Approval Date
Date of modification
Telmisartan Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Avoid use in pregnant women. Drugs that act directly on the renin-angiotensin system are capable of causing damage or even death to the developing embryo. When pregnancy is detected, temisartan Tablets should be discontinued immediately.
Drug Name
Generic name: Temisartan Tablets
Trade Name: Telmisartan Tablets
English Name: Telmisartan Tablets
Hanyu Pinyin: Timishatan Pian
Ingredients
The main ingredient of this product is telmisartan.
Chemical name: 4′-[[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-benzoic acid.
Chemical structure formula.
Molecular formula: C33H30N4O2
Molecular weight: 514.63
【Properties】.
This product is white to slightly yellow oval tablets
Indications
Hypertension
Used for the treatment of primary hypertension in adults.
Cardiovascular risk reduction
This product is indicated for patients aged 55 years and older who are at high risk of serious cardiovascular events and cannot be treated with angiotensin-converting enzyme (ACE) inhibitors to reduce their risk of myocardial infarction, stroke, or death due to cardiovascular disease.
High risk for cardiovascular events includes coronary artery disease, peripheral artery disease, stroke, transient ischemic attack, or a history of high-risk type 2 diabetes mellitus with evidence of end-organ damage. Temisartan may also be used concomitantly with other necessary therapy (e.g., antihypertensive drugs, antiplatelet agents, or lipid-lowering agents).
Concomitant use of temisartan with ACE inhibitors is not recommended.
Specification
40mg
Dosage]
This product can be taken with or after a meal.
Treatment of essential hypertension.
Dosing should be individualized. The common initial dose is 40 mg once daily. In the dose range of 20-80 mg, the antihypertensive efficacy of telmisartan is dose-dependent. If the desired blood pressure is not achieved after dosing, the dose may be increased to a maximum of 80 mg once daily.
This product can be combined with thiazide diuretics such as hydrochlorothiazide, which have a synergistic effect with this product. Because the maximum antihypertensive effect of telmisartan is usually achieved four to eight weeks after initiation of therapy, this should be taken into account when considering increasing the dose of the drug.
Cardiovascular risk reduction.
The recommended dose is 80 mg once daily. It is not known whether temisartan at doses below 80 mg is effective in reducing the risk of cardiovascular morbidity and mortality.
When initiating treatment with temisartan to reduce cardiovascular risk, close monitoring of blood pressure and appropriate adjustment of antihypertensive medication as necessary is recommended.
Special Populations
Patients with impaired renal function
Patients with mild or moderate renal impairment do not require dose adjustment for the administration of this product. Experience with this product in patients with severe renal impairment or hemodialysis is limited. A reduction in the starting dose to “20 mg once daily” is recommended in these patients. Regular monitoring of potassium and creatinine is recommended in patients with renal impairment (see [Precautions]). There is no experience with the use of telmisartan in recent renal transplant patients.
Patients with impaired hepatic function
In patients with mild or moderate hepatic impairment, the daily dose of this product should not exceed 40 mg (see [Precautions]).
[Adverse Reactions].
Placebo-controlled clinical studies for the treatment of hypertension showed an overall incidence of adverse events of 41.4% for temisartan and 43.9% for placebo, both being similar. These adverse reactions were non-dose dependent and were independent of patient gender, age and race. The safety data for telmisartan in patients used to reduce cardiovascular prevalence were consistent with those used in patients on antihypertensive therapy.
The following adverse drug reactions were derived from the cumulative results of controlled clinical studies and postmarketing reports in patients undergoing antihypertensive therapy. The list also considers reports of serious adverse events and adverse events leading to discontinuation from three long-term clinical studies including 21,642 patients treated with telmisartan for up to 6 years for cardiovascular morbidity reduction.
The adverse events were ranked according to the odds of occurrence as follows.
Very common (≥1/10); Common (≥1/100 to <1/10); Occasional (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1000); Very rare (<1/10,000); Unclear (could not be assessed based on available data).
Within each frequency group, adverse reactions were listed in descending order of severity.
Infections and Infections.
Occasional: upper respiratory tract infections including pharyngitis and sinusitis, urinary tract infections, including cystitis
Unspecified: sepsis including fatal outcome1
Blood and lymphatic system disorders.
Occasional: anemia
Rare: thrombocytopenia
Unspecified: eosinophilia
Immune system disorders.
