Telmisartan/ Amlodipine

Registered South African indications:

• Essential hypertension in patients who have been stabilised on the two component medicines used at the same dose
  - Replacement therapy
• Uncontrolled blood pressure in those on amlodipine monotherapy
  - Add on therapy

Should a woman become pregnant while receiving telmisartan/amlodipine, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Hypersensitivity to dihydropyridine derivatives
• History of angioedema related to previous therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs); these patients must never again be given these medicines
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Severe renal function impairment (CrCl<30ml/min)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic and mitral valve stenosis
• Concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene, or amiloride
• Porphyria
• Concomitant use with aliskiren-containing products
• Lithium therapy; concomitant administration with telmisartan/ amlodipine may lead to toxic blood concentrations of lithium
• Pregnancy
• Lactation
• Biliary obstructive disorders
• Severe hepatic impairment
• Cardiogenic shock
• Concomitant use of fluoroquinolones with ACE inhibitors/ARBs is contraindicated in patients with moderate to severe renal impairment (CrCl≤30ml/min) and in elderly patients

South African recommendations

Caution in the following patient groups:

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment

Hepatic impairment

• Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Amlodipine’s half-life is prolonged in patients with impaired liver functions and dosage recommendations have not been established
• Telmisartan/amlodipine should therefore be used with caution in patients with mild to moderate impairment of liver function, and should not be used in patients with severe liver impairment

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

• Evidence suggests that the combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren may increase the risk of hypotension, hyperkalaemia, and decreased renal function, including acute renal failure
• Dual blockade of RAAS through the use of telmisartan/ amlodipine with aliskiren is contraindicated
• Telmisartan/ amlodipine should not be used concomitantly with aliskiren

Renovascular hypertension

• Increased risk of severe hypotension and renal insufficiency exists when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicines affecting the renin-angiotensin-aldosterone system

Renal impairment and kidney transplant

• When telmisartan/amlodipine is used in patients with impaired renal function, periodic monitoring of potassium and creatinine serum levels is recommended
• No experience exists regarding the administration of telmisartan/amlodipine in patients with a recent kidney transplant
• Telmisartan and amlodipine are not dialysable

Intravascular hypovolaemia

• Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted due to factors such as vigorous diuretic therapy, dietary salt restriction, diarrhoea, or vomiting
• Such conditions should be corrected before the administration of telmisartan/amlodipine

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 telmisartan/amlodipine has been associated with acute hypotension, hyperazotaemia, oliguria, or, rarely, acute renal failure

Concomitant use of fluoroquinolones

• Concomitant use of fluoroquinolones and angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) may precipitate acute kidney injury, particularly in patients with moderate to severe renal impairment and elderly patients
• Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones, ACE inhibitors, or ARBs, whether used separately or concomitantly

Primary aldosteronism

• Patients with primary aldosteronism generally do not respond to antihypertensive medicines that act through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan/amlodipine is not recommended

Unstable angina pectoris, acute myocardial infarction

• There are no data supporting the use of telmisartan/amlodipine in unstable angina pectoris or during/within one month of a myocardial infarction

Heart failure

• In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema

Hyperkalaemia

• Hyperkalaemia may occur during treatment with telmisartan/amlodipine, especially in patients with renal impairment and/or heart failure. Monitoring of serum potassium is recommended for at-risk patients
• Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicines that may increase potassium levels (e.g., heparin) should be co-administered cautiously with telmisartan/amlodipine

Diabetes mellitus

• In diabetic patients with additional cardiovascular risks, such as diabetes mellitus and coexistent coronary artery disease (CAD), the risk of fatal myocardial infarction and unexpected cardiovascular death may increase with blood pressure-lowering agents like ARBs or ACE-inhibitors
• CAD in diabetic patients may be asymptomatic and undiagnosed. Patients should undergo appropriate diagnostic evaluations, such as exercise stress testing, to detect and treat CAD before initiating treatment with telmisartan/amlodipine

Other precautions

• Excessive reduction in blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease may lead to a myocardial infarction or stroke

Excipient precautions

• Telmisartan/amlodipine contains mannitol, which may have a laxative effect

Effects on ability to drive and use machines

• No specific studies have been conducted on the effects of telmisartan/amlodipine on driving or using machinery
• Patients may experience side effects such as syncope, somnolence, dizziness, or vertigo during treatment
• Caution is advised when driving or operating machinery
• If these side effects occur, patients should avoid potentially hazardous activities, including driving or operating machinery

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

South African registered indications and dosages

Essential hypertension in patients who have been stabilised on the two component medicines used at the same dose
- Replacement therapy

