| The following changes have been made to the SPC:
Section 2: Qualitative and quantitative composition
Addition of the wording ‘full list’ and ‘section’.
Section 4.1- Therapeutic indication:
Addition of new indication for ‘Treatment of renal disease’. The remainder of the text has been reworded but the information remains the same.
Section 4.2: The Entire section has been re-formatted and re-worded. The following changes to advice have been made;
Adults- Diuretic treated patients: the following advice has been added: ‘Renal function and serum potassium should be monitored’.
Hypertension: advice with regards to the initial recommended dose in patients not on diuretics and without congestive heart failure has changed from 1.25mg once daily to ‘2.5 mg daily’. Previous SPC advised that dosage should be increased incrementally at intervals of 1-2 weeks, where as the new SPC advises that the dose can be doubled at intervals of 2 to 4 weeks. Recommendation for 10mg as maximum dose remains the same. Advice for initial dosage in patients with coexisting conditions remains the same- 1.25mg daily and under close medical supervision.
Cardiovascular prevention
This information was previously under reducing the risk of myocardial infarction, stroke or cardiovascular death and/ or the need for revascularisation procedures- the information has been re-worded and re-formatted but content remains the same.
Treatment of renal disease AND In patients with diabetes and at least one cardiovascular risk- these are both new sections in the SPC. Guidance re: dosing in patients with renal impairment was provided in previous SPC, and this information is the same, just reworded and re-formatted into this section.
Treatment of renal disease
In patients with diabetes and microalbuminuria:
Starting dose:
The recommended initial dose is 1.25 mg of TRITACE once daily.
Titration and maintenance dose
Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.
In patients with diabetes and at least one cardiovascular risk
Starting dose:
The recommended initial dose is 2.5 mg of TRITACE once daily.
Titration and maintenance dose
Depending on the patient’s tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg TRITACE after one or two weeks and then to 10 mg TRITACE after a further two or three weeks is recommended. The target daily dose is 10 mg.
In patients with non-diabetic nephropathy as defined by macroproteinuria > 3g/day- NEW SECTION
Starting dose:
The recommended initial dose is 1.25 mg of TRITACE once daily.
Titration and maintenance dose
Depending on the patient’s tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.
Guidance for Secondary prevention after acute myocardial infacrtion and with heart failure, Elderky, and paediatric populations has been re-worded and re-formatted but remains the same.
The guidance for maximum dose in patients with hepatic impairment has changed from 1.25mg to 2.5mg.
Recommendation for dosing in patients with renal impairment in varying degrees of creatinine clearance are provided under special populations:
Patients with renal impairment
Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):
- if creatinine clearance is ≥ 60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 10 mg;
- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;
- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;
- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.
4.3 Contraindications:
Overall information remains the same, however it has been re-worded. Contraindication for ‘breast feeding women’ has been removed.
4.4 Special warnings and precautions:
The entire text from this section of the SPC has been deleted and re-worded and re-formatted under different headings.
The following new wording has been added:
- Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, 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 ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Under ‘Patients with strongly activated renin-angiotensin-aldosterone system’, new wording as been added for
- patients with unilateral renal artery stenosis with a second functioning kidney.
- And rather than stating ‘heart failure’ it now states- patients with decompensated congestive heart failure
The following new sections have been added:
- Patients at risk of cardiac or cerebral ischemia in case of acute hypotension
The initial phase of treatment requires special medical supervision.
- Elderly patients
See section 4.2.
- Surgery
It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.
- Anaphylactic reactions during desensitization
The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of TRITACE should be considered prior to desensitization. (this section has been deleted from section 4.5 and placed here)
- Ethnic differences
ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.
As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.
- Cough
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
4.5 Interaction with other medicinal products and other forms of interactions
The following text has been removed from this section:
Advise re: desensitization therapy and ‘ the protein of ramipril is about 73% and of ramiprilat about 56%.
This entire section has been re-worded to include specific examples of drugs that interact with ramipril and re-formatted as below:
Contra-indicated combinations:
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.
Precautions for use:
Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.
Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g.nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)
Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of TRITACE: Blood pressure monitoring is recommended.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).
Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.
Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.
Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of TRITACE is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.
4.6 Pregnancy and Lactation
This entire section has been reworded but the guidance remains the same.
4.7 Effects on ability to drive and use machines
This section has been re-worded but the guidance remains the same.
4.8 Undesirable effects
The entire section has been deleted and replaced by a table that provides a comprehensive listing of all undesirable effects associated with Tritace, as common, uncommon, rare, very rare and not known.
4.9 overdose
This section has been re-worded and re-formatted. Specific guidance re: use of activated charcoal 50g for adults, 1g/kg for children has been deleted. Overall guidance remains the same.
5.1 Pharmocodynamic properties
Pharmacotherapeutic group: ATC code changed from: CO2EAO5 to C09AA05.
The entire section has been deleted and then re-worded and re-formatted to include greater detail on cardiovascular prevention/ Nephroprotection- this includes more data from the HOPE and MICRO- HOPE studies, and the AIRE study for secondary prevention after acute myocardial infarction.
5.2 Pharmacokinetic properties
This section has been re-worded but details of the pharmacokinetic properties of the drug remain the same. The following sections have been added:
Patients with renal impairment (see section 4.2):
Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in subjects with normal renal function.
Patients with hepatic impairment (see section 4.2):
In patients with impaired liver function, the metabolism of ramipril to ramiprilat was delayed, due to diminished activity of hepatic esterases, and plasma ramipril levels in these patients were increased. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function.
5.3 Preclinical safety data
The following text has been added:
Oral administration of ramipril has been found to be devoid of acute toxicity in rodents and dogs. Studies involving chronic oral administration have been conducted in rats, dogs and monkeys. Indications of plasma electrolyte shifts and changes in blood picture have been found in the 3 species.
As an expression of the pharmacodynamic activity of ramipril, pronounced enlargement of the juxtaglomerular apparatus has been noted in the dog and monkey from daily doses of 250 mg/kg/d. Rats, dogs and monkeys tolerated daily doses of 2, 2.5 and 8 mg/kg/d respectively without harmful effects.
Extensive mutagenicity testing using several test systems has yielded no indication that ramipril possesses mutagenic or genotoxic properties.
6.6 special precautions for disposal
Previous SPC advised ‘none’. New SPC states:
Any unused product or waste material should be disposed of in accordance with local requirements.
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