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CAPTOPRIL TABLETS BP 25MG

Active substance(s): CAPTOPRIL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Captopril 25 mg Tablets BP, Kaplon 25mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 25 mg of Captopril.
Excipient(s) with known effect:
Each tablet contains 33.0 mg lactose
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
White biconvex tablets marked 7C2 with double breakline.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Hypertension
Captopril is indicated for the first line therapy of mild or moderate hypertension.
In severe hypertension captopril should be used where standard therapy is
inappropriate or ineffective.
Congestive heart failure
Captopril is indicated for the treatment of congestive heart failure. It should be used
in conjunction with diuretics and, where appropriate, digitalis.

4.2

Posology and method of administration
Posology
Hypertension
The lowest effective dosage of captopril should be titrated according to the
requirements of each patient.
Mild to moderate hypertension:
The starting dose is 12.5 mg twice daily. The usual maintenance dose is 25 mg twice
daily. This can be increased stepwise at 2-4 week intervals, until a satisfactory
response is achieved, to a maximum of 50 mg twice daily.
A thiazide diuretic may be added, if a satisfactory response is not achieved with
captopril alone.
Severe hypertension:
In severe hypertension where standard therapy is ineffective or inappropriate because
of adverse effects, the starting dose is 12.5 mg twice daily. The dosage may be
increased incrementally to a maximum of 50 mg three times a day. Captopril should
be used together with other anti-hypertensive agents (see sections 4.3, 4.4, 4.5 and
5.1) but the dose of these should be individually titrated. A daily dose of 150 mg of
captopril should not normally be exceeded.
Special populations
Patients with heart failure
Captopril therapy must be started under close medical supervision. Captopril should
be introduced when diuretic therapy (such as frusemide 40-80 mg or equivalent) is
insufficient to control symptoms. A starting dose of 6.25 mg or 12.5 mg may decrease
the possibility of a transient hypotensive effect. The potential of this happening may
be decreased further by a reduction or withdrawal of diuretic therapy before starting
captopril treatment. The usual maintenance dose is 25 mg two or three times a day,
which can be increased incrementally, with intervals of at least two weeks, until a
satisfactory response is achieved. The usual maximum dose is 150 mg of captopril
daily.
Older people:(older than 65 years of age)
The starting dose is 6.25 mg twice daily (mornings and evenings).
The usual maintenance dose is 25 - 50 mg of captopril per day in divided doses.
The usual maximum dose is 100 mg of captopril per day.

The dose should be titrated against the blood pressure response and kept as low as
possible to achieve adequate control.
Paediatric population
Captopril is not recommended for the treatment of mild to moderate hypertension in
children.
Lower doses of captopril should be used in neonates, particularly premature infants,
as renal function in infants is not equivalent to that of older children and adults.
Patients should be monitored under close medical supervision.
The starting dose should be 0.3 mg per Kg body weight up to a maximum of 6 mg per
Kg body weight daily, in divided doses. According to the response the dose should be
individualised and may be given two or three times daily.
Patients with hepatic impairment
The starting dose is 6.25 mg twice daily (mornings and evenings).
The usual maintenance dose is 25 - 50 mg of captopril per day in divided doses.
The usual maximum dose is 100 mg of captopril per day.
Patients with renal impairment
Mild or moderate renal impairment (creatinine clearance at least 30 ml/min/1.73 m2),
The starting dose is 6.25 mg twice daily (mornings and evenings).
The usual maintenance dose is 25 - 50 mg of captopril per day in divided doses.
The usual maximum dose is 75 mg of captopril per day in divided doses.
Patients with severely impaired renal function may respond to smaller or less frequent
doses as they will take longer to reach steady-state captopril levels and will reach
higher steady-state levels for a given daily dose than patients with normal renal
function. Therefore, the usual recommended daily dose should be 6.25 - 25 mg of
captopril per day in divided doses in patients with severe renal impairment (creatinine
clearance less than 30 ml/min/1.73 m2). The dose should be titrated against the
response but adequate time should be allowed between dosage adjustments. When
concomitant diuretic therapy is required, a loop diuretic rather than thiazide diuretic
should be the diuretic of choice. Captopril is readily eliminated by haemodialysis.

