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
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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-
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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 function, any sign with poor pre-existing kidney function. of allergy, change of The risk of angioedema may be increased in patients serum potassium level or receiving combinated therapy with ACE-inhibitors and blood pressure after mTOR-inhibitors (e.g. temsirolimus, sirolimus and initiation of combined everolimus). mTOR means ‘mechanistic target of therapy, and periodically rapamycin’. It is a protein involved in the regulation of hereafter. different cellular processes, like cell survival, cell Susceptible patients, motility or cell growth. mTOR inhibitors are used, e.g. therapy should be started to prevent transplant rejection.An increase in serum under medical potassium levels may occur with concomitant use of supervision and the ACE-inhibitors and cyclosporine (an patiens should be immunosuppresant drug used in organ followed closely transplantation to prevent rejection), and with whenever the dose of
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Splendris Pharmaceuticals GmbH Benazeprilhydrochloride “Splendris” RMP v. 1.0 02 October 2017
Risk What is known Preventability concomitant use of ACE-inhibitors and heparin (a benazepril and/or blood thinner used to treat deep vein thrombosis and combination medication lung embolism). In patients already initiated on is adjusted. diuretic therapy, and especially those recently placed The likelihood of adverse in diuretic therapy, a profound fall in blood pressure effects can be reduced by can occasionally be observed with therapy when discontinuation of benazepril is added diuretics, by increasing the intake of dietary salts prior to administration, and by initiation of therapy with lower doses of the ACE-inhibitor. Low blood pressure Decrease in blood pressure may occur during therapy In susceptible patients, (Hypotension) with benazepril. However, syptomatic decrease is rare in therapy should be started patients without any risk factors. Hypotension is more under medical supervision likely to occur in patients who are dehydrated, e.g. by and the patiens should be diuretic therapy, diarrhoea, vomiting or dialysis. followed closely whenever A transient hypotensive response is not a the dose of benazepril contraindication to further doses. and/or diuretics is adjusted. In patients already initiated on diuretic therapy, and Similar considerations may especially those recently placed in diuretic therapy, a apply to patients with profound fall in blood pressure can occasionally be ischaemic heart or observed when benazepril is added. cerebrovascular disease in whom an excessive fall in The likelihood of adverse effects can be reduced by blood pressure could result discontinuation of diuretics, by increasing the intake of in a heart infarction or dietary salts prior to administration, and by initiation of cerebrovascular accident. therapy with lower doses of the ACE-inhibitor. Further increases in dosage should be performed with caution. Foetotoxicity (with The use of ACE-inhibitors is not recommended during ACE-inhibitors should not use in 2nd and or 3rd the first trimester of pregnancy and is contraindicated be initiated during trimester of during the 2nd and 3rd trimester. pregnancy. pregnancy ACE-inhibitors, including benazepril have been shown to Patients planning induce adverse effects on the late foetal development, pregnancy should be resulting in e.g. foetal death and congenital effects, in changed to alternative particular affecting the skull. antihypertensive therapy, which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with benazepril should be stopped immediately. Infants whose mothers have taken ACE-inhibitors should be closely monitored for low blood pressure.
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Splendris Pharmaceuticals GmbH Benazeprilhydrochloride “Splendris” RMP v. 1.0 02 October 2017
Important potential risks Table 20: Potential Risks Potential risks What is known Teratogenicity (with The use of ACE-inhibitors is not recommended during the first trimester of pregnancy. use during 1st ACE-inhibitors, including benazepril have been shown to induce adverse effects on the trimester of late foetal development, resulting in e.g. foetal death and congenital effects, in pregnancy) particular affecting the skull. Patients planning pregnancy should be changed to antihypertensive therapy which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with benazepril shoud be stopped immediately. Infants whose mothers have taken ACE-inhibitors should be closely monitored for low bloos pressure. Increased Very rare cases of myocardial infarction with benazepril have been reported. In patients cardiovascular risk in with ischaemic heart disease a profound fall in blood pressure could result in patients with left myocardial infarction or cerebral haemorrhage. Heart disease describes a range of ventricular conditions that affect your heart and generally refers to conditions that involve dysfunction and narrowed or blocked blood vessels that can lead to a heart attack, chest pain (angina) ischaemic heart or stroke. Other heart conditions, such as those that affect your heart’s muscle, valves disease or rhythm, also are considered forms of heart disease. Syptoms can include: shortness of breath, chest pain, pain, numbness, pain in the neck, jaw, throat, upper abdomen or back, nausea and extreme fatigue. Treatment with benazepril alleviates symptoms in patients with cardiac insufficiency. The treatment of cardiac insufficiency is a special task and should be initiated at a hospital. Any sign of myocardial infarction should be closely monitored and discussed with your physician. In most cases, benazepril should be stopped and an alternative treatment used.
Missing information Table 21: Missing information Missing information What is known Use during Benazepril was found in small amounts in the breast milk. However, it is unknown, if breastfeeding this amount is low enough not to cause any effects on breastfed children. Benazepril is not recommended to be used by mothers breastfeeding pre-term infants and newborns few weeks after delivery, because of the potential risk of harmful effects to the heart and kidney and because, there is not enough clinical experience. Use in paediatric The safety and efficacy of benazepril in children and adolescents below 18 years has patients not been established.
VI.2.5 Summary of risk minimisation measures by safety concern
All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The information in these documents is known as routine risk minimisation measures. This medicine has no additional risk minimisation measures.
VI.2.6 Planned post authorisation development plan
A post-authorisation development plan is currently not planned.
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VI.2.7 Summary of changes to the Risk Management Plan over time
Not applicable.
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