Losartan Potassium
(British Approved Name Modified, US Adopted Name, rINNM)
Drug Nomenclature
INNs in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In US.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Losartan Potassium). A white to off-white powder. Freely soluble in water; slightly soluble in acetonitrile; soluble in isopropyl alcohol.
Adverse Effects
Adverse effects of losartan have been reported to be usually mild and transient, and include dizziness, headache, and dose-related orthostatic hypotension. Hypotension may occur particularly in patients with volume depletion (for example those who have received high-dose diuretics). Impaired renal function and, rarely, rash, urticaria, pruritus, angioedema, and raised liver enzyme values may occur. Hyperkalaemia, myalgia, and arthralgia have been reported. Losartan appears less likely than ACE inhibitors to cause cough. Other adverse effects that have been reported with angi-otensin II receptor antagonists include respiratory-tract disorders, back pain, gastrointestinal disturbances, fatigue, and neutropenia. Rhabdomyolysis has been reported rarely.
Angioedema. Angioedema is a recognised adverse effect of ACE inhibitors and is thought to be due to accumulation of bradykinins. Although angiotensin II receptor antagonists were thought to lack effects on bradykinin, several have been associated with reports of angioedema, and increased levels of bradykinin have been shown with losartan. In some cases patients had previously experienced angioedema with ACE inhibitors and caution is advised when using angiotensin II receptor antagonists in such patients
Effects on the blood. Symptomatic anaemia occurred in a patient with a renal transplant 6 weeks after starting therapy with losartan. Decreased haemoglobin concentrations have also been reported in patients with severe renal impairment undergoing haemodialysis.
Immune thrombocytopenia has been reported in a patient shortly after starting losartan.
Effects on the liver. Raised liver enzyme values have occurred rarely in patients receiving losartan. Severe, acute hepatotoxicity developed in a patient 1 month after losartan was substituted for enalapril because of ACE inhibitor-induced cough. The patient recovered when losartan was withdrawn but symptoms and raised liver enzyme concentrations recurred following rechallenge. Acute, reversible hepatotoxicity also occurred in a patient who had been taking losartan 150 mg daily for 6 weeks. A case of cholestatic jaundice associated with irbesartan therapy has also been reported; the jaundice resolved slowly once irbesartan was withdrawn.
Effects on the skin. Atypical cutaneous lymphoid infiltrates developed in 2 patients receiving losartan for hypertension. In both cases the lesions disappeared within a few weeks of stopping the drug.
Henoch-Schonlein purpura has been reported in patients taking losartan; in 1 case the reaction recurred on rechallenge. A purpuric rash with evidence of vasculitis has been reported with candesartan; the patient also developed acute nephritis. A polycyclic rash associated with systemic illness developed in a patient who had been taking irbesartan for 2 years; improvement occurred within 2 days of stopping the drug. There has also been a report of a number of patients in whom psoriasis either developed or was exacerbated following treatment with an angiotensin II receptor antagonist; the drugs involved included candesartan, irbesartan, losartan, and valsartan. In most cases the lesions regressed after the drug was withdrawn.
Effects on taste. Taste disturbances, in some cases progressing to complete taste loss, have occurred in patients receiving losartan for hypertension. In each case taste returned to normal after stopping losartan therapy. Taste impairment has also been reported with both candesartan and valsartan in healthy subjects.
Hypersensitivity. See Angioedema,and Effects on the Skin, above.
Migraine. Severe migraine has been reported in a patient after use of losartan. The patient had no history of migraine and symptoms recurred on rechallenge. However, angiotensin II receptor antagonists have also been reported to reduce the incidence of migraine (see under Uses and Administration, below).
Pancreatitis. Acute pancreatitis has been reported in 2 patients receiving losartan. However, 1 of the patients subsequently developed pancreatitis unrelated to losartan. The other patient had also developed acute pancreatitis during enalapril therapy. Acute pancreatitis has also been reported with irbesartan; the patient was also taking hydrochlorothiazide but in a dose lower than that usually associated with thiazide-induced pancreatitis. Biochemical alterations suggestive of acute pancreatitis have been reported after telmisartan overdosage.
Vasculitis. For mention of the development of Henoch-Schonlein purpura and other vasculitic disorders in patients receiving angiotensin II receptor antagonists see Effects on the Skin, above.
