Amtelip Tablets

Replacement therapy

Treatment of essential hypertension in patients who have been stabilised on the two component medicines used at the same dose.

Add on therapy

AMTELIP is indicated in patients whose blood pressure is not adequately controlled on amlodipine monotherapy.

Posology: AMTELIP should be taken once daily.

Replacement Therapy: Patients taking telmisartan and amlodipine as separate tablets can instead take AMTELIP containing the same component doses in one tablet once daily.

Add on therapy

AMTELIP may be administered in patients whose blood pressure is not adequately controlled with amlodipine alone. The usual starting dose of AMTELIP is 40/5 mg once daily. If additional blood pressure lowering is needed after at least 2 weeks of therapy, the dose may be titrated up to a maximum of 80/10 mg once daily.

Special populations:

Renal Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (see section 4.4). Amlodipine and telmisartan are not dialysable.

Hepatic impairment: In patients with mild to moderate hepatic impairment, AMTELIP should be administered with caution. For telmisartan, the dose should not exceed 40/5 mg or 40/10 mg once daily (see section 4.4).

Elderly: No dose adjustment is necessary for elderly patients.

Children and adolescents: AMTELIP is not recommended for use in patients aged below 18 years due to lack of data on safety and efficacy.

Method of administration: Oral use. AMTELIP may be taken with or without food.

• Known hypersensitivity to telmisartan, amlodipine or to any of the excipients of AMTELIP (see section 6.1).
• Hypersensitivity to dihydropyridine derivatives.
• A history of angioedema related to previous therapy with 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 (creatinine clearance less than 30 ml/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.4).
• Porphyria.
• Lithium therapy: Concomitant administration with AMTELIP may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of AMTELIP with aliskiren-containing medicines is contraindicated (see section 4.4).
• Biliary obstructive disorders.
• Severe hepatic impairment.
• Cardiogenic shock.
• Concomitant use of fluoroquinolones with Angiotensin-converting enzyme (ACE) inhibitors/Angiotensin receptor blockers (ARBs) is contraindicated in patients with moderate to severe renal impairment (creatinine clearance u2264 30 ml/min) and in elderly patients.

Pregnancy

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 may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of AMTELIP and aliskiren is therefore contra-indicated (see section 4.3). AMTELIP should not be used concomitantly with aliskiren (see section 4.3).

Hepatic Impairment: Should a woman become pregnant while receiving AMTELIP, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).

Telmisartan (ingredient of AMTELIP) is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Amlodipineu2019s half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. AMTELIP 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 (see section 4.3).

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 medicines that affect the renin-angiotensin-aldosterone system (see section 4.3).

Renal impairment and kidney transplant: When AMTELIP is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of AMTELIP 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 by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of AMTELIP.

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 AMTELIP, that affects this system, 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 in patients, especially those with moderate to severe renal impairment and elderly patients. (See section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or Angiotensin-converting enzymes (ACE) inhibitors/Angiotensin receptor blockers (ARBs) whether used separately and/or concomitantly.

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 AMTELIP is not recommended.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy: AMTELIP is contraindicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy.

Unstable angina pectoris, acute myocardial infarction: There are no data to support the use of AMTELIP in unstable angina pectoris and during or 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: During treatment with AMTELIP hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium in patients at risk is recommended. Based on experience with the use of medicines that affect the renin-angiotensin-system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicines that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co-administered cautiously with AMTELIP.

Diabetes mellitus: In diabetic patients with an additional cardiovascular risk, i.e. patients with diabetes mellitus and coexistent coronary artery disease (CAD), the risk of fatal myocardial infarction and unexpected cardiovascular death may be increased when treated with blood pressure lowering agents such as ARBs or ACE-inhibitors. In patients with diabetes mellitus CAD may be asymptomatic and therefore undiagnosed. Patients with diabetes mellitus should undergo appropriate diagnostic evaluation, e.g. exercise stress testing, to detect and to treat CAD accordingly before initiating treatment with AMTELIP.

Other: Excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease may result in a myocardial infarction or stroke.

Excipient: AMTELIP contains mannitol and may have a laxative effect.

