Unisia

Unisia

Manufacturer:

Takeda
Full Prescribing Info
Contents
Candesartan cilexetil, amlodipine.
Description
Each tablet contains Candesartan Cilexitil 8 mg and Amlodipine 5 mg (Amlodipine Besilate 6.43 mg).
Candesartan Cilexetil:
(1RS)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzo[d]imidazole-7-carboxylate. Molecular formula: C33H34N6O6. Molecular weight: 610.66.
Candesartan cilexetil occurs as white crystals or crystalline powder. It is soluble in acetic acid (100), sparingly soluble in methanol, slightly soluble in ethanol (99.5), and practically insoluble in water. A solution of Candesartan cilexetil in methanol (1 in 100) shows no optical rotation.
Amlodipine Besilate: 3-Ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methyl-1,4 dihydropyridine-3,5-dicarboxylate monobenzenesulfonate. Molecular formula: C20H25 Cl N2O5·C6H6 O3S. Molecular weight: 567.05
Amlodipine Besilate occurs as white to yellowish crystalline powder. It is freely soluble in methanol, sparingly soluble in ethanol (99.5), and slightly soluble in water. A solution of Amlodipine in methanol (1 in 100) shows no optical rotation.
Excipients/Inactive ingredients: D-Mannitol, Microcrystalline Cellulose, Hydroxypropylcellulose, Macrogol 6000, Croscarmellose Sodium, Magnesium Stearate, Red Ferric Oxide.
Action
Pharmacology: Mechanism of antihypertensive action: In the absorption process in the body, candesartan cilexetil is rapidly hydrolyzed to the active metabolite candesartan, which exerts its antihypertensive action primarily by inhibiting the potent vasoconstrictor effect of angiotensin II through its antagonistic action at the angiotensin II type 1 (AT1) receptor in vascular smooth muscle, thereby reducing peripheral vascular resistance.
In addition, inhibitory effect on the release of aldosterone from adrenal gland mediated by AT1 receptor is considered to play a role in the antihypertensive action.
Amlodipine besilate acts as a dihydropyridine calcium channel antagonist, and is characterized by gradual onset of action and continuous effect.
Dihydropyridine calcium channel antagonist selectively binds to the membrane potential-dependent L-type calcium channels and reduces calcium influx into cells, causing relaxation of coronary or peripheral vascular smooth muscle.
Effect on the renin-angiotensin system: When candesartan cilexetil was administered repeatedly at a once daily dose of 1 - 12 mg to 74 hypertensive patients (56 with essential hypertension, 18 with hypertension accompanied by renal dysfunction), plasma renin activity and the plasma levels of angiotensin I and II were elevated.
Clinical Studies: The result of double blind comparative study in patients with essential hypertension where a once daily dose of 8 mg/5 mg, 8 mg/2.5 mg, 8 mg/0 mg, or 0 mg/5 mg of candesartan cilexetil/amlodipine was administered for 12 weeks Note1) is as follows.
Significant differences in sitting diastolic blood pressure at trough and sitting systolic blood pressure at trough were observed in 8 mg/5 mg group compared to both 8 mg/0 mg and 0 mg/5 mg groups and in 8 mg/2.5 mg group compared to 8 mg/0 mg group. (See Table 1.)


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In the long-term study (52 weeks) of concomitant use of candesartan cilexetil and amlodipine besilate, hypotensive effect persisted, the effect did not decrease, and stable control of blood pressure was obtained.
Note 1) once a daily without setting the administration timing, before or after meals (See Pharmacology: Pharmacokinetics: Bioequivalence under Actions).
Pharmacokinetics: Blood concentration: After a single oral administration of a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet to healthy adults, active metabolite candesartan and inactive metabolite M-II and unchanged amlodipine were detected in the blood, but the unchanged candesartan cilexetil was undetected. Changes of blood concentrations of active metabolite candesartan and amlodipine are as indicated in Figures 1 and 2 and in Table 1. (See Figure 1 and Figure 2, Table 2.)


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Effect of meals: When a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet was administered to 12 healthy adults after meal, the Cmax of active metabolite candesartan were about 2.1 times higher (under fasting: 78.9 ng/mL, after meal: 160.0 ng/mL ) and the Cmax of active metabolite candesartan were about 1.2 times higher (under fasting: 1,171.1 ng·h/mL, after meal: 1,286.7 ng·h/mL) than those under fasting conditions. No changes were observed in the Cmax and AUC of amlodipine.
Bioequivalence: When the administration of a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet to healthy adults was compared with the concomitant use of each components, the bioequivalency of each components was confirmed both under fasting conditions or after meals. Cmax and AUC of each component under fasting conditions or after meals are as indicated in Table 3 and Table 4. (See Table 3 and Table 4.)


