Product Index

For the use of a registered Medical practitioner or a hospital or a laboratory only

Black Box Warning

Fetal Toxicity When pregnancy is detected, discontinue Telmisartan/Hydrochlorothiazide as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing foetus.

Qualitative and Quantitative Composition

CRESAR H

Each tablet contains:

Telmisartan…………………… 40 mg

Hydrochlorothiazide…………. 12.5 mg

CRESAR 80 H

Each tablet contains:

Telmisartan …………………….80 mg

Hydrochlorothiazide…………. 12.5 mg

Dosage Form(S) and Strength(S)

Tablet, Telmisartan/Hydrochlorothiazide 40/12.5 mg

Tablet, Telmisartan/Hydrochlorothiazide 80/12.5 mg

Clinical Particulars

Therapeutic Indications

CRESAR H / CRESAR 80 H (telmisartan and hydrochlorothiazide) tablets are indicated for the treatment of hypertension as second line therapy. This fixed dose combination is not indicated for initial therapy for the treatment of hypertension.

Posology and Method of Administration

Posology

General

CRESAR H / CRESAR 80 H should be taken in patients whose blood pressure is not adequately controlled by telmisartan alone. Individual dose titration with each of the two components is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

CRESAR H may be administered once daily in patients whose blood pressure is not adequately controlled by telmisartan 40 mg

CRESAR 80 H may be administered once daily in patients whose blood pressure is not adequately controlled by telmisartan 80 mg.

Special Populations

Dose Adjustment for Renal Impairment

Safety and effectiveness of CRESAR H / CRESAR 80 H in patients with severe renal impairment (creatinine clearance ≤30 mL/min) have not been established. In patients with severe renal impairment, CRESAR H / CRESAR 80 H tablets are not recommended.

No dose adjustment is required in patients with mild (creatinine clearance 60 to 90 mL/min) or moderate (creatinine clearance 30 to 60 mL/min) renal impairment.

Dose Adjustment for Hepatic Impairment

Initiate patients with biliary obstructive disorders or hepatic insufficiency under close medical supervision using the 40 mg/12.5 mg combination. CRESAR H/ CRESAR 80 H tablets are not recommended for patients with severe hepatic impairment.

Elderly Patients

No dose adjustment is necessary.

Paediatric Population

The safety and efficacy of CRESAR H / CRESAR 80 H in children and adolescents aged below 18 have not been established. No data are available.

Method of Administration

CRESAR H / CRESAR 80 H tablets are for once-daily oral administration and should be taken with liquid, with or without food.

Contraindications

• Patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, hydrochlorothiazide, or any other component of this product.
• Hypersensitivity to other sulfonamide-derived substances (Since hydrochlorothiazide sulfonamide-derived medicinal product.
• Patients with anuria
• Second and third trimesters of pregnancy
• Cholestasis and biliary obstructive disorders
• Severe hepatic impairment
• Severe renal impairment (creatinine clearance <30 ml/min)
• Refractory hypokalaemia, hypercalcemia
• Do not co-administer aliskiren with CRESAR H/ CRESAR 80 H in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²)

Special Warnings and Precautions for use

Pregnancy

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

Hepatic Impairment

CRESAR H / CRESAR 80 H should not be given to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan. In addition, CRESAR H / CRESAR 80 H should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with telmisartan/hydrochlorothiazide in patients with hepatic impairment.

Renovascular Hypertension

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

Renal Impairment and Kidney Transplantation

CRESAR H / CRESAR 80 H must not be used in patients with severe renal impairment (creatinine clearance <30 ml/min). There is no experience regarding the administration of telmisartan/hydrochlorothiazide in patients with recent kidney transplantation. Experience with telmisartan/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.

Intravascular Hypovolaemia

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, and diarrhoea or vomiting. Such conditions should be corrected before the administration of CRESAR / CRESAR 80 H.

Dual Blockade of the Renin-angiotensin-aldosterone System (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Other Conditions with Stimulation of the Renin-angiotensin-aldosterone System

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

Primary Aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of CRESAR H / CRESAR 80 H is not recommended.

Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy

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

Metabolic and Endocrine Effects

Thiazide therapy may impair glucose tolerance, whereas hypoglycaemia may occur in diabetic patients under insulin or antidiabetic therapy and telmisartan treatment. Therefore, in these patients blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required, 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 telmisartan/hydrochlorothiazide, minimal or no effects were reported. Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte Imbalance

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

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Hypokalaemia

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).

