Ramipril oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of ramipril
Drugs List
Therapeutic Indications
Uses
Congestive heart failure (adjunct)
Glomerular nephropathy: treatment
Hypertension
Management of post-myocardial infarct in patients with cardiac failure
Risk reduction of cardiovascular events
Dosage
Adults
Cardiovascular prevention
The recommended initial dose is 2.5 mg ramipril once daily. Depending on the tolerability, the dose should be gradually increased. It is recommended that the dose is increased after 1 to 2 weeks to 5 mg daily, then increased after a further 2 to 3 weeks to 10 mg once daily. The usual maintenance dose is 10 mg ramipril once daily. Patients already stabilised on lower doses of ramipril for other indications where possible should be titrated to 10 mg ramipril once daily.
Hypertension
Initial dosage in patients not on diuretics and without congestive heart failure
1.25 mg to 2.5 mg once daily.
Dosage should be gradually increased incrementally at intervals of 1 to 4 weeks, based on patient response, up to a maximum of 10 mg once daily.
Usual maintenance dose range 2.5 to 5 mg once daily. If the patient response is still unsatisfactory at a dose of 10 mg daily, combination treatment is recommended.
In diuretic treated patients
If possible the diuretic should be discontinued, or at least reduced, 2 to 3 days before starting ramipril (or longer, depending on duration of action) to reduce the likelihood of symptomatic hypotension. It may be resumed later if required. The initial daily dose in patients previously treated with a diuretic or in patients when the diuretic has not been discontinued is generally 1.25 mg ramipril.
In hypertensive patients who also have congestive heart failure , with or without associated renal insufficiency
Symptomatic hypotension has been observed after treatment with ACE inhibitors. In these patients, therapy should be started at a dose of 1.25 mg under close medical supervision in hospital.
Congestive heart failure
Patients stabilised on diuretic therapy - initial dose is 1.25 mg once daily under medical supervision. The dosage may be increased by doubling at intervals of 1 to 2 weeks depending on response. If the daily dose is more than 2.5 mg, it may be taken as a single dose or as two divided doses.
Maximum daily dose: 10 mg.
Patients with previous high dose diuretics should have this dose reduced before starting ramipril to minimise the possibility of symptomatic hypotension.
Secondary prevention, post myocardial infarction
Commence therapy at least 48 hours after myocardial infarction in clinically and haemodynamically stable patients. The starting dose is 2.5 mg twice daily, increased after 3 days to 5 mg twice daily. If the initial dose is not tolerated give 1.25 mg twice daily for two days before increasing to 2.5 mg and then 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice a day then treatment with ramipril should be withdrawn.
Maintenance dose: 2.5 to 5 mg twice a day.
Some brands state to commence therapy in hospital 3 to 10 days after infarction and increase this dose after two days to 5 mg twice daily. Consult specific product literature.
Maximum 5 mg twice daily.
Severe (NYHA IV) heart failure immediately after myocardial infarction
Sufficient experience is still lacking in the treatment of these patients. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.
Treatment of renal disease (nephropathy)
In patients with diabetes and microalbuminuria
Initial dose is 1.25 mg once daily, increased after 2 weeks to 2.5 mg once daily, then increased after a further 2 weeks to 5 mg once daily if tolerated.
In patients with non-diabetic nephropathy as defined by macroproteinuria equal or greater than 3 g/day
Initial dose is 1.25 mg once daily, increased after 2 weeks to 2.5 mg once daily, then increased after a further 2 weeks to 5 mg once daily if tolerated.
In patients with diabetes and at least one cardiovascular risk
Initial dose is 2.5 mg once daily, increased after 1 to 2 weeks to 5 mg daily, then increased after a further 2 to 3 weeks to 10 mg daily. The target daily dose is 10 mg.
Elderly
Caution in elderly patients with concomitant use of diuretics, congestive heart failure or renal or hepatic impairment. Initiate therapy with 1.25 mg of ramipril and titrate dose according to response.
Patients with Renal Impairment
Patients with renal impairment may require reduced or less frequent doses of ramipril. Renal function should be closely monitored.
For patients with a creatinine clearance greater than or equal to 60 ml/minute the maximum daily dose is 10 mg.
