Telmisartan/hidrohlorothiazide Krka

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Telmisartan/Hydrochlorothiazide Krka, 40 mg + 12.5 mg, tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 40 mg of telmisartan (telmisartanum) and 12.5 mg of hydrochlorothiazide (hydrochlorothiazidum).
Excipients with known effect: lactose monohydrate and sorbitol.
Each tablet contains 57 mg of lactose (in the form of lactose monohydrate) and 147.04 mg of sorbitol.
For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.
White to almost white or pinkish-white on one side and marbled pink on the other side, biconvex, oval tablets with dimensions of 15 mm x 7 mm.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of essential hypertension.
The combination product Telmisartan/Hydrochlorothiazide Krka (containing 40 mg of telmisartan and 12.5 mg of hydrochlorothiazide) is indicated for the treatment of adult patients whose blood pressure is not adequately controlled by telmisartan alone.

4.2 Posology and Method of Administration

Dosage
Telmisartan/Hydrochlorothiazide Krka should be used in patients whose blood pressure is not adequately controlled by telmisartan alone. It is recommended to adjust the dosage of each component individually before using the fixed combination. If considered clinically appropriate, a direct change from monotherapy to combination therapy may be considered.

• Telmisartan/Hydrochlorothiazide Krka 40 mg + 12.5 mg can be administered once daily to patients whose blood pressure is not adequately controlled by telmisartan 40 mg.
• Telmisartan/Hydrochlorothiazide Krka 80 mg + 12.5 mg can be administered once daily to patients whose blood pressure is not adequately controlled by telmisartan 80 mg.

Renal Impairment
Periodic monitoring of renal function is recommended (see section 4.4).
Hepatic Impairment
In patients with mild to moderate hepatic impairment, the dose of Telmisartan/Hydrochlorothiazide Krka should not exceed 40 mg + 12.5 mg once daily. Telmisartan/Hydrochlorothiazide Krka is not recommended for patients with severe hepatic impairment. In patients with hepatic impairment, thiazides should be used with caution (see section 4.4).
Elderly Patients
No dose adjustment is necessary.
Paediatric Population
The safety and efficacy of Telmisartan/Hydrochlorothiazide Krka in children and adolescents below the age of 18 have not been established. No data are available.

4.3 Contraindications

• Hypersensitivity to either active substance or to any of the excipients listed in section 6.1.
• Hypersensitivity to other sulfonamide derivatives (hydrochlorothiazide is a sulfonamide derivative).
• Second and third trimester of pregnancy (see sections 4.4 and 4.6).
• Biliary obstruction and cholestasis.
• Severe hepatic impairment.
• Severe renal impairment (creatinine clearance <30 ml min).< li>
• Refractory hypokalaemia, hypercalcaemia.

Concomitant use of Telmisartan/Hydrochlorothiazide Krka with aliskiren-containing products is contraindicated in patients with diabetes or renal impairment (GFR <60 ml min 1.73 m2) (see sections 4.5 and 5.1).< p>

4.4 Special Warnings and Precautions for Use

Pregnancy
Treatment with 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 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 (see sections 4.3 and 4.6).

• 4.3 and 4.6).

Hepatic Impairment
Since telmisartan is eliminated by the bile, Telmisartan/Hydrochlorothiazide Krka should not be used in patients with biliary obstruction, cholestasis or severe hepatic impairment (see section 4.3). In these patients, hepatic clearance of telmisartan may be reduced.

In addition, as with other angiotensin II receptor antagonists, caution is advised when administering Telmisartan/Hydrochlorothiazide Krka to patients with hepatic impairment or progressive liver disease, as minor changes in fluid and electrolyte balance may precipitate hepatic encephalopathy. There is no clinical experience with telmisartan in patients with hepatic impairment.

Hypertensive Heart Disease
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia, and decreased renal function (including acute renal failure). Dual blockade of the 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 necessary, this should only be 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 are predominantly dependent on the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, hyperazotemia, oliguria, and rarely acute renal failure. As with other drugs that affect the renin-angiotensin-aldosterone system, use of Telmisartan/Hydrochlorothiazide Krka in such patients should be undertaken with caution and close monitoring.

