Product Overview
[Drug Name]
Generic Name: Losartan Potassium Tablets
Trade Name: Cozaar Losartan Potassium Tablets 50mg x 7 tablets
[Main Ingredients]
The main ingredient of this product is losartan potassium.
[Appearance]
This product is a white, oval, film-coated tablet with a notch in the center of one side and 952 printed on the other side. The tablet appears white after the coating is removed.
[Indications/Main Functions]
This product is indicated for the treatment of essential hypertension.
[Specifications]
50mg x 7 tablets (Cozaar)
[Dosage and Administration]
This product can be used with other antihypertensive medications. This product can be taken with or without food. For most patients, the usual starting and maintenance dose is 50mg once daily. Maximum antihypertensive effect is achieved after 3 to 6 weeks of treatment. In some patients, increasing the dose to 100mg once daily may produce further antihypertensive effects. For patients with vascular volume depletion (e.g., those taking high-dose diuretics), a starting dose of 25mg once daily may be considered (see Precautions). No starting dose adjustment is necessary for elderly patients or patients with renal impairment, including those on dialysis. A lower dose should be considered for patients with a history of hepatic impairment (see Precautions).
[Adverse Reactions]
Clinical trials found that losartan was well tolerated, with mild and transient adverse reactions that generally did not require discontinuation of treatment. The overall incidence of adverse reactions with losartan was similar to that with placebo. In controlled clinical studies of essential hypertension, the only adverse reaction with an incidence ≥1%, drug-related, and higher than placebo was dizziness. Additionally, orthostatic hypotension, which was dose-related, occurred in less than 1% of patients. Although the incidence of rash was lower than with placebo in controlled clinical trials, it has been reported in isolated cases. In these double-blind, controlled clinical studies of essential hypertension, adverse reactions with an incidence of 1% or greater following losartan use, regardless of drug-relatedness, include the following: In addition to the adverse events listed above, the following are potential serious adverse events or other adverse events with an incidence of <1% in at least two patients/subjects treated with losartan in clinical studies. A causal relationship to losartan cannot be established for these events. (See instructions for details)
[Contraindications]
This product should not be used if you are allergic to any of its ingredients.
[Drug Interactions]
Clinical pharmacokinetic studies have confirmed no clinically significant drug interactions with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampicin and fluconazole have been reported to reduce levels of the active metabolite. The clinical consequences of these interactions have not been evaluated. 1. Like other drugs that inhibit angiotensin II and its effects, coadministration of this product with potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or potassium-containing salt substitutes may lead to elevated serum potassium. 2. Like other drugs that affect sodium excretion, lithium excretion may be reduced. Therefore, if lithium salts are coadministered with angiotensin I receptor antagonists, serum lithium levels should be carefully monitored. 3. Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), may reduce the effects of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effects of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors may be attenuated by NSAIDs, including COX-2 inhibitors. 4. For some patients with impaired renal function (e.g., elderly or volume-depleted patients, including those receiving diuretics) who are taking nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors, concomitant use of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors may result in further renal impairment, including the potential for acute renal failure. These effects are generally reversible. Therefore, caution should be exercised when administering these drugs together in patients with renal insufficiency.
[Precautions]
1. Hypersensitivity Reactions: Angioedema. 2. Hypotension and Electrolyte/Fluid Imbalance: Patients with volume depletion (e.g., those receiving high-dose diuretics) may experience symptomatic hypotension. These conditions should be corrected before treatment with this product, or a lower initial dose should be used. It should be noted that electrolyte imbalances are common in patients with renal insufficiency, with or without diabetes. In clinical studies in patients with type 2 diabetes and proteinuria, the incidence of hyperkalemia was higher in the losartan potassium group compared with the placebo group; however, few patients discontinued treatment due to hyperkalemia. 3. Hepatic Impairment: Pharmacokinetic data indicate that plasma concentrations of losartan are significantly increased in patients with cirrhosis. Therefore, a lower dose should be considered for patients with a history of hepatic impairment. 4. Renal Impairment: Due to inhibition of the renin-angiotensin system, changes in renal function, including renal failure, have been reported in susceptible individuals; these changes resolve after discontinuation of treatment. In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (such as those with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors can cause oliguria and/or progressive azotemia and (rarely) acute renal failure and/or death. Similar reports have also been reported with losartan. In patients with bilateral renal artery stenosis or renal artery stenosis in only one kidney, other drugs that affect the renin-angiotensin system can increase blood urea and serum creatinine. Similar effects have been reported with this drug. These changes in renal function resolve after discontinuation of treatment.
