Approval date: 01/16/2007
Modification date: 07/10/2007
April 17, 2009
September 01, 2009
March 05, 2012
October 30, 2012
May 02, 2013
September 07, 2013
Jun 16, 2014
February 03, 2015
Year
Month
Date
Valsartan Hydrochlorothiazide Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician.
Warning.
The hydrochlorothiazide contained in this product may cause a positive anti-doping test result and should be used with caution by athletes.
Discontinue this product immediately when pregnancy is detected. Drugs that act directly on the renin-angiotensin system can cause injury or even death in the developing fetus.
Drug Name
Generic name: Valsartan Hydrochlorothiazide Tablets
Trade name: Fodavin®/Co-Diovan®
English name: Valsartan and Hydrochlorothiazide Tablets
Hanyu Pinyin: Xieshatan Qinglüsaiqin Pian
Ingredients
This product is a compound preparation, its composition is: each tablet contains 80mg of valsartan and 12.5mg of hydrochlorothiazide.
Characteristic]
This product is film-coated tablets, white after removing the coating.
Indications
For the treatment of mild to moderate essential hypertension in which blood pressure cannot be adequately controlled by a single drug. This product is not suitable for the initial treatment of hypertension.
Specification
80/12.5mg: Each tablet contains 80mg of valsartan and 12.5mg of hydrochlorothiazide.
Dosage]
This product contains 80mg of valsartan and 12.5mg of hydrochlorothiazide per tablet. when blood pressure cannot be satisfactorily controlled with valsartan alone, or when blood pressure cannot be satisfactorily controlled with hydrochlorothiazide 25mg once daily or when hypokalemia occurs, this product (containing 80mg of valsartan/ 12.5mg of hydrochlorothiazide) can be used once a day for 2 to 4 weeks to achieve maximum antihypertensive effect.
Kidney Injury
No dose adjustment is required for patients with mild to moderate renal impairment (glomerular filtration rate (GFR) ≥ 30 mL/min). There is no information on the use of Fodavinâ in patients with severe renal insufficiency (GFR<30 mL/min) and dialysis. When diuretics are used in patients with severe renal impairment (GFR<30 mL/min), tab diuretics are preferred and therefore the use of this product is not recommended. Due to the presence of the hydrochlorothiazide component, fudavinâ is contraindicated in patients with anuria (see [Contraindications]).
Liver injury
Dose adjustment is not required in patients with mild to moderate hepatic impairment. There is no information on the use of valsartan in patients with severe hepatic insufficiency. Hepatic disease does not significantly alter the pharmacokinetics of hydrochlorothiazide. In patients with severe hepatic impairment, thiazide diuretics may lead to electrolyte disturbances, hepatic encephalopathy, and hepatorenal syndrome, and such patients should use thiazide diuretics with caution. Use with caution in patients with biliary obstructive disease or severe hepatic injury (see [Precautions]).
Adverse reactions]
The following is a list, by system organ classification, of the adverse drug reactions that were found to occur at a higher rate in the valsartan plus hydrochlorothiazide group than in the placebo group in clinical trials and laboratory tests and those reported by individuals after marketing. Adverse reactions that occurred when each drug was given alone but were not detected in clinical trials may occur during valsartan/hydrochlorothiazide treatment.
Adverse drug reactions are listed in descending order of frequency 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.
