Date of approval.
Date of revision.
Valsartan Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drugs that act directly on the renin-angiotensin system may cause damage or even death to the developing embryo. When pregnancy is detected, this product should be discontinued immediately.
Drug name]
Generic name: Valsartan Capsules
English name: Valsartan Capsules
Hanyu Pinyin: Xieshatan Jiaonang
Ingredients
Active ingredient: Valsartan
Chemical name: N-pentanoyl-N-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine
Chemical structure formula.
Molecular formula: C24H29N5O3
Molecular weight: 435.52
Properties
The content of this product is white or off-white granules or powder.
Indications】
Treatment of mild and moderate primary hypertension.
Specification
80mg
Dosage]
Recommended dose: 80mg or 160mg once daily. The dose is independent of race, age and gender. It can be taken with a meal or on an empty stomach (see [Pharmacokinetics]). Dosing at the same time of day (e.g., morning) is recommended.
The definite antihypertensive effect is achieved within 2 weeks of administration, and the maximum effect is achieved after 4 weeks. If the antihypertensive effect is not satisfactory, a diuretic may be added.
The starting dose does not usually need to be adjusted in the elderly.
Patients with mild to moderate renal impairment do not require adjustment of the starting dose. See [Contraindications] for severe renal impairment (creatinine clearance <30 ml/min).
No dose adjustment is required in patients with mild to moderate hepatic impairment of non-cholestatic origin and without cholestasis. There is no recommended dose available for patients with severe hepatic impairment.
The use of this product in patients with hepatic or renal impairment requires intensive monitoring.
Valsartan can be used in combination with other anti-hypertensive drugs.
[Adverse reactions].
In a placebo versus valsartan capsule controlled trial including 2316 patients with hypertension, the overall adverse event (AE) rate in the valsartan capsule group was similar to that in the placebo group.
In a 6-month open extension trial of 642 hypertensive patients treated with 320 mg valsartan, the overall incidence of adverse events was similar to that observed in the placebo-controlled trial.
The incidence of adverse events reported in 10 placebo-controlled trials with patients taking valsartan 10-320 mg/day until 12 weeks. 1281 and 660 of 2316 patients took valsartan 80 mg and 160 mg, respectively. the incidence of adverse events was independent of dose and duration of dosing and was not related to sex, age, or race.
Adverse reactions from clinical studies, post-marketing use experience and laboratory tests according to system organ classification are listed in the table below. Adverse reactions were categorized by incidence from highest to lowest as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); and very rare (<1/10,000). Within each group, adverse reactions were ranked from highest to lowest severity. For all reports of adverse reactions from postmarketing experience and laboratory tests, it was not appropriate to group them according to frequency, so their incidence was recorded as “unknown”.
Hematologic and lymphatic disorders unknown Hemoglobinopenia, erythropoietic cytopenia, neutropenia, thrombocytopenia
Immune system disorders unknown Hypersensitivity reactions, including serum sickness Metabolic and nutritional disorders unknown Hyperkalemia ear and inner ear vagus disorders unknown Vertigo vascular disorders unknown Vasculitis respiratory, thoracic and mediastinal disorders unknown Cough gastrointestinal disorders unknown Abdominal pain Hepatobiliary disorders unknown Abnormal liver function test results, including elevated serum bilirubin levels Skin and subcutaneous tissue disorders unknown Angioedema, rash, pruritus, maculopapular dermatitis pruritus, dermatitis herpetiformis Musculoskeletal and connective tissue disorders unknown Myalgia
Renal and urologic disorders unknown renal failure and renal impairment, elevated serum creatinine
Systemic disease and administration site reactions uncommon fatigue
The following adverse events were also observed in clinical trials in hypertensive patients (whether or not related to the study drug): arthralgia, weakness, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infection, palpitations, constipation, dry mouth, dyspepsia and flatulence, muscle cramps, anxiety, abnormal sensation, drowsiness, dyspnea, and impotence.
Other events that occurred less frequently in clinical trials included chest pain, syncope, anorexia, and vomiting.
Post-marketing experience
The following adverse reactions were received post-marketing.
