1. Name of the medicinal product

Telmisartan Tablets USP 20mg Taj Pharma
Telmisartan Tablets USP 40mg Taj Pharma
Telmisartan Tablets USP 80mg Taj Pharma

2. Qualitative and quantitative composition

a) Each Uncoated Tablet Contains:
Telmisartan USP? ? ? ? ? ? ? ? ? ? 20mg
Excipients? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?q.s

b) Each Uncoated Tablet Contains:
Telmisartan USP? ? ? ? ? ? ? ? 40mg
Excipients? ? ? ? ? ? ? ? ? ? ? ? ? ? q.s

c) Each Uncoated Tablet Contains:
Telmisartan USP? ? ? ? ? ? ? ?80mg
Excipients? ? ? ? ? ? ? ? ? ? ? ? ? ?q.s

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

4. Clinical particulars

4.1 Therapeutic indications

Hypertension

Treatment of essential hypertension in adults.

Cardiovascular prevention

Reduction of cardiovascular morbidity in adults with:

– manifest atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral arterial disease) or

– type 2 diabetes mellitus with documented target organ damage

4.2 Posology and method of administration

Posology

Treatment of essential hypertension

The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of 20 mg. In cases where the target blood pressure is not achieved, the dose of telmisartan can be increased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combination with thiazidetype diuretics such as hydrochlorothiazide which has been shown to have an additive blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne in mind that the maximum antihypertensive effect is generally attained four to eight weeks after the start of treatment (see section 5.1).

Cardiovascular prevention

The recommended dose is 80 mg once daily. It is not known whether doses lower than 80 mg of telmisartan are effective in reducing cardiovascular morbidity.

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

Special populations

Patients with renal impairment

Limited experience is available in patients with severe renal impairment or haemodialysis. A lower starting dose of 20 mg is recommended in these patients (see section 4.4). No posology adjustment is required for patients with mild to moderate renal impairment.

Patients with hepatic impairment

Telmisartan? is contraindicated in patients with severe hepatic impairment (see section 4.3).

In patients with mild to moderate hepatic impairment the posology should not exceed 40 mg once daily (see section 4.4).

Elderly patients

No dose adjustment is necessary for elderly patients.

Paediatric population

The safety and efficacy of telmisartan in children and adolescents aged below 18 years have not been established.

Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Telmisartan tablets are for once-daily oral administration and should be taken with liquid, with or without food.

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

– Second and third trimesters of pregnancy (see sections 4.4 and 4.6)

– Biliary obstructive disorders

– Severe hepatic impairment

The concomitant use of Telmisartan? withaliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Hepatic impairment

Telmisartan? is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic impairment (see section 4.3) since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan. Telmisartan? should be used only with caution in patients with mild to moderate hepatic impairment.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

When Telmisartan? is used in patients with impaired renal function, periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Telmisartan? in patients with recent kidney transplantation.

Intravascular hypovolaemia

Symptomatic hypotension, especially after the first dose of Telmisartan , may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Telmisartan? . Volume and/or sodium depletion should be corrected prior to administration of Telmisartan? .

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system such as telmisartan has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see section 4.8).

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Diabetic patients treated with insulin or antidiabetics

In these patients hypoglycaemia may occur under telmisartan treatment. Therefore, in these patients an approptiate blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required, when indicated.

Hyperkalaemia

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

In the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events, hyperkalaemia may be fatal.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated.

The main risk factors for hyperkalaemia to be considered are:

– Diabetes mellitus, renal impairment, age (> 70 years)

– Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Medicinal products or therapeutic class of medicinal products that may provoke hyperkalaemia are salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.

– Intercurrent events, in particular dehydratation, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extend trauma).

Close-monitoring of serum potassium in at risk patients is recommended (see section 4.5).

Ethnic differences

As observed for angiotensin converting enzyme inhibitors, telmisartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Other

As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemiccardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

4.5 Interaction with other medicinal products and other forms of interaction

Digoxin

When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. When initiating, adjusting, and discontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.

As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may provoke hyperkalaemia (see section 4.4). The risk may increase in case of treatment combination with other medicinal products that may also provoke hyperkalaemia (salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressives (cyclosporin or tacrolimus), and trimethoprim).

