Scientific conclusions and detailed explanation of the scientific grounds for the differences from the PRAC recommendation

Annex I Scientific conclusions, grounds for variation to the terms of the marketing authorisations and detailed explanation of the scientific grounds for the differences from the PRAC recommendation 1

Scientific conclusions and detailed explanation of the scientific grounds for the differences from the PRAC recommendation 1 Overall summary of the scientific evaluation by PRAC The renin-angiotensin system (RAS) is a hormone system that regulates blood pressure and fluid balance. RAS-acting agents act by blocking different stages of the renin-angiotensin system, lowering blood pressure and their use in the treatment of hypertension and its complications (including acute myocardial infarction, congestive heart failure and chronic kidney disease) is recommended in many current clinical guidelines. RAS-acting agents include angiotensinconverting enzyme inhibitors (ACE-inhibitors) such as benazepril, captopril, cilazapril, delapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril and zofenopril), angiotensin receptor blockers (ARBs) such as candesartan, telmisartan, valsartan, irbesartan, eprosartan, olmesartan, losartan and azilsartan and direct renin inhibitors such as aliskiren. The concept of dual RAS blockade through the combined use of several RAS-acting agents, emerged in the late 1990 s based on an experimental model hypothesising that the combined use of an ARB, an ACE-inhibitor or aliskiren could provide a more complete blockade of the RAS which could translate into better control of blood pressure and nephroprotective and cardioprotective effects. However, new data has emerged in the past years, raising doubts over the efficacy and identifying safety concerns associated with dual RAS blockade therapy through the combined use of ACE-inhibitors, ARBs or aliskiren. In particular, the publication of a metaanalysis by Makani et al 1 involving over 68,000 patients raised concerns that combining several RAS-acting agents may be associated with an increased risk of hyperkalaemia, hypotension and kidney failure, compared with the single use of one RAS-acting agent. In addition, the metaanalysis suggested that using multiple RAS-acting agents may not be more beneficial than using a single RAS-acting agent in terms of reducing overall mortality. It was noted that the Committee for Medicinal Products for Human Use (CHMP) had already conducted a review 2 under Article 20 of Regulation (EC) No 726/2004 for aliskiren-containing products, concluding that these products should be contraindicated in patients with diabetes mellitus or moderate to severe renal impairment who take ACE-inhibitors or ARBs. Having considered the new available evidence from the scientific literature and given the seriousness of the identified safety concerns, the Italian Medicines Agency (AIFA) decided to initiate a review under Article 31 of Council Directive 2001/83/EC on 17 April 2013, referring the matter to the Pharmacovigilance Risk Assessment Committee (PRAC) and requesting the PRAC to issue a recommendation on the benefit-risk of dual RAS blockade therapy through the combined use of ACE-inhibitors, ARBs or aliskiren and whether any regulatory measures should be taken on the marketing authorisations of the products involved in this procedure. The PRAC reviewed the totality of the available data, including clinical trials, meta-analysis and publications, the MAHs responses as well as the report from the Scientific Advisory Group in Cardiovascular Issues (SAG CVS). The PRAC was of the opinion that there is considerable evidence from large clinical trials and meta-analyses which conclusively demonstrates that dual RAS blockade therapy through the combined use of ACE-inhibitors, ARBs or aliskiren is associated with an increased risk of adverse events, including hypotension, hyperkalaemia and 1 Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the reninangiotensin system: meta-analysis of randomized trials. BMJ. 2013 Jan 28;346:f360. doi: 10.1136/bmj.f360. 2 European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines, 17/02/2012, http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/02/news_detail_001446.jsp&mid=wc0b01ac058004d5c1 2

