ACTELSAR HCT 80mg / 25mg tablets medication leaflet

Actelsar HCT 80 mg/25 mg tablets

Each tablet contains 80 mg telmisartan and 25 mg hydrochlorothiazide.

For the full list of excipients, see section 6.1.

Tablet.

Actelsar HCT 80 mg/25 mg tablets are white or almost white, 9.0 x 17.0 mm oval-shaped andbiconvex tablets marked with “TH” on one side and “25” on the other side.

Treatment of essential hypertension.

Actelsar HCT fixed dose combination (80 mg telmisartan/25 mg hydrochlorothiazide) is indicated inadults whose blood pressure is not adequately controlled on Actelsar HCT 80 mg/12.5 mg(80 mg telmisartan/12.5 mg hydrochlorothiazide) or adults who have been previously stabilised ontelmisartan and hydrochlorothiazide given separately.

Actelsar HCT should be taken in patients whose blood pressure is not adequately controlled bytelmisartan alone. Individual dose titration with each of the two components is recommended beforechanging to the fixed dose combination. When clinically appropriate, direct change from monotherapyto the fixed combination may be considered.

- Actelsar HCT 80 mg/25 mg may be administered once daily in patients whose blood pressure isnot adequately controlled by Actelsar HCT 80 mg/12.5 mg or in patients who have beenpreviously stabilised on telmisartan and hydrochlorothiazide given separately.

Actelsar HCT is also available at the dose strengths 40 mg/12.5 mg and 80 mg/12.5 mg

Experience in patients with mild to moderate renal impairment is modest but has not suggestedadverse renal effects and dose adjustment is not considered necessary. Periodic monitoring of renalfunction is advised (see section 4.4). Due to the hydrochlorothiazide component, the fixed dosecombination is contraindicated in patients with severe renal impairment (creatinine clearance< 30 mL/min) (see section 4.3).

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

In patients with mild to moderate hepatic impairment Actelsar HCT should be administered withcaution. For telmisartan, the posology should not exceed 40 mg once daily. Actelsar HCT iscontraindicated in patients with severe hepatic impairment (see section 4.3). Thiazides should be usedwith caution in patients with impaired hepatic function (see section 4.4).

No dose adjustment is necessary for elderly patients.

The safety and efficacy of Actelsar HCT has not been established in patients aged below 18 years. Useof Actelsar HCT is not recommended in children and adolescents.

Actelsar HCT tablets are for once-daily oral administration and should be swallowed whole withliquid. Actelsar HCT tablets can be taken with or without food.

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- Hypersensitivity to other sulphonamide-derived substances (since hydrochlorothiazide is asulphonamide-derived medicinal product).

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

- Cholestasis and biliary obstructive disorders.

- Severe hepatic impairment.

- Severe renal impairment (creatinine clearance <30 mL/min), anuria.

- Refractory hypokalaemia, hypercalcaemia.

The concomitant use of Actelsar HCT with aliskiren-containing products is contraindicated in patientswith diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.5 and 5.1).

Angiotensin II receptor blockers should not be initiated during pregnancy. Unless continuedangiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should bechanged to alternative antihypertensive treatments which have an established safety profile for use inpregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should bestopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and4.6).

Actelsar HCT must not be given to patients with cholestasis, biliary obstructive disorders or severehepatic insufficiency (see section 4.3) since telmisartan is mostly eliminated in the bile. These patientscan be expected to have reduced hepatic clearance for telmisartan.

In addition, Actelsar HCT should be used with caution in patients with impaired hepatic function orprogressive liver disease, since minor alterations of fluid and electrolyte balance may precipitatehepatic coma. There is no clinical experience with Actelsar HCT in patients with hepatic impairment.

Renovascular hypertension

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

Actelsar HCT must not be used in patients with severe renal impairment (creatinine clearance<30 mL/min) (see section 4.3). There is no experience regarding the administration oftelmisartan/hydrochlorothiazide in patients with recent kidney transplantation. Experience withtelmisartan/hydrochlorothiazide is modest in the patients with mild to moderate renal impairment,therefore periodic monitoring of potassium, creatinine and uric acid serum levels is recommended.

