Telar-AM

What are the side effects you encounter while taking this medicine?
advertisement

Telar-AM uses

Telar-AM consists of Amlodipine, Telmisartan.

Amlodipine:


1 INDICATIONS AND USAGE

Telar-AM besylate and benazepril hydrochloride capsules are a combination tablet of Telar-AM (Amlodipine), a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin converting enzyme (ACE) inhibitor. Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent. (1)

1.1 Hypertension

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.

2 DOSAGE AND ADMINISTRATION

  • Dose once-daily
  • May be used as add-on therapy for patients not adequately controlled with either a dihydropyridine calcium channel blocker or an ACE inhibitor
  • Patients who experience edema with Telar-AM (Amlodipine) may be switched to Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules containing a lower dose of Telar-AM (Amlodipine) (2.2)
  • Start Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules at 2.5 mg/10 mg in patients ≥ 75 years old or in patients with hepatic impairment (2)

2.1 General considerations

The recommended initial dose of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsule is one capsule of Telar-AM (Amlodipine) 2.5 mg/benazepril 10 mg orally once daily.

It is usually appropriate to begin therapy with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules only after a patient has either (a) failed to achieve the desired antihypertensive effect with Telar-AM (Amlodipine) or benazepril monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with Telar-AM (Amlodipine) therapy without developing edema.

The antihypertensive effect of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules is largely attained within 2 weeks. If blood pressure remains uncontrolled, the dose may be titrated up to Telar-AM (Amlodipine) 10 mg/benazepril 40 mg once daily. The dosing should be individualized and adjusted according to the patient’s clinical response.

Telar-AM (Amlodipine) is an effective treatment of hypertension in once-daily doses of 2.5 to 10 mg while benazepril is effective in doses of 10 to 80 mg. In clinical trials of amlodipine/benazepril combination therapy using Telar-AM (Amlodipine) doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of Telar-AM (Amlodipine) in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.

2.2 Dosage adjustment in renal impairment

Renal Impairment: Telar-AM besylate and benazepril hydrochloride capsules are not recommended in patients with creatinine clearance ≤ 30 mL/min. No dose adjustment of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are required in patients creatinine clearance > 30 mL/min (serum creatinine roughly ≤3 mg/dL or 265 μmol/L). [see Warnings and Precautions (5.7), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].

2.3 Replacement Therapy

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules may be substituted for the titrated components.

advertisement

3 DOSAGE FORMS AND STRENGTHS

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are available as follows:

2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, and 10 mg/40 mg.

Capsules (amlodipine/benazepril mg): 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, 10 mg/40 mg (3)

4 CONTRAINDICATIONS

  • Do not coadminister aliskiren with angiotensin receptor blockers, ACE inhibitors, including Telar-AM (Amlodipine) besylate and benazepril hydrochloride in patients with diabetes (4)
  • Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, or Telar-AM (Amlodipine), or to any of the excipients of Telar-AM (Amlodipine) besylate and benazepril hydrochloride.
  • Do not coadminister aliskiren with ARBs or ACEIs, including Telar-AM (Amlodipine) besylate and benazepril hydrochloride in patients with diabetes (4)
  • Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, or to Telar-AM (Amlodipine). (4)

5 WARNINGS AND PRECAUTIONS

  • Watch for anaphylactoid reactions, including angioedema (5.1).
  • Warn patients with severe obstructive coronary artery disease about the risk of myocardial infarction or increased angina (5.2)
  • Assess for hypotension and hyperkalemia (5.4) and (5.8)
  • Avoid fetal or neonatal exposure (5.5)
  • Titrate slowly in patients with impaired hepatic (5.6) or severely impaired renal (5.7) function

5.1 Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules) may be subject to a variety of adverse reactions, some of them serious. These reactions usually occur after one of the first few doses of the ACE inhibitor, but they sometimes do not appear until after months of therapy. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules and treat immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., administer subcutaneous epinephrine injection 1:1000 (0.3 to 0.5 mL), promptly [see Adverse Reactions (6)].

Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

5.2 Increased Angina and/or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Telar-AM, particularly in patients with severe obstructive coronary artery disease.

5.3 Patients with Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy

As with all other vasodilators, special caution is required when using Telar-AM (Amlodipine) in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

5.4 Hypotension

Telar-AM besylate and benazepril hydrochloride capsules can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume or salt depleted as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before starting therapy with benazepril. If hypotension occurs, the patient should be placed in the supine position and if necessary given physiological saline i.v. Treatment with benazepril can be continued once blood pressure and volume have returned to normal.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and (rarely) with acute renal failure and death. In such patients, start Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsule therapy under close medical supervision; follow closely for the first 2 weeks of treatment and whenever the dose of the benazepril component is increased or a diuretic is added or its dose increased.

Symptomatic hypotension is also possible in patients with severe aortic stenosis.

5.5 Fetal Toxicity

Pregnancy Category D

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 Telar-AM (Amlodipine) besylate and benazepril hydrochloride as soon as possible [see Use in Specific Populations ( 8.1 )].

5.6 Hepatitis and Hepatic Failure

There have been rare reports of predominantly cholestatic hepatitis and isolated cases of acute liver failure, some of them fatal, in patients on ACE inhibitors. The mechanism is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevation of hepatic enzymes should discontinue the ACE inhibitor and be kept under medical surveillance.

5.7 Impaired Renal Function

Monitor renal function periodically in patients treated with Telar-AM besylate and benazepril hydrochloride. Changes in renal function, including acute renal failure, can be caused by drugs that affect the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or who are on NSAIDS or angiotensin receptor blockers may be at particular risk of developing acute renal failure on Telar-AM (Amlodipine) besylate and benazepril hydrochloride. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Telar-AM (Amlodipine) besylate and benazepril hydrochloride.

5.8 Hyperkalemia

Monitor serum potassium periodically in patients receiving Telar-AM (Amlodipine) besylate and benazepril hydrochloride. Drugs that affect the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. In U.S. placebo-controlled trials of Telar-AM (Amlodipine) besylate and benazepril hydrochloride, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) not present at baseline occurred in approximately 1.5% of hypertensive patients receiving Telar-AM (Amlodipine) besylate and benazepril hydrochloride. Increases in serum potassium were generally reversible.

5.9 Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

5.10 Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

advertisement

6 ADVERSE REACTIONS

Discontinuation because of adverse reactions occurred in 4% of Telar-AM besylate and benazepril hydrochloride capsule-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules were cough and edema. (6)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safetyTelar-AM (Amlodipine)tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules have been evaluated for safety in over 2,991 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 400 were treated for more than 1 year.

In a pooled analysis of 5 placebo-controlled trials involving Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsule doses up to 5 mg/20 mg, the reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules and in 3% of patients treated with placebo.

The most common reasons for discontinuation of therapy with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules in these studies were cough and edema (including angioedema).

The peripheral edema associated with Telar-AM (Amlodipine) use is dose-dependent. When benazepril is added to a regimen of Telar-AM (Amlodipine), the incidence of edema is substantially reduced.

The addition of benazepril to a regimen of Telar-AM (Amlodipine) should not be expected to provide additional antihypertensive effect in African-Americans. However, all patient groups benefit from the reduction in amlodipine-induced edema.

The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are shown in the table below. Cough was the only adverse event with at least possible relationship to treatment that was more common on Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules (3.3%) than on placebo (0.2%).