No interactions between the two components of the fixed dose combinations have been observed in clinical studies.

Interactions common to the combination: No interaction studies have been performed with AMTELIP and other medicinal products.

Concomitant use to be taken into account:

Other antihypertensive medicines: The blood pressure lowering effect of AMTELIP can be increased by concomitant use of other antihypertensive medicines.

Medicines with blood pressure lowering potential: Based on their pharmacological properties it can be expected that the following medicines may potentiate the hypotensive effects of AMTELIP: e.g. baclofen, amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics, or antidepressants.

Corticosteroids (systemic route): Reduction of the antihypertensive effect.

Interactions linked to the telmisartan component of AMTELIP: Telmisartan may increase the hypotensive effect of other antihypertensive agents. Other interactions of clinical significance have not been identified. Co-administration of telmisartan does not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. For digoxin a 20 % increase in median plasma digoxin trough concentration has been observed (39 % in a single case); monitoring of plasma digoxin levels should be considered.

In one study the co-administration of telmisartan and ramipril led to an increase of up to 2,5 fold in the AUC 0-24 and C max of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin-converting enzyme (ACE) inhibitors. Increased serum levels have also been reported with telmisartan. Treatment with NSAIDs (i.e. aspirin at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and AMTELIP should be adequately hydrated and be monitored for renal function at the beginning of combined treatment. A reduced effect of antihypertensive medicines like AMTELIP by inhibition of vasodilating prostaglandins has been reported during combined treatment with NSAIDs.

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of angiotensin-converting enzyme (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 (see sections 4.3 and 4.4). Concomitant use of fluoroquinolones and Angiotensin-converting enzyme (ACE) inhibitors/Angiotensin receptor blockers (ARBs) may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Interactions linked to the amlodipine component of AMTELIP: Concomitant use requiring caution:

Grapefruit and grapefruit juice: Administration of AMTELIP with grapefruit or grapefruit juice is not recommended since bioavailability may be increased in certain patients resulting in increased blood pressure lowering effects.

CYP3A4 inhibitors: A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4 (plasma concentration increases by approximately 50 % and the effect of amlodipine is increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem cannot be excluded.

CYP3A4 inducers (anticonvulsant medicines [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum): Co-administration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and after its withdrawal.

Concomitant use to be taken into account:

Simvastatin: Co-administration of multiple doses of amlodipine with simvastatin 80 mg resulted in an increase in exposure to simvastatin up to 77 % compared to simvastatin alone. Therefore, limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Immunosuppressants: Amlodipine may increase the systemic exposure of ciclosporin or tacrolimus when co-administered. Frequent monitoring of trough blood levels of ciclosporin and tacrolimus and dose adjustment when appropriate is recommended.

Others: In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, non-steroidal anti-inflammatory medicines, antibiotics and oral hypoglycaemic medicines. When amlodipine and sildenafil were used in combination, each medicine independently exerted its own blood pressure lowering effect.

Additional information: Concomitant administration of 240 ml of grapefruit juice with a single oral dose of 10 mg amlodipine in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of amlodipine. Co-administration of amlodipine with cimetidine had no significant effect on the pharmacokinetics of amlodipine. Co-administration of amlodipine with atorvastatin, digoxin or warfarin had no significant effect on the pharmacokinetics or pharmacodynamics of these medicines.

AMTELIP should not be used during pregnancy and lactation. Effects related to the mono components are described below.

Pregnancy: Telmisartan: Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed, AMTELIP should be discontinued. Refer to sections 4.3 and 4.4. Medicines affecting the renin-angiotensin system, such as AMTELIP, 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 with AMTELIP should be stopped immediately, and, if appropriate, alternative therapy should be started. Should exposure to AMTELIP have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AMTELIP 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 (see section 5.3).

Lactation: It is not known whether telmisartan (as in AMTELIP) 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, AMTELIP should not be used by breastfeeding mothers (see section 4.3).

