DOSAGE FORMS & STRENGTHS SECTION.
3 DOSAGE FORMS AND STRENGTHS Tablets: 40 mg/12.5 mg, 80 mg/12.5 mg, 80 mg/25 mg (3) 40 mg/12.5 mg, biconvex two-layered, capsule-shaped uncoated tablets with telmisartan layer as white or off-white to yellowish but may contain yellow specks and hydrochlorothiazide layer as yellow but may contain white specks, telmisartan layer debossed with '1159' and plain on other side. 80 mg/12.5 mg, biconvex two-layered, capsule-shaped uncoated tablets with telmisartan layer as white or off-white to yellowish but may contain pink specks and hydrochlorothiazide layer as pink but may contain white specks, telmisartan layer debossed with '1160' and plain on other side. 80 mg/25 mg, biconvex two-layered, capsule-shaped uncoated tablets with telmisartan layer as white or off-white to yellowish but may contain yellow specks and hydrochlorothiazide layer as yellow but may contain white specks, telmisartan layer debossed with '1161' and plain on other side.
BOXED WARNING SECTION.
W ARN ING: FETAL TOXICITY S e e full prescribing information for complete boxed warning . W h e n pregnancy is detected, discontinue telmisartan and hydrochlorothiazide tablets as soon as possible. (5.1, 8.1) D r u g s that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1, 8.1) WARNING: FETAL TOXICITY When pregnancy is detected, discontinue telmisartan and hydrochlorothiazide tablets as soon as possible [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 80 mg/25 mg Cartons Telmisartan and Hydrochlorothiazide Tablets, USP 80 mg/25 mg Rx Only Important: Moisture sensitive tablets - do not remove from blisters until immediately before administration. PHARMACIST: Dispense the accompanying Patient Information Sheet to each patient. Manufactured by: TORRENT PHARMACEUTICALS LTD., Indrad-382 721, INDIA. Manufactured by: TORRENT PHARMACEUTICALS LTD., Bharuch-392130, INDIA.
ADVERSE REACTIONS SECTION.
6 ADVERSE REACTIONS The most common adverse reactions (2% of patients) were upper respiratory tract infection, dizziness, sinusitis, diarrhea, fatigue, influenza-like symptoms, and nausea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1- 800-912-9561, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following adverse reactions are discussed elsewhere in labeling: Hypotension [see Warnings and Precautions (5.2)] Renal Impairment [see Warnings and Precautions (5.3)] Electrolytes and Metabolic Disorders [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction 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. Telmisartan and hydrochlorothiazide tablets have been evaluated for safety in more than 1700 patients, including 716 treated for hypertension for longer than 6 months and 420 for more than 1 year. Adverse reactions have been limited to those that have been previously reported with telmisartan and/or hydrochlorothiazide. Adverse reactions occurring at an incidence of 2% in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo, are presented in Table 1 [see Clinical Studies (14)]. Table 1 Adverse Reactions Occurring at an Incidence of 2% in Patients Treated with Telmisartan/Hydrochlorothiazide and at a Greater Rate Than in Patients Treated with Placebo* * includes all doses of telmisartan (20 to 160 mg), hydrochlorothiazide (6.25 to 25 mg), and combinations thereof Telmisartan/ Hydrochlorothiazide (n = 414) Placebo (n = 74) Telmisartan (n = 209) Hydrochlorothiazide (n = 121) Body as a whole Fatigue 3% 1% 3% 3% Influenza-like symptoms 2% 1% 2% 3% Central/peripheral nervous system Dizziness 5% 1% 4% 6% Gastrointestinal system Diarrhea 3% 0% 5% 2 % Nausea 2% 0% 1% 2% Respiratory system disorder Sinusitis 4% 3% 3% 6% Upper respiratory tract infection 8% 7% 7% 10% Other adverse reactions observed for telmisartan/hydrochlorothiazide were: pain (including back and abdominal), dyspepsia, erythema, vomiting, bronchitis, and pharyngitis. Adverse reactions occurred at approximately the same rates in men and women, older and younger patients, and black and non-black patients. Telmisartan Other adverse events that have been reported with telmisartan are listed below: Autonomic Nervous System: impotence, increased sweating, flushing Body as a Whole: allergy, fever, leg pain, chest pain Cardiovascular: palpitation, angina pectoris, abnormal ECG, hypertension, peripheral edema Central Nervous System: insomnia, somnolence, migraine, paresthesia, involuntary muscle contractions, hypoesthesia Gastrointestinal: flatulence, constipation, gastritis, dry mouth, hemorrhoids, gastroesophageal reflux, toothache Hepato-biliary: elevations of liver enzymes or serum bilirubin Metabolic: gout, hypercholesterolemia, diabetes mellitus