Ramipril

Registered South African indications:

• Hypertension - mild to moderate
• Cardiac failure following myocardial infarction
• Reduction of proteinuria and the decline in glomerular filtration rate in patients with diabetic nephropathy and hypertension
• Risk reduction of myocardial infarction, stroke, or cardiovascular death, and reduction of the need for revascularisation procedures in patients with increased cardiovascular risk
  - Such as those with manifest coronary heart disease (with or without a history of myocardial infarction), a history of stroke, or a history of peripheral vascular disease
• Risk reduction of of myocardial infarction, stroke or cardiovascular death in diabetic patients

Should a woman become pregnant while receiving ramipril, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine. Should a woman contemplate pregnancy, the doctor should consider an alternative medicine.

 

Registered South African contraindications

Capsule

• Hypersensitivity to the active ingredient or any of its excipients
• Patients with a history of angioedema related to previous ACE- inhibitor therapy or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines
• Hereditary or idiopathic angioedema
• Aortic stenosis
• Hypertrophic obstructive cardiomyopathy
• Severe renal function impairment (CrCl below 30ml/min)
• Renal artery stenosis in patients with a single kidney
• Bilateral renal artery stenosis
• Coadministration with potassium-sparing diuretics such as spironolactone, triamterene, amiloride
• Porphyria
• Lithium therapy: Coadministration with ramipril may lead to toxic blood concentrations of lithium
• Coadministration with aliskiren-containing medicines
• Concomitant use of fluoroquinolones with ACE inhibitors/Angiotensin receptor blockers in patients with moderate to severe renal impairment and in elderly patients
• Pregnancy
• Breastfeeding
• Ramipril is not recommended for use in children
• Concomitant use with sacubitril/valsartan therapy is contraindicated
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces

Tablet

• Hypersensitivity to the active ingredient or any of its excipients
• Patients with a history of angioedema related to previous ACE- inhibitor therapy or angiotensin receptor blockers (ARBs)
• Hereditary or idiopathic angioedema
• Aortic stenosis
• Hypertrophic obstructive cardiomyopathy
• Severe renal function impairment (CrCl below 30ml/min)
• Renal artery stenosis in patients with a single kidney
• Coadministration with potassium-sparing diuretics such as spironolactone, triamterene, amiloride
• Porphyria

South African recommendations

Caution in the following patient groups

• Pregnancy (tab)
• Breastfeeding (tab)
• Mild to moderate renal impairment
• Hepatic impairment
• Elderly

Hypersensitivity/ angioedema

• Angioedema has been reported in patients treated with ACE inhibitors including ramipril. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx is observed, ramipril should be discontinued promptly. These patients should be monitored to ensure complete resolution of symptoms
• Angioedema associated with laryngeal oedema may be fatal. Where there is oedematous involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate emergency therapy should be administered, which may include the administration of epinephrine (adrenaline) and/or the maintenance of a patent airway
• The patient should be kept under close medical supervision for at least 12 to 24 hours and discharged after complete and sustained resolution of symptoms has occurred. These patients should never receive ramipril or any other ACE inhibitor or ARB again
• This risk of angioedema may be increased in patients taking concomitant medicines such as mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus), vildagliptin or neprilysin (NEP) inhibitors (such as racecadotril). The combination of ramipril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema
• Intestinal angioedema has been reported in patients treated with ACE inhibitors including ramipril. These patients presented with abdominal pain (with or without nausea or vomiting)

Cerebrovascular disease or ischaemic heart disease

• Reduction in blood pressure could aggravate these conditions and may result in myocardial infarction and cerebrovascular accidents

Volume depleted patients (e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting)

• Although it may occur in normovolemic patients, hypotension is more likely in volume depleted patients. A sudden reduction in angiotensin II may result in sudden and severe hypotension. There is also an increased risk of ramipril-induced renal failure, especially in those with congestive heart failure
• Patients at a high risk of symptomatic hypotension should have these conditions corrected before commencing therapy with ramipril. Monitoring is required after initiating therapy
• If hypotension occurs, the patient should be placed in the supine position and if necessary, receive an intravenous infusion of 0.9% saline

Severe autoimmune disease, especially systemic lupus erythematosus, other collagen vascular diseases or scleroderma

• Increases the risk for development of neutropenia or agranulocytosis. Neutropenia, agranulocytosis, as well as thrombocytopenia and anaemia, have been seen and bone marrow depression has also been reported
• It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease, and those treated with other medicines that can cause changes in the blood picture

