Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Organon Pharma Pty Ltd, Building A, 26 Talavera Road, Macquarie Park NSW 2113
1. History of previous hypersensitivity to RENITEC or to any component of the formulation and in patients with a history of angioneurotic oedema relating to previous treatment with an angiotensin-converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
2. Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
3. RENITEC should not be administered with aliskiren in patients with diabetes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
4. RENITEC is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer RENITEC within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor. (See Section 4.4 Special Warnings and Precautions for Use and Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including RENITEC. This may occur at any time during treatment. In such cases RENITEC should be promptly discontinued and the patient carefully observed until the swelling disappears. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway should be promptly administered (see Section 4.8 Adverse Effects (Undesirable Effects)).
The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom-free intervals. Angioedema may occur with or without urticaria. Black patients receiving ACE inhibitors have been reported to have higher incidence of angioedema compared to non-blacks.
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.
Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk for angioedema (see Section 4.3 Contraindications and Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients receiving concomitant ACE inhibitor and vildagliptin may be at increased risk for angioedema (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Rarely, patients receiving ACE inhibitors during desensitization with hymenoptera venom have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization.
Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible consequence of enalapril use in severely salt/volume depleted persons, such as those treated vigorously with diuretics or patients on dialysis or dietary salt restriction or those suffering from diarrhoea or vomiting. (See Section 4.4 Special Warnings and Precautions for Use, Section 4.5 Interactions with Other Medicines and Other Forms of Interactions and Section 4.8 Adverse Effects (Undesirable Effects)) In patients with heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotaemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs the patient should be placed in supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion.
Another angiotensin converting enzyme inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia/neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded.
It is recommended that periodic haematologic monitoring be considered in patients with diseases known to affect bone marrow function (e.g., renal dysfunction, collagen vascular disease, etc) and/or who are taking concomitant therapy known to be associated with bone marrow depression.
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., 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 a different class of antihypertensive agent.
Evaluation of the hypertensive patient should always include assessment of renal function. (See Section 4.2 Dose and Method of Administration.)
As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
(See also Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Agents Increasing Serum Potassium)
Elevated serum potassium (greater than 5.7 mmol/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalaemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. Risk factors for the development of hyperkalaemia may include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products), which should be used cautiously, if at all, with RENITEC.
The use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that may increase serum potassium, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias.
If concomitant use of RENITEC and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycaemia, especially during the first month of combined use. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Antidiabetics.)
In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril may block 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.
A persistent non-productive, ticklish cough has been reported in some patients undergoing treatment with enalapril and other ACE inhibiting drugs. The cough is often worse when lying down. The cough is commoner in women (who account for about two thirds of reported cases). The patients who cough may have increased bronchial reactivity compared to those who do not cough. It may disappear in some patients with continued use, or diminish or disappear if the dose of the drug is reduced.
In those in whom cough persists, the drug should be discontinued. The cough usually returns on rechallenge. No residual effects have been reported.
As a consequence of inhibiting the renin-angiotensin- aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including RENITEC, may be associated with oliguria and/or progressive azotaemia and rarely with acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when RENITEC has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of RENITEC and/or discontinuation of the diuretic may be required.
See Section 4.5 Interactions with other medicines and other forms of interactions and Section 4.2 Dose and Method of Administration.
RENITEC has not been studied in children.
No data available.
Hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia), hyponatraemia.
In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with RENITEC alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis. (see Section 4.4 Special Warnings and Precautions for Use).
Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in hypertensive patients treated with RENITEC but are rarely of clinical importance unless another cause of anaemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anaemia.
In marketing experience, rare cases of pancreatitis, neutropenia, thrombocytopenia, agranulocytosis and bone marrow depression have been reported.
A few cases of haemolysis have been reported in patients with G6PD deficiency.
Elevations of liver enzymes and/or serum bilirubin have occurred.
Patients on diuretics and especially those in whom diuretic therapy was recently instituted may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimised by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide medical supervision for at least one hour after the initial dose. (See Section 4.4 Special Warnings and Precautions for Use and Section 4.2 Dose and Method of Administration.)
The antihypertensive effect of RENITEC is augmented by antihypertensive agents that cause renin release (e.g., diuretics).
RENITEC has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of clinically significant adverse interactions.
(See also Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia)
RENITEC may attenuate potassium loss caused by thiazide-type diuretics. Risk factors for the development of hyperkalaemia include renal insufficiency and diabetes mellitus and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products), which may lead to significant increases in serum potassium. If concomitant use of RENITEC with potassium-sparing diuretics, potassium supplements, or potassium containing salt substitutes is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased bloodglucose-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. In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored for hypoglycaemia, especially during the first month of treatment with an ACE inhibitor.
As with other drugs which eliminate sodium, lithium clearance may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
These interactions should be considered in patients taking NSAIDs including selective COX2 inhibitors concomitantly with diuretics and ACE inhibitors. Therefore, the combination should be administered with caution, especially in the elderly.
The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an antiinflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with increased risks of hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on RENITEC and other agents that affect the RAAS. Do not coadminister aliskiren with RENITEC in patients with diabetes. Avoid use of aliskiren with RENITEC in patients with renal impairment (GFR<60 mL/min).
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.
Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see Section 4.4 Special Warnings and Precautions for Use).
Patients taking a concomitant neprilysin inhibitor (e.g., sacubitril) may be at increased risk for angioedema (see Section 4.3 Contraindications and Section 4.4 Special Warnings and Precautions for Use).
Patients taking concomitant vildagliptin may be at increased risk for angioedema (see Section 4.4 Special Warnings and Precautions for Use).
