Triplixam 5 mg/10 mg Film-Coated Tablets

Triplixam is indicated as substitution therapy for treatment of essential hypertension, in adult patients already controlled with amlodipine and the fixed dose combination perindopril/indapamide, taken at the same dose levels as contained in Triplixam.

Posology

One Triplixam film-coated tablet per day as a single dose, preferably to be taken in the morning and before a meal. Triplixam is not suitable for initial therapy. If a change of the posology is required, titration should be done with the individual components.

Special populations

Renal impairment (see sections 4.3 and 4.4) In severe renal impairment (creatinine clearance below 30 mL/min), treatment is contraindicated. In patients with moderate renal impairment (creatinine clearance 30 - 60 mL/min), Triplixam at the doses 10/2,5/5 mg and 10/2,5/10 mg is contraindicated. It is recommended to start treatment with appropriate doses of the individual components. Frequent monitoring of blood pressure, creatinine and potassium should be done.

Hepatic impairment (see sections 4.3, 4.4 and 5.2) Triplixam is contraindicated in patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. Safety of Triplixam has not been established in these patients.

Elderly (see section 4.4) Elimination of perindoprilat is decreased in the elderly (see section 5.2). Elderly can be treated with Triplixam according to renal function (see section 4.3).

Paediatric population The safety and efficacy of Triplixam in children and adolescents below 18 years of age, have not been established. No data are available.

Method of administration Oral use.

• Hypersensitivity to any of the ingredients of Triplixam.
• 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 4.5)
• Porphyria
• Lithium therapy: Concomitant administration with Triplixam may lead to toxic blood concentrations of lithium (see section 4.5)
• Pregnancy and lactation
• Concomitant use of Triplixam with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60mL/min/1,73m2) (see sections 4.5 and 5.1)
• Dialysis patients
• Patients with untreated decompensated heart failure
• Moderate renal impairment (creatinine clearance below 60 mL/min) for Triplixam doses containing 10/2,5 mg of perindopril/indapamide combination (i.e., Triplixam 10/2,5/5 mg and 10/2,5/10 mg)
• Hepatic encephalopathy
• Moderate hepatic impairment (Child Pugh B) and severe hepatic impairment (Child Pugh C)
• Hypokalaemia
• Severe hypotension
• Shock, including cardiogenic shock
• Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis)
• Haemodynamically unstable heart failure after acute myocardial infarction.
• Concomitant use with sacubitril/valsartan. Triplixam must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.4 and 4.5).
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5).
• Concomitant use of fluoroquinolones with ACE-inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (Creatinine Clearance u2264 30 mL/min) and in elderly patients.

All warnings related to each component, as listed below, should apply also to the fixed combination of Triplixam.

Special warnings

Lithium

Lithium should not be used in combination with perindopril/indapamide as contained in Triplixam (see sections 4.3 and 4.5).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

The concomitant use of ACE-inhibitors, such as contained in Triplixam angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Should a woman become pregnant while receiving Triplixam, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine (sections 4.3 and 4.6).

ACE-inhibitors such as contained in Triplixam and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Concomitant use of fluoroquinolones

Concomitant use of fluoroquinolones and ACE-inhibitors/Angiotensin such as contained in Triplixam or Angiotensin receptor blockers 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 ACE-inhibitors/Angiotensin receptor blockers whether used separately and/or concomitantly.

Potassium-sparing medicines, potassium supplements or potassium-containing salt substitutes

The combination of perindopril such as contained in Triplixam, and potassium-sparing medicines, potassium supplements or potassium-containing salt substitutes are not recommended (see section 4.5).

Neutropenia/agranulocytosis/thrombocytopenia/anaemia

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE-inhibitors such as contained in Triplixam. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodical monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever) (see section 4.8).

Renovascular hypertension

There is an increased risk of hypotension and renal insufficiency when a patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE-inhibitors such as contained in Triplixam (see section 4.3). Treatment with diuretics such as contained in Triplixam, may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine in patients with unilateral renal artery stenosis.

Hypersensitivity/angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including perindopril as contained in Triplixam. This may occur at any time during treatment. In such cases Triplixam should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1 000 (0,3 ml to 0,5 ml) and/or measures to ensure a patent airway, should be administered promptly. Black patients receiving ACE-inhibitors such as contained in Triplixam have been reported to have a higher incidence of angioedema compared to non-blacks. Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE-inhibitor (see section 4.3).

Intestinal angioedema has been reported in patients treated with ACE-inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE-inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE-inhibitors such as contained in Triplixam presenting with abdominal pain.

Sacubitril/valsartan

The combination of perindopril such as contained in Triplixam, with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

Concomitant use of NEP inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) Patients taking concomitant NEP inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in a patient already taking an ACE-inhibitor.

Anaphylactoid reactions during desensitisation

There have been reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE-inhibitors such as contained in Triplixam, during desensitisation treatment with hymenoptera (bees, wasps) venom. ACE-inhibitors should be used with caution in allergic patients treated with desensitisation, and avoided in those undergoing venom immunotherapy. However these reactions could be prevented by temporary withdrawal of the ACE-inhibitor for at least 24 hours before treatment in patients who require both ACE-inhibitors and desensitisation.

Anaphylactoid reactions during LDL apheresis

Patients receiving ACE-inhibitors such as contained in Triplixam, during low density lipoprotein (LDL)-apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis.

