Date of approval.
Date of revision.
Valsartan Amlodipine Tablets (I) Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug name]
Generic name: Valsartan and Amlodipine Tablets (I)
English name: Valsartan and Amlodipine Tablets (I)
Hanyu Pinyin: Xieshatan Anlüdiping Pian (I)
Ingredients
This product is a compound preparation, its composition is: each tablet contains 80mg of valsartan and 5mg of amlodipine.
Properties
This product is a film-coated tablet, which appears white after removing the coating.
Indications
Treatment of primary hypertension.
This product is used for patients whose blood pressure cannot be adequately controlled by monotherapy.
Specification
Each tablet contains 80mg of valsartan and 5mg of amlodipine.
Dosage]
Amlodipine 2.5 mg to 10 mg once daily is effective in the treatment of hypertension, while valsartan is effective at doses of 80 mg to 320 mg. In clinical trials of once-daily valsartan amlodipine tablets, the antihypertensive efficacy increased with higher doses using 5 mg to 10 mg of amlodipine and 80 mg to 320 mg of valsartan.
Adverse effects of valsartan are usually dose-independent; those of amlodipine are both dose-dependent (mainly peripheral edema) and dose-non-dependent, with the former being more common than the latter.
Patients whose blood pressure is not adequately controlled with monotherapy may be switched to this product.
Add-on therapy: Patients who fail to adequately control their blood pressure with amlodipine monotherapy or valsartan monotherapy may be switched to this product for combination therapy.
Patients who experience dose-limiting adverse reactions to amlodipine or valsartan monotherapy may be switched to this product to achieve blood pressure control with a lower dose of the single component in combination with another component. The vast majority of the therapeutic effect is usually achieved within 2 weeks after initiation of the drug or dose change.
Alternative therapy: Patients receiving the combination of amlodipine and valsartan monotherapy may be switched to the same dose of this product for ease of administration.
Both amlodipine and valsartan may be taken with food or on an empty stomach. It is recommended that this product be taken with water.
Hepatic and renal impairment
No dose adjustment is required in patients with mild to moderate renal impairment. Use with caution in severe renal impairment (see [Contraindications]). This product should also be used with caution in patients with hepatic injury or biliary obstructive disease (see [Precautions]).
Adverse reactions]
Five controlled clinical trials evaluated the safety of this product in a total of 5,175 patients, of which 2,613 were combined with valsartan and amlodipine. The safety of valsartan amlodipine tablets has been evaluated in more than 2,600 patients with hypertension; more than 1,440 of these patients were treated for more than 6 months and more than 540 patients were treated for more than 1 year. Adverse reactions were usually mild and transient, and only rarely required discontinuation of the drug.
The overall incidence of adverse reactions was non-dose dependent and independent of gender, age and race. In placebo-controlled clinical studies, 1.8% of patients in the valsartan amlodipine tablet treatment group discontinued the drug due to side effects compared to 2.1% in the placebo group. The most common reasons for discontinuation were peripheral edema (0.4%) and vertigo (0.2%).
Adverse reactions that occurred in at least 2% of patients treated with this product in placebo-controlled clinical trials and were more frequent in the valsartan amlodipine tablet group (n=1437) than in the placebo group (n=337) were peripheral edema (5.4% versus 3.0%), nasopharyngitis (4.3% versus 1.8%), upper respiratory tract infection (2.9% versus 2.1%), and dizziness ( 2.1% versus 0.9%).
Postural events (upright hypotension and postural dizziness) occurred in less than 1% of patients.
The incidence of adverse reactions or adverse experiences, in descending order, using the following terms: very common (≥ 1/10); common (≥ 1/100, < 1/10); occasional (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including individual case reports. Within each incidence group, adverse reactions are listed in order of decreasing severity.
Additional adverse reactions (≥0.2%) occurring in the valsartan amlodipine tablets group in placebo-controlled clinical trials of this product are listed below according to system organ classification. It could not be determined whether these adverse reactions were caused by this product.
Blood and lymphatic system disorders: lymphadenopathy
Cardiac disorders: palpitations, tachycardia
Ear and inner ear vagus disorders: ear pain
Gastrointestinal disorders: diarrhea, nausea, constipation, dyspepsia, abdominal pain, epigastric pain, gastritis, vomiting, abdominal discomfort, bloating, dry mouth, colitis
Systemic diseases and administration site conditions: fatigue, chest pain, debility, acupressure edema, fever, edema, facial edema
Immune system disorders: seasonal allergic reactions
Infections and infections: nasopharyngitis, sinusitis, bronchitis, pharyngitis, gastroenteritis, pharyngotonsillitis, acute bronchitis, tonsillitis, influenza
Injuries and poisoning: epicondylitis, joint sprains, limb injuries
Metabolic and nutritional disorders: gout, non-insulin-dependent diabetes, hypercholesterolemia
Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscle spasms, extremity pain, myalgia, osteoarthritis, joint swelling, musculoskeletal chest pain, heaviness
Neurological disorders: headache, sciatica, sensory abnormalities, head and arm syndrome, carpal tunnel syndrome, dullness of sensation, sinus headache, drowsiness
Mental disorders: insomnia, anxiety, depression
Kidney and urinary system disorders: hematuria, kidney stones, frequent urination, polyuria
Reproductive and breast disorders: erectile dysfunction
Respiratory, chest and mediastinal disorders: cough, sore throat, sinus congestion, dyspnea, rhinorrhea, expectorant cough, vocal difficulties, nasal congestion
Skin and subcutaneous tissue disorders: pruritus, rash, hyperhidrosis, eczema, erythema
Vascular disorders: flushing, hot flushes
The following clinically significant individual adverse reactions were also observed in clinical trials: rash, syncope, visual disturbances, hypersensitivity, tinnitus, and hypotension.