Hyperkalaemia

Conversely, due to the antagonism of the angiotensin II (AT1) receptors by the telmisartan component of CRESAR H / CRESAR 80 H, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not been documented with telmisartan/hydrochlorothiazide, risk factors for the development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be co-administered cautiously with CRESAR H / CRESAR 80 H.

Hyponatraemia and Hypochloraemic Alkalosis

There is no evidence that CRESAR H / CRESAR 80 H would reduce or prevent diuretic-induced hyponatraemia. 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 of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Hypomagnesaemia

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Ethnic differences

As with all other angiotensin II receptor antagonists, telmisartan is apparently less effective in lowering blood pressure in black patients than in non-blacks, possibly because of higher prevalence of low renin states in the black hypertensive population.

Other

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

General

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation 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. If a photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Choroidal Effusion, Acute Myopia and Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of telmisartan hydrochlorothiazide 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.

Non-melanoma Skin Cancer

An increased risk of non-melanoma skin cancer (NMSC) with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. 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 their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin 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.

Drug Interactions

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). Co-administration of lithium and telmisartan/hydrochlorothiazide is not recommended. If this combination proves essential, careful monitoring of serum lithium level is recommended during concomitant use.

Medicinal Products Associated with Potassium Loss and Hypokalaemia (e.g. Other Kaliuretic Diuretics, Laxatives, Corticosteroids, ACTH, Amphotericin, Carbenoxolone, Penicillin G Sodium, Salicylic Acid and Derivatives)

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 effect of hydrochlorothiazide on serum potassium.

Medicinal Products that may Increase Potassium Levels or Induce Hyperkalaemia (e.g. ACE Inhibitors, Potassium-sparing Diuretics, Potassium Supplements, Salt Substitutes Containing Potassium, Cyclosporin or 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 other medicinal products that blunt the renin-angiotensin system, concomitant use of the above medicinal products may lead to increases in serum potassium and is, therefore, not recommended.

Medicinal Products Affected by Serum Potassium Disturbances

Periodic monitoring of serum potassium and ECG is recommended when CRESAR H / CRESAR 80 H is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the following torsades de pointes inducing medicinal products (which include 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-induced arrhythmia.

Digoxin

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

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 associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.

Antidiabetic Medicinal Products (Oral Agents And Insulin)

Dose adjustment of the antidiabetic medicinal products may be required.

Metformin

Metformin should be used with precaution: risk of lactic acidosis induced by a possible functional renal 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 and non-selective NSAIDs) may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics and the antihypertensive effects of angiotensin II receptor antagonists. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated, and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

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

Non-depolarizing 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 raise the 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 calcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must be prescribed, serum calcium 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)

Anticholinergic agents may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Amantadine

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 their myelosuppressive effects.

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen, amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or antidepressants.

Use in Special Populations

Patients with Renal Impairment

Safety and effectiveness of on telmisartan/hydrochlorothiazide in patients with severe renal impairment (CrCl ≤30 mL/min) have not been established. In patients with severe renal impairment, on telmisartan/hydrochlorothiazide tablets are not recommended. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.

Patients with Hepatic Impairment

Patients with biliary obstructive disorders or hepatic insufficiency should initiate treatment under close medical supervision using the telmisartan/hydrochlorothiazide combination

Telmisartan

As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance and higher blood levels.

Hydrochlorothiazide

Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Telmisartan/hydrochlorothiazide tablets should therefore be used with caution in these patients.

Pregnant Women

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy.

There are no adequate data from the use of telmisartan/hydrochlorothiazide in pregnant women. Studies in animals have shown reproductive toxicity.

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 medicinal products. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and if appropriate, alternative therapy should be started.

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

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance 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 essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Lactating Women

Because no information is available regarding the use of telmisartan during breast-feeding, CRESAR H / CRESAR 80 H is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a new-born or preterm infant.

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

Paediatric Patients

Safety and effectiveness in paediatric patients have not been established.

Neonates with a History of In-Utero Exposure to Telmisartan and Hydrochlorothiazide Combination

If oliguria or hypotension occurs, attention should be directed towards support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Geriatric Patients

In the controlled clinical trials (n=1017), approximately 20% of patients treated with telmisartan/hydrochlorothiazide were 65 years of age or older, and 5% were 75 years of age or older. No overall differences in effectiveness and safety of telmisartan/hydrochlorothiazide were observed in these patients compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.

