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Telmisartan (Ti Yining)

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Indications: For the treatment of essential hypertension.

Approval date: April 29, 2008

Modified on June 27, 2008

Modified: October 17, 2011

Modified on: April 11, 2014

Modification date: March 31, 2016

Please read the instructions carefully and use under the guidance of a physician.

【Drug Name】

Common name: Telmisartan tablets

Commodity name: Di Yining

English name: Telmisartan Tablets

Phonetic script (Hanyu Pinyin): Timishatan Pian

[Ingredients]

Telmisartan

Chemical name: 4 '-[(1,4'-dimethyl-2'-propyl [2,6'-bis-1H-benzimidazole] -1'-yl) methyl]-[1,1 '-Biphenyl] -2-carboxylic acid

Molecular formula: C 33 H 30 N 4 O 2

Molecular weight: 514.63

[Character] This product is white or off-white tablet.

[Specifications] 40mg

【Dosage】

adult

It should be administered individually. The usual initial dose is one tablet (40 mg) once daily. In the dose range of 20 to 80 mg, the antihypertensive effect of telmisartan is dose-dependent. If the ideal blood pressure is not reached after the medication, the dose can be increased. The maximum dose is 80 mg once daily.

This product can be used in combination with thiazide diuretics such as hydrochlorothiazide. Such diuretics have a synergistic hypotensive effect with this product. Because telmisartan can exert its maximum effect four to eight weeks after the start of treatment, it should be considered if the drug dose is to be increased.

Patients with renal insufficiency: Patients with mild or moderate renal dysfunction do not need to adjust the dose when taking this product.

Telmisartan is not eliminated by hemofiltration.

Patients with liver dysfunction

For patients with mild or moderate liver dysfunction, the dosage of this product should not exceed 40 mg per day.

Seniors

No dosage adjustment is required to take this product.

Children and adolescents

For children and adolescents under 18 years of age, safety and efficacy data for this product have not been established.

【Adverse reactions】

In placebo-controlled trials, the overall incidence of adverse events for telmisartan (41.4%) was similar to placebo (43.9%). There was no correlation between the occurrence of adverse events and dose, and it had nothing to do with the sex, age and race of patients.

The adverse reactions listed below are cumulative from 5,788 patients with hypertension receiving telmisartan in clinical trials.

According to the frequency of adverse reactions, they are divided into: very common (> 1/10); common (> 1/100, <1/10); rare (> 1/1000, <1/100); rare (> 1/10000, <1/1000); very rare (<1/10000).

        Systemic reactions: common: back pain (such as sciatica), chest pain, flu-like symptoms, infection symptoms (such as urinary tract infections including cystitis); rare: visual abnormalities, sweating.

        Central and peripheral nervous system: common: dizziness.

        Gastrointestinal system: common: abdominal pain, diarrhea, indigestion, gastrointestinal disorders; rare: dry mouth, flatulence.

        Musculoskeletal system: common: joint pain, leg cramps or leg pain, myalgia; rare: tenosynovitis-like symptoms.

        Mental System: Rare: Anxiety.

        Respiratory System: Common: Upper respiratory infections include pharyngitis and rhinitis.

        Skin and accessory systems: Common: skin abnormalities such as eczema. Rare: Hypoglycemia (rarely in diabetic patients); angioedema (with fatal results); pain in extremities (pain in the legs).

Unclear: Septicemia including fatal outcomes (the prevalence of sepsis has increased in telmisartan compared to placebo in the PRoFESS study. This may be an accidental result or it may be related to a mechanism that is currently unclear.).

In addition, since the market of telmisartan, individual cases have reported erythema, pruritus, syncope, insomnia, depression, upset stomach, vomiting, hypotension, bradycardia, tachycardia, dyspnea, and eosinophilia. , Thrombocytopenia, weakness, and decreased work efficiency. Similar to other angiotensin II antagonists, very few cases have reported angioedema, urticaria and other related adverse reactions.

        The laboratory found that, compared with placebo, telmisartan-treated groups had occasionally noticed a decrease in hemoglobin or an increase in uric acid. Elevated serum creatinine or liver enzymes Telmisartan is similar to or lower than placebo.