Additional information on combination therapy
In completed double-blind, positive drug or placebo-controlled clinical trials, the incidence of peripheral edema was significantly lower in patients receiving valsartan amlodipine combination therapy (5.8%) than in patients receiving amlodipine monotherapy (9%).
Amlodipine studies.
Because amlodipine clinical trials are conducted under different conditions, the rates of adverse reactions observed in clinical trials of one drug are not directly comparable to the incidence observed in clinical trials of another drug and may not reflect the rates of adverse reactions observed in actual practice.
The safety of amlodipine besylate tablets has been evaluated in clinical trials in the United States and outside the United States in more than 11,000 patients. The following table lists other adverse events with uncertain drug-related relationships reported by <1% but >0.1% of patients in controlled clinical trials or under open trial conditions, or in post-marketing experience. Adverse drug reactions were ranked according to frequency, in descending order, using the following terms: very common (≥ 1/10); common (≥ 1/100,< 1/10); uncommon (≥ 1/1,000,< 1/100); rare (≥ 1/10,000,< 1/1,000); very rare (< 1/10,000) ; unknown (cannot be estimated from available data). Within each incidence group, adverse reactions are listed in order of decreasing severity.
Adverse reactions to amlodipine monotherapy
Eye disease uncommon diplopia blood and lymphatic system disorders extremely rare thrombocytopenia, leukopenia immune system disorders extremely rare allergic reactions metabolic and nutritional disorders extremely rare hyperglycemia psychiatric disorders uncommon insomnia, mood changes central nervous system disorders uncommon tremor, sensory dullness, taste disturbances extremely rare peripheral neuropathy, hypertonia cardiovascular disorders extremely rare arrhythmias, bradycardia, atrial Fibrillation, ventricular tachycardia, myocardial infarction Vascular disorders extremely rare vasculitis Respiratory, thoracic and mediastinal disorders uncommon dyspnea, rhinitis Gastrointestinal disorders uncommon vomiting, dyspepsia extremely rare pancreatitis, gastritis, gingival hyperplasia Hepatobiliary disorders extremely rare hepatitis, jaundice Skin and subcutaneous tissue disorders uncommon alopecia, purpura, skin discoloration, photosensitivity extremely rare angioedema, urticaria, erythema multiforme Steven Johnson syndrome musculoskeletal and connective tissue disorders uncommon myalgia renal and urinary disorders uncommon dysuria, nocturia genital and breast disorders uncommon gynecomastia systemic disorders and administration site conditions uncommon pain, discomfort, chest pain examination uncommon weight loss, weight gain very rare elevated liver enzymes (mostly consistent with manifestations of biliary obstruction or hepatitis) For adverse reactions reported with amlodipine in indications other than hypertension, see the instructions for amlodipine benzoate tablets.
Studies of valsartan.
Additional adverse reactions reported in clinical studies, postmarketing experience, and laboratory findings for hypertension indications are listed in the table below according to system organ classification.
It is not possible to express all adverse reactions and laboratory findings reported post-marketing using the frequency of adverse reaction reports, therefore “unknown” is indicated in the frequency column.
In clinical trials, the safety of valsartan was evaluated in more than 4,000 patients with hypertension. In clinical trials comparing valsartan with or without placebo to angiotensin-converting enzyme inhibitors (ACEI), the incidence of dry cough was significantly higher in the ACE inhibitor group (7.9%) than in the valsartan group (2.6%) or the placebo group (1.5%). In a study of 129 patients with a history of dry cough while taking ACE inhibitors, treated with valsartan, hydrochlorothiazide, or lenopril, respectively, the incidence of cough in patients was 20%, 19%, and 69%, respectively (p<0.001).
Adverse effects of valsartan monotherapy
Hematologic and lymphatic system disorders unknown decreased hemoglobin, erythrocyte specific volume pressure, neutropenia, thrombocytopenia Immune system disorders unknown hypersensitivity reactions, including serum sickness Metabolic and nutritional disorders unknown elevated blood potassium Vascular disorders unknown vasculitis Hepatobiliary disorders unknown abnormal liver function tests, including elevated blood bilirubin Skin and subcutaneous tissue disorders unknown angioedema, dermatitis herpetiformis Musculoskeletal and connective tissue disorders unknown myalgia renal and urinary disorders unknown renal failure and renal injury, elevated blood creatinine hypertensive patients The following events were also observed during clinical trials, whether or not causally related to the study drug: insomnia, decreased libido, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections, viral infections.