Benazepril/Amlodipine

N = 760


Benazepril

N = 554


Telar-AM (Amlodipine)

N = 475


Placebo

N = 408

Cough 3.3 1.8 0.4 0.2
Headache 2.2 3.8 2.9 5.6
Dizziness 1.3 1.6 2.3 1.5
EdemaEdema refers to all edema, such as dependent edema, angioedema, facial edema. 2.1 0.9 5.1 2.2

The incidence of edema was greater in patients treated with Telar-AM (Amlodipine) monotherapy (5.1%) than in patients treated with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules (2.1%) or placebo (2.2%).

Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules or in postmarketing experience were the following:

Body as a Whole: Asthenia and fatigue.

CNS: Insomnia, nervousness, anxiety, tremor, and decreased libido.

Dermatologic: Flushing, hot flashes, rash, skin nodule, and dermatitis.

Digestive: Dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, and esophagitis.

Hematologic: Neutropenia

Metabolic and Nutritional: Hypokalemia.

Musculoskeletal: Back pain, musculoskeletal pain, cramps, and muscle cramps.

Respiratory: Pharyngitis.

Urogenital: Sexual problems such as impotence, and polyuria.

Monotherapies of benazepril and Telar-AM (Amlodipine) have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, paresthesia, dysgeusia, orthostatic symptoms and hypotension, angina pectoris and arrhythmia, pruritus, photosensitivity reaction, arthralgia, arthritis, myalgia, BUN increase, serum creatinine increased, renal impairment, impaired vision, agranulocytosis, neutropenia.

Rare reports in association with use of Telar-AM (Amlodipine): gingival hyperplasia, tachycardia, jaundice, and hepatic enzyme elevations (mostly consistent with cholestasis severe enough to require hospitalization), leucocytopenia, allergic reaction, hyperglycemia, dysgeusia, hypoestheia, paresthesia, syncope, peripheral neuropathy, hypertonia, visual impairment, diplopia, hypotension, vasculitis, rhinitis, gastritis, hyperhidrosis, pruritis, skin discoloration, urticaria, erythema multiform, muscle spasms, arthralgia, micturition disorder, nocturia, erectile dysfunction, malaise, weight decrease or gain.

Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include: eosinophilic pneumonitis (ACE inhibitors) and gynecomastia (CCBs). Other infrequently reported events included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, alopecia, upper respiratory tract infection, palpitations and somnolence.

advertisement

7 DRUG INTERACTIONS

  • Potassium supplements / Potassium-sparing diuretics: risk of hyperkalemia
  • Lithium: Increased serum Lithium levels; toxicity symptoms (7.1)
  • Injectable gold: facial flushing, nausea, vomiting, or hypotension may occur (7.1)
  • NSAID: Risk of renal dysfunction, loss of antihypertensive effect ( 7.1 )
  • If simvastatin is coadministered with Telar-AM (Amlodipine), do not exceed doses greater than 20 mg daily of simvastatin (7.1)
  • Dual inhibition of the rennin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7.1)

7.1 Drug/Drug Interactions

Telar-AM (Amlodipine)

Simvastatin: Coadministration of simvastatin with Telar-AM (Amlodipine) increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on Telar-AM (Amlodipine) to 20 mg daily.

CYP3A4 Inhibitors: Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to Telar-AM (Amlodipine) and may require dose reduction. Monitor for symptoms of hypotension and edema when Telar-AM (Amlodipine) is coadministered with CYP3A4 inhibitors to determine the need for dose adjustment.

CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on Telar-AM (Amlodipine). Blood pressure should be monitored when Telar-AM (Amlodipine) is coadministered with CYP3A4 inducers.

Benazepril

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, the patient’s serum potassium should be monitored frequently.

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When coadministering Telar-AM (Amlodipine) besylate and benazepril hydrochloride and lithium, frequent monitoring of serum lithium levels is recommended.

Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.

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, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.

Antidiabetic agents: In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral antidiabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions, and should be monitored accordingly.

Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Telar-AM (Amlodipine) besylate and benazepril hydrochloride and other agents that block the RAS.

Do not coadminister aliskiren with Telar-AM (Amlodipine) besylate and benazepril hydrochloride in patients with diabetes. Avoid use of aliskiren with Telar-AM (Amlodipine) besylate and benazepril hydrochloride in patients with renal impairment (GFR <60 ml/min).

advertisement

8 USE IN SPECIFIC POPULATIONS

Nursing Mothers: It is not known whether Telar-AM is excreted in human milk. Nursing or drug should be discontinued. (8.3)

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category D

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 Telar-AM besylate and benazepril hydrochloride capsules as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

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. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. 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 Telar-AM (Amlodipine) besylate and benazepril hydrochloride for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

8.2 Labor and Delivery

The effect of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules on labor and delivery has not been studied.

8.3 Nursing Mothers

Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat.

It is not known whether Telar-AM is excreted in human milk. Nursing or drug should be discontinued.

8.4 Pediatric Use

Neonates with a history of in utero exposure to Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules:

If oliguria or hypotension occurs, direct attention toward support of 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. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers, but experience is limited.

8.5 Geriatric Use

In geriatrics, exposure to Telar-AM is increased, thus consider lower initial doses of Telar-AM (Amlodipine) besylate and benazepril hydrochloride .

Of the total number of patients who received Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules in U.S. clinical studies of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, over 19% were 65 or older while about 2% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. 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.

8.6 Hepatic Impairment

Exposure to Telar-AM (Amlodipine) is increased in patients with hepatic insufficiency, thus consider using lower doses of Telar-AM (Amlodipine) besylate and benazepril hydrochloride .

8.7 Renal Impairment

In patients with severe renal impairment systemic exposure to benazepril is increased. The recommended dose of benazepril in this subgroup is 5 mg which is not an available strength with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules. Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are not recommended in patients with severe renal impairment. No dose adjustment of Telar-AM (Amlodipine) besylate and benazepril hydrochloride is needed in patients with mild or moderate impairment of renal function .

10 OVERDOSAGE

Only a few cases of human overdose with Telar-AM (Amlodipine) have been reported. One patient was asymptomatic after a 250 mg ingestion; another, who combined 70 mg of Telar-AM (Amlodipine) with an unknown large quantity of a benzodiazepine, developed refractory shock and died.

Human overdoses with any combination of Telar-AM (Amlodipine) and benazepril have not been reported. In scattered reports of human overdoses with benazepril and other ACE inhibitors, there are no reports of death.

Treatment: Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate.

In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage and/or activated charcoal to remove the drug from the gastrointestinal tract (only if presented within 1 hour after ingestion of Telar-AM (Amlodipine) besylate and benazepril hydrochloride).

Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care.

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

The most likely effect of overdose with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules is vasodilation, with consequent hypotension and tachycardia. Simple repletion of central fluid volume (Trendelenburg positioning, infusion of crystalloids) may be sufficient therapy, but pressor agents (norepinephrine or high-dose dopamine) may be required. With abrupt return of peripheral vascular tone, overdoses of other dihydropyridine calcium channel blockers have sometimes progressed to pulmonary edema, and patients must be monitored for this complication.

Analyses of bodily fluids for concentrations of Telar-AM (Amlodipine), benazepril, or their metabolites are not widely available. Such analyses are, in any event, not known to be of value in therapy or prognosis.

No data are available to suggest physiologic maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Telar-AM (Amlodipine), benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of Telar-AM (Amlodipine) by hemodialysis or hemo-perfusion has not been reported, but amlodipine’s high protein binding makes it unlikely that these interventions will be of value.