4.3

Contraindications
Captopril is contra-indicated in patients with: hypersensitivity to the active substance,
to any other ACE inhibitor, or to any of the excipients listed in section 6.1, a history
of angioneurotic oedema associated with previous ACE inhibitor therapy, or
hereditary/idiopathic angioneurotic oedema. Second and third trimesters of pregnancy
(see sections 4.4 and 4.6).

The concomitant use of Captopril with aliskiren-containing products is
contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60
ml/min/1.73 m2 (see sections 4.5 and 5.1).

4.4

Special warnings and precautions for use
Hypotension
Rarely hypotension is observed in uncomplicated hypertensive patients. Symptomatic
hypotension is more likely to occur in hypertensive patients who are volume and/or
sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea,
vomiting, or haemodialysis. Volume and/or sodium depletion should be corrected
before the administration of an ACE inhibitor and a lower starting dose should be
considered. As with any antihypertensive agent, excessive blood pressure lowering in
patients with ischaemic cardiovascular or cerebrovascular disease may increase the
risk of myocardial infarction or stroke. If hypotension develops, the patient should be
placed in a supine position. Volume repletion with intravenous normal saline may be
required.

Renovascular hypertension
There is an increased risk of hypotension and renal insufficiency when patients with
bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
are treated with ACE inhibitors. Loss of renal function may occur with only mild
changes in serum creatinine. In these patients, therapy should be initiated under close
medical supervision with low doses, careful titration, and monitoring of renal
function.

Angioedema
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported in patients treated with angiotensin converting enzyme inhibitors,
including Captopril. This may occur at any time during treatment. In such cases,
Captopril should be discontinued promptly and appropriate monitoring should be
instituted to ensure complete resolution of symptoms prior to dismissing the patient.
In those instances where swelling has been confined to the face and lips the condition
generally resolved without treatment, although antihistamines have been useful in
relieving symptoms. Angioneurotic oedema associated with laryngeal oedema may be
fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause
airway obstruction, appropriate therapy, which may include subcutaneous epinephrine
solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should
be administered promptly.
Black patients receiving ACE inhibitors have been reported to have a higher
incidence of angioedema compared to non-blacks.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at
increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or
vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels
were normal. The angioedema was diagnosed by procedures including abdominal CT
scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE

inhibitor. Intestinal angioedema should be included in the differential diagnosis of
patients on ACE inhibitors presenting with abdominal pain (see section 4.8).

Cough
Cough has been reported with the use of ACE inhibitors. Characteristically, the cough
is non-productive,persistent and resolves after discontinuation of therapy.

Hepatic failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with
cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes)
death. The mechanism of this syndrome is not understood. Patients receiving ACE
inhibitors who develop jaundice or marked elevations of hepatic enzymes should
discontinue the ACE inhibitor and receive appropriate medical follow-up.

Hyperkalaemia
Elevations in serum potassium have been observed in some patients treated with ACE
inhibitors, including captopril. Patients at risk for the development of hyperkalaemia
include those with renal insufficiency, diabetes mellitus, or those using concomitant
potassium-sparing diuretics, potassium supplements or potassium-containing salt
substitutes; or those patients taking other drugs associated with increases in serum
potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed
appropriate, regular monitoring of serum potassium is recommended.
Aortic and mitral valve stenosis/Obstructive hypertrophic cardiomyopathy/
Cardiogenic shock
ACE inhibitors should be used with caution in patients with left ventricular valvular
and outflow tract obstruction and avoided in cases of cardiogenic shock and
hemodynamically significant obstruction.