Haemodialysis patients

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., AN 69u00ae) and treated concomitantly with an ACE-inhibitor such as contained in Triplixam. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive medicine.

Primary aldosteronism

Patients with primary hyperaldosteronism generally will not respond to anti-hypertensive medicines acting through inhibition of the renin-angiotensin system. Therefore, the use of Triplixam is not recommended.

Hepatic encephalopathy

When liver function is impaired, thiazide diuretics and thiazide-related diuretics such as contained in Triplixam may cause particularly in case of electrolyte imbalance, hepatic encephalopathy which can progress to hepatic coma. Administration of Triplixam should be stopped immediately if this occurs.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics such as contained in Triplixam (see section 4.8). If 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.

Dual blockade of the RAAS with ARBu2019s, ACE-inhibitors or aliskiren

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors such as contained in Triplixam, 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 (see sections 4.3, 4.4 and 5.1).

Medicines increasing the risk of angioedema

Concomitant use of ACE-inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see section 4.3 and 4.4). Sacubitril/valsartan must not be started until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).

Concomitant use of ACE-inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk for angioedema (see section 4.4).

Medicines inducing hyperkalaemia

Some medicines or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE-inhibitors such as contained in Triplixam, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. The combination of these medicine increases the risk of hyperkalaemia.

Therefore, the combination of Triplixam with the above-mentioned medicines is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Concomitant use with Triplixam is contraindicated (see section 4.3)

Aliskiren

Concomitant use with Triplixam in patients with diabetes mellitus or patients with impaired renal function, increases the risk of hyperkalaemia, further deterioration of renal function and cardiovascular morbidity and mortality.

Fluoroquinolones

Concomitant use of fluoroquinolones and ACE-inhibitors such as contained in Triplixam, Angiotensin receptor blockers 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).

Extracorporeal treatments

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Triplixam is contraindicated during pregnancy and lactation.

Pregnancy

The use of Triplixam is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take Triplixam during pregnancy (see section 4.3). Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with Triplixam should be stopped immediately and if appropriate, alternative therapy should be started. Foetal exposure to ACE-inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly, spina bifida) and of kidney malformations.

Triplixam passes through the placenta and causes disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns, have been reported after administration of ACE-inhibitors, such as Triplixam, during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (see section 4.3).

Indapamide

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a feto-placental ischemia and growth retardation. Moreover, cases of hypoglycemia and thrombocytopenia in neonates have been reported following exposure near term.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

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).

Breastfeeding

Triplixam is contraindicated during lactation.

Perindopril

Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

Indapamide

There is insufficient information on the excretion of indapamide/metabolites in human milk. Hypersensitivity to sulphonamide-derived medicines and hypokalaemia might occur. A risk to newborns/infants cannot be excluded. Indapamide is closely related to thiazide diuretics which have been associated, during breastfeeding, with a decrease or even suppression of milk lactation.

Amlodipine

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 u2013 7 %, with a maximum of 15 %. The effect of amlodipine on infants is unknown.

Fertility

Common to perindopril and indapamide Reproductive toxicity studies showed no effect on fertility in female and male rats (see section 5.3). No effects on human fertility are anticipated.

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. 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 of Triplixam on the ability to drive and use machines have been performed. Triplixam may affect the ability to drive and use machines. Patients should not drive and use machines until they know how the treatment with Triplixam affects them.

Perindopril and indapamide may cause hypotension which may affect the ability of patients to drive and use machines. Amlodipine can cause hypotension, dizziness, headache, visual impairment, fatigue, weariness or nausea, which may impair the ability to drive and use machines.

Summary of the safety profile. The most commonly reported adverse reactions with perindopril, indapamide and amlodipine given separately are: hypokalaemia, dizziness, headache, paraesthesia, somnolence, dysgeusia, visual impairment, diplopia, tinnitus, vertigo, palpitations, flushing, hypotension (and effects related to hypotension), cough, dyspnoea, gastro-intestinal disorders (abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, change of bowel habit), pruritus, rash, rash maculo-papular, muscle spasms, ankle swelling, asthenia, oedema and fatigue.

Tabulated list of adverse reactions The following undesirable effects have been observed with perindopril, indapamide or amlodipine during treatment and ranked under the following frequency: Very common ( u2265 1/10); common ( u2265 1/100 to < 1/10); uncommon ( u2265 1/1 000 to < 1/100); rare ( u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

There is no information on overdosage with Triplixam in humans.

For perindopril/indapamide combination Symptoms The most likely adverse reaction in cases of overdose is hypotension, sometimes associated with nausea, vomiting, cramps, dizziness, sleepiness, mental confusion, oliguria which may progress to anuria (due to hypovolaemia). Salt and water disturbances (low sodium levels, low potassium levels) may occur.

Management The first measures to be taken consist of rapidly eliminating the product(s) ingested by gastric lavage and/or administration of activated charcoal, and restoring the fluid and electrolyte balance. If marked hypotension occurs, this can be treated by placing the patient in a supine position with the head lowered. If necessary an intravenous infusion of 0,9 % sodium chloride (isotonic saline) may be given, or any other method of volaemic expansion may be used. Perindoprilat, the active form of perindopril, can be dialysed (see section 5.2).

For amlodipine, Experience with intentional overdose in humans is limited. Symptoms Available data suggest that gross overdosage could 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. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24 - 48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Management Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.