Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: SACUVAN 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
Dosage form and strength: Film coated tablets and 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
CLEAN PROFESSIONAL INFORMATION FOR SACUVAN  
SCHEDULING STATUS  
S3  
1 NAME OF THE MEDICINE  
SACUVAN 24 mg / 26 mg (film-coated tablets)  
SACUVAN 49 mg / 51 mg (film-coated tablets)  
SACUVAN 97 mg / 103 mg (film-coated tablets)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
SACUVAN tablets 24 mg / 26 mg  
Each film-coated tablets contains 24 mg of sacubitril and 26 mg of valsartan  
SACUVAN tablets 49 mg / 51 mg  
Each film-coated tablets contains 49 mg of sacubitril and 51 mg of valsartan  
SACUVAN tablets 97 mg / 103 mg  
Each film-coated tablets contains 97 mg of sacubitril and 103 mg of valsartan  
Contains no sugar  
‘for full list of excipients, see section 6.1’  
3 PHARMACEUTICAL FORM  
SACUVAN tablets 24 mg / 26 mg  
White coloured, oval shaped, film coated tablets debossed with 'H' on one side and 'S24' on the  
other side.  
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SACUVAN tablets 49 mg / 51 mg  
Blue coloured, oval shaped, film coated tablets debossed with 'H' on one side and 'S25' on the  
other side.  
SACUVAN tablets 97 mg / 103 mg  
Brown coloured, oval shaped, film coated tablets debossed with 'H' on one side and 'S26' on the  
other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
SACUVAN is indicated as a second-line therapy, replacing ACE inhibitors or ARB for treatment of  
symptomatic heart failure (NYHA class II-IV) in patients with systolic dysfunction. SACUVAN is  
administered in combination with other heart failure therapies as appropriate.  
4.2 Posology and method of administration  
Posology  
The target dose of SACUVAN is 200 mg twice daily. To avoid hypotension the recommended  
starting dose of SACUVAN in patients previously using high dose of ACE or ARB is 100 mg twice  
daily.  
A starting dose of 50 mg twice daily is recommended for patients currently taking low doses of ACE  
or ARB. Dose up titration by resembling the dose every 3 - 4 weeks is recommended until a dose  
of 200 mg twice daily is achieved of tolerance. Each dose increment should be preceded by clinical  
observation for hypotension and laboratory evaluation of serum potassium and renal function.  
SACUVAN must not be started until 36 hours after discontinuing ACE inhibitor therapy (see section  
4.3).  
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If patients experience tolerability issues (symptomatic hypotension, hyperkalemia, renal  
dysfunction), consideration should be given to adjustment of concomitant medications or to down-  
titration or discontinuation of SACUVAN.  
Special populations  
Renal impairment  
SACUVAN is contraindicated in patients with severe impaired renal function.  
Elderly patients (older than 65 years)  
Patients over the age of 65 years may have impaired renal function, therefore a lower starting dose  
is recommended.  
Hepatic impairment  
No dose adjustment is required when administering SACUVAN to patients with mild to moderate  
hepatic impairment (Child-Pugh A and B classification).  
No studies have been conducted in patients with severe hepatic impairment (Child-Pugh C  
classification). Therefore, use of SACUVAN in these patients is not recommended (see section  
5.1).  
Paediatric population  
The safety and efficacy of SACUVAN in paediatric patients aged below 18 years has not been  
established.  
Method of administration  
Orally.  
SACUVAN may be administered with or without food.  
4.3 Contraindications  
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•
•
•
Hypersensitivity to the active substances, sacubitril, valsartan, or to any of the excipients  
listed in section 6.1  
Concomitant use with ACE inhibitors (see sections 4.2, 4.4 and 4.5). SACUVAN must not  
be administered until 36 hours after discontinuing ACE inhibitor therapy.  
A history of angioedema related to previous therapy with ACE inhibitors or angiotensin  
receptor blockers (ARBs): These patients must never again be given these medicines (see  
section 4.4).  
•
•
•
•
•
•
Hereditary or idiopathic angioedema (see section 4.4).  