Angiotensin II could presumably serve as a specific antagonist-antidote to benazepril, but angiotensin II is essentially unavailable outside of scattered research laboratories.

11 DESCRIPTION

Benazepril hydrochloride is a white to off-white crystalline powder, soluble (> 100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is:

C24H28N2O5-HCl M.W. 460.96

Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.

Telar-AM (Amlodipine) besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Its chemical name is (R,S)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate; its structural formula is:

C20H25ClN2O5-C6H6O3S M.W. 567.1

Telar-AM (Amlodipine) besylate is the besylate salt of Telar-AM (Amlodipine), a dihydropyridine calcium channel blocker.

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are a combination of Telar-AM (Amlodipine) besylate and benazepril hydrochloride. The capsules are formulated in six different strengths for oral administration with a combination of Telar-AM (Amlodipine) besylate equivalent to 2.5 mg, 5 mg or 10 mg of Telar-AM (Amlodipine), with 10 mg, 20 mg or 40 mg of benazepril hydrochloride providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg and 10 mg/40 mg. The inactive ingredients of the capsules are black iron oxide, calcium phosphate dibasic anhydrous, colloidal silicon dioxide, corn starch, crospovidone, gelatin, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, pregelatinized starch, propylene glycol, shellac, sodium starch glycolate, and titanium dioxide. The imprinting ink may contain potassium hydroxide. In addition, the 5 mg/10 mg capsule contains red iron oxide and yellow iron oxide; the 5 mg/20 mg capsule contains D&C Red 28, FD&C Blue 1, and FD&C Red 40; the 10 mg/20 mg capsule contains FD&C Blue 1 and FD&C Red 3; and the 5 mg/40 mg and 10 mg/40 mg capsules contain FD&C Blue 1.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benazepril

Benazepril and benazeprilat inhibit angiotensin-converting enzyme in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril and Telar-AM (Amlodipine) for up to 56 weeks had elevations of serum potassium up to 0.2 mEq/L [see Warnings and Precautions (5)].

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules remains to be elucidated.

While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.

Telar-AM (Amlodipine)

Telar-AM (Amlodipine) is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that Telar-AM (Amlodipine) binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Telar-AM (Amlodipine) inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by Telar-AM (Amlodipine). Within the physiologic pH range, Telar-AM (Amlodipine) is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Telar-AM (Amlodipine) is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

12.2 Pharmacodynamics

Benazepril

Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. For up to 4 hours after a 10 mg dose, pressor responses to exogenous angiotensin I were inhibited by 60% to 90%.

Administration of benazepril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent, with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt and/or volume depleted [see Warnings and Precautions (5)].

The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets.

In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

Telar-AM (Amlodipine)

Following administration of therapeutic doses to patients with hypertension, Telar-AM (Amlodipine) produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with Telar-AM (Amlodipine) is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of Telar-AM (Amlodipine) resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with Telar-AM (Amlodipine) have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, Telar-AM (Amlodipine) has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when coadministered with beta-blockers to humans.

Telar-AM (Amlodipine) does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which Telar-AM (Amlodipine) was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Telar-AM (Amlodipine) has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

12.3 Pharmacokinetics

The rate and extent of absorption of benazepril and Telar-AM (Amlodipine) from Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are same as when administered as individual tablets. Absorption from the individual tablets is not influenced by the presence of food in the gastrointestinal tract; food effects on absorption from Telar-AM (Amlodipine) besylate and benazepril hydrochloride have not been studied.

Absorption: Following oral administration of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, peak plasma concentrations of Telar-AM (Amlodipine) are reached in 6 to 12 hours. Absolute bioavailability has been calculated as between 64% and 90%. Following oral administration of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, the peak plasma concentrations of benazepril are reached in 0.5 to 2 hours. The cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat, which reaches peak plasma concentrations in 1.5 to 4 hours. The extent of absorption of benazepril is at least 37%. Telar-AM (Amlodipine) and benazepril exhibit dose proportional pharmacokinetics between the therapeutic dose range of 2.5 and 10 mg and 10 and 20 mg, respectively.

Distribution: The apparent volume of distribution of Telar-AM (Amlodipine) is about 21 L/kg. In vitro studies indicate that approximately 93% of circulating Telar-AM (Amlodipine) is bound to plasma proteins in hypertensive patients. The apparent volume of distribution of benazeprilat is about 0.7 L/kg. Approximately 93% of circulating Telar-AM (Amlodipine) is bound to plasma proteins, and the bound fraction of benazeprilat is slightly higher. On the basis of in vitro studies, benazeprilat’s degree of protein binding should be unaffected by age, by hepatic dysfunction, or-over the therapeutic concentration range-by concentration.

Metabolism: Telar-AM (Amlodipine) is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Benazepril is extensively metabolised to form benazeprilat as the main metabolite, which occur by enzymatic hydrolysis, mainly in the liver. Two minor metabolites are the acyl glucuronide conjugates of benazepril and benazeprilat.

Elimination: Telar-AM (Amlodipine) elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. 10% of unchanged drug and 60% of Telar-AM (Amlodipine) metabolites are excreted in urine. Effective elimination half-life of Telar-AM (Amlodipine) is 2 days. Benazepril is eliminated mainly by metabolic clearance. Benazeprilat is eliminated via the kidneys and the bile; renal excretion is the main route in patients with normal renal function. In the urine, benazepril accounts for less than 1 % and benazeprilat for about 20 % of an oral dose. Elimination of benazeprilat is biphasic with an initial half-life of about 3 hours and a terminal half-life of about 22 hours. Benazeprilat’s effective elimination half-life is 10 to 11 h, while that of Telar-AM (Amlodipine) is about 2 days, so steady-state levels of the two components are achieved after about a week of once-daily dosing.

Special populations

Geriatric patients: No specific clinical studies were performed to understand the impact of age on the pharmacokinetics of Telar-AM (Amlodipine) and benazepril as fixed dose combination. As individual component Telar-AM (Amlodipine) is extensively metabolized in the liver. In the elderly, clearance of Telar-AM (Amlodipine) is decreased with resulting increases in peak plasma levels, elimination half-life and area-under-the-plasma-concentration curve .

Hepatic impairment: Patients with hepatic insufficiency have decreased clearance of Telar-AM (Amlodipine) with a resulting increase in AUC of approximately 40 to 60%. Pharmacokinetics of benazepril is not significantly influenced by hepatic impairment .

Renal impairment : The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance > 30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance ≤ 30 mL/min, peak benazeprilat levels and the effective half-life increase, resulting in higher systemic exposures. Pharmacokinetics of Telar-AM (Amlodipine) is not significantly influenced by renal impairment .

Drug interactions

Telar-AM (Amlodipine)

In vitro data in human plasma indicate that Telar-AM (Amlodipine) has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine: Coadministration of Telar-AM (Amlodipine) with cimetidine did not alter the pharmacokinetics of Telar-AM (Amlodipine).

Grapefruit juice: Coadministration of 240 mL of grapefruit juice with a single oral dose of Telar-AM (Amlodipine) 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of Telar-AM (Amlodipine).

Maalox® (antacid): Coadministration of the antacid Maalox with a single dose of Telar-AM (Amlodipine) had no significant effect on the pharmacokinetics of Telar-AM (Amlodipine).