renal failure compared to monotherapy, in particular in patients with diabetic nephropathy. This is of particular concern, as these patients and patients with renal impaired are already particularly prone to developing hyperkalaemia. The PRAC considered that the available efficacy data indicates that dual RAS blockade therapy does not provide significant benefit in the general patient population, although there is evidence to suggest that some selected patient subpopulations may benefit from this dual RAS blockade therapy. In particular, a number of trials in heart failure patients have shown that the addition of a second RAS-acting agent may reduce hospital admissions for heart failure in patients with heart failure, which is considered a meaningful clinical endpoint. The PRAC therefore concluded that dual RAS blockade therapy should not be routinely used in the treatment of heart failure and is not recommended in the general population although it may benefit certain patients who remain symptomatic while receiving monotherapy or who cannot otherwise use alternative therapies, including potentially patients with diabetic nephropathy. Treatment should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. The PRAC considered that the overall available data strongly suggests that the concerns identified with regard to safety and the lack of efficacy are a class effect and therefore considered that the conclusions of the review apply to all the active substances involved in the procedure. The PRAC was of the opinion that the concerns identified during this procedure with regard to the safety and the lack of efficacy of dual RAS blockade therapy could be adequately managed through changes to the product information, without the need for additional risk minimisation measures. The PRAC therefore concluded that the product information of all RAS-acting agents should be revised to reflect the identified risks and provide guidance to prescribers and patients. A warning was introduced to state that dual RAS blockade therapy through the combined use of ACE-inhibitors, ARBs or aliskiren is not recommended and, if considered absolutely necessary, should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. The PRAC however clearly specified, based on data from the ONTARGET 3 and VA NEPHRON-D 4 studies that ACE-inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy. The PRAC was also of the opinion that the contraindication based on the ALTITUDE 5 study data regarding the concomitant use of ACEinhibitors or ARBs with aliskiren-containing products in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 ml/min/1.73 m 2 ) was confirmed by the additional data reviewed and that it should also be implemented in the product information of ARBs and ACE-inhibitors. For candesartan- and valsartan-containing products, which are also authorised in the treatment of heart failure, additional information was agreed upon to reflect the fact that dual RAS blockade therapy in combination with an ACE-inhibitor may be of benefit in certain patients who cannot use other heart failure treatments, provided that they are used under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. 3 ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial 4 Veterans Affairs Nephropathy in Diabetes 5 Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints 3

Overall conclusion The PRAC concluded that the benefit-risk balance of RAS-acting agents remains favourable, including in the context of dual RAS blockade therapy, subject to the agreed revisions to the product information. Grounds for PRAC recommendation Whereas The PRAC considered the procedure under Article 31 of Directive 2001/83/EC initiated by Italy following the emergence of new evidence on the efficacy and safety of dual RAS blockade therapy through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren, to determine whether any regulatory measures should be taken on the marketing authorisations of the products involved in this procedure; The PRAC reviewed the totality of the available data, including clinical trials, meta-analysis and publications, the MAHs responses as well as the report from the Scientific Advisory Group in Cardiovascular Issues; The PRAC was of the view that there is considerable evidence, in particular from the ONTARGET, ALTITUDE and VA NEPHRON-D trials which conclusively demonstrates that dual RAS blockade therapy through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with an increased risk of adverse events, including hypotension, hyperkalaemia and renal failure compared to monotherapy; The PRAC considered that the available efficacy data indicates that dual RAS blockade therapy does not provide significant benefit in the general patient population although certain patient subpopulations may benefit from treatment, provided that it occurs only under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure; The PRAC was of the opinion that the concerns identified with regard to safety and the lack of additional efficacy of dual RAS blockade therapy are a class effect and that the conclusions of the review therefore apply to all the active substances involved in this procedure; The PRAC was of the opinion that the concerns identified with regard to the safety and the lack of additional efficacy of dual RAS blockade therapy can be adequately managed through changes to the product information, without the need for additional risk minimisation measures. The PRAC, as a consequence, concluded that the benefit-risk balance of RAS-acting agents remains favourable, provided that their product information is revised to reflect the concerns associated with dual RAS blockade therapy. Having considered the matter, the PRAC therefore recommended the variation of the marketing authorisations for RAS-acting agents. 4

2 Detailed explanation of the scientific grounds for differences from the PRAC recommendation Having reviewed the PRAC recommendation, the CHMP agreed with the overall scientific conclusions and grounds for recommendation. However, the CHMP considered that minor additional changes were necessary to the wording proposed for the Summary of Product Characteristics. Changes were made to the heart failure indication in section 4.4 for candesartan-containing products and in sections 4.2 and 4.4 for valsartan-containing products, in order to further harmonise the wording for the two substances. In addition, a number of typographical and QRD-related changes were made. In particular the contraindication statements recommended by the PRAC were deleted from sections 5.1 (where proposed) and from section 4.4 for aliskiren, as these were already proposed in section 4.3 and therefore considered redundant. Corresponding changes were made, where relevant, to the currently approved product information. CHMP opinion The CHMP, having considered the PRAC recommendation, agrees with the overall scientific conclusions by the PRAC and is of the opinion that the marketing authorisations for RAS-acting agents should be varied. 5

