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Product Name
:
LOSARTAN-ELSaad
Chemical Name
:
Losartan Potassium
Therapeutic Category
:
Cardiovascular drugs
Pharmacologic Category
:
Angiotensin II Receptor Blocker
Pharmaceutical Form
:
Tablets
Composition
:
Losartan Potassium 25mg / 50mg / 100mg
Dosing
 
Dosing: Adult
Hypertension: Oral: Usual starting dose: 50 mg once daily; can be administered once or twice daily with total daily doses ranging from 25-100 mg
Usual initial doses in patients receiving diuretics or those with intravascular volume depletion: 25 mg once daily
Nephropathy in patients with type 2 diabetes and hypertension: Oral: Initial: 50 mg once daily; can be increased to 100 mg once daily based on blood pressure response
Stroke reduction (HTN with LVH): Oral: 50 mg once daily (maximum daily dose: 100 mg); may be used in combination with a thiazide diuretic

Dosing: Pediatric

Hypertension: Oral: Children 6-16 years:
U.S. labeling: 0.7 mg/kg once daily (maximum: 50 mg/day); doses >1.4 mg/kg (maximum: 100 mg) have not been studied
Canadian labeling:
≥20 kg to <50 kg: 25 mg once daily (maximum: 50 mg once daily)
≥50 kg: 50 mg once daily (maximum: 100 mg once daily)
Aortic-root dilation with Marfan’s syndrome (unlabeled use): Children 14 months to 16 years: Initial: 0.6 mg/kg/day; can be increased to a maximum of 1.4 mg/kg/day (not to exceed adult maximum of 100 mg/day)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Children: Use is not recommended if GFR <30 mL/minute/1.73 m2
Adults: No adjustment necessary.

Dosing: Hepatic Impairment

Children 6-16 years:
U.S. labeling: No specific dosing recommendations are provided in the approved labeling, however it may be advisable to initiate therapy at a reduced dosage.
Canadian labeling: Use is not recommended.
Adults: Reduce the initial dose to 25 mg/day.
Use
 
Treatment of hypertension (HTN); treatment of diabetic nephropathy in patients with type 2 diabetes mellitus (noninsulin dependent, NIDDM) and a history of hypertension; stroke risk reduction in patients with HTN and left ventricular hypertrophy (LVH)
Use - Unlabeled/Investigational
To slow the rate of progression of aortic-root dilation in pediatric patients with Marfan’s syndrome
Adverse Reactions
 
Note: The incidence of some adverse reactions varied based on the underlying disease state. Notations are made, where applicable, for data derived from trials conducted in diabetic nephropathy and hypertensive patients, respectively.
>10%:
Cardiovascular: Chest pain (12% diabetic nephropathy)
Central nervous system: Fatigue (14% diabetic nephropathy)
Endocrine: Hypoglycemia (14% diabetic nephropathy)
Gastrointestinal: Diarrhea (2% hypertension to 15% diabetic nephropathy)
Genitourinary: Urinary tract infection (13% diabetic nephropathy)
Hematologic: Anemia (14% diabetic nephropathy)
Neuromuscular & skeletal: Weakness (14% diabetic nephropathy), back pain (2% hypertension to 12% diabetic nephropathy)
Respiratory: Cough (≤3% to 11%; similar to placebo; incidence higher in patients with previous cough related to ACE inhibitor therapy)
1% to 10%:
Cardiovascular: Hypotension (7% diabetic nephropathy), orthostatic hypotension (4% hypertension to 4% diabetic nephropathy), first-dose hypotension (dose related: <1% with 50 mg, 2% with 100 mg)
Central nervous system: Dizziness (4%), hypoesthesia (5% diabetic nephropathy), fever (4% diabetic nephropathy), insomnia (1%)
Dermatology: Cellulitis (7% diabetic nephropathy)
Endocrine: Hyperkalemia (<1% hypertension to 7% diabetic nephropathy)
Gastrointestinal: Gastritis (5% diabetic nephropathy), weight gain (4% diabetic nephropathy), dyspepsia (1% to 4%), abdominal pain (2%), nausea (2%)
Neuromuscular & skeletal: Muscular weakness (7% diabetic nephropathy), knee pain (5% diabetic nephropathy), leg pain (1% to 5%), muscle cramps (1%), myalgia (1%)
Respiratory: Bronchitis (10% diabetic nephropathy), upper respiratory infection (8%), nasal congestion (2%), sinusitis (1% hypertension to 6% diabetic nephropathy)
Miscellaneous: Infection (5% diabetic nephropathy), flu-like syndrome (10% diabetic nephropathy)
<1% (Limited to important or life-threatening): Acute psychosis with paranoid delusions, ageusia, allergic reaction, alopecia, anaphylactic reactions, anemia, angina, angioedema, anorexia, anxiety, arrhythmia, arthralgia, arthritis, ataxia, AV block (second degree), bilirubin increased, blurred vision, bradycardia, bronchitis, BUN increased, confusion, conjunctivitis, constipation, CVA, depression, dermatitis, dysgeusia, dyspnea, ecchymosis, epistaxis, erythroderma, erythema, facial edema, fever, flatulence, flushing, gastritis, gout, hematocrit decreased, hemoglobin decreased, Henoch-Schönlein purpura, hepatitis, hyponatremia, hypotension, impotence, joint swelling, maculopapular rash, malaise, memory impairment, MI, migraine, muscle weakness, myositis, neoplasm, nervousness, orthostatic effects, pancreatitis, paresthesia, peripheral neuropathy, pharyngitis, photosensitivity, pruritus, rash, rhabdomyolysis, rhinitis, serum creatinine increased, sleep disorder, somnolence, syncope, tachycardia, taste perversion, thrombocytopenia, tinnitus, transaminases increased, tremor, urinary frequency, urticaria, vasculitis, ventricular arrhythmia, vertigo, visual acuity decreased, vomiting, xerostomia
Contraindications
 