Frequency of adverse drug reactions to valsartan/hydrochlorothiazide
Hematologic and lymphatic disorders unknown Neutropenia Metabolic and nutritional disorders uncommon Dehydration unknown Hypokalemia, hyponatremia Neurologic disorders extremely rare Dizziness uncommon Sensory abnormalities unknown Syncope Eye disorders uncommon Blurred vision Ear and vagus disorders uncommon Tinnitus Vascular disorders uncommon Hypotension Respiratory, thoracic, and mediastinal disorders uncommon Cough unknown Noncardiogenic pulmonary edema Gastrointestinal disorders extremely rare Diarrhea Musculoskeletal and connective tissue disorders uncommon myalgia very rare arthralgia renal and urologic disorders unknown renal injury systemic disorders and administration site conditions uncommon fatigue tests unknown elevated blood uric acid, elevated blood bilirubin and creatinine, elevated blood urea nitrogen
The following events were also observed during clinical trials in hypertensive patients, whether or not they were related to the study drug. abdominal pain, epigastric pain, anxiety, arthritis, weakness, back pain, bronchitis, acute bronchitis, chest pain, postural dizziness, dyspepsia, dyspnea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis, headache, hyperhidrosis, hyperalgesia, hypokalemia, hypotension, influenza, insomnia, muscle cramps, muscle tension, nasopharyngitis, nausea, nasal congestion, neck pain, edema, peripheral edema, otitis media, pain in the extremities , palpitations, abnormal sensation, sore throat, frequent urination, fever, rash, sinus congestion, sinusitis, drowsiness, sprains and strains, syncope, tachycardia, tinnitus, upper respiratory tract infection, urinary tract infection, vertigo, viral infection, blurred vision, visual abnormalities.
Additional information on individual ingredients.
It is possible that adverse reactions previously reported for each constituent drug may also occur with the use of Fudavinâ, even if not observed in clinical trials or during the post-marketing surveillance phase.
Valsartan
Frequency of adverse reactions to valsartan
Hematologic and lymphatic disorders unknown Decreased hemoglobin, decreased erythrocyte pressure product, thrombocytopenia Immune system disorders unknown Hypersensitivity reactions, including serum sickness Metabolic and nutritional disorders unknown Elevated blood potassium Ear and vagus disorders uncommon Vertigo Vascular disorders unknown Vasculitis Gastrointestinal disorders uncommon Abdominal pain Hepatobiliary disorders unknown Abnormal liver function test results Skin and subcutaneous tissue disorders unknown Angioedema, rash, pruritus Dermatitis herpetiformis Renal and urinary disorders unknown Renal failure in hypertensive patients The following events were also observed during the clinical trial, whether or not there was a causal relationship with the study drug: arthralgia, weakness, back pain, diarrhea, dizziness, headache, insomnia, decreased libido, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections, viral infections.
Hydrochlorothiazide
Frequency of hydrochlorothiazide adverse reactions
Blood and lymphatic system disorders Rare: thrombocytopenia, sometimes with purpura. Very rare: leukopenia, granulocyte deficiency, bone marrow failure and hemolytic anemia Unknown: aplastic anemia Immune system disorders Extremely rare: hypersensitivity reactions-necrotizing vasculitis, respiratory distress (including pneumonia and pulmonary edema) Metabolic and nutritional disorders Very common: elevated lipids, mainly at higher doses Common: hypomagnesemia, hyperuricemia Rare: hypercalcemia, hyperglycemia, glycosuria and worsening of diabetic metabolic status Extremely rare: hypochlorhydria Psychiatric disorders Rare: sleep disorders,. Depression Neurological disorders rare: headache, dizziness, and sensory abnormalities Ocular disorders rare: impaired vision, especially in the first weeks of treatment Unknown: closed-angle glaucoma. Cardiac disorders rare: arrhythmias Vascular disorders common: postural hypotension, may be exacerbated by ingestion of alcohol, narcotics, or sedatives Gastrointestinal disorders common: mild nausea and vomiting rare: abdominal discomfort, constipation, and diarrhea very rare: pancreatitis Hepatobiliary disorders rare: cholestasis or jaundice Skin and subcutaneous tissue disorders common: urticaria and other forms of rash rare: photosensitivity reactions very rare: toxic Epidermolysis bullosa, cutaneous lupus erythematosus-like reaction, cutaneous lupus erythematosus relapse Unknown: Erythema multiforme Musculoskeletal and connective tissue disorders Unknown: Muscle cramps Renal and urinary disorders Unknown: Acute renal failure, renal disorders Genital and breast disorders Common: Erectile dysfunction Systemic disorders and administration site conditions Unknown: Fever, weakness
[Contraindicated].
– Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide derivatives, or any of the ingredients in this product.
– Pregnancy (see [Pregnant and lactating women’s medication]).
– Biliary cirrhosis or biliary depression.
– Anuria.
– Combination of angiotensin receptor antagonists (ARBs) (including valsartan) or angiotensin-converting enzyme inhibitors (ACEIs) with aliskiren in patients with type 2 diabetes (see [Drug Interactions]).
[Precautions].
Changes in serum electrolytes
Caution is needed when combining with potassium-preserving diuretics, potassium-supplementing preparations, salt substitutes containing potassium, or other drugs that can increase potassium levels (e.g., heparin). Thiazide diuretics can trigger new hypokalemia or exacerbate existing hypokalemia. Caution is needed when using thiazide diuretics in patients with severe potassium loss conditions (e.g., salt-losing nephropathy and prenephrotic (cardiogenic) renal impairment). If hypokalemia is accompanied by clinical signs (e.g., muscle weakness, bradykinesia, or electrocardiographic changes), fudavin should be discontinued.â It is recommended that hypokalemia or any concomitant hypomagnesemia be corrected prior to initiation of thiazides. Blood potassium and magnesium concentrations should be tested regularly. Electrolyte imbalance, especially potassium, should be monitored in all patients receiving thiazide diuretics.
Thiazide diuretics are capable of triggering new hyponatremia and hypochloremic alkalosis or exacerbating pre-existing hyponatremia. Hyponatremia with neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Regular monitoring of blood sodium concentration is recommended.
Patients with sodium and/or blood volume deficiency
In rare cases, symptomatic hypotension may occur at the start of Fotavon® treatment in patients with severe sodium and/or blood volume deficiency (e.g., high dose application of diuretics). Hyponatremia and/or hypovolemia should be corrected prior to initiating treatment with Fodavin®, otherwise the treatment should be closely monitored medically.
If hypotension occurs, the patient should be placed on his or her back and saline may be given if necessary. Treatment can be resumed after blood pressure has stabilized.
Patients with renal artery stenosis
Because blood urea and serum creatinine may be elevated, use this product with caution in patients with unilateral or bilateral renal artery stenosis or isolated renal artery stenosis for the treatment of hypertension.
Patients with renal injury
No dose adjustment is required for patients with mild to moderate renal impairment (glomerular filtration rate (GFR) ≥30 mL/min). There is no information on the use of Fodavin® in patients with severe renal insufficiency (GFR less than 30 mL/min) and in patients on dialysis. In the use of diuretics in patients with severe renal impairment (GFR<30 mL/min), a collaterals diuretic is preferred and therefore it is not recommended. Due to the presence of the hydrochlorothiazide component, Fudavin® is contraindicated in patients with anuria (see [Contraindications]).
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 liver injury
Patients with mild to moderate hepatic impairment do not require dose adjustment. There is no information on the use of valsartan in patients with severe hepatic insufficiency. Hepatic disease does not significantly alter the pharmacokinetics of hydrochlorothiazide. In patients with severe hepatic impairment, thiazide diuretics may lead to electrolyte disturbances, hepatic encephalopathy and hepatorenal syndrome, and such patients should be treated with caution with thiazide diuretics. Use with caution in patients with biliary obstructive disease or severe hepatic injury (see [Dosage] and [Pharmacokinetics]).
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 fudavinâ immediately and should not be reintroduced.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, have been reported to trigger or exacerbate SLE.
Other metabolic disorders
Thiazide diuretics, including hydrochlorothiazide, can affect glucose tolerance and increase serum cholesterol and triglyceride levels.
As with other thiazide diuretics, hydrochlorothiazide can increase serum uric acid levels due to decreased uric acid clearance and can cause or exacerbate hyperuricemia and gout in susceptible patients.
Thiazides may reduce urinary calcium excretion and may mildly elevate blood calcium in the absence of known abnormalities in calcium metabolism. Because hydrochlorothiazide may increase blood calcium concentrations, caution should be exercised when using it in patients with hypercalcemia. Significant hypercalcemia that does not respond to discontinuation of thiazides or ≥ 12 mg/dL may suggest an underlying non-thiazide-dependent process of elevated blood calcium.