Primary Hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Telmisartan/Hydrochlorothiazide Krka in such patients is not recommended.

Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy
As with other vasodilators, telmisartan should be used with caution in patients with obstructive hypertrophic cardiomyopathy or aortic stenosis.

Metabolic and Endocrine Effects
Thiazide diuretics may impair glucose tolerance and may increase the risk of new onset diabetes. In addition, latent diabetes mellitus may become manifest during thiazide therapy. In diabetic patients, dose adjustment of insulin or oral hypoglycemic agents may be necessary.

Electrolyte Imbalance
As with other diuretics, hypokalaemia may occur with concomitant use of hypokalaemic diuretics, and the risk of hypokalaemia is greater in patients with cirrhosis of the liver, in patients undergoing prolonged diuresis or in patients receiving concomitant corticosteroids or adrenocorticotropic hormone (ACTH) (see section 4.5).

• Hypokalaemia Although hypokalaemia has been observed with thiazide diuretics, concurrent therapy with telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with cirrhosis of the liver, in patients undergoing prolonged diuresis or in patients receiving concomitant corticosteroids or adrenocorticotropic hormone (ACTH) (see section 4.5).
• Hyperkalaemia On the other hand, because of the antagonistic effect of telmisartan on angiotensin II receptors, the component of Telmisartan/Hydrochlorothiazide Krka, hyperkalaemia may occur. Although clinically significant hyperkalaemia has not been observed in trials with telmisartan/hydrochlorothiazide combination, risk factors for the development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be used with caution with Telmisartan/Hydrochlorothiazide Krka (see section 4.5).
• Hypontremia and hypochloremic alkalosis There is no evidence that Telmisartan/Hydrochlorothiazide Krka reduces or prevents hypontremia induced by thiazide diuretics. Chloride deficit is generally mild and usually does not require treatment.
• Hypercalcaemia Thiazides may reduce urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be a sign of hidden hyperparathyroidism.
• Hypomagnesemia Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see section 4.5).

Lactose monohydrate, sorbitol and sodium
The medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Telmisartan/Hydrochlorothiazide Krka 40 mg/12.5 mg contains 147.04 mg of sorbitol per tablet, corresponding to 5 mg/kg/day if body mass is 29.8 kg. The additive effect of concomitant administration of products containing sorbitol (or fructose) and the consumption of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other orally administered medicinal products.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.
Ethnic Differences
As with other angiotensin II receptor antagonists, telmisartan is apparently less effective in lowering blood pressure in black patients than in non-black patients, possibly due to a lower prevalence of low renin states in the black hypertensive population.

Other
As with other antihypertensive agents, excessive blood pressure decrease in patients with coronary heart disease or heart failure may result in myocardial infarction or stroke.

General Information
Hypersensitivity reactions to hydrochlorothiazide may occur in patients who have exhibited hypersensitivity or allergy to penicillin.

Photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If restart of therapy is deemed necessary, it is recommended to protect the skin from the sun and UV radiation.

Acute transient myopia and acute angle-closure glaucoma
Sulfonamides and sulfonamide derivatives can cause idiosyncratic reactions resulting in transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain, typically within hours to weeks of treatment initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Acute Respiratory Distress Syndrome
Very rare severe cases of acute respiratory distress syndrome have been reported with hydrochlorothiazide. Pulmonary oedema usually develops within minutes to hours after hydrochlorothiazide intake. Symptoms include dyspnoea, fever, and cough with or without pulmonary congestion on the chest X-ray. If a diagnosis of ARDS is suspected, Telmisartan/Hydrochlorothiazide Krka should be discontinued and appropriate treatment should be started. Hydrochlorothiazide should not be administered to patients who have previously experienced ARDS.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin-converting enzyme inhibitors. Rare cases have also been reported with angiotensin II receptor antagonists (including telmisartan/hydrochlorothiazide combination). Concomitant use of lithium and Telmisartan/Hydrochlorothiazide Krka is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Medicinal Products that May Increase Potassium Levels and Induce Hyperkalaemia (e.g. potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes):
When these medicinal products are used concomitantly with Telmisartan/Hydrochlorothiazide Krka, the monitoring of potassium plasma levels is recommended (see section 4.4).