Fertility

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

Effects on Ability to Drive and Use Machines

CRESAR H / CRESAR 80 H can have influence on the ability to drive and use machines. Dizziness or drowsiness may occasionally occur when taking CRESAR H / CRESAR 80 H.

Undesirable Effects

Summary of the Safety Profile

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

The overall incidence of adverse reactions reported with telmisartan/hydrochlorothiazide was comparable to those reported with telmisartan alone in randomised controlled trials involving 1,471 patients randomised to receive telmisartan plus hydrochlorothiazide (835) or telmisartan alone (636). Dose-relationship of adverse reactions was not established and they showed no correlation with gender, age or race of the patients.

Tabulated List of Adverse Reactions

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

Adverse reactions have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

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

Infections and infestations
Rare:	Bronchitis, pharyngitis, sinusitis
Immune system disorders
Rare:	Exacerbation or activation of systemic lupus erythematosus1
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, sleep disorders
Eye disorders
Rare:	Visual disturbance, vision blurred
Ear and labyrinth disorders
Uncommon:	Vertigo
Cardiac disorders
Uncommon:	Tachycardia, arrhythmias
Vascular disorders
Uncommon:	Hypotension, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Rare:	Dyspnoea
Uncommon:	Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders
Uncommon:	Diarrhoea, dry mouth, flatulence
Rare:	Abdominal pain, constipation, dyspepsia, vomiting, gastritis
Hepatobiliary disorders
Rare:	Abnormal hepatic function/liver disorder2
Skin and subcutaneous tissue disorders
Rare:	Angioedema (also with fatal outcome), erythema, pruritus, rash, hyperhidrosis, urticarial
Musculoskeletal, connective tissue and bone disorders
Uncommon:	Back pain, muscle spasms, myalgia
Rare:	Arthralgia, muscle cramps, pain in limb
Reproductive system and breast disorders
Uncommon:	Erectile dysfunction
General disorders and administration site conditions
Uncommon:	Chest pain
Rare:	Influenza-like illness, pain
Investigations
Uncommon:	Blood uric acid increased
Rare:	Blood creatinine increased, blood creatine phosphokinase increased, hepatic enzyme increased

¹ Based on post-marketing experience

² For further description, please see sub-section “Description of selected adverse reactions”

Additional Information on Individual Components

Adverse reactions previously reported with one of the individual components may be potential adverse reactions with telmisartan plus hydrochlorothiazide, even if not observed in clinical trials with this product.

Telmisartan

Adverse reactions occurred with similar frequency in placebo and telmisartan treated patients. The overall incidence of adverse reactions reported with telmisartan (41.4%) was usually comparable to placebo (43.9%) in placebo controlled trials. The following adverse reactions listed below have been accumulated from all clinical trials in patients treated with telmisartan for hypertension or in patients 50 years or older at high risk of cardiovascular events.

Infections and infestations
Uncommon:	Upper respiratory tract infection, urinary tract infection including cystitis
Rare:	Sepsis including fatal outcome3
Blood and lymphatic system disorders
Uncommon:	Anaemia
Rare:	Eosinophilia, thrombocytopenia
Immune system disorders
Rare:	Hypersensitivity, anaphylactic reactions
Metabolism and nutrition disorders
Uncommon:	Hyperkalaemia
Rare:	Hypoglycaemia (in diabetic patients)
Cardiac disorders
Uncommon:	Bradycardia
Nervous system disorder
Rare:	Somnolence
Respiratory, thoracic and mediastinal disorders
Uncommon:	Cough
Very rare:	Interstitial lung disease3
Gastrointestinal disorders
Rare:	Stomach discomfort
Skin and subcutaneous tissue disorders
Rare:	Eczema, drug eruption, toxic skin eruption
Musculoskeletal, connective tissue and bone disorders
Rare:	Arthrosis, tendon pain
Renal and urinary disorders
Uncommon:	Renal impairment (including acute renal failure)
General disorders and administration site conditions
Uncommon:	Asthenia
Investigations
Rare:	Haemoglobin decreased

³ For further description, please see sub-section “Description of selected adverse reactions”.