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Urinary excretion: After a single oral administration of a 8 mg/5 mg of candesartan cilexetil/amlodipine combination tablet to 12 healthy adults, unchanged candesartan cilexetil was not detected in the urine, but the active metabolite candesartan, inactive metabolite M-II and unchanged amlodipine were excreted in the urine. The 48-hour cumulative excretion rates in the urine were 11.9% for candesartan and M-II combined, and 4.8% for unchanged amlodipine.
Metabolism: Candesartan cilexetil is metabolized to an active metabolite candesartan by carboxylesterase, and a part of it is further metabolized to inactive metabolite M-II by CYP2C9. However, compared with the blood concentration and urinary excretion of candesartan, those of M-II after administration of this drug to patients with essential hypertension are lower, indicating that the influence of genetic polymorphism of CYP2C9 on the blood concentration of candesartan is negligible.
Candesartan does not inhibit the metabolic activity of CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9-Arg, 2C19, 2D6, 2E1 and 3A4 (in vitro).
Amlodipine is mainly metabolized by CYP3A4, and unchanged component as well as nine metabolites are detected in the urine.
Population Pharmacokinetics (PPK) analysis using blood candesartan concentration levels: 2,886 time point samples of blood candesartan concentration obtained from total of 224 cases - 168 healthy male adults, 30 patients with essential hypertention and elderly essential hypertention, 18 hypertensive patients with renal dysfunction and 8 hypertensive patients with hepatic dysfunction were used to study relationship between sex/age/body weight/hepatic function parameter (AST (GOT), ALT (GPT))/renal function parameter (serum creatinine, BUN)/blood albumin level/existence of hypertension and candesartan clearance/distribution volume/relative bioavailability. It is suggested that clearance in patients with hepatic dysfunction (AST (GOT) > 40 or ALT (GPT) >35) decreases by 45%.
Indications/Uses
Hypertension.
Precautions for Indications: Since this drug may cause excessively decreased blood pressure etc., do not use this drug as a primary drug for the treatment of hypertension.
Dosage/Direction for Use
For adults, orally administer one tablet once daily (8 mg/5 mg as candesartan cilexetil/amlodipine). Do not use this drug as a primary drug for the treatment of hypertension.
Precautions for Dosage & Administration: Dosage should be determined for each patient based on the following dosage and administration of candesartan cilexetil and amlodipine besilate.
Candesartan cilexetil: hypertension: Usually, for adults, a dose of 4-8 mg of candesartan cilexetil is orally administered once a day. The dosage may be increased up to 12 mg if necessary. For patients with renal dysfunction, the starting dose is 2 mg once a day and may be increased up to 8 mg if necessary.
Amlodipine besilate: hypertension: Usually, for adults, a dose of 2.5-5 mg of amlodipine is orally administered once a day. The dosage may be appropriately adjusted according to the patient's symptom, and dose can be increased up to 10 mg once a day when the effect is insufficient.
In principle, switching to UNISIA Tablets should be considered when candesartan cilexetil 8 mg and amlodipine 2.5-5 mg are coadministrated, or when the blood pressure is not controlled sufficiently by administration of one of them.
Overdosage
Symptoms: Over dose of UNISIA Tablets may cause marked decrease in blood pressure, including shock, and reflex tachycardia.
Treatment: Cardiac and respiratory function should be monitored and blood pressure should be measured frequently. If marked decrease in blood pressure occur, provide cardiovascular support including elevation of the extremities and the administration of fluids. If the symptom does not improve, administration of vasopressors should be considered with careful attention to circulating blood volume and urine output. Since candesartan and amlodipine, components of UNISIA Tablets, have high protein binding rates, hemodialysis is not effective for elimination. Charcoal administration is reported to be effective for inhibition of absorption since AUC of amlodipine decreased by 99% and 49% when activated charcoal was administered immediately after the use of amlodipine and 2 hours after the use of amlodipine, respectively.
Contraindications
UNISIA Tablets are contraindicated in the following patients: Patients with a history of hypersensitivity to any of the ingredients of this drug or dihydropyridines.
Pregnant women or women having possibilities of being pregnant (See Use in Pregnancy & Lactation).
Patients with diabetes on aliskiren fumarate (excluding patients with significantly uncontrolled blood pressure despite treatment with other antihypertensive therapy) [Increased risks of non-fatal stroke, renal dysfunction, hyperkalemia or hypotension has been reported] (See Precautions).
Special Precautions
Careful Administration (UNISIA Tablets should be administered with care in the following patients.): Patients with bilateral or unilateral renal artery stenosis: [Candesartan cilexetil may aggravate renal function.] (See Important Precautions.)