Fertility: 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 (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as syncope (fainting), somnolence, dizziness, or vertigo during treatment. Therefore, caution should be recommended when driving a vehicle or operating machinery. If patients experience these adverse effects, they should avoid potentially hazardous tasks such as driving or operating machinery.

a) Summary of adverse effects

The most frequent adverse reactions include dizziness and peripheral oedema. Serious syncope may occur less frequently. Adverse reactions previously reported with one of the individual components (telmisartan or amlodipine) may be potential adverse reactions with AMTELIP as well, even if not observed in clinical trials or during the post-marketing period.

b) Tabulated summary of adverse events

The safety and tolerability have been evaluated in five controlled clinical studies with over 3,500 patients, over 2,500 of whom received telmisartan in combination with amlodipine. Adverse reactions have been ranked under headings of frequency using the following convention: frequent; less frequent and not known (cannot be estimated from the available data).

MedDRA system organ class

Fixed dose combination of Telmisartan and Amlodipine

Telmisartan

Amlodipine

Infections and infestations:

Less frequent

Cystitis

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

Leukocytopenia, thrombocytopenia

Immune system disorders:

Hypersensitivity, anaphylactic reaction

Hypersensitivity

Metabolism and nutrition disorders:

Less frequent

Hyperkalaemia, hypoglycaemia (in diabetic patients)

Hyperglycaemia

Psychiatric disorders:

Less frequent

Depression, anxiety, insomnia

Mood change, confusion

Nervous system disorders:

Frequent

Dizziness

Less frequent

Somnolence, migraine, headache, paraesthesia, syncope, peripheral neuropathy, hypoaesthesia, dysgeusia, tremor

Extrapyramidal syndrome, hypertonia

Eye disorders:

Frequent

Visual disturbance (including diplopia)

Less frequent

Visual disturbance

Visual impairment

Ear and labyrinth disorders:

Less frequent

Vertigo

Tinnitus

Cardiac disorders:

Less frequent

Bradycardia, palpitations

Tachycardia

Myocardial infarction, dysrhythmia, ventricular tachycardia, atrial fibrillation

Less frequent

Hypotension, orthostatic hypotension, flushing

Vasculitis

Respiratory, thoracic and mediastinal disorders:

Less frequent

Cough, interstitial lung disease

Dyspnoea

Dyspnoea, rhinitis

Gastrointestinal disorders:

Frequent

Altered bowel habits (including diarrhoea and constipation)

Less frequent

Abdominal pain, diarrhoea, nausea, vomiting, gingival hypertrophy, dyspepsia, dry mouth

Flatulence, stomach discomfort

Pancreatitis, gastritis

Hepatobiliary disorders:

Less frequent

Abnormal hepatic function, liver disorder

Skin and subcutaneous tissue disorders:

Less frequent

Pruritus, eczema, erythema, rash

Hyperhidrosis, angioedema (with fatal outcome), drug eruption, toxic skin eruption, urticaria

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

Less frequent

Arthralgia, muscle spasms (cramps in legs), myalgia, back pain, pain in extremity (leg pain)

Tendon pain (tendinitis like symptoms)

Renal and urinary disorders:

Less frequent

Nocturia

Renal impairment including acute renal failure

Micturition disorder, pollakiuria

Reproductive system and breast disorders

Less frequent

Erectile dysfunction

General disorders and administration site conditions:

Frequent

Peripheral oedema

Less frequent

Asthenia, chest pain, fatigue, oedema, malaise

Influenza-like illness

Pain

Investigations:

Less frequent

Increased hepatic enzymes, increased blood uric acid

Increased blood creatinine, blood creatine phosphokinase increased, Decreased haemoglobin

Increased Weight, decreased weight

1: the event may be a chance finding or related to a mechanism currently not known

2: 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.

3: cases of interstitial lung disease (predominantly interstitial pneumonia and eosinophilic pneumonia) have been reported from post-marketing experience with telmisartan

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d found online under SAHPRAu2019s publications: https://www.sahpra.org.za/

Symptoms

Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects. The most prominent manifestations of telmisartan overdose are expected to be hypotension and tachycardia; bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported. Overdose with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment

The patient should be closely monitored, and the treatment should be symptomatic and supportive. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Telmisartan and amlodipine are not removed by haemodialysis.