NIKP-Losartan

NIKP-Losartan

losartan

Manufacturer:

Nichi-Iko

Distributor:

DKSH
Full Prescribing Info
Contents
Losartan Potassium.
Description
NIKP-Losartan tablet 50 mg: Listed in the Japanese Pharmacopoeia as "Losartan Potassium Tablets". Each tablet contains 50 mg of losartan potassium.
NIKP-Losartan tablet 100 mg: Listed in the Japanese Pharmacopoeia as "Losartan Potassium Tablets". Each tablet contains 100 mg of losartan potassium.
Losartan Potassium occurs as a white crystalline powder.
It is very soluble in water, and freely soluble in methanol and in ethanol (99.5).
Chemical name: Monopotassium 5{-[4' (-2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl) methyl] biphenyl-2-yl}-1H-tetrazol-1-ide.
Molecular formula: C22H22ClKN6O.
Molecular weight: 461.00.
Excipients/Inactive Ingredients: lactose, partly pregelatinized starch, cellulose, hydroxypropyl cellulose, magnesium stearate, hypromellose, titanium oxide, and carnauba wax.
Action
Pharmacology: Pharmacokinetics: Bioequivalence Study: When a single oral dose of one tablet of NIKP-Losartan tablet 25mg or one tablet of the reference product (both tablets contain 25 mg of losartan potassium) was given to healthy male adults during fasting with a cross-over method, the plasma concentration of active metabolite carboxylate form was measured. In a statistical analysis for the obtained pharmacokinetic parameters (AUC and Cmax), calculation results of 90% confidence intervals for the parameters were within a range between log (0.80) and log (1.25), demonstrating the bioequivalence of the two formulations.
Similarly, the results of administration of one tablet of NIKP-Losartan tablet 50mg or one tablet of the reference product (both tablets contain 50 mg of losartan potassium) and one tablet of NIKP-Losartan tablet 100mg or one tablet of the reference product (both tablets contain 100 mg of losartan potassium) showed bioequivalence between the two formulations. (See Tables 1,2,3 and Figures 1,2 and 3.)