Precautions
Losartan is contra-indicated in pregnancy (see below). It should be used with caution in patients with renal artery stenosis. Losartan is excreted in urine and in bile and reduced doses may therefore be required in patients with renal impairment and should be considered in patients with hepatic impairment. Patients with volume depletion (for example those who have received high-dose diuretic therapy) may experience hypotension; volume depletion should be corrected before starting therapy, or a low initial dose should be used. Since hyperkalaemia may occur, serum-potassium concentrations should be monitored, especially in the elderly and patients with renal impairment, and potassium-sparing diuretics should generally be avoided.
Diabetes m el I it us. After reports of reduced awareness of hypoglycaemia in type 1 diabetic patients receiving losartan, a study in healthy subjects found that losartan slightly attenuated the symptomatic and hormonal responses to hypoglycaemia. Although the clinical significance was not established, the authors recommended that losartan should be used with caution in diabetics with reduced awareness of hypoglycaemia. However, losartan and other angiotensin II receptor antagonists may have a role in type 2 diabetics with nephropathy (see Kidney Disorders under Uses, below). There is also some evidence that angiotensin II receptor antagonists may prevent the development of diabetes in non-diabetic patients.
Pregnancy. Losartan is contra-indicated in pregnancy since it has been associated with fetal toxicity in animal studies and other drugs that act on the renin-angiotensin system, such as ACE inhibitors, have been associated with fetal toxicity in humans. Oligohydramnios with subsequent fetal death occurred in a patient who received losartan during weeks 20 to 31 of pregnancy; the effects on the fetus were similar to those reported with ACE inhibitors. A number of similar cases have subsequently been reported with losartan, candesartan, and valsartan.
Interactions
The antihypertensive effects of losartan may be potentiated by drugs or other agents that lower blood pressure. An additive hyperkalaemic effect is possible with potassium supplements, potassium-sparing diuretics, or other drugs that can cause hyperkalaemia; losartan and potassium-sparing diuretics should not generally be given together. NSAIDs should be used with caution in patients taking losartan as the risk of renal impairment may be increased, particularly in those who are inadequately hydrated; use of NSAIDs may also attenuate the hypotensive effect of losartan. Losartan and some other angiotensin II receptor antagonists are metabolised by cytochrome P450 isoenzymes and interactions may occur with drugs that affect these enzymes.
Lithium. For reference to a possible interaction between lithium and angiotensin II receptor antagonists.
Pharmacokinetics
Losartan is readily absorbed from the gastrointestinal tract after oral doses, but undergoes substantial first-pass metabolism resulting in a systemic bioavailability of about 33%. It is metabolised to an active carboxylic acid metabolite E-3174 (EXP-3174), which has greater pharmacological activity than losartan; some inactive metabolites are also formed. Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of losartan and E-3174 occur about 1 hour and 3 to 4 hours, respectively, after an oral dose. Both losartan and E-3174 are more than 98% bound to plasma proteins. Losartan is excreted in the urine, and in the faeces via bile, as unchanged drug and metabolites. About 4% of an oral dose is excreted unchanged in urine and about 6% is excreted in urine as the active metabolite. The terminal elimination half-lives of losartan and E-3174 are about 1.5 to 2.5 hours and 3 to 9 hours, respectively.
Uses and Administration
Losartan is an angiotensin II receptor antagonist with antihypertensive activity due mainly to selective blockade of AT1 receptors and the consequent reduced pressor effect of angiotensin II. It is used in the management of hypertension, particularly in patients who develop cough with ACE inhibitors and to reduce the risk of stroke in patients with left ventricular hypertrophy, and in the treatment of diabetic nephropathy (see Kidney Disorders, below). It has also been tried in heart failure (below) and in myocardial infarction.
Losartan is given orally as the potassium salt. The maximum hypotensive effect is achieved in about 3 to 6 weeks after starting treatment.
In hypertension the usual dose of losartan potassium is 50 mg once daily. The dose may be increased, if necessary, to 100 mg daily as a single dose or in two divided doses. An initial dose of 25 mg once daily should be given to patients with intravascular fluid depletion, and is recommended in the UK in patients over 75 years of age. Similar reductions may be appropriate in patients with hepatic or renal impairment (but see below). There are limited data on the use of losartan in children with hypertension. In the UK, the recommended initial dose of losartan potassium for children weighing between 20 and 50 kg is 25 mg once daily; this may be increased to a maximum of 50 mg once daily. In the USA, children aged 6 years or over may be given an initial dose of 700 micrograms/kg once daily, with a maximum of 50 mg, adjusted according to response.