There were no adverse effects on reproductive performance in male and female rats treated with 10 to 90 mg/kg/day of enalapril.
(Pregnancy Category D)
As with all ACE inhibitors, RENITEC should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with RENITEC and avoided during treatment.
If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment.
If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
There are no adequate and well-controlled studies of enalapril in pregnant women. Data, however, show that enalapril crosses the human placenta. Post marketing experience with all ACE inhibitors suggest that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero. There have been reports of foetal hypotension, renal failure, hyperkalaemia, skull hypoplasia and death when ACE inhibitors have been used during the second and third trimesters of pregnancy.
A historical cohort study in over 29,000 infants born to non-diabetic mothers has shown 2.7 times higher risk for congenital malformations in infants exposed to any ACE inhibitor during the first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02) respectively compared to no exposure.
There is a potential risk of foetal hypotension, decreased birth weight and decreased renal perfusion or anuria in the foetus from in utero exposure to ACE inhibitors. Oligohydramnios in the mother has also been reported, presumably representing decreased renal function in the foetus and may result in limb contractures, craniofacial deformations and hypoplastic lung development. Any neonate exposed to enalapril in utero should be observed closely for adequate urine output, blood pressure and hyperkalaemia. If required, appropriate medical measures should be initiated including administration of fluids or dialysis to remove enalaprilat from the circulatory system.
The maternal and foetal toxicity occurred in some rabbits at doses of 1mg/kg/day or more. Saline supplementation prevented the maternal and foetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day. Enalapril was not teratogenic in rabbits. There was no foetotoxicity of teratogenicity in rats treated with up to 200mg/kg/day of enalapril. Foetotoxicity expressed as a decrease in average foetal weight occurred in rats given 1200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline.
It is not known if RENITEC is secreted in human milk. However, RENITEC has been demonstrated to be secreted into the milk of lactating rats. In view of this and a lack of knowledge of the effects of enalapril on neonates, this product should not be used during lactation or else breast feeding should be discontinued.
When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur. (See Section 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS).
RENITEC has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. RENITEC has been found to be generally well tolerated in controlled clinical trials involving 2677 patients.
The most frequent clinical adverse experiences in controlled trials were: headache (4.8 percent), dizziness (4.6 percent) and fatigue (2.8 percent). For the most part, adverse experiences were mild and transient in nature. Discontinuation of therapy was required in 6.0 percent of patients. In clinical trials, the overall frequency of adverse experiences was not related to total daily dosage within the range of 10 to 40 mg. The overall percentage of patients treated with RENITEC reporting adverse experiences was comparable to placebo.
Adverse experiences occurring in greater than one percent of patients treated with RENITEC in controlled clinical trials are shown below:
Table 2. Percent of Patients in Controlled Studies:
| RENITEC (n=26771) Incidence (discontinuation) | Placebo (n=230) Incidence | |
|---|---|---|
| Headache | 4.8 (0.3) | 9.1 |
| Dizziness | 4.6 (0.4) | 4.3 |
| Fatigue | 2.8 (<0.1) | 2.6 |
| Diarrhoea | 1.6 (0.2) | 1.7 |
| Rash | 1.5 (0.3) | 0.4 |
| Hypotension | 1.4 (0.3) | 0.4 |
| Cough2 | 1.3 (0.2) | 0.9 |
| Nausea | 1.3 (0.2) | 1.7 |
| Orthostatic Effects | 1.3 (<0.1) | 0.0 |
1 Includes 363 patients treated for congestive heart failure receiving concomitant digoxin and diuretic therapy.
2 See Section 4.4 Special Warnings and Precautions for Use
Clinical adverse experiences occurring since the drug was marketed or in 0.5 to 1.0 percent of patients in the controlled trials are listed below and, within each category, are in order of decreasing severity.
Cardiovascular: Myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Section 4.4 Special Warnings and Precautions for Use, Hypotension), syncope, orthostatic hypotension, palpitations, chest pain, rhythm disturbances, angina pectoris, Raynaud’s phenomenon.
Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Gastrointestinal system: Ileus, pancreatitis, hepatic failure, hepatitis either hepatocellular or cholestatic, jaundice, abdominal pain, vomiting, dyspepsia, constipation, anorexia, stomatitis.
Metabolic: Cases of hypoglycaemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Nervous system/Psychiatric: Depression, confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, dream abnormality.
Renal: Renal failure, oliguria, renal dysfunction. (See Section 4.4 Special Warnings and Precautions for Use and Section 4.2 Dose and Method of Administration.)
Respiratory: Pulmonary infiltrates, bronchospasm/asthma, dyspnoea, rhinorrhoea, sore throat and hoarseness.
Skin: diaphoresis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigus, pruritus, urticaria, alopecia.
Other: Vasculitis, muscle cramps, hyperhidrosis, impotence, asthenia, photosensitivity, flushing, taste alteration, tinnitus, glossitis, blurred vision.
A symptom complex has been reported which may include fever, serositis, myalgia and arthralgia/arthritis; an elevated ESR, a positive ANA, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur. These symptoms have disappeared after discontinuation of therapy.
Angioedema has been reported in patients receiving RENITEC (0.2 percent). Angioedema associated with laryngeal oedema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with RENITEC should be discontinued and appropriate therapy instituted immediately (See Section 4.4 Special Warnings and Precautions for Use). In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including enalapril.
Combining the results of clinical trials in patients with hypertension or congestive heart failure, hypotension (including postural hypotension, and other orthostatic effect) was reported in 2.3 percent of patients following the initial dose of enalapril or during extended therapy. In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. (See Section 4.4 Special Warnings and Precautions for Use.)
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
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