Patients with renal dysfunction: [Renal function may be aggravated by excessive decrease in blood pressure.]
Patients with hyperkalemia: [Candesartan cilexetil may aggravate hyperkalemia.] (See Important Precautions.)
Patients with hepatic dysfunction: Candesartan cilexetil may aggravate hepatic function, and decrease in clearance of candesartan active metabolite is anticipated. (See Pharmacology: Pharmacokinetics under Actions).
Since amlodipine besilate is mainly metabolized in the liver, blood concentration half life may prolong and area under the blood concentration - time curve (AUC) may increase in the patients with hepatic dysfunction.
Patients with a history of drug hypersensitivity.
Elderly patients (see Use in the Elderly as follows.)
Important Precautions: This drug is a combination of candesartan cilexetil 8 mg and amlodipine 5 mg. Since adverse reactions by both candesartan cilexetil and amlodipine besilate may occur, the use of this drug should be considered appropriately.
Since candesartan cilexetil may rapidly deteriorate renal function in patients with bilateral or unilateral artery stenosis due to a decrease in renal blood flow and/or glomerular filtration pressure, administration of this drug should be avoided unless it is considered therapeutically essential.
Since candesartan cilexetil may aggravate hyperkalemia in patients with hyperkalemia, administration of this drug should be avoided unless it is considered therapeutically essential.
Additionally, since hyperkalemia may occur in patients whose serum potassium level is liable to increase due to renal dysfunction or uncontrolled diabetes mellitus, etc., caution should be paid to serum potassium levels. In patients receiving concomitant administration of aliskiren fumarate, since renal dysfunction, hyperkalemia or hypotension may occur, UNISIA Tablets should be administered carefully while closely observing the patients' condition. In patients with renal dysfunction (eGFR <60mL/min/1.73m2), concomitant administration of aliskiren fumarate should be avoided unless it is considered therapeutically essential.
Candesartan cilexetil may rarely cause a sudden fall in blood pressure, resulting in shock, syncope, transient unconsciousness, or renal hypofunction. Therefore, blood pressure, renal function and the patient's condition should be closely observed while administration of this drug especially to the following patients. (See Adverse Reactions).
Patients on hemodialysis; Patients on strict dietary salt restriction; Patients under diuretic therapy (especially patients who have recently started diuretic therapy); Patients with hyponatremia; Patients with renal dysfunction; Patients with heart failure.
Since dizziness and lightheadedness may occur due to antihypertensive action of this drug, patients should be cautioned against engaging operation of machinery involving risk, such as working at a height, operating machinery or driving motor vehicles.
It is recommended not to administer this drug within 24 hours before surgery. (Patients on angiotensin II receptor antagonists may develop a severe fall in blood pressure during anesthesia and surgery due to inhibitory action on renin-angiotensin system.)
Mild hypotensive effect remains after the termination of the administration of amlodipine besilate due to its long blood concentration half life. Therefore, when using other antihypertensive after the termination of the administration of this drug, patient's condition should be closely observed, such as paying attention to dosage and intervals of administration etc.
Other Precautions: Although the causal relationship has not been established, myocardial infarction and arrhythmia (including ventricular tachycardia) were reported during the administration of amlodipine besilate.
Pediatric Use: The safety of UNISIA Tablets in low birth weight infants, neonates, nursing infants, infants and children has not been established (no clinical experience).
Elderly patients: UNISIA Tablets should be administered carefully while closely observing the patients' condition with attention to following points: It is generally acknowledged that an excessive fall of blood pressure should be avoided in the elderly (cerebral infarction, etc., may occur).
In the pharmacokinetics study of amlodipine besilate in the elderly, tendency of higher blood concentration and longer half life were observed. Therefore, UNISIA Tablets should be administered carefully, taking such measures as starting with a lower dose.
Use In Pregnancy & Lactation
UNISIA Tablets should not be administered to pregnant women or women having possibilities of being pregnant. If pregnancy is detected during treatment, this drug should be discontinued immediately.
[1. In patients with hypertension who were given angiotensin II receptor antagonists including candesartan cilexetil or angiotensin converting enzyme inhibitors in the second and third trimesters of pregnancy, it has been reported that oligohydramnios, fetal and neonatal death, neonatal hypotension, renal failure, hyperkalemia, cranial hypoplasia and the following events those are supposed to be due to oligohydramnios, cranial hypoplasia, limb contractures, craniofacial deformation and lung hypoplasia etc. occurred.