The occurrence of hyperkalaemia depends on associated risk factors. The risk is increased in case of the above-mentioned treatment combinations. The risk is particularly high in combination with potassium sparing-diuretics and when combined with salt substitutes containing potassium. A combination with ACE inhibitors or NSAIDs, for example, presents a lesser risk provided that precautions for use are strictly followed.

Concomitant use not recommended

Potassium sparing diuretics or potassium supplements

Angiotensin II receptor antagonists such as telmisartan attenuate diuretic induced potassium loss. Potassium sparing diuretics e.g. spirinolactone, eplerenone, triamterene, or amiloride, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with angiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Non-steroidal anti-inflammatory medicinal products

NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and nonselective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.

In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC_0-24?and C_max?of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Diuretics (thiazide or loop diuretics)

Prior treatment with high dose diuretics such as furosemide (loop diuretic) and hydrochlorothiazide (thiazide diuretic) may result in volume depletion and in a risk of hypotension when initiating therapy with telmisartan.

To be taken into account with concomitant use

Other antihypertensive agents

The blood pressure lowering effect of telmisartan can be increased by concomitant use of other antihypertensive medicinal products.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen, amifostine.

Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or antidepressants.

Corticosteroids (systemic route)

Reduction of the antihypertensive effect.

4.6 Fertility, pregnancy and lactation

Pregnancy:

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

There are no adequate data from the use of Telmisartan? in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).

Breast-feeding

Because no information is available regarding the use of Telmisartan? during breast-feeding, Telmisartan? is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility

In preclinical studies, no effects of telmisartan on male and female fertility were observed.

4.7 Effects on ability to drive and use machines

When driving vehicles or operating machinery it should be taken into account that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy such as Telmisartan .

4.8 Undesirable effects

Summary of the safety profile

Serious adverse drug reactions include anaphylactic reaction and angioedema which may occur rarely (?1/10,000 to <1/1,000), and acute renal failure.

The overall incidence of adverse reactions reported with telmisartan was usually comparable to placebo (41.4% vs 43.9%) in placebo controlled trials in patients treated for hypertension. The incidence of adverse reactions was not dose related and showed no correlation with gender, age or race of the patients. The safety profile of telmisartan in patients treated for the reduction of cardiovascular morbidity was consistent with that obtained in hypertensive patients.

The adverse reactions listed below have been accumulated from controlled clinical trials in patients treated for hypertension and from post-marketing reports. The listing also takes into account serious adverse reactions and adverse reactions leading to discontinuation reported in three clinical long-term studies including 21642 patients treated with telmisartan for the reduction of cardiovascular morbidity for up to six years.

Tabulated list of adverse reactions

Adverse reactions have been ranked under headings of frequency using the following convention: very common (? 1/10); common (? 1/100 to < 1/10); uncommon (? 1/1,000 to < 1/100); rare (? 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations
Uncommon: Rare:	Urinary tract infection including cystitis, upper respiratory tract infection including pharyngitis and sinusitis Sepsis including fatal outcome1
Blood and the lymphatic system disorders
Uncommon:	Anaemia
Rare:	Eosinophilia, thrombocytopenia
Immune system disorders
Rare:	Anaphylactic reaction, hypersensitivity
Metabolism and nutrition disorders
Uncommon:	Hyperkalaemia
Rare: Psychiatric disorders	Hypoglycaemia (in diabetic patients)
Uncommon:	Insomnia, depression
Rare:	Anxiety
Nervous system disorders
Uncommon:	Syncope
Rare:	Somnolence
Eye disorders
Rare:	Visual disturbance
Ear and labyrinth disorders
Uncommon:	Vertigo
Cardiac disorders
Uncommon:	Bradycardia
Rare:	Tachycardia
Vascular disorders
Uncommon:	Hypotension2, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon:	Dyspnoea, cough
Very rare:	Interstitial lung disease4
Gastrointestinal disorders
Uncommon: Rare:	Abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting Dry mouth, stomach discomfort, dysgeusia
Hepatobiliary disorders
Rare:	Hepatic function abnormal/liver disorder3
Skin and subcutaneous tissue disorders
Uncommon: Rare:	Pruritus, hyperhidrosis, rash Angioedema (also with fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption
Muscoloskeletal and connective tissue disorders
Uncommon: Rare:	Back pain (e.g. sciatica), muscle spasms, myalgia Arthralgia, pain in extremity, tendor pain (tendinitis like symptoms)
Renal and urinary disorders
Uncommon:	Renal impairment including acute renal failure
General disorders and administration site conditions
Uncommon: Rare:	Chest pain, asthenia (weakness) Influenza-like illness
Investigations
Uncommon:	Blood creatinine increased
Rare:	Haemoglobin decreased, blood uric acid increased, hepatic enzyme increased, blood creatine phosphokinase increased