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Telar-AM (Amlodipine). When Telar-AM (Amlodipine) and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin: Coadministration of multiple 10 mg doses of Telar-AM (Amlodipine) with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin: Coadministration of Telar-AM (Amlodipine) with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of Telar-AM (Amlodipine) had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Coadministration of Telar-AM (Amlodipine) with warfarin did not change the warfarin prothrombin response time.

Simvastatin: Coadministration of multiple doses of 10 mg of Telar-AM (Amlodipine) with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.

CYP3A inhibitors: Coadministration of a 180 mg daily dose of diltiazem with 5 mg Telar-AM (Amlodipine) in elderly hypertensive patients resulted in a 60% increase in Telar-AM (Amlodipine) systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change Telar-AM (Amlodipine) systemic exposure. However, strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of Telar-AM (Amlodipine) to a greater extent.

Benazepril

The pharmacokinetic properties of benazepril are not affected by hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, Telar-AM (Amlodipine), naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially affect the pharmacokinetics of these medications.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with this combination. However, these studies have been conducted with Telar-AM and benazepril alone. No adverse effects on fertility occurred when the benazepril:amlodipine combination was given orally to rats of either sex at doses up to 15:7.5 mg (benazepril:amlodipine)/kg/day, prior to mating and throughout gestation.

Benazepril

No evidence of carcinogenicity was found when benazepril was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body surface area, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg). No mutagenic activity was detected in the Ames test in bacteria, in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50 to 500 mg/kg/day (6 to 60 times the maximum recommended human dose on a body surface area basis), benazepril had no adverse effect on the reproductive performance of male and female rats.

Telar-AM (Amlodipine)

Rats and mice treated with Telar-AM (Amlodipine) maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5 mg, 1.25 mg, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a body surface area basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a body surface area basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.) Mutagenicity studies conducted with Telar-AM (Amlodipine) maleate revealed no drug-related effects at either the gene or chromosome level. There was no effect on the fertility of rats treated orally with Telar-AM (Amlodipine) maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a body surface area basis).

13.3 Reproductive Toxicity

When rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, dystocia was observed at an increasing dose-related incidence at all doses tested. On a body surface area basis, the 2.5 mg/kg/day dose of Telar-AM (Amlodipine) is 3.6 times the Telar-AM (Amlodipine) dose delivered when the maximum recommended dose of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules is given to a 50 kg woman. Similarly, the 5 mg/kg/day dose of benazepril is approximately twice the benazepril dose delivered when the maximum recommended dose of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules is given to a 50 kg woman. No teratogenic effects were seen when benazepril and Telar-AM (Amlodipine) were administered in combination to pregnant rats or rabbits. Rats received doses of up to 50:25 mg (benazepril:amlodipine)/kg/day (24 times the maximum recommended human dose on a body surface area basis, assuming a 50 kg woman). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent to the maximum recommended dose of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules given to a 50 kg woman).

Benazepril

No teratogenic effects of benazepril were seen in studies of pregnant rats, mice, and rabbits. On a body surface area basis, the maximum doses used in these studies were 60 times (in rats), 9 times (in mice), and about equivalent to (in rabbits) the maximum recommended human dose (assuming a 50 kg woman).

Telar-AM (Amlodipine)

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with Telar-AM (Amlodipine) maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose [MRHD] of 10 mg Telar-AM (Amlodipine) on a body surface area basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5 fold) for rats receiving Telar-AM (Amlodipine) maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Telar-AM (Amlodipine) maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Telar-AM (Amlodipine) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

14 CLINICAL STUDIES

Over 950 patients received Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules once daily in six double-blind, placebo-controlled studies. The antihypertensive effect of a single dose persisted for 24 hours, with peak reductions achieved 2 to 8 hours after dosing.

Once-daily doses of benazepril/amlodipine using benazepril doses of 10 to 20 mg and Telar-AM (Amlodipine) doses of 2.5 to 10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10 to 25/6 to 13 mmHg.

In two studies in patients not adequately controlled on either benazepril 40 mg alone (n = 329) or Telar-AM (Amlodipine) 10 mg alone (n = 812) once daily doses of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, 10 mg/40 mg further decreased seated blood pressure compared to the respective monotherapy alone.

Combination therapy was effective in blacks and nonblacks. Both components contributed to the antihypertensive efficacy in nonblacks, but virtually all of the antihypertensive effect in blacks could be attributed to the Telar-AM (Amlodipine) component. Among nonblack patients in placebo-controlled trials comparing Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules to the individual components, the blood pressure lowering effects of the combination were shown to be additive and in some cases synergistic.

During chronic therapy with Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, the maximum reduction in blood pressure with any given dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules have continued during therapy for at least 1 year. Abrupt withdrawal of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules have not been associated with a rapid increase in blood pressure.

16 HOW SUPPLIED/STORAGE AND HANDLING

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are available as capsules containing Telar-AM (Amlodipine) besylate equivalent to 2.5 mg, 5 mg or 10 mg of Telar-AM (Amlodipine), with 10 mg, 20 mg, or 40 mg of benazepril hydrochloride providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, and 10 mg/40 mg. All six strengths are packaged with a desiccant in bottles. They are available as follows:

2.5 mg/10 mg capsules: a hard gelatin capsule with a white opaque cap and body, filled with white to off-white powder, imprinted "TEVA" on the cap and "7370" on the body in bottles of 100.

5 mg/10 mg capsules: a hard gelatin capsule with an orange opaque cap and white opaque body, filled with white to off-white powder, imprinted "TEVA" on the cap and “7371” on the body in bottles of 100.

5 mg/20 mg capsules: a hard gelatin capsule with a pink opaque cap and white opaque body, filled with white to off-white powder, imprinted "TEVA" on the cap and “7372” on the body in bottles of 100.

5 mg/40 mg capsules: a hard gelatin capsule with a light turquoise blue opaque cap and light turquoise blue opaque body, filled with white to off-white powder, body and cap imprinting "TEVA" and “7670” in bottles of 100.

10 mg/20 mg capsules: a hard gelatin capsule with a blue violet opaque cap and body, filled with white to off-white powder, imprinted "TEVA" on the cap and “7373” on the body in bottles of 100.

10 mg/40 mg capsules: a hard gelatin capsule with a light blue opaque cap and light blue opaque body, filled with white to off-white powder, body and cap imprinting "TEVA" and “7671” in bottles of 100.

Store at 20° to 25°C (68° to 77°F). Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

17 PATIENT COUNSELING INFORMATION

Information for Patients

Female patients of childbearing age should be told about the consequences of exposure to Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. R 10/2012

PATIENT INFORMATION

Telar-AM (Amlodipine) Besylate and Benazepril Hydrochloride Capsules

2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, 10 mg/40 mg

Read this Patient Information leaflet before you start taking Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules and each time you get a refill. There may be new information. This leaflet does not replace talking with your doctor. If you have any questions, ask your doctor or pharmacist.

What is the most important information I should know about Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

  • Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules 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 Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, tell your doctor right away.

What are Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules contain two prescription medicines that work together to lower blood pressure: Telar-AM (Amlodipine) besylate (the active ingredient found in Norvasc®), a calcium channel blocker, and benazepril hydrochloride (Lotensin®), an ACE inhibitor. Your doctor will prescribe Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules only after other medicines haven’t worked.

High Blood Pressure (hypertension). Blood pressure is the force of blood in your blood vessels. You have high blood pressure when the force is too much. Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules can help your blood vessels relax so your blood pressure is lower.

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules have not been studied in children.