Medicinal Products that May Reduce Potassium Levels and Induce Hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and its derivatives):
When these medicinal products are used concomitantly with Telmisartan/Hydrochlorothiazide Krka, the monitoring of potassium plasma levels is recommended (see section 4.4).

Digoxin
A 49% increase in the median peak plasma concentration (49%) and a 20% increase in the median trough plasma concentration (20%) of digoxin were reported when telmisartan was co-administered with digoxin. When initiating, titrating, and discontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.

Other Antihypertensive Medicinal Products
Telmisartan may increase the hypotensive effect of other antihypertensive medicinal products.

Non-Steroidal Anti-Inflammatory Medicinal Products (NSAIDs) Including Selective Cyclooxygenase-2 (COX-2) Inhibitors
When angiotensin II receptor blockers are used in combination with NSAIDs, the antihypertensive effect of the angiotensin II receptor blocker may be attenuated. Furthermore, in some patients with compromised renal function (e.g. dehydrated patients or patients with renal artery stenosis), the co-administration of NSAIDs and angiotensin II receptor blockers may result in a 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 renal function after initiation of concomitant therapy, and periodically thereafter.

In one study, co-administration of telmisartan and ramipril resulted in a 2.5-fold increase in the AUC and C of ramipril and ramiprilat. The clinical significance of this observation is not known.

Vasoconstrictors (e.g. noradrenaline):
The antihypertensive effect of these agents may be reduced.

Non-Depolarizing Muscle Relaxants (e.g. tubocurarine):
The effect of non-depolarizing muscle relaxants may be potentiated by hydrochlorothiazide.

Medicinal Products Used in Gout (e.g. probenecid, sulfinpyrazone, and allopurinol):
It may be necessary to adjust the dose of uricosuric medicinal products as hydrochlorothiazide may increase serum uric acid levels. Increase of the dose of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Calcium Salts
Thiazide diuretics may increase serum calcium levels by decreasing its excretion. If calcium supplements or calcium sparing medicinal products (e.g. vitamin D) are prescribed, serum calcium levels should be monitored and the dose of calcium adjusted accordingly.

Beta-Adrenergic Blocking Agents and Diazoxide
Thiazides may decrease arterial responsiveness to noradrenaline, but this is not usually a problem with clinical use. Thiazides may increase the responsiveness to tubocurarine.

Anticholinergic Agents (e.g. atropine, biperiden):
Thiazides may increase the bioavailability of thiazide diuretics by decreasing gastrointestinal motility and lowering the rate of gastric emptying.

Amantadine
Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic Agents (e.g. cyclophosphamide, methotrexate):
Thiazides may reduce the renal clearance of cytotoxic agents and enhance their myelosuppressive effects.

It can be expected that the following medicinal products may enhance the hypotensive effects of all antihypertensive drugs, including telmisartan:
baclofen, amifostine.

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

4.6 Fertility, Pregnancy and Lactation

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 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 (see sections 4.3 and 4.4).

There is no clinical experience with Telmisartan/Hydrochlorothiazide Krka in pregnant women. Animal studies 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 antagonists during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull hypoplasia). 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).

Hydrochlorothiazide crosses the placenta. Based on the mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may compromise foeto-placental perfusion and may cause foetal and neonatal effects like jaundice, electrolyte disturbances and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for the treatment of essential hypertension in pregnant women, except in rare situations where no other treatment could be used.

Breast-feeding
Due to the lack of information on the use of Telmisartan/Hydrochlorothiazide Krka during breast-feeding, this medicinal product is not recommended during breast-feeding, especially in newborns or preterm infants. In case of use during breast-feeding of Telmisartan/Hydrochlorothiazide Krka, close monitoring of the infant's blood pressure is recommended.

Small amounts of hydrochlorothiazide are excreted in breast milk. Thiazides in high doses causing intense diuresis can inhibit the milk production. If Telmisartan/Hydrochlorothiazide Krka is used during breast-feeding, doses should be kept as low as possible.

Fertility
In preclinical studies, no effects on fertility were observed in male and female rats.

