NIKP-Amlodipine/Valsartan

NIKP-Amlodipine/Valsartan

amlodipine + valsartan

Manufacturer:

Nichi-Iko

Distributor:

DKSH
Full Prescribing Info
Contents
Amlodipine, valsartan.
Description
Each tablet of NIKP-Amlodipine/Valsartan tablet 5mg/80mg contains 80 mg of valsartan and 6.93 mg of amlodipine besilate (5mg of amlodipine).
Valsartan: Nonproprietary name: Valsartan.
Chemical name: (2S)-3-Methyl-2-(N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid.
Molecular formula: C24H29N5O3.
Molecular weight: 435.52.
Description: Valsartan occurs as a white powder.
It is very soluble in methanol and in ethanol (99.5), and practically insoluble in water.
Amlodipine: Nonproprietary name: Amlodipine Besilate.
Chemical name: 3-Ethyl 5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylatemonobenzenesulfonate.
Molecular formula: C20H25ClN2O5 · C6H6O3S.
Molecular weight: 567.05.
Description: Amlodipine Besilate occurs as a white to yellowish white crystalline powder.
It is freely soluble in methanol, sparingly soluble in ethanol (99.5), and slightly soluble in water.
A solution of Amlodipine Besilate in methanol (1 in 100) shows no optical rotation.
Melting point: About 198°C (with decomposition).
Excipients/Inactive Ingredients: Its excipients are microcrystalline cellulose, low substituted hydroxypropylcellulose, magnesium carbonate, light anhydrous silicic acid, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, talc, yellow ferric oxide, and carnauba wax.
Action
Pharmacology: Valsartan: Valsartan is an antagonist of angiotensin II receptor subtype AT1 receptors. It exerts an antihypertensive action by competitively antagonizing the endogenous pressor substance angiotensin II at the receptor level.
Amlodipine: Amlodipine acts as a dihydropyridine calcium channel blocker and is characterized by its gradual and long-lasting action.
Dihydropyridine calcium channel blockers bind specifically to L-type voltage dependent calcium channels and decrease the flow of calcium into cells. This causes smooth muscle in the coronary vasculature and the peripheral vasculature to relax.
Pharmacokinetics: Bioequivalence study: When a single oral dose of one tablet of NIKP-Amlodipine/Valsartan tablet 5mg/80mg or one tablet of the reference product (both tablets contain 80 mg of valsartan and 5 mg of amlodipine) was given to healthy male adults during fasting with a cross-over method, the plasma valsartan and amlodipine concentrations were 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.
Valsartan: See Table 1 and Figure 1.

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Amlodipine: See Table 2 and Figure 2.