Acute myocardial infarction

• In acute myocardial infarction, treatment with ramipril should not be initiated in patients with evidence of renal dysfunction (serum creatinine concentrations exceeding 177 micromol/l or proteinuria exceeding 500 mg/24 hours). If renal dysfunction develops during treatment, then ramipril may need to be withdrawn
• In acute myocardial infarction, patients may develop persistent hypotension and/or impaired renal function

Hypotension in acute myocardial infarction

• Treatment with ramipril must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These include patients with systolic blood pressure of 100 mmHg or lower, or cardiogenic shock
• During the first 3 days following the infarction, the dose should be reduced if the systolic blood pressure is 120 mmHg or lower. Maintenance doses should be reduced to 5 mg or temporarily to 2,5 mg if systolic blood pressure is 100 mmHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than 1 hour) then ramipril should be withdrawn

Diabetes mellitus

• Increased risk of hyperkalaemia, as well as hypoglycaemia may occur

Renovascular disease

• Ramipril should not be used in patients with renovascular disease or suspected renovascular disease but it may be used cautiously in severe resistant hypertension in such patients under specialist supervision. The elderly, patients with peripheral vascular diseases or generalised atherosclerosis may have asymptomatic renovascular disease

Renal artery stenosis, bilateral or in one kidney, or renal transplant

• Increased risk of renal function impairment may increase blood urea and serum creatinine concentrations, which may be reversible upon discontinuation of therapy. There is also an increased risk of agranulocytosis and neutropenia when immunosuppressants are concurrently administered

Renal function impairment

• In renal function impairment, decreased elimination of ramipril will result in an increased risk of hyperkalaemia. These patients may require lower doses

Anaphylactoid reactions

• Anaphylactoid reactions have occurred in patients using ACE inhibitors during desensitising protocols involving, for example, hymenoptera venom. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of ramipril should be considered prior to desensitization
• Anaphylactoid reactions have been reported in patients exposed to either high-flux membrane dialysis or low-density lipoprotein apheresis with dextran sulfate absorption

Surgery

• In patients undergoing major surgery or during anaesthesia with medicines that produce hypotension, ramipril may block angiotensin II formation secondary to complementary renin release. If hypotension occurs and is due to this mechanism, it can be corrected by volume expansion

Ethnic differences

• Ramipril causes a higher rate of angioedema in black patients than in non-black patients. 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

Effects on ability to drive and use machines

• Ramipril has minor influence on the ability to drive and or operate machinery. Since adverse reactions such as dizziness and visual disturbances have been reported in patients receiving ramipril patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that ramipril does not adversely affect their ability to do so

Additional precautions (cap)

Patients with strongly activated renin-angiotensin-aldosterone system

• These patients are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase. Medical supervision and blood pressure monitoring is necessary for patients with severe hypertension, decompensated congestive heart failure, fluid/salt depletion, liver cirrhosis, or those undergoing major surgery

Dual blockade of the renin-angiotensin-aldosterone system

• Concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function. Dual blockade through the combined use of ramipril and aliskiren is contraindicated

Electrolyte monitoring: Hyperkalemia

• Ramipril may cause an increase in serum potassium levels. Patients at risk include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts or other plasma potassium increasing medicines. Regular monitoring of serum potassium is recommended

Electrolyte monitoring: Hyponatremia

• Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatremia has been observed. Serum sodium levels should be monitored regularly in the elderly and other patients at risk

Blood urea and serum creatinine

• Increases in blood urea and serum creatinine may occur in patients with no apparent pre-existing vascular disease, especially when ramipril has been given concomitantly with a diuretic. Dosage reduction or discontinuation may be required

Cough

• A non-productive, persistent cough has been reported with the use of ACE inhibitors and resolves after discontinuation of therapy

Fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers

• Concomitant use may precipitate acute kidney injury, especially in patients with moderate to severe renal impairment and elderly patients. Renal function should be assessed before and monitored during treatment
• The treatment of hypertension with ramipril must be carried out under regular medical supervision

Forms avail. in SA and covered in this monograph: cap, tab

South African registered indications and dosages

Hypertension - mild to moderate

Patients not on diuretics

• Oral (tab, cap): Initial: 2.5mg, once dly; Adjust according to blood pressure response; Increase to 5-10mg, once dly at intervals of 1 to 2 weeks: Therapeutic dose range: 2.5-10mg; Max: 10mg/24hrs

---

The full therapeutic effect may take several weeks. Therefore, if the desired effect has not been achieved within 2 to 4 weeks the dose may be increased

---

Diuretic-treated patients

• Oral (tab, cap): 1.25mg, once dly; Subsequent dosage adjustments will depend on the therapeutic response