Who should not take Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Don’t take Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules if you are allergic to any of the ingredients. There is a complete list at the end of this leaflet.

What should I tell my Doctor before taking Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Tell your doctor about all your medical conditions, including if:

  • you are pregnant or plan to become pregnant. See “What is the most important information I should know about Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?
  • you are breastfeeding. Telar-AM (Amlodipine) besylate and benazepril hydrochloride may pass into your milk. Don’t breastfeed while you are taking Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules.
  • you have a heart condition
  • you have liver problems
  • you have kidney problems
  • you are about to have an operation (including dental surgery) or emergency treatment
  • you are suffering from several episodes of vomiting or diarrhea
  • you are treated for hyperkalemia (too much potassium in the blood)
  • you are taking already a diuretic (a medicine to increase the amount of urine you produce)

Keep a list of your medicines with you, including vitamins and natural or herbal remedies, to show your doctor or pharmacist. Some of your other medicines and Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules could affect each other, causing serious side effects. Tell your doctor about all your medicines, especially:

  • Simvastatin, (a medicine used to control elevated cholesterol)
  • medicines for high blood pressure or heart failure
  • water pills, extra potassium or a salt substitute
  • Lithium (Eskalith®, Lithobid®)
  • potassium-containing medicines, potassium supplements or salt substitutes containing potassium;
  • ciclosporin, an immunosuppressant medicine used in transplanted patients to reduce the risk of organ rejection;
  • indomethacin and other non-steroidal anti-inflammatory agents, medicines used to relieve pain and inflammation;
  • insulin or oral antidiabetics, medicines that help a person with diabetes to control their level of glucose (sugar) in the blood;
  • gold for the treatment of rheumatoid arthritis;
  • probenecid, a medicine used to treat gout and hyperuricemia;
  • medicines used to prevent and treat fungal skin infections (e.g. ketoconazole, itraconazole)
  • medicines used to treat AIDS or HIV infections (e.g. ritonavir, indinavir)
  • medicines used to treat bacterial infections (e.g. clarithromycin)

Avoid alcohol until you have discussed the matter with your doctor. Alcohol may make blood pressure fall more and/or increase the possibility of dizziness or fainting.

How do I take Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

  • Take Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules exactly as your doctor tells you.
  • Take Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules at the same time each day, with or without food.
  • If you miss a dose, take it as soon as you remember. If it is more than 12 hours, just take your next dose at the regular time.
  • Your doctor may test for kidney problems or check your blood potassium level.
  • If you take too many Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules, call your doctor or Poison Control Center, or go to the emergency room.
  • Tell all your doctors or dentist you are taking Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules if you:

    - are going to have surgery

    - are getting allergy shots for bee stings

    - go for kidney dialysis


What are the possible side effects of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules can cause serious side effects including:

  • serious allergic reactions that can be life threatening.

Stop Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules and get emergency help right away if you get:

  • - swelling of your face, eyelids, lips, tongue or throat
  • - have trouble swallowing
  • - asthma (wheezing) or other breathing problems

These allergic reactions are rare but happen more times in people who are African-American.

  • low blood pressure (hypotension). Low blood pressure is most likely to happen if you also take water pills, are on a low salt diet, get dialysis treatments, have heart problems or get sick with vomiting or diarrhea. Lie down if you feel faint or dizzy.
  • liver problems. Call your doctor if:
    • you have nausea
    • you feel more tired or weaker than usual
    • you have itching
    • your skin or eyes look yellow
    • you have pain in your upper right stomach
    • you have flu-like symptoms
  • kidney problems. Some people will have changes on blood tests for kidney function and need a lower dose of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules. Call your doctor if you get swelling in your feet, ankles, or hands or unexplained weight gain.
  • more chest pain and heart attacks in people that already have severe heart problems. Get emergency help if you get worse chest pain or chest pain that does not go away.

The more common side effects of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules are:

  • dizziness, fainting on standing up
  • cough (dry, non-productive, mainly at night, continuing)
  • swelling of the feet, ankles, and hands

If any of these affects you severely, tell your doctor.

These are not all the side effects of Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules. For a complete list, ask your doctor or pharmacist.

How do I store Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

  • Store Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules at 20° to 25°C (68° to 77°F).
  • Keep Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules in a closed container in a dry place.
  • Keep Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules and all medicines out of the reach of children.

General Information about Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules

Doctors can also use medicine for a condition that is not in the patient information leaflet. Take Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules the way your doctor tells you. Do not share them with other people. They may harm them.

For more information, ask your doctor or pharmacist, or call 1-866-832-8537, MEDICAL AFFAIRS.

What are the ingredients in Telar-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Active ingredients: Telar-AM (Amlodipine) besylate (the active ingredient found in Norvasc®), benazepril hydrochloride (Lotensin®)

Inactive ingredients: black iron oxide, calcium phosphate dibasic anhydrous, colloidal silicon dioxide, corn starch, crospovidone, gelatin, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, pregelatinized starch, propylene glycol, shellac, sodium starch glycolate, and titanium dioxide. The imprinting ink may contain potassium hydroxide. In addition, the 5 mg/10 mg capsule contains red iron oxide and yellow iron oxide; the 5 mg/20 mg capsule contains D&C Red 28, FD&C Blue 1, and FD&C Red 40; the 10 mg/20 mg capsule contains FD&C Blue 1 and FD&C Red 3; and the 5 mg/40 mg and 10 mg/40 mg capsules contain FD&C Blue 1.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. G 10/2012

Amlodipine/ Benazepril HCL 5/ 40mg Cap

benazepril hydrochloride structural formula Telar-AM (Amlodipine) besylate structural formula

Telmisartan:


WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue Telar-AM (Telmisartan) as soon as possible .
  • Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus .

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

  • When pregnancy is detected, discontinue Telar-AM (Telmisartan) as soon as possible (5.1)
  • Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus (5.1) .

1  INDICATIONS AND USAGE

Telar-AM is an angiotensin II receptor blocker (ARB) indicated for:

  • Treatment of hypertension (1.1)
  • Cardiovascular (CV) risk reduction in patients unable to take ACE inhibitors (1.2)

1.1  Hypertension

Telar-AM (Telmisartan) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents [seeClinical Studies (14.1)].

1.2  Cardiovascular Risk Reduction

Telar-AM (Telmisartan) is 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.

High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage . MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy) .

Studies of Telar-AM (Telmisartan) in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves.

Use of Telar-AM (Telmisartan) with an ACE inhibitor is not recommended .

2  DOSAGE AND ADMINISTRATION

  • May be administered with or without food
  • When used for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary (2.2)
Indication Starting Dose Dose Range
Hypertension (2.1) 40 mg once

daily

40 to 80 mg once

daily

Cardiovascular

Risk Reduction (2.2)

80 mg once

daily

80 mg once

daily

2.1  Hypertension

Dosage must be individualized. The usual starting dose of Telar-AM (Telmisartan) tablets is 40 mg once a day. Blood pressure response is dose-related over the range of 20 to 80 mg .

Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. When additional blood pressure reduction beyond that achieved with 80 mg Telar-AM (Telmisartan) is required, a diuretic may be added.

No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored.

Telar-AM (Telmisartan) tablets may be administered with other antihypertensive agents.

Telar-AM (Telmisartan) tablets may be administered with or without food.

2.2  Cardiovascular Risk Reduction

The recommended dose of Telar-AM (Telmisartan) tablets is 80 mg once a day and can be administered with or without food. It is not known whether doses lower than 80 mg of Telar-AM (Telmisartan) are effective in reducing the risk of cardiovascular morbidity and mortality.