Telmisartan/ Amlodipine
40/5 (mg)
40/10 (mg)
80/5 (mg)
80/10 (mg)

• Oral (tab): 1 tab, once dly

---

Patients taking telmisartan and amlodipine as separate tablets can instead take the combination product containing the same component doses in one tablet once daily

---

Uncontrolled blood pressure in those on amlodipine monotherapy
- Add on therapy

Telmisartan/ Amlodipine
40/5 (mg)
40/10 (mg)
80/5 (mg)
80/10 (mg)

• Oral (tab): Initial: 40/5 mg, once dly; Titrate at intervals of 2 weeks if additional blood pressure lowering is needed; Max: 80/10mg/24hrs

---

May be administered in patients whose blood pressure is not adequately controlled with amlodipine alone

---

Method of administration

May be taken orally, with or without food

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• Telmisartan/amlodipine should not be used during pregnancy

Telmisartan

• Safety in pregnancy has not been established
• When pregnancy is planned or confirmed, telmisartan/amlodipine should be discontinued
• Medicines affecting the renin-angiotensin system, such as telmisartan/amlodipine, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women
• Women of childbearing age should ensure effective contraception. 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 should be stopped immediately, and, if appropriate, alternative therapy should be started
• Should exposure to telmisartan/amlodipine have occurred from the second trimester of pregnancy, an ultrasound check of renal function and skull is recommended
• Infants whose mothers have taken telmisartan/amlodipine should be closely observed for hypotension

Amlodipine

• The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses

Breastfeeding

South African recommendations

• Contraindicated
• It is not known whether telmisartan is excreted in human milk
• Animal studies have shown excretion of telmisartan in breastmilk. Amlodipine has been identified in breastfed infants of treated women. The effect of amlodipine on infants is unknown. Because of the potential adverse reactions in breastfed infants, telmisartan/amlodipine should not be used by breastfeeding mothers

Fertility

South African recommendations

• No data from controlled clinical studies with the fixed dose combination or with the individual components are available
• Separate reproductive toxicity studies with the combination of telmisartan and amlodipine have not been conducted. In preclinical studies, no effects of telmisartan on male and female fertility were observed. In some patients treated by calcium channel blockers, reversible biochemical changes in the head of spermatozoa have been reported
• Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated
• Coadministration with fluoroquinolones in moderate to severe renal impairment (CrCl≤30ml/min): Contraindicated

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
• Severe: Contraindicated

South African recommendations

• No dose adjustment recommended
• Coadministration with fluoroquinolones: Contraindicated

Telmisartan/ Amlodipine

Infections and Infestations

Less frequent

• Cystitis

Psychiatric Disorders

Less frequent

• Depression
• Anxiety
• Insomnia

Nervous System Disorders

Frequent

• Dizziness

Less frequent

• Somnolence
• Migraines
• Headaches
• Paraesthesia
• Syncope
• Peripheral neuropathy
• Hypoaesthesia
• Dysgeusia
• Tremors

Ear and labyrinth disorders

Less frequent

• Vertigo

Cardiac Disorders

Less frequent

• Bradycardia
• Palpitations

Vascular Disorders

Less frequent

• Hypotension
• Orthostatic hypotension
• Flushing

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Coughing
• Interstitial lung disease

Gastrointestinal Disorders

Less frequent

• Abdominal pain
• Diarrhoea
• Nausea
• Vomiting
• Gingival hypertrophy
• Dyspepsia
• Dry mouth

Skin and Subcutaneous Tissue Disorders

Less frequent

• Pruritus
• Eczema
• Erythema
• Rash

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Arthralgia
• Muscle spasms (Cramps in legs)
• Myalgia
• Back pain
• Pain in extremity (leg pain)

Renal and Urinary Disorders

Less frequent

• Nocturia

General Disorders and Administration Site Conditions

Frequent

• Peripheral oedema

Investigations

Less frequent

• Increased hepatic enzymes
• Increased blood uric acid

Telmisartan

Infections and Infestations

Less frequent

• Upper respiratory tract infection including pharyngitis and sinusitis
• Urinary tract infection including cystitis
• Sepsis including fatal outcome

Blood and Lymphatic System Disorders

Less frequent

• Anaemia
• Thrombocytopenia
• Eosinophilia

Immune System Disorders

Less frequent

• Hypersensitivity
• Anaphylactic reaction

Metabolism and Nutrition Disorders

Less frequent

• Hyperkalaemia
• Hypoglycaemia (in diabetic patients)

