Losagen

Losartan potassium.

Losartan potassium Tablets is an angiotensin II receptor (type AT1) antagonist. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[p -(o 1H -tetrazol-5-ylphenyl) benzyl]imidazole-5-methanol monopotassium salt.
Its empirical formula is C₂₂H₂₂ClKN₆O.
Losartan potassium is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.
Losartan Potassium is available as tablets for oral administration containing 50 mg or 100 mg of losartan potassium.
Excipients/Inactive Ingredients: Cellulose Microcrystalline, Lactose Monohydrate, Starch pregelatinized, Low substituted hydroxyl propyl cellulose, Crospovidon, Magnesium stearate, and Opadry white (Hypromellose, Titanium dioxide & carnauba wax).

Pharmacology: Pharmacodynamics: Mechanism of Action: Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Pharmacodynamics and Clinical Effects: Adult Hypertension: Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.
In a single-dose study in normal volunteers, losartan had no effects on glomerular filtration rate, renal plasma flow or filtration fraction. In multiple-dose studies in hypertensive patients, there were no notable effects on systemic or renal prostaglandin concentrations, fasting triglycerides, total cholesterol or HDL-cholesterol or fasting glucose concentrations. There was a small uricosuric effect leading to a minimal decrease in serum uric acid (mean decrease <0.4 mg/dL) during chronic oral administration.
The antihypertensive effects of Losartan Potassium Tablets were demonstrated principally in 4 placebo-controlled, 6- to 12- week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparisons of two doses (50-100 mg/day) as once-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Three additional studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination.
The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of losartan and 334 to placebo. The 10- and 25-mg doses produced some effect at peak (6 hours after dosing) but small and inconsistent trough (24 hour) responses. Doses of 50, 100 and 150 mg once daily gave statistically significant systolic/diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5-10.5/3.5-7.5 mmHg, with the 150-mg dose giving no greater effect than 50-100 mg. Twice-daily dosing at 50-100 mg/day gave consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately, larger than trough effects, with the trough-to-peak ratio for systolic and diastolic responses 50-95% and 60-90%, respectively.
Addition of a low dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily resulted in placebo-adjusted blood pressure reductions of 15.5/9.2 mmHg.
Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65, had generally similar responses. Losartan Potassium Tablets was effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population).
The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials.
Reduction in the Risk of Stroke: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a multinational, double-blind study comparing Losartan Potassium Tablets and atenolol in 9193 hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial infarction or stroke within six months prior to randomization were excluded. Patients were randomized to receive once daily Losartan Potassium Tablets 50 mg or atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of Losartan Potassium Tablets or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (e.g., increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium-channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure.
Of the randomized patients, 4963 (54%) were female and 533 (6%) were Black. The mean age was 67 with 5704 (62%) age ≥65. At baseline, 1195 (13%) had diabetes, 1326 (14%) had isolated systolic hypertension, 1469 (16%) had coronary heart disease, and 728 (8%) had cerebrovascular disease. Baseline mean blood pressure was 174/98 mmHg in both treatment groups. The mean length of follow-up was 4.8 years. At the end of study or at the last visit before a primary endpoint, 77% of the group treated with Losartan Potassium Tablets and 73% of the group treated with atenolol were still taking study medication. Of the patients still taking study medication, the mean doses of Losartan Potassium Tablets and atenolol were both about 80 mg/day, and 15% were taking atenolol or losartan as monotherapy, while 77% were also receiving hydrochlorothiazide (at a mean dose of 20 mg/day in each group). Blood pressure reduction measured at trough was similar for both treatment groups but blood pressure was not measured at any other time of the day. At the end of study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/81.3 mmHg for the group treated with Losartan Potassium Tablets and 145.4/80.9 mmHg for the group treated with atenolol [the difference in systolic blood pressure (SBP) of 1.3 mmHg was significant (p<0.001), while the difference of 0.4 mmHg in diastolic blood pressure (DBP) was not significant (p=0.098)].
Table 1 shows the results for the primary composite endpoint and the individual endpoints. The primary endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an intention-to-treat (ITT) approach. The table shows the number of events for each component in two different ways. The Components of Primary Endpoint (as a first event) counts only the events that define the primary endpoint, while the Secondary Endpoints count all first events of a particular type, whether or not they were preceded by a different type of event. (See Table 1.)