Musculoskeletal: arthritis, arthralgia, leg cramps, myalgia Psychiatric: anxiety, depression, nervousness Resistance Mechanism: infection, abscess, otitis media Respiratory: asthma, rhinitis, dyspnea, epistaxis Skin: dermatitis, eczema, pruritus Urinary: micturition frequency, cystitis Vascular: cerebrovascular disorder Special Senses: abnormal vision, conjunctivitis, tinnitus, earache Hydrochlorothiazide Other adverse events that have been reported with hydrochlorothiazide are listed below: Body as a Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: hyperglycemia, glycosuria Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Clinical Laboratory Findings Creatinine, Blood Urea Nitrogen (BUN): Increases in BUN (11.2 mg/dL) and serum creatinine (0.5 mg/dL) were observed in 2.8% and 1.4%, respectively, of patients with essential hypertension treated with telmisartan and hydrochlorothiazide tablets in controlled trials. No patient discontinued treatment with telmisartan and hydrochlorothiazide tablets because of an increase in BUN or creatinine [see Warnings and Precautions (5.3)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of telmisartan and hydrochlorothiazide tablets. 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: eosinophilia Cardiac Disorders: atrial fibrillation, congestive heart failure, myocardial infarction, tachycardia, bradycardia Ear and Labyrinth Disorders: vertigo General Disorders and Administration Site Conditions: asthenia, edema Hepatobiliary: Abnormal hepatic function / liver disorder Immune System Disorders: anaphylactic reaction Infections and Infestations: urinary tract infection Investigations: increased CPK Metabolism and Nutrition Disorders: hypoglycemia (in diabetic patients) Musculoskeletal and Connective Tissue Disorders: tendon pain (including tendonitis, tenosynovitis), rhabdomyolysis Nervous System Disorders: syncope, headache Renal and Urinary Disorders: renal failure, renal impairment including acute renal failure Reproductive System and Breast Disorders: erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: coughing Skin and Subcutaneous Tissue Disorders: drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), angioedema (with fatal outcome) Vascular Disorder: orthostatic hypotension
INDICATIONS & USAGE SECTION.
1 INDICATIONS AND USAGE Telmisartan and hydrochlorothiazide tablets are combination of an angiotensin II receptor blocker (ARB) and a thiazide diuretic indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1) Telmisartan and hydrochlorothiazide tablets are not indicated for initial therapy (1) Telmisartan and hydrochlorothiazide tablets, are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the classes to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with telmisartan and hydrochlorothiazide tablets. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy [see Clinical Studies (14)]. Telmisartan and hydrochlorothiazide tablets are not indicated for initial therapy for the treatment of hypertension [see Dosage and Administration (2.1)]. Telmisartan and hydrochlorothiazide tablets may be used alone or in combination with other antihypertensive agents.
DOSAGE & ADMINISTRATION SECTION.
2 DOSAGE AND ADMINISTRATION Usual starting dose is 80 mg/12.5 mg once daily (2.1) Titrate up to 160 mg/25 mg as needed (2.1) Initiate patients with biliary obstructive disorders or hepatic insufficiency at 40 mg/12.5 mg (2.2) 2.1 Dosing Information Initiate a patient whose blood pressure is not adequately controlled with telmisartan monotherapy 80 mg on telmisartan and hydrochlorothiazide tablets, 80 mg/12.5 mg once daily. Dose can be titrated up to 160 mg/25 mg after 2 to 4 weeks, if necessary. Initiate a patient whose blood pressure is not adequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen on telmisartan and hydrochlorothiazide tablets 80 mg / 12.5 mg once daily. Dose can be titrated up to 160 mg/25 mg after 2 to 4 weeks, if necessary. Patients titrated to the individual components (telmisartan and hydrochlorothiazide) may instead receive the corresponding dose of telmisartan and hydrochlorothiazide tablets. Telmisartan and hydrochlorothiazide tablets may be administered with other antihypertensive drugs. 2.2 Dose Adjustment for Hepatic Impairment Initiate patients with biliary obstructive disorders or hepatic insufficiency under close medical supervision using the 40 mg/12.5 mg combination. Telmisartan and hydrochlorothiazide tablets are not recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. 2.3 Important Administration Instructions Telmisartan and hydrochlorothiazide tablets should not be removed from blisters until immediately before administration.