Thiazide diuretic associated azotaemia may occur in patients with impaired renal function.

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

Volume and/or sodium depleted patients

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/orsodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Suchconditions, especially volume and/or sodium depletion, should be corrected before the administrationof Actelsar HCT.

Isolated cases of hyponatraemia accompanied by neurological symptoms (nausea, progressivedisorientation, apathy) have been observed with the use of HCTZ.

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers oraliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (includingacute 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 specialistsupervision 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 withdiabetic 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 renaldisease, including renal artery stenosis), treatment with medicinal products that affect this system hasbeen associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (seesection 4.8).

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal productsacting through inhibition of the renin-angiotensin system. Therefore, the use of Actelsar HCT is notrecommended.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor blockers (seesection 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea.

Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedemais diagnosed, telmisartan/hydrochlorothiazide should be discontinued and appropriate monitoringshould be initiated until complete resolution of symptoms has occurred.

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

Thiazide therapy may impair glucose tolerance, whereas hypoglycaemia may occur in diabetic patientsunder insulin or antidiabetic therapy and telmisartan treatment. Therefore, in these patients bloodglucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may berequired, when indicated. Latent diabetes mellitus may become manifest during thiazide therapy.

An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy;however, at the 12.5 mg dose contained in Actelsar HCT, minimal or no effects were reported.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazidetherapy.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should beperformed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (includinghypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyteimbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain orcramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such asnausea or vomiting (see section 4.8).

- Hypokalaemia

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy withtelmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patientswith cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequateoral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or

Adrenocorticotropic hormone (ACTH) (see section 4.5).

- Hyperkalaemia

Conversely, due to the antagonism of the angiotensin II (AT1) receptors by the telmisartan componentof Actelsar HCT, hyperkalaemia might occur. Although clinically significant hyperkalaemia has notbeen documented with Actelsar HCT, risk factors for the development of hyperkalaemia include renalinsufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassiumsupplements or potassium-containing salt substitutes should be co-administered cautiously with

Actelsar HCT (see section 4.5).

- Hypochloraemic alkalosis

Chloride deficit is generally mild and usually does not require treatment.

- Hypercalcaemia

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation ofserum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemiamay be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying outtests for parathyroid function.

- Hypomagnesaemia

Thiazides have been shown to increase the urinary excretion of magnesium, which may result inhypomagnesaemia (see section 4.5).

Ethnic differences

As with all other angiotensin II receptor blockers, telmisartan is apparently less effective in loweringblood pressure in black patients than in non blacks, possibly because of higher prevalence of low reninstates in the black hypertensive population.

Ischaemic heart disease

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

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history ofallergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation oractivation of systemic lupus erythematosus has been reported with the use of thiazide diuretics,including hydrochlorothiazide.

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If aphotosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If are-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas tothe sun or to artificial UVA.

Choroidal effusion, acute Myopia and Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidaleffusion with visual field defect, acute transient myopia and acute angle-closure glaucoma. Symptomsinclude acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeksof telmisartan hydrochlorothiazide initiation. Untreated acute angle-closure glaucoma can lead topermanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly aspossible. Prompt medical or surgical treatments may need to be considered if the intraocular pressureremains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a historyof sulfonamide or penicillin allergy.

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamouscell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure hasbeen observed in two epidemiological studies based on the Danish National Cancer Registry (seesection 4.8). Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check theirskin for any new lesions and promptly report any suspicious skin lesions. Possible preventivemeasures such as limited exposure to sunlight and UV rays and, in case of exposure, adequateprotection should be advised to the patients in order to minimize the risk of skin cancer. Suspiciousskin lesions should be promptly examined potentially including histological examinations of biopsies.

The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC(see also section 4.8).

Acute respiratory toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome(ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically developswithin minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea,fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Actelsar HCTshould be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administeredto patients who previously experienced ARDS following hydrochlorothiazide intake.

Excipient(s)

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

Reversible increases in serum lithium concentrations and toxicity have been reported duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases havealso been reported with angiotensin II receptor blockers (including telmisartan/hydrochlorothiazide).

Co-administration of lithium and Actelsar HCT is not recommended (see section 4.4). If thiscombination proves essential, careful monitoring of serum lithium level is recommended duringconcomitant use.

Medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics,laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid andderivatives)

If these substances are to be prescribed with the hydrochlorothiazide-telmisartan combination,monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effectof hydrochlorothiazide on serum potassium (see section 4.4).

Iodinated contrast products

In the event of dehydration caused by diuretics, there is an increased risk of acute functional renalfailure, particularly during use of high doses of iodinated contrast products. Rehydration beforeadministration of the iodinated product is required.

Medicinal products that may increase potassium levels or induce hyperkalaemia (e.g. ACE inhibitors,potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporinor other medicinal products such as heparin sodium).

If these medicinal products are to be prescribed with the hydrochlorothiazide-telmisartan combination,monitoring of potassium plasma levels is advised. Based on the experience with the use of othermedicinal products that blunt the renin-angiotensin system, concomitant use of the above medicinalproducts may lead to increases in serum potassium and is, therefore, not recommended (see section4.4).

Periodic monitoring of serum potassium and ECG is recommended when Actelsar HCT isadministered with medicinal products affected by serum potassium disturbances (e.g. digitalisglycosides, antiarrhythmics) and the following torsades de pointes inducing medicinal products (whichinclude some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes.

- class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)

- class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)

- some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine,cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)

- others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin,pentamidine, sparfloxacine, terfenadine, vincamine IV)

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia favours the onset of digitalis-inducedarrhythmia (see section 4.4).

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

Other antihypertensive agents

Telmisartan may increase the hypotensive effect of other antihypertensive agents.

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 associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting agent (seesections pct. 4.3, pct. 4.4 and 5.1).

Antidiabetic medicinal products (oral agents and insulin)

Dose adjustment of the antidiabetic medicinal products may be required (see section 4.4).

Metformin should be used with precaution: risk of lactic acidosis induced by a possible functionalrenal failure linked to hydrochlorothiazide.

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

Non-steroidal anti-inflammatory medicinal products (NSAIDs)

NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dose regimens, COX-2 inhibitors andnon-selective NSAIDs) may reduce the diuretic, natriuretic and antihypertensive effects of thiazidediuretics and the antihypertensive effects of angiotensin II receptor blockers.

In some patients with compromised renal function (e.g. dehydrated patients or elderly patients withcompromised renal function) the co-administration of angiotensin II receptor blockers and agents thatinhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acuterenal failure, which is usually reversible. Therefore the combination should be administered withcaution, especially in the elderly. Patients should be adequately hydrated and consideration should begiven to monitoring of renal function after initiation of concomitant therapy and periodicallythereafter.

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.

Pressor amines (e.g. noradrenaline)

The effect of pressor amines may be decreased.

Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine)

The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Medicinal products used in the treatment for gout (e.g. probenecid, sulfinpyrazone and allopurinol)

Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raisethe level of serum uric acid. Increase in dose of probenecid or sulfinpyrazone may be necessary.

Co-administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.

Calcium salts

Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If calciumsupplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be prescribed, serumcalcium levels should be monitored and calcium dose adjusted accordingly.

Beta-blockers and diazoxide

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-typediuretics by decreasing gastrointestinal motility and stomach emptying rate.

Thiazides may increase the risk of adverse events caused by amantadine.

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate theirmyelosuppressive effects.

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

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

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

There are no adequate data from the use of Actelsar HCT in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in riskcannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin IIreceptor blockers, similar risks may exist for this class of medicinal products. Unless continuedangiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should bechanged to alternative antihypertensive treatments which have an established safety profile for use inpregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should bestopped immediately, and if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor blocker therapy during the second and third trimesters is known toinduce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation)and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure toangiotensin II receptor blockers have occurred from the second trimester of pregnancy, ultrasoundcheck of renal function and skull is recommended.

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

There is limited experience with hydrochlorothiazide during pregnancy, especially during the firsttrimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on thepharmacological mechanism of action of hydrochlorothiazide its use during the second and thirdtrimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects likeicterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not beused for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreasedplasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in raresituations where no other treatment could be used.

