telmisartan: prescribing information – dosing, contraindications, interactions, side effects

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

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. When considering raising the dose, it must be borne in mind that the maximum antihypertensive effect is generally attained 4 to 8 weeks after the start of treatment (see section 5.1). Alternatively, telmisartan may be used in combination with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive blood pressure lowering effect with telmisartan.

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.

Elderly
No dose adjustment is necessary for elderly patients.

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

Hepatic impairment
Micardis 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).

Paediatric population
The safety and efficacy of Micardis 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 swallowed whole with liquid, with or without food.

Precautions to be taken before handling or administering the medicinal product.
Telmisartan should be kept in the sealed blister due to the hygroscopic property of the tablets. Tablets should be taken out of the blister shortly before administration (see section 6.6).

• 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 Micardis with aliskiren-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).

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 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 21 642 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:
Urinary tract infection, cystitis, upper respiratory tract infection including pharyngitis and sinusitis Rare:
Sepsis including fatal outcome1

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

Psychiatric disorders
Uncommon:
Insomnia, depression
Rare:
Anxiety

Nervous system disorders
Uncommon:
Syncope, dizziness
Rare:
Somnolence

Eye disorders
Rare:
Visual impairment

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:
Abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting
Rare:
Dry mouth, abdominal discomfort, dysgeusia

Hepato-biliary disorders
Rare:
Hepatic function abnormal/liver disorder3

Skin and subcutaneous tissue disorders
Uncommon:
Pruritus, hyperhidrosis, rash
Rare:
Angioedema (including fatal outcome), eczema, erythema, urticaria, drug eruption, toxic skin eruption

Muscoloskeletal and connective tissue disorders
Uncommon:
Back pain (e.g. sciatica), muscle spasms, myalgia
Rare:
Arthralgia, pain in extremity, tendon pain (tendonitis like symptoms)

Renal and urinary disorders
Uncommon:
Renal impairment (including acute kidney injury)

General disorders and administration site conditions
Uncommon:
Chest pain, asthenia (weakness)
Rare:
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 description, please see sub-section “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 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 Japanese patients. Japanese patients 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.

Intestinal angioedema
Cases of intestinal angioedema have been reported after the use of angiotensin II receptor blockers (see section 4.4).

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Pregnancy
Angiotensin II receptor blockers should not be initiated during pregnancy. Unless continued angiotensin II receptor blocker 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 blockers should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Hepatic impairment
Micardis 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. Micardis 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 Micardis 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 Micardis in patients with recent kidney transplantation.
Telmisartan is not removed from blood by haemofiltration and is not dialyzable.

Volume- and/or sodium-depleted patients
Symptomatic hypotension, especially after the first dose of Micardis, 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 should be corrected before the administration of Micardis. Volume and/or sodium depletion should be corrected prior to administration of Micardis.

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 appropriate 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 classes of medicinal products that may provoke hyperkalaemia are 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 (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 II receptor blockers 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.

Intestinal angioedema
Intestinal angioedema has been reported in patients treated with angiotensin II receptor blockers (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea.
Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, telmisartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Sorbitol
Micardis 20 mg tablets
Micardis 20 mg tablets contain 84.32 mg sorbitol in each tablet.

Micardis 40 mg tablets
Micardis 40 mg tablets contain 168.64 mg sorbitol in each tablet.

Micardis 80 mg tablets
Micardis 80 mg tablets contain 337.28 mg sorbitol in each tablet. Patients with hereditary fructose

intolerance (HFI) should not take this medicinal product.

Sodium
Each tablet contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’.

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 blockers, 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 blockers 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 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 non- selective 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.

In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC0-24 and Cmax 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.

Pregnancy

The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor blockers 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 Micardis 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 blockers, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor blocker 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 blockers should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor blocker 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 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 (see sections 4.3 and 4.4).

Breast-feeding
Because no information is available regarding the use of Micardis during breast-feeding, Micardis 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 Micardis on male and female fertility were observed.

When driving vehicles or operating machinery it should be taken into account that syncope or vertigo may occasionally occur when taking antihypertensive therapy such as Micardis.

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.

Management
Telmisartan is not removed by haemofiltration and is not dialyzable. 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

Pharmacotherapeutic group: Angiotensin II receptor blockers (ARBs), plain, ATC Code: C09CA07.

Mechanism of action
Telmisartan is an orally active and specific angiotensin II receptor (type AT1) blocker. 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.

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 (AUC0-∞) 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. Cmax 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 (Vdss) 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 (Cmax) 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 (Cltot) is high (approximately 1 000 mL/min) compared with hepatic blood flow (about 1 500 mL/min).

Paediatric population