Annex II Amendments to relevant sections of the summary of product characteristics and package leaflet 6

For products containing the angiotensin-converting enzyme inhibitors (ACE-inhibitors) benazepril, captopril, cilazapril, delapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril and zofenopril, the existing product information shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the agreed wording as provided below I. Summary of Product Characteristics Section 4.1 - Therapeutic indications For all ACE-inhibitors with wording in section 4.1 stating that they can be used alone or in combination with other antihypertensive agents, the following cross-reference should be added: (see sections 4.3, 4.4, 4.5 and 5.1). Section 4.2 - Posology and method of administration For all ACE-inhibitors with wording in section 4.2 stating that they can be used alone or in combination with other antihypertensive agents, the following cross-reference should be added: (see sections 4.3, 4.4, 4.5 and 5.1). Section 4.3 Contraindication The following contraindication should be added to this section: The concomitant use of [Product name] with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m 2 ) (see sections 4.5 and 5.1). Section 4.4 - Special warnings and precautions for use The following wording should be incorporated in this section: 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 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. Section 4.5 Interaction with other medicinal products and other forms of interaction The following wording should be added to this section: 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 7

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). Section 5.1 Pharmacodynamic properties The following wording should be added to this section: 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. II. Package leaflet The following wording should be included in the specified sections: Section 2. What you need to know before you <take> <use> X Do not <take> <use> X <:> if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warnings and precautions Talk to your doctor <or> <pharmacist> <or nurse> before <taking> <using> X if you are taking any of the following medicines used to treat high blood pressure: 8

- an angiotensin II receptor blocker (ARBs) (also known as sartans - for example valsartan, telmisartan, irbesartan), in particular if you have diabetes-related kidney problems. - aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading Do not <take> <use> X Other medicines and X Tell your <doctor> <or> <pharmacist> if you are <taking> <using>, have recently <taken> <used> or might <take> <use> any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the headings Do not <take> <use> X and Warnings and precautions ) 9

For products containing the angiotensin II receptor blockers azilsartan, eprosartan, irbesartan, losartan, olmesartan and telmisartan, the existing product information shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the agreed wording as provided below I. Summary of Product Characteristics Section 4.1 - Therapeutic indications For angiotensin II receptor blockers with wording in section 4.1 stating that they can be used alone or in combination with other antihypertensive agents, the following cross-reference should be added: (see sections 4.3, 4.4, 4.5 and 5.1). Section 4.2 - Posology and method of administration For angiotensin II receptor blockers with wording in section 4.2 stating that they can be used alone or in combination with other antihypertensive agents, the following cross-reference should be added: (see sections 4.3, 4.4, 4.5 and 5.1). Section 4.3 Contraindication The following contraindication should be added to this section: The concomitant use of [Product name] with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m 2 ) (see sections 4.5 and 5.1). Section 4.4 - Special warnings and precautions for use The following wording should be incorporated in this section: 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 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. Section 4.5 Interaction with other medicinal products and other forms of interaction The following wording should be added to this section: 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 10

function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Section 5.1 Pharmacodynamic properties The following wording should be added to this section (for telmisartan-containing products that already have an extensive wording on ONTARGET in section 5.1, the following wording should be added in addition to the existing text, which should be maintained): 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. II. Package leaflet The following wording should be included in the specified sections: PL Section 2. What you need to know before you <take> <use> X Do not <take> <use> X <:> if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warnings and precautions Talk to your doctor <or> <pharmacist> <or nurse> before <taking> <using> X if you are taking any of the following medicines used to treat high blood pressure: 11

- an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetesrelated kidney problems. - aliskiren Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading Do not <take> <use> X Other medicines and X Tell your <doctor> <or> <pharmacist> if you are <taking> <using>, have recently <taken> <used> or might <take> <use> any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings Do not <take> <use> X and Warnings and precautions ) 12