Rare: allergy
Unspecified: allergic reactions, hypersensitivity reactions
Metabolic and nutritional system disorders.
Occasional: hyperkalemia
Rare: hypoglycemia (seen in diabetic patients)
Mental disorders.
Occasional: depression, insomnia
Rare: anxiety
Neurological disorders.
Occasionally: syncope
Ocular disorders.
Rare: visual disturbances
Ear and vagus disorders.
Occasional: vertigo
Diseases of the cardiac system.
Occasional: bradycardia
Rare: Tachycardia
Diseases of the vascular system.
Occasional: hypotension2, postural hypotension
Respiratory, thoracic and mediastinal disorders.
Occasional: dyspnea
Gastrointestinal disorders.
Common: abdominal pain, diarrhea, indigestion, flatulence, vomiting
Occasional: dry mouth, stomach discomfort
Hepatobiliary system disorders.
Rare: abnormal liver function / liver disease3
Skin and subcutaneous tissue disorders.
Occasional: hyperhidrosis, pruritus, rash
Rare: erythema, angioedema (with fatal outcome), drug rash, toxic rash, eczema
Uncertain: rubella
Musculoskeletal and connective tissue disorders.
Occasional: arthritis, back pain (e.g., sciatica), muscle spasms
Rare: arthralgia, extremity pain (leg pain)
Unspecified: tendon pain (tendonitis-like symptoms)
Renal and urologic disorders.
Occasional: renal impairment, including acute renal failure
General disorders and administration sites.
Occasionally: chest pain, malaise (weakness)
Rare: flu-like symptoms
Laboratory Tests.
Occasionally: elevated blood creatinine
Rare: elevated blood uric acid, elevated liver enzymes, elevated blood creatine phosphokinase, decreased hemoglobin
1 There was an increased incidence of sepsis in the PRoFESS study with temisartan compared with placebo. This may be a coincidental result or may be related to a currently unclear mechanism.
2 A reduction in cardiovascular prevalence was reported as “common” in patients who had controlled blood pressure and received telmisartan in addition to standard therapy.
3 Most of the events of hepatic abnormalities/hepatic disease stem from the postmarketing experience with temisartan in Japan, and Japanese patients may be more susceptible to such events.
The TRANSCEND study of this product for cardiovascular risk reduction
(N=5926, follow-up 4 years and 8 months), 8.4% of the temisartan group discontinued because of adverse events, compared with 7.6% in the placebo group. The only serious adverse events that occurred at a 1% higher rate in the temisartan group than in the placebo group were intermittent claudication (7% vs. 6%) and skin ulcers (3% vs. 2%).
The most frequently spontaneously reported events after marketing included: headache, dizziness, malaise, cough, nausea, fatigue, weakness, edema, facial edema, lower extremity edema, angioneurotic edema, urticaria, allergy, increased sweating, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, elevated blood pressure, exacerbation of hypertension, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including calf cramps), muscle pain, bradycardia, eosinophilia, thrombocytopenia, elevated uric acid, abnormal liver function or liver disease, kidney injury including acute renal failure, anemia, elevated CPK, anaphylactic reactions, and tendon pain (including tendonitis, tendon synovitis). Very rare cases of rhabdomyolysis have been reported in patients treated with angiotensin II receptor inhibitors including this product.
Contraindications
Hypersensitivity to the active ingredient or any of the excipient ingredients of this product.
Women in mid to late pregnancy (during the middle and last trimester of pregnancy) (see [Precautions] and [Use in Pregnant and Lactating Women]).
Patients with obstructive biliary tract disease.
Patients with severe hepatic impairment.
Do not use this product and aliskiren concomitantly in patients with diabetes or renal insufficiency (glomerular filtration rate (GRF) <60 ml/min/1.73m2).
[Precautions].
1. Prevalence and morbidity and mortality in fetuses or neonates
Drugs that act directly on the renin-angiotensin system can cause embryonic or neonatal morbidity and mortality when used in pregnant women. Several such cases have been reported in the worldwide literature in patients taking angiotensin-converting enzyme inhibitors. When pregnancy is detected, the product should be discontinued immediately.