Hypersensitivity to losartan or any component of the formulation
Warnings / Precautions Drug
 
Boxed warnings:
• Pregnancy: See “Special populations” below.
Concerns related to adverse effects:
• Angioedema: At any time during treatment (especially following first dose), angioedema may occur rarely. It may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE-inhibitor therapy may be at an increased risk. Prolonged frequent monitoring may be required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early management is critical. Intramuscular (I.M.) administration of epinephrine may be necessary.
• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.
Disease-related concerns:
• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be needed.
• Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first.
• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution with pre-existing renal insufficiency and severe renal impairment.
Concurrent drug therapy issues:
• Angiotensin-converting enzyme (ACE) inhibitors: Concurrent use of ACE inhibitors may increase the risk of clinically-significant adverse events (eg, renal dysfunction, hyperkalemia).
Special populations:   
• African-American patients: When used to reduce the risk of stroke in patients with HTN and LVH, may not be effective in the African-American population.
• Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Angiotensin receptor blockers should be discontinued as soon as possible once pregnancy is detected.
Metabolism/Transport Effects
Substrate (major) of CYP2C9, 3A4; Inhibits CYP1A2 (weak), 2C8 (moderate), 2C9 (moderate), 2C19 (weak), 3A4 (weak)
Interactions
 
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Losartan. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy
CYP2C8 Substrates (High risk): CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
CYP2C9 Substrates (High risk): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of Losartan. Risk C: Monitor therapy
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Milk Thistle: May increase the serum concentration of Losartan. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pregnancy
 
C (1st trimester); D (2nd and 3rd trimesters )
Pregnancy Implications
Medications which act on the renin-angiotensin system are reported to have the following fetal/neonatal effects: Hypotension, neonatal skull hypoplasia, anuria, renal failure, and death; oligohydramnios is also reported. These effects are reported to occur with exposure during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Angiotensin receptor blockers should be discontinued as soon as possible once pregnancy is detected.
Lactation
 
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known if losartan is found in breast milk; the manufacturer recommends discontinuing the drug or discontinuing nursing based on the importance of the drug to the mother.
Monitoring Parameters
 
Supine blood pressure, electrolytes, serum creatinine, BUN, urinalysis, symptomatic hypotension and tachycardia, CBC
Mechanism of Action
 
As a selective and competitive, nonpeptide angiotensin II receptor antagonist, losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II; losartan interacts reversibly at the AT1 and AT2 receptors of many tissues and has slow dissociation kinetics; its affinity for the AT1 receptor is 1000 times greater than the AT2 receptor. Angiotensin II receptor antagonists may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, they do not affect the response to bradykinin, and are less likely to be associated with nonrenin-angiotensin effects (eg, cough and angioedema). Losartan increases urinary flow rate and in addition to being natriuretic and kaliuretic, increases excretion of chloride, magnesium, uric acid, calcium, and phosphate.
Pharmacodynamics / Kinetics
 
Onset of action: 6 hours
Distribution: Vd: Losartan: 34 L; E-3174: 12 L; does not cross blood brain barrier
Protein binding, plasma: High
Metabolism: Hepatic (14%) via CYP2C9 and 3A4 to active metabolite, E-3174 (40 times more potent than losartan); extensive first-pass effect
Bioavailability: 25% to 33%; AUC of E-3174 is four times greater than that of losartan
Half-life elimination: Losartan: 1.5-2 hours; E-3174: 6-9 hours
Time to peak, serum: Losartan: 1 hour; E-3174: 3-4 hours
Excretion: Urine (4% as unchanged drug, 6% as active metabolite)
Clearance: Plasma: Losartan: 600 mL/minute; Active metabolite: 50 mL/minute
 
   
 
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