[Taboo]

1. Those who are allergic to the active ingredients of this product and any of the excipient ingredients.

2. Those in the middle and late pregnancy and breastfeeding.

3. Patients with biliary obstructive disease.

4. Patients with severe liver dysfunction.

5. Patients with severe renal dysfunction (creatinine clearance <30ml / min).

【Precautions】

        Liver dysfunction

This product should not be used in patients with cholestasis, biliary obstructive disease or severe liver dysfunction, because telmisartan is mostly excreted through the bile, and the clearance of this product may be reduced in these patients. This product should be used with caution in patients with mild to moderate liver dysfunction.

        Renovascular hypertension

In cases of bilateral renal artery stenosis or unilateral renal renal artery stenosis, the use of drugs that affect the renin-angiotensin-aldosterone system leads to an increased risk of severe hypotension and renal insufficiency.

        Renal insufficiency and kidney transplant patients

This product should not be used in patients with severe renal insufficiency (creatinine clearance ﹤ 30ml / min, see contraindications). For patients with renal insufficiency, serum potassium levels and serum creatinine values should be regularly checked during the use of this product. There are no data on the use of this product in patients shortly after a recent kidney transplant.

      Hypovolemic patients

For patients with hypovolemia or hyponatremia due to the use of strong diuretics, salt-restricted diet, nausea or vomiting, taking this product, especially after the first dose, may cause symptomatic hypotension. Therefore, blood sodium and blood volume levels should be corrected before using this product.

Other conditions related to stimulation of the renin-angiotensin-aldosterone system

For patients whose vascular tone and renal function are mainly dependent on the activity of the renin-angiotensin-aldosterone system (such as patients with severe congestive heart failure or underlying kidney disease including renal artery stenosis), the use of drugs that can affect the system can be Causes acute hypotension, hyperazoemia, oliguria, or rare acute renal failure.

        Primary hyperaldosteronism

Antihypertensive drugs that inhibit the renin-angiotensin-aldosterone system are generally ineffective in patients with primary aldosteronism. Therefore, this product is not recommended for this type of patients.

Aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, patients with aortic or mitral valve stenosis and obstructive hypertrophic cardiomyopathy should pay special attention to this product.

        Electrolyte Imbalance: Hyperkalemia

The use of drugs that can affect the renin-angiotensin-aldosterone system may cause hyperkalemia, especially for patients with renal dysfunction and / or heart failure and diabetes, but for patients at risk during this product, Blood potassium levels should be closely monitored.

Based on experience with other drugs that affect the renin-angiotensin system, this product is used in combination with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that increase blood potassium levels (such as heparin) Can cause elevated potassium levels. Therefore, caution should be used in combination with this product. (See Drug Interactions).

Diabetics

Patients with diabetes with additional cardiovascular risk factors, such as patients with diabetic white coronary artery disease (CAD), use of antihypertensive drugs such as angiotensin receptor antagonists or ACE inhibitors may increase fatal myocardial infarction and cardiovascular disease Outside the risk of death. CAD in diabetic patients with CAD may be asymptomatic. Therefore, before using this product, diabetic patients should undergo appropriate diagnostic evaluation, such as exercise compliance test, etc., to find out whether they have CAD, and then carry out corresponding treatment.

other

Similar to angiotensin-converting enzyme inhibitors, the antihypertensive effect of this product and other angiotensin antagonists in blacks is lower than that of other races, which may be higher than the low renin status of black hypertensive people. Advantages.

As with other antihypertensive drugs, in patients with ischemic heart disease or ischemic cardiovascular disease, excessive hypotension can cause myocardial infarction or stroke.

Impact on driving and operating machines

The effects on driving and operating machines have not been studied. However, care must be taken when driving and operating machines, as antihypertensive treatments can sometimes cause dizziness and drowsiness.

[Medication for pregnant and lactating women]

Use during pregnancy

There is not enough data to show whether this product can be used in pregnant women. Animal tests did not show teratogenicity but showed embryo toxicity. Therefore, it is prudent not to use telmisartan in the first trimester of pregnancy. Before planning a pregnancy, appropriate alternative therapies should be taken.

In the middle and late stages of pregnancy (during the second and third trimesters), drugs that act directly on the renin-angiotensity system can cause fetal damage and even death. Therefore, telmisartan is contraindicated in the late and third trimester. Once pregnancy is confirmed, this product should be discontinued as soon as possible.

