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Guidance on Format of the RMP in the EU in Integrated Format

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Guidance on Format of the RMP in the EU in Integrated Format Splendris Pharmaceuticals GmbH Benazeprilhydrochloride “Splendris” RMP v. 1.0 02 October 2017 VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Hypertension, is a long term medical condition in which the blood pressure is persistently elevated. Usually it does not cause symptoms, but it is a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, vision loss, and chronic kidney disease. It is the most important preventable risk factor for premature death worldwide. Hypertension results from a complex interaction of genes and environmental factors like rising age, high salt intake, lack of exercise, obesity, or depression. As mechanisms the most evident are disturbance in the kidneys’ salt and water handling and/or abnormalities of the sympathic nervous system. Approximately one billion adults worldwide are affected. In Europe hypertension occurs in 30-43% of adult people, 1 to 5% of children and adolescents and 0.2 to 3% of newborns. Treatment options include changes in lifestyle, like dietary changes, physical exercise, weight loss, and medications, like ACE-inhibitors or calcium channel blockers. VI.2.2 Summary of treatment benefits The benazepril formulation described is a generic equivalent to the innovator formulation. Clinical studies have been performed with benazepril in hypertensive patients showing that blood pressure is significantly reduced. When given with other blood lowering agents e.g. betablockers, the antihypertensive effect is greater than for benazepril alone. In different studies, it has been shown that benazepril was similar or superior in lowering blood pressure and reducing proteinuria or myocardial ischaemia when compared with hydrochlorthiazide, metoprolol, captopril, nifedipine or nitrendipine. In patients with kidney disease, the metabolite benazeprilat accumulates so dosing need to be adapted. Safety studies show the the adverse effects profile is similar to other Angiotensin-Converting Enzyme Inhibitors. The overall conclusion is that benazepril is safe and efficacious. VI.2.3 Unknowns relating to treatment benefits The efficacy and safety in children and adolescents (under 18 years) has not been established. Treatment with benazepril is not recommended. Black patients show a weaker response to treatment with ACE-inhibitors. There is currently no evidence that benazepril may be less effective in other patient groups. VI.2.4 Summary of safety concerns Important identified risks Table 19: Important identified risks Risk What is known Preventability Hypersensitivity Angioedema may occur in the first weeks of treatment Any sign of allergy or skin reactions, including and in rare cases it may occur after long-term use. abnormalities should be swelling of the skin Angioedema is a rapid swelling of the skin. It can be closely monitored. In most (Angioedema) and caused by allergy or as side effect to medications, cases, benazepril should be Stevens-Johnson particularly ACE-inhibitors. ACE-inhibitors cause a higher stopped immediately and syndrome rate of angioedema in black patients than in non-black an alternative treatment Page 51 of 85 Splendris Pharmaceuticals GmbH Benazeprilhydrochloride “Splendris” RMP v. 1.0 02 October 2017 Risk What is known Preventability patients. ACE-inhibitors block the enzyme ACE, which used, which did not affect can no longer degradate a protein called bradykinin. bradykinin. Bradykinin is an inflammatory mediator which then accumulates and causes angioedema. Rapidly progressing cases should be treated as medical emergency as airway obstruction and suffocation can occur. The risk of angioedema may be increased in patients receiving combinated therapy with ACE-inhibitors and mTOR-inhibitors (e.g. temsirolimus, sirolimus and everolimus). Stevens-Johnson syndrome (SJS) is a special form of a life-threatening and sometimes fatal skin condition, in which cell death causes the upper part of the skin to separate from the lower part of the skin. The syndrome may be related to hypersensitivity complexes affecting skin and mucousa. The main known causes are certain medications. A few reports of SJS have been reported after use of benazepril. Increased blood levels An increase in serum potassium levels has been Frequent monitoring of of potassium observed in patients taking benazepril. Risk factors for serum potassium is (Hyperkalaemia) the increase are kidney failure, diabetes mellitus, recommended, if kidney concomitant treatment with potassium-sparing problems are known, if the diuretics, potassium supplements or potassium- patient has diabetes containing