Neutropenia/Agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in
patients receiving ACE inhibitors, including captopril. In patients with normal renal
function and no other complicating factors, neutropenia occurs rarely. Captopril
should be used with extreme caution in patients with collagen vascular disease,
immunosuppressant therapy, treatment with allopurinol or procainamide, or a
combination of these complicating factors, especially if there is pre-existing impaired
renal function. Some of these patients developed serious infections which in a few
instances did not respond to intensive antibiotic therapy.
If captopril is used in such patients, it is advised that white blood cell count and
differential counts should be performed prior to therapy, every 2 weeks during the
first 3 months of captopril therapy, and periodically thereafter. During treatment all
patients should be instructed to report any sign of infection (e.g. sore throat, fever)
when a differential white blood cell count should be performed.
Captopril and other concomitant medication (see section 4.5) should be withdrawn if
neutropenia (neutrophils less than 1000/mm3) is detected or suspected.

In most patients neutrophil counts rapidly return to normal upon discontinuing
captopril.

Proteinuria
Proteinuria may occur particularly in patients with existing renal function impairment
or on relatively high doses of ACE inhibitors.
Total urinary proteins greater than 1 g per day were seen in about 0.7% of patients
receiving captopril.
The majority of patients had evidence of prior renal disease or had received relatively
high doses of captopril (in excess of 150 mg/day), or both. Nephrotic syndrome
occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided
or cleared within six months whether or not captopril was continued. Parameters of
renal function, such as BUN and creatinine, were seldom altered in the patients with
proteinuria.
Patients with prior renal disease should have urinary protein estimations (dip-stick on
first morning urine) prior to treatment, and periodically thereafter.

Anaphylactoid reactions during desensitisation
Sustained life-threatening anaphylactoid reactions have been rarely reported for
patients undergoing desensitising treatment with hymenoptera venom while receiving
another ACE inhibitor. In the same patients, these reactions were avoided when the
ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent
rechallenge.
Therefore, caution should be used in patients treated with ACE inhibitors undergoing
such desensitisation procedures.

Anaphylactoid reactions during high-flux dialysis/lipoprotein apheresis
membrane exposure
Anaphylactoid reactions have been reported in patients haemodialysed with high-flux
dialysis membranes or undergoing low-density lipoprotein apheresis with dextran
sulphate absorption. In these patients, consideration should be given to using a
different type of dialysis membrane or a different class of medication.
Surgery/Anaesthesia
Hypotension may occur in patients undergoing major surgery or during treatment
with anaesthetic agents that are known to lower blood pressure. If hypotension
occurs, it may be corrected by volume expansion.
Diabetic patients
The glycaemia levels should be closely monitored in diabetic patients previously
treated with oral antidiabetic drugs or insulin, namely during the first month of
treatment with an ACE inhibitor.

Risk of hypokalaemia

The combination of an ACE inhibitor with a thiazide diuretic does not rule out the
occurrence of hypokalaemia. Regular monitoring of kalaemia should be performed.

Combination with lithium
Captopril is not recommended in association with lithium due to the potentiation of
lithium toxicity (see section 4.5).
Ethnic differences
As with other angiotensin converting enzyme inhibitors, Captopril is apparently less
effective in lowering blood pressure in black people than in non-blacks, possibly
because of higher prevalence of low-renin states in the black hypertensive population.
Renal function should be assessed before therapy is started, as part of the patient
evaluation, and assessed at appropriate intervals during therapy, especially in patients
with salt and/or body fluid deficiencies, severe or renal hypertension, severe
congestive heart failure and in older people (> 65 years).
Captopril should be avoided in the treatment of patients with acute hypertensive
crises, as there is limited experience.
Patients with primary aldosteronism should not be treated with captopril as their
renin-angiotensin system is affected by the primary disease.
Pregnancy:
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE
inhibitor therapy is considered essential, patients planning pregnancy should be
changed to alternative antihypertensive treatments which have an established safety
profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE
inhibitors should be stopped immediately, and, if appropriate, alternative therapy
should be started (see sections 4.3 and 4.6).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor
blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased
renal function (including acute renal failure). Dual blockade of RAAS through the
combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is
therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur
under specialist supervision and subject to frequent close monitoring of renal
function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor
blockers should not be used concomitantly in patients with diabetic nephropathy.

