Date of approval.
Date of revision.
Candesartanate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician.
The use of this product should be discontinued as soon as pregnancy is detected. Drugs that act directly on the renin-angiotensin system may cause damage or even death in the developing embryo.
Concomitant use of this product with aliskiren is contraindicated in patients with diabetes because it may increase the risk of nonfatal stroke, renal insufficiency, hyperkalemia, or hypotension.
Drug Name]
Generic Name: Candesartanate Tablets
Trade name: Velia
English Name: Candesartan Cilexetil Tablets
Hanyu Pinyin: Kandishatanzhi Pian
Ingredients
Ingredients
Chemical name: (±)-1-[(Cyclohexyloxy)carbonyl oxy]ethyl-2-ethoxy-1-[[2´-(1H-tetrazolyl-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate
The chemical structure formula is
Molecular formula: C33H34N6O6
Molecular weight: 610.67
Properties
Appearance
This product is white or off-white film-coated tablets, which appear white or off-white after removing the coating.
Application
Indications
Indications
Primary hypertension.
Specification
Specification
(1) 4mg; (2) 8mg
Dosage
Oral, 4-8mg of candesartanate once a day for adults, if necessary, the dose can be increased to 16mg.
[Adverse reactions].
1. Clinically important adverse reactions (incidence unknown).
Angioedema: Sometimes angioedema with edema of the face, lips, tongue, pharynx, and larynx as a symptom should be carefully observed, and when abnormalities are seen, the drug should be stopped and treated appropriately.
Shock, fainting and loss of consciousness: Hypotension may cause shock, fainting and loss of consciousness. In such cases, the patient should be closely observed. If chills, vomiting, or loss of consciousness are observed, appropriate treatment should be administered immediately. Treatment with this drug should be started at a lower dose. If it is necessary to increase the dose, the patient should be closely observed and proceed slowly, especially in patients undergoing hemodialysis, patients on strict salt restriction therapy, patients taking diuretics, and patients with heart failure.
Acute renal failure: Acute renal failure may occur, and patients should be closely observed. If abnormalities are detected, medication should be discontinued and treated appropriately.
Patients with hyperkalemia: Given the possibility of hyperkalemia, patients should be closely observed. If abnormalities are detected, medication should be discontinued and appropriate management should be performed.
Deteriorating liver function or jaundice: Given the possibility of liver dysfunction or jaundice with elevated AST (GOT), ALT (GPT), and γ-GTP values, the patient should be closely monitored. If abnormalities are detected, medication should be discontinued and treated appropriately.
Granulocyte deficiency: Granulocyte deficiency may occur and the patient should be closely observed. If abnormalities are found, medication should be discontinued and appropriate treatment should be administered.
Rhabdomyolysis: may occur as manifested by myalgia, weakness, increased phosphocreatine kinase (CK), and myosin in the blood and urine. If any of these occur, the medication should be discontinued and treated appropriately.
Interstitial pneumonia: Interstitial pneumonia with manifestations such as fever, cough, dyspnea, and abnormal chest x-ray may occur. If any of these conditions occur, medication should be stopped and appropriate treatment, such as treatment with adrenocorticosteroids, should be administered.
Hypoglycemia: Due to the possibility of hypoglycemia (which tends to occur in patients undergoing diabetes treatment) patients should be closely monitored. If weakness or hunger, cold sweat, trembling hands, loss of concentration, convulsions, or impaired consciousness are observed, the medication should be stopped and treated appropriately.
2. Other adverse reactions
0.1-＜5%＜0.1% 1) AllergyNote 1) rash, eczema, urticaria, pruritus, photosensitivity 2) circulatory system dizzinessNote 2), waddlingNote 2)
dizziness on standing upNote 2), palpitations, fever, hypotension precordial contractions, atrial fibrillation
3) Psychoneurological system headache, head heaviness, insomnia, drowsiness, tongue numbness limb numbness 4) Digestive system nausea, vomiting, loss of appetite, stomach discomfort
pain under the sword, diarrhea, stomatitis abnormal taste 5) Liver AST (GOT), ALT (GPT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-GTP elevation, hepatitis 6) Blood anemia, leukopenia, leukocytosis,
eosinophilia, decreased platelet count 7) renal BUN, creatinine elevation, proteinuria 8) other lethargy, fatigue, rhinorrhea, urinary frequency, edema, cough
Elevated potassium, total cholesterol, phosphocreatine kinase, C-reactive protein, uric acid, decreased total serum protein hyponatremia, low back pain, back pain, muscle pain Note 1): In this case, it should be discontinued.
