Cardiovascular

Therapeutic indications:

Aprovel® is indicated in adults for the treatment of essential hypertension.
It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1).

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel® at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years.
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel® can be increased to 300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel® (see section 4.5).
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
The demonstration of renal benefit of Aprovel® in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1).

Special Populations

No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4).

Hepatic impairment

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.

Older people

Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for older people.

Paediatric population

The safety and efficacy of Aprovel® in children aged 0 to 18 has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.

Method of Administration

For oral use.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel®.

Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists.

Renal impairment and kidney transplantation: when Aprovel® is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel® in patients with a recent kidney transplantation.

Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1).

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.

Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5).

Lithium: the combination of lithium and Aprovel® is not recommended (see section 4.5).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of Aprovel® is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are 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 (see section 5.1).

Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA 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 AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2).

Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

INTERACTIONS

Diuretics and other antihypertensive agents

Other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel® has been safely administered with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Aprovel® (see section 4.4).

Aliskiren-containing products or ACE-inhibitors

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 (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4).

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists 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. 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.

Additional information on irbesartan interactions

In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.

PREGNANCY AND LACTATION

Pregnancy

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

Breast-feeding

Aprovel® is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

UNDESIRABLE EFFECTS

Nervous system disorders: dizziness, orthostatic dizziness^*
Vascular disorders: orthostatic hypotension^*
Gastrointestinal disorders: nausea/vomiting
Musculoskeletal and connective tissue disorders: musculoskeletal pain^*
General disorders and administration site conditions: fatigue

For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

No specific information is available on the treatment of overdose with Aprovel®. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Angiotensin-II antagonists, plain.
ATC code: C09C A04.

Date of SmPC text revision: 11 April 2019;
Date of last abbreviation of prescribing information: November 2020.
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, 2nd Floor Yekeima Square,
No_ 6 Goerge Walker Bush Highway Dzorwulu, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

Therapeutic indications

Treatment of essential arterial hypertension.
Aprovasc® is indicated in hypertensive adult patients whose blood pressure could not be adequately controlled with Irbesartan or Amlodipine monotherapy.

POSOLOGY AND METHOD OF ADMINISTRATION

The usual, initial, and maintenance dose of Aprovasc® is one tablet once a day. It can be administered with or without food.
Aprovasc® should be administered in patients whose blood pressure is not adequately controlled during monotherapy with Irbesartan or amlodipine or for continued treatment for patients receiving Irbesartan and amlodipine as separate tablets. Dose should be individualized based on the response to therapy with individual components and the required antihypertensive response. The maximum recommended dose of Aprovasc® is 300 mg/10 mg daily.

Treatment must be adjusted according to blood pressure response.

Pediatric patients: Safety and efficacy of Aprovasc® has not been established.
Elderly patients and patients with renal failure: It is usually not necessary to reduce the dosage in elderly patients or in patients with impaired renal function (regardless of grade).
Patients with impaired hepatic function: Due to the presence of amlodipine, APROVASC ® should be administered with caution (see Section 7).
For oral administration.
Aprovasc® can be administered with food or fasting.

CONTRA-INDICATIONS

Due to the presence of both, Irbesartan and amlodipine, Aprovasc® is contraindicated in:

• hypersensitivity to the active substances or to any formulation component
• hypersensitivity to dihydropyridines
• cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal’s angina)
• pregnancy and lactation (see Warnings and section 8, Restrictions during pregnancy and lactation).

Do not co-administer Aprovasc® with medications containing aliskiren in patients with diabetes or with moderate to severe renal impairment (Glomerular Filtration Rate (GFR) <60 mL/min/1.73 m2).
Do not co-administer Aprovasc® with angiotensin-converting enzyme inhibitors (ACEIs) in patients with diabetic nephropathy.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Dual blockade of the Renin-Angiotensin-Aldosterone system (RAAS)

The dual blockade of the renin angiotensin aldosterone system with the combination of Aprovasc® with angiotensin-converting enzyme inhibitors (ACEIs) or with aliskiren is not recommended since there is an increased risk of hypotension, hyperkalemia, and changes in renal function compared to monotherapy. The use of Aprovasc® in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal failure (Glomerular Filtration Rate (GFR) <60 mL/min/1.73 m2).
The use of Aprovasc® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy.
The use of Aprovasc® in patients with psoriasis or with a history of psoriasis should be weighed carefully as it may exacerbate psoriasis.