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Plasma concentration and pharmacokinetic parameters such as AUC and Cmax may vary depending on study conditions including selection of subjects, body fluid sampling frequency/sampling time, etc.
Dissolution behavior: NIKP-Losartan tablet 50mg and 100mg have been shown to meet the dissolution regulations for "Losartan Potassium Tablets" set forth in the Official Monographs of the Japanese Pharmacopoeia.
Indications/Uses
Hypertension.
Diabetic nephropathy in type 2 diabetes, followed with hypertension and proteinuria.
Precautions for diabetic nephropathy in type 2 diabetes, followed with hypertension and proteinuria: Efficacy and safety of NIKP-Losartan tablet 50 mg, and NIKP-Losartan tablet 100 mg have not been confirmed for patients that do not have hypertension or proteinuria complications (urinary albumin to creatinine ratio ≥300 mg/g).
Dosage/Direction for Use
Hypertension: Normally, the usual adult oral dose of NIKP-Losartan tablet 50mg or 100mg is 25 to 50 mg of losartan potassium once a day. Dose can be suitably increased or decreased in accordance with age or symptoms, but the dose can only be increased up to 100 mg per day.
Diabetic nephropathy in type 2 diabetes, followed with hypertension and proteinuria: Normally, the usual adult oral dose of NIKP-Losartan tablet 50mg or 100mg is 50 mg of losartan potassium once a day. The dose can be increased up to 100 mg per day while observing blood pressure values. However, for patients at risk of an excessive decrease in blood pressure, start administration from 25 mg.
Precautions Regarding Dosage and Administration: For diabetic nephropathy in type 2 diabetes, followed with hypertension and proteinuria, if after administration of NIKP-Losartan tablet 50mg, or NIKP-Losartan tablet 100mg, serum creatinine levels increase by 30% (or 1 mg/dL) or greater compared to previous testing levels, and if the propagation rate of renal function disorder is accelerating as assessed by glomerular filtration rate, slope of 1/serum creatinine levels, etc., consideration should be made into lowering the dosage or discontinuing administration.
Contraindications
Patients with a history of hypersensitivity to any of the ingredients of NIKP-Losartan tablet 50 mg or 100 mg.
Pregnant women or women suspected of being pregnant (See Use in Pregnancy & Lactation.)
Patients with severe hepatic disorder (see Careful administration under Precautions).
The concomitant use of NIKP-Losartan tablet 50 mg or 100 mg with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73m2). (See Precautions.)
Special Precautions
Careful administration (NIKP-Losartan tablet 50mg and 100mg should be administered with care in the following patients): (1) Patients with unilateral or bilateral renal artery stenosis (see Important Precautions).
(2) Patients with hyperkalemia (see Important Precautions).
(3) Patients with severe renal function disorder [Hyperkalemia may occur more easily. As there is also a risk of worsening renal function, if serum creatinine is 2.5 mg/dL or greater, administration should be done carefully, e.g., at a lower dose, etc. (See Important Precautions.)
(4) Patients with hepatic function disorder or a history of hepatic function disorder [It has been reported overseas that, compared to healthy adults, patients with mild to moderate alcoholic cirrhosis had a delay in elimination of losartan, and plasma concentrations of losartan and carboxylic acid bodies increased five-fold and two-fold, respectively.]
(5) Patients with cerebrovascular disorders [Excessive decrease in pressure may lead to incomplete cerebral blood flow, possibly making the patient's condition worse.]
(6) Patients with decreased bodily fluids (being administered with antihypertensive diuretic, under severe limitation of salt intake, undergoing hemodialysis) (see Important Precautions).
(7) Elderly patients (see Elderly).
Important Precautions: (1) For patients with unilateral or bilateral renal artery stenosis, there is a risk of sudden worsening of renal function due to decreased renal blood flow and decreased glomerular filtration pressure, and therefore use should be avoided unless it is judged to be therapeutically unavoidable.
(2) For patients with hyperkalemia, there is a risk that hyperkalemia may become worse, and therefore use should be avoided unless it is judged to be therapeutically unavoidable. Furthermore, for patients for whom elevated serum potassium levels occur more readily due to renal function disorder, poorly controlled diabetes, etc., there is a risk of hyperkalemia, and therefore attention should be paid to serum potassium levels.
(3) Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
(4) The administration of NIKP-Losartan tablet 50mg or 100mg risks causing transient blood pressure to drop (accompanied by shock symptoms, loss of consciousness, breathing difficulty, etc.). If these symptoms develop, administration should be discontinued and appropriate therapeutic measures should be taken. Blood pressure should be monitored regularly (at the start of administration: every 2 weeks, after stabilization: monthly) during administration of NIKP-Losartan tablet 50mg or 100mg. For the following patients especially, administration should start at a low dose, and if dose is increased, it should be done gradually while carefully observing the patient's condition.
(i) Patients being administered with antihypertensive diuretic.
(ii) Patients under severe limitation of salt intake.
(iii)Patients undergoing hemodialysis.
(5) Since NIKP-Losartan tablet 50mg and 100mg may induce dizziness or lightheadedness due to its hypotensive effects, patients should be instructed to use with caution when operating hazardous machinery such as working at heights or driving a car.
(6) Administration within the 24 hours before surgery is undesirable.
(7) There have been reports of rare cases of development of hepatitis and other severe hepatic disorders during administration of angiotensin II receptor antagonist, which includes the losartan potassium preparation. Observe the patient carefully, with measures such as hepatic function testing, and take appropriate therapeutic measures, such as discontinuing administration if any abnormality is observed.
(8) Because anemia may occur more easily in patients with diabetic nephropathy in type 2 diabetes, patients should be observed carefully, such as by performing regularly (at the start of administration: every 2 weeks, after stabilization: monthly) blood tests, during administration of NIKP-Losartan tablet 50mg, or NIKP-Losartan tablet 100mg, and if an abnormality is observed, consideration should be paid to a cause of anemia, and appropriate therapeutic measures should be taken.