Note 2): In this case the dosage should be reduced or discontinued for appropriate treatment.
[Contraindication
Contraindication】
Patients with a history of hypersensitivity to the ingredients of this preparation
Pregnant or potentially pregnant women (refer to [Pregnant and lactating women medication] item)
Concomitant administration of Aliskiren is prohibited in patients with diabetes mellitus or moderate to severe renal impairment (GFR<60ml/min/1.73 m2).
[Precautions].
Use with caution (the drug should be used with caution in the following patients)
Patients with bilateral or unilateral renal artery stenosis (see 2. Important basic precautions)
Patients with hyperkalemia (see 2. Important basic precautions)
Patients with hepatic dysfunction (There is a risk of worsening liver function. Also, the clearance of the active metabolite candesartan is presumed to be reduced, so the drug should be administered with caution starting with a small dose) (refer to the item [Pharmacokinetics]).
Patients with severe renal dysfunction (due to excessive hypotension, there is a risk of deterioration of renal function, so 1 dose once a day, starting at 2 mg, should be administered with caution).
Patients with a history of drug allergy.
Elderly patients (refer to the item [Medication for elderly patients]).
Important basic precautions
Patients with bilateral or unilateral renal artery stenosis who are taking drugs of the renin-angiotensin-aldosterone system should avoid taking this drug unless it is considered therapeutically necessary due to the potential for increased risk of renal function due to decreased renal blood flow and filtration pressure.
Due to the possibility of aggravating hyperkalemia, avoid taking this drug in patients with hyperkalemia unless it is considered therapeutically necessary. In addition, patients with renal dysfunction and uncontrollable diabetes mellitus should pay close attention to blood potassium levels due to the tendency of these patients to develop hyperkalemia.
Since the administration of this preparation may sometimes cause a sharp drop in blood pressure, leading to shock, fainting, and temporary loss of consciousness, it should be started in small doses especially for the following patients, and when increasing the dose, the patient’s blood pressure, renal function and condition should be carefully observed and proceeded slowly. (See [Adverse Reactions] 1. Clinically important adverse reactions)
Patients undergoing hemodialysis.
Patients undergoing strict salt restriction therapy.
Patients taking diuretic antihypertensive drugs (especially those who have recently started taking diuretic antihypertensive drugs).
Patients with hyponatremia
Patients with renal dysfunction
Patients with heart failure
Because of the hypotensive effect, dizziness and stumbling sometimes occur, so care should be taken when performing maneuvers such as working at heights and driving vehicles.
It is best to stop taking it 24 hours before surgery. (Due to the inhibitory effect on the renin-angiotensin system, patients taking angiotensin receptor antagonists can produce a sharp drop in blood pressure during anesthesia and surgery.)
When the drug is delivered: PTP-packaged drugs should be taken after removal from the PTP sheet (there have been reports of serious comorbidities such as perforation and complications such as mediastinitis due to misuse of the PTP sheet and puncture of the hard sharp corner into the esophageal mucosa, which in turn occurred).
Renin-angiotensin-aldosterone system (RAAS) dual blockade: The dual blockade of RAAS increases the risk of hypotension, hyperkalemia, and abnormal renal function compared to single agents, and therefore concomitant use of this product with angiotensin-converting enzyme inhibitors (ACEI) or aliskiren is not recommended. Concomitant administration of aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m2) while using this product. This product should not be used in combination with angiotensin-converting enzyme inhibitors (ACEIs) in patients with diabetic nephropathy. (See [Drug Interactions])
Pregnant and lactating women]
An increased occurrence of pyelomeningocele in neonates has been seen in the perinatal and lactating rat groups administered above 10 mg/kg/day after gavage administration of this agent, and also in hypertensive patients given angiotensin II receptor antagonists including candesartanate or angiotensin converting enzyme inhibitors in mid and late gestation, with amniotic fluid hypersecretion, fetal and neonatal death, neonatal hypotension, renal failure, hyperkalemia, craniosynostosis, and possible tetany and craniofacial malformations due to hypohydramnios. This drug is contraindicated in pregnant women or women at risk of pregnancy. In case of pregnancy, stop taking candesartanate as soon as possible. (See [Contraindications])
After gavage administration of this preparation to perinatal as well as lactating rats, an increased occurrence of pelvic effusion in neonates was seen in the group administered above 10 mg/kg/day. Also only in rats given this preparation at the end of gestation or during lactation, an increase in hydronephrosis was seen in neonates in the 300 mg/kg/day dosing group. Candesartanate can be secreted through the milk of lactating rats. Avoid using the drug in nursing women, and stop nursing when it is necessary to take the drug.
