MIZART Tablet Ref.[50304] Active ingredients: Telmisartan

Diabetes Mellitus

Exploratory post-hoc analyses of two placebo-controlled telmisartan trials suggested an increased risk of fatal myocardial infarction and unexpected cardiovascular death (death occurring within 24 hours of the onset of symptoms without confirmation of cardiovascular cause, and without clinical or post mortem evidence of other etiology) in patients with diabetes mellitus who have no documented medical history of either coronary heart disease or myocardial infarction. In patients with diabetes mellitus, coronary heart disease may be asymptomatic and can therefore remain undiagnosed. Treatment with blood pressure lowering agent telmisartan may further reduce coronary perfusion in these patients. For this reason, patients with diabetes mellitus should undergo specific diagnostics and be treated accordingly before initiating therapy with telmisartan.

Aortic and Mitral Valve Stenosis, and Obstructive Hypertrophic Cardiomyopathy

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

Hyperkalaemia

During treatment with medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium levels in patients at risk is recommended.

Based on experience with the use of medicinal products that affect the renin-angiotensin system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase the potassium level (e.g., heparin, etc.) may lead to an increase in serum potassium and should, therefore, be co-administered cautiously with telmisartan.

Sodium- and/or Volume-Depleted Patients

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

Use in Cardiac Failure

Telmisartan may be used in patients with congestive heart failure. However patients should be carefully observed for hypotension when initiating therapy.

Ethnic Differences

As observed for angiotensin converting enzyme inhibitors, angiotensin receptor blockers including telmisartan 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.

Ischaemic Heart Disease

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

Use in Hepatic Impairment

The majority of telmisartan is eliminated in the bile. Patients with biliary obstructive disorders or severe hepatic insufficiency can be expected to have reduced clearance. Telmisartan is, therefore, contraindicated for use in these patients.

Telmisartan should only be used with caution in patients with mild to moderate hepatic impairment (see Section 4.2 DOSE AND METHOD OF ADMINISTRATION).

Use in Renal Impairment

Renal artery stenosis and kidney transplant

There are no data available on the use of telmisartan in patients who have had a kidney transplant.

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.

Increases in serum creatinine have been observed in studies with ACE-inhibitors in patients with single or bilateral renal artery stenosis. An effect similar to that observed with ACE inhibitors should be anticipated with telmisartan.

Impaired renal function

When telmisartan is used in patients with impaired renal function, periodic monitoring of potassium and creatinine serum levels is recommended.

Telmisartan is not removed from blood by haemofiltration and is not dialysable.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. 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 angiotensin converting enzyme inhibitors and angiotensin II receptor blockers has been associated with acute hypotension, oliguria and/or progressive uraemia and rarely with acute renal failure and/or death.

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 in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of the renin-angiotensin-aldosterone system (e.g. by adding an ACE-inhibitor or the direct renin-inhibitor aliskiren to an angiotensin II receptor blocker) is not recommended and should therefore be limited to individually defined cases with close monitoring of renal function (see Section 4.3 CONTRAINDICATIONS).

In the ONTARGET trial, patients receiving the combination of telmisartan and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of hyperkalaemia, renal failure, hypotension and syncope compared with groups receiving telmisartan alone or ramipril alone (see also Section 5.1 PHARMACODYNAMIC PROPERTIES, CLINICAL TRIALS). Concomitant use of telmisartan and ramipril is therefore not recommended in patients with already controlled blood pressure.

Combination use of ACE inhibitors or angiotensin receptor blockers, anti-inflammatory drugs and thiazide diuretics

The use of an ACE-inhibitor or angiotensin receptor blocker, an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

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.

Use in Elderly

No data available

Paediatric Use

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

Effects on Laboratory Tests

No significant differences in changes in laboratory test parameters were observed in clinical studies with telmisartan.

Haemoglobin decreased: A greater than 2 g/dL decrease in haemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anaemia.

Blood creatinine increased: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen.

Hepatic enzyme increased: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function.

Other interactions of clinical significance have not been identified. Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine.

When telmisartan was co-administered with digoxin, an increase in digoxin AUC (22%), C_max (50%), and C_min (13%) values was observed. It is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible over- or under- digitalisation.

In one study, the co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C_max and AUC of ramipril 2.3- and 2.1 fold, respectively, and C_max and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C_max and AUC of telmisartan decrease by 31% and 16% respectively. The clinical relevance of this observation is not fully known. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamics effects of the combined drugs and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Combining telmisartan with ramipril in the ONTARGET trial resulted in a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope compared to telmisartan alone or ramipril alone (see also Section 5.1 PHARMACODYNAMIC PROPERTIES, CLINICAL TRIALS). Concomitant use of telmisartan and ramipril is therefore not recommended in patients with already controlled blood pressure and should be limited to individually defined cases with close monitoring of renal function (see also Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE).

