Telmisartan Drug Information

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Hypertension Telmisartan has been evaluated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy.

In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20 to 160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo. Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1. Table 1 Adverse Events Occurring at an Incidence of ≥1% in Patients Treated with Telmisartan and at a Greater Rate Than Patients Treated with Placebo Telmisartan n=1455 % Placebo n=380 % Upper respiratory tract infection 7 6 Back pain 3 1 Sinusitis 3 2 Diarrhea 3 2 Pharyngitis 1 0 In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with telmisartan tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials.

The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to telmisartan tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, nonspecific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache.

During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of telmisartan tablets. Hemoglobin : A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy because of anemia.

Creatinine : A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy because of increases in creatinine and blood urea nitrogen. Liver Enzymes : Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo.

No telmisartan-treated patients discontinued therapy because of abnormal hepatic function. Cardiovascular Risk Reduction Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo.

The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of telmisartan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Anemia, eosinophilia, thrombocytopenia Gastrointestinal Disorders: Abdominal pain, diarrhea, dyspepsia, nausea General Disorders and Administration Site Conditions: Asthenia, chest pain, edema, face edema, fatigue, lower limb edema, pain, weakness Hepato-biliary: Abnormal hepatic function/liver disorder Immune System Disorders: Anaphylactic reaction, hypersensitivity Investigations: Increased CPK, uric acid increased Metabolism and Nutrition Disorders: Hyperkalemia, hypoglycemia (in diabetic patients), hyponatremia Musculoskeletal and Connective Tissue Disorders: Myalgia Nervous System Disorders: Dizziness, headache, syncope Renal and Urinary Disorders: Renal impairment including acute renal failure Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Coughing Skin and Subcutaneous Tissue Disorders: Angioedema (with fatal outcome), angioneurotic edema, drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), erythema, sweating increased, urticaria Vascular Disorder: Hypotension (including postural hypotension) Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including telmisartan.

• Aliskiren: Do not co-administer aliskiren with telmisartan in patients with diabetes. Avoid use of aliskiren with telmisartan in patients with renal impairment (GFR <60 mL/min).
• Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range.
• Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including telmisartan. Therefore, monitor serum lithium levels during concomitant use. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective 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.
• NSAIDs: Increased risk of renal impairment and loss of anti-hypertensive effect Do not co-administer aliskiren with telmisartan in patients with diabetes

Pregnancy Risk Summary Telmisartan can cause fetal harm when administered to a pregnant woman. 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 (see Clinical Considerations ). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Studies in rats and rabbits with telmisartan showed fetotoxicity only at maternally toxic doses (see Data ). When pregnancy is detected, discontinue telmisartan as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal adverse reactions Use of drugs that act on the RAS in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. In patients taking telmisartan during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation.

If oligohydramnios is observed, discontinue telmisartan, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to telmisartan for hypotension, oliguria, and hyperkalemia.

If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function . Data Animal Data 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.

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/m 2 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. 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/m 2 basis, the maximum recommended human dose of telmisartan (80 mg/day).

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Neonates with a history of in utero exposure to telmisartan If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Telmisartan is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product. Do not co-administer aliskiren with telmisartan in patients with diabetes.. Known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or any other component of this product Do not co-administer aliskiren with telmisartan in patients with diabetes

Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with telmisartan tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Telmisartan is not removed by hemodialysis.