Hypersensitivity reactions: Angioedema has been reported rarely. In some of these patients, angioedema had previously occurred during treatment with other drugs, including ACE inhibitors. Patients who have experienced angioedema should not be rechallenged with this product.
Gastrointestinal: elevated liver enzyme levels and extremely rare reports of hepatitis
Renal: renal impairment, renal failure
Clinical laboratory tests: hyperkalemia
Dermatologic: alopecia, dermatitis herpetiformis
Blood and lymphoid tissue: extremely rare reports of thrombocytopenia have been received
Vascular: vasculitis
Rare cases of rhabdomyolysis have been reported in patients treated with angiotensin II receptor blockers.
Because these reactions were voluntarily reported from a population of uncertain size, it is not possible to reliably estimate their frequency or to determine a causal relationship with drug exposure.
[Contraindication].
Hypersensitivity to valsartan or any other excipient in this product.
Pregnancy (see [Use in Pregnant and Lactating Women]).
No dosing data are available for patients with severe renal impairment (creatinine clearance <30 ml/min).
This product should not be used in combination with aliskiren in patients with diabetes mellitus.
Precautions]
Fetus and neonate: Application of drugs that act directly on the renin-angiotensin system during the middle and last trimester of pregnancy may impair embryonic renal function and increase the risk of embryonic and neonatal disease and death. It may lead to low amniotic fluid, lung hypoplasia, and skeletal malformations. Potential neonatal adverse effects include: craniosynostosis, anuria, hypotension, renal failure, and death. When pregnancy is detected, the product should be discontinued immediately.
Hyponatremia and/or hypovolemia: In rare cases, patients with severe sodium deficiency and/or hypovolemia (e.g., high dose application of diuretics) may develop symptomatic hypotension at the beginning of treatment with this product. Hyponatremia and/or hypovolemia should be corrected, e.g., by reducing the diuretic dose, prior to drug administration. If hypotension occurs, the patient should be placed in a flat position and, if necessary, intravenous saline should be administered. Treatment with this product can be continued after the blood pressure is stabilized.
Renal artery stenosis: 12 patients with secondary renal vascular hypertension due to unilateral renal artery stenosis who were given this product for a short period of 4 days did not cause significant changes in renal hemodynamics, creatinine, or urea nitrogen (BUN). Because other drugs acting on the renin-angiotensin-aldosterone system (RAAS) may elevate BUN and creatinine in patients with unilateral or bilateral renal artery stenosis, monitoring of BUN and creatinine is recommended as a safe means.
Renal impairment: No adjustment of the starting dose is required in patients with mild to moderate renal impairment. Intensive monitoring is required for the use of this product in patients with renal impairment. There is no information on the use of this product in patients with severe renal impairment (creatinine clearance <30 ml/min) and it is not recommended (see [Contraindications]). This product should not be used in combination with aliskiren in patients with diabetes mellitus. Avoid combining this product with aliskiren in patients with impaired renal function (creatinine clearance < 60 ml/min).
Changes in renal function may occur in susceptible individuals due to inhibition of the renin-angiotensin-aldosterone system (RAAS). In patients whose renal function may be partially dependent on RAAS activity (e.g., renal artery stenosis, chronic renal impairment, severe congestive heart failure, or blood volume deficiency), there is an increased risk of acute renal impairment (including acute renal failure) with the use of RAAS-inhibiting agents, including valsartan capsules.
Such sensitive patients should be monitored regularly for renal function when using this product.
Hepatic impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment of non-biliary origin and without cholestasis. Valsartan is excreted primarily from the bile as a prototype, with reduced excretion in patients with biliary obstruction (see [Pharmacokinetics]). This product should be used with caution in patients with biliary obstruction and cholestasis. There is no recommended dose for patients with severe hepatic impairment. The use of this product in patients with hepatic impairment requires intensive monitoring.
Angioedema: Patients treated with valsartan have reported the occurrence of angioedema, including laryngeal and vocal edema, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue; some of these patients have a history of angioedema with other drugs, including ACE inhibitors. Patients who develop angioedema should discontinue valsartan capsules immediately and should not be reintroduced.