When initiating Telar-AM (Telmisartan) therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary.

3  DOSAGE FORMS AND STRENGTHS

  • 20 mg, white or off-white, round, uncoated tablets imprinted with BI logo on one side and 50 H on the other side
  • 40 mg, white or off-white, oblong, uncoated tablets imprinted with BI logo on one side and 51 H on the other side
  • 80 mg, white or off-white, oblong, uncoated tablets imprinted with BI logo on one side and 52 H on the other side
  • Tablets: 20 mg, 40 mg, 80 mg (3)

4  CONTRAINDICATIONS

Telar-AM (Telmisartan) is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to Telar-AM (Telmisartan) or any other component of this product .

  • Known hypersensitivity (e.g., anaphylaxis or angioedema) to Telar-AM (Telmisartan) or any other component of this product (4)

5  WARNINGS AND PRECAUTIONS

  • Avoid fetal or neonatal exposure
  • Hypotension: Correct any volume or salt depletion before initiating therapy. Observe for signs and symptoms of hypotension (5.2)
  • Monitor carefully in patients with impaired hepatic (5.4) or renal function (5.5)
  • Avoid concomitant use of an ACE inhibitor and angiotensin receptor blocker (5.6)

5.1  Fetal Toxicity

Pregnancy Category D

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 Telar-AM (Telmisartan) as soon as possible .

5.2  Hypotension

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients, symptomatic hypotension may occur after initiation of therapy with Telar-AM (Telmisartan). Either correct this condition prior to administration of Telar-AM (Telmisartan), or start treatment under close medical supervision with a reduced dose.

If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.3  Hyperkalemia

Hyperkalemia may occur in patients on 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.

5.4  Impaired Hepatic Function

As the majority of Telar-AM is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate Telar-AM (Telmisartan) at low doses and titrate slowly in these patients .

5.5  Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with Telar-AM (Telmisartan) .

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of Telar-AM (Telmisartan) in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.

5.6  Dual Blockade of the Renin-Angiotensin-Aldosterone System

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.

The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to Telar-AM (Telmisartan) only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of Telar-AM (Telmisartan) and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acuterenal failure) compared with groups receiving Telar-AM (Telmisartan) alone or ramipril alone. Concomitant use of Telar-AM (Telmisartan) and ramipril is not recommended.

6  ADVERSE REACTIONS

The following adverse reaction is described elsewhere in labeling:

Renal dysfunction upon use with ramipril

  • Hypertension: The most common adverse events (≥1%) reported in hypertension trials are back pain, sinusitis, and diarrhea (6.1)
  • Cardiovascular risk reduction: The serious adverse events (≥1%) reported in cardiovascular risk reduction trials were intermittent claudication and skin ulcer (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1  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

MICARDIS 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 Telar-AM (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 Telar-AM (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 Telar-AM (Telmisartan) and at a Greater Rate Than Patients Treated with Placebo

Telar-AM (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 treatedwith Telar-AM (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 Telar-AM (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 Telar-AM (Telmisartan) monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to Telar-AM (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, non-specific 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 Telar-AM (Telmisartan) tablets.

Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% Telar-AM (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% Telar-AM (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 Telar-AM (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 Telar-AM (Telmisartan) in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of Telar-AM (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 Telar-AM (Telmisartan) and 7.6% on placebo. The only serious adverse events at least 1% more common on Telar-AM (Telmisartan) than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%).

6.2  Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Telar-AM (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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Telar-AM (Telmisartan).

The most frequent spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome).

Rare cases of rhabdomyolysis have been reported in patientsreceiving angiotensin II receptor blockers, including Telar-AM (Telmisartan).

7  DRUG INTERACTIONS

Digoxin : When Telar-AM (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 Telar-AM (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 Telar-AM (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 Telar-AM (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 Telar-AM (Telmisartan) and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Telar-AM (Telmisartan) may be attenuated by NSAIDs including selective COX-2 inhibitors.

Ramipril and Ramiprilat : Co-administration of Telar-AM (Telmisartan) 80 mg once daily and ramipril 10 mg once daily to healthysubjects 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 Telar-AM (Telmisartan) decrease by 31% and 16%, respectively. When co-administering Telar-AM (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 Telar-AM (Telmisartan). Concomitant use of Telar-AM (Telmisartan) and ramipril is not recommended.

Other Drugs : Co-administration of Telar-AM (Telmisartan) did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telar-AM (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. Telar-AM (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.

  • NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect (7)

8  USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: Choose to discontinue nursing or drug
  • Geriatric Patients: No overall difference in efficacy or safety vs younger patients, but greater sensitivity of some older individuals cannot be ruled out (8.5)

8.1  Pregnancy

Pregnancy Category D. .

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 Telar-AM (Telmisartan) as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

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. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Telar-AM (Telmisartan), unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. 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 Telar-AM (Telmisartan) for hypotension, oliguria, and hyperkalemia .

8.3  Nursing Mothers

It is not known whether Telar-AM is excreted in human milk, but Telar-AM (Telmisartan) was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4  Pediatric Use

Neonates with a history of in utero exposure to Telar-AM (Telmisartan):

If oliguria or hypotension occurs, direct attention toward support of 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.

Safety and effectiveness in pediatric patients have not been established .

8.5  Geriatric Use

Of the total number of patients receiving Telar-AM in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and 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.

Of the total number of patients receiving Telar-AM (Telmisartan) in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and 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.

8.6  Hepatic Insufficiency

Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency .

10  OVERDOSAGE

Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with Telar-AM (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. Telar-AM (Telmisartan) is not removed by hemodialysis.

11  DESCRIPTION

Telar-AM (Telmisartan) is a non-peptide angiotensin II receptor (type AT1) antagonist.

Telar-AM (Telmisartan) 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 C33H30N4O2, its molecular weight is 514.63, and its structural formula is:

Telar-AM (Telmisartan) 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.

Telar-AM (Telmisartan) is available as tablets for oral administration, containing 20 mg, 40 mg or 80 mg of Telar-AM (Telmisartan). The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate. Telar-AM (Telmisartan) tablets are hygroscopic and require protection from moisture.

Telar-AM (Telmisartan) structure

12  CLINICAL PHARMACOLOGY

12.1  Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme. Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effectsthat include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telar-AM (Telmisartan) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 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 AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telar-AM (Telmisartan) has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Telar-AM (Telmisartan) does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telar-AM (Telmisartan) does not 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 Telar-AM (Telmisartan) on blood pressure.

12.2  Pharmacodynamics

In normal volunteers, a dose of Telar-AM (Telmisartan) 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.

Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of Telar-AM (Telmisartan) to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg Telar-AM (Telmisartan) to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significantchanges in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).

In 30 hypertensive patients with normal renal function treated for 8 weeks with Telar-AM (Telmisartan) 80 mg or Telar-AM (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.

12.3  Pharmacokinetics

Following oral administration, peak concentrations (Cmax) of Telar-AM (Telmisartan) are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of Telar-AM (Telmisartan), with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of Telar-AM (Telmisartan) is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered Telar-AM (Telmisartan) are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Telar-AM (Telmisartan) shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of Telar-AM (Telmisartan) with once daily dosing are about 10% to 25% of peak plasma concentrations. Telar-AM (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 α1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for Telar-AM (Telmisartan) is approximately 500 liters indicating additional tissue binding.