Hypertrophic obstructive cardiomyopathy (HOCM)  
Bilateral renal artery stenosis  
Renal artery stenosis in patients with a single kidney  
Aortic valve stenosis  
Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene,  
amiloride (see section 4.5)  
•
•
Porphyria  
Lithium therapy: Concomitant administration with SACUVAN may lead to toxic blood  
concentrations of lithium (see section 4.5).  
•
Concomitant use with aliskiren-containing medicines in patients with diabetes mellitus or in  
patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see sections 4.4 and 4.5).  
Severe hepatic impairment, biliary cirrhosis and cholestasis (see section 4.2).  
Pregnancy and lactation (see section 4.6).  
•
•
•
Severe renal function impairment (creatinine clearance less than 30 ml/min)  
4.4 Special warnings and precautions for use  
Should a woman become pregnant while receiving SACUVAN. The treatment should  
be stopped promptly and switched to a different class of anti-hypertensive medicine  
(see sections 4.3 and 4.6)  
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Dual blockade of the renin-angiotensin-aldosterone system (RAAS)  
•
The combination of sacubitril/valsartan with an ACE inhibitor is contraindicated due to the  
increased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated  
until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with  
sacubitril/valsartan is stopped, ACE inhibitor therapy must not be initiated until 36 hours  
after the last dose of sacubitril/valsartan (see sections 4.2, 4.3 and 4.5).  
•
•
The combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is not  
recommended (see section 4.5). The combination of sacubitril/valsartan with aliskiren-  
containing medicines is contraindicated in patients with diabetes mellitus or in patients with  
renal impairment (eGFR <60 ml/min/1.73 m2) (see sections 4.3 and 4.5).  
SACUVAN contains valsartan, and therefore should not be co- administered with another  
ARB containing medicines (see sections 4.2 and 4.5).  
Hypotension  
Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were  
not studied (see section 5.1). Cases of symptomatic hypotension have been reported in patients  
treated with sacubitril/valsartan during clinical studies (see section 4.8), especially in patients ≥ 65  
years old, patients with renal disease and patients with low SBP (<112 mmHg). When initiating  
therapy or during dose titration with sacubitril/valsartan, blood pressure should be monitored  
routinely. If hypotension occurs, temporary down-titration or discontinuation of sacubitril/valsartan is  
recommended (see section 4.2). Dose adjustment of diuretics, concomitant antihypertensives and  
treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. Symptomatic  
hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic  
therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be  
corrected before starting treatment with sacubitril/valsartan, however, such corrective action must  
be carefully weighed against the risk of volume overload.  
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Impaired renal function  
Evaluation of patients with heart failure should always include assessment of renal function.  
Patients with mild and moderate renal impairment are more at risk of developing hypotension (see  
section 4.2). There is very limited clinical experience in patients with severe renal impairment  
(estimated GFR <30 ml/min/1.73m2) and these patients may be at greatest risk of hypotension (see  
section 4.2). There is no experience in patients with end-stage renal disease and use of  
sacubitril/valsartan is not recommended.  
Worsening renal function  
Use of sacubitril/valsartan may be associated with decreased renal function. The risk may be  
further increased by dehydration or concomitant use of non-steroidal anti-inflammatory medicines  
(NSAIDs) (see section 4.5). Down-titration should be considered in patients who develop a  
clinically significant decrease in renal function.  
Hyperkalaemia  
Treatment should not be initiated if the serum potassium level is> 5,4 mmol/l. Use of  
sacubitril/valsartan may be associated with an increased risk of hyperkalaemia, although  
hypokalaemia may also occur (see section 4.8). Monitoring of serum potassium is recommended,  
especially in patients who have risk factors such as renal impairment, diabetes mellitus or  
hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists (see  
section 4.2). If patients experience clinically significant hyperkalaemia adjustment of concomitant  
medicines, or temporary down–titration or discontinuation is recommended. If serum potassium  
level is >5.4 mmol/l discontinuation should be considered.  