Because no information is available regarding the use of telmisartan during breast-feeding, Actelsar

HCT is not recommended and alternative treatments with better established safety profiles duringbreast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causingintense diuresis can inhibit the milk production. The use of hydrochlorothiazide during breast feedingis not recommended. If hydrochlorothiazide is used during breast-feeding, doses should be kept as lowas possible.

No studies on fertility in humans with the fixed dose combination or with the individual componentshave been performed.

In preclinical studies, no effects of telmisartan and hydrochlorothiazide on male and female fertilitywere observed.

Actelsar HCT can have influence on the ability to drive and use machines. Dizziness, syncope orvertigo may occasionally occur when taking antihypertensive therapy such as Actelsar HCT.

If patients experience these adverse events, they should avoid potentially hazardous tasks such asdriving or operating machinery.

The most commonly reported adverse reaction is dizziness. Serious angioedema may occur rarely(≥1/10 000 to <1/1 000).

The overall incidence and pattern of adverse reactions reported with telmisartan/hydrochlorothiazide80 mg/25 mg was comparable with telmisartan/hydrochlorothiazide 80 mg/12.5 mg. A dose-relationship of adverse reaction was not established and they showed no correlation with gender, ageor race of the patients.

Adverse reactions reported in all clinical trials and occurring more frequently (p≤0.05) withtelmisartan plus hydrochlorothiazide than with placebo are shown below according to system organclass. Adverse reactions known to occur with each component given singly but which have not beenseen in clinical trials may occur during treatment with Actelsar HCT.

Adverse reactions previously reported with one of the individual components may be potential adversereactions with Actelsar HCT, even if not observed in clinical trials with this product.

Adverse reactions have been ranked under headings of frequency using the following convention: verycommon (≥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), not known (cannot be estimated from the available data).

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

Table 1: Tabulated list of adverse reactions (MedDRA) from placebo-controlled studies and frompost-marketing experience

MedDRA Adverse Reactions Frequency

System Organ Actelsar

Class HCT Telmisartana Hydrochlorothiazide

Infections and Sepsis includinginfestations fatal outcome rare2

Bronchitis rare

Pharyngitis rare

Sinusitis rare

Upper respiratorytract infection uncommon

Urinary tractinfection uncommon

Cystitis uncommon

Neoplasms Non-melanomabenign, skin cancer (Basalmalignant and cell carcinoma andunspecified (incl. Squamous cellcysts and polyps) carcinoma) not known2

Blood and Anaemia uncommonlymphatic Eosinophilia raresystem disorders

Thrombocytopenia rare rare

Thrombocytopenicpurpura rare

Aplastic anaemia not known

Haemolyticanaemia very rare

Bone marrowfailure very rare

Leukopenia very rare

Agranulocytosis very rare

Immune system Anaphylacticdisorders reaction rare

Hypersensitivity rare very rare

Metabolism and Hypokalaemia uncommon very commonnutrition Hyperuricaemia rare commondisorders

Hyponatraemia rare rare common

Hyperkalaemia uncommon

Hypoglycaemia (indiabetic patients) rare

Hypomagnesaemia common

Hypercalcaemia rare

Alkalosishypochloraemic very rare

Decreased appetite common

Hyperlipidaemia very common

Hyperglycaemia rare

Diabetes mellitusinadequate control rare

Psychiatric Anxiety uncommon raredisorders Depression rare uncommon rare

Insomnia rare uncommon

Sleep disorders rare rare

Nervous system Dizziness common raredisorders Syncope uncommon uncommon

Paraesthesia uncommon rare

Somnolence rare

Headache rare

Eye disorders Visual impairment rare rare rare

Vision blurred rare

Acute angle closureglaucoma not known

Choroidal effusion not known

Ear andlabyrinthdisorders Vertigo uncommon uncommon

Cardiac Tachycardia uncommon raredisorders Arrhythmias uncommon rare

Bradycardia uncommon

Vascular Hypotension uncommon uncommondisorders Orthostatichypotension uncommon uncommon common

Vasculitisnecrotising very rare

Respiratory, Dyspnoea uncommon uncommonthoracic and Respiratory distress rare very raremediastinal Pneumonitis rare very raredisorders Pulmonaryoedema rare very rare