Hydrochlorothiazide

Hydrochlorothiazide may cause or exacerbate hypovolaemia which could lead to electrolyte imbalance. Adverse reactions of unknown frequency reported with the use of hydrochlorothiazide alone include:

Infections and infestations
Not known:	Sialadenitis
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Not known:	Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)
Blood and lymphatic system disorders
Rare:	Thrombocytopenia (sometimes with purpura)
Not known:	Aplastic anaemia, haemolytic anaemia, bone marrow failure, leukopenia, neutropenia, agranulocytosis,
Immune system disorders
Not known:	Anaphylactic reactions, hypersensitivity
Endocrine disorders
Not known:	Diabetes mellitus inadequate control
Metabolism and nutrition disorders
Common:	Hypomagnesaemia
Rare:	Hypercalcaemia
Very rare:	Hypochloraemic alkalosis
Not known:	Anorexia, appetite decreased, electrolyte imbalance, hypercholesterolaemia, hyperglycaemia, hypovolaemia
Psychiatric disorders
Not known:	Restlessness
Nervous system disorders
Rare:	Headache
Not known:	Light-headedness
Eye disorders
Not known:	Xanthopsia, choroidal effusion, acute myopia, acute angle-closure glaucoma
Vascular disorders
Not known:	Vasculitis necrotizing
Gastrointestinal disorders
Common:	Nausea
Not known:	Pancreatitis, stomach discomfort
Hepatobiliary disorders
Not known:	Jaundice hepatocellular, jaundice cholestatic
Skin and subcutaneous tissue disorders
Not known:	Lupus-like syndrome, photosensitivity reactions, skin vasculitis, toxic epidermal necrolysis, erythema multiforme
Musculoskeletal, connective tissue and bone disorders
Not known:	Weakness
Renal and urinary disorders
Not known:	Nephritis interstitial, renal dysfunction, glycosuria
General disorders and administration site conditions
Not known:	Pyrexia
Investigations
Not known:	Triglycerides increased

Description of selected adverse reactions

Hepatic function abnormal / liver disorder

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

Sepsis

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

Interstitial Lung Disease

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

Non-melanoma Skin Cancer

Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed.

Reporting of Suspected Adverse Reactions

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779.

By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

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

Symptoms

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

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate arrhythmia associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

Treatment

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

Pharmacological Properties

Mechanism of Action

Telmisartan

Telmisartan is a non-peptide ARB. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS), with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an angiotensin type 2 (AT₂) receptor found in many tissues, but AT₂ is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3000-fold) for the AT₁ receptor than for the AT₂ receptor.

Telmisartan does not inhibit the ACE (kininase II) nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity (PRA) and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in PRA, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood.

Pharmacodynamic Properties

Telmisartan

In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.

Plasma concentration of angiotensin II and PRA increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum/ potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).

The antihypertensive effects of telmisartan have been studied in six placebo-controlled clinical trials including a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once-daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.

The onset of antihypertensive activity occurs within 3 hours, with a maximal reduction by approximately 4 weeks. At doses of 20, 40, and 80 mg, the antihypertensive effect of once-daily administration of telmisartan was maintained for the full 24-hour dose interval.

In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate (GFR), filtration fraction, renovascular resistance, or creatinine clearance.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Drug Interactions

Hydrochlorothiazide

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.

Pharmacokinetic Properties

Absorption

Telmisartan

Following oral administration, peak concentrations of telmisartan are reached in 0.5-1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration time curve of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. Telmisartan /hydrochlorothiazide can be administered with or without food. The absolute bioavailability of telmisartan is dose-dependent. At 40 mg and 160 mg, the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range of 20-160 mg, with greater than proportional increases of plasma concentrations (C_max and AUC) with increasing doses.

Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10-25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5-2.0 upon repeated once daily dosing.

Hydrochlorothiazide

When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. Following oral administration of telmisartan/hydrochlorothiazide, peak concentrations of hydrochlorothiazide are reached in approximately 1.0-3.0 hours after dosing. Based on cumulative renal excretion of hydrochlorothiazide the absolute bioavailability was about 60%.

Distribution

Telmisartan

Telmisartan is highly bound to plasma proteins (more than 99.5%), mainly albumin and alpha₁-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters, indicating additional tissue binding.

Hydrochlorothiazide

Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 l/kg. Hydrochlorothiazide crosses the placenta, but not the blood-brain barrier and is excreted in breast milk.

Metabolism

Telmisartan

Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized.