For products containing candesartan, the existing product information shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the agreed wording as provided below I. Summary of Product Characteristics Section 4.1 - Therapeutic indications For candesartan-containing products with wording in section 4.1 stating that they can be used alone or in combination with other antihypertensive agents, the following cross-reference should be added: (see sections 4.3, 4.4, 4.5 and 5.1). In addition, the existing heart failure indication should be revised as follows: The treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction 40%) when ACE-inhibitors are not tolerated or as add-on therapy to ACE-inhibitors in patients with symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated (see sections 4.2, 4.4, 4.5 and 5.1). Section 4.2 - Posology and method of administration The following cross-reference should be added to the Posology in Hypertension section: (see sections 4.3, 4.4, 4.5 and 5.1). The following wording should be added in the Posology in Heart Failure section: [Product name] can be administered with other heart failure treatment, including ACE-inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicinal products. [Product name] may be co-administered with an ACE-inhibitor in patients with symptomatic heart failure despite optimal standard heart failure therapy when mineralocorticoid receptor antagonists are not tolerated. The combination of an ACE-inhibitor, a potassium-sparing diuretic and [Product name] is not recommended and should be considered only after careful evaluation of the potential benefits and risks (see sections 4.4, 4.8 and 5.1). Section 4.3 Contraindication The following contraindication should be added to this section: The concomitant use of [Product name] with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m 2 ) (see sections 4.5 and 5.1). Section 4.4 - Special warnings and precautions for use The following wording should be incorporated in this section: Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 13

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. The following wording should be incorporated in the Heart failure section: Concomitant therapy with an ACE-inhibitor in heart failure The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when [Product name] is used in combination with an ACEinhibitor. Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and candesartan is also not recommended. Use of these combinations should be 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. Section 4.5 Interaction with other medicinal products and other forms of interaction The following wording should be added to this section: 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). Section 5.1 Pharmacodynamic properties The following wording should be added to this section: 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 14

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. II. Package leaflet The following wording should be included in the specified sections: Section 1. What X is and what it is used for X can be used to treat adult heart failure patients with reduced heart muscle function when Angiotensin Converting Enzyme (ACE) inhibitors cannot be used or in addition to ACE-inhibitors when symptoms persist despite treatment and mineralocorticoid receptor antagonists (MRA) cannot be used. (ACE-inhibitors and MRAs are medicines used to treat heart failure). Section 2. What you need to know before you <take> <use> X Do not <take> <use> X <:> if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren Warnings and precautions Talk to your doctor <or> <pharmacist> <or nurse> before <taking> <using> X if you are taking any of the following medicines used to treat high blood pressure: - an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetesrelated kidney problems. - aliskiren if you are taking an ACE-inhibitor together with a medicine which belongs to the class of medicines known as mineralocorticoid receptors antagonists (MRA). These medicines are for the treatment of heart failure (see Other medicines and X ). Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading Do not <take> <use> X Other medicines and X Tell your <doctor> <or> <pharmacist> if you are <taking> <using>, have recently <taken> <used> or might <take> <use> any other medicines. 15

Your doctor may need to change your dose and/or to take other precautions: - If you are taking an ACE-inhibitor or aliskiren (see also information under the headings Do not <take> <use> X and Warnings and precautions ) - If you are being treated with an ACE-inhibitor together with certain other medicines to treat your heart failure, which are known as mineralocorticoid receptors antagonists (MRA) (for example spironolactone, eplerenone). 16

For products containing valsartan, the existing product information shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the agreed wording as provided below I. Summary of Product Characteristics Section 4.1 - Therapeutic indications For valsartan-containing products with wording in section 4.1 stating that they can be used alone or in combination with other antihypertensive agents, the following cross-reference should be added: (see sections 4.3, 4.4, 4.5 and 5.1). In addition, for products authorised in the treatment of heart failure, the existing heart failure indication should be revised as follows: Heart Failure Treatment of adult patients with symptomatic heart failure when ACE-inhibitors are not tolerated or in beta-blocker intolerant patients as add-on therapy to ACE-inhibitors when mineralocorticoid receptor antagonists cannot be used (see sections 4.2, 4.4, 4.5 and 5.1). Section 4.2 - Posology and method of administration For valsartan-containing products with wording in section 4.2 stating that they can be used alone or in combination with other antihypertensive agents, the following cross-reference should be added: (see sections 4.3, 4.4, 4.5 and 5.1). In addition, for products authorised in the treatment of heart failure, the following wording should be added in the Heart failure section: Valsartan may be administered with other heart failure therapies. However, the triple combination of an ACE-inhibitor, valsartan and a beta blocker or a potassium-sparing diuretic is not recommended (see sections 4.4 and 5.1). Evaluation of patients with heart failure should always include assessment of renal function. Section 4.3 Contraindication The following contraindication should be added to this section: The concomitant use of [Product name] with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m 2 ) (see sections 4.5 and 5.1). Section 4.4 - Special warnings and precautions for use The following wording should be incorporated in this section: Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 17