Cough uncommon

Interstitial lungdisease very rare1,2

Acute respiratorydistress syndrome(ARDS)(see section 4.4) very rare

Gastrointestinal Diarrhoea uncommon uncommon commondisorders Dry mouth uncommon rare

Flatulence uncommon uncommon

Abdominal pain rare uncommon

Constipation rare rare

Dyspepsia rare uncommon

Vomiting rare uncommon common

Gastritis rare

Abdominaldiscomfort rare rare

Nausea common

Pancreatitis very rare

Hepatobiliary Abnormal hepaticdisorders function/liverdisorder rare2 rare2

Jaundice rare

Cholestasis rare

Skin and Angioedemasubcutaneous (including fataltissue disorders outcome) rare rare

Erythema rare rare

Pruritus rare uncommon

Rash rare uncommon common

Hyperhidrosis rare uncommon

Urticaria rare rare common

Eczema rare

Drug eruption rare

Toxic skin eruption rare

Lupus-likesyndrome very rare

Photosensitivityreaction rare

Toxic epidermalnecrolysis very rare

Erythemamultiforme not known

Muscoloskeletal, Back pain uncommon uncommonconnective tissue Muscle spasmsand bone (cramps in leg) uncommon uncommon not knowndisorders Myalgia uncommon uncommon

Arthralgia rare rare

Pain in extremity(leg pain) rare rare

Tendon pain(tendonitis-likesymptoms) rare

Systemic lupuserythematosus rare1 very rare

Renal and Renal impairment uncommon not knownurinary Acute renal failure uncommon uncommondisorders Glucosuria rare

Reproductivesystem andbreast disorders Erectile dysfunction uncommon common

General Chest pain uncommon uncommondisorders and Influenza-likeadministration illness rare raresite conditions Pain rare

Asthenia(weakness) uncommon not known

Pyrexia not known

Investigations Blood uric acidincreased uncommon rare

Blood creatinineincreased rare uncommon

Blood creatinephosphokinaseincreased rare rare

Hepatic enzymeincreased rare rare

Haemoglobindecreased rare1 Based on post-marketing experience2 See subsections below for additional informationa Adverse reactions occurred with similar frequency in placebo and telmisartan treated patients. Theoverall incidence of adverse reactions reported with telmisartan (41.4%) was usually comparable toplacebo (43.9%) in placebo controlled trials. The adverse reactions listed above have been accumulatedfrom all clinical trials in patients treated with telmisartan for hypertension or in patients 50 years orolder at high risk of cardiovascular events.

Hepatic function abnormal/liver disorder

Most cases of hepatic function abnormal/liver disorder from post-marketing experience withtelmisartan occurred in Japanese patients. Japanese patients are more likely to experience theseadverse reactions.

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

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

Based on available data from epidemiological studies, cumulative dose-dependent association between

HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited information available for telmisartan with regard to overdose in humans. The degreeto which hydrochlorothiazide is removed by haemodialysis has not been established.

The most prominent manifestations of telmisartan overdose were hypotension and tachycardia;bradycardia, dizziness, vomiting, increase in serum creatinine, and acute renal failure have also beenreported. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia,hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs andsymptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/oraccentuate arrhythmia associated with the concomitant use of digitalis glycosides or certainanti-arrhythmic medicinal products.

Telmisartan is not removed by haemofiltration and is not dialysable. The patient should be closelymonitored, and the treatment should be symptomatic and supportive. Management depends on thetime since ingestion and the severity of the symptoms. Suggested measures include induction ofemesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serumelectrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient shouldbe placed in a supine position, with salt and volume replacements given quickly.

Pharmacotherapeutic group: Angiotensin II receptor blockers (ARBs) and diuretics, ATC code:

C09DA07

Actelsar HCT is a combination of an angiotensin II receptor blocker, telmisartan, and a thiazidediuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensiveeffect, reducing blood pressure to a greater degree than either component alone. Actelsar HCT oncedaily produces effective and smooth reductions in blood pressure across the therapeutic dose range.

Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (AT1) blocker.

Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptorsubtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit anypartial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. Thebinding is long-lasting. Telmisartan does not show affinity for other receptors, including AT2 andother less characterised AT receptors. The functional role of these receptors is not known, nor is theeffect 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 plasmarenin 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 potentiatebradykinin-mediated adverse events.