Pathologic changes in the parathyroid glands have been observed in a small number of patients with hypercalcemia and hypophosphatemia on long-term thiazide therapy. If hypercalcemia occurs, further definitive diagnosis is necessary.
Systemic conditions
Patients with allergies and asthma are prone to allergic reactions to hydrochlorothiazide.
Acute closed-angle glaucoma
Hydrochlorothiazide (a sulfonamide) can cause acute transient myopia and atopic reactions to acute closed-angle glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within a few hours to a few weeks after initiation of the drug. Untreated acute closed-angle glaucoma can lead to permanent blindness.
The primary treatment is to discontinue hydrochlorothiazide as soon as possible. If intraocular pressure remains uncontrolled, immediate pharmacologic or surgical treatment needs to be considered. Risk factors for the development of acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.
Patients with heart failure/post-myocardial infarction
In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist therapy is associated with oliguria and/or progressive azotemia and, in rare cases, acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction following the use of this product 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]).
Effects on the ability to drive and operate machinery
As with other antihypertensives, caution should be exercised when driving and operating machinery in patients taking the drug.
Effects on athletes
This product contains hydrochlorothiazide, thiazide diuretics can affect the metabolism and excretion of stimulants, so it may reduce the sensitivity of urine test of stimulants, so athletes should use with caution.
[For pregnant and lactating women].
Women of childbearing age.
As a drug that acts directly on renin-angiotensin-aldosterone (RAAS), Fodavin must be contraindicated in women preparing for pregnancy.â When drugs acting on RAAS are prescribed by healthcare professionals, women of childbearing age should be informed of the possible hazards of taking these drugs during pregnancy.
During Pregnancy
As a drug that acts directly on the RAAS, Fodavinâ should be contraindicated in pregnant women (see [Contraindications]). Based on the mechanism of action of angiotensin II receptor antagonists, embryonic damage cannot be excluded. Intrauterine exposure to angiotensin-converting enzyme inhibitors (the class of drugs that act on the renin-angiotensin aldosterone RAAS system) during the fourth to sixth and seventh to ninth months of pregnancy can lead to fetal injury and death. In addition, retrospective data suggest that patients using angiotensin (ACE) inhibitors in the first trimester are at risk for potential birth defects. Spontaneous abortions, hypohydramnios, and neonatal renal insufficiency have been reported in pregnant women following inadvertent valsartan administration.
Intrauterine exposure to thiazide diuretics (including hydrochlorothiazide) can cause fetal or neonatal jaundice or thrombocytopenia and may be associated with other adverse reactions that occur in adults.
If pregnancy is detected during administration, the drug should be discontinued as soon as possible.
Lactation
It is not known whether valsartan is excreted through human milk. Valsartan is excreted in the milk of lactating rats. Hydrochlorothiazide crosses the placental barrier and is secreted into breast milk. There are no studies in lactating women; therefore, Fudavin® should not be used during lactation.
Fertility
There is no information to suggest that valsartan or hydrochlorothiazide affects human fertility. Fertility has not been shown to be affected by valsartan or hydrochlorothiazide in rat studies (see [Pharmacology and Toxicology]).
Pediatric Dosage]
There are insufficient studies on the therapeutic use of Fudavin® in children.
Geriatric Use
Some older adults had slightly increased concentrations of valsartan compared to young volunteers, but it was not clinically significant.
Some data suggest that hydrochlorothiazide systemic clearance is reduced in older adults compared to younger healthy volunteers.
[Drug Interactions].
Valsartan-hydrochlorothiazide
The following drug interactions may occur between the two components of FudavinÒ (valsartan and/or hydrochlorothiazide).