Lactose
Captopril tablets contain lactose and therefore should not be used in cases of
congenital galactosaemia and malabsorption of glucose and galactose or in lactasedeficient syndromes (rare metabolic diseases).

4.5

Interaction with other medicinal products and other forms of interaction
Potassium-sparing diuretics or potassium supplements:
Captopril attenuates diuretic induced potassium loss. Potassium sparing
diuretics eg spironolactone, triamterene or amiloride, potassium supplements,
potassium-containing salt substitutes or other potassium-increasing medical
products (eg heparin) may lead to significant increases in serum potassium. If
concomitant use is indicated because of demonstrated hypokalaemia such
medicines should be used with caution and with frequent monitoring of serum
potassium.
Diuretics:
Patients on diuretics and especially those who are volume- and/or salt
depleted, may experience an excessive reduction of blood pressure after
initiation of therapy with captopril. The possibility of hypotensive effects can
be reduced by discontinuation of the diuretic, by increasing volume or salt
intake prior to intake and by initiation of therapy with lower doses of captopril.
Further increases in dosage should be performed with caution. However, no
clinically significant drug interactions have been found in specific studies with
hydrochlorothiazide or furosemide.
Lithium: reversible increases in serum lithium concentrations and toxicity
have been reported during concomitant administration of lithium with ACE
inhibitors. Concomitant use of thiazide diuretics may increase the risk of
lithium toxicity and enhance the already increased risk of lithium toxicity with
ACE inhibitors. The combination of captopril with lithium is therefore not
recommended and careful monitoring of serum lithium levels should be
performed if the combination proves necessary.
Anaesthetic drugs: Captopril may enhance the hypotensive effects of certain
anaesthetic drugs.
Other antihypertensive agents: captopril has been safely co-administered
with other commonly used antihypertensive agents (e.g. beta-blockers and
long-acting calcium channel blockers). Concomitant use of these agents may
increase the hypotensive effects of captopril. Treatment with nitroglycerine
and other nitrates, or other vasodilators, should be used with caution.
Clinical trial data has shown that dual blockade of the renin-angiotensinaldosterone system (RAAS) through the combined use of ACE-inhibitors,
angiotensin II receptor blockers or aliskiren is associated with a higher
frequency of adverse events such as hypotension, hyperkalaemia and decreased
renal function (including acute renal failure) compared to the use of a single
RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Alpha blocking agents: concomitant use of alpha blocking agents may
increase the antihypertensive effects of captopril and increase the risk of
orthostatic hypotension.

Treatments of acute myocardial infarction: captopril may be used
concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics,
beta-blockers and/or nitrates in patients with myocardial infarction.
Narcotic drugs/Tricyclic antidepressants/Antipsychotics: ACE inhibitors
may enhance the hypotensive effects of certain narcotic drugs, tricyclic
antidepressants and antipsychotics. Postural hypotension may occur.
Allopurinol, procainamide, cytostatic or immunosuppressive agents:
concomitant administration with ACE inhibitors may lead to an increased risk
for leucopenia especially when the latter are used at higher than currently
recommended doses.
Clonidine: It has been suggested, when patients treated with clonidine are
changed to captopril, the anti-hypertensive effect of captopril can be delayed.
Systemic corticosteroids have been associated with blood dyscrasias in
patients with renal failure who were also taking captopril.
Non-Steroidal Anti-Inflammatory drugs (NSAIDs) : The administration of
non-steroidal anti-inflammatory agents, eg indomethacin, may reduce the
antihypertensive effect of captopril. Furthermore, it has been reported that
NSAIDs and ACE inhibitors exert an additive effect on the increase in serum
potassium, whereas renal function may decrease. These effects are in principle
reversible. Rarely, acute renal failure may occur, particularly in patients with
compromised renal function such as older or dehydrated people. Chronic
administration of NSAIDs may reduce the antihypertensive effect of an ACE
inhibitor.
Antidiabetics: pharmacological studies have shown that ACE inhibitors,
including captopril, can potentiate the blood glucose-reducing effects of
insulin and oral antidiabetics such as sulphonylurea in diabetics. Should this
very rare interaction occur, it may be necessary to reduce the dose of the
antidiabetic during simultaneous treatment with ACE inhibitors.
Antacids: Induce decreased bioavailability of captopril.
Sympathomimetics: May reduce the antihypertensive effects of captopril,
patients should he carefully monitored to confirm that the desired effect is
being obtained.
Probenecid: In the presence of probenecid, the renal clearance of captopril is
reduced.
Alcohol: Enhances the hypotensive effect.
Clinical Chemistry
Captopril may cause a false-positive urine test for acetone.