2. It has been reported that gestation period and duration of delivery are prolonged when amlodipine besilate is administered in the third trimester of pregnancy in animal studies.]
UNISIA Tablets should not be administered to nursing mothers. If indispensable, however, the patient should be instructed to discontinue lactation.
[1. Oral administration of candesartan cilexetil to rats during the perinatal and lactation periods by gavage at 10 mg/kg/day or higher produced an increased incidence of neonatal hydronephrosis. Administration of candesartan cilexetil to rats only during the third trimester of pregnancy or during the lactation period at 300 mg/kg/day also resulted in an increased incidence of neonatal hydronephrosis.
2. It has been reported that amlodipine besilate transfers to mother's milk in animal studies.]
Adverse Reactions
Adverse reactions to this drug, including abnormalities in laboratory data, were observed in 35 (11.6%) of 302 patients in the clinical study before approval.
Following adverse reactions were observed in either in the above study or spontaneous reports of candesartan cilexetil or amlodipine besilate, and so on. If any adverse reaction is observed, appropriate measures should be taken, such as discontinuation of this drug.
Clinically significant adverse reactions (frequency unknown): Angioedema: Since angioedema manifested by facial, labial, glossal and laryngopharyngeal swellings may occur, patients should be closely observed. If any abnormality is observed, UNISIA Tablets should be discontinued, and appropriate measures should be taken.
Shock, syncope or unconsciousness: Since shock, syncope or unconsciousness due to lowering of blood pressure may occur, close observation should be made. If coldness, vomiting, unconsciousness, etc. are observed, appropriate measures should be immediately taken. Condition of the patients should be closely observed while administration of UNISIA Tablets, especially in patients on hemodialysis, those on strict low-salt diets, those taking diuretics, and those with heart failure.
Acute renal failure: Since acute renal failure may occur, patients should be closely observed. If any abnormality is observed, UNISIA Tablets should be discontinued, and appropriate measures should be taken.
Hyperkalemia: Since severe hyperkalemia may occur, patients should be closely observed. If any abnormality is observed, appropriate measures should immediately be taken.
Hepatic dysfunction or jaundice: Since hepatic dysfunction, including increased AST(GOT), ALT(GPT), γ-GTP etc., or jaundice may occur, patients should be closely observed. If any abnormality is observed, UNISIA Tablets should be discontinued, and appropriate measures should be taken.
Agranulocytosis, white blood cell decreased: Since agranulocytosis and white blood cell decreased may occur, patients should be closely observed. If any abnormality is observed, UNISIA Tablets should be discontinued, and appropriate measures should be taken.
Rhabdomyolysis: Since rhabdomyolysis, which is characterized by muscle ache, weakness, increased CK (CPK), and increased blood and urinary myoglobin, may occur, patient should be closely observed. In such a case, administration of UNISIA Tablets should be immediately discontinued, and appropriate measures should be taken.
Interstitial pneumonia: Interstitial pneumonia with fever, coughing, dyspnea, abnormal chest X-ray, etc, may occur. In such a case, UNISIA Tablets should be discontinued and appropriate measures, such as treatment with an adrenocortical hormone, should be taken.
Hypoglycemia: Since hypoglycemia may occur (liable to occur in patients on diabetic therapy), close observation should be made. If feeling of weakness or hungry, cold sweat, tremor of hands, decreased mental concentration, convulsions, disturbed consciousness, etc. are observed, UNISIA Tablets should be discontinued, and appropriate measures should be taken.
Platelet count decreased: Since platelet count decreased may occur, patients should be closely observed. If any abnormality is observed, UNISIA Tablets should be discontinued, and appropriate measures should be taken.
Atrioventricular block: Since atrioventricular block (initial symptoms: bradycardia, dizziness etc.) may occur, if any abnormality is observed, UNISIA Tablets should be discontinued, and appropriate measures should be taken.
Other adverse reactions: (See Table 5.)


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Drug Interactions
It is considered that enzyme CYP3A4 mainly contributes to amlodipine metabolism.
Precautions for coadministration (UNISIA Tablets should be administered with care when coadministered with the following drugs.) (See Table 6.)


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Caution For Usage
When dispensing the drug: The patient must be instructed to remove the tablets from the press-through package (PTP) before they are ingested.
[It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, and this could result in serious complications such as mediastinitis.]
Storage
Store below 30°C.
Shelf-Life: 3 years.
ATC Classification
C09DB07 - candesartan 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
Tab (light red) 2 x 10's.
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