For patients with a creatinine clearance between 30 to 60 ml/minute, it is not necessary to adjust the initial dose. The maximum daily dose is 5 mg.
For patients with a creatinine clearance between 10 to 30 ml/minute, the initial dose should be 1.25 mg once daily, and the maximum dose 5mg once daily.
The Renal Drug Handbook states the following doses:
Glomerular Filtration Rate (GFR)
GFR of 20 to 50 ml/minute: dose as in normal renal function.
GFR of 10 to 20 ml/minute: initial dose of 1.25 mg daily and increase according to response.
GFR of below 10 ml/minute: initial dose of 1.25 mg daily and increase according to response.
For haemodialysed hypertensive patients: ramipril is slightly dialysed; some manufacturers recommend the initial dose is 1.25 mg daily and the maximum daily dose is 5 mg. The medicinal product should be administered a few hours after haemodialysis is preformed.
Patients with Hepatic Impairment
As ramipril is a prodrug metabolised to its active moiety in the liver, particular caution and close monitoring should be applied to patients with hepatic impairment, especially those with hepatic cirrhosis with oedema and/or ascites. The metabolism of the parent compound, and therefore the formation of the bioactive metabolite ramiprilat, may be diminished resulting in markedly elevated plasma levels of the parent compound (due to reduced activity of esterases on the liver).
Metabolism of parent compound and subsequent formation of the active metabolite is delayed in those with hepatic impairment.
Initiate treatment at a dose of 1.25 mg daily under close medical supervision. Maximum daily dose is 2.5 mg.
Contraindications
Children under 18 years
Desensitisation therapy
Within 36 hours of discontinuing a sacubitril containing product
Breastfeeding
Haemodialysis with high flux membranes
Haemodynamic instability
Hereditary angioneurotic oedema
Hypotension
Idiopathic angioneurotic oedema
Pregnancy
Renal artery stenosis
Precautions and Warnings
Elderly
Immunosuppression
Aortic stenosis
Atherosclerosis
Cerebral ischaemia
Collagen vascular disease
Diabetes mellitus
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic cirrhosis
Hepatic cirrhosis with ascites
Hepatic impairment
Hyperkalaemia
Hypertrophic cardiomyopathy
Hyponatraemia
Hypovolaemia
Ischaemic heart disease
Kidney transplantation
Lactose intolerance
Left ventricular outflow obstruction
Metabolic acidosis
Mitral stenosis
Peripheral vascular disease
Renal impairment
Renovascular disorder
Severe renin-dependent hypertension
Uncontrolled cardiac failure
Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
Anaphylactoid reactions possible with highly permeable dialysis membranes
Anaphylaxis possible with concomitant hyposensitisation to wasp/bee venom
Reduce dose in patients with creatinine clearance below 30ml/min
Advise ability to drive/operate machinery may be affected by side effects
Afro-Caribbean or black patients may show reduced response
Correct volume and/or salt depletion before initiating therapy
Not all available brands are licensed for all indications
Some formulations contain lactose
Evaluate renal function before and during treatment
Exclude pregnancy prior to initiation of treatment
Monitor serum electrolytes before and during treatment
Consider monitoring white blood cell counts in collagen vascular disease
Monitor patients with renovascular disease
Advise patient to report symptoms of infection immediately
Higher incidence of angioedema in black patients
Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
May cause anaphylactic / anaphylactoid reactions
Discontinue temporarily in LDL apheresis or desensitisation therapy
Advise patient to seek advice at first indications of pregnancy
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if laryngeal stridor/angioedema of face/tongue or glottis
Discontinue prior to surgery
Advise patient not to take NSAIDs unless advised by clinician
Advise patient to moderate alcohol intake during treatment
Hypotensive effects may be potentiated by alcohol
Advise on problems of salt substitutes/high intake of potassium-rich food
Female: Ensure adequate contraception during treatment
Patients haemodialysed using high flux polyacrylonitrile (AN69) membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes for dialysis.
Agranulocytosis and bone marrow depression, as well as a reduction in red cell count, haemoglobin content and platelet count have been seen rarely in patients on ACE inhibitors. These are more frequent in patients with renal impairment, especially if they have a collagen vascular disease. Regular monitoring of white blood cell counts should be considered in patients with collagen vascular disease (e.g. lupus erythematosus and scleroderma), especially associated with impaired renal function and concomitant therapy particularly with corticosteroids and anti-metabolites. Patients on allopurinol, immunosuppressants and other substances that may change the blood picture also have increased likelihood of other blood picture changes and patients should be instructed to report any signs of infection.