Changes in the renal function of susceptible individuals can be expected as a consequence of the inhibition of the renin-angiotensin-aldosterone system. In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (hypertensive patients with stenosis of the renal artery of one or both kidneys, or patients with severe congestive heart failure), treatment with other drugs that affect this system has been associated with oliguria and/or progressive azotemia elevation and rarely with acute renal failure and/or death. The possibility of a similar effect occurring with the use of an angiotensin II receptor antagonist, including Irbesartan, cannot be excluded.

Pediatric use

Safety and efficacy in pediatric patients have not been established.

Geriatric use

In elderly patients, with volume depletion (including those on therapy with diuretics), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, can cause a deterioration of renal function, including a possible acute renal failure. These effects are usually reversible. Renal function should be monitored periodically in patients receiving periodic treatment with Irbesartan and NSAIDs. The antihypertensive effect of angiotensin II receptor antagonists can be attenuated by NSAIDs including selective COX-2 inhibitors. In patients receiving Irbesartan in clinical studies no overall differences were observed in terms of efficacy and safety in older patients (65 years or older) or in younger patients.

Hypotension

Patients with volume depletion: Irbesartan has rarely been associated with hypotension in hypertensive patients who have no other concomitant condition. Symptomatic hypotension may occur, such as with ACE inhibitors, in patients with sodium/volume depletion and in those under intensive treatment with diuretics and/or salt restriction or in hemodialysis. The depletion of volume and/or sodium should be corrected before starting treatment with Aprovasc® or the start of treatment with the lowest possible dose should be considered.

Patients with heart failure: In a long-term placebo-controlled study (PRAISE-2) of amlodipine in patients with non-ischemic etiology heart failure class NYHA III and IV, the use of amlodipine was associated with an increase in the reports of pulmonary edema although there was no significant difference in the incidence of heart failure worsening when compared with placebo (see Pharmacodynamics).

Hepatic impairmen

As with other calcium antagonists, amlodipine half-life is prolonged in patients with impaired liver function and no dose recommendations have been established for them. Therefore, Aprovasc® should be administered with caution in these patients.

Hypertensive crisis

The safety and efficacy of Aprovasc® in the treatment of hypertensive crisis has not been established.

Lithium

The concomitant use of angiotensin II receptor blockers and calcium channel blockers may reduce renal lithium clearance and the increase of serum levels that may reach toxic levels. Lithium levels should be monitored in patients who are receiving Aprovasc®.

INTERACTIONS

For Irbesartan and amlodipine combination

Based on a pharmacokinetic study where Irbesartan and amlodipine were administered alone or in combination, there is no pharmacokinetic interaction between Irbesartan and amlodipine.
No drug interaction studies have been conducted with Aprovasc® and other medicinal products.

Irbesartan

Based on in vitro information, no interactions are expected with drugs whose metabolism is dependent on CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, or CYP3A4 cytochrome isoenzymes.

Irbesartan is metabolized mainly by CYP2C9; however, no significant interactions were observed during clinical interaction studies when Irbesartan was administered concomitantly with warfarin (a drug metabolized by CYP2C9).
The pharmacokinetics of Irbesartan is not affected by concomitant administration of nifedipine or hydrochlorothiazide Irbesartan does not affect the pharmacokinetics of simvastatin (metabolized by CYP3A4) or digoxin (substrate of P-glycoprotein efflux transporter).

The combination of Aprovasc® with medications containing aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal failure (glomerular filtration rate (GFR) <60 mL/min/1.73 m2) and is not recommended in other patients.
Angiotensin-converting enzyme inhibitors (ACE inhibitors): Use of Aprovasc® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Based on the experience with the use of other medications that affect the renin-angiotensin system, the concomitant use of Irbesartan with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medications that may increase kalaemia with irbesartan can cause an increase in serum potassium, sometimes severe, and requires close monitoring of serum potassium.