Application of drugs that act directly on the renin-angiotensin system during the middle and last trimesters of pregnancy can lead to embryonic and neonatal damage, including hypotension, neonatal craniosynostosis, anuria, reversible or irreversible renal failure, and death. There have also been reports of low amniotic fluid, possibly due to reduced embryonic kidney function. In this case low amniotic fluid can lead to embryonic limb contractures, craniofacial malformations and pulmonary hypoplasia. There is also preterm delivery, intrauterine growth retardation, and ductus arteriosus, and it is unclear whether the occurrence of these conditions is related to drug exposure.
Patients with intrauterine drug exposure limited to the first trimester of pregnancy have not experienced these adverse effects. Patients with embryonic and fetal exposure to angiotensin II receptor antagonists in the first trimester of pregnancy should be informed that most reports of fetal toxicity are associated with drug exposure in mid- to late pregnancy. In addition, patients should be advised to discontinue this product immediately if they are pregnant or are considering pregnancy.
Rarely (likely less than 1 in 1000 pregnancies) there will be no alternative to angiotensin II receptor antagonists. In these rare cases, the pregnant patient should be informed of the potential risk to the fetus and a serial ultrasound should be performed to assess the intra-amniotic environment.
If hypohydramnios is observed, the drug should be discontinued unless it is life-saving treatment for the pregnant patient. Depending on the number of weeks of gestation, a contraction stress test (CST), no stress test (NST), or biophysical analysis (BPP) may be performed. However, patients and physicians should be aware that hypohydramnios can only occur after irreversible fetal damage.
Infants with a history of intrauterine angiotensin II receptor antagonist exposure should be closely monitored for hypotension, oliguria, and hyperkalemia. If oliguria is present, direct support for blood pressure and renal perfusion should be performed. Replacement therapy with plasma exchange or dialysis to reverse hypotension and/or renal dysfunction may be required.
2. ACE inhibitors should be considered first for “cardiovascular risk reduction” indications
The results of the clinical trial related to the reduction of cardiovascular risk with telmisartan (ONTARGET study) do not exclude that the drug may not retain some of the meaningful effects of ACE inhibitors compared to ACE inhibitors. Therefore, for people with this indication, consider using an ACE inhibitor first and, if discontinuing the drug due to adverse cough reactions only, consider retrying an ACE inhibitor after the cough has resolved.
3. Hypotension
In patients with activation of the renin-angiotensin system, such as in patients with volume or sodium failure (e.g., being treated with high-dose diuretics, salt-restricted diet, nausea or vomiting causing hypovolemia or low blood sodium levels), administration of telmisartan, especially after the initial dose, may result in symptomatic hypotension. Thus, the blood sodium and blood volume levels should be corrected or the therapeutic dose should be reduced under close medical observation prior to the use of this product.
If hypotension occurs, the patient should be placed in a lying position and saline may be administered intravenously if needed. Transient hypotensive reactions are not a contraindication to further treatment, and treatment can usually be continued once the blood pressure has stabilized.
4. Hyperkalemia
Patients treated with angiotensin II receptor antagonists (ARBs) may develop hyperkalemia, especially in patients with progressive renal impairment, heart failure, or those undergoing renal replacement therapy; or those being treated with potassium supplementation, potassium-preserving diuretics, potassium-containing salt substitutes, or other medications that may increase blood potassium concentrations. In such patients with risk factors for hyperkalemia, serum electrolyte levels should be closely monitored during the application of this product to detect possible electrolyte disturbances in a timely manner.
Hyperkalemia can be fatal in the elderly, in patients with renal insufficiency, in patients with diabetes mellitus, with concomitant use of other drugs that increase potassium levels, and/or in patients with co-morbidities.
The benefit-risk ratio should be fully evaluated before considering concomitant use of medications affecting the renin-angiotensin-aldosterone system.
The major risk factors for hyperkalemia include.
– diabetes mellitus, renal impairment, age (> 70 years)
– and the combination of one or more other drugs and/or potassium supplements that affect the renin-angiotensin-aldosterone system. Drugs and classes of drugs that may contribute to hyperkalemia: salt substitutes containing potassium, potassium-conserving diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and methotrexate.
– Concomitant events, especially in dehydration, acute cardiac failure, metabolic acidosis, deteriorating renal function, sudden deterioration of renal status (e.g., infectious disease), cytolysis (e.g., acute limb ischemia, rhabdomyolysis, extended trauma)
5. Impaired hepatic function
Telmisartan is excreted primarily through the bile, and clearance of this product may be reduced in patients with biliary obstructive disease or hepatic insufficiency. Therefore, this product should not be used in patients with cholestasis, biliary obstructive disease, or severe hepatic dysfunction. It should be used with caution in patients with mild-to-moderate hepatic insufficiency, in whom telmisartan therapy should be started at a low dose while slowly adjusting the therapeutic dose.