[Pediatric Use]
The antihypertensive effect of this drug has been established in hypertensive children aged >1 month to 16 years. Evidence from adequate controlled studies in children and adults and literature reports on its use in children supports its use in this age group. The pharmacokinetics of losartan were studied in 50 hypertensive children aged >1 month to <16 years at a once-daily oral dose of approximately 0.54-0.77 mg/kg (mean dose). Losartan formed active metabolites in all age groups. Overall, the pharmacokinetics of losartan and its active metabolite were similar across the age groups studied and consistent with available adult pharmacokinetic data. In a clinical study of 177 hypertensive children aged 6-16 years, patients weighing 20 kg or more to less than 50 kg received losartan at doses of 2.5, 25, or 50 mg daily, while those weighing 50 kg or more received losartan at doses of 5, 50, or 100 mg daily. Once-daily dosing resulted in a dose-related reduction in trough blood pressure. Dose-related effects were observed across all subgroups (e.g., age, Tanner stage, sex, and race). However, the lowest doses studied, 2.5 mg and 5 mg, equivalent to an average daily dose of 0.7 mg/kg, did not demonstrate the same antihypertensive effect as the other doses. In this study, losartan was generally well tolerated. For patients weighing 20 kg or more to less than 50 kg who are able to swallow tablets, the recommended dose is 25 mg once daily. The maximum dose can be increased to 50 mg once daily. For patients weighing more than 50 kg, the starting dose is 50 mg once daily. The maximum dose can be increased to 100 mg once daily. For pediatric patients with volume depletion, these conditions should be corrected before taking this drug. The adverse event profile in pediatric patients is similar to that observed in adults. This drug is not recommended for children with a glomerular filtration rate <30 mL/min/1.73 m2 or those with hepatic impairment. Since no data are available for use in neonates, this drug is also not recommended.
[Use in Elderly Patients]
In clinical studies, there were no age differences in the efficacy and safety of this drug.
[Overdose]
There is limited data on human overdose. The most likely manifestations of overdose would be hypotension and tachycardia. Bradycardia may occur due to parasympathetic (vagal) stimulation. If symptomatic hypotension occurs, supportive care should be administered. Neither losartan nor its active metabolite can be eliminated by hemodialysis.
[Pharmacology and Toxicology]
1. Mechanism of Action: Angiotensin is the primary active substance in the renin-angiotensin system. It is a potent vasoconstrictor and plays a major role in the pathophysiology of hypertension. Angiotensin II binds to AT1 receptors in various tissues (such as vascular smooth muscle, adrenal glands, kidneys, and heart), producing a variety of important biological effects, including vasoconstriction and aldosterone release. It also stimulates smooth muscle cell proliferation. Another angiotensin II receptor subtype, AT2, has been identified, but its role in cardiovascular homeostasis remains unclear. Losartan is a synthetic, potent, orally active drug. Binding studies and pharmacological bioassays have demonstrated its selective binding to AT1 receptors. In vitro and in vivo studies have demonstrated that losartan and its pharmacologically active carboxylic acid metabolite (E-3174) can block the physiological effects of angiotensin II synthesized from any source or route. Compared to other peptide angiotensin III antagonists, losartan lacks agonist effects. Losartan selectively acts on the AT1 receptor, does not affect the function of other hormone receptors or important ion channels in the cardiovascular system, and does not inhibit angiotensin-converting enzyme (kininase I) that degrades bradykinin. Therefore, effects not directly related to blocking the AT1 receptor, such as bradykinin-mediated effects or edema (losartan 1.7% and placebo 1.9%), are not related to losartan. 2. Toxicology Studies: The LD50 of losartan potassium was 2248 mg/kg (6744 mg/m2) for oral administration to male mice (1124 times the recommended maximum daily dose for adults). The significant minimum lethal dose for oral administration of this product to mice and rats was 1000 mg/kg (3000 mg/m2) and 2000 mg/kg (11800 mg/m2), respectively, which are 500 times and 1000 times the recommended maximum daily dose for adults (calculated based on a body weight of 50 kg). A series of toxicity studies evaluating the potential toxicity of losartan potassium, conducted over three months in monkeys and one year in rats and dogs, revealed no findings that would preclude its use at therapeutic doses. No carcinogenic effects were observed in rats and mice at the maximum tolerated dose for 105 and 92 weeks, respectively. In vitro alkaline elution and chromosomal aberration studies demonstrated no direct mutagenic effects at plasma concentrations 1700 times the maximum achieved at the recommended human therapeutic dose. Daily oral administration of losartan potassium at 150 and 30 mg/kg doses in male and female rats, respectively, did not reveal any effects on fertility. Losartan potassium has been associated with adverse reactions in rat embryos and neonates, including weight loss, mortality, and/or nephrotoxicity. Furthermore, elevated concentrations of losartan potassium and its active metabolites were observed in the milk of treated rats.