Click on icon to see table/diagram/image

Although the LIFE study favored Losartan Potassium Tablets over atenolol with respect to the primary endpoint (p=0.021), this result is from a single study and, therefore, is less compelling than the difference between Losartan Potassium Tablets and placebo. Although not measured directly, the difference between Losartan Potassium Tablets and placebo is compelling because there is evidence that atenolol is itself effective (vs. placebo) in reducing cardiovascular events, including stroke, in hypertensive patients.
Other clinical endpoints of the LIFE study were: total mortality, hospitalization for heart failure or angina pectoris, coronary or peripheral revascularization procedures, and resuscitated cardiac arrest. There were no significant differences in the rates of these endpoints between the Losartan Potassium Tablets and atenolol groups.
For the primary endpoint and stroke, the effects of Losartan Potassium Tablets in patient subgroups defined by age, gender, race and presence or absence of isolated systolic hypertension (ISH), diabetes, and history of cardiovascular disease (CVD). Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
Race: In the LIFE study, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with Losartan Potassium Tablets. In the subgroup of Black patients (n=533; 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on Losartan Potassium Tablets. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study provides no evidence that the benefits of Losartan Potassium Tablets on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients.
Pharmacokinetics: General: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of 14C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.
The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.
The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulate in plasma upon repeated once-daily dosing.
Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).
The pharmacokinetics of losartan and its active metabolite were also determined after IV doses of each component separately in healthy volunteers. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.
Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Special Populations: Geriatric and Gender: Losartan pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary (see Dosage & Administration).
Race: Pharmacokinetic differences due to race have not been studied (see Precautions and Pharmacology: Pharmacodynamics: Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race).
Renal Insufficiency: Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50-90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55-85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis.
Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about 2-times higher. A lower starting dose is recommended for patients with a history of hepatic impairment (see Dosage & Administration).
Drug Interactions: In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE-inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) as compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Losartan and other agents that affect the RAAS. Do not co-administer aliskiren with Losartan in patients with diabetes. Avoid use of aliskiren with Losartan in patients with renal impairment (GFR <60 ml/min).

Hypertension: Losartan Potassium Tablets is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics.
Hypertensive Patients with Left Ventricular Hypertrophy: Losartan Potassium Tablets is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy. (See Precautions and Pharmacology: Pharmacodynamics: Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race.)

Adult Hypertensive Patients: Losartan potassium tablets may be administered with or without food.
Losartan potassium tablets may be administered with other anti-hypertensive agents.
Hypertension: The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once daily.
For patients with intravascular volume-depletion (e.g., those treated with high-dose diuretics), a starting dose of 25 mg once daily should be considered (see Precautions).
No initial dosage adjustment is necessary for elderly patients up to 75 years of age, or for patients with mild renal impairment. For patients above 75 years of age, patients with moderate to severe renal impairment and patients on dialysis, a lower starting dose of 25 mg is recommended. A lower dose should be considered for patients with a history of hepatic impairment (see Precautions).
Reduction in the Risk of Stroke in Hypertensive Patients with Left Ventricular Hypertrophy: The usual starting dose is 50 mg of Losartan tablets once daily. A low dose of hydrochlorothiazide should be added and/or the dose of Losartan Potassium tablets should be increased to 100 mg once daily based on blood pressure response.

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m² basis.
Limited data are available in regard to overdosage in humans. The most likely manifestation of overdose 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.

Losartan should not be administrated with Aliskiren in patients with diabetes. Losartan Potassium Tablets is contraindicated in patients who are hypersensitive to any component of this product.

Hypotension Volume-Depleted Patients: In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with Losartan Potassium Tablets. These conditions should be corrected prior to administration of Losartan Potassium Tablets, or a lower starting dose should be used (see Dosage & Administration).