There are no data to recommend doses for children with glomerular filtration rate below 30 mL/min per 1.73 m, and in the UK losartan should not be given to children with hepatic impairment. In diabetic nephropathy losartan potassium is given in an initial dose of 50 mg once daily, increased to 100 mg once daily depending on the blood pressure.
Administration in hepatic or renal impairment. Licensed product information in both the UK and the USA recommend a reduced dose of losartan in patients with hepatic impairment; the suggested initial dose in the USA is 25 mg daily. In the UK an initial dose of 25 mg daily is also recommended in those with moderate to severe renal impairment (creatinine clearance less than 20 mL/minute), but in the USA dosage reduction is considered unnecessary.
Cardiac arrhythmias. See under Heart Failure, below.
Cardiovascular risk reduction. The benefits of ACE inhibitors in patients with high cardiovascular risk are well-established (see Cardiovascular Risk Reduction) but whether angiotensin II receptor antagonists have comparable effects is less clear. In the LIFE study, losartan reduced cardiovascular events more than a beta blocker (atenolol), despite a similar effect on blood pressure. In VALUE, there was no difference in the incidence of cardiovascular events between valsartan and a calcium-channel blocker (amlodipine), although the calcium-channel blocker reduced blood pressure to a greater extent. However, in hypertensive stroke patients, eprosartan reduced the risk of cardiovascular and cerebrovascular events more than another calcium-channel blocker (nitrendipine); blood pressure reduction was similar with both drugs. A study comparing telmisartan with the ACE inhibitor ramipril, found that both reduced cardiovascular events to a similar extent; there was no additional benefit in patients given both drugs.
Based on the results of VALUE, there has been concern that angiotensin II receptor antagonists may increase the risk of myocardial infarction, but a systematic review was unable to confirm a significant effect.
Erythrocytosis. For reference to the use of losartan in the management of secondary erythrocytosis, see under ACE inhibitors
Heart failure. Diuretics, ACE inhibitors, and beta blockers are the standard drugs used in the management of heart failure. Angiotensin II receptor antagonists have been studied as an alternative to ACE inhibitors since they may be better tolerated. In the ELITE study, which compared losartan with cap-topril, both drugs had similar effects on renal function but other adverse effects were fewer with losartan and there was also a reduction in mortality in patients receiving losartan. However, the larger ELITE II study failed to confirm any survival benefit with losartan, and studies with losartan and valsartan in patients with heart failure following myocardial infarction have also failed to show superiority over ACE inhibitors. ACE inhibitors therefore remain first-line therapy, although angiotensin II receptor antagonists may be used as an alternative, particularly in patients unable to tolerate ACE inhibitors. The combination of angiotensin II receptor antagonists with ACE inhibitors has also shown some benefit. In the ValHeFT study, valsartan was added to standard therapy (including ACE inhibitors in most patients) and reduced the combined end-point of death or hospital-isation for heart failure, although the effect on mortality alone was not significant. In the CHARM-Added trial, addition of candesartan to therapy including an ACE inhibitor also led to a reduction in cardiovascular events. However, in the VALIANT study, no additional benefit was found from using valsartan with captopril. There has been some concern that use of triple therapy with angiotensin II receptor antagonists, ACE inhibitors, and beta blockers, might be detrimental, but this has not been confirmed. In ValHeFT, mortality appeared to be increased in patients receiving all three drug classes, but in both CHARM-Added and VALIANT use of beta blockers had no effect on the results. Use of ACE inhibitors and angiotensin II receptor antagonists together may therefore be considered in patients who remain symptomatic despite standard therapy, including patients receiving beta blockers.
There is some evidence that angiotensin II receptor antagonists may reduce the incidence of arrhythmias in patients with heart failure.
Kidney disorders. ACE inhibitors have an established role in the management of Type 1 and type 2 diabetics with nephropathy, whether or not they are hypertensive, and may also slow the progression of nephropathy in diabetics with microalbuminuria. A number of studies have investigated the effects of angiotensin II receptor antagonists in type 2 diabetics with varying degrees of nephropathy (see Diabetic Complications). Irbesartan, losartan, and valsartan have all been reported to reduce the progression of nephropathy independently of their effect on blood pressure. The magnitude of the benefit in retarding progression of nephropathy seems to be similar with angiotensin II receptor antagonists and ACE inhibitors, and the American Diabetes Association considers them equal first choices in the management of the condition.