4.7 Effects on Ability to Drive and Use Machines

Telmisartan/Hydrochlorothiazide Krka 40 mg + 12.5 mg may cause dizziness or drowsiness and, therefore, may affect the ability to drive or use machines.

4.8 Undesirable Effects

Summary of the Safety Profile
The most commonly reported adverse reaction is dizziness. In rare cases (<1>

In a controlled, randomised, double-blind study of 1471 patients with essential hypertension treated with telmisartan and hydrochlorothiazide (835 patients) or telmisartan alone (636 patients), the overall incidence of adverse reactions was similar with the combination and with telmisartan alone. Dose-dependent adverse reactions were not identified. Adverse reactions were not significantly different from those reported for placebo.

Tabular List of Adverse Reactions
Adverse reactions reported in all clinical trials with the combination of telmisartan and hydrochlorothiazide, and occurring more frequently (p ≤ 0.05) on the combination than on placebo are presented below, according to system organ class.

Adverse reactions that have been reported with telmisartan and/or hydrochlorothiazide from post-marketing experience are also included.

Adverse reactions are ranked according to system organ class and then by frequency, using the following convention:
very common (≥1/10); common (≥1/100 to <1>

Within each system organ class, adverse reactions are ranked in order of decreasing seriousness.

Infections and Infestations
Rare:
bronchitis, pharyngitis, sinusitis

Immune System Disorders
Rare:
systemic lupus erythematosus

Metabolism and Nutrition Disorders
Uncommon: hypokalaemia
Rare: hyperuricaemia, hyponatraemia

Psychiatric Disorders
Uncommon: anxiety
Rare: depression

Nervous System Disorders
Common: dizziness
Uncommon: syncope, paraesthesia
Rare: insomnia, somnolence

Eye Disorders
Rare: visual disturbance, blurred vision

Ear and Labyrinth Disorders
Uncommon: vertigo

Cardiac Disorders
Uncommon: tachycardia, arrhythmias

Vascular Disorders
Uncommon: hypotension, orthostatic hypotension

Respiratory, Thoracic and Mediastinal Disorders
Uncommon: cough, dyspnoea
Rare: interstitial lung disease (including pneumonitis and pulmonary fibrosis)

Gastrointestinal Disorders
Uncommon: diarrhoea, dry mouth, abdominal pain, dyspepsia, vomiting

Hepatobiliary Disorders
Rare: abnormal hepatic function, hepatitis

Skin and Subcutaneous Tissue Disorders
Rare: angioedema (rash, urticaria), pruritus, allergic dermatitis

Musculoskeletal and Connective Tissue Disorders
Uncommon: back pain, muscle spasms, myalgia
Rare: arthritis, muscle weakness

Renal and Urinary Disorders
Uncommon: renal impairment, pollakiuria

General Disorders and Administration Site Conditions
Uncommon: chest pain, asthenia, fatigue
Rare: influenza-like symptoms, pain

Investigations
Uncommon: increased uric acid, increased creatinine

Additional Information on Special Warning and Precautions for Use
Abnormal Liver Function
Most cases of abnormal liver function tests (liver function disorders) reported with telmisartan were observed in Japanese patients. Japanese patients are more likely to experience these adverse reactions.

Sepsis
In the PRoFESS trial, an increased risk of sepsis was observed with telmisartan compared with placebo. The incidence of sepsis in the telmisartan arm was 0.7% vs. 0.5% in the placebo arm.