1,2,3,4: for further descriptions, please see sub-section 4 ?Description of selected adverse reactions?

Description of selected adverse reactions

Sepsis

In the PRoFESS trial, an increased incidence of sepsis was observed with telmisartan compared with placebo. The event may be a chance finding or related to a mechanism currently not known (see also section 5.1).

Hypotension

This adverse drug reaction?was reported as common in patients with controlled blood pressure who were treated with telmisartan for the reduction of cardiovascular morbidity on top of standard care.

Hepatic function abnormal / liver disorder

Most cases of hepatic function abnormal / liver disorder from post-marketing experience occurred in patients in Japan, who are more likely to experience these adverse reactions.

Interstitial lung disease

Cases of interstitial lung disease have been reported from post-marketing experience in temporal association with the intake of telmisartan. However, a causal relationship has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

There is limited information available with regard to overdose in humans.

Symptoms:?The most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia dizziness, increase in serum creatinine, and acute renal failure have also been reported.

Treatment:?Telmisartan is not removed by haemodialysis. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and / or gastric lavage. Activated charcoal may be useful in the treatment of overdosage. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacement given quickly.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II Antagonists.

Mechanism of action

Telmisartan is an orally active and specific angiotensin II receptor (type AT₁) antagonist.

Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT₁?receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT₁?receptor. Telmisartan selectively binds the AT₁?receptor. The binding is long-lasting. Telmisartan does not show affinity for other receptors, including AT₂?and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan.

Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse effects.

In human, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.

Clinical efficacy and safety

Treatment of essential hypertension

After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start of treatment and is sustained during long-term therapy.

The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies.

There is an apparent trend to a dose relationship to a time to recovery of baseline systolic blood pressure (SBP). In this respect data concerning diastolic blood pressure (DBP) are inconsistent.

In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of the medicinal product’s diuretic and natriuretic effect to its hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable to that of agents representative of other classes of antihypertensive medicinal products (demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).

Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.

The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.

Cardiovascular prevention

ONTARGET?(ONgoing?Telmisartan?Alone and in Combination with?Ramipril?Global?Endpoint?Trial) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25620 patients aged 55 years or older with a history of coronary artery disease, stroke, TIA, peripheral arterial disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which is a population at risk for cardiovascular events.

Patients were randomized to one of the three following treatment groups: telmisartan 80 mg (n = 8542), ramipril 10 mg (n = 8576), or the combination of telmisartan 80 mg plus ramipril 10 mg (n = 8502), and followed for a mean observation time of 4.5 years.

Telmisartan showed a similar effect to ramipril in reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7%) and ramipril (16.5%) groups. The hazard ratio for telmisartan vs. ramipril was 1.01 (97.5% CI 0.93 – 1.10, p (non-inferiority) = 0.0019 at a margin of 1.13). The all-cause mortality rate was 11.6 % and 11.8 % among telmisartan and ramipril treated patients, respectively.

Telmisartan was found to be similarly effective to ramipril in the pre-specified secondary endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [0.99 (97.5% CI 0.90 – 1.08), p (non-inferiority) = 0.0004], the primary endpoint in the reference study HOPE (The?Heart?Outcomes?Prevention?Evaluation Study), which had investigated the effect of ramipril vs. placebo.