Post-marketing application experience
Amlodipine: Rare reports of mastodynia in men with an uncertain causal relationship. Jaundice and elevated liver enzymes (mostly consistent with cholestasis or hepatitis), with some more severe cases requiring hospitalization, have been reported in association with amlodipine administration.
Valsartan: The following additional adverse reactions have been reported after the launch of valsartan.
Hematologic and lymphatic: very rare reports of thrombocytopenia.
Hypersensitivity reactions: rare reports of angioedema.
Digestive: elevated liver enzymes and very rare reports of hepatitis.
Renal: impaired renal function.
Clinical laboratory tests: hyperkalemia
Skin: hair loss
Vascular: vasculitis
Rare cases of rhabdomyolysis in patients receiving angiotensin II receptor antagonists.
Clinical laboratory tests
Creatinine: In patients with hypertension, the proportion of patients with creatinine elevations of 50% or more was 0.4% in the valsartan amlodipine tablet treatment group and 0.6% in the placebo group.
Liver function: Elevated liver blood biochemical parameters (greater than 150% of normal) were occasionally seen in patients treated with this product.
Serum potassium: In patients with hypertension, the proportion of patients with elevated serum potassium of 20% or more was 2.8% in the valsartan amlodipine tablet-treated group and 3.4% in the placebo-treated group.
Blood urea nitrogen (BUN): The proportion of patients with a BUN elevation of 50% or more in hypertensive patients was 5.5% in the valsartan amlodipine tablet-treated group and 4.7% in the placebo-treated group.
Neutropenia: Neutropenia was observed in 1.9% of patients in the valsartan-treated group and 0.8% of patients in the placebo group.
[Contraindication].
Contraindicated in patients with hypersensitivity to the active ingredient or any of the excipients.
Contraindicated in pregnant and lactating women (see [Use in Pregnant and Lactating Women]).
No data are available on dosing in patients with severe renal impairment (creatinine clearance <10 mL/min).
This product should be contraindicated in patients with hereditary angioedema and in patients who develop angioedema early in treatment with ACE inhibitors or angiotensin II receptor antagonists.
Angiotensin receptor antagonists (ARBs) (including valsartan) or angiotensin-converting enzyme inhibitors (ACEIs) should not be combined with aliskiren in patients with type 2 diabetes (see [Drug Interactions]).
[Precautions].
Patients with reduced sodium and/or blood volume
In placebo-controlled trials, 0.4% of uncomplicated hypertensive patients treated with valsartan amlodipine tablets developed excessive hypotension. Symptomatic hypotension may occur in patients with an activated renin-angiotensin system (e.g., patients on high doses of diuretics with blood and/or salt deficiencies) receiving angiotensin II receptor antagonists. Altered renal function may occur due to inhibition of the renin-angiotensin-aldosterone system, particularly in patients with hypovolemia. Correction of the hypovolemic condition prior to administration of this product or close clinical monitoring at the time of initiation of therapy is recommended.
Caution is required when initiating therapy in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Administration of valsartan in patients with heart failure or post-myocardial infarction usually causes a decrease in blood pressure, but if dosing instructions are followed, treatment usually does not need to be discontinued because of persistent symptomatic hypotension. In controlled clinical trials in patients with heart failure, the incidence of hypotension was 5.5% in patients treated with valsartan and 1.8% in the placebo group. In the Valsartan Acute Myocardial Infarction Trial (VALIANT), the proportion of patients with permanent discontinuation due to hypotension after myocardial infarction was 1.4% in the valsartan-treated group and 0.8% in the captopril-treated group.
Because of the gradual onset of vasodilatory effects induced by amlodipine, acute hypotension has rarely been reported after oral administration. Nevertheless, as with any other peripheral vasodilator, amlodipine should be administered with caution, especially in patients with severe aortic stenosis.
If excessive hypotension occurs while taking this product, the patient should be placed in a flat position and, if necessary, given intravenous saline. Transient hypotension is not a contraindication to taking this product, and it can usually be continued after the blood pressure has stabilized.
Increased risk of myocardial infarction or angina pectoris
The frequency, duration, or severity of angina pectoris or acute myocardial infarction has rarely increased in patients (especially in patients with severe obstructive coronary artery disease) when calcium channel blocker therapy is initiated or at increased doses. The mechanism of this effect is not known.
Hepatic impairment
Amlodipine studies: Amlodipine is extensively metabolized by the liver and has a plasma clearance half-life (t1/2) of 56 hours in patients with hepatic impairment; therefore, amlodipine should be used with caution in patients with severe hepatic impairment.
Studies of valsartan: Valsartan is primarily cleared by bile and exposure (in terms of AUC values) in patients with mild to moderate chronic liver disease, including those with biliary obstructive disease, is on average twice as high as in healthy volunteers (age, sex and weight matched). This product should be used with caution in patients with hepatic disease or biliary obstructive disease.