As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may provoke hyperkalaemia (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). 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 blockers, non-steroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressives (ciclosporin or tacrolimus), and trimethoprim.

The occurrence of hyperkalaemia depends on associated risk factors. The risk is increased in case of the abovementioned 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 blockers such as telmisartan, attenuate diuretic induced potassium loss. Potassium sparing diuretics e.g. spironolactone, 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 blockers 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 blockers. 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 blockers 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.

Diuretics (thiazide or loop diuretics)

Prior treatment with high dose diuretics such as furosemide (frusemide) (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 Section 4.3 CONTRAINDICATIONS, Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE and Section 5.1 PHARMACODYNAMIC PROPERTIES).

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.

Effects on Fertility

No studies on fertility in humans have been performed. Fertility of male and female rats was unaffected at oral telmisartan doses up to 100 mg/kg/day.

Use in Pregnancy

Pregnancy Category D.

Angiotensin II receptor blockers should not be initiated during pregnancy. The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stopped immediately, and, if appropriate, alternative therapy should be started.

Unless continued angiotensin II receptor blocker 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.

Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity.

The use of angiotensin II receptor blockers is contraindicated during the second and third trimester of pregnancy.

Although there is no clinical experience with telmisartan in pregnant women, in utero exposure to drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and even death. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. Therefore, when pregnancy is detected, telmisartan should be discontinued as soon as possible.

Angiotensin II receptor blocker exposure 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). Oligohydramnios reported in this setting, presumably resulting from decreased fetal renal function, has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to occur when drug exposure has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor blocker only during the first trimester should be so informed. Women of child-bearing age should be warned of the potential hazards to their fetus should they become pregnant.

Should exposure to angiotensin II receptor blockers 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 blockers should be closely observed for hypotension, oliguria and hyperkalaemia.

Telmisartan has been shown to cross the placenta in rats. There were no teratogenic effects when telmisartan was administered orally to rats and rabbits during the period of organogenesis at doses up to 50 and 45 mg/kg/day, respectively. However, fetal resorptions were observed at the highest dose level in rabbits. Administration of 50 mg/kg/day telmisartan to rats during pregnancy and lactation caused a decrease in birth weight and suppression of postnatal growth and development of the offspring.

The no-effect dose level in rabbits was 15 mg/kg/day, and corresponded to a plasma AUC value that was about 9 times higher than that anticipated in women at the highest recommended dose. Plasma drug levels were not measured at the high dose level in rats, but data from other studies suggest that they would have been similar to those in women at the maximum recommended dose.

Use in Lactation

Telmisartan is contraindicated during lactation since it is not known whether it is excreted in human milk. Animal studies have shown excretion of telmisartan in breast milk. No clinical trials have been carried out in lactating women. Therefore, lactating women should either not be prescribed telmisartan or should discontinue breastfeeding, if telmisartan is administered.

Telmisartan is excreted in the milk of lactating rats. When administered orally to lactating rats at 50 mg/kg/day, telmisartan suppressed postnatal growth and development of the offspring.

There are no data to suggest that telmisartan affects the ability to drive and use machines. However, when driving or operating machinery it should be taken into account that with antihypertensive therapy, occasionally drowsiness, syncope or vertigo may occur.

Adverse reactions have usually been mild and transient in nature and have only infrequently required discontinuation of therapy. The incidence of adverse reactions was not dose related and showed no correlation with gender, age or race of the patients.

Treatment of Hypertension

The overall incidence of adverse reactions reported with telmisartan was comparable to placebo in placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160 mg) for up to 12 weeks. Therefore, the following information refers to adverse events irrespective of their causal relationship.

Adverse events with an incidence of 1% or more in telmisartan-treated patients and greater than placebo are shown in Table 1. The frequency of these adverse events was not significantly different between the telmisartan-treated and placebo patients.

Table 1. Frequency of adverse events (%) in placebo-controlled trials:

In addition, the following adverse events occurred in more than 1% of the 3455 patients treated in all trials with telmisartan although causal association of these events with telmisartan could not be established: bronchitis, insomnia, arthralgia, anxiety, depression, palpitation, muscle spasms (cramps in legs) and rash. In addition to those listed above, adverse events that occurred in less than 1% but more than 0.3% of 3500 patients treated with telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to telmisartan tablets: Infections and infestations: upper respiratory tract infections (including rhinitis), bronchitis, urinary tract infections, cystitis, infection, fungal infection, abscess, otitis media.