salt substitutes as well as concomitant mellitus and if he/she treatment with other medicines that can leed to an concomitantly uses increase in serum potassium values (e.g. ACE-inhibitors, medicinal products that can cyclosporin or heparin). leed to an increase in serum potassium values. Dual blockade of the The renin-angiotension-aldosteron-system (RAAS) is a If dual blockade therapy is renin-angiotensin- hormone system involved in the regulation of the salt considered absolutely aldosterone system balance and the arterial blood pressure. There is necessary, this should only (RAAS) evidence that the use of ACE-inhibitors in combination occur under specialist with angiotensin II receptor blockers (pharmaceuticals supervision and close that modulate the renin-angiotensin system) or aliskiren monitoring of kidney (a direct renin inhibitor) increases the risk of low blood function, electrolytes and pressure, increased blood levels of potassium and blood pressure. ACE- decreased kidney function (including acute kidney inhibitors, aliskiren and failure), compared to the use of a single RAAS-acting angiotensin II receptor agent. Dual blockade of RAAS through the combined use blockers should not be used of ACE-inhibitors, angiotensin II receptor blockers or in combination in patients aliskiren is therefore not recommended. with diabetic nephropathy. Use in patients with Impaired kidney function or worsening of impaired Routine monitoring of kidney (renal) kidney function associated with the use of benazepril kidney function is necessary impairment has been reported as common side effect. Kidney failure in patients with mild to has been reported in very rare cases, especially in moderate kidney patients with severe heart failure or kidney disease. In dysfunction and patients patients with severe renal impairment the elimination is concomitantly using reduced leading to accumulation of benazepril. In NSAIDs. The dose shoud be patients with moderate impairment only minor changes reduced, if the creatinine were observed which did not require dose adjustment. clearance is below 30 When ACE-inhibitors are administered combined with ml/min and a maximum non-steroid anti-inflammatory drugs (NSAIDs), dose of 10 mg should not attenuation of the blood lowering effect may occur. be exceeded. NSAIDs are drugs which provide pain-killing and fever- Page 52 of 85 Splendris Pharmaceuticals GmbH Benazeprilhydrochloride “Splendris” RMP v. 1.0 02 October 2017 Risk What is known Preventability reducing effects, e.g.acetylsalicylic acid, ibuprofen or naproxen. Combined use of ACE-inhibitors and NSAIDs may lead to an increased risk of worsening of kidney function, including possible acute kidney failure, and an increase in serum potassium, especially in patients with poor pre-existing kidney function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically hereafter. If diagnosed promptly and treated appropriately, kidney failure under benazepril is usually avoidable or reversible. Impaired liver Rare case reports of benazepril related liver injury, In patients with liver function (Hepatic where liver function test rose are reported with a disease frequent impairment) sydrome that starts with jaundice and progresses to monitoring of liver function fulminat liver necrosis and sometimes death. The tests during benazepril mechanism of this syndrome is not known administration is recommended. Patients who develop jaundice or significant elevation of liver enzymes must discontinue treatment with benazepril and receive appropriate medical treatment. Drug interactions Benazepril should be used with extreme caution in Though strictly speaking patients with collagen vascular disease, not preventable, any sign immunosuppressant therapy, treatment with of reduced number of allopurinol or procainamide, or a combination of blood cells should be these. Some of these patients develop severe considered and infections, which in a few instances did not respond to appropriate treatment, intensive antibiotic therapy. including medical advice, Concomitant use of certain anaesthetics, tricyclic sought. antidepressants and antipsychotics with ACE- Combinations in general inhibitors may cause lowering of the blood pressure. should be administered When ACE-inhibitors are administered combined with with caution, especially in non-steroid anti-inflammatory drugs (NSAIDs), the elderly. Patients attenuation of the blood lowering effect may occur. should be adequately Combined use of ACE-inhibitors and NSAIDs may lead hydrated and to an increased risk of worsening of kidney function, consideration should be including possible acute kidney failure, and an given to monitoring increase in serum potassium, especially in patients kidney
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