Renal Impairment
Patients with an activated renin-angiotensin system (e.g., patients taking high doses of diuretics who are blood and/or salt deficient) receiving angiotensin II receptor antagonists may experience altered renal function due to inhibition of the renin-angiotensin-aldosterone system, particularly in patients who are blood volume deficient. Correction of the hypovolemic condition prior to administration of this product or close clinical monitoring at the time of initiation of therapy is recommended. Renal function in patients with severe heart failure may be dependent on the activity of the renin-angiotensin-aldosterone system, and treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists given may cause oliguria and/or progressive azotemia, and (rarely) acute renal failure and/or death.
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. There is no significant correlation between renal function (as creatinine clearance) and valsartan exposure (as AUC) in patients with different degrees of renal impairment. Therefore, patients with mild to moderate renal impairment can receive treatment at the usual starting dose. No dosing data are available for patients with severe renal impairment (creatinine clearance <10mL/min). It should be used with caution in patients with severe renal impairment.
Avoid the combination of angiotensin receptor antagonists (ARBs) (including valsartan) or angiotensin-converting enzyme inhibitors (ACEIs) with aliskiren in patients with severe renal impairment (GFR<30mL/min) (see [Drug Interactions]).
Patients with renal artery stenosis
This product should be used with caution in patients with unilateral or bilateral renal artery stenosis, or arterial stenosis to the point of unilateral renal loss, because blood urea and serum creatinine levels may be elevated in such patients. In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, elevated serum creatinine and blood urea nitrogen were found. No significant elevations in serum creatinine or blood urea nitrogen were observed in a 4-day study of valsartan in 12 patients with unilateral renal artery stenosis with hypertension. Long-term treatment with valsartan has not been studied in patients with unilateral or bilateral renal artery stenosis, although similar effects to ACE inhibitors are expected.
Renal transplant patients
To date, no safety data have been obtained for the use of this product in patients who have recently undergone renal transplantation.
Congestive Heart Failure
Studies with Amlodipine: In general, calcium channel blockers, including amlodipine, should be used with caution in patients with severe congestive heart failure (New York Heart Association (NYHA) functional class III-IV). In a placebo-controlled trial, amlodipine (5-10 mg/day) was studied in 1153 patients with NYHA class III and IV heart failure treated with stable doses of ACE inhibitors, digoxin, and diuretics. The minimum follow-up was 6 months and the mean was 14 months. There was no adverse effect on survival or cardiac morbidity (defined as life-threatening arrhythmias, acute myocardial infarction, or hospitalization due to worsening heart failure). Amlodipine was compared with placebo in four studies of patients with NYHA class II/III heart failure at 8 to 12 weeks, which included 697 patients. In these studies, there was no evidence of worsening heart failure as assessed by exercise tolerance, NYHA class, symptoms, or LVEF.
Studies with Valsartan: Some patients with heart failure experienced elevated blood urea nitrogen, serum creatinine and potassium concentrations while on valsartan therapy. These reactions are usually mild and transient and are more likely to occur in patients with renal insufficiency. Dose reduction and/or discontinuation of diuretics and/or valsartan may be required. In the Heart Failure with Valsartan study, 93% of patients receiving concomitant ACE inhibitor dosing discontinued dosing due to elevated creatinine or potassium levels (total 1.0% valsartan, 0.2% placebo). In the Acute Myocardial Infarction with Valsartan study (VALIANT), discontinuation due to various types of renal insufficiency was 1.1% in patients treated with valsartan and 0.8% in patients treated with captopril. Renal function in patients with severe heart failure may be dependent on the activity of the renin-angiotensin-aldosterone system, and treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists given may cause oliguria and/or progressive azotemia, as well as (rarely) acute renal failure and/or death. Evaluation of patients after heart failure or myocardial infarction with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists should always include evaluation of renal function.
Hyperkalemia
This product should be used with caution and close monitoring of potassium concentrations when concomitantly taking potassium supplements, potassium-preserving diuretics, salt substitutes containing potassium, or other drugs that increase potassium concentrations (heparin, etc.).
Angioedema
Angioedema, including laryngeal and vocal edema, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue, has been reported in patients treated with valsartan; some of these patients have a history of angioedema with other medications, including ACE inhibitors. Patients who develop angioedema should discontinue this product immediately and should not be reintroduced.
Patients with heart failure/post-myocardial infarction
In general, calcium channel blockers, including amlodipine, should be used with caution in patients with severe congestive heart failure (New York Heart Association (NYHA) functional class III-IV).
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists is associated with oliguria and/or progressive azotemia and, in rare cases, acute renal failure and/or death. Evaluation of this product in patients with heart failure or post-myocardial infarction should always include evaluation of renal function.
Dual blockade of the renin-angiotensin system (RAS)
Great caution should be exercised when combining angiotensin receptor antagonists (ARBs) (including valsartan) with other drugs that block the renin-angiotensin system (RAS), such as angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren (see [Drug Interactions]).
Patients with acute myocardial infarction
Angina pectoris and acute myocardial infarction can be exacerbated by amlodipine initiation therapy or by increasing the dose of amlodipine, especially in patients with severe obstructive coronary artery disease.