4.9 Overdose

Data on telmisartan overdose in humans are limited. The degree to which hydrochlorothiazide can be removed by hemodialysis has not been established.
Symptoms
The most prominent symptoms of telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, vomiting, elevated blood creatinine levels, and acute renal failure have also been reported. Hydrochlorothiazide overdose may be associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia resulting from excessive diuresis. The most common subjective and objective symptoms of overdose are nausea and drowsiness. Hypokalemia can cause muscle cramps and (or) acceleration of heart rate associated with concomitant administration of digitalis glycosides or certain antiarrhythmic drugs.
Treatment
Telmisartan is not removed by hemodialysis. The patient should be closely monitored, and supportive and symptomatic treatment should be applied. The procedure depends on the time elapsed since the intake of the drug and the severity of the symptoms. Induction of vomiting and (or) gastric lavage is recommended. Activated charcoal may be useful in the treatment of overdose. Electrolyte and creatinine serum levels should be frequently monitored. If hypotension occurs, the patient should be placed in a supine position, and salts and fluids should be administered quickly.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Therapeutic category: drugs acting on the renin-angiotensin system: angiotensin II antagonists and diuretics, ATC code: C09DA07.
Telmisartan/Hydrochlorothiazide Krka is a combination product containing an angiotensin II receptor antagonist, telmisartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these components has an additive antihypertensive effect, resulting in a greater reduction in blood pressure than either component alone. Telmisartan/Hydrochlorothiazide Krka administered once daily produces effective and consistent blood pressure reduction at all doses tested.
Mechanism of action
Telmisartan is an orally active, selective antagonist of the angiotensin II receptor subtype 1 (AT1). Telmisartan has a high affinity for the AT1 receptor, displacing angiotensin II from its binding site. Telmisartan does not exhibit agonist activity at the AT1 receptor. Telmisartan selectively binds to the AT1 receptor, and binding is long-lasting. Telmisartan does not have affinity for other receptors, including the AT2 receptor and other less well-characterized angiotensin II receptors. The function of these receptors is not known, nor is the effect of their overstimulation by angiotensin II, whose levels increase with telmisartan. Telmisartan reduces aldosterone levels in the serum. Telmisartan does not inhibit renin activity in the serum and does not block ion channels. Telmisartan does not inhibit the angiotensin-converting enzyme (kininase II), an enzyme also responsible for the breakdown of bradykinin. Therefore, it is not expected to enhance the adverse effects associated with bradykinin action. In healthy volunteers, a dose of 80 mg almost completely inhibits the angiotensin II-induced blood pressure increase. This inhibitory effect persists over 24 hours and is still measurable after 48 hours.
Hydrochlorothiazide is a thiazide diuretic. The antihypertensive mechanism of thiazides is not fully understood. Thiazides affect the reabsorption of electrolytes in the renal tubules, directly increasing the excretion of sodium and chloride in approximately equal amounts. The diuretic effect of hydrochlorothiazide leads to a reduction in blood volume, an increase in renin activity in the serum, an increase in aldosterone secretion, resulting in increased potassium and bicarbonate loss in the urine and a decrease in serum potassium levels. It is assumed that concomitant administration of telmisartan leads to the prevention of potassium loss associated with diuretic action through blockade of the renin-angiotensin-aldosterone system. In the case of hydrochlorothiazide, diuresis begins after 2 hours, and the maximum effect is achieved after about 4 hours, while the effect persists for 6-12 hours.
Clinical efficacy and safety
Treatment of essential hypertension
After the first dose of telmisartan, the hypotensive effect develops gradually over 3 hours. Maximum blood pressure reduction is usually achieved after 4 to 8 weeks of treatment and is maintained throughout the treatment period. Ambulatory blood pressure measurements have shown that the hypotensive effect persists at a stable level over 24 hours after administration, including the last 4 hours before the next dose. This is confirmed by the results of clinical trials controlled with placebo, in which measurements of maximum blood pressure reduction and blood pressure reduction before the next dose (parameter called "through to peak ratio") were consistently above 80%, both after administration of 40 mg and 80 mg doses. Telmisartan administered to patients with hypertension reduces diastolic and systolic blood pressure without affecting heart rate. The efficacy of telmisartan's antihypertensive effect is comparable to that of other antihypertensive products (as shown in clinical comparative studies of telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).
In the event of sudden discontinuation of telmisartan, blood pressure returns to pre-treatment values gradually, over several days, without rebound hypertension. In clinical trials directly comparing two antihypertensive treatment regimens, the incidence of dry cough after telmisartan was lower than after ACE inhibitors.
Prevention of cardiovascular disease
In the ONTARGET clinical trial (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), the effects of telmisartan, ramipril, and concomitant administration of telmisartan and ramipril on cardiovascular outcomes were compared in 25,620 patients aged 55 or older with a history of coronary artery disease, stroke, transient ischemic attack (TIA), peripheral artery disease, or type 2 diabetes with documented target organ damage (e.g., retinopathy, left ventricular hypertrophy, macro- and microalbuminuria), which constitutes a population at risk of cardiovascular events.
Patient were randomly assigned to one of three groups: a group receiving telmisartan 80 mg (n = 8,542), a group receiving ramipril 10 mg (n = 8,576), or a group receiving both telmisartan 80 mg and ramipril 10 mg (n = 8,502). The median follow-up period was 4.5 years.