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. In addition, for products authorised in the treatment of heart failure, the following wording should be incorporated in the Heart failure section: Heart failure The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when [Product name] is used in combination with an ACEinhibitor. In patients with heart failure, the triple combination of an ACE-inhibitor, a beta blocker and [Product name] has not shown any clinical benefit (see section 5.1). This combination apparently increases the risk for adverse events and is therefore not recommended. Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and valsartan is also not recommended. Use of these combinations should be under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. Caution should be observed when initiating therapy in patients with heart failure. Evaluation of patients with heart failure should always include assessment of renal function (see section 4.2). Use of [Product name] in patients with heart failure commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed (see section 4.2). In patients whose renal function may depend on the activity of the renin-angiotensin-aldosteronesystem (e.g. patients with severe congestive heart failure), treatment with ACE-inhibitors has been associated with oliguria and/or progressive azotaemia and in rare cases with acute renal failure and/or death. As valsartan is an angiotensin II receptor blocker, it cannot be excluded that the use of [Product name] may be associated with impairment of the renal function. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Section 4.5 Interaction with other medicinal products and other forms of interaction The following wording should be added to this section: 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 18

function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Section 5.1 Pharmacodynamic properties The following wording should be added to this section: 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. II. Package leaflet The following wording should be included as applicable in the specified sections: Section 1. What X is and what it is used for X can be used to treat symptomatic heart failure in adult patients. X is used when a group of medicines called Angiotensin Converting Enzyme (ACE) inhibitors (a medication to treat heart failure) cannot be used or it may be used in addition to ACE-inhibitors when other medications to treat heart failure cannot be used. Section 2. What you need to know before you <take> <use> X Do not <take> <use> X <:> if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren 19

Warnings and precautions Talk to your doctor <or> <pharmacist> <or nurse> before <taking> <using> X if you are taking any of the following medicines used to treat high blood pressure: - an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetesrelated kidney problems. - aliskiren - if you are being treated with an ACE-inhibitor together with certain other medicines to treat your heart failure, which are known as mineralocorticoid receptors antagonists (MRA) (for example spironolactone, eplerenone) or betablockers (for example metoprolol). Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading Do not <take> <use> X Other medicines and X Tell your <doctor> <or> <pharmacist> if you are <taking> <using>, have recently <taken> <used> or might <take> <use> any other medicines. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings Do not <take> <use> X and Warnings and precautions ) If you are being treated with an ACE-inhibitor together with certain other medicines to treat your heart failure, which are known as mineralocorticoid receptors antagonists (MRA) (for example spironolactone, eplerenone) or betablockers (for example metoprolol). 20

For products containing aliskiren, the existing product information shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the agreed wording as provided below I. Summary of Product Characteristics Section 4.3 Contraindication The following contraindication should be reflected in this section: The concomitant use of [Product name] with an ACE-inhibitor or an angiotensin II receptor blocker is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m 2 ) (see sections 4.4, 4.5 and 5.1). Section 4.4 - Special warnings and precautions for use The following wording should be reflected in this section: Dual blockade of the renin-angiotensin-aldosterone-system (RAAS) Hypotension, syncope, stroke, hyperkalaemia and decreased renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system (see section 5.1). Dual blockade of the RAAS by combining aliskiren with an ACEinhibitor or an angiotensin II receptor blocker is therefore not recommended. 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. Section 4.5 Interaction with other medicinal products and other forms of interaction The following wording should be added to this section: 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, stroke, 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). II. Package leaflet The following wording should be included in the specified sections: Section 2. What you need to know before you <take> <use> X Do not <take> <use> X <:> if you have diabetes mellitus or impaired kidney function and you are treated with either of the following classes of medicines used to treat high blood pressure: - an ACE-inhibitor such as enalapril, lisinopril, ramipril. or - an angiotensin II receptor blocker such as valsartan, telmisartan, irbesartan. 21

Warnings and precautions Talk to your doctor <or> <pharmacist> <or nurse> before <taking> <using> X if you are taking either of the following classes of medicines used to treat high blood pressure: - an ACE-inhibitor such as enalapril, lisinopril, ramipril. or - an angiotensin II receptor blocker such as valsartan, telmisartan, irbesartan. Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals. See also information under the heading Do not <take> <use> X Other medicines and X If you are taking an angiotensin II receptor blocker (ARB) or an ACE-inhibitor, (see also information under the headings Do not <take> <use> X and Warnings and precautions ) 22