Patients with aortic and mitral valve stenosis and obstructive myocardial hypertrophy
As with all other vasodilators, special care should be taken in patients with aortic or mitral stenosis, or obstructive myocardial hypertrophy.
Effects on Driving and Operation of Machinery
Studies of the effects of drugs on the ability to drive and use machinery have not been performed. Consider that adverse reactions such as occasional dizziness or fatigue may occur and that caution should be exercised when driving and operating machinery.
Pregnant women and nursing mothers
Women of childbearing age
As a drug that acts directly on renin-angiotensin-aldosterone (RAAS), this product should be contraindicated in women who are preparing for pregnancy. Healthcare professionals who prescribe drugs that act on RAAS should inform women of childbearing age of the possible hazards of taking these drugs during pregnancy.
During Pregnancy
As a drug that acts directly on the RAAS, this product should be contraindicated in pregnant women ([contraindicated]). Given the mechanism of action of angiotensin II antagonists, fetal hazards cannot be excluded. In utero administration of angiotensin-converting enzyme inhibitors (a specific class of drugs that act on the renin-angiotensin-aldosterone system 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. In addition, there are retrospective data on the potential risk of congenital defects associated with the use of angiotensin-converting enzyme inhibitors in the first trimester of pregnancy. Spontaneous abortions, hypohydramnios, and neonatal renal insufficiency have been reported in pregnant women who were unintentionally administered valsartan. Similar to other drugs that act directly on the RAAS, this product should not be used in women during pregnancy (see [Contraindications]). For women of childbearing age, physicians prescribing drugs that act on the RAAS should be informed of the potential risks of these drugs during pregnancy. If pregnancy is detected during administration, the product should be discontinued immediately.
There are no adequate clinical data on the use of amlodipine in pregnant women. Animal studies with amlodipine have shown reproductive toxicity at doses up to 8 times the maximum recommended dose of 10 mg (see [Pharmacology and Toxicology]). The possible risk to humans is unknown.
Lactation
It is not known whether valsartan and/or amlodipine are excreted via human breast milk. Valsartan is excreted in the milk of lactating rats. Therefore, this product is contraindicated in lactating women.
Fertility
There is no information that amlodipine or valsartan affects human fertility. Fertility has not been shown to be affected by amlodipine or valsartan in rat studies (see [Pharmacology and Toxicology]).
Pediatric Dosage]
The safety and efficacy of this product in pediatric patients have not been established.
Geriatric Use]
In controlled clinical studies, 323 (22.5%) patients with hypertension treated with this product were ≥65 years of age and 79 (5.5%) patients were ≥75 years of age. No overall differences in the efficacy and safety of this product were observed in this patient population, but it cannot be excluded that some elderly patients are more sensitive to the drug.
Amlodipine: The number of subjects aged 65 years and older in the study of amlodipine benzoate tablets was insufficient to determine whether their drug response differed from that of younger subjects. Other clinical experiences have not found different responses between older and younger patients. In general, dosing in elderly patients needs to be carefully selected, generally starting with the lowest dose. Elderly patients have a higher incidence of reduced hepatic, renal and cardiac function and are often associated with other medical conditions or are receiving other medications. Amlodipine has reduced clearance in elderly patients, resulting in an elevated AUC of approximately 40-60%. Therefore, treatment with amlodipine in the elderly is usually initiated with a lower starting dose of 2.5 mg/day.
Valsartan: In controlled clinical studies of valsartan, 1214 (36.2%) hypertensive patients treated with valsartan were 65 years of age or older and 265 (7.9%) were 75 years of age or older. No overall differences in the efficacy or safety of valsartan were observed in this patient population, but it cannot be ruled out that some older individuals were more sensitive to the drug.
[Drug Interactions].
Amlodipine
Amlodipine can be combined with thiazide diuretics, alpha-receptor antagonists, beta-receptor antagonists, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral hypoglycemic drugs.
Calcium channel blockers can interfere with the cytochrome P450-dependent metabolism of theophylline and ergotamine. Because no data are available on in vivo or in vitro interaction studies of amlodipine in combination with theophylline or ergotamine, it is recommended that blood concentrations of theophylline or ergotamine be monitored regularly at the time of initiation of combination use.
In vitro studies with human plasma have shown that amlodipine does not affect the plasma protein binding of digoxin, phenytoin, coumadin, warfarin, and indomethacin.
Simvastatin: Combined administration of multiple doses of 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin given alone. It is recommended that the dose of simvastatin be limited to 20 mg per day in amlodipine administered patients.
CYP3A4 inhibitors: Administration of 180 mg diltiazem and 5 mg amlodipine daily in elderly patients with hypertension resulted in a 1.6-fold increase in systemic exposure to amlodipine. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentrations more than diltiazem. Caution should therefore be exercised when amlodipine is given in combination with CYP3A4 inhibitors.
CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Adequate clinical action monitoring of patients should be performed when amlodipine is co-administered with CYP3A4 inducers.
Special Studies: Effects of Other Active Substances on Amlodipine
Cimetidine
The combination of amlodipine and cimetidine does not alter the pharmacokinetics of amlodipine.