Lithium: The combined use of lithium with ACE inhibitors, angiotensin II receptor antagonists, or thiazide diuretics has been reported to cause reversible elevated serum lithium concentrations and lithium toxicity. Because thiazide diuretics reduce the renal clearance of lithium, the risk of lithium toxicity may be further increased with the use of FudavinÒ. Therefore, careful monitoring of serum lithium concentration levels is recommended during combined dosing.
Valsartan.
FudavinÒ contains valsartan and the following drug interactions may occur.
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 acting on the RAS increases the risk of hypotension, hyperkalemia, and abnormal renal function compared to 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 should not be combined with aliskiren in patients with type 2 diabetes (see [Contraindications]).
Potassium agents: Caution and monitoring of blood potassium levels is required in combination with potassium-preserving diuretics, potassium-supplementing preparations or salt substitutes containing potassium, or other drugs that can alter serum potassium (e.g., heparin).
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors): Angiotensin II receptor antagonists may diminish their antihypertensive effects when used in combination with NSAIDs. In addition, the combined use of angiotensin II receptor antagonists and NSAIDs in elderly patients, in patients with hypovolemia (including those treated with diuretics), or in patients with renal impairment may increase the risk of developing worsening renal function. Therefore, patients on valsartan therapy should be monitored for renal function when starting combination therapy with NSAIDs or when adjusting therapy.
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 sex transfer protein inhibitors (e.g., rifampin, cyclosporine) or efflux transfer protein inhibitors (e.g., ritonavir) may increase systemic exposure to valsartan.
Hydrochlorothiazide: Fudavinâ contains components of thiazide diuretics and the following drug interactions may occur.
Other antihypertensive drugs: Thiazide diuretics may increase the antihypertensive effects of other antihypertensive drugs such as guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers (ARB), and direct renin inhibitors (DRI).
Skeletal muscle relaxants: Thiazide diuretics (including hydrochlorothiazide) can increase the effects of skeletal muscle relaxants (e.g., arrow toxin derivatives).
Drugs affecting blood potassium levels: thiazide diuretics may enhance their potassium-lowering effects when combined with potassium-eliminating diuretics, corticosteroids, adrenocorticotropic hormones (ACTH), amphotericin, glyburic acid, penicillin G or salicylic acid derivatives, or antiarrhythmic drugs (see [Precautions]).
Drugs affecting blood sodium levels: The combination of thiazide diuretics with antidepressants, antipsychotics, and antiepileptic drugs may enhance their sodium-lowering effects. Therefore, caution is recommended when using these drugs for a long period of time (see [Precautions]).
Anti-diabetic drugs: Thiazides alter glucose tolerance. Therefore adjustment of the dose of insulin or oral antidiabetic drugs may be necessary.
Digitalis glycosides: Low potassium or magnesium due to thiazides can increase the risk of arrhythmias in patients taking digitalis glycosides (see [Precautions]).
NSAIDs and selective Cox-2 inhibitors: Combination with NSAIDs (e.g., salicylic acid derivatives, indomethacin) may diminish the diuretic and antihypertensive activity of the thiazide component of Fodavinâ. If there is concomitant hypovolemia, it may lead to acute renal failure.
Allopurinol: Combination with thiazide diuretics (including hydrochlorothiazide) may increase the chances of allergic reactions to allopurinol.
Amantadine: Concomitant use with thiazide diuretics (including hydrochlorothiazide) may increase the risk of adverse reactions to amantadine.
Antineoplastic agents (e.g., cyclophosphamide, methotrexate): co-administration with thiazide diuretics may reduce renal excretion of cytotoxic drugs and increase their myelosuppressive effects.
Anticholinergic drugs: concomitant administration of anticholinergic drugs (e.g., atropine, biperiden) increases the bioavailability of thiazide diuretics, which may be the result of reduced gastrointestinal motility and slower gastric emptying rate. Conversely, pro-gastrointestinal motility drugs (e.g., cisapride) may decrease the bioavailability of thiazide diuretics.