Metabolism and Elimination

Following either intravenous or oral administration of 14C-labeled Telar-AM (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).

Telar-AM (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 andurine. 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 Telar-AM (Telmisartan).

Total plasma clearance of Telar-AM (Telmisartan) is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.

Specific Populations

Renal Insufficiency

No dosage adjustment is necessary in patients with decreased renal function. Telar-AM (Telmisartan) is not removed from blood by hemofiltration .

Hepatic Insufficiency

In patients with hepatic insufficiency, plasma concentrations of Telar-AM (Telmisartan) are increased, and absolute bioavailability approaches 100% .

Gender

Plasma concentrations of Telar-AM (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 Telar-AM (Telmisartan) do not differ between the elderly and those younger than 65 years .

Pediatric Patients

Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of carcinogenicity when Telar-AM 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 Telar-AM (Telmisartan). These same doses have been shown to provide average systemic exposures to Telar-AM (Telmisartan) >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (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/m2 basis, the MRHD oftelmisartan. 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).

13.3  Developmental Toxicity

There is no clinical experience with the use of Telar-AM (Telmisartan) tablets in pregnant women. No teratogenic effects were observed when Telar-AM (Telmisartan) was administered to pregnant rats at oral doses of up to 50mg/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/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) Telar-AM (Telmisartan) doses of 15 mg/kg/day (about 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. Telar-AM (Telmisartan) has been shown tobe 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/m2 basis,the maximum recommended human dose of Telar-AM (Telmisartan) (80 mg/day).

14  CLINICAL STUDIES

14.1  Hypertension

The antihypertensive effects of Telar-AM have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of these examined the antihypertensive effects of Telar-AM (Telmisartan) and hydrochlorothiazide in combination. The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with Telar-AM (Telmisartan). Following once dailyadministration of Telar-AM (Telmisartan), the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.

Upon initiation of antihypertensive treatment with Telar-AM (Telmisartan), blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with Telar-AM (Telmisartan) tablets,blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of Telar-AM (Telmisartan) appeared to be maintained for up to at least one year. The antihypertensive effect of Telar-AM (Telmisartan) is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors.

In a controlled study, the addition of Telar-AM (Telmisartan) to hydrochlorothiazide produced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with Telar-AM (Telmisartan) monotherapy. Hydrochlorothiazide also had an added blood pressure effect when added to Telar-AM (Telmisartan).

The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of Telar-AM (Telmisartan) ismaintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40 to 80 mg doses of Telar-AM (Telmisartan) was 70 to 100% for bothsystolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%).

There were no changes in the heart rate of patients treated with Telar-AM (Telmisartan) in controlled trials.

14.2  Cardiovascular Risk Reduction

Support for use to reduce therisk of cardiovascular events was obtained in a pair of studies. Both enrolledsubjects age ≥55 years, at high cardiovascular risk as evidenced by coronary artery disease (75%), diabetesmellitus (27%) accompanied with end-organ damage (e.g., retinopathy, leftventricular hypertrophy, and, in ONTARGET only, macro- or microalbuminuria),stroke (16%), peripheral vascular disease (13%), or transient ischemic attack(4%). Patients without a history of intolerance to ACE inhibitors enteredONTARGET, and those with such a history, usually cough (90%), entered TRANSCEND,but patients with >1+ proteinuria on dipstick were excluded from TRANSCEND. For both ONTARGET and TRANSCEND trials, the primary4-component composite endpoint was death from cardiovascular causes, myocardialinfarction, stroke, and hospitalization for heart failure. The secondary3-component composite endpoint was death from cardiovascular causes, myocardialinfarction, and stroke.

ONTARGET was a randomized, active-controlled, multinational,double-blind study in 25,620 patients who were randomized to Telar-AM (Telmisartan) 80 mg,ramipril 10 mg, or their combination. The population studied was 73%male, 74% Caucasian, 14% Asian, and 57% were 65 years of age or older. Baseline therapy included acetylsalicylic acid (76%), lipid lowering agents(64%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%), anddiuretics (28%). The mean duration of follow up was about 4 years and 6months. During the study, 22.0% (n=1878) of Telar-AM (Telmisartan) patientsdiscontinued the active treatment, compared to 24.4% (n=2095) of ramiprilpatients and 25.3% (n=2152) of telmisartan/ramipril patients.

TRANSCEND randomized patientsto Telar-AM (Telmisartan) 80 mg (n=2954) or placebo (n=2972). The mean duration of followup was 4 years and 8 months. Thepopulation studied was 57% male, 62% Caucasian, 21% Asian, and 60% were 65years of age or older. Baseline therapy included acetylsalicylic acid(75%), lipid lowering agents (58%), beta-blockers (58%), calcium channelblockers (41%), nitrates (34%) and diuretics (33%). During the study, 17.7%(n=523) of Telar-AM (Telmisartan) patients discontinued the active treatment, compared to19.4% (n=576) of placebo patients.

The results for the TRANSCENDtrial are summarized in Table 2, and the results for ONTARGET are summarized inTable 3, below:

*The primary endpoint was defined as the time to first event. In case of multiple simultaneous events, all individual events were considered; the sum of patients with individual outcomes may exceed the number of patients with composite (primary or secondary) outcomes.

**For individual components of the primary composite endpoints, all events, regardless whether or not they were the first event, were considered. Therefore, they are more than the first events considered for the primary or secondary composite endpoint.

Telar-AM (Telmisartan) vs. Placebo

(n=2954) (n=2972)

No. of Events

Telar-AM (Telmisartan) / Placebo

Hazard Ratio

95% CI

p-value
*Composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure 465 (15.7%) / 504 (17.0%) 0.92 (0.81 – 1.05) 0.2129
*Composite of CV death, myocardial infarction, or stroke 384 (13.0%) / 440 (14.8%) 0.87 (0.76 – 1.00) 0.0483
Individual components of the primary composite endpoint No. of Events

Telar-AM (Telmisartan) / Placebo

Hazard Ratio

95% CI

p-value
**All non-fatal MI 114 (3.9%) / 145 (4.9%) 0.79 (0.62 – 1.01) 0.0574
**All non-fatal strokes 112 (3.8%) / 136 (4.6%) 0.83 (0.64 – 1.06) 0.1365
Telar-AM (Telmisartan) vs. Ramipril

(n=8542) (n=8576)

No. of Events

Telmisartan / Ramipril

Hazard Ratio

97.5% CI

Composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure 1423 (16.7%) / 1412 (16.5%) 1.01 (0.93 – 1.10)
Composite of CV death, myocardial infarction, or stroke 1190 (13.9%) / 1210 (14.1%) 0.99 (0.90 – 1.08)

Althoughthe event rates in ONTARGET were similar on Telar-AM (Telmisartan) and ramipril, theresults did not unequivocally rule out that Telar-AM (Telmisartan) may not preserve ameaningful fraction of the effect of ramipril in reducing cardiovascular events. However, theresults of both ONTARGET and TRANSCEND do adequately support Telar-AM (Telmisartan) beingmore effective than placebo would be in this setting, particularly for the end pointof time to cardiovascular death, myocardial infarction, or stroke.

In ONTARGET, there was noevidence that combining ramipril and Telar-AM (Telmisartan) reduced the risk of death fromcardiovascular causes, myocardial infarction, stroke, or hospitalization for heartfailure greater than ramipril alone; instead, patients who received thecombination of ramipril and Telar-AM (Telmisartan) in ONTARGET experienced an increasedincidence of clinically important renal dysfunction (e.g., acute renal failure)compared to patients receiving Telar-AM (Telmisartan) or ramipril alone.