4.6

Fertility, pregnancy and lactation
Pregnancy:

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see
section 4.4). The use of ACE inhibitors is contraindicated during the second and third
trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to
ACE inhibitors during the first trimester of pregnancy has not been conclusive;
however a small increase in risk cannot be excluded. Unless continued ACE inhibitor
therapy is considered essential, patients planning pregnancy should be changed to
alternative antihypertensive treatments which have an established safety profile for
use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors
should be stopped immediately, and, if appropriate, alternative therapy should be
started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to
induce human foetotoxicity (decreased renal function, oligohydramnios, skull
ossification retardation) and neonatal toxicity (renal failure, hypotension,
hyperkalaemia). (see section 5.3). Should exposure to ACE inhibitors have occurred
from the second trimester of pregnancy, ultrasound check of renal function and skull
is recommended. Infants whose mothers have taken ACE inhibitors should be closely
observed for hypotension (see sections 4.3 and 4.4).
Breast-feeding:
Limited pharmacokinetic data demonstrate very low concentrations in breast milk
(see section 5.2). Although these concentrations seem to be clinically irrelevant, the
use of Captopril in breastfeeding is not recommended for preterm infants and for the
first few weeks after delivery, because of the hypothetical risk of cardiovascular and
renal effects and because there is not enough clinical experience.
In the case of an older infant, the use of Captopril in a breast-feeding mother may be
considered if this treatment is necessary for the mother and the child is observed for
any adverse effect.

4.7

Effects on ability to drive and use machines
As with other antihypertensives, the ability to drive and use machines may be
reduced, e.g. at the start of the treatment or when the dose is modified, and also when
used in combination with alcohol, but these effects depend on the individual's
susceptibility.
Avoid driving vehicles or operating machinery until the effects of the drug are
established, as it may cause weariness, dizziness and fainting.

4.8

Undesirable effects
List of adverse reactions
The frequencies of adverse events are defined using the following convention: very
common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100),
rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated
from the available data).
Undesirable effects reported for captopril and/or ACE inhibitor therapy include:
Blood and lymphatic system disorders:
Very rare: neutropenia/agranulocytosis (see section 4.4), pancytopenia particularly in
patients with renal dysfunction (see section 4.4), anaemia (including aplastic and
haemolytic), thrombocytopenia, lymphadenopathy, eosinophilia, auto-immune
diseases and/or positive ANA-titres.
Not known: leucocytosis
Metabolism and nutrition disorders:
Rare: anorexia
Very rare: hyperkalaemia, hypoglycaemia (see section 4.4)
Psychiatric disorders:
Common: sleep disorders
Very rare: confusion, depression.
Nervous system disorders:
Common: taste impairment, dizziness.
Rare: drowsiness, headache and paraesthesia.
Very rare: cerebrovascular incidents, including stroke, and syncope.
Eye disorders:
Very rare: blurred vision.

Ear and labyrinth disorders:
Not known: tinnitus, disorders of balance
Cardiac disorders:
Uncommon: tachycardia or tachyarrhythmia, angina pectoris, palpitations.
Very rare: cardiac arrest, cardiogenic shock.