Similar effects of telmisartan and ramipril were demonstrated in terms of reducing the incidence of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure). The primary endpoint occurred with similar frequency in the telmisartan (16.7%) and ramipril (16.5%) groups. The hazard ratio for telmisartan versus ramipril was 1.01 (97.5% CI 0.93-1.10, p [non-inferiority] = 0.0019 with a margin of 1.13). The percentage of deaths from any cause in patients receiving telmisartan and ramipril was 11.6% and 11.8%, respectively.
Similar efficacy of telmisartan and ramipril was demonstrated in terms of the secondary endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [0.99 (97.5% CI 0.90-1.08), p (non-inferiority) = 0.0004], which was the primary endpoint in the HOPE clinical trial (The Heart Outcomes Prevention Evaluation Study), which compared the effects of ramipril and placebo.
In the TRANSCEND clinical trial, patients intolerant to ACE inhibitors who met the remaining inclusion criteria used in the ONTARGET trial were randomly assigned to receive either telmisartan 80 mg (n = 2,954) or placebo (n = 2,972), in addition to standard treatment. The median follow-up period was 4 years and 8 months. No statistically significant difference was found in the incidence of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) [15.7% in the telmisartan group and 17.0% in the placebo group, with a hazard ratio of 0.92 (95% CI 0.81-1.05, p = 0.22)].
In terms of the secondary composite endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), a benefit was demonstrated with telmisartan compared to placebo [0.87 (95% CI 0.76-1.00, p = 0.048)]. No differences were found between the groups in terms of cardiovascular mortality (hazard ratio 1.03; 95% CI 0.85-1.24).
Patient receiving telmisartan reported less cough and angioedema than those receiving ramipril, but more frequently reported hypotension.
Concomitant administration of telmisartan and ramipril did not provide additional benefits compared to ramipril or telmisartan monotherapy. In the group concomitantly receiving telmisartan and ramipril, the percentage of cardiovascular deaths and deaths from any cause was higher. Additionally, in the group concomitantly receiving telmisartan and ramipril, hyperkalemia, renal failure, hypotension, and syncope occurred more frequently. Therefore, concomitant use of telmisartan and ramipril is not recommended in this patient population.
In the PRoFESS clinical trial (Prevention Regimen For Effectively avoiding Second Strokes) involving patients aged 50 and older who had recently experienced a stroke, an increased incidence of sepsis was observed in the telmisartan group compared to the placebo group, 0.70% vs. 0.49% [increased risk 1.43 (95% confidence interval 1.00-2.06)]; the incidence of fatal sepsis was increased in patients receiving telmisartan (0.33%) compared to patients receiving placebo (0.16%) [increased risk 2.07 (95% confidence interval 1.14-3.76)]. The observed increase in the incidence of sepsis associated with telmisartan may be either random or caused by an currently unknown mechanism.
Currently, there are no data on the impact of telmisartan on mortality and morbidity due to cardiovascular disease in patients treated with telmisartan.
Two large randomized, controlled clinical trials, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nefropathy in Diabetes), investigated the concomitant use of an ACE inhibitor with an angiotensin II receptor antagonist.
The ONTARGET trial was conducted in patients with cardiovascular disease, cerebrovascular disease, or type 2 diabetes with documented target organ damage. The VA NEPHRON-D trial was conducted in patients with type 2 diabetes and diabetic nephropathy.
These trials demonstrated a lack of significant beneficial effect on renal and (or) cardiovascular outcomes, while an increased risk of hyperkalemia, acute kidney injury, and (or) hypotension was observed compared to monotherapy. Due to the similarities in the pharmacodynamic properties of these drugs, the results also apply to other ACE inhibitors and angiotensin II receptor antagonists.
Therefore, in patients with diabetic nephropathy, concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended.
The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to investigate the benefits of adding aliskiren to standard treatment with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease and (or) cardiovascular disease. The trial was prematurely terminated due to an increased risk of adverse events. Cardiovascular deaths and strokes occurred more frequently in the aliskiren group compared to the placebo group. The aliskiren group also reported more adverse events, including serious adverse events (hyperkalemia, hypotension, and renal failure), compared to the placebo group.
Epidemiological studies on long-term use of hydrochlorothiazide have shown that it reduces mortality and morbidity in patients with heart disease. The impact of the combination of fixed doses of telmisartan and hydrochlorothiazide on mortality and morbidity in patients with cardiovascular disease is currently unknown.
Non-melanoma skin cancers
Based on available data from epidemiological studies, a relationship has been found between the cumulative dose of HCTZ and the occurrence of NMSC. In one study, 71,533 patients with BCC and 8,629 patients with SCC were compared with control groups from the same population, including 1,430,833 and 172,462 patients, respectively. High exposure to HCTZ (cumulative dose ≥50,000 mg) was associated with an adjusted OR for BCC of 1.29 (95% CI 1.23-1.35) and for SCC of 3.98 (95% CI 3.68-4.31). A clear dose-response relationship was observed for both BCC and SCC. In another study, a possible relationship was found between the degree of exposure to HCTZ and the occurrence of malignant tumors of the lip (SCC): the study compared 633 cases of lip cancer and 63,067 patients from the same population, using a concurrent risk collection strategy. A dose-response relationship was observed with an adjusted OR of 2.1 (95% CI 1.7-2.6), which increased to an OR of 3.9 (3.0-4.9) with high exposure (~25,000 mg) and an OR of 7.7 (5.7-10.5) for the highest cumulative doses (~100,000 mg) (see also section 4.4).