6. Patients with impaired renal function and renal transplantation
After initiation of renin-angiotensin-aldosterone system inhibitor therapy, changes in renal function may occur in sensitive patients. In patients whose renal function is largely dependent on renin-angiotensin-aldosterone system activity (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists can lead to oliguria and/or progressive azotemia and, in rare cases, acute renal failure and/or death. Similar results have been reported with telmisartan.
ACE inhibitors have been observed in studies of patients with unilateral or bilateral renal artery stenosis with elevated serum creatinine or blood urea nitrogen levels. Long-term use of temisartan was not available in patients with unilateral or bilateral renal artery stenosis, but the results are expected to be similar to those seen with ACE inhibitors.
Regular monitoring of blood potassium and creatinine levels is recommended for use in patients with renal impairment.
There is no experience with the use of temisartan in recent renal transplant patients.
7. Dual blockade of the renin-angiotensin-aldosterone system
Changes in renal function (including acute renal failure) have been reported after initiation of renin-angiotensin-aldosterone system inhibition therapy. Dual blockade of the renin-angiotensin-aldosterone system (e.g., combination of an ACE inhibitor and/or direct renin inhibitor aliskiren with an angiotensin II receptor inhibitor) should be used to closely monitor renal function (see [Contraindications]).
The ONTARGET study enrolled 25,620 diabetic patients aged ≥55 years with atherosclerotic disease or with end-organ damage. These patients were randomized to either temisartan alone, ramipril alone, or a combination of the two drugs, with a median follow-up time of 56 months. Patients receiving the combination of telmisartan and ramipril did not receive additional benefit compared with monotherapy, but had an increased incidence of renal insufficiency (e.g., acute renal failure) compared with the group receiving telmisartan or ramipril alone. The combination of temisartan and ramipril is not recommended (see [Drug Interactions]).
8. Other conditions that activate the renin-angiotensin-aldosterone system
In patients whose vascular tone and renal function are largely dependent on the activity of the renin-angiotensin-aldosterone system (e.g., those with severe congestive heart failure or occult renal disease, including renal artery stenosis), application of drugs that inhibit this system (e.g., temisartan) can cause acute hypotension, hyperazotemia, oliguria, or, rarely, acute renal failure.
9, renal vascular hypertension
The use of drugs that inhibit the renin-angiotensin-aldosterone system in patients with bilateral renal artery stenosis or stenosis of the renal artery in only one kidney increases the risk of severe hypotension and renal insufficiency. There is no experience with long-term use of telmisartan in patients with unilateral or bilateral renal artery stenosis.
10.Primary aldosteronism
Patients with primary aldosteronism usually do not respond to antihypertensive drugs that work by inhibiting the renin-angiotensin system. Therefore, the use of telmisartan is not recommended.
11.Aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy
As with other vasodilators, it should be used with caution in patients with aortic and mitral stenosis or hypertrophic obstructive cardiomyopathy.
12. Effects on the ability to drive and operate machinery
No studies have been conducted on the effects of temisartan on the ability to drive and operate machinery. However, when driving transportation or operating machinery, it should be noted that dizziness and drowsiness may occasionally occur during antihypertensive therapy.
13. Racial differences
Consistent with angiotensin-converting enzyme inhibitors, the antihypertensive effect of temisartan and other angiotensin II receptor antagonists is worse in black people than in other non-black people, probably because black hypertensive patients are more likely to have low plasma renin status.
14. Patients with diabetes mellitus
Patients with diabetes mellitus with additional cardiovascular risk factors, such as diabetes mellitus with coronary artery disease (CAD), may be at increased risk of fatal myocardial infarction and accidental death from cardiovascular disease with antihypertensive agents such as angiotensin receptor antagonists or ACE inhibitors. Patients with diabetes combined with CAD may have undiagnosed CAD because they are asymptomatic. therefore, patients with diabetes should undergo appropriate diagnostic evaluation, such as an exercise stress test, to detect the presence of CAD and treat accordingly before using this product.
15.Other
As with other antihypertensive drugs, excessive lowering of blood pressure in patients with ischemic cardiomyopathy or ischemic cardiovascular disease may lead to myocardial infarction or stroke.
