Source: Health Products Regulatory Authority (ZA) Publisher: Ranbaxy Pharmaceuticals (Pty) Ltd, 14 Lautre Road, Stormill Ext. 1, Roodepoort, 1724, South Africa
Should a woman become pregnant while receiving SINOPREN, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine. Should a woman contemplate pregnancy, the doctor should institute alternative medication (see Section 4.3 and 4.6).
ACE inhibitors can cause foetal and neonatal morbidity and mortality when administered pregnant women.
ACE inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios, which may result in limb contractures, craniofacial deformities and hypoplastic lung development; as well as hypotension, renal failure, hyperkalaemia, oliguria and anuria in new-borns have been reported after administration of ACE inhibitors in the second and third trimesters. Cases of detective skull ossification have been observed. Prematurity and low birth mass can occur.
The adverse effects to the embryo and foetus do not appear to have resulted from intra-uterine ACE inhibitor exposure limited to the first trimester.
Infants whose mothers may have taken SINOPREN should be closely observed for hypotension, oliguria and hyperkalaemia.
Lisinopril crosses the human placenta. Limited experience indicates that peritoneal dialysis may be of some benefit in the clearance of lisinopril from the neonatal circulation. Lisinopril can theoretically be removed from the neonatal circulation by exchange transfusion.
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of SINOPREN and aliskiren is therefore contraindicated (see Section 4.3).
Symptomatic hypotension may occur in uncomplicated hypertensive patients. In hypertensive patients receiving SINOPREN, hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction; dialysis, diarrhoea or vomiting. In patients with congestive heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In these patients, initiation of therapy and dose adjustment should be monitored under close medical supervision.
In these patients, therapy should be started under medical supervision and the patients should be followed closely whenever the dose of SINOPREN and/or diuretic is adjusted. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contra-indication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion. In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with SINOPREN.
If hypotension becomes symptomatic, a reduction of dose or discontinuation of SINOPREN may be necessary.
Treatment with SINOPREN must not be initiated in acute myocardial infarction patients who are at risk of further serious haemodynamic deterioration after treatment with a vasodilator. These are 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 mgHg or lower. If hypotension persists (systolic blood pressure less than 90 mmHg for more than 1 hour) then SINOPREN inhibitors, increases of blood urea and serum should be withdrawn.
In patients with congestive heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure has been reported in this situation.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme creatinine, reversible upon discontinuation of therapy have been seen. This is especially likely in patients with renal insufficiency. Therefore SINOPREN is contraindicated in these patients. Some hypertensive patients, with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine especially when SINOPREN has been given concurrently with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of SINOPREN and/or discontinuation of the diuretic and/or SINOPREN may be required.
In acute myocardial infarction, treatment with SINOPREN should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 micromol/l and/or proteinuria exceeding 500 mg/24 hr. If renal dysfunction develops during treatment with SINOPREN (serum creatinine concentration exceeding 265 micromol/l or a doubling from the pre-treatment value) then the doctor should consider withdrawal of SINOPREN.
Anaphylactoid reactions have been reported in patients undergoing certain haemodialysis procedures (e.g. with the high flux membrane AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.
Angioedema of the face, lips, tongue, glottis and/or larynx and extremities has been reported in patients treated with angiotensin converting enzyme inhibitors (including SINOPREN). This may occur at any time during therapy. In such cases, SINOPREN should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those cases where the swelling is confined to the face and lips, the condition may resolve without treatment, although anti-histamines may be useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate emergency therapy should be administered promptly. This may include the administration of epinephrine (adrenaline) and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred. These patients should never receive any ACE-inhibitor again.
SINOPREN causes a higher rate of angioedema in black patients than in non-black patients. 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)
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent rechallenge.
Cough has been reported with the use of ACE-inhibitors such as SINOPREN. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE-inhibitor induced cough should be considered as part of the differential diagnosis of cough.
In patients undergoing major surgery or during anaesthesia with medicines that produce hypotension, SINOPREN may block the angiotensin-II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
See Section 4.5.
Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see Section 4.3). Renal function should be assessed before initiating treatment, and monitored during treatment, with fluoroquinolones or ACE inhibitors/renin-angiotensin receptor blockers.
Rarely, patients receiving ACE inhibitors during low-density lipoproteins (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving lisinopril who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril and receive appropriate medical follow-up.
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Lisinopril 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 lisinopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor.
SINOPREN contains mannitol and may have a laxative effect.
When lisinopril is combined with other antihypertensive agents (e.g. glyceryl trinitrate and other nitrates, or other vasodilators), additive falls in blood pressure may occur. Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone- 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 (see Section 4.3 and 4.4). ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
When a diuretic is added to the therapy of a patient receiving SINOPREN, the antihypertensive effect is additive.