Pediatric Use]
The safety of the drug in children has not been established (no experience with its use).
Use in elderly patients
It is generally believed that excessive blood pressure lowering should not be used in the elderly (it may cause cerebral infarction, etc.). It should be taken with caution under observation of the patient’s condition.
Drug Interactions]
Caution and use (care should be taken when combining drugs)
Drug name Clinical manifestations, treatment mechanism – Risk factors Potassium-protective diuretics
Spironolactone
Aminopterin, etc.
Potassium-replenishing drugs may increase serum potassium concentration. Attention should be paid to the inhibitory effect of this preparation on aldosterone secretion, coupled with the inhibitory effect of potassium-protective diuretics on potassium excretion.
Risk factors.
Diuretic antihypertensive drugs especially for patients with renal dysfunction
Furosemide
Trichlormethiazide and other diuretic antihypertensive drugs may enhance the antihypertensive effect of this preparation when first administered to patients receiving diuretic antihypertensive drugs, so it should be administered with caution, starting with small doses. In patients treated with diuretic antihypertensive drugs, there are more patients with hyperrenin activity, and this preparation is easy to work. Lithium has previously been reported as a toxic reaction to lithium, and careful monitoring of serum lithium levels is recommended during the combination of lithium and this product. Lithium reabsorption is increased in the renal tubules.
The antihypertensive effect of non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors may be diminished. Because NSAIDs, COX-2 selective inhibitors can inhibit prostaglandin synthesis, which has a vasodilatory effect, it is thought that the hypotensive effect may be diminished. Their use in patients with renal insufficiency may cause further impairment of renal function. It is thought that the inhibitory effect of NSAIDs, COX-2 selective inhibitors on prostaglandin synthesis may make the renal perfusion reduced. Renin-angiotensin system (RAS) inhibitors may lead to hypotension compared to monotherapy, and the combination of RAS inhibitors with ARBs, ACEIs or aliskiren may lead to hypotension, hyperkalemia and altered renal function (including acute renal failure).
The combination of candesartanate, an ACEI and a salt corticosteroid receptor antagonist is not recommended. Closely monitor blood pressure, renal function, and electrolytes in patients taking candesartanate and other drugs that act on the RAS. [Drug overdose].
Symptoms
Based on pharmacological considerations, the main manifestations of drug overdose may be symptomatic hypotension and dizziness. Case reports have shown that patients recover normally from candesartanate at doses up to 672 mg.
Treatment
If symptomatic hypotension occurs, symptomatic treatment and monitoring of vital signs should be performed. Patients should lie on their backs while elevating their legs. If the effect is not significant, fluids (e.g., isotonic saline) should be administered to increase plasma volume. If none of these methods are effective, sympathomimetic drugs may be administered. Candesartan cannot be cleared by hemodialysis.
Pharmacology and Toxicology
Candesartan ester is rapidly hydrolyzed in the body to the active metabolite candesartan. Candesartan is an angiotensin II AT1 receptor antagonist, which antagonizes the vasoconstrictive effect of angiotensin II by binding to vascular smooth muscle AT1 receptors, thereby reducing peripheral vascular resistance. It is also believed that candesartan may exert some antihypertensive effects by inhibiting aldosterone secretion by the adrenal glands.
Tests conducted in hypertensive patients showed that multiple doses of this product increased plasma renin activity, angiotensin I concentration and angiotensin II concentration; continuous use of 2-8 mg once daily decreased systolic and diastolic blood pressure, left ventricular myocardial weight and peripheral vascular resistance, but had no significant effect on cardiac output, ejection fraction, renal vascular resistance, renal blood flow and glomerular filtration rate. In patients with essential hypertension with cerebrovascular disorders, there was no effect on cerebral blood flow.