Not known: myocardial infarction
Vascular disorders:
Uncommon: hypotension (see section 4.4), Raynaud syndrome, flush, pallor.
Not known: vasculitis
Respiratory, thoracic and mediastinal disorders:
Common: dry, irritating (non-productive) cough (see section 4.4) and dyspnoea.
Rare: sinusitis, bronchitis
Very rare: bronchospasm, rhinitis, allergic alveolitis/eosinophilic pneumonia.
Gastrointestinal disorders:
Common: nausea, vomiting, gastric irritations, abdominal pain, diarrhoea,
constipation, dry mouth.
Rare: stomatitis/aphthous ulcerations, intestinal angioedema (see section 4.4).
Very rare: glossitis, peptic ulcer, pancreatitis.
Not known: indigestion, ileus
Hepatobiliary disorders:
Very rare: impaired hepatic function and cholestasis (including jaundice), hepatitis
including necrosis, elevated liver enzymes and bilirubin.
Skin and subcutaneous tissue disorders:
Common: pruritus with or without a rash, rash, and alopecia.
Uncommon: angioedema (see section 4.4).
Very rare: urticaria, Stevens Johnson syndrome, erythema multiforme, photo
sensitivity, erythroderma, pemphigoid reactions and exfoliative dermatitis.
Not known: toxic epidermic necrolysis, psoriasis-like efflorescences, oncholysis
Musculoskeletal and connective tissue disorders:
Very rare: myalgia, arthralgia.
Renal and urinary disorders:
Rare: renal function disorders including renal failure, polyuria, oliguria, increased
urine frequency
Very rare: nephrotic syndrome.
Reproductive system and breast disorders:
Very rare: impotence, gynaecomastia.

General disorders and administration site conditions:
Uncommon: chest pain, fatigue, malaise
Very rare: fever.
Investigations:
Very rare: proteinuria, eosinophilia, increase of serum potassium, decrease of serum
sodium, elevation of BUN, serum creatinine and serum bilirubin, decreases in
haemoglobin, haematocrit, leucocytes, thrombocytes, positive ANA-titre, elevated
ESR.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms of overdosage are severe hypotension, shock, stupor, bradycardia,
electrolyte disturbances and renal failure.
After ingestion of an overdose, the patient should be kept under close supervision,
preferably in an intensive care unit. Serum electrolytes and creatinine should be
monitored frequently, as well as blood pressure. Therapeutic measures depend on the
nature and severity of the symptoms. Measurements to prevent absorption such as
gastric lavage, administration of adsorbents and sodium sulphate within 30 minutes
after intake and to hasten elimination should be applied if ingestion is recent. If
hypotension occurs, the patient should be placed in the shock position and salt and
volume supplementation should be given rapidly. Treatment with angiotensin II
should be considered. Bradycardia or extensive vagal reactions should be treated by
administering atropine. The use of a pacemaker may be considered. Captopril may be
removed from the circulation by haemodialysis. The use of high-flux polyacrylonitrile
membranes should be avoided.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitors, ATC code: CO9A AO1 (Agents acting
on the renin-angiotensin system, converting enzyme blocker).
The beneficial effects of ACE inhibitors in hypertension and in heart failure appear to
result primarily from the suppression of the plasma renin-angiotensin aldosterone
system. Renin is an endogenous enzyme synthesized by the kidneys and released into
the circulation where it converts angiotensinogen to angiotensin I, a relatively