Pregnant women and nursing mothers
Pregnant women
Angiotensin II receptor antagonists are not recommended for use during the first trimester of pregnancy (see [Precautions]). The middle and last trimesters of pregnancy are contraindications to the use of angiotensin II receptor antagonists (see [Contraindications] and [Precautions]).
There are insufficient data on the use of telmisartan in pregnant women. Studies in animals have shown reproductive toxicity (see [Pharmacologic Toxicology]).
No definitive conclusions have been made regarding teratogenic toxicity following exposure to angiotensin-converting enzyme inhibitors in the first trimester of pregnancy, but a small increase in risk cannot be excluded. Although there are no epidemiologically controlled data on the risk of angiotensin II receptor antagonists, there is a similar risk with this class of drugs. Unless continued angiotensin II antagonist therapy is deemed necessary, patients planning pregnancy should be switched to antihypertensive alternative therapy with definite evidence of safety of use in pregnancy. Angiotensin II antagonist therapy should be discontinued immediately after the definitive diagnosis of pregnancy, and replacement therapy should be initiated whenever possible.
Exposure to angiotensin II receptor antagonist therapy in the middle and last trimesters of pregnancy can result in human fetal toxicity (decreased renal function, hypohydramnios, delayed cephalic calcification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see [Pharmacologic Toxicology] and [Precautions]). If angiotensin II receptor antagonist therapy has been used since the middle trimester of pregnancy, ultrasound examination of renal function and fetal cranium is recommended. In newborns whose mothers have already taken angiotensin II receptor antagonists, they should be closely monitored for hypotension (see [Contraindications] and [Precautions]).
Use during lactation
There is no information on the use of telmisartan during lactation, therefore, the use of this product is not recommended.
[Pediatric use].
There is a lack of evidence on the safety and efficacy of this product in children and adolescents under 18 years of age; therefore, this product is not recommended for use in children and adolescents under 18 years of age.
Geriatric Use]
No dose adjustment is usually necessary in the elderly.
Of all patients treated with telmisartan in the hypertension clinical study, 551 (19%) were between the ages of 65 and 74 years and 130 (4%) were at the age of 75 years or older. There were no overall differences in efficacy or safety in these patients compared with younger patients, and other reported clinical experience has not found differences in response to the drug between older and younger patients, although a higher sensitivity in some older patients cannot be excluded.
The percentage of all patients treated with telmisartan in the Cardiovascular Risk Reduction Study (ONTARGET) was 42% for patients aged ≥65 to <75 years and 15% for patients aged ≥75 years. There were no overall differences in efficacy and safety in these patients compared with younger patients, and other reported clinical experience has not found differences in drug response between older and younger patients, although a higher sensitivity in some older patients cannot be excluded.
[Drug Interactions].
Interaction studies have been done only in adults.
As with other drugs that act on the renin-angiotensin-aldosterone system, telmisartan may cause hyperkalemia (see [Precautions]). This risk is increased when combined with other drugs that may also cause hyperkalemia (salt substitutes containing potassium, potassium-preserving diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and methotrexate).
Concomitant use is not recommended for.
Potassium-preserving diuretics or potassium supplements.
Angiotensin II receptor antagonists, including temisartan, reduce potassium loss due to diuresis. Potassium-preserving diuretics such as spironolactone, eplerenone, aminoglutethimide or amiloride, potassium supplements, or salt substitutes containing potassium may cause a significant increase in blood potassium. If concomitant use is due to well-documented hypokalemia, use with caution and monitor blood potassium levels closely.
Lithium salts.
When lithium salts are administered concomitantly with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, including telmisartan, reversible increases in serum lithium concentrations and toxicity have been reported; therefore, careful monitoring of blood lithium levels is recommended if the combination is necessary.
ACE inhibitors
Ramipril: The combination of telmisartan 80 mg once daily and ramipril 10 mg once daily increased the steady-state Cmax and AUC of ramipril by 2.3-fold and 2.1-fold, respectively, and increased the steady-state Cmax and AUC of ramiprilat by 2.4-fold and 1.5-fold, respectively, in healthy subjects. In contrast, the Cmax and AUC of telmisartan decreased by 31% and 16%, respectively. When temisartan is combined with ramipril, the response may be stronger due to the possible increased pharmacodynamic effects of the combination and the increased exposure to ramipril and ramiprilat in the presence of temisartan. Combined use of telmisartan and ramipril is not recommended. (See [Precautions])
Combinations requiring caution.