5.2 Pharmacokinetic properties

The concomitant administration of hydrochlorothiazide and telmisartan does not appear to affect the pharmacokinetics of either substance in healthy patients.
Absorption
Telmisartan: After oral administration, the maximum concentration is reached after 0.5 to 1.5 hours.
The absolute bioavailability of telmisartan in doses of 40 mg and 160 mg was 42% and 58%, respectively. Food slightly reduces the bioavailability of telmisartan, with the area under the concentration-time curve (AUC) decreasing by approximately 6% after administration of a 40 mg tablet and by approximately 19% after a 160 mg dose. After three hours of administration, the telmisartan concentration in the serum reaches a similar level, regardless of whether telmisartan was taken on an empty stomach or after a meal. The slight reduction in AUC should not lead to a reduction in therapeutic efficacy. During repeated administration, telmisartan does not accumulate significantly in the serum.
Hydrochlorothiazide: After oral administration of the Telmisartan/Hydrochlorothiazide Krka product, the maximum hydrochlorothiazide concentration is reached after 1 to 3 hours. Based on the cumulative renal excretion of hydrochlorothiazide, its absolute bioavailability is approximately 60%.
Distribution
Telmisartan strongly binds to plasma proteins (>99.5%), mainly to albumin and alpha-1 acid glycoprotein. The apparent volume of distribution of telmisartan is approximately 500 liters, indicating additional binding to tissues.
Hydrochlorothiazide binds to plasma proteins at 68%, and its apparent volume of distribution is 0.83-1.14 L/kg.
Metabolism
Telmisartan is metabolized by conjugation to a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the only metabolite found in humans. After administration of a single dose of radiolabeled telmisartan, the glucuronide accounted for approximately 11% of the measured radioactivity in the serum. Telmisartan metabolism does not involve cytochrome P450 isoenzymes. Hydrochlorothiazide is not metabolized in the human body.
Elimination
Telmisartan: After intravenous or oral administration of radiolabeled telmisartan, most of the dose (>97%) was eliminated in the feces via biliary excretion. Only small amounts were detected in the urine. The total plasma clearance of telmisartan after oral administration is greater than 1500 mL/min. The terminal elimination half-life is >20 hours.
Hydrochlorothiazide is almost completely excreted in the urine in unchanged form. Approximately 60% of the oral dose is eliminated within 48 hours of administration. The renal clearance is approximately 250-300 mL/min. The terminal elimination half-life is 10 to 15 hours.
Linearity or non-linearity
Telmisartan: The pharmacokinetics of orally administered telmisartan is non-linear in the dose range of 20 mg to 160 mg, with an increase in serum concentration (C and AUC) greater than proportional to the increase in dose.
Hydrochlorothiazide exhibits linear pharmacokinetics.
Elderly patients
The pharmacokinetics of telmisartan does not differ in the elderly population and in patients under 65 years of age.
Sex
Telmisartan serum concentrations are generally 2-3 times higher in women than in men. However, clinical trials have not shown an increased response to the drug or an increased incidence of orthostatic hypotension in women. Therefore, there is no need to adjust the dose. A tendency towards higher hydrochlorothiazide serum concentrations has been observed in women than in men. It is not considered clinically significant.
Renal impairment
Renal excretion does not affect telmisartan clearance. Based on limited experience with patients with mild and moderate renal impairment (creatinine clearance 30-60 mL/min, mean approximately 50 mL/min), no dose adjustment is necessary in patients with reduced renal function. Telmisartan cannot be removed from the blood by hemodialysis. In patients with impaired renal function, the rate of elimination of hydrochlorothiazide is decreased. In a typical study, in patients with a mean creatinine clearance of 90 mL/min, the elimination half-life of hydrochlorothiazide was increased. In anephric patients, the elimination half-life is 34 hours.
Hepatic impairment
Pharmacokinetic studies in patients with hepatic impairment have shown an increase in the absolute bioavailability to almost 100%. The terminal elimination half-life remained unchanged in patients with liver failure.

