Arbitel

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Arbitel uses


WARNING: FETAL TOXICITY


WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

1  INDICATIONS AND USAGE

Arbitel is an angiotensin II receptor blocker indicated for:

1.1  Hypertension

Arbitel 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

Arbitel 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 Arbitel 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 Arbitel with an ACE inhibitor is not recommended .

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2  DOSAGE AND ADMINISTRATION

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 Arbitel 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 Arbitel 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.

Arbitel tablets may be administered with other antihypertensive agents.

Arbitel tablets may be administered with or without food.

2.2  Cardiovascular Risk Reduction

The recommended dose of Arbitel 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 Arbitel are effective in reducing the risk of cardiovascular morbidity and mortality.

When initiating Arbitel therapy for cardiovascular risk reduction, monitoring of blood pressure is recommended, and if appropriate, adjustment of medications that lower blood pressure may be necessary.

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3  DOSAGE FORMS AND STRENGTHS

4  CONTRAINDICATIONS

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

5  WARNINGS AND PRECAUTIONS

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 Arbitel 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 Arbitel. Either correct this condition prior to administration of Arbitel, 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 Arbitel is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate Arbitel 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 Arbitel .

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 Arbitel 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 Arbitel only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of Arbitel 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 Arbitel alone or ramipril alone. Concomitant use of Arbitel and ramipril is not recommended.

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6  ADVERSE REACTIONS

The following adverse reaction is described elsewhere in labeling:

Renal dysfunction upon use with ramipril


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 Arbitel (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 Arbitel 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 Arbitel and at a Greater Rate Than Patients Treated with Placebo

Arbitel

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 Arbitel 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 Arbitel 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 Arbitel monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to Arbitel 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 Arbitel tablets.

Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% Arbitel 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% Arbitel 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 Arbitel; 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 Arbitel in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of Arbitel for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on Arbitel and 7.6% on placebo. The only serious adverse events at least 1% more common on Arbitel 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 Arbitel. 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 Arbitel.

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 Arbitel.

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7  DRUG INTERACTIONS

Digoxin : When Arbitel 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 Arbitel 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 Arbitel. 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 Arbitel, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Arbitel and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Arbitel may be attenuated by NSAIDs including selective COX-2 inhibitors.

Ramipril and Ramiprilat : Co-administration of Arbitel 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 Arbitel decrease by 31% and 16%, respectively. When co-administering Arbitel 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 Arbitel. Concomitant use of Arbitel and ramipril is not recommended.

Other Drugs : Co-administration of Arbitel did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Arbitel is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Arbitel 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.

8  USE IN SPECIFIC POPULATIONS

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 Arbitel 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 Arbitel, 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 Arbitel for hypotension, oliguria, and hyperkalemia .

8.3  Nursing Mothers

It is not known whether Arbitel is excreted in human milk, but Arbitel 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 Arbitel:

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 Arbitel 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 Arbitel 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 Arbitel tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Arbitel is not removed by hemodialysis.

11  DESCRIPTION

Arbitel is a non-peptide angiotensin II receptor (type AT1) antagonist.

Arbitel 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:

Arbitel 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.

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

Arbitel 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. Arbitel 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. Arbitel 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 Arbitel does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Arbitel 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 Arbitel on blood pressure.

12.2  Pharmacodynamics

In normal volunteers, a dose of Arbitel 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 Arbitel to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg Arbitel 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 Arbitel 80 mg or Arbitel 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 Arbitel are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of Arbitel, 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 Arbitel is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered Arbitel are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Arbitel shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of Arbitel with once daily dosing are about 10% to 25% of peak plasma concentrations. Arbitel 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 Arbitel is approximately 500 liters indicating additional tissue binding.

Metabolism and Elimination

Following either intravenous or oral administration of 14C-labeled Arbitel, 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).

Arbitel 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 Arbitel.

Total plasma clearance of Arbitel 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. Arbitel is not removed from blood by hemofiltration .

Hepatic Insufficiency

In patients with hepatic insufficiency, plasma concentrations of Arbitel are increased, and absolute bioavailability approaches 100% .