Dual blockade of the renin-angiotensin-aldosterone system: Great caution should be exercised in the combination of angiotensin II receptor antagonists (including valsartan capsules) with ACE inhibitors or aliskiren. Blood pressure, renal function and electrolytes should be closely monitored when combining this product with other drugs that block the renin-angiotensin-aldosterone system.
Pregnant women and nursing mothers
Women of childbearing age: For women who are likely to become pregnant, physicians should inform them of the potential risks of this class of drugs during pregnancy when prescribing drugs that act on RAAS. As a drug that also acts directly on the RAAS, valsartan capsules should be contraindicated in women who are preparing for pregnancy.
Pregnancy: Given the mechanism of action of angiotensin II antagonists, a fetal hazard from this product cannot be excluded. Intrauterine administration of angiotensin-converting enzyme inhibitors (a specific class of drugs acting on RAAS) during the 2nd and 3rd trimesters of pregnancy has been reported to cause damage to the developing fetus or to result in fetal death. Therefore, similar to other drugs that act directly on the RAAS, this product should not be used in women during pregnancy (see [Contraindications]). In addition, there is a potential risk of congenital defects associated with the use of angiotensin-converting enzyme inhibitors in the first trimester of pregnancy in retrospective data. Spontaneous abortion, hypohydramnios, and neonatal renal insufficiency have been reported in pregnant women who were unintentionally administered valsartan. All newborns who have been exposed to this product in utero should be closely monitored to ensure adequate urine output, prevent hyperkalemia, and monitor blood pressure. Use appropriate therapeutic measures (e.g., rehydration) to clear the drug if necessary.
Lactation: It is not known whether valsartan is excreted in human milk. Since valsartan is excreted in the milk of lactating rats. Therefore, this product should not be used in nursing women.
Fertility: There is no information to suggest that valsartan capsules affect human fertility. Studies in rats have not shown an effect of valsartan on fertility (see [Pharmacology and Toxicology]).
Pediatric use】.
There are no studies on the efficacy and safety of this product in children and adolescents (under 18 years of age).
Geriatric Use]
Clinical trial data show that no significant differences in efficacy or safety have been observed with valsartan in the elderly (≥65 and ≥75 years of age); however, it cannot be ruled out that some elderly patients may be more sensitive to this product.
Drug Interactions]
Interactions have been studied with the following drugs: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, and glibenclamide, and no significant drug interactions were found.
Because valsartan undergoes little or no metabolism, no clinical interactions have been found with drugs that induce or inhibit the cytochrome P450 system.
Although valsartan is mostly bound to plasma proteins, in vitro experiments have not found it to interact with other plasma protein-binding drugs (e.g., diclofenac, furosemide, warfarin) at this level.
Potassium: The combination of valsartan with renin-angiotensin system blockers, potassium-preserving diuretics (e.g., spironolactone, aminoglutethimide, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that increase blood potassium concentrations (heparin, etc.) can lead to elevated blood potassium concentrations and cause elevated serum creatinine in patients with heart failure. Therefore, care needs to be taken to monitor serum potassium when co-administering medications.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase 2 inhibitors (COX-2): When angiotensin II receptor antagonists and NSAIDs are taken together, the anti-hypertensive effect is reduced. In addition, concomitant use of angiotensin II receptor antagonists and NSAIDs in elderly patients, patients with reduced blood volume (including those receiving diuretics), or those with renal impairment may put them at increased risk of worsening renal function. Therefore, renal function should be monitored in patients on NSAIDs who are starting or adjusting treatment with valsartan.
Lithium: Combined use of lithium with ACE inhibitors or angiotensin II receptor antagonists (including valsartan capsules) has been reported to cause reversible elevated serum lithium concentrations and lithium toxicity. Therefore, careful monitoring of serum lithium concentration levels is recommended during the combined use of medications. The risk of lithium toxicity may be further increased with the use of valsartan capsules if diuretics are used concomitantly.
Transporter proteins: Results from an in vitro study in human liver tissue indicate that valsartan is a substrate for the hepatic uptake transporter protein OATP1B1 and the hepatic efflux transporter protein MRP2. Combined use of uptake transporter protein inhibitors (e.g., rifampin, cyclosporine) or efflux transporter protein inhibitors (e.g., ritonavir) may increase systemic exposure to valsartan.