inactive decapeptide. Angiotensin I is then converted by angiotensin converting
enzyme, a peptidyldipeptidase, to angiotensin II. Angiotensin II is a potent
vasoconstrictor responsible for arterial vasoconstriction and increased blood pressure,
as well as for stimulation of the adrenal gland to secrete aldosterone. Inhibition of
ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor
activity and to reduced aldosterone secretion. Although the latter decrease is small,
small increases in serum potassium concentrations may occur, along with sodium and
fluid loss. The cessation of the negative feedback of angiotensin II on the renin
secretion results in an increase of the plasma renin activity.
Another function of the converting enzyme is to degrade the potent vasodepressive
kinin peptide bradykinin to inactive metabolites. Therefore inhibition of ACE results
in an increased activity of circulating and local kallikrein-kinin system which
contributes to peripheral vasodilation by activating the prostaglandin system. It is
possible that this mechanism is involved in the hypotensive effect of ACE inhibitors
and is responsible for certain side effects.
In patients with hypertension administration of ACE inhibitors results in a reduction
of supine and standing blood pressure to about the same extent with no compensatory
increase of the heart rate. Peripheral arterial resistance is reduced with either no
change or an increase in cardiac output.
There is an increase in renal blood flow and glomerular filtration rate is usually
unchanged. Achievement of optimal blood pressure reduction may require several
weeks of therapy in some patients. The antihypertensive effects are maintained during
long term therapy. Abrupt withdrawal of therapy has not been associated with a rapid
increase in blood pressure.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone
and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D
(The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the
combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or
cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of endorgan damage. VA NEPHRON-D was a study in patients with type 2 diabetes
mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or
cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia,
acute kidney injury and/or hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for
other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used
concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal
Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a
standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients
with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or
both. The study was terminated early because of an increased risk of adverse
outcomes. Cardiovascular death and stroke were both numerically more frequent in
the aliskiren group than in the placebo group and adverse events and serious adverse

events of interest (hyperkalaemia, hypotension and renal dysfunction) were more
frequently reported in the aliskiren group than in the placebo group.

5.2

Pharmacokinetic properties
Approximately 70% - 75 % of an oral dose of captopril is absorbed by healthy fasting
volunteers. Peak blood concentrations are achieved 0.5 - 1.5 hours after
administration. Ingestion of captopril in the non-fasting state reduces absorption by
35 %. Captopril is an unstable compound in vivo. The formation of disulphide dimers
and mixed conjugates occur rapidly and complicates measurement of drug levels.
Captopril is covalently bound to plasma proteins. Peak blood levels are reached about
an hour after an oral dose. Approximately 25 to 30% of the circulating drug is bound
to plasma proteins. Excretion is delayed in the presence of renal impairment.
Captopril is dialysable.
Breast-feeding:
In the report of twelve women taking oral captopril 100 mg 3 times daily, the average
peak milk level was 4.7 µg/L and occurred 3.8 hours after the dose. Based on these
data, the maximum daily dosage that a nursing infant would receive is less than
0.002% of the maternal daily dosage.

5.3

Preclinical safety data
Pre-clinical information has not been included because the safety profile of captopril
has been established after many years of clinical use. Please refer to section 4.
Captopril is safe with regard to genotoxicity. 2 year carcinogenicity studies with
captopril in rats and mice failed to show any evidence of carcinogenic effects.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose Monohydrate
Microcrystalline Cellulose
Pregelatinised Maize Starch
Stearic Acid.

6.2

Incompatibilities
Not applicable

6.3

Shelf life
36 months

6.4

Special precautions for storage
Do not store above 25°C. Store in the original package in order to protect from
moisture.

6.5

Nature and contents of container
HDPE containers with caps or child resistant closures in packs of 14, 20, 21, 28, 30,
50, 56, 60, 84, 100, 112, 120, 168, 250, 500, 1000 or 5000 tablets.
Blister strips (PVC/PVdC Al) in packs of 14, 20, 21, 28, 30, 56, 60, 84, 100, 112, 120
or 168 tablets.
Not all pack sizes may be marketed

6.6

Special precautions for disposal

No special requirements

7

MARKETING AUTHORISATION HOLDER
Teva UK Limited
Brampton Road,
Hampden Park,
Eastbourne BN22 9AG
England.

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/0313

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
6 August 1996 / 6 August 2001

10

DATE OF REVISION OF THE TEXT
18/12/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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