Gender

Plasma concentrations of Arbitel 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 Arbitel 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 Arbitel was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice 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 Arbitel. These same doses have been shown to provide average systemic exposures to Arbitel >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 Arbitel tablets in pregnant women. No teratogenic effects were observed when Arbitel 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) Arbitel 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. Arbitel 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 Arbitel (80 mg/day).

14  CLINICAL STUDIES

14.1  Hypertension

The antihypertensive effects of Arbitel 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 Arbitel and hydrochlorothiazide in combination. The studies involved a total of 1773 patients with mild to moderate hypertension, 1031 of whom were treated with Arbitel. Following once dailyadministration of Arbitel, 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 Arbitel, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with Arbitel 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 Arbitel appeared to be maintained for up to at least one year. The antihypertensive effect of Arbitel 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 Arbitel to hydrochlorothiazide produced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with Arbitel monotherapy. Hydrochlorothiazide also had an added blood pressure effect when added to Arbitel.

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 Arbitel 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 Arbitel 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 Arbitel 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 Arbitel 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 Arbitel patientsdiscontinued the active treatment, compared to 24.4% (n=2095) of ramiprilpatients and 25.3% (n=2152) of telmisartan/ramipril patients.

TRANSCEND randomized patientsto Arbitel 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 Arbitel 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.

Arbitel vs. Placebo

(n=2954) (n=2972)

No. of Events

Arbitel / 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

Arbitel / 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
Arbitel 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 Arbitel and ramipril, theresults did not unequivocally rule out that Arbitel may not preserve ameaningful fraction of the effect of ramipril in reducing cardiovascular events. However, theresults of both ONTARGET and TRANSCEND do adequately support Arbitel 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 Arbitel 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 Arbitel in ONTARGET experienced an increasedincidence of clinically important renal dysfunction (e.g., acute renal failure)compared to patients receiving Arbitel 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

Arbitel is available as white or off-white, uncoated tablets containing Arbitel 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:

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

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

Arbitel 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 Arbitel 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

Arbitel® (my-CAR-dis)

(telmisartan)

Tablets

Read this Patient Information before you start taking Arbitel 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 Arbitel tablets?

Arbitel 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 Arbitel, tell your doctor right away.

What is Arbitel?

Arbitel is a prescription medicine used:


It is not known if Arbitel is safe and effective in children.

Who should not take Arbitel?

You should not take Arbitel 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 Arbitel tablets?

Before you take Arbitel tablets, tell your doctor if you:


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

Arbitel may affect the way other medicines work, and other medicines may affect how Arbitel works. Especially tell your doctor if you take:


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 Arbitel tablets?


What are the possible side effects of Arbitel tablets?

Arbitel tablets may cause serious side effects, including:


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


The most common side effects of Arbitel tablets include:


These are not all the possible side effects with Arbitel 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 Arbitel tablets?


Keep Arbitel tablets and all medicines out of the reach of children.

General information about Arbitel tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Arbitel 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 Arbitel tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor forinformation about Arbitel 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 Arbitel tablets?

Active Ingredient: Arbitel

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. Arbitel 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)

Arbitel 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.


Arbitel 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.


Arbitel 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.


Arbitel 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.


Arbitel 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.


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References

  1. Dailymed."MICARDIS (TELMISARTAN) TABLET [LAKE ERIE MEDICAL & SURGICAL SUPPLY DBA QUALITY CARE PRODUCTS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. 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).
  3. "Telmisartan". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Arbitel?

Depending on the reaction of the Arbitel after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Arbitel 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 Arbitel 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.

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Review

sdrugs.com conducted a study on Arbitel, 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 Arbitel 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

One visitor reported doses

What is the dose of Arbitel drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 11-50mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
11-50mg1
100.0%

One visitor reported time for results

What is the time duration Arbitel drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 1 day to notice the result from using Arbitel drug. The time needed to show improvement in health condition after using the medicine Arbitel need not be same for all the users. It varies based on other factors.
Visitors%
1 day1
100.0%

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

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

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