Grapefruit juice
Because of the inhibitory effect of grapefruit juice on CYP3A4, consumption of grapefruit juice while taking the drug would result in increased amlodipine exposure. However, in a study of 20 healthy volunteers, no significant effect on amlodipine pharmacokinetics was observed with a single oral dose of 10 mg of amlodipine accompanied by 240 mL of grapefruit juice.
Aluminum/Magnesium (Antacids)
The combination of an aluminum/magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil
A single dose of sildenafil (100 mg) does not affect the pharmacokinetic parameters of amlodipine in patients with essential hypertension. When amlodipine was combined with sildenafil, each drug exerted its own antihypertensive effect independently.
Special Studies: Effects of Amlodipine on Other Active Substances
Atorvastatin
The steady-state pharmacokinetic parameters of atorvastatin were not significantly altered by multiple dosing of amlodipine (10 mg) in combination with atorvastatin (80 mg).
Digoxin
Results from a study in healthy volunteers showed no change in plasma concentrations or renal clearance of digoxin when amlodipine was combined with digoxin.
Ethanol (alcohol)
Amlodipine (10 mg) had no significant effect on the pharmacokinetics of ethanol with single and multiple doses.
Warfarin
The effect of warfarin on prothrombin time was not significantly altered in healthy male volunteers when amlodipine was combined with warfarin.
Cyclosporine
Pharmacokinetic studies have shown no significant effect of amlodipine on the pharmacokinetics of cyclosporine.
Valsartan
Because valsartan undergoes little or no metabolism, no clinical interactions with drugs that induce or inhibit the cytochrome P450 system have been observed.
Although valsartan is mostly plasma protein bound, in vitro experiments have not found it to interact at this level with other plasma protein binding drugs (e.g., diclofenac, furosemide, warfarin).
Potassium: Use with caution in combination with potassium supplements, potassium-containing diuretics, salt substitutes containing potassium, or other drugs that increase potassium concentrations (heparin, etc.), and potassium concentrations should be monitored closely.
Angiotensin receptor antagonists (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), or aliskiren dual blockade of the renin-angiotensin system (RAS): The combination of ARBs (including valsartan) with other drugs that act on the RAS increases the risk of hypotension, hyperkalemia, and abnormal renal function compared with monotherapy. Blood pressure, renal function, and electrolytes should be monitored closely when combining this product with other drugs that affect the RAS (see [Precautions]).
Avoid combining ARBs (including valsartan) or ACEIs with aliskiren in patients with severely impaired renal function (GRF<30mL/min) (see [Precautions]).
ARBs (including valsartan) or ACEIs with aliskiren should not be combined in patients with type 2 diabetes (see [Contraindications]).
Non-steroidal anti-inflammatory drugs (NSAIDs) that include selective cyclooxygenase-2 inhibitors (COX-2 inhibitors).
Angiotensin II receptor antagonists may diminish their antihypertensive effects when combined with NSAIDs. Furthermore, combination of angiotensin II receptor antagonists with NSAIDs drug therapy in elderly, reduced fluid volume (patients treated with diuretics) or renal impairment patients may lead to an increased risk of deterioration of renal function. Therefore, patients on valsartan therapy should be monitored for renal function when starting combination therapy with NSAIDs or when adjusting therapy.
Lithium: Combined use of lithium with ACE inhibitors or angiotensin II receptor antagonists has been reported to cause reversible elevated serum lithium concentrations and lithium toxicity. Therefore, careful monitoring of serum lithium concentration levels is recommended during combined use. The risk of lithium toxicity may be further increased with the use of this product if a diuretic is 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 transport protein inhibitors (e.g., rifampin, cyclosporine) or efflux transport protein inhibitors (e.g., ritonavir) may increase systemic exposure to valsartan.
[Drug Overdose
No overdose events have been obtained with this product. The primary symptom of valsartan overdose may be hypotension accompanied by dizziness. Amlodipine overdose may result in peripheral vasodilation and may cause reflex tachycardia. Significant and prolonged systemic hypotension and fatal shock have been reported.
Vomiting or gastric lavage may be considered if the dose is not prolonged. The absorption of amlodipine can be significantly reduced by taking activated charcoal immediately or two hours after amlodipine administration in healthy volunteers. Clinically significant hypotension due to this overdose requires aggressive and effective cardiovascular support therapy, including close monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. To restore vascular tone and blood pressure, vasoconstrictive drugs may also be used when not contraindicated. Intravenous infusion of calcium gluconate is also useful to reverse the effects of calcium channel blockers.
Amlodipine overdose may cause peripheral vasodilation and possible reflex tachycardia. Significant and possibly prolonged systemic hypotension and even fatal outcomes, including shock, have been reported in patients. Clinically significant hypotension due to amlodipine overdose requires aggressive cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating blood volume and urination.
In the absence of contraindications to their use, vasoconstrictors may be helpful in restoring vascular tone and blood pressure.
If newly ingested, consider inducing vomiting or gastric lavage. The use of activated charcoal immediately or no more than two hours after amlodipine administration in healthy volunteers may significantly reduce amlodipine absorption. Intravenous administration of calcium gluconate may help reverse the effects of calcium channel blockade.