Pharmacokinetics
1. Blood concentration
In 8 patients (38-68 years old) with essential hypertension, the active metabolite candesartan as well as the inactive metabolite M-II were detected in the blood when the drug was first administered once a day, 4 mg after breakfast, then, stopped for 1 day, and then repeatedly for 7 consecutive days, but almost no prodrug was detected. The blood concentrations of candesartan on day 1 (after initial dosing) and day 9 (after 7 days of repeated dosing) are shown below. It peaks at 4-6 hours of dosing and then decreases slowly.
In 6 cases of elderly patients with essential hypertension (65-70 years old), when the first dose was given once a day, 4 mg after breakfast, then stopped for 1 day, and then repeatedly for 7 consecutive days, the blood concentration showed almost no difference from that of patients with essential hypertension. In addition, in 18 hypertensive patients with renal dysfunction (serum creatinine 0.6 to 3.6 mg/dl) and in 8 hypertensive patients with hepatic dysfunction (ICGR15: 15.0 to 28.0%), when the same 4 mg was taken once a day, the blood concentration was barely seen to differ from that of the patients with essential hypertension.
Measurement
Substance Dosing
Days Cmax
(ng/ml)Tmax
(h)AUC0 to 30h
(ng-h/ml)T1/2aa)
(h)T1/2ba)
(h)Candi
Sartan -_- Day 1 55.1±19.95.0±1.1428±91b) 2.2±1.49.5±5.1°_° Day 9 57.7±14.14.5±1.3509±1512.0±0.711.2±7.2M-II -_- Day 1 8.3±2.78.0±1.9 136±48b) –8.9±2.6°_° Day 9 10.9±3.46.8±1.5197±64–13.7±6.1a) Inferred from atrial model (mean±standard deviation, n=8)
b) n=7
[Resolution of overall pharmacokinetics using measured blood candesartan concentrations]
A total of 168 healthy adult males, 30 patients with essential hypertension as well as elderly patients with essential hypertension, 18 patients with hypertension with renal dysfunction, and 8 patients with hypertension with hepatic dysfunction, for a total of 224 cases, were studied for the 2886 points of blood candesartan concentration measurements obtained for gender, age, weight, liver function indices (GOT, GPT), renal function indices ( serum creatinine, BUN), blood albumin values and the presence of hypertension were correlated with the clearance, volume of distribution and relative bioavailability of candesartan, the results of which were presumed to be 45% lower in patients with hepatic dysfunction (GOT > 40 or GPT > 35).
2. Urinary excretion rate
In 8 cases of patients with essential hypertension (38-68 years old), 6 cases of elderly patients with essential hypertension (65-70 years old), 18 cases of hypertensive patients with renal dysfunction, and 8 cases of hypertensive patients with hepatic dysfunction, the prodrug was not detected in the urine when the drug was first administered once a day at 4 mg after breakfast, stopped for 1 day, and then repeatedly administered for 7 consecutive days, and the active metabolite candesartan as well as the the inactive metabolite M-II was excreted. The total urinary excretion of candesartan and M-II from dosing to 24 hours was 11-12% in patients with essential hypertension, 10-12% in elderly patients with essential hypertension, and approximately 10-11% in patients with hepatic dysfunction, with little difference seen between the three. Urinary excretion rates in hypertensive patients with renal dysfunction: 1.1% on day 1 and 1.8% on day 9 in patients with serum creatinine greater than 3.0 mg/dl, and 6.8% on day 1 and 9.3% on day 9 in patients with normal renal function with serum creatinine less than 1.5 mg/dl. From the above blood concentration and urinary excretion rate at repeated dosing, it can be concluded that drug accumulation was not seen in patients with essential hypertension, elderly patients with essential hypertension, hypertensive patients with hepatic dysfunction, and hypertensive patients with renal dysfunction.
Storage
Storage]: Store at room temperature (10-30℃).
Package
Package】Polyvinyl chloride solid pharmaceutical hard tablets/aluminum foil for pharmaceutical packaging, 7 tablets/box, 14 tablets/box, 28 tablets/box.
Available
Efficacy
Period】24 months
Execution Standard】XXXXX
Approval number】
4mg：Guohuazhenzhi H20030771
8mg：GuoYaoZhenZi H20041988
Manufacturer
Company Name: Chongqing Shenghuaxi Pharmaceutical Co.
Address: No. 8, Jiangqiao Road, Nanan District, Chongqing
Postal Code: 401336
Telephone number: 023-62520206
Fax number: 023-62510800
Web
Address: www.shenghuaxi.com