---

In order to minimise the possibility of sudden and severe hypotension which may occur within the first 1 to 5 hours after the initial dose of ramipril, diuretics should be discontinued 2 to 3 days before beginning therapy with ramipril. In patients where diuretic therapy cannot be discontinued, treatment with ramipril should be initiated with a 1.25mg once daily dose

---

Renovascular hypertension: Dose should be lowered and the patient should be monitored

---

Reduction of the risk of myocardial infarction, stroke, or cardiovascular death, and reduction of the need for revascularisation procedures in patients with increased cardiovascular risk
- Such as those with manifest coronary heart disease (with or without a history of myocardial infarction), a history of stroke, or a history of peripheral vascular disease
Reduction of risk of myocardial infarction, stroke or cardiovascular death in diabetic patients

• Oral (tab, cap): Initial: 2.5mg, once dly; May be increased at intervals of 4 weeks until therapeutic effect is reached: Adjust according to clinical response; Increase should be implemented by doubling dose after one week of treatment, 3 weeks later, double the dose again to the normal maintenance dose; Maintenance: 10mg, once dly

Reduction of proteinuria and the decline in glomerular filtration rate in patients with diabetic nephropathy and hypertension

Non-diabetic and diabetic nephropathy

• Oral (tab, cap): Initial: 1.25mg, once dly; Adjust according to clinical response; If dose increase required, implement by doubling dose at intervals of 2-3 weeks; Max: 10mg/24hrs

Cardiac failure following myocardial infarction

• Oral (tab, cap): Initiate in hospital 3-10 days after acute myocardial infarction if the patient manifests with evidence of heart failure and is haemodynamically stable; Initial: 2.5mg, twice dly for 2 days; If well tolerated, increase to: 5mg, twice dly; If patients are unable to tolerate 2.5mg initially: Initial: 1.25mg, twice dly, and later increased to 2.5mg, twice dly

---

Method of administration

For oral administration. May be taken with/without meals preferably at the same time every day

Not established for use in children (see Contraindications)

Pregnancy

South African recommendations

Capsule

• Contraindicated
• The use of ramipril is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take ramipril during pregnancy
• 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 ramipril should be stopped immediately and if appropriate, alternative therapy should be started
• Foetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spins bifida) and of kidney malformations
• Ramipril passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns, have been reported after administration of ramipril in the second and third trimester. Cases of defective skull ossification have been observed
• Prematurity and low birth mass can occur. In addition, use of ramipril during the first trimester of pregnancy has been associated with an increased risk of birth defects, in particular of the cardiovascular and the central nervous system

Tablet

• First trimester: Caution
• 2nd and 3rd trimester: Caution; not recommended
• Use of ramipril limited to the first trimester does not appear to present a significant risk to the foetus, but foetal exposure after this time has been associated with teratogenicity and severe toxicity in the foetus and newborn, including death
• Ramipril crosses the placenta. Foetal exposure to ACE inhibitors during the second and third trimester can cause hypotension, renal failure, anuria, skull hypoplasia, hyperkalaemia and oliguria
• Oligohydramnios may occur resulting in pulmonary hypoplasia, limb contractures and craniofacial deformations. Infants who have been exposed in utero to ramipril should be closely monitored. Peritoneal dialysis may be of some benefit in the clearance of ramipril from the neonatal circulation

Breastfeeding

South African recommendations

Capsule

• Contraindicated
• Safety in lactation has not been established. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant

Tablet

• Caution; not recommended
• Safety in lactation has not been established

Fertility

South African recommendations

• No information available

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  In renal function impairment, decreased elimination of ramipril will result in an increased risk of hyperkalaemia. These patients may require lower doses
• Severe (CrCl below 30ml/min): Contraindicated

South African recommendations

• Caution; not recommended
  In patients with impaired liver function, the metabolism of the parent compound ramipril, as in ramipril, and therefore the formation of the bioactive metabolite ramiprilat is decelerated resulting in markedly elevated plasma ramipril levels due to a diminished activity of esterases in the liver

South African recommendations

• Caution; no dose adjustment recommended
  It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatremia

Central Nervous System Disorders

• Depressed mood
• Anxiety
• Nervousness
• Restlessness
• Sleep disorder including somnolence
• Confusional state
• Disturbance in attention
• Headache
• Dizziness
• Vertigo
• Paraesthesia
• Ageusia
• Dysgeusia
• Tremor
• Cerebral ischaemia 
• Impaired psychomotor skills
• Burning sensation
• Parosmia
• Fatigue