Neither valsartan nor amlodipine can be removed by hemodialysis treatment.
Pharmacology and Toxicology
This product includes two antihypertensive active ingredients, valsartan and amlodipine, which have complementary mechanisms of action in the control of blood pressure: amlodipine is a calcium channel blocker and valsartan is an angiotensin II receptor antagonist. The combination of the two components is more effective than either component alone in lowering blood pressure.
Preclinical Safety Information
Amlodipine/Valsartan
Various preclinical safety studies with amlodipine/valsartan in several animal species have not resulted in adverse findings affecting the use of therapeutic doses of amlodipine/valsartan in humans. Animal studies in rats and marmosets with fixed-dose combination formulations lasting 13 weeks and studies of embryotoxicity in rats.
Results of a 13-week oral toxicity study in rats showed amlodipine-/valsartan-associated gonadal gastric inflammation following administration of doses of ≥3/48 mg/kg/day in male rats and ≥120/7.5 mg/kg/day in female rats. In a 13-week study in velvet monkeys, no glandular gastric inflammation was observed after administration of any dose, although colorectal inflammation was observed in the high-dose group (not detected at doses ≤5/80 mg/kg/day). The results of clinical trials of this product showed that the incidence of gastrointestinal adverse reactions was not elevated in the compounded formulation compared to monotherapy with each component.
Treatment-related maternal and fetal effects (delayed and altered development with significant maternal toxicity) were found in the high-dose combination dosing group in an embryo-fetal development study in rats administered orally at dose levels of 5:80 mg/kg/day amlodipine:valsartan, 10:160 mg/kg/day amlodipine:valsartan and 20:320 mg/kg/day amlodipine:valsartan . No adverse effect levels (NOAEL) were observed for embryo-fetal effects at 10:160 mg/kg/day amlodipine:valsartan. These doses were 4.3 and 2.7 times higher than the systemic exposure of patients on MRHD (10/320 mg/60 kg), respectively.
Amlodipine:valsartan combination was not tested for mutagenicity, teratogenicity, effects on reproductive behavior, or carcinogenicity because there was no evidence of interaction between the two drugs.
Amlodipine.
There are adequate clinical and non-clinical safety data for amlodipine. No relevant findings were observed in carcinogenicity studies, mutagenicity studies.
Carcinogenicity
Amlodipine was added to food at daily doses of 0.5, 1.25 and 2.5 mg/kg for two years in rats and mice, and no signs of carcinogenicity were observed. The highest dose (in mg/m2, similar to the clinically recommended maximum dose of 10 mg in mice and twice that in rats*) was close to the maximum tolerated dose in mice, but not in rats.
Mutagenicity
Mutagenicity studies have shown no drug-related effects at the genetic or chromosomal level.
Effects on Fertility
Amlodipine given to rats at doses up to 10 mg/kg/day (64 days for males and 14 days for females prior to mating) had no effect on fertility, which is 8 times the maximum human recommended dose of 10 mg (in mg/m2) for a patient weighing 50 kg.
No teratogenicity or embryonic/fetal toxicity was observed in pregnant rats and rabbits given orally at doses up to 10 mg amlodipine/kg/day amlodipine maleate during their respective major organogenesis stages. However, litter size was significantly lower (~50%) and the number of intrauterine deaths was significantly higher (~5-fold). Amlodipine at this dose prolonged the duration of gestation and parturition in rats.
Amlodipine was tested separately for mutagenicity, teratogenicity, reproductive behavior effects, and carcinogenicity, and the results were negative.
Valsartan
Preclinical studies based on conventional safety pharmacology, genotoxicity, carcinogenicity and effects on fertility have shown no particular hazard in humans.
Safety pharmacology and long-term toxicity: Various preclinical safety studies in several animal species did not affect the adverse findings with therapeutic doses of valsartan in humans. In preclinical safety studies, high doses of valsartan (200-600 mg/kg body weight/day) caused a decrease in erythrocyte parameters (erythrocytes, hemoglobin, erythrocyte pressure product) and renal hemodynamic changes (slight elevation of blood urea nitrogen in male rats, as well as renal tubular hyperplasia and basophilia) in rats. These doses (200 and 600 mg/kg/day) in the rat test were approximately 6 and 18 times the maximum recommended human dose (in mg/m2), respectively (calculated assuming an oral dose of 320 mg/day for a patient weighing 60 kg). Similar changes occurred in marmosets using similar doses, although more severe, particularly renal changes developing into nephropathy, including elevated blood urea nitrogen and creatinine. Paraglomerular cell hyperplasia was also found in both animals. All changes were caused by the pharmacological effects of valsartan, resulting in prolonged hypotension, particularly in marmosets. Therapeutic doses of valsartan in humans were not associated with paraglomerular cell hyperplasia.
