Telmisartan/ Hydrochlorothiazide

Registered South African indications:

• Essential hypertension - mild to moderate

Contraindications

South African recommendations

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to other sulphonamide-derived substances
• Pregnancy 
• Breastfeeding
• Severe renal impairment (CrCl<30ml/min)
• Severe hepatic impairment
• Porphyria 
• Anuria  
• Biliary obstructive disorders, biliary cirrhosis and cholestasis 
• History of angioedema related to previous therapy with angiotensin-converting enzyme inhibitors (ACE-inhibitors) or angiotensin receptor blockers (ARBs) 
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic stenosis
• Addison’s disease
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia
• History of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip
• Coadministration with potassium-sparing diuretics such as spironolactone, triamterene, amiloride
• Coadministration with lithium therapy
• Coadministration with aliskiren-containing products
• Rare hereditary conditions that may be incompatible with an excipient in this combination product e.g fructose intolerance, galactosaemia

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to other sulphonamide-derived substances
• Second and third trimester of pregnancy
• Severe renal impairment (CrCl<30ml/min) 
• Severe hepatic impairment 
• Porphyria
• Cholestasis  and biliary obstructive disorders
• Refractory hypokalaemia and hypercalcaemia 
• Coadministration with aliskiren-containing products  in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73m²)

Cautions

• Women of childbearing potential not using effective contraception
• Mild to moderate renal impairment 
• Mild to moderate hepatic impairment  
• Progressive liver disease
• Black patients 
• Recent kidney transplant
• Volume and/or sodium depletion
  - Vigorous diuretic therapy
  - Dietary salt restriction
  - Diarrhoea or vomiting
• Severe congestive heart failure
• Primary aldosteronism 
• Mitral stenosis 
• Ischaemic cardiomyopathy or ischaemic cardiovascular disease
• Risk factors for hyperkalaemia
  - Renal impairment and/or heart failure
  - Diabetes mellitus
  - Coadministration with other medicinal products that may increase potassium levels
• Risk factors for hypokalaemia
  - Liver cirrhosis
  - Patients experiencing brisk diuresis
  - Patients receiving inadequate oral intake of electrolytes
  - Coadministration with corticosteroids or adrenocorticotropic hormone (ACTH)
• Systemic lupus erythematosus
• Diabetes mellitus
  - With coexistent coronary artery disease
  - Treated with insulin or antidiabetics
• Risk factors for developing acute angle-closure glaucoma
  - History of sulfonamide or penicillin allergy
• History of allergy or bronchial asthma
• May impair ability to drive and operate machinery 

Recommendations in other jurisdictions

• First trimester of pregnancy
• Breastfeeding
• Mild to moderate renal impairment
• Mild to moderate hepatic impairment  
• Progressive liver disease 
• Black patients 
• Japanese patients 
• Recent kidney transplant
• Bilateral renal stenosis 
• Stenosis of the artery to a single functioning kidney
• Volume and/or sodium depletion
  - Vigorous diuretic therapy
  - Dietary salt restriction
  - Diarrhoea or vomiting
• History of previous non-melanoma skin cancer
• Severe congestive heart failure
• Primary aldosteronism 
• Aortic stenosis
• Mitral stenosis 
• Obstructive hypertrophic cardiomyopathy
• Ischaemic cardiomyopathy or ischaemic cardiovascular disease
• Risk factors for hyperkalaemia
  - Renal impairment and/or heart failure
  - Diabetes mellitus
  - Coadministration with other medicinal products that may increase potassium levels 
• Risk factors for hypokalaemia
  - Liver cirrhosis
  - Patients experiencing brisk diuresis
  - Patients receiving inadequate oral intake of electrolytes
  - Coadministration with corticosteroids or adrenocorticotropic hormone (ACTH)
• Systemic lupus erythematosus
• Diabetes mellitus
  - Coadministration of ACE-inhibitors and ARBs in those with diabetic neuropathy
  - Treated with insulin or antidiabetics
• Risk factors for developing acute angle-closure glaucoma
  - History of sulfonamide or penicillin allergy
• History of allergy or bronchial asthma
• Galactose intolerance 
• Total lactase deficiency
• Glucose-galactose malabsorption 
• Hereditary fructose intolerance
• May impair ability to drive and operate machinery 