Use during lactation

As it is unknown whether this product is excreted through milk, it is forbidden during breastfeeding.

[Child medication]

For children and adolescents under 18 years of age, safety and efficacy data for this product have not been established.

[Medicine for the elderly]

No adjustments are required to take this product.

【medicine interactions】

1. Lithium: The combination of lithium and angiotensin-converting enzyme inhibitors can cause reversible increase in blood lithium levels and toxic reactions. There are also individual cases caused by the combination of lithium with angiotensin II receptor antagonists. Therefore, the combination of lithium agent and this product must be cautious. If combined, blood lithium levels should be monitored during the combined period.

2.Some drugs can affect blood potassium levels or cause hyperkalemia (such as ACE inhibitors, potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, cyclosporin A or other drugs such as heparin sodium ); If this product needs to be combined with these drugs, it is recommended to monitor blood potassium levels. Based on the experience of using other drugs that affect the renin-angiotensin system, the combination of this product with the above drugs can cause an increase in blood potassium levels (see note).

3. Pharmacokinetic experiments have studied the interaction between this product and digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, and amlodipine. It can increase the average trough blood concentration of digoxin by 20% (in individual cases, 39%), so the digoxin plasma concentration must be monitored.

4. This product can strengthen the antihypertensive effect of other antihypertensive drugs. Other clinically meaningful interactions have not been confirmed.

5. Based on its pharmacological properties, the following drugs can enhance the antihypertensive effect of antihypertensive drugs including telmisartan: baclofen, amifostine. In addition, alcohol, barbiturates, sedatives or antidepressants can enhance orthostatic hypotension effects.

6. When combined with telmisartan, the Cmax of simvastatin metabolite (simvastatin acid) slightly increased (1.34 times) and elimination was accelerated.

[Drug overdose]

No cases of overuse have been reported. Telmisartan overdose is most likely hypotension and tachycardia: bradycardia can also occur. Telmisartan cannot be cleared by hemodialysis. Once overdose occurs, the patient should be closely observed and symptomatic and supportive treatment should be done. Treatment should be based on the timing of the medication and the severity of the symptoms. Recommended measures include vomiting and / or gastric lavage. Activated carbon may be effective in treating overdose. Blood electrolytes and creatinine should be closely monitored. If hypotension occurs, the patient should lie flat, and add salt and volume as soon as possible.

[Pharmacology and Toxicology]

Pharmacological action

Telmisartan is an orally active, specific angiotensin II receptor (AT 1 ) antagonist, and angiotensin II receptor AT 1 subtype (known site of action of angiotensin II) ) High affinity binding. This combination is durable. But without any partial agonist effect. Because of the increased angiotensin Ⅱ level by telmisartan, the possible over-stimulating effect of the receptor is unknown. Telmisartan can cause a decrease in blood aldosterone levels. Telmisartan does not inhibit human plasma renin, nor does it block ion channels. Angiotensin-converting enzyme (kininase II) can also degrade bradykininase. Since telmisartan does not inhibit angiotensin-converting enzyme, there are no adverse reactions caused by the enhancement of bradykinin. Telmisartan has no affinity for other receptors, including AT 2 and other less-recognized AT receptors, whose function is unknown.

Administration of 80 mg of telmisartan in humans can almost completely suppress the increase of blood pressure caused by angiotensin II, and the inhibitory effect lasts for 24 hours, and it can still be measured at 48 hours.

The antihypertensive effect is gradually obvious within 3 hours after the first dose of telmisartan, and the maximum antihypertensive effect can be obtained 4 weeks after the start of treatment, and can be maintained during long-term treatment.

Ambulatory blood pressure monitoring shows that the antihypertensive effect lasts for more than 24 hours after taking the drug, including 4 hours before the next dose. This result was confirmed in a placebo-controlled clinical trial study: taking telmisartan 40mg and 80mg troughs and crests consistently exceeded 80%.

There was a clear dose-time dependence of SBP return to baseline. Data on DBP are inconsistent in this regard.

For patients with hypertension, telmisartan can reduce systolic and diastolic blood pressure without affecting heart rate. The antihypertensive effect of telmisartan is comparable to other types of antihypertensive drugs. (Clinical experimental studies have compared telmisartan with amlodipine, atenolol, enalapril, dihydrochlorothiazide, losartan, and lisinopril).