An 80 mg dose of telmisartan administered to healthy volunteers almost completely inhibits theangiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours andstill measurable up to 48 hours.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazidediuretics is not fully known. Thiazides have an effect on the renal tubular mechanisms of electrolytereabsorption, directly increasing excretion of sodium and chloride in approximately equivalentamounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma reninactivity, increases aldosterone secretion, with consequent increases in urinary potassium andbicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of telmisartan tends to reverse the potassium lossassociated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peakeffect occurs at about 4 hours, while the action persists for approximately 6-12 hours.

Treatment of essential hypertension

After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within3 hours. The maximum reduction in blood pressure is generally attained 4-8 weeks after the start oftreatment and is sustained during long-term therapy. The antihypertensive effect persists constantlyover 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatoryblood pressure measurements. This is confirmed by measurements made at the point of maximumeffect and immediately prior to the next dose (through to peak ratios consistently above 80% afterdoses of 40 and 80 mg of telmisartan in placebo controlled clinical studies).

In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure withoutaffecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of agentsrepresentative of other classes of antihypertensive medicinal products (demonstrated in clinical trialscomparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).

In a double-blind controlled clinical trial (n = 687 patients evaluated for efficacy) in non-respondersto the 80 mg/12.5 mg combination, an incremental blood pressure lowering effect of the 80 mg/25 mgcombination compared to continued treatment with the 80 mg/12.5 mg combination of 2.7/1.6 mm Hg(SBP/DBP) was demonstrated (difference in adjusted mean changes from baseline). In a follow-uptrial with the 80 mg/25 mg combination, blood pressure was further decreased (resulting in an overallreduction of 11.5/9.9 mm Hg (SBP/DBP).

In a pooled analysis of two similar 8 week double-blind placebo-controlled clinical trials vs.valsartan/hydrochlorothiazide 160 mg/25 mg (n = 2 121 patients evaluated for efficacy) a significantlygreater blood pressure lowering effect of 2.2/1.2 mm Hg (SBP/DBP) was demonstrated (difference inadjusted mean changes from baseline, respectively) in favour of telmisartan/hydrochlorothiazide80 mg/25 mg combination.

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

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

Cardiovascular prevention

ONTARGET (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial)compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril oncardiovascular outcomes in 25 620 patients aged 55 years or older with a history of coronary arterydisease, stroke, TIA, peripheral arterial disease, or type 2 diabetes mellitus accompanied by evidenceof end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria),which is a population at risk for cardiovascular events.

Patients were randomized to one of the three following treatment groups: telmisartan 80 mg(n = 8 542), ramipril 10 mg (n = 8 576), or the combination of telmisartan 80 mg plus ramipril 10 mg(n = 8 502), and followed for a mean observation time of 4.5 years.

Telmisartan showed a similar effect to ramipril in reducing the primary composite endpoint ofcardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization forcongestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7%)and ramipril (16.5%) groups. The hazard ratio for telmisartan vs. ramipril was 1.01 (97.5% CI0.93-1.10, p (non-inferiority) = 0.0019 at a margin of 1.13). The all-cause mortality rate was 11.6%and 11.8% among telmisartan and ramipril treated patients, respectively.

Telmisartan was found to be similarly effective to ramipril in the pre-specified secondary endpoint ofcardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [0.99 (97.5% CI 0.90-1.08),p (non-inferiority) = 0.0004], the primary endpoint in the reference study HOPE (The Heart Outcomes

Prevention Evaluation Study), which had investigated the effect of ramipril vs. placebo.

TRANSCEND randomized ACE-I intolerant patients with otherwise similar inclusion criteria as

ONTARGET to telmisartan 80 mg (n = 2 954) or placebo (n = 2 972), both given on top of standardcare. The mean duration of follow up was 4 years and 8 months. No statistically significant differencein the incidence of the primary composite endpoint (cardiovascular death, non-fatal myocardialinfarction, non-fatal stroke, or hospitalization for congestive heart failure) was found [15.7% in thetelmisartan and 17.0% in the placebo groups with a hazard ratio of 0.92 (95% CI 0.81-1.05, p=0.22)].

