Telmisartan

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of non-steroidal anti-inflammatory agents (NSAIDs), including selective selective cyclooxygenase-2 (COX-2) inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Do not co-administer aliskiren with Micardis in patients with diabetes. Avoid use of aliskiren with Micardis in patients with renal impairment (GFR <60 mL/min).

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including Micardis. Therefore, monitor serum lithium levels during concomitant use.

Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of Micardis and ramipril is not recommended.

For more Interactions (Complete) data for TELMISARTAN (6 total), please visit the HSDB record page.

IDENTIFICATION AND USE: Telmisartan is a white to slightly yellowish solid that is formulated into oral tablets. Telmisartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive in the management of hypertension. It is also indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of telmisartan overdose include hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. The use of telmisartan during pregnancy is contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to both pressor agents and volume expansion may occur in the newborn following in utero exposure to telmisartan. ANIMAL STUDIES: Telmisartan was not carcinogenic when administered by dietary administration to mice and rats for up to 2 years. Also, the fertility of male and female rats was unaffected by administration of the drug. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses as high as 50 mg/kg/day or pregnant rabbits at oral doses as high as 45 mg/kg/day. However, in rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed. In rats, the maternally toxic dose was 15 mg/kg/day. When this dose was administered during late gestation and lactation it produced adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Genotoxicity assays did not reveal any drug-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames test), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

/SIGNS AND SYMPTOMS/ Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.

/CASE REPORTS/ Angiotensin II (A-II) is the main effector of the renin-angiotensin system. A-II functions by binding its type 1 (AT1) receptors to cause vasoconstriction and retention of sodium and fluid. Several AT1 receptor antagonists-a group of drugs collectively called "sartans"-have been marketed during the past few years for treatment of hypertension and heart failure. At least 15 case reports describe oligohydramnios, fetal growth retardation, pulmonary hypoplasia, limb contractures, and calvarial hypoplasia in various combinations in association with maternal losartan, candesartan, valsartan, or telmisartan treatment during the second or third trimester of pregnancy. Stillbirth or neonatal death is frequent in these reports, and surviving infants may exhibit renal damage. The fetal abnormalities, which are strikingly similar to those produced by maternal treatment with angiotensin-converting enzyme (ACE) inhibitors during the second and third trimesters of pregnancy, are probably related to extreme sensitivity of the fetus to the hypotensive action of these drugs. Very little information is available regarding the outcome of human pregnancies in which the mother was treated with an AT1 receptor antagonist during the first trimester, but animal studies have not demonstrated teratogenic effects after maternal treatment with large doses of AT1 receptor antagonists during organogenesis. We conclude that pharmacological suppression of the fetal renin-angiotensin system through ACE inhibition or AT1 receptor blockade seems to disrupt fetal vascular perfusion and renal function. We recommend that maternal treatment with AT1 receptor antagonists be avoided during the second and third trimesters of pregnancy and that women who become pregnant while taking one of these medications be changed to an antihypertensive drug of a different class as soon as the pregnancy is recognized.

/OTHER TOXICITY INFORMATION/ Drugs that act directly on the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Telmisartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.

/OTHER TOXICITY INFORMATION/ In July 2010, the US Food and Drug Administration (FDA) initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis suggested a possible association between the use of these agents and an increased risk of cancer. The meta-analysis, which combined cancer-related findings from 5 randomized, controlled trials in over 60,000 patients, found a modest but significant increase in the risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist (mostly telmisartan) compared with those in control groups (7.2 versus 6%, respectively; risk ratio 1.08). However, because of several limitations of the study (e.g., trials included in the meta-analysis were not specifically designed to evaluate cancer outcomes, lack of individual patient data), the validity of these findings has been questioned. Subsequent studies, including a larger, more comprehensive meta-analysis conducted by FDA, have not shown an increased risk of cancer in patients receiving angiotensin II receptor antagonists. FDA's meta-analysis, which included trial-level data from 31 randomized studies (total of approximately 156,000 patients), found no evidence of an increased risk of cancer in patients who received an angiotensin II receptor antagonist compared with those who received other treatments (placebo or active control). The overall rate of new cancer occurrence was essentially the same in both groups of patients (1.82 and 1.84 cases per 100 patient-years, respectively). In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups. Based on these results and a review of all currently available data related to this potential safety concern, FDA has concluded that use of angiotensin II receptor antagonists is not associated with an increased risk of cancer.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Telmisartan

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day (about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/sq m basis). In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/sq m basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/sq m basis, the maximum recommended human dose of telmisartan (80 mg/day).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/sq m basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).

/GENOTOXICITY/ Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

/OTHER TOXICITY INFORMATION/ ... In the present study, ... the effect of the angiotensin II type 1 receptor antagonist telmisartan on the development of NASH in a rat model /is examined/. Telmisartan, but not the angiotensin receptor antagonist valsartan, markedly attenuated hepatic steatosis, inflammation, and fibrosis in these rats. The quantitative parameters of steatosis, inflammation, and fibrosis were also ameliorated by treatment with telmisartan. Compared with telmisartan, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone attenuated hepatic steatosis and fibrosis of the liver to a similar degree. However, telmisartan, but not pioglitazone, dramatically decreased both subcutaneous and visceral fat. In conclusion, these results indicated that telmisartan should be the drug of first choice for the treatment of patients with NASH.

Hyperkalemia may occur in patients on angiotensin II receptor blockers (ARBs), particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.

Sensitivity reactions, including various anaphylactoid reactions and/or angioedema, have been reported with use of angiotensin II receptor antagonists, including telmisartan. Extreme caution in patients with history of angioedema associated with or unrelated to ACE or angiotensin II receptor antagonist therapy.

Because the renin-angiotensin-aldosterone (RAA) system appears to contribute substantially to maintenance of glomerular filtration in patients with congestive heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly (e.g., renal failure) in these patients during therapy with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor antagonist (e.g., telmisartan). Renal artery stenosis also is a risk factor for renal impairment during therapy with drugs that inhibit the RAA system. Although reports received to date have involved patients treated with ACE inhibitors, this adverse effect also would be expected to occur when drugs with similar pharmacologic activity (e.g., angiotensin II receptor antagonists) are used in a similar manner

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Treatment and supportive measures. Monitor blood pressure and heart rate for 6 hours after ingestion. If symptomatic or significant hypotension develops, observe for at least 24 hours. 1. If hypotension occurs, treat it with supine positioning and IV fluids. Vasopressors are rarely necessary. 2. Treat angioedema with usual measures (eg, diphenhydramine, corticosteroids) and discontinue the ACE inhibitors. Switching to an AR blocker may not be appropriate as angioedema has also been reported with these agents. 3. Treat hyperkalemia if it occurs. /Angiotensin blockers and ACE inhibitors/

For more Antidote and Emergency Treatment (Complete) data for TELMISARTAN (6 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including telmisartan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents

Use (kg; approx.) in Germany (2009): >10000

Table: Telmisartan Preparations [Table#7277]

Table: Irbesartan Combination Preparations [Table#7278]

Trade Name: Pritor. /From table/