If telmisartan treatment is suddenly interrupted, blood pressure gradually returns to the pre-treatment level after a few days without rebound hypertension.

In a clinical experimental study comparing two antihypertensive drugs directly, the incidence of dry cough was significantly lower in the telmisartan-treated group than in the angiotensin-converting enzyme inhibitor group.

The role of telmisartan in improving mortality and cardiovascular disease prevalence is unknown.

toxicology

The dose used in the preclinical safety study is equivalent to the clinical treatment dose, which can cause reduction of red blood cell index (erythrocyte, hemoglobin, hematocrit) and renal hemodynamic changes (increased blood urea nitrogen and creatinine) and normal blood pressure animals. Elevated blood potassium. Dilation and atrophy of renal tubules are seen in dogs. Gastrointestinal mucosal damage (erosion, ulcers or inflammation) is also seen in rats and dogs. These pharmacological adverse reactions are known from preclinical studies to be a reaction common to angiotensin-converting enzyme inhibitors and angiotensin II antagonists, and can be prevented by oral salt supplements.

Increased plasma renin activity and glomerular mesangial cell hypertrophy / proliferation can be seen in both species. The above changes are also a response common to angiotensin-converting enzyme inhibitors and other angiotensin II antagonists, and have no clinical specificity.

Animal experiments have shown that telmisartan has some potential adverse effects on postnatal development of fetuses, including weight loss, delayed eye opening, and increased mortality.

No mutagenicity and related mutagenic activity were found in vitro, and no carcinogenicity was found in mice and rats.

【Pharmacokinetics】

absorb

After oral administration, telmisartan is rapidly absorbed with an average absolute bioavailability of approximately 50%. When telmisartan is ingested with food at the same time, the area under the drug curve (AUC 0 ~ ∞ ) decreases by 6% (40mg dose) to 19% (160mg dose). Take telmisartan for 3 hours on an empty stomach or diet After plasma concentrations were similar. A slight reduction in AUC does not cause a reduction in efficacy.

Wireless relationship between dose and plasma levels. At doses above 40 mg, Cmax slightly increased disproportionately to AUC.

Different genders have different plasma concentrations, and Cmax and AUC of women are nearly two to three times higher than men, respectively.

distributed

Telmisartan mostly binds to plasma proteins (> 99.5%), mainly albumin and a-1 acid glycoprotein. The average steady state apparent distribution volume (Vss) is about 500L.

metabolism

Telmisartan is metabolized by the parent compound in combination with glucuronide. The combination product has no pharmacological activity.

eliminate

Telmisartan is eliminated according to the second power pharmacokinetics, and the final elimination half-life is> 20 hours. The maximum plasma concentration (C max ) does not increase proportionally with increasing dose, and the area under the curve (AUC) at the time of drug administration does not increase proportionally with increasing dose. When taken at the recommended dose, no clinically relevant accumulation of telmisartan was seen. Plasma concentrations were higher in women than men, but had no effect on efficacy.

When taken orally (or intravenously), telmisartan is almost completely excreted in the feces, mainly in the form of unchanged compounds. Cumulative urine excretion is less than 2% of the dose. The total plasma clearance (CLtot) (about 1000ml / min) is higher than the liver blood flow (about 1500ml / min)

Seniors

There was no difference in the pharmacokinetics of telmisartan between elderly and young people.

Patients with renal insufficiency

Patients with renal insufficiency undergoing dialysis have lower plasma concentrations. Telmisartan is highly bound to plasma proteins in patients with renal insufficiency and cannot be cleared by dialysis. The half-life of telmisartan is unchanged in patients with renal insufficiency.

Patients with liver dysfunction

Pharmacokinetic studies have shown that absolute bioavailability of patients with liver dysfunction increases by approximately 100%. Clearance half-life is unchanged in patients with liver dysfunction.

[Storage] shading and sealed.

[Packing] Aluminum aluminum packaging, 7 pieces / plate, 1 plate / box, 2 plates / box, 3 plates / box, 4 plates / box or 5 plates / box.

[Validity] 24 months

[Executive Standard] YBH00082016

[Approval number] National Medicine Standard H20051524

【manufacturer】