Ion-exchange resin-based drugs: Colesevelam and Colestipol are able to reduce the absorption of thiazide diuretics (including hydrochlorothiazide). However, staggering the timing of administration of hydrochlorothiazide and resinous drugs, such as giving hydrochlorothiazide at least 4 hours before or 4 to 6 hours after resinous drugs, minimizes this interaction.
Vitamin D: Combined use of thiazide diuretics (including hydrochlorothiazide) with vitamin D or calcium salts can cause an increase in blood calcium.
Cyclosporine: Combined use of cyclosporine may increase the risk of hyperuricemia and gout complications.
Calcium salts: Combined use of thiazide diuretics may cause hypercalcemia by increasing calcium absorption from the renal tubules.
Diazoxide: Thiazide diuretics may potentiate the blood glucose raising effects of diazoxide.
Methyldopa: Combined use of hydrochlorothiazide and methyldopa has been reported in the literature to cause hemolytic anemia.
Alcohol, barbiturates or anesthetics: Combined use of thiazide diuretics with alcohol, barbiturates or anesthetics may cause postural hypotension.
Ascending amines: Hydrochlorothiazide may attenuate the effects of ascending amines (e.g., norepinephrine). The clinical significance of this effect is uncertain and therefore not sufficient to prohibit this class of drugs.
[Drug Overdose].
An overdose of valsartan may result in significant hypotension, which in turn may cause decreased level of consciousness, circulatory collapse, and/or shock. If consumed shortly after, it will cause vomiting. In addition, the conventional treatment is intravenous saline infusion.
Because of its strong binding capacity in plasma, valsartan cannot be removed by hemodialysis, but hydrochlorothiazide can be removed by dialysis.
[Pharmacology and Toxicology
Valsartan.
Angiotensin I (AngⅠ) is formed by the action of angiotensin converting enzyme (ACE) to form angiotensin II (AngⅡ).AngⅡ is an important active component of the renin-angiotensin-aldosterone system (RAAS) and binds to specific receptors on the membranes of various tissues to exert a wide range of physiological effects, including direct or indirect involvement in blood pressure regulation.AngⅡ is a strong vasoconstrictor Ang II is a strong vasoconstrictor that exerts a direct blood pressure-raising effect and also promotes sodium reabsorption and stimulates aldosterone secretion.
Valsartan is a specific Ang II receptor antagonist that acts selectively on the AT1 receptor subtype with 20,000-fold greater affinity for the AT1 receptor than for the AT2 receptor. the AT1 receptor subtype mediates the physiological response to Ang II, while the AT2 receptor subtype is not associated with cardiovascular effects. valsartan has no partial agonist activity on the AT1 receptor.
Valsartan does not inhibit ACE, an enzyme that converts Ang I to Ang II and degrades bradykinin. Valsartan does not inhibit ACE and does not cause retention of bradykinin and substance P. Therefore, it is less likely to cause cough.
Hydrochlorothiazide.
The main site of action of thiazide diuretics is in the proximal part of the distal convoluted tubule. Studies have shown that there are high-affinity receptors in the renal cortex, which are the main binding site and site of action of thiazide diuretics, inhibiting sodium chloride transport in the proximal part of the distal convoluted tubule. The mode of action of thiazides is to inhibit the cotransport of sodium and chloride ions. Competition for the chloride ion site of action can affect electrolyte reabsorption, which will directly increase sodium and chloride excretion and indirectly decrease plasma volume, which subsequently increases plasma renin activity, aldosterone secretion and potassium excretion, resulting in a decrease in serum potassium.
Because the renin-aldosterone system is Ang II-dependent, combined use of Ang II receptor antagonists may reduce potassium loss associated with thiazides.
Toxicological studies
Decreases in erythrocyte parameters (erythrocytes, hemoglobin, erythrocyte pressure product) and changes in renal hemodynamics (slight increase in plasma urea nitrogen levels, renal tubular hyperplasia and basophilia in male rats) were seen with oral administration of valsartan (doses of 200-600 mg/kg/day) at doses of 200 and 600 mg/kg/day, respectively, the maximum recommended human dose (MRHD 320 mg/day) (60 kg body weight, based on body surface area), approximately 6 and 18 times the maximum recommended human dose (MRHD, 320 mg/day), respectively. Similar changes of greater severity were seen in marmosets given comparable doses orally, particularly renal changes developing into nephropathy, including elevated blood urea nitrogen and creatinine, and paraglomerular cell hyperplasia was also seen in both of these animals. The above changes may be related to the prolonged duration of hypotension due to valsartan.