Angioedema  
Angioedema has been reported in patients treated with sacubitril/valsartan. If angioedema occurs,  
sacubitril/valsartan should be immediately discontinued, and appropriate therapy and monitoring  
should be provided until complete and sustained resolution of signs and symptoms has occurred. It  
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must not be re-administered. In cases of confirmed angioedema where swelling has been confined  
to the face and lips, the condition has generally resolved without treatment, although antihistamines  
have been 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 therapy, e.g. adrenaline solution 1 mg/1 ml (0,3-0,5 ml), and/or measures necessary to  
ensure a patent airway, should be promptly administered. Patients with a prior history of  
angioedema were not studied. As they may be at higher risk for angioedema, caution is  
recommended if sacubitril/valsartan is used in these patients sacubitril/valsartan is contraindicated  
in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy or  
with hereditary or idiopathic angioedema (see section 4.3). Black patients have an increased  
susceptibility to develop angioedema (see section 4.8).  
Patients with renal artery stenosis  
Sacubitril/valsartan may increase blood urea and serum creatinine levels in patients with bilateral  
or unilateral renal artery stenosis. Caution is required in patients with renal artery stenosis and  
monitoring of renal function is recommended.  
Patients with NYHA functional classification IV  
Caution should be exercised when initiating sacubitril/valsartan in patients with NYHA functional  
classification IV due to limited clinical experience in this population.  
B-type natriuretic peptide (BNP)  
BNP is not a suitable biomarker of heart failure in patients treated with sacubitril/valsartan because  
it is a neprilysin substrate (see section 5.1).  
Patients with hepatic impairment  
There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B  
classification) or with AST/ALT values more than twice the upper limit of the normal range. In these  
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patients, exposure may be increased, and safety is not established. Caution is therefore  
recommended when using it in these patients (see sections 4.2 and 5.2). Sacubitril/valsartan is  
contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-  
Pugh C classification) (see section4.3).  
Psychiatric disorders  
Psychiatric events such as hallucinations, paranoia and sleep disorders, in context of psychotic  
events, have been associated with sacubitril/valsartan use. If a patient experiences such events,  
discontinuation of sacubitril/valsartan treatment should be considered.  
Interactions with statins  
Statins: In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters.  
SACUVAN may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates  
such as statins. Co-administration of SACUVAN increased the Cmax, of atorvastatin and its  
metabolites by up to 2-fold and AUC by up to 1.3-fold. Therefore. caution should be exercised upon  
co-administration of SACUVAN with statins as the adverse effects of statins are dose/exposure  
related.  
4.5 Interaction with other medicines and other forms of interaction  
Interactions resulting in a contraindication  
ACE inhibitors  
The concomitant use of sacubitril/valsartan with ACE inhibitors is contraindicated, as the  
concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema.  
Sacubitril/valsartan must not be started until 36 hours after taking the last dose of ACE inhibitor  
therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of  
sacubitril/valsartan (see sections 4.2 and 4.3).  
Aliskiren  
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The concomitant use of sacubitril/valsartan with aliskiren- containing medicines is contraindicated  
in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2)  
(see section 4.3). The combination of sacubitril/valsartan with direct renin inhibitors such as  
aliskiren is not recommended (see section 4.4). Combination of sacubitril/valsartan with aliskiren is  
potentially associated with a higher frequency of adverse events such as hypotension,  
hyperkalaemia and decreased renal function (including acute renal failure) (see sections 4.3 and  
4.4).  
Interactions resulting in concomitant use not being recommended  
Sacubitril/valsartan contains valsartan, and therefore should not be co- administered with another  
ARB containing medicines (see section 4.4).  
Interactions requiring precautions  
OATP1B1 and OATP1B3 substrates, e.g. statins  
In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. SACUVAN may  
therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins.  
Co-administration of sacubitril/valsartan increased the Cmax of atorvastatin and its metabolites by  
up to 2-fold and AUC by up to 1.3-fold. Caution should be exercised when co- administering  
sacubitril/valsartan with statins. No clinically relevant interaction was observed when simvastatin  
and SACUVAN were co-administered.  