In elderly patients, with volume depletion (including those on treatment with diuretics), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists , including Irbesartan, can cause impaired renal function, including possible acute renal failure. These effects are usually reversible. Renal function should be monitored periodically in patients receiving periodic treatment with Irbesartan and NSAIDs. The antihypertensive effect of angiotensin II receptor antagonists, including Irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

Amlodipine

Amlodipine has been safely administered concomitantly with thiazide diuretics, beta blockers, alpha blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs, and oral hypoglycemic drugs.
Data obtained from in vitro studies with human plasma show that amlodipine has no effect on protein binding with the medications studied (digoxin, phenytoin, warfarin, or indomethacin).

• Cimetidine: Co-administration of amlodipine with cimetidine did not alter amlodipine pharmacokinetics.
• Grapefruit juice: Simultaneous administration of 240 mL of grapefruit juice with a single oral dose of 10 mg of amlodipine in 20 healthy volunteers had no significant effect on amlodipine pharmacokinetics.
• Aluminum/magnesium (antacid): Simultaneous administration of an aluminum/magnesium antacid with a single dose of amlodipine had no significant effect on amlodipine pharmacokinetics.
• Sildenafil: When using amlodipine and sildenafil in combination, each agent independently exerted its own blood pressure reductive effect.
• Atorvastatin: Simultaneous administration of multiple doses of 10 mg of amlodipine with 80 mg of atorvastatin showed no significant change in the steady-state of atorvastatin pharmacokinetic parameters.
• Digoxin: Simultaneous administration of amlodipine with digoxin did not modify serum concentrations of digoxin or its renal clearance in healthy volunteers.
• Warfarin: Simultaneous administration of amlodipine did not significantly modify the effect of warfarin on prothrombin time.
• Cyclosporine: Pharmacokinetic studies with cyclosporine have shown that amlodipine does not significantly modify its pharmacokinetics.
• Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported with the concomitant use of Irbesartan. Monitor levels in patients receiving Irbesartan and lithium.

UNDESIRABLE EFFECTS

Nervous system disorders: Dizziness, headache, somnolence
Gastrointestinal disorders: Gingival swelling
General disorders and conditions of the administration site: Peripheral edema, edema
Cardiac disorders: Palpitations
Vascular disorders: Orthostatic hypotension
Renal and urinary disorders: Proteinuria

For uncommon, rare and very rare side effects see full prescribing information.

OVERDOSE

Suggested measures include gastric lavage. The administration of activated carbon to healthy individuals immediately or up to two hours after the ingestion of 10 mg of amlodipine has shown a significant decrease in the absorption of amlodipine.
If massive overdose occurs, initiate active cardiorespiratory monitoring. Frequent measurement of blood pressure is essential. Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support including limb elevation and monitoring of circulating volume and urinary output. A vasoconstrictor can help restore vascular tone and blood pressure, when there is no contraindication to its use.
Intravenous calcium gluconate may be of benefit in reversing the effects of calcium channel blockade.

PHARMACODYNAMIC PROPERTIES

Amlodipine is a calcium dihydropyridine antagonist.
Irbesartan is a specific antagonist of angiotensin II receptors (subtype AT1).

Date of SmPC text revision: 29 May 2015;
Date of last abbreviation of prescribing information: September 2017.
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, Volta Place,
35 Patrice Lumumba Road, Airport Residential Area, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

Therapeutic indications

Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

CoAprovel® can be taken once daily, with or without food.
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be considered:

• CoAprovel® 150 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;

• CoAprovel® 300 mg/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by CoAprovel® 150 mg/12.5 mg.;

• CoAprovel® 300 mg/25 mg may be administered in patients insufficiently controlled by CoAprovel® 300 mg/12.5 mg.

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, CoAprovel® may be administered with another antihypertensive medicinal product (see sections 4.3, 4.4, 4.5 and 5.1).

Special Populations

Renal impairment: Due to the hydrochlorothiazide component, CoAprovel® is not recommended for patients with severe renal dysfunction (creatinine clearance < 30 ml/min). Loop diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients with renal impairment whose renal creatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).

Hepatic impairment: CoAprovel® is not indicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function. No dosage adjustment of CoAprovel® is necessary in patients with mild to moderate hepatic impairment (see section 4.3).

Older people: No dosage adjustment of CoAprovel® is necessary in older people.

Paediatric population: CoAprovel® is not recommended for use in children and adolescents because the safety and efficacy have not been established. No data are available.

Method of Administration

For Oral Use.