Multiple sub-group analysesdid not demonstrate any differences in the 4-component composite primaryendpoint based on age, gender, or ethnicity for either ONTARGET or TRANSCENDtrial.

16  HOW SUPPLIED/STORAGE AND HANDLING

Telar-AM (Telmisartan) is available as white or off-white, uncoated tablets containing Telar-AM (Telmisartan) 20 mg, 40 mg, or 80 mg. Tablets are marked with the BOEHRINGER INGELHEIM logo on one side, and on the other side, with either 50H, 51H, or 52H for the 20 mg, 40 mg, and 80 mg strengths, respectively. Tablets are provided as follows:

Telar-AM (Telmisartan) tablets 20 mg are round and individually blister-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0039-37).

Telar-AM (Telmisartan) tablets 40 mg are oblong shaped and individually blister-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0040-37).

Telar-AM (Telmisartan) tablets 80 mg are oblong shaped and individually blister-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0041-37).

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Tablets should not be removed from blisters until immediately before administration.

17  PATIENT COUNSELING INFORMATION

See FDA-approved Patient Labeling

17.1  Pregnancy

Female patients of childbearing age should be told about the consequences of exposure to Telar-AM (Telmisartan) during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible .

Distributed by:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany

Copyright 2012 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

OT1200SA252012

090340194/12

IT12004O

10005385/9

Patient Information

Telar-AM (Telmisartan)® (my-CAR-dis)

(telmisartan)

Tablets

Read this Patient Information before you start taking Telar-AM (Telmisartan) 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 Telar-AM (Telmisartan) tablets?

Telar-AM (Telmisartan) 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 Telar-AM (Telmisartan), tell your doctor right away.

What is Telar-AM (Telmisartan)?

Telar-AM (Telmisartan) is a prescription medicine used:

  • to treat high blood pressure (hypertension)
  • in certain high risk people aged 55 years and older to help lower their risk of having certain cardiovascular problems such as stroke, heart attack, or death

It is not known if Telar-AM (Telmisartan) is safe and effective in children.

Who should not take Telar-AM (Telmisartan)?

You should not take Telar-AM (Telmisartan) tablets if you are allergic (hypersensitive) to the active ingredient (telmisartan) or any of the other ingredients listed at the end of this leaflet.

What should I tell my doctor before taking Telar-AM (Telmisartan) tablets?

Before you take Telar-AM (Telmisartan) tablets, tell your doctor if you:

  • have liver problems
  • have kidney problems
  • have heart problems
  • have any other medical conditions
  • are pregnant or are planning to become pregnant. See "What is the most important information I shouldknow about Telar-AM (Telmisartan) tablets?"
  • are breast-feeding or plan to breast-feed. It is not known if Telar-AM (Telmisartan) passes into your breast milk. You and your doctor should decide if you will take Telar-AM (Telmisartan) tablets or breast-feed. You should not do both. Talk with your doctor about the best way to feed your baby if you take Telar-AM (Telmisartan) tablets.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Telar-AM (Telmisartan) may affect the way other medicines work, and other medicines may affect how Telar-AM (Telmisartan) works. Especially tell your doctor if you take:

  • digoxin (Lanoxin®, Lanoxicaps®)
  • lithium (Eskalith®, Lithobid®)
  • medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors
  • ramipril (Altace®) or other medicines used to treat your high blood pressure or heart problem
  • water pills (diuretic)

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 Telar-AM (Telmisartan) tablets?

  • Take Telar-AM (Telmisartan) tablets exactly as your doctor tells you to take it.
  • Your doctor will tell you how much Telar-AM (Telmisartan) to take and when to take it.
  • Do not change your dose unless your doctor tells you to.
  • Take Telar-AM (Telmisartan) one time each day at the same time.
  • Take Telar-AM (Telmisartan) tablets with or without food.
  • If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.
  • If you take too much Telar-AM (Telmisartan), 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 Telar-AM (Telmisartan). Talk with your doctor if you do not understand the instructions.

What are the possible side effects of Telar-AM (Telmisartan) tablets?

Telar-AM (Telmisartan) 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 Telar-AM (Telmisartan) 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
  • 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 Telar-AM (Telmisartan) 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.
  • High potassium in the blood (hyperkalemia). Your doctor may check your potassium levels as needed.

Rare, serious allergic reactions may happen. Tell your doctor right away if you get any of these symptoms:

  • swelling of the face, tongue, throat
  • difficulty breathing
  • skin rash

The most common side effects of Telar-AM (Telmisartan) tablets include:

  • sinus pain and congestion (sinusitis)
  • back pain
  • diarrhea

These are not all the possible side effects with Telar-AM (Telmisartan) 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 Telar-AM (Telmisartan) tablets?

  • Store Telar-AM (Telmisartan) tablets between 59°F to 86°F (15°C to 30°C).
  • Do not remove Telar-AM (Telmisartan) tablets from blisters until right before you take them.

Keep Telar-AM (Telmisartan) tablets and all medicines out of the reach of children.

General information about Telar-AM (Telmisartan) tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Telar-AM (Telmisartan) tablets for a condition for which it was not prescribed. Do not give MICARDIStablets 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 Telar-AM (Telmisartan) tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor forinformation about Telar-AM (Telmisartan) tablets that is written for health professionals.

For more information, call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906.

What are the ingredients in Telar-AM (Telmisartan) tablets?

Active Ingredient: Telar-AM (Telmisartan)

Inactive Ingredients: sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate

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. Telar-AM (Telmisartan) tablets can help your blood vessels relax so your blood pressure is lower. High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to the blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure, and vision problems.

What is Cardiovascular Risk?

Patients older than 55 years of age who have been diagnosed with blood vessel disease in the heart, legs, or brain (coronary, peripheral, or cerebral vascular disease) or diabetes with end organ damage (for example: kidney, heart, and brain) are at higher risk of cardiovascular events (for example: death from cardiovascular causes, stroke, and/or heart attack).

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)

Distributed by:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany

Copyright 2012 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

Revised: January 2012

OT1200SA252012

090340194/12

IT12004O

10005385/9

Tear the blister apart Peel off the paper layer from the aluminum foil Push (Push the tablet through the foil)

Telar-AM pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Telar-AM available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Telar-AM destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Telar-AM Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Telar-AM pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


advertisement

References

  1. "AMLODIPINE - National Library of Medicine HSDB Database". https://toxnet.nlm.nih.gov/cgi-bin/... (accessed August 28, 2018).
  2. Dailymed."MICARDIS (TELMISARTAN) TABLET [LAKE ERIE MEDICAL & SURGICAL SUPPLY DBA QUALITY CARE PRODUCTS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."AMLODIPINE BESYLATE; TELMISARTAN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Telar-AM?

Depending on the reaction of the Telar-AM after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Telar-AM not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Telar-AM addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

advertisement

Review

sdrugs.com conducted a study on Telar-AM, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Telar-AM consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

Visitor reported doses

No survey data has been collected yet

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

Visitor reviews


There are no reviews yet. Be the first to write one!


Your name: 
Email: 
Spam protection:  < Type 28 here

The information was verified by Dr. Rachana Salvi, MD Pharmacology

© 2002 - 2024 "sdrugs.com". All Rights Reserved