Dual blockade of the renin-angiotensin-aldosterone system: compared with monotherapy
The combination of an angiotensin II receptor antagonist, ACE inhibitor
or aliskiren and thus dual blockade of the RAS system increases the risk of hypotension, hyperkalemia, and abnormal renal function, including acute renal failure. Therefore, great caution should be exercised in combining angiotensin II receptor antagonists (including valsartan capsules) with ACE inhibitors or aliskiren. Blood pressure, renal function and electrolytes should be closely monitored when combining this product with other drugs that block the renin-angiotensin-aldosterone system.
This product should not be combined with aliskiren in patients with diabetes mellitus. Avoid combining this product with aliskiren in patients with renal impairment (creatinine clearance < 60 ml/min).
Overdose]
Overdose may result in significant hypotension, which may cause decreased level of consciousness, circulatory collapse, and/or shock. If the drug is not taken for a long time, it should be treated with emetic, otherwise routine treatment is given with saline IV infusion. Hemodialysis does not clear valsartan.
Pharmacology and toxicology]
Pharmacological effects
The activator of renin-angiotensin-aldosterone system (RAAS) is angiotensin II, which is formed by angiotensin I under the action of angiotensin-converting enzyme (ACE). Angiotensin II binds to specific receptors on the cell membranes of various tissues. It has a variety of physiological effects, including direct or indirect involvement in blood pressure regulation. Angiotensin II is a potent vasoconstrictor with direct blood pressure elevating effects, as well as promoting sodium reabsorption and stimulating aldosterone secretion.
Valsartan is an orally effective specific angiotensin (AT) II receptor antagonist that acts selectively on the AT1 receptor subtype, producing pharmacological effects on vascular smooth muscle and adrenal glands, etc. The AT2 receptor subtype is not associated with cardiovascular effects. Valsartan does not have any partial agonist activity on AT1 receptors. Valsartan has a 20,000-fold stronger affinity for the AT1 receptor than the AT2 receptor.
ACE converts angiotensin I to angiotensin II and degrades bradykinin. The angiotensin II receptor antagonist, valsartan, has no inhibitory effect on ACE and does not cause retention of bradykinin or substance P, so it does not cause cough. Valsartan has no effect on other hormone receptors or ion channels that are known to play an important role in cardiovascular regulation.
Valsartan reduces elevated blood pressure while not affecting heart rate. In most patients, a single oral dose produces a hypotensive effect within 2 hours, with a peak effect at 4 to 6 hours, and the hypotensive effect is maintained until more than 24 hours after dosing. When repeatedly administered, maximum antihypertensive efficacy is achieved after 2-4 weeks of treatment and maintained during long-term treatment. Combination with thiazide diuretics may further significantly enhance the antihypertensive effect. Abrupt termination of valsartan therapy did not cause a “rebound” of hypertension or other clinical adverse events. In a multi-dose study of hypertensive patients, valsartan had no significant effect on total cholesterol, fasting triglycerides, fasting glucose, or uric acid levels.
Toxicological Studies
Genotoxicity
Valsartan Ames test, Chinese hamster V79 cell gene mutation test, Chinese hamster ovary cell chromosome aberration test and rat micronucleus test results were negative.
Reproductive toxicity
Oral administration of valsartan to rats at doses up to 200 mg/kg/d did not show any significant adverse effects on fertility in female and male rats, which was 6 times the maximum recommended human dose (320 mg/d for human administration at 60 kg body weight based on body surface area). No significant effects on offspring growth and development were observed in pregnant mice and pregnant rats given valsartan at doses up to 600 mg/kg/d orally, and in pregnant rabbits at doses up to 10 mg/kg/d orally. In pregnant rats given maternal toxicity (decreased body weight gain values and food intake) at doses of 600 mg/kg orally during organogenesis, late gestation and lactation, significant reductions in embryonic body weight, fetal birth weight and survival were seen, and fetal growth was retarded. Embryo-fetal toxicity (e.g., embryo resorption, whole litter loss, abortion, and low fetal weight) in pregnant rabbits was associated with maternal toxicity (mortality) at doses of 5 mg/kg/d and 10 mg/kg/d. NOAEL values were 600 mg/kg/d in mice, 200 mg/kg/d in rats, and 2 mg/kg/d in rabbits, which correspond to the maximum human dose of valsartan. The NOAEL values in mice, rats and rabbits were 600 mg/kg/d, 200 mg/kg/d and 2 mg/kg/d, respectively, which were 9, 6 and 0.1 times the maximum recommended human dose (320 mg/d at 60 kg body weight based on body surface area).