Elimination

Telmisartan

Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (more than 97%) was eliminated unchanged in the feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).

Total plasma clearance of telmisartan is more than 800 mL/min. Terminal half-life and total clearance appear to be independent of dose.

Hydrochlorothiazide

Hydrochlorothiazide eliminated rapidly by the kidneys. Hydrochlorothiazide is excreted almost entirely as unchanged substance in urine. At least 61% of the oral dose is eliminated unchanged within 24 hours. About 60% of the oral dose is eliminated within48 hours. Renal clearance is about 250-300 ml/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hours.

Special Populations

Geriatric Populations

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

Gender

Plasma concentrations of telmisartan are generally 2-3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. There was a trend towards higher plasma concentrations of hydrochlorothiazide in female than in male subjects. This is not considered to be of clinical relevance.

Renal Impairment

Renal excretion does not contribute to the clearance of telmisartan. Based on modest experience in patients with mild to moderate renal impairment (creatinine clearance of 30-60 ml/min, mean about 50 ml/min) no dose adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by haemodialysis. In patients with impaired renal function the rate of hydrochlorothiazide elimination is reduced. In a typical study in patients with a mean creatinine clearance of 90 ml/min the elimination half-life of hydrochlorothiazide was increased. In functionally anephric patients the elimination half-life is about 34 hours.

Hepatic Impairment

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

Drug Interaction Studies

Telmisartan

Ramipril: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C and AUC of ramipril 2.3- and 2.1-fold, respectively, and C and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan.

Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro oncytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Nonclinical Properties

Animal Toxicology or Pharmacology

In preclinical safety studies performed with co-administration of telmisartan and hydrochlorothiazide in normotensive rats and dogs, doses producing exposure comparable to that in the clinical therapeutic range caused no additional findings not already observed with administration of either substance alone. The toxicological findings observed appear to have no relevance to human therapeutic use.

Toxicological findings also well-known from preclinical studies with angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists were: a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit), changes of renal haemodynamics (increased blood urea nitrogen and creatinine), increased plasma renin activity, hypertrophy/hyperplasia of the juxtaglomerular cells and gastric mucosal injury. Gastric lesions could be prevented/ameliorated by oral sodium chloride solution supplementation and group housing of animals. In dogs renal tubular dilation and atrophy were observed. These findings are considered to be due to the pharmacological activity of telmisartan.

No clear evidence of a teratogenic effect was observed, however at toxic dose levels of telmisartan an effect on the postnatal development of the offsprings such as lower body weight and delayed eye opening was observed. Telmisartan showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice. Studies with hydrochlorothiazide have shown equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the extensive human experience with hydrochlorothiazide has failed to show an association between its use and an increase in neoplasms. For the foetotoxic potential of the telmisartan/hydrochlorothiazide combination

Description

CRESAR H / CRESAR 80 H is a combination of two drugs with antihypertensive properties: a thiazide diuretic, hydrochlorothiazide, and an angiotensin II receptor blocker (ARB), telmisartan.

Pharmaceutical Particulars

Incompatibilities

Not applicable

Shelf-life

Two years

Packaging Information

CRESAR H: Aluminium Strip of 10 tablets

CRESAR 80 H: Aluminium Strip of 10 tablets

Storage and Handling Instruction

Store in a cool dry place

Patient Counselling Information

CRESAR H/CRESAR 80 H (telmisartan/hydrochlorothiazide)

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

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

What is in this leaflet?

1. What CRESAR H/CRESAR 80 H is and what it is used for?
2. What you need to know before you take CRESAR H/CRESAR 80 H?
3. How to take CRESAR H/CRESAR 80 H?
4. Possible side effects
5. How to store CRESAR H/CRESAR 80 H?
6. Contents of the pack and other information

1. What CRESAR H/CRESAR 80 H is and what it is used for?

CRESAR H/CRESAR 80 H is a combination of two active substances, telmisartan and hydrochlorothiazide in one tablet. Both of these substances help to control high blood pressure.

• Telmisartan belongs to a group of medicines called angiotensin II receptor antagonists. Angiotensin-II is a substance produced in your body which causes your blood vessels to narrow thus increasing your blood pressure. Telmisartan blocks the effect of angiotensin II so that the blood vessels relax, and your blood pressure is lowered.
•  Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics, which cause your urine output to increase, leading to a lowering of your blood pressure.