HOW SUPPLIED SECTION.
16 HOW SUPPLIED/STORAGE AND HANDLING Telmisartan and hydrochlorothiazide tablets, USP are available in three strengths as biconvex two-layered, capsule-shaped, uncoated tablets containing telmisartan and hydrochlorothiazide: 40 mg/12.5 mg tablet: Biconvex two-layered, capsule-shaped uncoated tablets with telmisartan layer as white or off-white to yellowish but may contain yellow specks and hydrochlorothiazide layer as yellow but may contain white specks, telmisartan layer debossed with '1159' and plain on other side. Bottles of 30 NDC 13668-159-30 Bottles of 100 NDC 13668-159-01 30 Unit dose Tablets NDC 13668-159-72 100 Unit dose Tablets NDC 13668-159-74 80 mg/12.5 mg tablet: Biconvex two-layered, capsule-shaped uncoated tablets with telmisartan layer as white or off-white to yellowish but may contain pink specks and hydrochlorothiazide layer as pink but may contain white specks, telmisartan layer debossed with '1160' and plain on other side. Bottles of 30 NDC 13668-160-30 Bottles of 100 NDC 13668-160-01 30 Unit dose Tablets NDC 13668-160-72 100 Unit dose Tablets NDC 13668-160-74 80 mg/25 mg tablet: Biconvex two-layered, capsule-shaped uncoated tablets with telmisartan layer as white or off-white to yellowish but may contain yellow specks and hydrochlorothiazide layer as yellow but may contain white specks, telmisartan layer debossed with '1161' and plain on other side. Bottles of 30 NDC 13668-161-30 Bottles of 100 NDC 13668-161-01 30 Unit dose Tablets NDC 13668-161-72 100 Unit dose Tablets NDC 13668-161-74 Storage Store at 20 to 25C (68 to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Protect from moisture. Tablets should not be removed from containers and blisters until immediately before administration.
11 DESCRIPTION Telmisartan and hydrochlorothiazide tablets, USP are a combination of telmisartan, an orally active angiotensin II antagonist acting on the AT 1 receptor subtype, and hydrochlorothiazide, a thiazide diuretic. Telmisartan, a non-peptide molecule, is chemically described as 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C 33H 30N 4O 2, its molecular weight is 514.63, and its structural formula is: Telmisartan, USP is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base. Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder with a molecular weight of 297.74. It is slightly soluble in water, and freely soluble in sodium hydroxide solution. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7H 8ClN 3O 4S 2, and its structural formula is: Telmisartan and hydrochlorothiazide tablets, USP are formulated for oral administration in three combinations of 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg telmisartan and hydrochlorothiazide, respectively. The tablets contain the following inactive ingredients: hypromellose, lactose monohydrate, mannitol, meglumine, povidone, sodium hydroxide, sodium stearyl fumarate. As coloring agents, the 40 mg/12.5 mg and 80 mg/25 mg tablets contain ferric oxide yellow, and the 80 mg/12.5 mg tablets contain ferric oxide red. Telmisartan and hydrochlorothiazide tablets, USP are hygroscopic and require protection from moisture. Meets USP Dissolution Test 2.
10 OVERDOSAGE Telmisartan Limited data are available with regard to overdosage of telmisartan in humans. The most likely manifestations of overdosage with telmisartan are 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. Hydrochlorothiazide The most common signs and symptoms observed in patients with a hydrochlorothiazide overdose are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.
WARNINGS AND PRECAUTIONS SECTION.