Carcinogenicity
Valsartan was given to mice and rats at doses of 160 and 200 mg/kg/day, respectively, for 2 years, and was not found to be carcinogenic, which was 2.6 and 6 times of the maximum recommended human dose (320 mg/d at 60 kg body weight, based on body surface area).
Pharmacokinetics]
Absorption: plasma concentration peaks 2-4 hours after oral administration of one drug, valsartan.
The average absolute bioavailability of this product is 23%. Taking valsartan with meals reduced the AUC by 48%, but blood concentrations were similar after 8 hours with or without meals. the reduction in AUC had no significant effect on clinical efficacy, and the product can be taken with meals or on an empty stomach.
Distribution.
The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating that valsartan is not widely distributed into the tissues. The vast majority of valsartan (94-97%) is bound to serum proteins (mainly albumin).
Biotransformation: Most valsartan is not biotransformed, and only about 20% of valsartan is converted to metabolites. The hydroxyl metabolite is present in plasma but at very low concentrations (less than 10% of the AUC of valsartan). This metabolite has no pharmacological activity.
Clearance: Valsartan is metabolized with multi-exponential decay kinetics (a-phase half-life <1 hour, terminal half-life approximately 9 hours). Valsartan is excreted as a prototype primarily via feces (~83%) and urine (~13%). After intravenous administration, the plasma clearance of valsartan is approximately 2 L/h and the renal clearance is 0.62 L/h (approximately 30% of the total clearance). The half-life of valsartan is 6 hours.
The pharmacokinetic profile of valsartan was linear over the dose range studied. When repeatedly administered, the pharmacokinetic profile of valsartan was similar to that of a single dose; when taken once daily, valsartan rarely caused accumulation, and plasma concentrations were similar in men and women.
Plasma clearance is relatively slow (approximately 2 L/h) compared to hepatic blood flow (30 L/h).
Pharmacokinetics in special clinical situations
Elderly: Some elderly people (> 65 years) have slightly increased systemic tissue concentrations of valsartan compared to young volunteers, but they are not clinically significant.
Patients with renal impairment: since only 30% of valsartan is excreted from the kidney, there is no clear correlation between renal function and systemic exposure to valsartan. Therefore, no dose adjustment is required in patients with mild-moderate renal impairment (see [contraindications] for severe renal impairment). No studies have been seen in hemodialysis patients, but given the high degree of binding of valsartan to serum proteins, clearance by dialysis is unlikely.
Patients with hepatic impairment: Approximately 70% of valsartan is excreted as a prototype via bile and valsartan is not biotransformed; therefore, systemic exposure to valsartan is not associated with hepatic insufficiency. No dose adjustment is necessary in patients with mild to moderate hepatic insufficiency of non-cholestatic origin and without biliary sludge. The AUC of valsartan is increased approximately 1-fold in patients with biliary hepatic sclerosis or biliary obstruction (see [Precautions]).
[Storage].
Store under 30℃ under light, sealed.
Package】
Aluminum-plastic packaging, 7 capsules/box, 12 capsules/box, 14 capsules/box, 24 capsules/box, 28 capsules/box, 36 capsules/box, 48 capsules/box, 72 capsules/box.
Expiration date
18 months
Execution Standard
Approval number】
State Drug Certificate H20103521
Manufacturer
Company Name: Hunan Qianjin Xiangjiang Pharmaceutical Co.
Address: No. 1, Jinlong East Road, Hetang District, Zhuzhou City, Hunan Province
Postal Code: 412003
Telephone number: 0731-22131224 22131536
Fax number: 0731-22131717 22131626
Web
Address: www. qjxy.com.cn