5.3 Preclinical safety data

In preclinical studies, the concomitant administration of telmisartan and hydrochlorothiazide in rats and dogs with normal blood pressure did not produce any additional changes that had not been previously observed with either substance administered alone. Toxicological observations made in these studies appear to be of no relevance to therapeutic use in humans.
Toxicological observations from preclinical studies of ACE inhibitors and angiotensin II receptor antagonists indicate: decreased red blood cell parameters (erythrocytes, hemoglobin, hematocrit), hemodynamic changes in the kidneys (increased blood urea nitrogen and creatinine levels), increased renin activity in the serum, hypertrophy or hyperplasia of juxtaglomerular cells, and gastric mucosal damage. Gastric mucosal damage can be prevented by oral administration of a sodium chloride solution and by isolating animals in groups. In dogs, dilation and atrophy of renal tubules have been observed. It is believed that this effect is related to the pharmacological activity of telmisartan.
No unequivocal evidence of teratogenic effects of the product has been observed; however, after administration of toxic doses of telmisartan, effects on fetal development, such as lower body weight or delayed eye opening, have been observed.
In vitro studies have not shown any mutagenic or clastogenic effects of telmisartan; there is also no evidence of carcinogenic effects in rats and mice. Studies with hydrochlorothiazide in some experimental models have shown ambiguous genotoxic or carcinogenic effects.
For information on the fetal toxicity of the combination product containing telmisartan and hydrochlorothiazide, see section 4.6.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Meglumine
Sodium hydroxide
Povidone K30
Lactose monohydrate
Sorbitol
Magnesium stearate
Mannitol
Red iron oxide (E 172)
Hydroxypropyl cellulose
Colloidal anhydrous silica
Sodium stearyl fumarate

6.2 Incompatibilities

None

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30°C.
Store in the original packaging to protect from light.

6.5 Nature and contents of container

OPA/Aluminum/PVC/Aluminum blisters: 10, 14, 28, 30, 56, 60, 84, 90, and 98 tablets, in a cardboard box
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORIZATION NUMBER

Marketing authorization number: 21448

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

DATE OF LAST RENEWAL

Date of first authorization: 13.09.2013
Date of last renewal: 07.08.2018

10. DATE OF REVISION OF THE TEXT

PRODUCT CHARACTERISTICS

• 14.12.2023