CONTRA-INDICATIONS

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or to other sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
• Severe renal impairment (creatinine clearance < 30 ml/min)
• Refractory hypokalaemia, hypercalcaemia
• Severe hepatic impairment, biliary cirrhosis and cholestasis
• The concomitant use of CoAprovel® with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

See full prescribing information

Hypotension - Volume-depleted patients:

CoAprovel® has been rarely associated with symptomatic hypotension in hypertensive patients without other risk factors for hypotension. Symptomatic hypotension may be expected to occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before initiating therapy with CoAprovel.

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.

INTERACTIONS

See full prescribing information

Other antihypertensive agents: the antihypertensive effect of CoAprovel® may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with other antihypertensive agents including calcium channel blockers and beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless the volume depletion is corrected first (see section 4.4).

Aliskiren-containing products or ACE-inhibitors: 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 (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

UNDESIRABLE EFFECTS

Common

The most commonly reported ADRs were dizziness (5.6%), fatigue (4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood urea nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in the trials.

For uncommon, rare and very rare side effects see full prescribing information.

OVERDOSE

The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.

PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: angiotensin-II antagonists, combinations;
ATC code: C09DA04.

Therapeutic indications

Secondary prevention of atherothrombotic events

Clopidogrel is indicated in:

Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.

Adult patients suffering from acute coronary syndrome:
• Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).
• ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.

Prevention of atherothrombotic and thromboembolic events in atrial fibrillation

In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.

POSOLOGY AND METHOD OF ADMINISTRATION

POSOLOGY

Adults and elderly Plavix 75 mg film-coated tablets Clopidogrel should be given as a single daily dose of 75 mg. In patients suffering from acute coronary syndrome:

• Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300-mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months (see section 5.1).

• ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300-mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting (see section 5.1).

In patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel (see section 5.1).
If a dose is missed:

• Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.

• For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.

Paediatric population

Clopidogrel should not be used in children because of efficacy concerns (see section 5.1).

• Renal impairment: Therapeutic experience is limited in patients with renal impairment
• Hepatic impairment: Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses.

Method of Administration

For oral use.
It may be given with or without food.

CONTRA-INDICATIONS

• Hypersensitivity to the active substance or to any of the excipients listed
• Severe hepatic impairment.
• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Bleeding and haematological disorders

Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or other medicinal products associated with bleeding risk such as pentoxifylline (see section 4.5). Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.5).

If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular).

Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician.

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Acquired haemophilia

Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.

Recent ischaemic stroke

In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.

Cytochrome P450 2C19 (CYP2C19)

Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Tests are available to identify a patient's CYP2C19 genotype. Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see section 4.5 for a list of CYP2C19 inhibitors, see also section 5.2).

CYP2C8 substrates

Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal products (see section 4.5).

Cross-reactions among thienopyridines

Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.

Renal impairment

Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients (see section 4.2).

Hepatic impairment

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see section 4.2).

Excipients

Plavix contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. This medicinal product contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

Fertility, pregnancy and lactation

Pregnancy

As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure.

Breast-feeding

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with Plavix.

Fertility

Clopidogrel was not shown to alter fertility in animal studies.

INTERACTIONS

Medicinal products associated with bleeding risk

There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicinal products associated with bleeding risk should be undertaken with caution (see section 4.4).

Oral anticoagulants

The concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see section 4.4). Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.

Glycoprotein IIb/IIIa inhibitors

Clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see section 4.4).

Acetylsalicylic acid (ASA)

ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see section 5.1).

Heparin

In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4).

Thrombolytics

The safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA (see section 4.8).

NSAIDs

In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see section 4.4).

SSRIs

since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.

Other concomitant therapy

Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see sections 4.4 and 5.2).

Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, carbamazepine, and efavirenz.

Proton Pump Inhibitors (PPI): Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel.Inconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged (see section 4.4).

Less pronounced reductions of metabolite exposure has been observed with pantoprazole orlansoprazole.

The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole.

There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers or antacids interfere with antiplatelet activity of clopidogrel.

Other medicinal products: A number of other clinical studies have been conducted with clopidogrel and other concomitant medicinal products to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observedwhen clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine.

Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital or oestrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption. Data from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by CYP2C9 can be safely coadministered with clopidogrel. CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4).