Genotoxicity.
Valsartan.
Valsartan Ames test, Chinese hamster V79 cell gene mutation test, Chinese hamster ovary cell chromosome aberration test and rat micronucleus test results were all negative.
Hydrochlorothiazide.
The results of hydrochlorothiazide Ames test, CHO cell chromosome aberration test, mouse germ cell chromosome aberration test, Chinese hamster bone marrow chromosome aberration test and Drosophila companion recessive lethal gene test were all negative. The results of CHO sister chromosome exchange test and mouse lymphocyte test were positive for hydrochlorothiazide at the concentration of 43-1300 µg/ml.
Reproductive toxicity.
Valsartan.
No significant effects on fertility were seen in rats given valsartan orally at doses up to 200 mg/kg/d, which was 6 times higher than MRHD in females and males. No significant effects on offspring growth and development were seen in pregnant mice and pregnant rats given transoral doses of valsartan up to 600 mg/kg/d and in pregnant rabbits given transoral doses up to 10 mg/kg/d. In pregnant rats, a significant reduction in embryonic weight, fetal birth weight and survival, and retarded fetal development was seen in pregnant rats given maternally at doses of 600 mg/kg of valsartan at maternal toxicity (decreased body weight gain values and food intake) during organogenesis, late gestation and lactation. Embryo-fetal toxicity (e.g., embryo uptake, whole litter loss, abortion, and low fetal weight) in rabbits was associated with maternal toxicity (occurrence of death) at valsartan doses of 5 mg/kg/d and 10 mg/kg/d. NOAEL values were 600 mg/kg/d, 200 mg/kg/d, and 2 mg/kg/d in mice, rats, and rabbits, respectively, corresponding to 9 times, 6 times, and 0.1 times the MRHD , 6 times and 0.1 times of MRHD.
Hydrochlorothiazide.
Hydrochlorothiazide was administered to mice and rats at doses up to 4 and 100 mg/kg by adulteration, equivalent to 0.7 and 9 times the MRHD, respectively, and no significant effect on fertility was observed. In lactating rats, oral administration of hydrochlorothiazide at a dose 15 times the human dose was associated with reduced weight gain in lactating pups.
Carcinogenicity.
Valsartan.
No carcinogenicity was seen in mice and rats given valsartan at doses up to 160 and 200 mg/kg/day, respectively, for 2 years by adulteration, which was 2.6 and 6 times the MRHD, respectively.
Hydrochlorothiazide.
In a 2-year adulterated administration carcinogenicity test, no carcinogenicity was seen in female mice at doses up to 600 mg/kg/day (53 times the MRHD) and in male and female rats at doses up to 100 mg/kg/day (18 times the human MRHD). Hepatocellular carcinoma was seen in male mice, but the significance is unclear.
Pharmacokinetics]
Valsartan
After oral administration of valsartan alone, the plasma concentration peaks in 2-4 hours. The mean absolute bioavailability is 23%. Valsartan is metabolized with multi-exponential decay kinetics (a-phase half-life <1 hour, beta-phase half-life approximately 9 hours).
The pharmacokinetic profile was linear over the dose range studied. Pharmacokinetics were unchanged with repeated dosing, and when administered once daily, valsartan rarely caused accumulation, with similar plasma concentrations in men and women.
Distribution
The vast majority of valsartan (94-97%) is bound to serum proteins, primarily serum albumin. The steady-state volume of distribution of valsartan after intravenous administration is approximately 17 liters, indicating that valsartan is not widely distributed to tissues.