Cardiovascular Disorders

• Myocardial ischaemia
• Tachycardia
• Arrhythmia
• Palpitations
• Oedema
• Hypotension
• Decreased orthostatic blood pressure
• Syncope
• Flushing
• Vascular stenosis
• Hypoperfusion
• Vasculitis
• Raynaud's phenomenon
• Chest pain

Respiratory Disorders

• Non-productive tickling cough
• Bronchitis
• Sinusitis
• Dyspnea
• Bronchospasm
• Nasal congestion

Gastrointestinal Disorders

• Gastrointestinal inflammation
• Digestive disturbances
• Abdominal discomfort
• Dyspepsia
• Diarrhoea
• Nausea and vomiting
• Pancreatitis
• Increased pancreatic enzymes
• Small bowel angioedema
• Gastritis
• Constipation
• Dry mouth
• Glossitis
• Aphtous stomatitis

Hepatobiliary Disorders

• Increased hepatic enzymes
• Increased conjugated bilirubin
• Cholestatic jaundice
• Hepatocellular damage
• Acute hepatic failure
• Cholestatic or cytolytic hepatitis 

Genitourinary Disorders

• Renal impairment
• Acute renal failure acute
• Increased urine output
• Worsening of a pre-existing proteinuria
• Haematuria
• Transient erectile impotence
• Libido decreased

Endocrine and Metabolic Disorders

• Syndrome of inappropriate anti-diuretic hormone secretion
• Hyperkalaemia
• Anorexia
• Hyponatraemia
• Gynaecomastia

Musculoskeletal Disorders

• Muscle spasms
• Myalgia
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Rash in particular maculo-papular rash
• Angioedema
• Pruritus
• Hyperhidrosis
• Exfoliative dermatitis
• Urticaria
• Onycholysis
• Photosensitivity reaction
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Erythema multiforme
• Pemphigus
• Aggrevation of psoriasis
• Dermatitis psoriasiform
• Pemphigoid or lichenoid exanthema
• Alopecia

Immune, Blood and Lymphatic System Disorders

• Eosinophilia
• Leukopenia
• Decreased red blood cell count
• Anaemia
• Thrombocytopenia
• Bone marrow failure
• Pancytopenia
• Haemolytic anaemia
• Anaphylactic reactions
• Increased antinuclear antibody
• Pyrexia

Sensory Disorders

• Blurred vision
• Conjunctivitis
• Tinnitus
• Impaired hearing

• Potassium-sparing diuretics
• Spironolactone
• Triamterene
• Amiloride
• Fluoroquinolones
• Sacubitril/valsartan
• Diuretics
• Aliskiren agents
• Agents that act on the renin-angiotensin-aldosterone system
• Agents that increase serum potassium
• Drugs and substances that decreased blood pressure
• Sympathomimetics
• Allopurinol
• Immunosupressants
• Corticosteroids
• Procainamide
• Cytostatics
• Lithium
• Antidiabetic agents
• Acetylsalicylic acid
• Non-steroidal anti-inflammatory drugs
• mTOR inhibitors
• Dipeptidyl-peptidase 4 inhibitors

Other interactions

• Extracorporeal treatments leading to contact of blood with negatively charged surfaces

• Renal function

Specific cases may require:

• Electrolytes
• Full blood count

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor. This enzyme functions to convert angiotensin I to angiotensin II which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion. By inhibiting the ACE, ramipril thus prevents the downstream vasopressor activity and aldosterone secretion effected by angiotensin II.

Capsule 1.25mg

• Austell-Ramipril (Austell)
• Rampil (Pharmacare)

Capsule 2.5mg

• Apex-Ramipril (Camox)
• Austell-Ramipril (Austell)
• Rampil (Pharmacare)
• Ramiwin (Zentiva) originator
• Retace (Sandoz)

Capsule 5mg

• Apex-Ramipril (Camox)
• Austell-Ramipril (Austell)
• Liracen (Aurobindo)
• Rampil (Pharmacare)
• Ramiwin (Zentiva) originator
• Retace (Sandoz)

Capsule 10mg

• Apex-Ramipril (Camox)
• Austell-Ramipril (Austell)
• Liracen (Aurobindo)
• Rampil (Pharmacare)
• Ran-Ramipril (Ranbaxy)
• Simayla Ramipril (Ranbaxy)
• Tritace (Sanofi) originator

Tablet 2.5mg 

• Ramace (AstraZeneca) originator
• Ramipril-Hexal (Sandoz)
• Retace (Sandoz)
• Tritace (Sanofi) originator

Tablet 5mg

• Ramipril-Hexal (Sandoz)
• Tritace (Sanofi) originator