Apart from the specific medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

UNDESIRABLE EFFECTS

Common

Vascular disorders: Haematoma
Respiratory, thoracic and mediastinal disorders: Epistaxis
Gastrointestinal disorders: Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia
Skin and subcutaneous tissue disorders: Bruising

General disorders and administration site conditions: Bleeding at puncture site For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed.
No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.

PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin;
ATC code: B01AC-04.

Date of SmPC approval: 15 July 2008;
Date of abbreviated prescribing information: November 2020..
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, 2nd Floor Yekeima Square,
No_ 6 Goerge Walker Bush Highway Dzorwulu, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.

Therapeutic indications:

Treatment of hypertension.

Cardiovascular prevention

Reduction of cardiovascular morbidity and mortality in patients with manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or  diabetes with at least one cardiovascular risk factor (see section 5.1).

Treatment of renal disease

• Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,
• Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1), • Manifest glomerular non diabetic nephropathy as defined by macroproteinuria ≥ 3 g/day (see section 5.1).

Treatment of symptomatic heart failure

Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

It is recommended that Tritace® is taken each day at the same time of the day.
Tritace® can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2).
Tritace® has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients.
Hypotension may occur following initiation of therapy with TRITACE; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.
If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with Tritace® (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with Tritace® should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of Tritace® should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.
Tritace® may be used in monotherapy or in combination with other classes of antihypertensive medicinal products (see sections 4.3, 4.4, 4.5 and 5.1).
Starting dose: Tritace® should be started gradually with an initial recommended dose of 2.5 mg daily. Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose.
The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of Tritace® is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose: The recommended initial dose is 2.5 mg of Tritace® once daily.

Titration and maintenance dose: Depending on the patient’s tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg Tritace® once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose: The recommended initial dose is 1.25 mg of Tritace® once daily.

Titration and maintenance dose: Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk:

Starting dose: The recommended initial dose is 2.5 mg of Tritace® once daily.

Titration and maintenance dose: Depending on the patient’s tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg Tritace® after one or two weeks and then to 10 mg Tritace® after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria ≥ 3 g/day:

Starting dose: The recommended initial dose is 1.25 mg of Tritace® once daily.

Titration and maintenance dose: Depending on the patient’s tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure:

Starting dose: In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose: Tritace® should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure:

Starting dose: After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.
See also posology on diuretic treated patients above.

Titration and maintenance dose: The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.
The maintenance dose is divided in 2 administrations per day where possible.
If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. 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.

Method of Administration

For oral use.

CONTRA-INDICATIONS

• Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or any other ACE (Angiotensin Converting Enzyme) inhibitors
• History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)
• Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney
• Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
• Ramipril must not be used in patients with hypotensive or haemodynamically unstable states
• The concomitant use of Tritace® with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73m2) (see sections 4.5 and 5.1).

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

See full Prescribing Information

INTERACTIONS

See full Prescribing Information

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 (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

mTOR inhibitors or vildagliptin: An increased risk of angioedema is possible in patients taking concomitant medications such as mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin.
Caution should be used when starting therapy (see section 4.4).

PREGNANCY AND LACTATION

Pregnancy

Tritace® is not recommended during the first trimester of Pregnancy and is contraindicated during the second and third trimesters of pregnancy.

Lactation

Tritace® is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

UNDESIRABLE EFFECTS

Blood potassium increased, Headache, dizziness, Hypotension, orthostatic blood pressure decreased, syncope, Non-productive tickling cough, bronchitis, sinusitis, dyspnoea, Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting, Rash in particular maculo-papular, Muscle spasms, myalgia, Chest pain, fatigue.

For uncommon, rare and very rare side effects see full prescribing information

OVERDOSE

The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: ACE Inhibitors, plain.
ATC code: C09AA05.

Date of last abbreviation of prescribing information: July 2019.
More detailed Information on request:
Refer to Summary of Product Characteristics or
Sanofi, Japaul House, Plot 8,
Dr. Nurudeen Olowopopo Avenue, Ikeja Central Business District, Agidingbi, Lagos, Nigeria.
Tel: +234 1 2710135/2800994;

Sanofi Office, 2nd Floor Yekeima Square,
No_ 6 Goerge Walker Bush Highway Dzorwulu, Accra.
Tel: +233 302 734772;

For Pharmacovigilance (reporting adverse events), please contact: ng-gh.pv@sanofi.com.