Non-steroidal anti-inflammatory drugs.
NSAIDs (e.g., anti-inflammatory doses of acetylsalicylic acid, COX-2 inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists. In some patients with renal impairment (e.g., dehydrated patients or elderly patients with renal impairment), the combination of angiotensin II receptor antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination of drugs should be used with caution, especially in the elderly. Patients should be adequately rehydrated, and renal function and potassium should be monitored at the start of combination therapy and periodically thereafter.
Diuretics (thiazide or myeloid diuretics).
Treatment with high-dose diuretics (e.g., the medullary diuretic furosemide and the thiazide hydrochlorothiazide) prior to application of this product may result in a reduction in blood volume, at which point there is a risk of hypotension when treatment with telmisartan is initiated.
Combined medications that must be taken into account.
Other antihypertensive drugs.
Combination with other antihypertensive drugs may increase the antihypertensive effect of temisartan.
Based on their pharmacological properties, the following drugs can be expected to potentiate the antihypertensive effect of all antihypertensive drugs, including temisartan: baclofen, amphotericin. In addition, alcohol, barbiturates, narcotics or antidepressants may exacerbate postural hypotension.
Digoxin: The median peak plasma concentration of digoxin was increased (49%) in combination of telmisartan and digoxin, along with an increase in trough concentrations (20%). Therefore, digoxin concentrations should be monitored at the initiation, adjustment and discontinuation of telmisartan therapy to keep digoxin concentrations within the therapeutic range.
Corticosteroids (systemic route).
Decreases the antihypertensive effect.
Other drugs.
Combination with telmisartan does not result in clinically significant interactions with: acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan does not metabolize drugs through the cytochrome P450 system, has no effect on cytochrome P450 enzymes in vitro, and only partially inhibits CYP2C19. Temisartan does not interact with drugs that inhibit the function of cytochrome P450 enzymes and is not expected to react with drugs that are metabolized by cytochrome P450 enzymes and may only partially inhibit the metabolism of drugs that are metabolized by CYP2C19.
[Drug overdose].
Data on overdose in humans are limited.
Symptoms: The most significant clinical manifestations of temisartan overdose are hypotension and tachycardia. Bradycardia, elevated blood creatinine, and acute renal failure have also been reported.
Treatment: Temisartan cannot be eliminated by hemodialysis. Close monitoring of the patient, symptomatic and supportive treatment is required, and treatment depends on the duration of dosing and the severity of symptoms. Emetic and/or gastric lavage is recommended, and activated charcoal may be effective in treating drug overdose. Close monitoring of serum electrolytes and creatinine levels is also required. If hypotension occurs, the patient should be placed in a supine position and blood volume and sodium-containing electrolyte salts should be replenished rapidly.
Pharmacology and Toxicology
Pharmacological effects
Angiotensin I (AⅠ) is catalyzed by angiotensin-converting enzyme (ACE, kinase II) to produce angiotensin (AⅡ), which is the main pressure-raising substance of renin-angiotensin system (RAS) and has the effects of vasoconstriction, promotion of aldosterone synthesis and release, cardiac excitation and sodium reabsorption by kidney. Telmisartan selectively blocks the binding of AII to AT1 receptors in most tissues (e.g., vascular smooth muscle and adrenal glands), thereby inhibiting the vasoconstrictive and aldosterone-secreting effects of AII. AT2 receptors are also present in most tissues, and the cardiovascular effects of AT2 are unknown. Temisartan binds much more strongly to AT1 than to AT2 (>3000-fold).
Toxicological studies
Genotoxicity.
Temisartan Ames test, Chinese hamster V79 cell gene mutation test, human lymphocyte genotoxicity test and mouse micronucleus test were all negative.
Reproductive toxicity.
Oral administration to rats at doses up to 100 mg/kg/d, calculated as mg/m2 and mean systemic exposure (at day 6 of gestation), was 13 and 50 times the maximum recommended human dose of 80 mg/d, respectively, and no significant effects on maternal fertility or offspring growth and development were observed.
Carcinogenicity.