TRANSCEND randomized ACE-I intolerant patients with otherwise similar inclusion criteria as ONTARGET to telmisartan 80 mg (n = 2954) or placebo (n = 2972), both given on top of standard care. The mean duration of follow up was 4 years and 8 months. No statistically significant difference in the incidence of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure) was found [15.7% in the telmisartan and 17.0% in the placebo groups with a hazard ratio of 0.92 (95% CI 0.81-1.05, p = 0.22)]. There was evidence for a benefit of telmisartan compared to placebo in the pre-specified secondary composite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [0.87 (95% CI 0.76-1.00, p = 0.048)], There was no evidence for benefit on cardiovascular mortality (hazard ratio 1.03, 95% CI 0.85-1.24).

Two large randomised, controlled trials (ONTARGET (ONgoingTelmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.

Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. CV mortality and all cause mortality were numerically higher with the combination. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination arm. Therefore the use of a combination of telmisartan and ramipril is not recommended in this population.

In the “Prevention Regimen For Effectively avoiding Second Strokes” (PRoFESS) trial in patients 50 years and older, who recently experienced stroke, an increased incidence of sepsis was noted for telmisartan compared with placebo, 0.70% vs. 0.49% [RR 1.43 (95% confidence interval 1.00- 2.06)]; the incidence of fatal sepsis cases was increased for patients taking telmisartan (0.33%) vs. patients taking placebo (0.16%) [RR 2.07 (95% confidence interval 1.14 3.76)]. The observed increased occurrence rate of sepsis associated with the use of telmisartan may be either a chance finding or related to a mechanism not currently known.

Paediatric population

The safety and efficacy of telmisartan in children and adolescents aged below 18 years have not been established.

The blood pressure lowering effects of two doses of telmisartan were assessed in 76 hypertensive, largely overweight patients aged 6 to < 18 years (body weight ? 20 kg and ? 120 kg, mean 74.6 kg), after taking telmisartan 1 mg/kg (n = 29 treated) or 2 mg/kg (n = 31 treated) over a four-week treatment period. By inclusion the presence of secondary hypertension was not investigated. In some of the investigated patients the doses used were higher than those recommended in the treatment of hypertension in the adult population, reaching a daily dose comparable to160 mg, which was tested in adults. After adjustment for age group effects mean SBP changes from baseline (primary objective) were -14.5 (1.7) mm Hg in the telmisartan 2 mg/kg group, -9.7 (1.7) mm Hg in the telmisartan 1 mg/kg group, and -6.0 (2.4) in the placebo group. The adjusted DBP changes from baseline were -8.4 (1.5) mm Hg, -4.5 (1.6) mm Hg and -3.5 (2.1) mm Hg respectively. The change was dose dependent. The safety data from this study in patients aged 6 to < 18 years appeared generally similar to that observed in adults. The safety of long term treatment of telmisartan in children and adolescents was not evaluated.

An increase in eosinophils reported in this patient population has not been recorded in adults. Its clinical significance and relevance is unknown.

These clinical data do not allow to make conclusions on the efficacy and safety of telmisartan in hypertensive paediatric population.

5.2 Pharmacokinetic properties

Absorption

Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50%.

When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC_0-?) of telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). By 3 hours after administration plasma concentrations are similar whether telmisartan is taken fasting or with food.

Linearity/non-linearity

The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.

There is no linear relationship between doses and plasma levels. C_max?and to a lesser extent AUC increase disproportionately at doses above 40 mg.

Distribution

Telmisartan is largely bound to plasma protein (> 99.5%), mainly albumin and alpha-1 acid glycoprotein. The mean steady state apparent volume of distribution (V_dss) is approximately 500 l.

Biotransformation

Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.

Elimination

Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of > 20 hours. The maximum plasma concentration (C_max) and, to a smaller extent, the area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma concentrations were higher in females than in males, without relevant influence on efficacy.

After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the faeces, mainly as unchanged compound. Cumulative urinary excretion is < 1% of dose. Total plasma clearance (Cl_tot) is high (approximately 1,000 ml/min) compared with hepatic blood flow (about 1,500 ml/min).

Special Populations

Paediatric population

The pharmacokinetics of two doses of telmisartan were assessed as a secondary objective in hypertensive patients (n = 57) aged 6 to < 18 years after taking telmisartan 1 mg/kg or 2 mg/kg over a four-week treatment period. Pharmacokinetic objectives included the determination of the steady-state of telmisartan in children and adolescents, and investigation of age-related differences. Although the study was too small for a meaningful assessment of the pharmacokinetics of children under 12 years of age, the results are generally consistent with the findings in adults and confirm the non-linearity of telmisartan, particularly for C_max.