5 WARNINGS AND PRECAUTIONS Avoid fetal or neonatal exposure (5.1) Correct volume or salt depletion before initiating therapy. Observe for signs and symptoms of hypotension (5.2) Monitor renal function and potassium in susceptible patients (5.3) Observe for clinical signs of fluid or electrolyte imbalance (5.4) Hypersensitivity Reaction (5.5) Acute Myopia and Secondary Angle-Closure Glaucoma (5.6) 5.1 Fetal Toxicity Telmisartan 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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue telmisartan and hydrochlorothiazide tablets as soon as possible. Hydrochlorothiazide Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia [see Use in Specific Populations (8.1)]. 5.2 Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initialization of treatment with telmisartan and hydrochlorothiazide tablets. Correct volume or salt depletion prior to administration of telmisartan and hydrochlorothiazide tablets. 5.3 Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the rennin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia, or acute renal failure on telmisartan and hydrochlorothiazide tablets. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on telmisartan and hydrochlorothiazide tablets. 5.4 Electrolytes and Metabolic Disorders Drugs, including telmisartan, that inhibit the renin-angiotensin system can cause hyperkalemia, particularly in patients with renal insufficiency, diabetes, or combination use with other angiotensin receptor blockers or ACE inhibitors and the concomitant use of other drugs that raise serum potassium levels [see Drug Interactions (7.1,7.4)]. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically. In controlled trials using the telmisartan/hydrochlorothiazide combination treatment, no patient administered 40 mg/12.5 mg, 80 mg/12.5 mg, or 80 mg/25 mg experienced a decrease in potassium 1.4 mEq/L, and no patient experienced hyperkalemia. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Because telmisartan decreases uric acid, telmisartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia. 5.5 Hypersensitivity Reaction Hydrochlorothiazide Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history [see Contraindications (4)]. 5.6 Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. 5.7 Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.8 Postsympathectomy Patients The antihypertensive effects of hydrochlorothiazide may be enhanced in the postsympathectomy patient.
DRUG INTERACTIONS SECTION.
7 DRUG INTERACTIONS Lithium: Risk of lithium toxicity (7.2) Non-steroidal anti-inflammatory drugs (NSAIDs): Reduced diuretic, natriuretic, and antihypertensive effects; increased risk of renal impairment (7.3) Dual blockade of renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7.4) Antidiabetic drugs: Dosage adjustment may be required (7.6) Cholestyramine and colestipol: Reduced absorption of thiazides (7.7) 7.1 Agents Increasing Serum Potassium Co-administration of telmisartan with other drugs that raise serum potassium levels may result hyperkalemia. Monitor serum potassium in such patients. 7.2 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of thiazide diuretics or angiotensin II receptor antagonists, including telmisartan. Monitor lithium levels in patients receiving telmisartan and hydrochlorothiazide tablets and lithium. 7.3 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors Telmisartan 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 ARBs, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. The antihypertensive effect of ARBs may be attenuated by NSAIDs. Therefore, monitor renal function and blood pressure periodically in patients receiving telmisartan and hydrochlorothiazide tablets and NSAIDs. Hydrochlorothiazide Administration of a non-steroidal anti-inflammatory agent, including a selective COX-2 inhibitor, can reduce the diuretic, natriuretic, and antihypertensive effects of diuretics. Therefore, when telmisartan and hydrochlorothiazide and non-steroidal anti-inflammatory agents including selective COX-2 inhibitors are used concomitantly, observe closely to determine if the desired effect of the diuretic is obtained. 7.4 Dual Blockade of the Renin-Aldosterone System and Changes in Renal Function Dual blockade of the renin-angiotensin-aldosterone system (RAS) with angiotensin blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and renal impairment. The ONTARGET trial enrolled 25,620 patients 55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan (ARB) only, ramipril (ACE inhibitor) only, or the combination, and followed them for a median of 56 months. Patients who received the combination of ARB and ACE inhibitor did not obtain any additional benefit (no additional reduction of risk of cardiovascular death, myocardial infarction, stroke, or hospitalization from heart failure) compared to ARB monotherapy or ACE inhibitor monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with monotherapy groups. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on telmisartan and hydrochlorothiazide and other agents that affect the RAS. Do not co-administer aliskiren with telmisartan and hydrochlorothiazide tablets in patients with diabetes. Avoid concomitant use of aliskiren with telmisartan and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 mL/min/1.73 m 2). 7.5 Digoxin When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Monitor digoxin levels in patients taking concomitant telmisartan and hydrochlorothiazide and digoxin. 7.6 Antidiabetic Drugs (Oral Agents and Insulin) Dosage adjustment of antidiabetic drugs may be required when coadministered with hydrochlorothiazide. 7.7 Cholestyramine and Colestipol Resins Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Stagger the dosage of hydrochlorothiazide and the resin such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of the resin.
NONCLINICAL TOXICOLOGY SECTION.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Telmisartan and Hydrochlorothiazide No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide. Telmisartan 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/m 2 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 of telmisartan (80 mg/day). 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. 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/m 2 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). Hydrochlorothiazide Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, in the Mouse Lymphoma Cell (mutagenicity) assay, and in the Aspergillus nidulans non-disjunction assay. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.