There was evidence for a benefit of telmisartan compared to placebo in the pre-specified secondarycomposite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke[0.87 (95% CI 0.76-1.00, p=0.048)]. There was no evidence for benefit on cardiovascular mortality(hazard ratio 1.03, 95% CI 0.85-1.24).

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and incombination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs

Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with anangiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovasculardisease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. For more detailedinformation see above under the heading “Cardiovascular prevention”.

VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

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

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

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

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

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

In the “Prevention Regimen For Effectively avoiding Second Strokes” (PRoFESS) trial in patients50 years and older, who recently experienced stroke, an increased incidence of sepsis was noted fortelmisartan compared with placebo, 0.70% vs. 0.49% [RR 1.43 (95% confidence interval 1.00-2.06)];the incidence of fatal sepsis cases was increased for patients taking telmisartan (0.33%) vs. patientstaking placebo (0.16%) [RR 2.07 (95% confidence interval 1.14-3.76)]. The observed increasedoccurrence rate of sepsis associated with the use of telmisartan may be either a chance finding orrelated to a mechanism not currently known.

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces therisk of cardiovascular mortality and morbidity.

The effects of fixed dose combination of telmisartan/HCT on mortality and cardiovascular morbidityare currently unknown.

Based on available data from epidemiological studies, cumulative dose-dependent association between

HCTZ and NMSC has been observed. One study included a population comprised of 71 533 cases of

BCC and of 8 629 cases of SCC matched to 1 430 833 and 172 462 population controls, respectively.

High HCTZ use (≥50 000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationshipwas observed for both BCC and SCC. Another study showed a possible association between lip cancer(SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63 067 population controls,using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with anadjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25 000 mg) and OR7.7 (5.7-10.5) for the highest cumulative dose (~100 000 mg) (see also section 4.4).

The European Medicines Agency has waived the obligation to submit the results of studies withtelmisartan hydrochlorothiazide in all subsets of the paediatric population in hypertension (see section4.2 for information on paediatric use).

Concomitant administration of hydrochlorothiazide and telmisartan does not appear to affect thepharmacokinetics of either substance in healthy subjects.

Telmisartan: Following oral administration, peak concentrations of telmisartan are reached in 0.5-1.5 hafter dosing. The absolute bioavailability of telmisartan at 40 mg and 160 mg was 42% and 58%,respectively. Food slightly reduces the bioavailability of telmisartan with a reduction in the area underthe plasma concentration time curve (AUC) of about 6% with the 40 mg tablet and about 19% after a160 mg dose. By 3 hours after administration plasma concentrations are similar whether telmisartan istaken fasting or with food. The small reduction in AUC is not expected to cause a reduction in thetherapeutic efficacy. Telmisartan does not accumulate significantly in plasma on repeatedadministration.

Hydrochlorothiazide: Following oral administration of telmisartan/hydrochlorothiazide, peakconcentrations of hydrochlorothiazide are reached in approximately 1.0-3.0 hours after dosing. Basedon cumulative renal excretion of hydrochlorothiazide the absolute bioavailability was about 60%.

Telmisartan is highly bound to plasma proteins (>99.5%) mainly albumin and alpha l-acidglycoprotein. The apparent volume of distribution for telmisartan is approximately 500 litresindicating additional tissue binding.

Hydrochlorothiazide is 64% protein bound in the plasma and its apparent volume of distribution is0.8±0.3 L/kg.

Telmisartan is metabolised by conjugation to form a pharmacologically inactive acylglucuronide. Theglucuronide of the parent compound is the only metabolite that has been identified in humans. After asingle dose of 14C-labelled telmisartan the glucuronide represents approximately 11% of the measuredradioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism oftelmisartan.

Hydrochlorothiazide is not metabolised in man.

Telmisartan: Following either intravenous or oral administration of 14C-labelled telmisartan most ofthe administered dose (>97%) was eliminated in faeces via biliary excretion. Only minute amountswere found in urine. Total plasma clearance of telmisartan after oral administration is >1 500 mL/min.

Terminal elimination half-life was >20 hours.