Gender

Gender differences in plasma concentrations were observed, C_max?and AUC being approximately 3-and 2-fold higher, respectively, in females compared to males.

Elderly

The pharmacokinetics of telmisartando not differ between the elderly and those younger than 65 years.

Renal impairment

In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations was observed. However, lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient patients and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.

Hepatic impairment

Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100 %. The elimination half-life is not changed in patients with hepatic impairment.

5.3 Preclinical safety data

In preclinical safety studies, doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit), changes in renal haemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive animals. In dogs renal tubular dilation and atrophy were observed. Gastric mucosal injury (erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically-mediated undesirable effects, known from preclinical studies with both angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, were prevented by oral saline supplementation.

In both species, increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of angiotensin converting enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical significance.

No clear evidence of a teratogenic effect was observed, however at toxic dose levels of telmisartan an effect on the postnatal development of the offsprings such as lower body weight and delayed eye opening was observed.

There was no evidence of mutagenicity and relevant clastogenic activity in?in vitro?studies and no evidence of carcinogenicity in rats and mice.

6. Pharmaceutical particulars

6.1 List of excipients

Magnesium stearate, Croscarmellose sodium, Mannitol, Povidone, Potassium Hydroxide Pellets.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Al/Al blisters:

Keep the container tightly closed in order to protect from light.

6.5 Nature and contents of container

Al/Al blisters Packs.

Pack sizes: 7, 14, 28, 30, 50, 90, 100 or 500 tablets.

Pack sizes: 30 or 250 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of ?Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail:?tajgroup@tajpharma.com

Telmisartan Tablets USP 20mg/40mg/80mg Taj Pharma
(Telmisartan)

Package leaflet: Information for the user

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Telmisartan is and what it is used for
   2. What you need to know before you take Telmisartan
   3. How to take Telmisartan
   4. Possible side effects
   5. How to store Telmisartan
   6. Contents of the pack and other information

 

1. What Telmisartan is and what it is used for

Telmisartan? contains the active substance telmisartan which belongs to a class of medicines known as angiotensin II receptor antagonists.

Angiotensin II is a substance produced in your body, which causes your blood vessels to narrow, thus increasing your blood pressure. Telmisartan? blocks the effect of angiotensin II so that the blood vessels relax, and your blood pressure is lowered.

Telmisartan? tablets are used to treat essential hypertension (high blood pressure) in adults.

?Essential? means that the high blood pressure is not caused by any other condition.

High blood pressure, if not treated, can damage blood vessels in several organs which could lead sometimes to heart attacks, heart or kidney failure, strokes or blindness. There are usually no symptoms of high blood pressure before damage occurs. Thus it is important to regularly measure blood pressure to verify if it is within the normal range.

Telmisartan? is also used to reduce cardiovascular events (i.e. heart attack or stroke) in adults who are at risk because they have a reduced or blocked blood supply to the heart or legs, or have had a stroke or have high risk diabetes. Your doctor can tell you if you are at high risk for such events.

2. What you need to know before you take Telmisartan

Do not take Telmisartan

• If you are allergic to telmisartan or any other ingredients of this medicine (listed in section 6).
• If you are more than 3 months pregnant. (It is also better to avoid Telmisartan in early pregnancy ? see pregnancy section).
• If you have severe liver problems such as cholestasis or biliary obstruction (problems with the drainage of the bile from the liver and gall bladder) or any other severe liver disease.
• If you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren.

If any of the above applies to you, tell your doctor or pharmacist before taking Telmisartan .

Warnings and precautions

Talk to your doctor if you are suffering or have ever suffered from any of the following conditions or illnesses:

• Kidney disease or kidney transplant.
• Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
• Liver disease.
• Heart trouble.
• Raised aldosterone levels (water and salt retention in the body along with imbalance of various blood minerals).
• Low blood pressure (hypotension), likely to occur if you are dehydrated (excessive loss of body water) or have salt deficiency due to diuretic therapy (?water tablets?), low salt diet, diarrhoea, or vomiting.
• Elevated potassium levels in your blood.

