Triapin 2.5mg/2.5mg prolonged release tablet

Section 4.3 added:-

concomitant use with sacubitril/valsartan therapy (see sections 4.4 and 4.5).

 

Section 4.4 added:-

Wording added:-

of angioedema which may cause angioedema inhibitors (e.g. temsirolimus, everolimus, sirolimus),  or neprilysin (NEP) inhibitors (such as racecadotril). The combination of ramipril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see sections 4.3 and 4.5)..

Section 4.5 added:-

Contraindicated associations

The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see sections 4.3 and 4.4). Treatment with ramipril must not be started until 36 hours after taking the last dose of sacubitril/valsartan. Sacubitril/valsartan must not be started until 36 hours after the last dose of Triapin.

Neprilysin (NEP) inhibitors replaces Racecadotril

Increased replaces potential

For a  replaces with

Sacubitril/valsartan

The concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema.

Section 4.6

Lactation replaces breast feeding

The Summary of Product Characteristics (SmPC) of Triapin 2.5mg/2.5mg prolonged release tablets and Triapin 5mg /5mg prolonged release tablets is updated with information concerning the concomitant use with racecadotril that may lead to an increased risk of angioedema, in Sections 4.4 “Special Warnings and Precautions for use” and 4.5 “Interaction with other medicinal products”. The package leaflet (PL) is impacted by these changes in Section 2 "Warnings and precautions" and "Other medicines and TM".

 

Electrolyte Monitoring: Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors, including ramipril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, age (>70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium-retaining diuretics; or other active substances increasing potassium (e.g. heparin, trimethoprim and in fixed dose combination with sulfamethoxazole, tacrolimus, ciclosporin); or condition such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).


4.5

Medicinal products causing hyperkalaemia

Potassium salts, heparin, potassium-retaining diuretics and other active substances causing hyperkalaemia (e.g trimetoprimtrimethoprim and in fixed dose combination with sulfamethoxazole, tacrolimus, ciclosporin). Hyperkalaemia may occur, therefore, close monitoring of serum potassium is required (see section 4.4).

.

Section 4.3 updated

Triapin must not be used:

 

·          in patients with hypersensitivity to felodipine (or other dihydropyridines), ramipril, other angiotensin converting enzyme (ACE) inhibitors or any of the excipients listed in section 6.1.

·          in patients with a history of angioedema.

·          in unstable haemodynamic conditions:  cardiovascular shock, untreated heart failure, acute myocardial infarction, unstable angina pectoris, stroke.

·          haemodynamically significant cardiac valvular obstruction.

·          dynamic cardiac outflow obstruction.

·          in patients with AV block II or III.

·          in patients with severely impaired hepatic function.

·          in patients with severely impaired renal function (creatinine clearance less than 20 ml/min) and in patients on dialysis.

·          during pregnancy.

·          during lactation.

The concomitant use of Triapin with aliskiren-containing product is contraindicated with aliskiren-containing medicinal products in patients with diabetes mellitus or with moderate to severe renal impairment (creatinine clearance GFR <60 ml/min/1.73 m²) (see sections 4.5 and 5.1)

Section 4.4 updated:

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren-containing medicinal products

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 (see sections 4.5 and 5.1).

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.

Dual blockade of the renin-angiotensin-aldosterone system by combining Triapin with aliskiren is not recommended since there is an increased risk of hypotension, hyperkalemia and changes in renal function.

The use of Triapin in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (creatinine clearance < 60 ml/min) (see section 4.3).

Section 4.5 updated:

Contraindicated combinations

 

Aliskiren-containing medicinal products: The combination of Tazko mite with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60 ml/min/1.73m²) (see sections 4.3, 4.4 and 5.1).

 

Not recommended associations

 

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 (see sections 4.3, 4.4 and 5.1).

 

Not recommended associations

 

Potassium salts, potassium-retaining diuretics: Rise in serum potassium concentration is to be anticipated. Concomitant treatment with potassium-retaining diuretics (e.g. spironolactone, triamterene, or amiloride) or with potassium salts requires close monitoring of serum potassium.

Section 5.1 new text included:

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

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Section 4.4 updated to include a new paragraph:

Pregnancy

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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Section 4.6: Title updated to change 'lactation' to 'breast feeding' with the following changes to the text:

When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

 

 Fetal exposure to ACE inhibitors during the second and third trimesters has been associated with neonatal hypotension, renal failure, face or skull deformities and/or death. Maternal oligohydramnios have also been reported reflecting decreasing renal function in the fetus. Limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation have been reported in association with oligohydramnios. Intrauterine growth retardation, prematurity, persistent ductus arteriosus and fetal death have also been reported, but it is not clear whether they are related to the ACE inhibitor or to the underlying maternal disease. Whether exposure limited to the first trimester can adversely effect fetal outcome is not known. ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure 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). (See also section 5.3). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4).

Type of the Variation Application(s): Type IA Grouping of 7 type IA variations:

• Type B.III.2. Change to comply with Ph. Eur. or with a national pharmacopoeia of a Member State

            a.2) Change in specifications of Pre-gelatinized maize starch, Polyoxyl 40 hydrogenated castor oil, Sodium stearyl fumarate and Na Aluminum silicate from a former non EU Pharmacopoeia (USP/NF) to fully comply with the Ph. Eur.: 4 variations

c) Change in specifications of Ethanol and Propyl Gallate from a national pharmacopoeia of a Member State (British Pharmacopoeia) to the Ph. Eur.: 2 variations

B.II.e.1. Change in immediate packaging of the finished product

b.3) Deletion of one immediate packaging container, HDPE bottle that does not lead to the complete deletion of a strength or pharmaceutical form : 1 variation

Type II No. C.1.4 to implement the update of the Sanofi ramipril/felodipine CCDS version 5.

Type II No. C.1.4 to implement the update of the Sanofi ramipril/felodipine CCDS version 5.

Type II Procedure in order to implement the update of the Sanofi remipril-felodipine CCDS version 3.

Update to storage condition and shelf life. Trading style update to change 'Sanofi aventis' to Sanofi'.

Update to sections 6.3 and 6.4

Updates to section 7.

Section 4.8 side-effects - update to QRD template