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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.
Indications/Uses
Hypertension.
Precautions: Due to the risk of an excessive decrease in blood pressure, NIKP-Amlodipine/Valsartan tablet 5mg/80mg should not be used as a first-line treatment for hypertension.
Dosage/Direction for Use
The adult dosage is one tablet (containing 80 mg of valsartan and 5 mg of amlodipine) administered orally once daily. NIKP-Amlodipine/Valsartan tablet 5mg/80mg should not be used as a first-line treatment for hypertension.
Precautions Regarding Dosage and Administration: Whether to use NIKP-Amlodipine/Valsartan tablet 5mg/80mg should be determined on a patient-by-patient basis while considering the following dosage and administration information for valsartan and amlodipine.
Valsartan: The normal adult dosage is 40 to 80 mg of valsartan administered orally once daily.
The dosage may be adjusted based on age and symptoms up to a maximum dose of 160 mg/day.
Amlodipine: Hypertension: The normal adult dosage is 2.5 to 5 mg of amlodipine administered orally once daily. The dosage may be adjusted based on symptoms.
If a sufficient effect is not achieved, the dose can be increased to a maximum of 10 mg/day.
In general, switching to NIKP-Amlodipine/Valsartan tablet 5mg/80mg should be considered if a patient is using both valsartan 80mg and amlodipine 5mg, or if blood pressure control is insufficient with one of these drugs alone.
Overdosage
Signs and symptoms: Overdosage of valsartan can cause a marked decrease in blood pressure that may lead to a decreased level of consciousness or circulatory collapse. Overdosage of amlodipine can cause excessive peripheral vasodilatation that may lead to a marked decrease in blood pressure (including shock) and reflex tachycardia.
Treatment: The following treatment measures should typically be taken: Administer an emetic and activated carbon: Administration of activated carbon has been reported as an effective means of inhibiting amlodipine absorption after amlodipine overdose. The AUC of amlodipine decreased 99% when activated carbon was administered immediately after administration of amlodipine and 49% when activated carbon was administered 2 hours after.
Monitor cardiac and respiratory function and measure blood pressure frequently. If a marked decrease in blood pressure is observed, cardiovascular measures such as elevating the limbs and administering intravenous fluid therapy should be taken. If symptoms do not improve, consider administering a vasopressor while carefully monitoring blood circulation volume and urine output.
Caution: Valsartan and amlodipine cannot be removed by hemodialysis because they bind to plasma proteins at rates of 93% to 96% and 98%, respectively.
Contraindications
NIKP-Amlodipine/Valsartan tablet 5mg/80mg is contraindicated in the following patients: Patients with a history of sensitivity to any of the ingredients of NIKP-Amlodipine/Valsartan tablet 5mg/80mg.
Patients with a history of sensitivity to dihydropyridine compounds.
Pregnant women or women suspected of being pregnant (see Use in Pregnancy & Lactation).
The concomitant use of NIKP-Amlodipine/Valsartan tablet 5mg/80mg with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60ml/min/1.73m2).
Special Precautions
Careful Administration: NIKP-Amlodipine/Valsartan tablet 5mg/80mg should be administered with care in the following patients: Patients with bilateral or unilateral renal artery stenosis (see Important Precautions as follows).
Patients with hyperkalemia (see Important Precautions as follows).
Patients with severe renal impairment: There is a risk of worsening renal impairment, and therefore it should be administered with care in patients with a serum creatinine level of not less than 3.0 mg/dL.
Patients with hepatic disorder, particularly those with biliary cirrhosis and cholestasis: Valsartan is primarily eliminated in bile, so the blood concentration may increase in these patients. Outside of Japan, the plasma concentration of valsartan in patients with mild to moderate hepatic disorder has been reported to be about two times higher than that in healthy adults. In addition, as amlodipine is primarily metabolized in the liver, the blood concentration half-life may be prolonged or the area under the blood concentration-time curve (AUC) may increase in patients with liver disorder.
Patients with cerebrovascular disease: There is a risk of worsening their condition because an excessive decrease in blood pressure may cause cerebral vascular insufficiency.
Elderly patients (see Use in Elderly as follows).
Important Precautions: As NIKP-Amlodipine/Valsartan tablet 5mg/80mg is a combination drug containing valsartan 80mg and amlodipine 5mg, adverse reactions of both valsartan and amlodipine may occur. Proper caution should be taken when considering whether to use NIKP-Amlodipine/Valsartan tablet 5mg/80mg. (See Precautions Regarding Dosage and Administration under Dosage & Administration.)
For patients with bilateral or unilateral 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.
For patients with hyperkalemia, there is a risk that valsartan worsens hyperkalemia, 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 impairment, poorly controlled diabetes, etc., there is a risk of hyperkalemia, and therefore attention should be paid to serum potassium levels.
The administration of NIKP-Amlodipine/Valsartan tablet 5mg/80mg risks causing a transient rapid drop in blood pressure (accompanied by fainting, loss of consciousness, etc.). If these symptoms develop, administration should be discontinued and appropriate therapeutic measures should be taken. For the following patients especially, careful attention should be paid to the patient's condition: Patients undergoing hemodialysis.
Patients being administered with antihypertensive diuretic: Particularly patients with severely decreased sodium or body fluid levels (May cause symptomatic hypotension in rare cases).
Patients under severe limitation of salt intake.
There have been reports of cases of development of hepatitis and other severe hepatic disorders during administration of angiotensin II receptor antagonist, which includes valsartan.
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.
Administration within the 24 hours before surgery is undesirable.
Since NIKP-Amlodipine/Valsartan tablet 5mg/80mg may induce dizziness or lightheadedness due to its hypotensive effects, patients should be instructed to use with caution when working at heights or operating hazardous machinery, such as driving a car.
Amlodipine has a long blood concentration half-life, and has been shown to have a gradual hypotensive effect even after discontinuation. As such, use of other antihypertensives after discontinuation of NIKP-Amlodipine/Valsartan tablet 5mg/80mg should be done with care by considering the doses and dose intervals while observing the patient's condition.
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.
Other Precautions: Myocardial infarction and arrhythmia (including ventricular tachycardia) have been reported in patients being treated with amlodipine, though the causality of these reactions is unknown.