Immune system disorders: allergy.

Metabolism and nutrition disorders: gout, hypercholesterolaemia, diabetes mellitus.

Psychiatric disorders: anxiety, insomnia, depression, nervousness.

Nervous system disorders: somnolence, migraine, paraesthesia, hypoaesthesia.

Eye disorders: visual disturbance, conjunctivitis.

Ear and labyrinth disorders: vertigo, tinnitus, earache.

Cardiac disorders: tachycardia, palpitation, angina pectoris.

Vascular disorders: flushing, cerebrovascular disorder.

Respiratory disorders: dyspnoea, asthma, epistaxis.

Gastrointestinal disorders: dry mouth, flatulence, stomach discomfort, vomiting, constipation, gastritis, haemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache.

Skin and subcutaneous tissue disorders: eczema, pruritus, hyperhidrosis, rash, dermatitis.

Musculoskeletal, connective tissue and bone disorders: arthralgia, involuntary muscle contractions or muscle spasms (cramps in legs) or pain in extremity (leg pain), arthritis.

Renal and urinary tract disorders: micturition frequency.

Reproductive system and breast disorders: impotence.

General disorders and administration site conditions: malaise, fever, leg oedema, dependent oedema.

Investigations: abnormal ECG.

Prevention of Cardiovascular Morbidity and Mortality

Because common adverse reactions were well characterised in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan in the prevention of cardiovascular morbidity and mortality.

The safety profile of telmisartan in patients treated for the prevention of cardiovascular morbidity and mortality was consistent with that obtained in hypertensive patients.

In ONTARGET (N=25620, 4.5 years mean duration of follow up), discontinuations due to adverse events were 8.7% on telmisartan, 11.0% on ramipril and 12.4% on combination of telmisartan and ramipril.

In TRANSCEND (N=5926, 4 years and 8 months of follow up), discontinuations due to adverse events were 8.4% on telmisartan and 7.6% on placebo.

In PRoFESS (N=20332, 2.5 years follow up), discontinuations due to adverse events were 14.5% on telmisartan and 11.2% on placebo. Because of the factorial design of the PRoFESS trial, the discontinuation rates observed in the telmisartan and placebo groups could also be due in part to the concomitant administration of either antiplatelet study medication (clopidogrel or aspirin + dipyridamole).

Adverse events in TRANSCEND occurring at least 1% more common in telmisartan-treated patients than in placebo-treated patients are shown in Table 2. Additionally for these events the incidences from ONTARGET are also presented. The data is derived from all serious adverse events reported during the study.

Table 2. TRANSCEND adverse events () occurring at least 1 or more common in patients treated with telmisartan than in patients treated with placebo, including ONTARGET incidences:

^* Based on serious adverse events collected during the trial.

Combining telmisartan with ramipril in the ONTARGET study resulted in a higher incidence of hyperkalemia, renal failure, hypotension and syncope compared to telmisartan or ramipril alone.

In clinical studies with patients at high risk of developing major cardiovascular events, cases of sepsis, including some with fatal outcomes, have been reported. In the PRoFESS trial, an increased incidence of sepsis was noted for telmisartan compared with placebo, 0.70 % versus 0.49 %; the incidence of fatal sepsis cases was increased for patients taking telmisartan (0.33 %) versus patients taking placebo (0.16 %). 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.

Post-Marketing Experience

In addition, the following have also been reported since the introduction of telmisartan in the market:

Blood and lymphatic system disorders

Uncommon: anaemia

Rare: eosinophilia, thrombocytopenia

Immune system disorders

Rare: anaphylactic reaction, hypersensitivity

Metabolism and nutrition disorders

Uncommon: hyperkalaemia

Rare: hypoglycaemia (in diabetic patients), hyponatraemia

Nervous system disorders

Uncommon: syncope (faint).

Cardiac disorders

Uncommon: bradycardia

Vascular disorders

Uncommon: hypotension, orthostatic hypotension

Hepatobiliary disorders

Rare: hepatic function abnormal/liver disorder*

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

Skin and subcutaneous tissue disorders

Rare: angioedema (including fatal outcome), erythema, urticaria, drug eruption, toxic skin eruption

Musculoskeletal, connective tissue and bone disorders

Rare: tendon pain (tendinitis like symptoms)

Renal and urinary tract disorders

Uncommon: renal impairment including acute kidney injury (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE)

General disorders and administration site conditions

Uncommon: asthenia (weakness)

Investigations

Rare: blood uric acid increased, blood creatine phosphokinase (CPK) increased

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.