedema (swelling of the lips and eyelids and facial rash) which returned to normal 5 days after therapy was discontinued.
Superficial peeling of palms and hemolysis were reported in one subject who has received losartan. In addition to the adverse events mentioned previously, potentially significant adverse events occurred during the clinical monotherapy of losartan (<1% of patients or more than two patients) are listed as follows. It has not been determined whether these events were related to the drug: General system: facial edema, fever, orthostatic effects, syncope.
Cardiovascular system: angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, and ventricular fibrillation.
Gastrointestinal system: anorexia, constipation, dental pain, dry mouth, gastritis, vomiting.
Hematologic system: anemia.
Metabolic system: gout.
Musculoskeletal system: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness.
Nervous System Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, nightmare, hypoesthesia, decreased sexual desire, memory impairment, migraine, nervousness, paresthesia, peripheral neuropathy, panic disorder, sleep disorder, tremor.
Respiratory System: bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion.
Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, photosensitivity, pruritus, rash, sweating, urticaria.
Special senses: blurred vision, burning/stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity.
Urinary System: Impotence, nocturia, urinary tract infection.
Persistent dry cough associated with ACE-inhibitor use has been reported. This can be a cause of the discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (n=97) or hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown as follows: (See Table 2.)

Click on icon to see table/diagram/image

The studies have demonstrated that the recurrence of cough associated with losartan therapy, among patients coughed after taking ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo treatment. Cases of cough, including positive re-challenges, have been reported with the use of losartan in post-marketing experience.
The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: angioedema (swelling of the larynx and glottis that can cause airway obstruction, swelling of the lace/lips/pharynx/tongue) has been rarely reported in patients treated with losartan; some of these patients have previously experienced angioedema with other drugs including ACE inhibitors as well. Vasculitis (Henoch-Schonlein purpura) and anaphylactic reactions have once been reported.
Digestive: Hepatitis (reported rarely), hepatic dysfunction.
General disorder and Administration Site Conditions: malaise.
Hematologic system: anemia, thrombocytopenia (rarely reported).
Musculoskeletal system: rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Nervous system disorder: dysgeusia.
Respiratory: dry cough.
Skin: erythroderma.
Metabolic and Nutrition: hyperkalemia, hyponatremia have been reported in patients who have received losartan alone.
ALT elevations occurred rarely, but disappeared with the discontinuation of treatment.
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of losartan.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with losartan.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (approximately 0.11 grams percent and 0.09 volume percent, respectively) occurred in patients treated with losartan alone, but were rarely of clinical importance. No patients were discontinued the treatment due to anemia.
Liver Function Tests: Occasional elevations of liver enzymes or serum bilirubin have occurred. One patient (<0.1%) discontinued due to abnormal liver function among patients with essential hypertension treated with losartan alone.
Syncope, Apsychia: Transient symptomatic shock associated with hypotension can be occurring. Treatment should be discontinued and proper actions should be taken with the onset of related symptoms.
Acute hepatitis or fulminant hepatitis can be occurring. Treatment should be discontinued and proper actions should be taken with the onset of related symptoms.
Anaphylactic reaction.

Blood pressure lowering effect of FAVOTAN may increase with other antihypertensive agents. Therefore, concomitant medication should be decided carefully.
Drug interactions reported with amlodipine or losartan single agents are summarized as follows: Amlodipine: Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory medicines, antibiotics and oral hypoglycemic medicines.
In vitro human plasma data indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Effect of other agents on amlodipine tablets: Cimetidine: The co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit juice: The co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Aluminium/Magnesium (antacid): The co-administration of the antacid Aluminium/Magnesium with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Effect of amlodipine tablets on other agents: Atorvastatin: The co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.
Digoxin: The co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: The co-administration of amlodipine with warfarin did not change the warfarin-prothrombin response time.
Cyclosporin: In pharmacokinetics study for cyclosporine, the co-administration of amlodipine did not significantly change the pharmacokinetics of cyclosporin.
Losartan: No significant drug interactions have been found in clinical pharmacokinetics study with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However antihypertensive effects of losartan are potentiated by addition of hydrochlorothiazide. Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite. In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of the drug to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan concentration. The pharmacodynamic interaction between losartan and inhibitors of P450 2C9 have not been examined. Subjects who were not able to metabolize this drug have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggested that the major enzyme that plays an important role in converting the drug to its active metabolite is not P450 3A4, but P450 2C9.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increase in serum potassium.
In patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), the co-administration of angiotensin II receptor antagonists like losartan may result in the further deterioration of renal function. These effects are usually reversible. NSAIDs including selective COX-2 inhibitors may diminish the effect of angiotensin II receptor antagonists like losartan. This interaction should be given consideration in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with angiotensin II receptor antagonists.

Do not change container to store contents. Keep only in the original one in order to avoid misuse and keep the product quality.
Store in an airtight container at room temperature (Store below 30°C).
Expiry date: 24 months from manufacture date.

Angiotensin II 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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