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

CRESAR H/CRESAR 80 H is used to treat high blood pressure (essential hypertension) in adults whose blood pressure is not controlled enough when telmisartan is used alone.

2. What you need to know before you take CRESAR H/CRESAR 80 H?

Do not take CRESAR H/CRESAR 80 H

• If you are allergic to telmisartan or any of the other ingredients of this medicine
• If you are allergic to hydrochlorothiazide or to any other sulfonamide-derived medicines.
• If you are more than 3 months pregnant. (It is also better to avoid CRESAR H/CRESAR 80 H in early pregnancy – see pregnancy section).
• If you have severe liver problems such as cholestasis or biliary obstruction (problems with drainage of the bile from the liver and gall bladder) or any other severe liver disease.
• If you have severe kidney disease.
• If your doctor determines that you have low potassium levels or high calcium levels in your blood that do not get better with treatment.
• If you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren.

If any of the above applies to you, tell your doctor before taking CRESAR H/CRESAR 80 H.

Warnings and Precautions

Talk to your doctor before taking CRESAR H/CRESAR 80 H if you are suffering or have ever suffered from any of the following conditions or illnesses:

• Low blood pressure (hypotension), likely to occur if you are dehydrated (excessive loss of body water) or have salt deficiency due to diuretic therapy (water tablets), low-salt diet, diarrhoea, vomiting, or haemodialysis.
• Kidney disease or kidney transplant.
• Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
• Liver disease.
• Heart trouble.
• Diabetes.
• Gout.
• Raised aldosterone levels (water and salt retention in the body along with imbalance of various blood minerals).
• Systemic lupus erythematosus (also called “lupus” or “SLE”) a disease where the body’s immune system attacks the body.
• The active substance hydrochlorothiazide can cause an unusual reaction, resulting in a decrease in vision and eye pain. These could be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or an increase of pressure in your eye and can happen within hours to weeks of taking CRESAR H/CRESAR 80 H. This can lead to permanent vision impairment, if not treated.
• If you have had skin cancer or if you develop an unexpected skin lesion during the treatment.

Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun exposure and UV rays while taking CRESAR H/CRESAR 80 H

Talk to your doctor before taking CRESAR H/CRESAR 80 H, if you are taking:

• Any of the following medicines used to treat high blood pressure

• An ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes related kidney problems.
• aliskiren.
• Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.
• Digoxin.

You must tell your doctor if you think you are (or might become) pregnant. CRESAR H/CRESAR 80 H is not recommended in early pregnancy and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

Treatment with hydrochlorothiazide may cause electrolyte imbalance in your body. Typical symptoms of fluid or electrolyte imbalance include dry mouth, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, nausea (feeling sick), vomiting, tired muscles, and an abnormally fast heart rate (faster than 100 beats per minute). If you experience any of these, you should tell your doctor.

You should also tell your doctor if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such as redness, itching, swelling, blistering) occurring more quickly than normal.

In case of surgery or anaesthetics, you should tell your doctor that you are taking CRESAR H/CRESAR 80 H.

Children and Adolescents

The use of CRESAR H/CRESAR 80 H in children and adolescents up to the age of 18 years is not recommended.

Other medicines and CRESAR H/CRESAR 80 H

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may need to change the dose of these other medicines or take other precautions. In some cases you may have to stop taking one of the medicines. This applies especially to the medicines listed below taken at the same time with CRESAR H/CRESAR 80 H:

• Lithium containing medicines to treat some types of depression.
• Medicines associated with low blood potassium (hypokalaemia) such as other diuretics, (“water tablets”), laxatives (e.g. castor oil), corticosteroids (e.g. prednisone), ACTH (a hormone),
• Amphotericin (an antifungal medicine), carbenoxolone (used to treat mouth ulcers), penicillin G
• Sodium (an antibiotic), and salicylic acid and derivatives.
• Medicines that may increase blood potassium levels such as potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, ACE inhibitors, cyclosporin (an immunosuppressant drug) and other medicinal products such as heparin sodium (an anticoagulant).
• Medicines that are affected by changes of the blood potassium level such as heart medicines (e.g. digoxin) or medicines to control the rhythm of your heart (e.g. quinidine, disopyramide, amiodarone, sotalol), medicines used for mental disorders (e.g. thioridazine, chlorpromazine, levomepromazine) and other medicines such as certain antibiotics (e.g. sparfloxacine, pentamidine) or certain medicines to treat allergic reactions (e.g. terfenadine).
• Medicines for the treatment of diabetes (insulins or oral agents such as metformin). Cholestyramine and colestipol, medicines for lowering blood fat levels. Medicines to increase blood pressure, such as noradrenaline. Muscle relaxing medicines, such as tubocurarine.
• Calcium supplements and/or vitamin D supplements.
• Anti-cholinergic medicines (medicines used to treat a variety of disorders such as  gastrointestinal cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms,
• Parkinson's disease and as an aid to anaesthesia) such as atropine and biperiden.
• Amantadine (medicine used to treat Parkinson’s disease and also used to treat or prevent certain illnesses caused by viruses).
• Other medicines used to treat high blood pressure, corticosteroids, painkillers (such as non-steroidal anti-inflammatory drugs ), and medicines to treat cancer, gout, or arthritis. If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take CRESAR H/CRESAR 80 H” and “Warnings and precautions”)
• Digoxin.

CRESAR H/CRESAR 80 H may increase the blood pressure lowering effect of other medicines used to treat high blood pressure or of medicines with blood pressure lowering potential (e.g. baclofen, amifostine). Furthermore, low blood pressure may be aggravated by alcohol, barbiturates, narcotics or antidepressants. You may notice this as dizziness when standing up. You should consult with your doctor if you need to adjust the dose of your other medicine while taking CRESAR H/CRESAR 80 H.

The effect of CRESAR H/CRESAR 80 H may be reduced when you take NSAIDs (non-steroidal anti-inflammatory medicines, e.g. acetylsalicyl acid or ibuprofen).

CRESAR H/CRESAR 80 H with food and alcohol

• You can take CRESAR H/CRESAR 80 H with or without food.
• Avoid taking alcohol until you have talked to your doctor. Alcohol may make your blood pressure fall more and/or increase the risk of you becoming dizzy or feeling faint.

Pregnancy and Breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking CRESAR H/CRESAR 80 H before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of CRESAR H/CRESAR 80 H.

CRESAR H/CRESAR 80 H is not recommended during pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. CRESAR H/CRESAR 80 H is not recommended for mothers who are breast-feeding and your doctor may choose another treatment for you if you wish to breast-feed.

Driving and using machines

Some people feel dizzy or tired when taking CRESAR H/CRESAR 80 H. If you feel dizzy or tired, do not drive or operate machinery.

3. How to take CRESAR H/CRESAR 80 H?

• Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.
• The recommended dose is one tablet a day.
• Try to take the tablet at the same time each day. You can take CRESAR H/CRESAR 80 H with or without food. The tablets should be swallowed with some water.

If you take more CRESAR H/CRESAR 80 H than you should

If you accidentally take too many tablets you may experience symptoms such as low blood pressure and rapid heartbeat. Slow heartbeat, dizziness, vomiting, reduced kidney function including kidney failure, have also been reported. Due to the hydrochlorothiazide component, markedly low blood pressure and low blood levels of potassium can also happen, which may result in nausea, sleepiness and muscle cramps and/or irregular heartbeat associated with the concomitant use of drugs such as digitalis or certain anti-arrhythmic treatments. Contact your doctor or your nearest hospital emergency department immediately.

If you forget to take CRESAR H/CRESAR 80 H

If you forget to take a dose, do not worry.

Take it as soon as you remember, then carry on as before.

If you do not take your tablet on one day, take your normal dose on the next day. Do not take a double dose to make up for a forgotten dose.

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

4. Possible side effects

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

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

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

Sepsis* (often called “blood poisoning”), is a severe infection with whole-body inflammatory response, rapid swelling of the skin and mucosa (angioedema); blistering and peeling of the top layer of skin (toxic epidermal necrolysis) these side effects are rare (may affect up to 1 in 1,000 people) or of unknown frequency (toxic epidermal necrolysis) but are extremely serious and patients should stop taking the medicine and see their doctor immediately.

If these effects are not treated, they could be fatal. Increased incidence of sepsis has been observed with telmisartan only, however it cannot be ruled out for CRESAR H/CRESAR 80 H.