USE IN SPECIFIC POPULATIONS SECTION.
8 USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed during treatment with telmisartan and hydrochlorothiazide tablets (8.2) Severe Hepatic Impairment: Use not recommended (8.6) Severe Renal Impairment: Use not recommended (8.7) 8.1 Pregnancy Risk Summary Telmisartan and hydrochlorothiazide tablets 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 rennin-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 and hydrochlorothiazide tablets 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 Telmisartan 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 and hydrochlorothiazide tablets 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 and hydrochlorothiazide tablets, 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 and hydrochlorothiazide tablets 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 replacing renal function [see Use in Specific Populations (8.4)]. Hydrochlorothiazide Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions that have occurred in adults. Data Animal Data Telmisartan and hydrochlorothiazide tablets A developmental toxicity study was performed in rats with telmisartan/hydrochlorothiazide doses of 3.2/1.0, 15/4.7, 50/15.6, and 0/15.6 mg/kg/day. Although the two higher dose combinations appeared to be more toxic (significant decrease in body weight gain) to the dams than either drug alone, there did not appear to be an increase in toxicity to the developing embryos. Telmisartan 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 of up to 45 mg/kg/day. In rabbits, embryo lethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day (approximately 12 times the maximum recommended human dose [MRHD] of 80 mg on a mg/m 2 basis). In rats, maternally toxic (reduced body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (approximately 1.9 times the MRHD on a mg/m2 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 approximately 0.64 and 3.7 times, respectively, on a mg/m2 basis, the MRHD of telmisartan (80 mg/day). Hydrochlorothiazide Studies in which hydrochlorothiazide was administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD), provided no evidence of harm to the fetus. Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should be avoided. 8.2 Lactation Risk Summary There is no information regarding the presence of telmisartan and hydrochlorothiazide or telmisartan in human milk, the effects on the breastfed infant or the effects on milk production. Limited published studies report that hydrochlorothiazide is present in human milk. However, there is insufficient information to determine the effects of hydrochlorothiazide on the breastfed infant or the effects of hydrochlorothiazide on milk production. Telmisartan is present in the milk of lactating rats. (see Data). Because of the potential for serious adverse reactions in the breastfed infant including hypotension, hyperkalemia and renal impairment, advise a nursing woman not to breastfeed during treatment with telmisartan and hydrochlorothiazide tablets. Data Telmisartan was present in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma from 4 to 8 hours after administration. 8.4 Pediatric Use Safety and effectiveness of telmisartan and hydrochlorothiazide tablets in pediatric patients have not been established. Neonates with a history of in utero exposure to Telmisartan and Hydrochlorothiazide tablets: If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. 8.5 Geriatric Use In the controlled clinical trials (n=1017), approximately 20% of patients treated with telmisartan/hydrochlorothiazide were 65 years of age or older, and 5% were 75 years of age or older. No overall differences in effectiveness and safety of telmisartan/hydrochlorothiazide were observed in these patients compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy. 8.6 Use in Patients with Hepatic Impairment Patients with biliary obstructive disorders or hepatic insufficiency should initiate treatment under close medical supervision using the 40 mg/12.5 mg combination . Telmisartan As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance and higher blood levels . Hydrochlorothiazide Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease. 8.7 Use in Patients with Renal Impairment Safety and effectiveness of telmisartan and hydrochlorothiazide tablets in patients with severe renal impairment (CrCl 30 mL/min) have not been established. In patients with severe renal impairment, telmisartan and hydrochlorothiazide tablets are not recommended. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.
INFORMATION FOR PATIENTS SECTION.
