Indications:
Treatment of hypertension: Losartan may be used alone or in combination with other antihypertensive agents (e.g thiazide diuretics). Losartan should be used in patients intolerant of angiotensin-converting enzyme inhibitors (ACE).
Administration, dosage:
Administration: Losartan is taken orally, can be taken with or without food.
Dosage:
Dosage must be individualized and adjusted according to blood pressure response.
Adults:
The usual starting dose of losartan is 50 mg/once/daily, lower dose may be given (e.g 25 mg/once/daily) to patients with intravascular fluid depletion, including those who are taking diuretics, or with liver failure.
The usual maintenance dose is 25 – 100 mg as a single dose or in two divided doses. No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis.
Generally, if administered dosage cannot control blood pressure, dosage of antihypertensive drugs should be adjusted periodically at 1 – 2 months intervals.
If blood pressure is not controlled by losartan alone, a low dose diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect. Losartan may be administered with other antihypertensive agents. Losartan should not be combined with potassium-sparing diuretics, due to the increased risk of hyperkalemia.
Children:
Losartan is not recommended for use in children from 6 months to less than 6 years of age and children with liver failure because there is no scientific data proving the effectiveness and safety of the drug for these subjects.
Children 6 – 18 years of age and weight from 20 to less than 50 kg: The recommended dose is 25 mg/once/daily. The maximum dose is 50 mg/once/daily. Dosage adjustment according to blood pressure response.
Children from 6 – 18 years of age and weight over 50 kg: The recommended dose is 50 mg/once/daily. The maximum dose is 100 mg/once/daily.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling the drug after use.
Contraindications:
Hypersensitivity to any of the ingredients.
Pregnant women.
People with severe hepatic failure.
The concomitant use of losartan with aliskiren-containing products is contraindicated in patients with diabetes or renal failure (GFR < 60 mL/min).
Warnings and precautions for use:
Close monitoring should be exercised and/or dose reduction should be considered in patient with dehydration, who is being treated with diuretic agents, and having risk factors leading to hypotension. Patients with unilateral or bilateral renal artery stenosis, patient with a solitary kidney are also at high risk of unwanted effects (increased creatinine and blood urea) and should be closely monitored during treatment.
A lower dose should be considered for patients with a history of hepatic impairment.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and lactation:
Pregnancy:
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can cause oligohydramnios, hypotension, anuria, oliguria, fetal craniofacial deformation and death. Although, losartan use during the first trimester of pregnancy has not been found related to the risk to the fetus, when pregnancy is detected, losartan should be stopped as soon as possible.
Lactation:
It is not known whether losartan is excreted in human milk, but there are significant amounts of losartan and its active metabolite in the rat milk. 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.
Effects on ability to drive, use machines:
As other antihypertensive drugs, caution should be taken when driving a vehicle and operating machines.
Interactions, incompatibilities of medicine:
Interaction of the drug with other drugs and other types of interactions:
Losartan did not affect the pharmacokinetics of oral or intravenous digoxin.
Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite.
Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite.
There is no pharmacokinetic interaction between losartan and hydrochlorothiazide.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Undesirable effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); cannot be estimated from the available data “Not known”.
Most undesirable effects are mild and disappear over time.
Common
Cardiovascular: Hypotension.
Nervous system: Insomnia, vertigo.
Endocrine – metabolic: Hyperkalemia.
Digestive: Diarrhea, dyspepsia.
Hematologic: Small decreases in hemoglobin and hematocrit.
Musculoskeletal: Back pain, leg pain, muscle pain.
Renal: Decreased serum uric acid levels (at high doses).
Respiratory: Cough (less likely to cause an uncontrollable cough than ACE inhibitors), nasal congestion, sinusitis.
Uncommon
Cardiovascular: Orthostatic hypotension, chest pain, second degree AV block, palpitations, sinus bradycardia, tachycardia, facial edema, flushing.
Nervous system: Anxiety, ataxia, confusion, depression, migraine, sleep disorder, fever, vertigo.
Skin: Alopecia, dermatitis, dry skin, erythema, photosensitivity, pruritus, urticarial, bruising, rash.
Endocrine – metabolic: Gout.
Digestive: Anorexia, constipation, flatulence, vomiting, loss of appetite, gastritis.
Urogenital: Impotence, decreased libido, urinary frequency, nocturia.
Liver: Mild elevations of liver enzymes and serum bilirubin.
Musculoskeletal: Paresthesia, tremor, musculoskeletal pain, muscle weakness, joint swelling, fibromyalgia.
Eyes: Blurred vision, conjunctivitis, decreased vision, burning/stinging in the eye.
Ears: Tinnitus.
Kidneys: Urinary tract infections, increase in blood urea, serum creatinine.
Respiratory: Dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion.
Other effects: Sweating.
Contact your doctor if you experience these side effects.
Overdose and management:
Overdose: Limited data are available in regard to overdose in humans.
The most likely manifestation of overdose would be hypotenslon and tachycardia, bradycardia may also be found resulting from parasympathetic (vagal) stimulation
Management: If symptomatic hypotension occurs, supportive treatment should be applied. Neither losartan nor its active metabolite can be removed by hemodialysis.
Pharmacodynamics:
Pharmacological group: Angiotensin II receptor (type AT1) antagonist.
ATC code: C09CA01
Losartan, the first of a new class of antihypertensives, which is an angiotensin II receptor (type AT1) antagonist.
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. 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. Angiotensin II antagonists and ACE inhibitors also have similar hemodynamic effects, but angiotensin II antagonists have no popular adverse effect of ACE inhibitors, that is dry cough.
Pharmacokinetics:
Absorption: Following oral administration, losartan is well absorbed and undergoes first-pass metabolism by cytochrome P450 enzymes. Bioavailability of losartan is approximately 33%.
Distribution: · Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin and they do not cross the blood-brain barrier. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively.
Metabolism: Approximately 14% of the oral dose losartan is converted to an active metabolite that is responsible for most of the angiotensin II receptor antagonism. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6 – 9 hours. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 – 4 hours, respectively.
Elimination: 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. Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. In patients with mild to moderate cirrhosis, the area under the curve (AUC) of losartan and the active metabolite were, respectively, 5 times and 2 times higher than in patients with normal liver.
Storage conditions, shelf life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf life: 24 months from the manufacture date.
Quality specification: In house.