Possible side effects of CRESAR H/CRESAR 80 H:

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

 Dizziness

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

Decreased blood potassium levels, anxiety, fainting (syncope), sensation of tingling, pins and needles (paraesthesia), feeling of spinning (vertigo), fast heart beat (tachycardia), heart rhythm disorders, low blood pressure, a sudden fall in blood pressure when you stand up, shortness of breath (dyspnoea), diarrhoea, dry mouth, flatulence, back pain, muscle spasm, muscle pain, erectile dysfunction (inability to get or keep an erection), chest pain, increased blood uric acid levels.

Rare (may affect up to 1 in 1000 people):

Inflammation of the lungs (bronchitis), activation or worsening of systemic lupus erythematosus (a disease where the body’s immune system attacks the body, which causes joint pain, skin rashes and fever); sore throat, inflamed sinuses, feeling sad (depression), difficulty falling asleep (insomnia), impaired vision, difficulty breathing, abdominal pain, constipation, bloating (dyspepsia), feeling sick (vomiting), inflammation of the stomach (gastritis), abnormal liver function (Japanese patients are more likely to experience this side effect), redness of the skin (erythema), allergic reactions such as itching or rash, increased sweating, hives (urticaria), joint pain (arthralgia) and pain in extremities, muscle cramps, flu-like-illness, pain, low levels of sodium, increased levels of creatinine, hepatic enzymes or creatine phosphokinase in the blood.

Adverse reactions reported with one of the individual components may be potential adverse reactions with CRESAR H/CRESAR 80, even if not observed in clinical trials with this product.

Telmisartan

In patients taking telmisartan alone the following additional side effects have been reported:

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

Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), urinary tract infections, deficiency in red blood cells (anaemia), high potassium levels, slow heart rate (bradycardia), kidney impairment including acute kidney failure, weakness, cough.

Rare (may affect up to 1 in 1000 people):

Low platelet count (thrombocytopenia), increase in certain white blood cells (eosinophilia), serious allergic reaction (e.g. hypersensitivity, anaphylactic reaction, drug rash), low blood sugar levels (in diabetic patients), upset stomach, eczema (a skin disorder), arthrosis, inflammation of the tendons, decreased haemoglobin (a blood protein), somnolence.

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

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

*The event may have happened by chance or could be related to a mechanism currently not known.

**Cases of progressive scarring of lung tissue have been reported during intake of telmisartan.

However, it is not known whether telmisartan was the cause.

Hydrochlorothiazide

In patients taking hydrochlorothiazide alone the following additional side effects have been reported: 

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

Feeling sick (nausea), low blood magnesium level.

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

Reduction in blood platelets, which increases risk of bleeding or bruising (small purple-red marks in skin or other tissue caused by bleeding), high blood calcium level, headache.

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

Increased pH (disturbed acid-base balance) due to low blood chloride level.

Side effects of unknown frequency (frequency cannot be estimated from the available data) Inflammation of the salivary gland, skin and lip cancer (Non-melanoma skin cancer), decreases in the number (or even lack) of cells in the blood, including low red and white blood cell count, serious allergic reactions (e.g. hypersensitivity, anaphylactic reaction), decreased or loss of appetite, restlessness, light-headedness, blurred or yellowing of vision, decrease in vision and eye pain (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute myopia or acute-angle closure glaucoma), inflammation of blood vessels (vasculitis necrotising), inflamed pancreas, upset stomach, yellowing of the skin or eyes (jaundice), lupus-like syndrome (a condition mimicking a disease called systemic lupus erythematosus where the body’s immune system attacks the  body); skin disorders such as inflamed blood vessels in the skin, increased sensitivity to sunlight, rash, redness of the skin, blistering of the lips, eyes or mouth, skin peeling , fever (possible signs of erythema multiforme), weakness, kidney inflammation or impaired kidney function, glucose in the urine (glycosuria), fever, impaired electrolyte balance, high blood cholesterol levels, decreased blood volume, increased blood levels of glucose, difficulties in controlling blood/ urine levels of glucose in patients with a diagnosis of diabetes mellitus or fat in the blood.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store CRESAR H/CRESAR 80 H?

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the strip after “EXP”. The expiry date refers to the last day of that month.
• Store in a cool dry place.
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

 What CRESAR H/CRESAR 80 H contains?

The active substances are telmisartan and hydrochlorothiazide. Each tablet contains 40 mg telmisartan and 12.5 mg hydrochlorothiazide.

Details of Manufacturer

Mfd. By Cipla Ltd.

Registered Office:

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

MNB/05/109

Date of Revision

September 2020