General: Hypersensitivity: Angioedema. (See Post-Marketing Experience: Impaired Hepatic Function under Adverse Reactions).
Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with impaired liver function (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with Losartan Potassium Tablets; in some patients, these changes in renal function were reversible upon discontinuation of therapy.
In patients whose renal function may depend on the activity of the 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 Potassium Tablets.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Similar effects have been reported with Losartan Potassium Tablets; in some patients, these effects were reversible upon discontinuation of therapy.
Electrolyte Imbalance: Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with Losartan Potassium Tablets as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see Adverse Reactions).
Information for Patients: Potassium Supplements: A patient receiving Losartan Potassium Tablets should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician (see Interactions).
Race: Based on the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study, the benefits of Losartan on cardiovascular morbidity and mortality compared to atenolol do not apply to Black patients with hypertension and left ventricular hypertrophy although both treatment regimens effectively lowered blood pressure in Black patients. In the overall LIFE study population (n=9193), treatment with Losartan resulted in a 13.0% risk reduction (p=0.021) as compared to atenolol for patients reaching the primary composite endpoint of the combined incidence of cardiovascular death, stroke, and myocardial infarction. In this study, Losartan decreased the risk of cardiovascular morbidity and mortality compared to atenolol in non-Black, hypertensive patients with left ventricular hypertrophy (n=8660) as measured by the primary endpoint of the combined incidence of cardiovascular death, stroke, and myocardial infarction (p=0.003). In this study, however, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with Losartan (p=0.03). In the subgroup of Black patients (n=533; 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 25.9 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 41.8 per 1000 patient-years) on Losartan.
Use in pregnancy: Use of drugs that act on the renin-angiotensin system during the second and third trimester of pregnancy reduces fetal renal function and increases feral and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losartan Potassium Tablets as soon as possible.
Use in lactation: It is not known whether losartan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: Safety and effectiveness in children have not been established.
Neonates with a history of in utero exposure to Losartan: If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Use in the Elderly: In clinical studies there was no age-related difference in the efficacy or safety profile of losartan.
Presently there is limited clinical experience in patients above 75 years of age, a lower starting dose of 25 mg once daily is recommended.

Pregnancy: Use of drugs that act on the renin-angiotensin system during the second and third trimester of pregnancy reduces fetal renal function and increases feral and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losartan Potassium Tablets as soon as possible.
When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, Losartan potassium Tablets should be discontinued as soon as possible.
Lactation: It is not known whether losartan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Losartan has been found to be generally well tolerated in controlled clinical trials for hypertension; side effects have usually been mild and transient in nature and have not required discontinuation of therapy. The overall incidence of side effects reported with Losartan was comparable to placebo.
In controlled clinical trials for essential hypertension, dizziness was the only side effect reported as drug related that occurred with an incidence greater than placebo in one percent or more of patients treated with Losartan. In addition, dose-related orthostatic effects were seen in less than one percent of patients. Rarely, rash was reported, although the incidence in controlled clinical trials was less than placebo.
In these double-blind controlled clinical trials for essential hypertension, the following adverse experiences reported with Losartan occurred in ≥1 percent of patients, regardless of drug relationship: (See Table 2).

Click on icon to see table/diagram/image

Losartan was generally well tolerated in a controlled clinical trial in hypertensive patients with left ventricular hypertrophy. The most common drug-related side effects were dizziness, asthenia/fatigue, and vertigo.
In the LIFE study, among patients without diabetes at baseline, there was a lower incidence of new onset diabetes mellitus with Losartan as compared to atenolol (242 patients versus 320 patients versus 320 patients, respectively, p<0.001). Because there was no placebo group included in the study, it is not known if this represents a beneficial effect of Losartan or an adverse effect of atenolol.
Losartan was generally well tolerated in a controlled clinical trial in type 2 diabetic patients with proteinuria. The most common drug-related side effects were asthenia/fatigue, dizziness, hypotension and hyperkalemia (see Hypotension and Electrolyte/Fluid Imbalance under Precautions).
The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Anaphylactic reactions, 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 rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.
Gastrointestinal: Hepatitis (reported rarely), liver function abnormalities, vomiting.
General disorders and administration site conditions: Malaise.
Hematologic: Anemia, thrombocytopenia (reported rarely).
Musculoskeletal: Myalgia, arthralgia.
Nervous System/Psychiatric: Migraine, dysgeusia.
Reproductive system and breast disorders: Erectile dysfunction/impotence.
Respiratory: Cough.
Skin: Urticaria, pruritus, erythroderma, photosensitivity.
Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Losartan Potassium Tablets.
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 Potassium Tablets alone (see Impaired Renal Function under Precautions).
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.11 grams percent and 0.09 volume percent, respectively) occurred frequently in patients treated with Losartan Potassium Tablets alone, but were rarely of clinical importance. No patients were discontinued due to anemia.
Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with Losartan Potassium Tablets alone, one patient (<0.1%) was discontinued due to these laboratory adverse experiences.

In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE-inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) as compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Losartan Potassium Tablets and other agents that affect the RAAS. Do not co-administer aliskiren with Losartan Potassium Tablets in patients with diabetes. Avoid use of aliskiren with Losartan Potassium Tablets in patients with renal impairment (GFR <60 ml/min).

Store at below 30°C and protect from moisture.

Angiotensin II Antagonists

C09CA01 - losartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.

POM