Hydrochlorothiazide is excreted almost entirely as unchanged substance in urine. About 60% of theoral dose is eliminated within 48 hours. Renal clearance is about 250-300 mL/min. The terminalelimination half-life of hydrochlorothiazide is 10-15 hours.

Telmisartan: The pharmacokinetics of orally administered telmisartan are non-linear over doses from20-160 mg with greater than proportional increases of plasma concentrations (Cmax and AUC) withincreasing doses. Telmisartan does not accumulate significantly in plasma on repeated administration.

Hydrochlorothiazide exhibits linear pharmacokinetics.

Pharmacokinetics of telmisartan do not differ between the elderly and younger patients.

Plasma concentrations of telmisartan are generally 2-3 times higher in females than in males. Inclinical trials however, no significant increases in blood pressure response or in the incidence oforthostatic hypotension were found in women. No dose adjustment is necessary. There was a trendtowards higher plasma concentrations of hydrochlorothiazide in female than in male subjects. This isnot considered to be of clinical relevance.

Lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis.

Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed bydialysis. The elimination half-life is not changed in patients with renal impairment.

In patients with impaired renal function the rate of hydrochlorothiazide elimination is reduced. In atypical study in patients with a mean creatinine clearance of 90 mL/min the elimination half-life ofhydrochlorothiazide was increased. In functionally anephric patients the elimination half-life is about34 hours.

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

No additional preclinical studies have been performed with the Fixed Dose Combination product80 mg/25 mg. Previous preclinical safety studies performed with co-administration of telmisartan andhydrochlorothiazide in normotensive rats and dogs, in doses producing exposure comparable to that inthe clinical therapeutic range, caused no additional findings not already observed with administrationof either substance alone. The toxicological findings observed appear to have no relevance to humantherapeutic use.

Toxicological findings also well known from preclinical studies with angiotensin converting enzymeinhibitors and angiotensin II receptor blockers were: a reduction of red cell parameters (erythrocytes,haemoglobin, haematocrit), changes of renal haemodynamics (increased blood urea nitrogen andcreatinine), increased plasma renin activity, hypertrophy/hyperplasia of the juxtaglomerular cells andgastric mucosal injury. Gastric lesions could be prevented/ameliorated by oral saline supplementationand group housing of animals. In dogs renal tubular dilation and atrophy were observed. Thesefindings are considered to be due to the pharmacological activity of telmisartan. No effects oftelmisartan on male or female fertility were observed.

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

Telmisartan showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studiesand no evidence of carcinogenicity in rats and mice. Studies with hydrochlorothiazide have shownequivocal evidence for a genotoxic or carcinogenic effect in some experimental models.

For the foetotoxic potential of the telmisartan/hydrochlorothiazide combination see section 4.6.

Magnesium stearate (E470b)

Potassium hydroxide

Meglumine

Povidone

Sodium starch glycolate (type A)

Microcrystalline cellulose

Mannitol (E421)

Not applicable.

For Al/Al blisters and HDPE tablet container:2 years.

For Al/PVC/PVDC blister:1 year.

Al/Al blisters and HDPE tablet container:

This medicinal product does not require any special storage conditions.

Al/PVC/PVDC blister:

Do not store above 30ºC.

Al/Al blister, Al/PVC/PVDC blister and HDPE tablet container with LDPE cap and HDPE desiccantwith silica filling.

Al/Al blister: 14, 28, 30, 56, 84, 90 and 98 tablets

Al/PVC/PVDC blister: 28, 56, 84, 90 and 98 tablets

Tablet container: 30, 90 and 250 tablets

Not all pack sizes may be marketed.

No special requirements.

Actavis Group PTC ehf.

Dalshraun 1220 Hafnarfjörður

Iceland

EU/1/13/817/045

EU/1/13/817/029

EU/1/13/817/046

EU/1/13/817/030

EU/1/13/817/031

EU/1/13/817/032

EU/1/13/817/033

EU/1/13/817/034

EU/1/13/817/035

EU/1/13/817/036

EU/1/13/817/037

EU/1/13/817/038

EU/1/13/817/039

EU/1/13/817/040

EU/1/13/817/041

Date of first authorisation: 13 March 2013

Date of latest renewal: 15 December 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.