Angioedema has been reported in patients treated with ACE inhibitors, although it is uncommon. If laryngeal stridor or angioedema of the face, tongue, lips, larynx or glottis occurs, treatment with ramipril must be discontinued and appropriate therapy instituted immediately. The patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting).
Pregnancy and Lactation
Pregnancy
Ramipril is contraindicated in pregnancy.
Unless treatment with ramipril is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatment with an established safety profile in pregnancy. Guidelines published from NICE recommend that women with chronic hypertension on ACE inhibitors are informed that there is a risk of congenital abnormalities if the drugs are taken during pregnancy and other antihypertensive treatments for management their condition should be discussed if they are planning pregnancy.
Epidemiology of the risk of teratogenicity following exposure in the first trimester in human has not be conclusive, however, the MHRA recommends that a risk can not be excluded. The MHRA states that the use of ACE inhibitors in late pregnancy has been associated with adverse effects on the kidney and other congenital anomalies, therefore ACE inhibitors should not be used at any stage during of pregnancy unless absolutely necessary and only then after the potential risks and benefits have been discussed with the patient. Briggs (2011) comments that ramipril and other ACE inhibitors appear to be human teratogens when used in the second and third trimester, producing foetal hypocalvaria and renal defects. ACE inhibitor therapy exposure during the second and third trimester is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation). Anuria-associated oligohydramnios may produce pulmonary hypoplasia, limb contractures, persistent patent ductus arteriosus, craniofacial deformation and neonatal death. Interuterine growth retardation, prematurity and severe neonatal hypotension may also been seen.
Should exposure to ramipril have occurred from the first trimester, an ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken an ACE inhibitor during pregnancy should be closely observed for hypotension, oliguria and hyperkalaemia. Schaefer (2007) states that accidental exposure does not require invasive diagnosis procedures or termination of pregnancy but if there has been long term exposure to ACE inhibitor then it is recommended to monitor for oligohydramnios and foetal growth via an ultrasound.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Ramipril is contraindicated in breastfeeding.
There is insufficient data on ramipril in breastfeeding. Animal studies have indicated that ramiprilat is transferred into milk in concentrations about one third of those found in serum, but animal studies are always high and do not correlate with humans. The MHRA states that ACE inhibitors have a small molecular size so transfer into human breast milk is possible. With the exception of captopril, the active metabolites of ACE inhibitors have long estimated half lives; however these metabolites are poorly absorbed orally.
Advice on LactMed, via TOXNET, suggests as no information is available on the use of ramipril during breastfeeding, an alternate drug may be preferred, especially whilst nursing a newborn or preterm infant. Schaefer (2007) advises that nursing mothers who are accidentally exposed to ramipril do not need to stop breastfeeding but therapy should be changed.