Forms avail. in SA and covered in this monograph: fct, tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Essential hypertension - mild to moderate

Telmisartan/ Hydrochlorothiazide
40/12.5 (mg)
80/12.5 (mg)

• Oral (tab): 1 tab, dly with or without food

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Telmisartan/hydrochlorothiazide is indicated in adult patients whose blood pressure has been stabilised at the same dosage of the individual components given together. The patient should be stabilised at the relevant dosage of the individual components given together and then changed to the appropriate combination dosage

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Maximum antihypertensive effect is generally attained after 4-8 weeks of treatment

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Indications and dosages registered in other jurisdictions

Essential hypertension
- In those whose blood pressure is not adequately controlled on telmisartan alone

Telmisartan/ Hydrochlorothiazide
40/12.5 (mg)
80/12.5 (mg)

• Oral (tab): 1 tab, dly with or without food

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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

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Safety in pregnancy has not been established. Telmisartan/hydrochlorothiazide should not be initiated during pregnancy. When pregnancy is planned or confirmed telmisartan/hydrochlorothiazide should be discontinued and patients should be changed to alternative antihypertensive treatments, which have an established safety profile for use in pregnancy
• Preclinical studies with telmisartan, as contained in this combination, do not indicate teratogenic effect, but have shown fetotoxicity. Medicines affecting the renin-angiotensin system, such as telmisartan/hydrochlorothiazide, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. Should exposure to telmisartan/hydrochlorothiazide have occurred during pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken telmisartan/hydrochlorothiazide should be closely observed for hypotension
• Thiazides, as contained in this combination, cross the placental barrier and appear in cord blood. They may cause foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal thrombocytopaenia and foetal, or neonatal, jaundice have been reported with maternal thiazide therapy
• Women of childbearing age should ensure effective contraception

Recommendations in other jurisdictions

• First trimester: Caution; not recommended
• Second and third trimester: Contraindicated
• 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 angiotensin-converting enzyme inhibitors (ACE-inhibitors) during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative 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

Breastfeeding

South African recommendations

• Contraindicated 
• Safety in breastfeeding has not been established. Telmisartan/hydrochlorothiazide is contraindicated during breastfeeding
• It is not known whether telmisartan is excreted in human milk. Animal studies have shown excretion of telmisartan in breast milk. Thiazides appear in human milk and may inhibit lactation

Recommendations in other jurisdictions

• Caution; not recommended
• Because no information is available regarding the use of telmisartan/hydrochlorothiazide during breastfeeding, telmisartan/hydrochlorothiazide is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while breastfeeding a newborn or preterm infant
• Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. If telmisartan/hydrochlorothiazide is used during breastfeeding, doses should be kept as low as possible

Fertility

South African recommendations

• No studies on fertility in humans have been performed. In preclinical studies, an effect of telmisartan and hydrochlorothiazide on male and female fertility was not observed

Recommendations in other jurisdictions

• In preclinical studies, no effects of telmisartan and hydrochlorthiazide on male and female fertility were observed

Renal Impairment

• Mild to moderate (CrCl≥30ml/min): Caution; no dose adjustment recommended 
• Severe (CrCl<30ml/min): Contraindicated 

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended
  Dosage should not exceed 40/12.5mg (1 tab), dly
• Severe: Contraindicated

Elderly

• No dose adjustment recommended 

Race

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

Porphyria Information

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Possibly porphyrinogenic (PSP)

Drugs in Sport

• Prohibited - At all times

Telmisartan/Hydrochlorothiazide

Central Nervous System Disorders 

• Depression
• Insomnia
• Sleep disturbances
• Anxiety
• Syncope
• Paraesthesia
• Dizziness