Reproductive toxicity: At oral doses up to 200 mg/kg/day, valsartan had no adverse effects on fertility in male and female rats. In embryo-fetal development studies (phase II) in mice, rats and rabbits, fetal and maternal toxicity was observed in rats given ≥600 mg/kg/day of valsartan, and fetal and maternal toxicity was observed in rabbits at doses ≥10 mg/kg/day. In perinatal and postnatal developmental toxicity (phase III) studies, slightly reduced survival and slightly delayed development were found in rat offspring given 600 mg/kg/day of drug during late gestation and lactation.
Mutagenicity: In various standard in vitro and in vivo genotoxicity studies, valsartan was not potentially mutagenic at the genetic or chromosomal level.
Carcinogenicity: No carcinogenicity was observed in mice and rats fed diets with valsartan at maximum doses of 160 and 200 mg/kg/day for two years, respectively.
[Pharmacokinetics].
Linearity
Both valsartan and amlodipine have linear pharmacokinetics.
Amlodipine
Absorption
After a single oral dose of therapeutic amlodipine, the plasma concentration of amlodipine peaks within 6 to 12 hours. Absolute bioavailability is 64% to 80%. Food does not affect the bioavailability of amlodipine.
Distribution
The volume of distribution is approximately 21 L/kg. In vitro studies of amlodipine have shown that approximately 97.5% of the circulating drug is bound to plasma proteins in hypertensive patients.
Biotransformation
Amlodipine is extensively (approximately 90%) metabolized to inactive substances in the liver.
Excretion
Amlodipine is eliminated from plasma in a biphasic manner with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma concentrations are achieved after 7 to 8 days of continuous administration. 10% of amlodipine prototype and 60% of amlodipine metabolites are excreted in the urine.
Valsartan
Absorption
Following a single oral dose of valsartan, absorption is rapid, but absorption fluctuates over a wide range. The mean absolute bioavailability of valsartan was 23% (range 23±7). The pharmacokinetics of valsartan were linear over the range of doses studied. There was little accumulation of valsartan when administered orally once daily. Blood levels were similar in men and women.
Food reduced the area under the drug-time curve (AUC) of valsartan by 48% and the Cmax by 59%. However, blood concentrations were similar in the fed and fasted states from 8 h after dosing. the reduction in AUC and Cmax did not result in a clinically significant reduction in therapeutic effect and, therefore, valsartan can be administered in the fed or fasted state.
Distribution
Valsartan is highly bound to serum proteins (94-97%), primarily to serum albumin. Steady state is reached within 1 week. The steady-state volume of distribution is approximately 17 liters. Plasma clearance is relatively low (~2 L/h) compared to hepatic blood flow (~30 L/h).
Elimination
Valsartan shows multi-exponential decay kinetics (initial, alpha half-life <1 h; terminal, beta half-life of approximately 9 h).
Absorbed valsartan is excreted primarily as a prototype, with approximately 70% excreted in the feces and 30% excreted in the urine.
Valsartan/amlodipine
Following oral administration of valsartan amlodipine tablets, plasma concentrations of valsartan and amlodipine peak within 3 and 6-8 h, respectively. The rate and extent of absorption of this product is comparable to the bioavailability of valsartan and amlodipine tablets when taken alone.
Special Groups
Children
Pharmacokinetic data are not available for the pediatric population.
Geriatric Patients
The time to peak plasma concentration of amlodipine was similar in younger and older patients. There was a trend toward lower amlodipine clearance in older patients, resulting in higher AUCs and longer elimination half-lives.
Systemic exposure to valsartan was slightly elevated in elderly patients compared to younger patients, but did not show any clinical significance.
Renal Impairment
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. There was no significant correlation between renal function (as measured by creatinine clearance) and valsartan exposure (as measured by AUC) in patients with different degrees of renal impairment. Therefore, patients with mild to moderate renal impairment can receive treatment at the usual starting dose.
No dosing data are available for patients with severe renal impairment (creatinine clearance <10mL/min). It should be used with caution in patients with severe renal impairment.
Hepatic Impairment
Amlodipine is extensively metabolized by the liver. In patients with hepatic impairment, clearance of amlodipine is reduced, resulting in an approximately 40-60% increase in AUC. There is primarily biliary elimination of valsartan, and exposure to valsartan (in terms of AUC values) in patients with mild to moderate chronic liver disease is on average twice that of healthy volunteers (age, sex, and weight matched). This product should be used with caution in patients with hepatic disease or biliary obstructive disease.
Storage】Seal and store below 30℃.
Package】Aluminum-plastic package, 7 tablets/plate×1 plate/box.
Expiration date】24 months
Execution Standard
Approval number】
【Marketing license holder】 【Approval number
Company Name: Garden Pharmaceutical Co.
Address: Garden Industrial Zone, Nama Town, Dongyang City, Zhejiang Province
Postal code: 322121
Telephone number: 0579-86271661
Fax number: 0579-86271658
Web address: http://www.gardenyy.com
【Manufacturing enterprise
Company name: Garden Pharmaceutical Co.
Address: Garden Industrial Zone, Nama Town, Dongyang City, Zhejiang Province
Postcode：322121
Telephone number: 0579-86271661
Fax number: 0579-86271658
Web address: http://www.gardenyy.com