Eye Disorders

Less frequent

• Visual disturbance

Cardiac Disorders

Less frequent

• Tachycardia

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Dyspnoea

Gastrointestinal Disorders

Less frequent

• Flatulence
• Stomach discomfort

Hepatobiliary Disorders

Less frequent

• Abnormal hepatic function
• Liver disorder

Skin and Subcutaneous Tissue Disorders

Less frequent

• Hyperhidrosis
• Angioedema (with fatal outcome)
• Drug eruption
• Toxic skin eruption
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Tendon pain (tendinitis like symptoms)

Renal and Urinary Disorders

Less frequent

• Renal impairment including acute renal failure

General Disorders and Administration Site Conditions

Less frequent

• Influenza-like illness

Investigations

Less frequent

• Increased blood creatinine
• Increased blood creatine phosphokinase
• Decreased haemoglobin

Amlodipine

Blood and Lymphatic System Disorders

Less frequent

• Leukocytopenia
• Thrombocytopenia

Immune System Disorders

Less frequent

• Hypersensitivity

Metabolism and Nutrition Disorders

Less frequent

• Hyperglycaemia

Psychiatric Disorders

Less frequent

• Mood change
• Confusion

Nervous System Disorders

Less frequent

• Extrapyramidal syndrome
• Hypertonia

Eye Disorders

Frequent

• Visual disturbance (including diplopia)

Less frequent

• Visual impairment

Ear and Labyrinth Disorders

Less frequent

• Tinnitus

Cardiac Disorders

Less frequent

• Myocardial infarction
• Dysrhythmia
• Ventricular tachycardia
• Atrial fibrillation

Vascular Disorders

Less frequent

• Vasculitis

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Dyspnoea
• Rhinitis

Gastrointestinal Disorders

Frequent

• Altered bowel habits (including diarrhoea and constipation)

Less frequent

• Pancreatitis
• Gastritis

Skin and Subcutaneous Tissue Disorders

Less frequent

• Alopecia
• Purpura
• Skin discolouration
• Hyperhidrosis
• Angioedema
• Erythema multiforme
• Urticaria
• Exfoliative dermatitis
• Stevens-Johnson syndrome
• Photosensitivity

Frequency unknown

• Toxic epidermal necrolysis

Musculoskeletal and Connective Tissue Disorders

Frequent

• Ankle swelling

Renal and Urinary Disorders

Less frequent

• Micturition disorder
• Pollakiuria

General Disorders and Administration Site Conditions

Less frequent

• Pain

Investigations

Less frequent

• Increased weight
• Decreased weight

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Telmisartan/ amlodipine

• Potassium-sparing diuretics
• Spironolactone
• Triamterene
• Amiloride
• Aliskiren-containing products
• Lithium
• Fluoroquinolones
• Other antihypertensive medicines
• Medicines with blood pressure lowering potential
• Baclofen
• Amifostine
• Barbiturates
• Narcotics
• Antidepressants
• Corticosteroids (systemic route)

Telmisartan

• Other antihypertensive medicines
• Digoxin
• Ramipril
• Ramiprilat
• Lithium
• Angiotensin-converting enzyme (ACE) inhibitors
• NSAIDs (non-steroidal anti-inflammatory medicines)
• Aspirin (anti-inflammatory dosage)
• COX-2 inhibitors
• Non-selective NSAIDs
• Angiotensin II receptor blockers (ARBs)
• Aliskiren
• Fluoroquinolones

Amlodipine

• CYP3A4 inhibitors
• Diltiazem
• Ketoconazole
• Itraconazole
• Ritonavir
• CYP3A4 inducers
• Anticonvulsant medicines
• Carbamazepine
• Phenobarbital
• Phenytoin
• Fosphenytoin
• Primidone
• Rifampicin
• Simvastatin
• Immunosuppressants
• Ciclosporin
• Tacrolimus
• Sildenafil

Other interactions

• Alcohol
• Grapefruit and grapefruit juice
• Hypericum perforatum (St John's Wort)

None routine. Specific cases may require

• Renal function
• Serum potassium
• Serum creatinine

Telmisartan/ Amlodipine combines two antihypertensive medicines with different mechanisms of action: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridinic calcium channel blocker, amlodipine. The combination of these medicines has an additive antihypertensive effect.

Telmisartan
Telmisartan is a specific angiotensin II receptor (type AT1) antagonist. Telmisartan 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. The binding is long lasting.

Amlodipine
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, leading to reductions in peripheral vascular resistance and in blood pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.

COMBINATION PREPARATIONS

Telmisartan/ Amlodipine

Tablet 40mg/5mg 

• Twynsta (ingelheim) originator

Tablet 80mg/5mg 

• Twynsta (ingelheim) originator

Tablet 40mg/10mg 

• Twynsta (ingelheim) originator

Tablet 80mg/10mg 

• Twynsta (ingelheim) originator