PDE5 inhibitors including sildenafil  
Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients with  
hypertension was associated with a significantly greater blood pressure reduction compared to  
administration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil  
or another PDE5 inhibitor is initiated in patients treated with sacubitril/valsartan.  
Potassium  
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Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid  
antagonists (e.g. spironolactone, eplerenone), potassium supplements, salt substitutes containing  
potassium or other medicines (such as heparin) may lead to increases in serum potassium, and to  
increases in serum creatinine. Monitoring of serum potassium is recommended if  
sacubitril/valsartan is co-administered with these medicines (see section 4.4).  
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective  
cyclooxygenase-2 (COX-2) inhibitors  
In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with  
compromised renal function, concomitant use of sacubitril/valsartan and NSAIDs may lead to an  
increased risk of worsening of renal function. Therefore, monitoring of renal function is  
recommended when initiating or modifying treatment in patients on sacubitril/valsartan who are  
taking NSAIDs concomitantly (see section 4.4).  
Lithium  
Reversible increases in serum lithium concentrations and toxicity have been reported during  
concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists (see  
section 4.3) including sacubitril/valsartan. Therefore, this combination is not recommended. If the  
combination proves necessary, careful monitoring of serum lithium levels is recommended. If a  
diuretic is also used, the risk of lithium toxicity may be increased further.  
Furosemide  
Co-administration of sacubitril/valsartan and furosemide had no effect on the pharmacokinetics of  
sacubitril/valsartan but reduced Cmax and AUC of furosemide by 50 % and 28 %, respectively.  
While there was no relevant change in urine volume, the urinary excretion of sodium was reduced  
within 4 hours and 24 hours after co-administration. The average daily dose of furosemide was  
unchanged from baseline until the end of the PARADIGM-HF study in patients treated with  
sacubitril/valsartan.  
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Nitrates, e.g. nitroglycerine  
There was no drug-drug interaction between sacubitril/valsartan and intravenously administered  
nitroglycerin with regard to blood pressure reduction. Co-administration of nitroglycerin and  
sacubitril/valsartan was associated with a treatment difference of 5 bpm in heart rate compared to  
the administration of nitroglycerine alone. A similar effect on the heart rate may occur when  
sacubitril/valsartan is co-administered with sublingual, oral or transdermal nitrates. In general, no  
dose adjustment is required.  
OATP and MRP2 transporters  
The active metabolite of sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3, OAT1 and  
OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of  
sacubitril/valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 MRP2 (e.g. ritonavir) may  
increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be exercised  
when initiating or ending concomitant treatment with such medicines.  
Metformin  
Co-administration of sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin  
by 23 %. The clinical relevance of these findings is unknown. Therefore, when initiating therapy  
with sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be  
evaluated.  
No significant interaction  
No clinically meaningful drug-drug interaction was observed when sacubitril/valsartan was co-  
administered with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a  
combination of levonorgestrel/ethinyl estradiol. No Interaction is expected with atenolol  
indomethacin, glyburide, or cimetidine.  
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CYP450 Interactions  
ln vitro metabolism studies indicate that the potential for CYP45D based interactions is low since  
there is limited metabolism of SACUVAN via the CYP450 enzymes. SACUVAN does not induce or  
inhibit CYP450 enzymes.  
4.6 Fertility, pregnancy and lactation  
Pregnancy  
SACUVAN is contraindicated in pregnancy.  
Safety in pregnancy has not been established.  
When pregnancy is planned or confirmed SACUVAN should be discontinued. Medicines affecting  
the renin angiotensin system, such as SACUVAN, can cause embryonal toxicity, foetal and  
neonatal morbidity and mortality when administered to pregnant women.  
Breastfeeding  
SACUVAN is contraindicated in lactation.  
Safety in lactation has not been established.  
4.7 Effects on ability to drive and use machines  
SACUVAN has a minor influence on the ability to drive and use machines. When driving vehicles or  
operating machines it should be taken into account that occasional dizziness or fatigue may occur.  