Use in Elderly: Excessive decrease in blood pressure is generally regarded as undesirable in the elderly. (Cerebral infarction, etc. may occur.)
Therefore, administration should be done carefully while observing the patient's condition.
A pharmacokinetic study of valsartan monotherapy in the elderly showed that the plasma concentration of valsartan is higher in the elderly than in the non-elderly. In addition, a pharmacokinetic study of amlodipine monotherapy in the elderly showed that the plasma concentration was higher and the blood concentration half-life tended to be longer.
Use in Children: The safety of NIKP-Amlodipine/Valsartan tablet 5mg/80mg in low-birth-weight newborns, newborns, nursing infants, toddlers, and children has not been established (no clinical experience).
Use In Pregnancy & Lactation
NIKP-Amlodipine/Valsartan tablet 5mg/80mg should not be administered to pregnant women or women suspected of being pregnant. If pregnancy is discovered during administration, discontinue administration immediately.
Reactions such as fetal/neonatal death, oligohydramnios, and fetal/neonatal hypotension, renal failure, hyperkalemia, cranial hypoplasia, limb contractures estimated to be due to oligohydramnios, cerebral/craniofacial anomalies, and lung agenesis have been reported in patients who used angiotensin II receptor antagonists (including valsartan) and angiotensin-convertase inhibitors during the second or third trimester of pregnancy. Additionally, a retrospective epidemiological study on angiotensin-convertase inhibitors conducted outside Japan reported that the patient group that received an angiotensin-convertase inhibitor during the first trimester of pregnancy had a higher relative risk of fetal malformations than the patient group that did not receive an antihypertensive. Moreover, animal studies of amlodipine have shown that administration during the third trimester prolongs the duration of pregnancy and the duration of delivery.
Administration of NIKP-Amlodipine/Valsartan tablet 5mg/80mg during lactation should be avoided. If the administration is unavoidable, the patient should be instructed to stop lactation while using it.
Animal studies (of oral administration to rats during the lactation period) have reported that valsartan is transferred into breast milk at 3 mg/kg/day. Animal studies of amlodipine have shown that it is also transferred into breast milk. In other animal studies of valsartan (of oral administration to rats during the perinatal and lactation period), decreased body weight and a decreased survival rate were observed in offspring at 600 mg/kg/day, and delayed external differentiation was observed at not less than 200 mg/kg/day.
Adverse Reactions
Surveys or studies that demonstrate the frequency of adverse reactions have not been conducted.
Clinically significant adverse reactions (Frequency unknown): Angioedema: Swelling, etc. of the face, lips, pharynx, and tongue may manifest as symptoms, so observe the patient carefully, discontinue administration if any abnormality is observed, and take appropriate therapeutic measures.
Fulminant hepatitis, hepatitis, hepatic impairment, and jaundice: Fulminant hepatitis, hepatitis, hepatic impairment, and jaundice may occur, so observe the patient carefully, discontinue administration if any abnormality is observed, and take appropriate therapeutic measures.
Renal failure: Renal failure may occur, so observe the patient carefully, discontinue administration if any abnormality is observed, and take appropriate therapeutic measures.
Hyperkalemia: Severe hyperkalemia may occur, so observe the patient carefully, discontinue administration if any abnormality is observed, and take appropriate therapeutic measures immediately.
Shock, fainting, and loss of consciousness: Shock, fainting following blood pressure reduction, and loss of consciousness may occur, so observe the patient carefully, discontinue administration if chills, vomiting, loss of consciousness, etc. occur, and take appropriate therapeutic measures immediately. Especially for patients undergoing hemodialysis, under severe limitation of salt intake, or being administered with antihypertensive diuretic, observe the patients' condition carefully.
Agranulocytosis, leukopenia, and thrombopenia: Agranulocytosis, leucopenia, and thrombopenia may occur, so observe the patient carefully, discontinue administration if any abnormality is observed, and take appropriate therapeutic measures immediately.
Interstitial pneumonia: Interstitial pneumonia accompanied by symptoms such as fever, coughing, dyspnea, and abnormalities in chest X-rays may occur. If any such symptom appears, discontinue administration and take appropriate therapeutic measures (e.g., administration of an adrenal corticosteroid).
Hypoglycemia: Hypoglycemia may occur (this symptom is common in patients being treated for diabetes), so observe the patient carefully, discontinue administration if any of the following symptoms developed: torpor, hunger sensation, cold sweat, hand tremors, reduced concentration, twitching, disturbance of consciousness, etc., and take appropriate therapeutic measures.
Atrioventricular block: Atrioventricular block (early symptoms include bradycardia and dizziness) may occur, so discontinue administration if any abnormality is observed, and take appropriate therapeutic measures.
Rhabdomyolysis: Rhabdomyolysis, characterized by myalgia, torpor, increased CK (CPK), and increased myoglobin in blood and urine, may occur, so observe the patient carefully, and if these symptoms develop, discontinue administration immediately, and take appropriate therapeutic measures. It is also necessary to observe patients for onset of acute kidney injury caused by rhabdomyolysis.
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, and erythema multiforme: Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme may occur, so observe the patient carefully, discontinue administration if any abnormality is observed, and take appropriate therapeutic measures.
Pemphigus and pemphigoid: Pemphigus and pemphigoid may occur, so consult a dermatologist if symptoms such as blisters and erosions appear, and take appropriate therapeutic measures (e.g., discontinuation of administration).
Other adverse reactions: If symptoms or abnormalities such as the following appear, take appropriate therapeutic measures such as discontinuing administration. (See Table 3.)

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Drug Interactions
Amlodipine is believed to be primarily metabolized by the drug-metabolizing enzyme CYP3A4.
Clinical trial data has shown that dual blockade of the RAAS through the combined use 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 4.)

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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
Shelf-life: 2 years.
Store below 25°C.
ATC Classification
C09DB01 - valsartan and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.
Presentation/Packing
5 mg/80 mg FC tab (yellowish white, weighs 210 mg, 8.6 mm in diameter, 3.9 mm in thickness) 10 x 10's.
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