Biotransformation/metabolism
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 shows multi-exponential decay kinetics (t1/2α<1h, t1/2ß of about 9 h). Valsartan is excreted as a prototype drug mainly via feces (about 83% of the dose) and urine (about 13% of the dose). 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.
Taking valsartan with a meal reduced the AUC by 48%. However, blood concentrations after 8 hours were similar with or without food. the reduction in AUC had no significant effect on clinical efficacy.
Hydrochlorothiazide
Absorption.
Hydrochlorothiazide is rapidly absorbed after oral administration (Tmax of approximately 2 hours). The mean AUC increases in a linear pattern and is proportional to the dose over the therapeutic range. Reports indicate that co-administration with food increases and decreases the systemic bioavailability of hydrochlorothiazide compared to the fasted state. The magnitude of these effects was small and of little clinical significance. The absolute bioavailability of hydrochlorothiazide after oral administration was 70 %.
Distribution.
The distribution and elimination kinetics of hydrochlorothiazide are biexponentially decaying. The apparent volume of distribution is 4 to 8 L/kg. hydrochlorothiazide in the circulation is bound to serum proteins (40 to 70%), primarily serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately three times the plasma level.
Biotransformation.
Hydrochlorothiazide is excreted primarily as a prototype.
Clearance.
Hydrochlorothiazide has an average half-life of 6 to 15 hours for plasma clearance in the terminal clearance phase. Multiple dosing does not alter the kinetics of hydrochlorothiazide. The accumulation of once-daily dosing is very small. more than 95% of the absorbed dose is excreted in the urine as a prototype.
Valsartan/Hydrochlorothiazide
Co-administration with valsartan reduces the bioavailability of hydrochlorothiazide by approximately 30%; co-administration with hydrochlorothiazide does not significantly affect the pharmacokinetics of valsartan. Interactions have no effect on the combination of valsartan/hydrochlorothiazide, which has been shown in controlled clinical trials to have a definite antihypertensive effect and to be more potent than either drug alone.
Pharmacokinetics in special clinical situations
Patients with renal impairment
Valsartan/hydrochlorothiazide
In patients with a glomerular filtration rate (GFR) of 30 to 70 mL/min, no dose adjustment of Fudavin® is required.
There is no information on the use of Fodavin® in patients with severe renal insufficiency (GFR less than 30 mL/min) and in patients on dialysis. Valsartan is highly bound to plasma proteins and is difficult to clear by dialysis.
In the presence of renal injury, it increases the mean peak plasma concentration and AUC of hydrochlorothiazide and decreases the urinary excretion rate. In patients with mild to moderate renal impairment, the mean clearance half-life becomes almost twofold. The renal clearance of hydrochlorothiazide was also greatly reduced compared to patients with normal renal function with a renal clearance of approximately 300 mL/min.
Patients with hepatic insufficiency
Pharmacokinetic studies in patients with mild (n=6) and moderate (n=5) hepatic insufficiency showed concentrations of valsartan approximately twice as high as those in healthy volunteers. There is no information on the application of valsartan in patients with severe hepatic insufficiency.
Hepatic disease does not significantly alter the pharmacokinetics of hydrochlorothiazide. In patients with severe hepatic impairment, thiazide diuretics may lead to electrolyte disturbances, hepatic encephalopathy and hepatorenal syndrome, and such patients should be treated with caution with thiazide diuretics.
This product should be used with caution in patients with biliary obstructive disease and severe liver injury (see [Precautions]).
Storage】Protect from moisture, store below 30℃
Package】Aluminum-plastic package, 7 tablets/box
Expiration date】36 months
Execution Standard
Imported drug registration certificate number
Manufacturer
Company Name: Novartis Pharma Schweiz AG, Switzerland
Production
Production
Plant: Novartis Farma S.p.A.(I), Italy
Production Address: Via Provinciale Schito 131,80058 Torre Annunziata (NA), Italy
Contact address: 31 Yong’an Road, Changping District, Beijing
Postal Code: 102200
Phone number: 400 621 3132
800 810 1555
Fax number: 010 6505 7099
Web
Address: www.novartis.com.cn