Talk to your doctor before taking Telmisartan :

• if you are taking digoxin
• if you are taking any of the following medicines used to treat high blood pressure:
  • an ACE inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes related kidney problems

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.

See also information under the heading ?Do not take Telmisartan ?.

You must tell your doctor if you think you are (or might become) pregnant. Telmisartan is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

In case of surgery or anaesthesia, you should tell your doctor that you are taking Telmisartan .

Telmisartan? may be less effective in lowering the blood pressure in black patients.

Children and adolescents

The use of Telmisartan? in children and adolescents up to the age of 18 years is not recommended.

Other medicines and Telmisartan

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Your doctor may need to change the dose of these other medicines or take other precautions. In some cases you may have to stop taking one of the medicines. This applies especially to the medicines listed below taken at the same time with Telmisartan

• Lithium containing medicines to treat some types of depression.
• Medicines that may increase blood potassium levels such as salt substitutes containing potassium, potassium sparing diuretics (certain ?water tablets?), ACE inhibitors (angiotensin-converting enzyme inhibitors, to treat high blood pressure), angiotensin II receptor antagonists (to treat high blood pressure), NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen), heparin (a medicine for thinning the blood), immunosuppressives (e.g. cyclosporin or tacrolimus), and the antibiotic trimethoprim.
• Diuretics (?water tablets?), especially if taken in high doses together with Telmisartan , may lead to excessive loss of body water and low blood pressure (hypotension).
• If you are taking an ACE inhibitor or aliskiren (see also information under the headings ?Do not take Telmisartan ? and ?Warnings and precautions?).

The effect of Telmisartan? may be reduced when you take NSAIDs (non steroidal anti?inflammatory drugs, e.g. aspirin or ibuprofen) or corticosteroids.

Telmisartan? may increase the blood pressure lowering effect of other medicines used to treat high blood pressure or of medicines with blood pressure lowering potential (e.g. baclofen, amifostine). Furthermore, low blood pressure may be aggravated by alcohol, barbiturates, narcotics or antidepressants. You may notice this as dizziness when standing up. You should consult with your doctor if you need to adjust the dose of your other medicine while taking Telmisartan .

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are?(or might become)?pregnant. Your doctor will normally advise you to stop taking Telmisartan? before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Telmisartan . Telmisartan? is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Telmisartan? is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines

Some people feel dizzy or tired when taking Telmisartan . If you feel dizzy or tired, do not drive or use machines.

3. How to take Telmisartan

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

For treatment of high blood pressure, the usual dose of Telmisartan? for most patients is one 40 mg tablet once a day to control blood pressure over the 24 hour period. However, sometimes your doctor may recommend a lower dose of 20 mg or a higher dose of 80 mg.

Alternatively, Telmisartan? may be used in combination with diuretics (?water tablets?) such as hydrochlorothiazide which has been shown to have an additive blood pressure lowering effect with telmisartan.

For reduction of cardiovascular events, the usual dose of Telmisartan? is one 80 mg tablet once a day. At the beginning of the preventive therapy with Telmisartan? 80 mg, blood pressure should be frequently monitored.

In patients with liver problems the usual dose should not exceed 40 mg once daily.

In patients with kidney problems a lower starting dose of 20 mg is recommended.

Try to take the tablet at the same time each day. You can take Telmisartan? with or without food. The tablets should be swallowed with some water or other non-alcoholic drink. It is important that you take Telmisartan? every day until your doctor tells you otherwise. If you have the impression that the effect of Telmisartan? is too strong or too weak, talk to your doctor or pharmacist.

If you take more Telmisartan? than you should

It is important to keep to the dose as prescribed by your doctor. If you accidentally take too many tablets ask your doctor what to do or contact your nearest hospital emergency department immediately.

The most common symptoms of telmisartan overdose are low blood pressure (hypotension) and fast heart beat (tachycardia). Slow heart beat (bradycardia), dizziness, higher levels of creatinine in the blood and sudden kidney failure have also been reported.

If you forget to take Telmisartan

If you forget to take your medicine you should take the dose as soon as you remember on the same day. If you do not take your tablet on one day, take your normal dose on the next day. Do not take a double dose to make up for a forgotten dose.