The MHRA states that the use of ramipril during breastfeeding is not recommended and that ACE inhibitors should not be used by breastfeeding mothers in the first few weeks after delivery because of possible profound neonatal hypotension; preterm babies may be at particular risk. If ACE inhibitor therapy is considered essential for the mother the use of captopril, enalapril or quinapril may be considered when the infant is older. Guidelines from NICE also advise that women who still need antihypertensive treatment in the post natal period should be informed that there is insufficient evidence on the safety in babies receiving breast milk of ACE inhibitors other than enalapril and captopril.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Abdominal discomfort
Acute hepatic disorders
Acute renal failure
Aggravation of existing asthma
Agranulocytosis
Alopecia
Anaemia
Anaphylactic reaction
Angina pectoris
Angioedema
Anorexia
Anxiety
Arthralgia
Asthenia
Bone marrow depression
Bronchitis
Bronchospasm
Cardiac arrhythmias
Confusion
Conjunctivitis
Cough
Decreased appetite
Depressed mood
Dizziness
Dry mouth
Dyspnoea
Eosinophilia
Erythema multiforme
Exacerbation of psoriasis
Fatigue
Flushing
Gastro-intestinal symptoms
Glossitis
Gynaecomastia
Haemolytic anaemia
Headache
Hearing disturbances
Hyperhidrosis
Hyperkalaemia
Hypersensitivity reactions
Hypoglycaemia
Hyponatraemia
Hypotension
Impotence
Increase in antinuclear antibodies (ANA)
Increases in hepatic enzymes
Jaundice
Leucopenia
Lichenoid rash
Loss of balance
Loss of libido
Maculopapular dermatitis
Muscle cramps
Myalgia
Myocardial infarction
Nasal congestion
Nausea
Nervousness
Neutropenia
Onycholysis
Palpitations
Pancreatitis
Pancytopenia
Paraesthesia
Parosmia
Pemphigoid reaction
Peripheral oedema
Photosensitivity
Proteinuria
Pruritus
Psoriasiform rash
Psychomotor impairment
Rash
Raynaud's syndrome
Renal impairment
Restlessness
Rhinitis
Serositis
Sinusitis
Sleep disturbances
Stevens-Johnson syndrome
Stomatitis
Stroke
Syncope
Tachycardia
Taste disturbances
Thrombocytopenia
Tinnitus
Toxic epidermal necrolysis
Transient ischaemic attack
Tremor
Urticaria
Vasculitis
Vertigo
Visual disturbances
Vomiting
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: October 2013
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Joint Formulary Committee. British National Formulary. 66th ed. London: BMJ Group and Pharmaceutical Press; 2013. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.
Summary of Product Characteristics: Ramipril 1.25mg capsules. Actavis UK Ltd. Revised July 2012.
Summary of Product Characteristics: Ramipril 2.5mg capsules. Actavis UK Ltd. Revised July 2012.
Summary of Product Characteristics: Ramipril 5mg capsules. Actavis UK Ltd. Revised July 2012.
Summary of Product Characteristics: Ramipril 10mg capsules. Actavis UK Ltd. Revised July 2012.
Summary of Product Characteristics: Ramipril 2.5mg tablets. Actavis UK Ltd. Revised August 2012.
Summary of Product Characteristics: Ramipril 5mg tablets. Actavis UK Ltd. Revised August 2012.
Summary of Product Characteristics: Ramipril 10mg tablets. Actavis UK Ltd. Revised August 2012.
Summary of Product Characteristics: Ramipril 5mg tablets. Aurobindo Pharma - Milpharm Ltd. Revised January 2010.
Summary of Product Characteristics: Ramipril 10mg tablets. Aurobindo Pharma - Milpharm Ltd. Revised January 2010.
Summary of Product Characteristics: Ramipril 2.5mg/5ml oral solution. Rosemont Pharmaceuticals Ltd. Revised August 2012.
Summary of Product Characteristics: Ramipril 1.25mg tablets. Sandoz Ltd. Revised October 2012.
Summary of Product Characteristics: Ramipril 2.5mg tablets. Sandoz Ltd. Revised October 2012.
Summary of Product Characteristics: Ramipril 5mg tablets. Sandoz Ltd. Revised October 2012.
Summary of Product Characteristics: Ramipril 10mg tablets. Sandoz Ltd. Revised October 2012.
Summary of Product Characteristics: Ramipril tablets. Winthrop Pharmaceuticals UK Ltd. Revised November 2010.
Summary of Product Characteristics: Tritace 1.25mg tablets. Sanofi. Revised April 2013.
Summary of Product Characteristics: Tritace 2.5mg tablets. Sanofi. Revised April 2013.
Summary of Product Characteristics: Tritace 5mg tablets. Sanofi. Revised April 2013.
Summary of Product Characteristics: Tritace 10mg tablets. Sanofi. Revised April 2013.
Summary of Product Characteristics: Tritace Tablet Titration Pack. Sanofi. Revised April 2013.
The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.
MHRA Drug Safety Update: Volume 2, Issue 10, May 2009.
https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON046451
Last accessed: October 23, 2013
NICE clinical guideline 107: Hypertension in pregnancy, the management of hypertensive disorders during pregnancy
Available at: https://www.nice.org.uk/nicemedia/live/13098/50418/50418.pdf
Issue date: August 2010
Last accessed: October 23, 2013
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Ramipril Last revised: September 7, 2013
Last accessed: October 23, 2013
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