Angiotensin II receptor antagonists have also reduced urinary albumin excretion in non-diabetic patients, including those with hypertension, and those with IgA nephropathy A study in diabetics using a combination of candesartan with lisinopril found that blood pressure and microalbuminuria were reduced more with combination therapy than with either drug alone. Benefit has also been reported with a combination of losartan and trandolapril in patients with non-diabetic renal disease.
Migraine. Angiotensin II receptor antagonists may reduce the incidence of headache. A randomised trial in 60 patients with migraine suggested that candesartan might be effective for prophylaxis, and beneficial results have also been reported with olmesartan. However, there has been a report of migraine caused by an angiotensin II receptor antagonist (see under Adverse Effects, above).
Uricosuric action. Losartan has been found to increase urinary uric acid excretion and reduce serum uric acid concentrations in healthy subjects and in hypertensive patients. However, the effect is generally small and the clinical significance is not clear. Other angiotensin II receptor antagonists do not appear to have such an effect.
Preparations
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed
Argentina: Cartan; Cliarvas; Corticosan; Cozaarex; Enromic; Fensartan; Klosartan; Loctenk; Loplac; Losacor; Niten; Paxon; Prelertan¤; Presinor; Tacardia; Tacicul; Temisartan; Tenopres¤; Australia: Cozaar; Austria: Cosaar; Belgium: Cozaar; Loortan; Brazil: Aradois; Corus; Cozaar; Lorsacor; Losartec; Losatal; Redupress; Torlos; Zaarpress; Canada: Cozaar; Chile: Aratan; Corodin; Cozaar; Losapres; Sanipresin; Simperten; Czech Republic: Cozaar; Lorista; Lozap; Denmark: Cozaar; Finland: Cozaar; France: Cozaar; Germany: Lorzaar; Greece: Cozaar; Hong Kong: Cozaar; Hungary: Cozaar; India: Alsartan; Covance; Losacar; Losanorm; Losium; Lozitan; Zart; Ireland: Cozaar; Israel: Ocsaar; Italy: Lortaan; Losaprex; Neo-Lotan; Japan: Nu-Lotan; Malaysia: Cozaar; Mexico: Cozaar; Netherlands: Cozaar; Norway: Cozaar; New Zealand: Cozaar; Portugal: Cozaar; Lortaan; Russia: Cozaar (Козаар); South Africa: Cozaar; Singapore: Cozaar; Spain: Cozaar; Sweden: Cozaar; Switzerland: Cosaar; Thailand: Cozaar; United Kingdom: Cozaar; United States: Cozaar; Venezuela: Biortan; Cormac; Cozaar; Hyzaar; Nefrotal; Presartan; Sortal; Tenserpil
Multi-ingredient Preparations
Argentina: Cozaarex D; Fensartan D; Klosartan D; Loplac-D; Losacor D; Niten D; Paxon-D; Presinor D; Tacardia D; Tenopres D¤; Austria: Cosaar Plus; Belgium: Cozaar Plus; Loortan Plus; Brazil: Aradois H; Corus H; Hipress¤; Hyzaar; Lorsar + HCT; Neopress; Torlos H; Canada: Hyzaar; Chile: Aratan D; Corodin D; Hyzaar; Losapres-D; Sanipresin-D; Simperten-D; Czech Republic: Hyzaar; Denmark: Cozaar Comp; Fortzaar; Finland: Cozaar Comp; France: Fortzaar; Hyzaar; Germany: Lorzaar plus; Greece: Hyzaar; Hong Kong: Hyzaar; Hungary: Hyzaar; India: Alsartan-AM; Alsartan-H; Amlopres Z; Losacar-H; Zaart-H; Ireland: Cozaar Comp; Israel: Ocsaar Plus; Italy: Forzaar; Hizaar; Losazid; Neo-Lotan Plus; Malaysia: Fortzaar; Hyzaar; Mexico: Hyzaar; Netherlands: Cozaar Plus; Fortzaar; Hyzaar; Norway: Cozaar Comp; New Zealand: Hyzaar; Portugal: Cozaar Plus; Fortzaar; Lortaan Plus; Russia: Hyzaar (Гизаар); South Africa: Cozaar Comp; Fortzaar; Singapore: Hyzaar; Spain: Cozaar Plus; Fortzaar; Sweden: Cozaar Comp; Switzerland: Cosaar Plus; Thailand: Fortzaar; Hyzaar; United Kingdom: Cozaar Comp; United States: Hyzaar; Venezuela: Cormatic; Hyzaar Plus; Nefrotal H
This post has been viewed 40390 times.
Comments are closed.