Cardiovascular Disorders 

• Tachycardia
• Hypotension
  - Orthostatic hypotension 
• Cardiac dysrhythmias
• Chest pain

Respiratory Disorders

• Dyspnoea
• Respiratory distress
  - Pneumonitis
  - Pulmonary oedema
• Bronchitis
• Pharyngitis
• Sinusitis

Gastrointestinal Disorders 

• Abdominal pain
• Diarrhoea
• Dyspepsia
• Flatulence
• Vomiting
• Constipation
• Dry mouth
• Gastritis

Hepatobiliary Disorders 

• Abnormal hepatic function/hepatic disorder
• Increased hepatic enzymes

Genitourinary Disorders

• Impotence
• Increased uric acid
• Increased blood creatinine

Endocrine and Metabolic Disorders 

• Hypoglycaemia
• Hyponatraemia
• Hypokalaemia
• Hyperuricaemia

Musculoskeletal Disorders 

• Myalgia
• Back pain
• Muscle spasm
• Arthralgia
• Cramps in legs
• Leg pain
• Increased blood creatine phosphokinase 

Skin and Subcutaneous Tissue Disorders 

• Increased sweating
• Pruritus
• Rash
• Angioedema (with fatal outcome)
• Erythema
• Urticaria

Immune, Blood and Lymphatic System Disorders 

• Influenza-like illness
• Exacerbation or activation of systemic lupus erythematosus

Sensory Disorders

• Abnormal vision
• Transient blurred vision
• Vertigo

Other

• Pain

Telmisartan

Central Nervous System Disorders 

• Asthenia

Cardiovascular Disorders 

• Bradycardia

Respiratory Disorders

• Upper respiratory tract infections
• Cough
• Interstitial lung disease

Gastrointestinal Disorders 

• Stomach discomfort

Genitourinary Disorders

• Urinary tract infections
  - Cystitis
• Renal impairment
• Acute renal failure

Endocrine and Metabolic Disorders 

• Hyperkalaemia
• Hypoglycaemia (in diabetic patients)

Musculoskeletal Disorders 

• Arthrosis
• Tendon pain (tendinitis like symptoms)

Skin and Subcutaneous Tissue Disorders 

• Eczema
• Drug eruption
• Toxic skin eruption

Immune, Blood and Lymphatic System Disorders 

• Anaemia
• Eosinophilia
• Thrombocytopenia
• Anaphylactic reaction
• Hypersensitivity
• Decreased haemoglobin
• Sepsis (including fatal outcome)

Hydrochlorothiazide

Central Nervous System Disorders 

• Restlessness
• Light-headedness

Cardiovascular Disorders 

• Necrotising angiitis (vasculitis)

Gastrointestinal Disorders 

• Sialoadenitis
• Upset stomach
• Nausea

Hepatobiliary Disorders 

• Cholestatic jaundice
• Hepatocellular jaundice
• Pancreatitis

Genitourinary Disorders

• Interstitial nephritis
• Renal dysfunction
• Glycosuria

Endocrine and Metabolic Disorders 

• Anorexia
• Loss of appetite
• Hypercholesterolaemia
• Hyperglycaemia
• Increased triglycerides
• Loss of diabetic control
• Hypomagnesaemia
• Hypercalcaemia
• Hypochloraemic alkalosis
• Electrolyte imbalance
• Hypovolaemia

Musculoskeletal Disorders 

• Weakness

Skin and Subcutaneous Tissue Disorders 

• Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of skin or lip)
• Cutaneous lupus erythematosus-like reactions (or reactivation of lupus erythematosus)
• Photosensitivity reactions
• Cutaneous vasculitis
• Toxic epidermal necrolysis
• Erythema multiforme

Immune, Blood and Lymphatic System Disorders 

• Aplastic anaemia
• Haemolytic anaemia
• Bone marrow depression
• Leukopenia
• Neutropenia
• Agranulocytosis
• Thrombocytopenia
• Hypersensitivity
• Allergy
• Anaphylactic reactions
• Fever