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Pregnancy Advise female patients of childbearing age about the consequences of exposure to telmisartan and hydrochlorothiazide tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1)] and Use in Specific Populations (8.1)]. Lactation Advise nursing women not to breastfeed during treatment with telmisartan and hydrochlorothiazide tablets [see Use in Specific Populations (8.2)]. Symptomatic Hypotension and Syncope Advise patients that lightheadedness can occur, especially during the first days of therapy, and to report it to their healthcare provider. Inform patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Advise patients to contact their healthcare provider if syncope occurs [see Warnings and Precautions (5.2)]. Potassium Supplements Advise patients not to use potassium supplements or salt substitutes that contain potassium without consulting the prescribing healthcare provider [see Warnings and Precautions (5.4) and Drug Interactions (7.1)]. Acute Myopia and Secondary Angle-Closure Glaucoma Advise patients to discontinue telmisartan and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms of Acute Myopia or Secondary Angle-Closure Glaucoma [see Warnings and Precautions (5.6]. Manufactured by: TORRENT PHARMACEUTICALS LTD. Indrad-382 721, INDIA. Manufactured for: TORRENT PHARMA INC. Basking Ridge, NJ 07920. 8068356Revised April 2018 Manufactured by: TORRENT PHARMACEUTICALS LTD. Bharuch-392130, INDIA. Manufactured for: TORRENT PHARMA INC. Basking Ridge, NJ 07920. 8068660Revised April 2018
CLINICAL STUDIES SECTION.
14 CLINICAL STUDIES Telmisartan and Hydrochlorothiazide In controlled clinical trials with more than 2500 hypertensive patients, 1017 patients were exposed to telmisartan (20 mg to 160 mg) and concomitant hydrochlorothiazide (6.25 mg to 25 mg). These trials included one factorial trial (Study 1) with combinations of telmisartan (20 mg, 40 mg, 80 mg, 160 mg, or placebo) and hydrochlorothiazide (6.25 mg, 12.5 mg, 25 mg, and placebo). The factorial trial randomized 818 patients, including 493 (60%) males; 596 (73%) Non-Black and 222 (27%) Blacks; and 143 (18%) 65 years of age (median age was 53 years old). The mean supine blood pressure at baseline for the total population was 154/101 mmHg. The combination of telmisartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressures at trough of 16 to 21/9 to 11 mmHg for doses between 40 mg/12.5 mg and 80 mg/25 mg, compared with 9 to 13/7 to 8 mmHg for telmisartan 40 mg to 80 mg monotherapy and 4/4 mmHg for hydrochlorothiazide 12.5 mg monotherapy. The antihypertensive effect was independent of age or gender. There was essentially no change in heart rate in patients treated with the combination of telmisartan and hydrochlorothiazide in the placebo-controlled trial. Four other studies of hypertensive patients of at least six months' duration allowed add-on of hydrochlorothiazide for patients who either were not adequately controlled on the randomized telmisartan monotherapy dose or had not achieved adequate blood pressure response after completing the up-titration of telmisartan. In active-controlled studies, the addition of 12.5 mg hydrochlorothiazide to titrated doses of telmisartan in patients who did not achieve or maintain adequate response with telmisartan monotherapy further reduced systolic and diastolic blood pressures.
PATIENT MEDICATION INFORMATION SECTION.
Patient Information Telmisartan and Hydrochlorothiazide ( TEL mi SAR tan and HYE droe KLOR oh THYE a zide) Tablets, USP Read this Patient Information before you start taking telmisartan and hydrochlorothiazide tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. What is the most important information I should know about telmisartan and hydrochlorothiazide tablets? Telmisartan and hydrochlorothiazide tablets can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking telmisartan and hydrochlorothiazide tablets, tell your doctor right away. What are telmisartan and hydrochlorothiazide tablets? Telmisartan and hydrochlorothiazide tablets are a prescription medicine used to treat high blood pressure (hypertension). Telmisartan and hydrochlorothiazide tablets contains: telmisartan, an angiotensin receptor blocker (ARB) hydrochlorothiazide, a water pill or diuretic Your doctor may prescribe other medicines for you to take along with telmisartan and hydrochlorothiazide tablets to treat your high blood pressure. It is not known if telmisartan and hydrochlorothiazide tablets are safe and effective in children. Do not take telmisartan and hydrochlorothiazide tablets if you: have low or no urine output are allergic (hypersensitive) to the active ingredients (telmisartan or hydrochlorothiazide) or any of the other ingredients listed at the end of this leaflet. What should I tell my doctor before using telmisartan and hydrochlorothiazide tablets? Before you take telmisartan and hydrochlorothiazide tablets, tell your doctor if you: are pregnant or are planning to become pregnant. See "What is the most important information I should know about telmisartan and hydrochlorothiazide tablets?" are breast-feeding or plan to breast-feed. Telmisartan and hydrochlorothiazide can pass into your breast milk and may harm your baby. You and your doctor should decide if you will take telmisartan and hydrochlorothiazide tablets or breast-feed. You should not do both. Talk with your doctor about the best way to feed your baby if you take telmisartan and hydrochlorothiazide tablets. have been told that you have abnormal body salt (electrolytes) levels in your blood