Mice and rats were given orally by adulteration with temisartan for up to 2 years at a maximum dose of 1000 mg/kg/d, which is 59 and 13 times the maximum recommended human dose on a mg/m2 basis, respectively, and no carcinogenic effects were observed. It has been shown that the above maximum dose can result in a mean systemic exposure of 100 and 25 times higher in mice and rats, respectively, than the recommended maximum human dose of 80 mg/d.
【Pharmacokinetics】.
Absorption.
Despite differences in absorption, telmisartan is rapidly absorbed with a mean absolute bioavailability of approximately 50%.
After oral administration of telmisartan, the peak concentration (Cmax) is reached after 0.5 to 1 hour after dosing. The bioavailability of telmisartan is mildly reduced by food, with the area under the plasma concentration curve (AUC) decreasing by approximately 6% for a 40 mg tablet and 20% for a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. The bioavailability was 42% and 58% at doses of 40 and 160 mg, respectively. In the dose range of 20 mg to 160 mg, the pharmacokinetics of oral telmisartan are nonlinear, with more pronounced increases in plasma concentrations (Cmax and AUC) than proportional increases when the dose is increased.
Distribution.
Temisartan has high plasma protein binding (>99.5%), mainly to albumin and α1-acid glycoprotein, with a mean steady-state apparent volume of distribution (Vss) of approximately 500 L.
Metabolism.
Telmisartan is metabolized by condensation reactions to pharmacologically inactive acyl glucosinolates; the glucosinolate bound form of the drug prototype is the only identified metabolite in human plasma and urine. The binding product is not pharmacologically active. After a single dose, the glucosinolate bound form accounts for approximately 11% of the metabolic activity measured in plasma. Cytochrome P450 isozymes are not involved in the metabolism of telmisartan.
Clearance.
Temisartan has a biexponentially decaying kinetics with a terminal clearance half-life of approximately 24 hours. The plasma trough concentration of telmisartan at once daily dosing is approximately 10% to 25% of the peak plasma concentration. The cumulative index in plasma at repeated administration of telmisartan is approximately 1.5 to 2.0 times that at each dose.
Tilmisartan is excreted almost exclusively in the feces as a prototype after oral administration (and intravenous application), and the cumulative urinary excretion is less than 1% of the dose.
The overall plasma clearance of telmisartan (Cltot, approximately 900 ml/min) is high relative to normal hepatic blood flow (approximately 1500 ml/min).
Special Populations.
Gender
There are gender differences in the blood concentrations of telmisartan, with Cmax and AUC being 3-fold and 2-fold higher in women compared to men, with no relevant effect on the clinical efficacy of the drug.
Geriatric population
There is no difference in the pharmacokinetics of telmisartan between elderly patients and patients younger than 65 years of age.
Patients with impaired renal function
Doubling of plasma concentrations was observed in patients with mildly to moderately impaired and severely impaired renal function. However, plasma concentrations were lower in patients with renal insufficiency undergoing hemodialysis. Temisartan is highly bound to plasma proteins in patients with renal insufficiency and therefore cannot be cleared by hemodialysis. The clearance half-life of temisartan in patients with renal impairment is unchanged.
Patients with hepatic impairment
Pharmacokinetic studies have shown that the absolute bioavailability of the product is increased in patients with hepatic impairment, reaching almost 100%. The clearance half-life is unchanged.
Storage】At 30℃.
Store below 30℃.
Package】Polyamide/aluminum/polyvinyl chloride cold pressed solid pharmaceutical compound hard tablets and pharmaceutical aluminum foil, 7 tablets/plate×1 plate/box, 7 tablets/plate×2 plate/box, 7 tablets/plate×3 plate/box, 7 tablets/plate×4 plate/box, 10 tablets/plate×3 plate/box.
【Validity】24 months
【Execution standard
【Approval number】State Drug Certificate H20060669
[Drug Marketing Licensee
Name: Beijing Tianheng Drug Research Institute Nanyang Tianheng Pharmaceutical Factory
Address: East section of Nanhuan Road, Dengzhou City, Henan Province
Postal Code: 474150
Telephone number: 0377-62185923
Fax number: 0377-62185923
Website: www.nythpharm.com
Manufacturer
Company Name: Beijing Tianheng Drug Research Institute Nanyang Tianheng Pharmaceutical Factory
Address: East section of Nanhuan Road, Dengzhou City
Postal Code: 474150
Telephone number: 0377-62185923
Fax number: 0377-62185923
Website: www.nythpharm.com