Sensory Disorders

• Xanthopsia
• Acute myopia
• Acute angle-closure glaucoma
• Choroidal effusion

• Digoxin
• Agents that increase serum potassium
• Kaliuretic diuretics
• Laxatives
• Corticosteroids
• Adrenocorticotropic hormone (ACTH)
• Amphotericin
• Carbenoxolone
• Penicillin G sodium
• Salicylic acid and derivatives
• Potassium supplements
• Potassium-sparing diuretics
• Spirinolactone
• Triamterene
• Amiloride
• Antidysrhythmics
• Class Ia antiarrythmics
• Quinidine
• Hydroquinidine
• Disopyramide
• Class III antiarrythmics
• Amiodarone
• Sotalol
• Dofetilide
• Ibutilide
• Antipsychotics
• Thioridazine
• Levomepromazine
• Trifluoperazine
• Cyamemazine
• Sulpiride
• Sultopride
• Amisulpride
• Tiapride
• Haloperidol
• Droperidol
• Bepridil
• Cisapride
• Diphemanil
• Pentamidine
• Sparfloxacine
• Terfenadine
• Vincamine 
• Agents known to induce torsades de pointes
• Erythromycin
• Halofantrine
• Dolasetron
• Clarithromycin
• Moxifloxacin
• Chlorpromazine
• Pimozide
• Ziprasidone
• Mizolastine
• Oral antidiabetics
• Insulin
• Metformin
• Angiotensin-converting enzyme inhibitors (ACE inhibitors)
• Angiotensin-II receptors antagonists (ARBs)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Aspirin
• COX-2 inhibitors
• Heparin
• Ciclosporin
• Agents that affect the renin-angiotensin-aldosterone system
• Aliskiren
• Lithium
• Baclofen
• Amifostine
• Antihypertensive agents 
• Barbiturates
• Narcotics
• Antidepressants
• Cholestyramine
• Colestipol
• Pressor amines
• Noradrenaline
• Nondepolarizing skeletal muscle relaxants
• Tubocurarine
• Uricosuric agents
• Calcium salts
• Probenecid
• Sulfinpyrazone
• Allopurinol
• Beta-blockers
• Diazoxide
• Anticholinergic agents
• Atropine
• Biperiden
• Amantadine
• Cytotoxic agents
• Cyclophosphamide
• Methotrexate
• Vitamin D
• Methyldopa

Other interactions

• Alcohol
• Salt substitutes containing potassium

• Blood pressure
• Electrolytes
• Serum creatinine
• Blood urea nitrogen

Specific cases may require

• Glucose

Precautions to be taken before handling or administration 

• Telmisartan/hydrochlorothiazide should be kept in the sealed blister due to the hygroscopic property of the tablets. Tablets should be taken out of the blister shortly before administration 

Telmisartan
Telmisartan is a specific angiotensin II receptor (type AT₁) antagonist. It displaces angiotensin II from its binding site at the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT₁ receptor. Telmisartan selectively binds at the AT₁ receptor. The binding is long-lasting. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. In man, an 80mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours. 

Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte re-absorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. 

COMBINATION PREPARATIONS

Telmisartan/ Hydrochlorothiazide

Tablet 40mg/12.5mg

• Co-Micardis (Ingelheim)
• Co-Pritor (Ingelheim) originator
• Co-Telza 40/12.5 (Forrester Pharma)
• Telpres Plus (Sandoz)
• Tesar Co 40/12.5mg (Pharma Dynamics)
• Ticarda Plus 40/12.5 (Accord Healthcare)
• Tremistan Plus (Sandoz)

Tablet 80mg/12.5mg

• Co-Micardis (Ingelheim)
• Co-Pritor (Ingelheim) originator
• Co-Telza 80/12.5 (Forrester Pharma)
• Telpres Plus (Sandoz)
• Tesar Co 80/12.5mg (Pharma Dynamics)
• Ticarda Plus 80/12.5 (Accord Healthcare)
• Tremistan Plus (Sandoz)