If you stop taking Telmisartan

Take Telmisartan? every day for as long as your doctor prescribes it in order to keep your blood pressure controlled. If you have the impression that the effect of Telmisartan? is too strong or too weak, talk to your doctor or pharmacist.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious and need immediate medical attention:

You should see your doctor immediately if you experience any of the following symptoms:

Sepsis* (often called ?blood poisoning?, is a severe infection with whole body inflammatory response), rapid swelling of the skin and mucosa (angioedema); these side effects are rare (may affect up to 1 in1,000 people) but are extremely serious and patients should stop taking the medicine and see their doctor immediately. If these effects are not treated they could be fatal.

Possible side effects of telmisartan:

Common side effects?(may affect up to 1 in 10 people):

Low blood pressure (hypotension) in users treated for reduction of cardiovascular events.

Uncommon side effects?(may affect up to 1 in 100 people):

Urinary tract infections, upper respiratory tract infections (e.g. sore throat, inflamed sinuses, common cold), deficiency in red blood cells (anaemia), high potassium levels, difficulty falling asleep, feeling sad (depression), fainting (syncope), feeling of spinning (vertigo), slow heart rate (bradycardia), low blood pressure (hypotension) in users treated for high blood pressure, dizziness on standing up (orthostatic hypotension), shortness of breath, cough abdominal pain, diarrhoea, discomfort in the abdomen, bloating, vomiting, itching, increased sweating, drug rash, back pain, muscle cramps, muscle pain (myalgia), kidney impairment including acute kidney failure, pain in the chest, feeling of weakness, and increased level of creatinine in the blood.

Rare side effects?(may affect up to 1 in 1,000 people):

Sepsis* (often called ?blood poisoning?, is a severe infection with whole body inflammatory response which can lead to death), increase in certain white blood cells (eosinophilia), low platelet count (thrombocytopenia), severe allergic reaction (anaphylactic reaction), allergic reaction (e.g. rash, itching, difficulty breathing, wheezing, swelling of the face or low blood pressure), low blood sugar levels (in diabetic patients), feeling anxious, somnolence, impaired vision, fast heart beat (tachycardia), dry mouth, upset stomach, taste disturbance (dysgeusia), abnormal liver function (Japanese patients are more likely to experience this side effect), rapid swelling of the skin and mucosa which can also lead to death (angioedema also with fatal outcome), eczema (a skin disorder), redness of skin, hives (urticaria), severe drug rash, joint pain (arthralgia), pain in extremity, tendon pain, flu like illness, decreased haemoglobin (a blood protein), increased levels of uric acid, increased hepatic enzymes or creatine phosphokinase in the blood.

Very rare side effects (may affect up to 1 in 10,000 people):

Progressive scarring of lung tissue (interstitial lung disease)**.

* The event may have happened by chance or could be related to a way that telmisartan works that is currently not known.

** Cases of progressive scarring of lung tissue have been reported during intake of telmisartan. However, it is not known whether telmisartan was the cause.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via

5. How to store Telmisartan

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, bottle or blister after ?EXP?. The expiry date refers to the last day of that month.

Al/Al blisters:

Store in the original package in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Telmisartan? contains

The active substance is telmisartan.

a) Each Uncoated Tablet Contains:
Telmisartan USP? ? ? ? ? ? ? ? ? ? 20mg
Excipients? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?q.s

b) Each Uncoated Tablet Contains:
Telmisartan USP? ? ? ? ? ? ? ? 40mg
Excipients? ? ? ? ? ? ? ? ? ? ? ? ? ? q.s

c) Each Uncoated Tablet Contains:
Telmisartan USP? ? ? ? ? ? ? ?80mg
Excipients? ? ? ? ? ? ? ? ? ? ? ? ? ?q.s

The other ingredients are magnesium stearate, croscarmellose sodium, mannitol, povidone, potassium hydroxide pellets.

Contents of pack:

Al/Al blisters Packs.

Pack sizes: 7, 14, 28, 30, 50, 90, 100 or 500 tablets.

Pack sizes: 30 or 250 tablets.

Not all pack sizes may be marketed.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of ?Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail:?tajgroup@tajpharma.com