have liver problems have asthma or history of asthma have lupus have diabetes have kidney problems have any other medical conditions Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Also, tell your doctor if you drink alcohol. Telmisartan and hydrochlorothiazide tablets may affect the way other medicines work, and other medicines may affect how telmisartan and hydrochlorothiazide tablets work. Especially tell your doctor if you take: aliskiren digoxin (Lanoxin ) lithium (Lithobid , lithium carbonate, lithium citrate) other medicines used to treat your high blood pressure or a heart problem water pills (diuretic) aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) potassium supplements or a salt substitute containing potassium medicine used to treat diabetes, including insulin narcotic pain medicines sleeping pills steroid medicine or Adrenocorticotrophic Hormone (ACTH) barbiturates certain cholesterol lowering medicines (resins that are used for cholesterol reduction, e.g.,cholestyramine and colestipol resins ) Ask your doctor if you are not sure if you are taking one of the medicines listed above. Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist when you get a new medicine. How should I take telmisartan and hydrochlorothiazide tablets? Take telmisartan and hydrochlorothiazide tablets exactly as your doctor tells you to take it. Your doctor will tell you how much telmisartan and hydrochlorothiazide tablets to take and when to take it. Do not change your dose unless your doctor tells you to. Take telmisartan and hydrochlorothiazide tablets once each day. Take telmisartan and hydrochlorothiazide tablets with or without food. If you take too much telmisartan and hydrochlorothiazide tablets, call your doctor, or go to the nearest hospital emergency room right away. Read the "How to open the blister" at the end of this leaflet before you use telmisartan and hydrochlorothiazide tablets. Talk with your doctor if you do not understand the instructions. What are the possible side effects of telmisartan and hydrochlorothiazide tablets? Telmisartan and hydrochlorothiazide tablets may cause serious side effects, including: Injury or death to your unborn baby. See " What is the most important information I should know about telmisartan and hydrochlorothiazide tablets? " Low blood pressure (hypotension) is most likely to happen if you also: take water pills (diuretics) are on a low-salt diet get dialysis treatments have heart problems get sick with vomiting or diarrhea do not drink enough fluids sweat a lot If you feel faint or dizzy, lie down and call your doctor right away. Kidney problems, which may get worse if you already have kidney disease. You may have changes in your kidney test results, and you may need a lower dose of telmisartan and hydrochlorothiazide tablets. Call your doctor if you get: swelling in your feet, ankles, or hands unexplained weight gain Call your doctor right away if you get any of the symptoms listed above. Liver problems, which may get worse in people who already have liver problems and take telmisartan and hydrochlorothiazide tablets. Eye problems . One of the medicines in telmisartan and hydrochlorothiazide tablets can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting telmisartan and hydrochlorothiazide tablets. Tell your doctor right away if you have: decrease in vision eye pain Allergic reactions. Tell your doctor right away if you get any of these symptoms: swelling of the face, tongue, throat difficulty breathing Worsening of lupus. Tell your doctor if your lupus gets worse or becomes active while taking telmisartan and hydrochlorothiazide tablets. Change in body salts (electrolytes) level in your blood and fluid problems. Your doctor may do tests to check your blood. Call your doctor right away if you have: dry mouth seizures thirst fast heartbeats tiredness weakness sleepiness muscle pain or cramps restlessness very low urine output confusion nausea or vomiting The most common side effects of telmisartan and hydrochlorothiazide tablets include: upper respiratory tract infections, including sinus pain/congestion and sore throat dizziness feeling tired flu-like symptoms back pain diarrhea nausea These are not all the possible side effects with telmisartan and hydrochlorothiazide tablets. Tell your doctor if you have any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store telmisartan and hydrochlorothiazide tablets? Store telmisartan and hydrochlorothiazide tablets at 20 to 25C (68 to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Protect from moisture. Do not remove telmisartan and hydrochlorothiazide tablets from containers and blisters until right before you take them. Keep telmisartan and hydrochlorothiazide tablets and all medicines out of the reach of children. General information about telmisartan and hydrochlorothiazide tablets Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use telmisartan and hydrochlorothiazide tablets for a condition for which it was not prescribed. Do not give telmisartan and hydrochlorothiazide tablets to other people, even if they have the same condition you have. It may harm them. This Patient Information leaflet summarizes the most important information about telmisartan and hydrochlorothiazide tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about telmisartan and hydrochlorothiazide tablets that is written for health professionals. For more information, call Torrent Pharma Inc. at 1-800-912-9561 What are the ingredients in telmisartan and hydrochlorothiazide tablets? Active Ingredients: telmisartan, USP and hydrochlorothiazide, USP Inactive Ingredients: hypromellose, lactose monohydrate, mannitol, meglumine, povidone, sodium hydroxide, sodium stearyl fumarate. As coloring agents, the 40 mg/12.5 mg and 80 mg/25 mg tablets contain ferric oxide yellow, and the 80 mg/12.5 mg tablets contain ferric oxide red. What is high blood pressure (hypertension)? Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack. High blood pressure makes the heart work harder to pump blood through the body and causes damage to the blood vessels. Telmisartan and hydrochlorothiazide tablets can help your blood vessels relax so your blood pressure is lower. How to open the blister: 1. Tear (You may also use scissors to tear the blister apart) 2. Peel (Peel off the paper layer from the aluminum foil) 3. Push (Push the tablet through the foil) This Patient Information has been approved by the U.S. Food and Drug Administration. Trademarks are the property of their respective owners. Manufactured by: TORRENT PHARMACEUTICALS LTD. Indrad-382 721, INDIA. Manufactured for: TORRENT PHARMA INC. Basking Ridge, NJ 07920. 8068357Revised April 2018 Manufactured by: TORRENT PHARMACEUTICALS LTD. Bharuch-392130, INDIA. Manufactured for: TORRENT PHARMA INC. Basking Ridge, NJ 07920. 8068662 Revised April 2018
CLINICAL PHARMACOLOGY SECTION.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Telmisartan and Hydrochlorothiazide Tablets Telmisartan and hydrochlorothiazide tablets are a combination of two drugs with antihypertensive properties: a thiazide diuretic, hydrochlorothiazide, and an angiotensin II receptor blocker (ARB), telmisartan. Telmisartan Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000-fold) for the AT 1 receptor than for the AT 2 receptor. Telmisartan does not inhibit ACE (kininase II) nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure. Hydrochlorothiazide Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an ARB tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood. 12.2 Pharmacodynamics Telmisartan In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by approximately 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours. Plasma concentration of angiotensin II and plasma renin activity increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium) or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid). The antihypertensive effects of telmisartan have been studied in six placebo-controlled clinical trials including a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once-daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6 to 8/6 mmHg for 20 mg, 9 to 13/6 to 8 mmHg for 40 mg, and 12 to 13/7 to 8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure. The onset of antihypertensive activity occurs within 3 hours, with a maximal reduction by approximately 4 weeks. At doses of 20, 40, and 80 mg, the antihypertensive effect of once-daily administration of telmisartan was maintained for the full 24-hour dose interval. In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance. Hydrochlorothiazide After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts approximately 6 to 12 hours. Drug Interactions Hydrochlorothiazide Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia. Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use. 12.3 Pharmacokinetics Telmisartan Absorption: Following oral administration, peak concentrations (C max) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of approximately 6% with 40 mg and approximately 20% after a 160 mg dose telmisartan and hydrochlorothiazide tablets can be administered with or without food. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of telmisartan with orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (C max and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Trough plasma concentrations of telmisartan with once-daily dosing are approximately 10% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once-daily dosing. Distribution: Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and 1-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters, indicating additional tissue binding. Metabolism: Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan. Elimination: Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively). Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose. Hydrochlorothiazide Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. Specific Populations Telmisartan Renal Insufficiency: Telmisartan is not removed from blood by hemofiltration [see Warnings and Precautions (5.3), and Use in Specific Populations (8.7)]. Hepatic Insufficiency: In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Use in Specific Populations (8.6)]. Gender: Plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. Geriatric Patients: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years of age. Drug Interaction Studies Telmisartan Ramipril: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C max and AUC of ramipril 2.3- and 2.1-fold, respectively, and C max and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C max 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. Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.
4 CONTRAINDICATIONS Hypersensitivity to telmisartan or any component (4) Anuria (4). Co-Administration with aliskiren in patients with diabetes (4) Telmisartan and hydrochlorothiazide tablets are contraindicated: In patients who are hypersensitive to any component of this product [see Warnings and Precautions (5.5)]. In patients with anuria. For co-administration with aliskiren in patients with diabetes [see Drug Interactions (7.4)].