Patients already on diuretics and especially those, in whom diuretic therapy was recently instituted, may experience an excessive reduction of blood pressure when SINOPREN is added. The possibility of symptomatic hypotension with SINOPREN can be minimised by discontinuing the diuretic prior to initiation of treatment with SINOPREN.
Indomethacin may diminish the antihypertensive efficacy of concomitantly administered SINOPREN. In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs (NSAIDS), the co-administration of SINOPREN may result in further deterioration in renal function.
SINOPREN has been used concomitantly with nitrates without evidence of clinically significant adverse interactions.
Lithium elimination may be reduced by SINOPREN. Therefore the concomitant use with SINOPREN is contraindicated (see Section 4.3).
Hyperkalaemia may occur during concomitant use of ACE inhibitors with ciclosporin. Monitoring of serum potassium is recommended.
Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is recommended.
Potassium supplements, potassium-sparing agents or potassium-containing salt substitutes:
Serum potassium tends to rise but usually remains within normal limits; however, hyperkalaemia may occur.
Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes (see Section 4.3).
The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium.
If concomitant use of SINOPREN and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury. See Section 4.3.
A case series of 16 reports of acute kidney injury (AKI) associated with enalapril and ciprofloxacin as co-suspect or interacting medicines was identified in VigiBase, the WHO global database of individual case safety reports. Analysis of 11 cases indicated that in most patients although clinical conditions and a number of medicines were likely to have increased their risk of AKI, including ACE inhibitor-related AKI, the event did not occur until after a ciprofloxacin prescription, lending weight to ciprofloxacin being the cause or a combined action of ciprofloxacin and enalapril. Furthermore, the interaction between ACE inhibitors and fluoroquinolones to precipitate acute kidney injury is a class effect for all ACE inhibitors and not just enalapril, and also a class effect of all the fluoroquinolones not just with ciprofloxacin. Thus, concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury. See Section 4.3.
Concomitant treatment of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or neutral endopeptidase (NEP) inhibitors (e.g. racecadotril) or tissue plasminogen activator may increase the risk of angioedema.
When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. These effects are usually reversible. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure.
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk for hyperkalaemia.
Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, beta-blockers and/or nitrates.
The use of SINOPREN is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take SINOPREN during pregnancy (see Section 4.3). 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 SINOPREN 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 (spina bifida) and of kidney malformations.
SINOPREN passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms.
Should exposure to SINOPREN have occurred during the second or third trimesters of pregnancy, serial ultrasound examinations should be performed to assess the intra-amniotic environment. Patients and physicians should.be aware that oligohydrammos may not appear until after the foetus has sustained irreversible injury.
Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of Sinopren during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (see Section 4.3 and 4.4).
When driving vehicles or operating machines, it should be taken into account that dizziness or tiredness may occur during treatment with SINOPREN.
| System Organ Class | Frequent | Less frequent | Frequency Unknown |
|---|---|---|---|
| Blood and the lymphatic system disorders | anaemia, haemolytic anaemia, neutropenia, decreases in haemoglobin, decreases in haematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leucopenia, lymphadenopathy, autoimmune diseases. | ||
| Immune system disorders | anaphylactoid reactions, angioedema | ||
| Endocrine disorders | syndrome of inappropriate antidiuretic hormone secretion (SIADH) | ||
| Metabolism and nutrition disorders | hypoglycaemia | ||
| Psychiatric disorders | mood alterations, mental confusion | depressive symptoms | |
| Nervous system disorders | headache, dizziness | paraesthesia, vertigo, taste disturbance, sleep disturbances, olfactory disturbance | syncope |
| Cardiac disorders | orthostatic effects (including hypotension) | myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients, chest pain, palpitations, tachycardia | |
| Vascular disorders | Raynaud’s phenomenon | ||
| Respiratory, thoracic and mediastinal disorders | cough | rhinitis, bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia | |
| Gastrointestinal disorders | diarrhoea, vomiting | nausea, abdominal pain, indigestion, dry mouth, pancreatitis, intestinal angioedema, stomatitis | |
| Hepatobiliary disorders1 | hepatitis – either hepatocellular or cholestatic, jaundice and hepatic failure | ||
| Skin and subcutaneous tissue disorders2 | rash, pruritus, urticaria, alopecia, psoriasis, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx, sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma, diaphoresis | ||
| Musculoskeletal and connective tissue disorders | muscle cramps | ||
| Renal and urinary disorders | renal dysfunction | uraemia, acute renal failure, oliguria/anuria | |
| Reproductive system and breast disorders | impotence, gynaecomastia | ||
| General disorders and administration site conditions | asthenia, fatigue | ||
| Investigations | increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia, increases in serum bilirubin, hyponatraemia, decrease in haemoglobin |
1 Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving SINOPREN who develop jaundice or marked elevation of hepatic enzymes should discontinue SINOPREN and receive appropriate medical follow up.
2 A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive anti-nuclear antibody (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia, and leucocytosis, rash, photosensitivity or other dermatologic manifestations may occur
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.