(9) Because increased serum potassium and serum creatinine may occur more easily in patients with diabetic nephropathy in type 2 diabetes, patients should undergo regular monitoring (at the start of administration: every 2 weeks, after stabilization: monthly) of serum potassium and serum creatinine levels during administration of NIKP-Losartan tablet 50mg, or NIKP-Losartan tablet 100mg, and careful observation should be given. If an abnormality is observed in serum potassium or serum creatinine levels, appropriate therapeutic measures should be taken.
Elderly: (1) Since physiological functions generally decline with age, attention should be paid to the patient's condition.
(2) Excessive decrease in blood pressure is generally regarded as undesirable in the elderly. (Cerebral infarction, etc. may occur.)
Therefore, administration should be done carefully, such as by starting at a low dose, while observing the patient's condition.
(3) Internal pharmacokinetics testing in the elderly has observed higher plasma concentrations of losartan and carboxylate forms than in non-elderly subjects (compared to non-elderly subjects, plasma concentrations of losartan and carboxylate forms were elevated to approximately 2 times and approximately 1.3 times, respectively).
(4) No difference has been observed regarding occurrence of hypotensive effect and adverse reactions between elderly and non-elderly.
Children: The safety of NIKP-Losartan tablet 50mg or 100mg in children has not been established (No clinical experience).
Use In Pregnancy & Lactation
Pregnancy, Delivery or Lactation: NIKP-Losartan tablet 50mg or 100mg should not be administered to pregnant women or women suspected of being pregnant. If pregnancy is discovered during administration, discontinue administration immediately. [In hypertension patients in the second or third trimester of pregnancy who were administered angiotensin II receptor antagonist, which includes ingredients of losartan potassium preparation, there are reports of oligohydramnios, fetal and newborn death, newborn hypotension, renal failure, multiple organ failure, cranial deformity, limb deformity estimated to be due to oligohydramnios, craniofacial deformity, pulmonary agenesis, etc.]
Administration of NIKP-Losartan tablet 50mg or 100mg should be discontinued during lactation. [Based on animal studies (rats), the drug has been reported to pass into the mother's milk.]
Adverse Reactions
Surveys or studies that demonstrate frequency of adverse reaction have not been conducted.
Clinically significant adverse reactions (Frequency unknown): Adverse reactions such as the following may occur, so if these symptoms develop, discontinue administration and take appropriate therapeutic measures.
Anaphylaxis: Symptoms including discomfort, oral cavity discomfort, sweating, hives, breathing difficulty, generalized flushing, and edema may develop, so careful observation is required.
Angioedema: Swelling of the face, lips, pharynx, tongue, and elsewhere may manifest as symptoms, so careful observation is required.
Acute hepatitis or fulminant hepatitis.
Renal failure.
Shock, fainting, loss of consciousness: Shock, fainting followed with blood pressure reduction, and loss of consciousness may occur, so observe the patient carefully, and take appropriate therapeutic measures immediately if chills, vomiting, loss of consciousness, etc. occur. Especially for patients undergoing hemodialysis, under severe limitation of salt intake, or being administered with antihypertensive diuretic, administration should start at a low dose, and if dose is increased, it should be done gradually while observing the patient's condition.
Rhabdomyolysis: Rhabdomyolysis, characterized by myalgia, torpor, increased CK (CPK), and increased myoglobin in blood and urine, may occur, so if these symptoms develop, discontinue administration and take appropriate therapeutic measures. Also pay attention for the onset of acute renal failure due to rhabdomyolysis.
Hyperkalemia: Severe hyperkalemia may occur, so observe the patient carefully, and take appropriate therapeutic measures immediately if any abnormality is observed.
Arrhythmia: Arrhythmias such as premature ventricular contraction and atrial fibrillation may occur, so observe the patient carefully, and take appropriate therapeutic measures immediately if any abnormality is observed.
Pancytopenia, leucopenia, and thrombopenia: Pancytopenia, leucopenia, and thrombopenia may occur, so observe the patient carefully, and take appropriate therapeutic measures immediately if any abnormality is observed.
Hypoglycemia: Hypoglycemia may occur (this symptom is common in patients being treated for diabetes), so observe the patient carefully, and discontinue administration and take appropriate therapeutic measures if any of the following symptoms developed: torpor, hunger sensation, cold sweat, hand tremors, reduced concentration, twitching, disturbance of consciousness, etc.
Hyponatremia: Hyponatremia followed with malaise, loss of appetite, nausea, vomiting, twitching, disturbance of consciousness, etc. may occur, so observe the patient carefully, and discontinue administration and take appropriate therapeutic measures immediately if any abnormality is observed.
Other adverse reactions: If any of the following symptoms or abnormalities occur, take appropriate therapeutic measures, such as discontinuing administration. (See Table 4.)

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Drug Interactions
NIKP-Losartan tablet 50mg and 100mg are metabolized into active metabolite carboxylate forms, mainly by the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9).
Clinical trial data has shown that dual blockade of the RAAS through the combined used of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent. (See Table 5.)

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Caution For Usage
Precautions for dispensing: Patients should be instructed to remove the tablets from the blister package prior to use. (It has been reported that, if the blister is swallowed, its sharp corners may puncture the esophageal mucosa, and resulting in serious complications such as mediastinitis.)
Storage
Store below 25°C.
Shelf-Life: 2 years.
ATC Classification
C09CA01 - losartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Presentation/Packing
FC tab (white, scored on one side) 50 mg x 10 x 10's. 100 mg x 10 x 10's.
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