4.8 Undesirable effects  
a. Summary of the safety profile  
The most frequently reported adverse reactions during treatment with sacubitril/valsartan were  
hypotension, hyperkalaemia and renal impairment (see section 4.4). Angioedema was reported in  
patients treated with sacubitril/valsartan (see description of selected adverse reactions).  
b. Tabulated list of adverse reactions  
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SYSTEM ORGAN CLASS  
Blood and lymphatic system  
disorders  
FREQUENCY  
ADVERSE REACTION  
Frequent  
Anaemia  
Immune system disorders  
Less frequent  
Frequent  
Hypersensitivity  
Hyperkalaemia*,  
Metabolism  
disorders  
and  
nutrition  
hypokalaemia, hypoglycaemia  
Psychiatric disorders  
Less frequent  
Frequent  
Hallucinations**,  
sleep  
disorders, paranoia  
Nervous system disorders  
Dizziness,  
syncope  
headache,  
Less frequent  
Frequent  
Dizziness postural  
Vertigo  
Ear and labyrinth disorders  
Vascular disorders  
Frequent  
Hypotension*, orthostatic  
hypotension  
Respiratory,  
thoracic  
and  
Frequent  
Frequent  
Cough  
mediastinal disorders  
Gastrointestinal disorders  
Diarrhoea, nausea,  
gastritis  
Skin and subcutaneous tissue  
disorders  
Less frequent  
Frequent  
Pruritus, rash, angioedema*  
Renal and urinary disorders  
Renal impairment*, renal  
failure (renal failure, acute  
renal failure)  
General  
disorders  
and  
Frequent  
Fatigue, asthenia  
administration site conditions  
*See description of selected adverse reactions.  
**Including auditory and visual hallucinations  
c. Description of selected adverse reactions  
Angioedema  
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Angioedema has been reported in patients treated with sacubitril/valsartan. In PARADIGM-HF,  
angioedema was reported in patients treated with sacubitril/valsartan, compared with patients  
treated with enalapril. A higher incidence of angioedema was observed in Black patients treated  
with sacubitril/valsartan and enalapril (see section 4.4).  
Hyperkalaemia and serum potassium  
In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5,4 mmol/l were reported  
in sacubitril/valsartan-treated patients and enalapril-treated patients, respectively.  
Blood pressure  
In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (<90 mmHg and  
decrease from baseline of >20 mmHg) were reported in sacubitril/valsartan-treated patients  
compared with enalapril-treated patients, respectively.  
Renal impairment  
In PARADIGM-HF, renal impairment was reported in sacubitril/valsartan-treated patients and  
enalapril- treated patients.  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of SACUVAN is important. It allows  
continued monitoring of the benefit/risk balance of the SACUVAN. Healthcare professionals are  
asked to report any suspected adverse to report any suspected adverse reactions to SAHPRA via  
the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on  
SAHPRA website or to the Holder of certificate of registration through the mail:  
pvg.cdma@heterogroups.com.  
4.9 Overdose  
Hypotension is the most likely symptom of overdose due to the blood pressure lowering effects of  
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sacubitril/valsartan. Symptomatic treatment should be provided. The medicine is unlikely to be  
removed by haemodialysis due to high protein binding (see section 5.2).  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Pharmacotherapeutic group: Agents acting on the renin- angiotensin system; angiotensin II  
receptor blockers (ARBs), other combinations, ATC code: C09DX04  
PHARMACOLOGICAL CLASSIFICATION  
A7.6 Vascular medicines Others  
Mechanism of action  
Sacubitril/valsartan exhibits the mechanism of action of an angiotensin receptor neprilysin inhibitor  
by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active  
metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via  
valsartan.  
The complementary cardiovascular benefits of sacubitril/valsartan in heart failure patients are  
attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic  
peptides (NP), by LBQ657 and the simultaneous inhibition of the effects of angiotensin II by  
valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled  
receptors, resulting in increased concentrations of the second messenger cyclic guanosine  
monophosphate (cGMP), which could result in vasodilation, natriuresis and diuresis, increased  
glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction  
of sympathetic activity, and anti- hypertrophic and anti-fibrotic effects.  
Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively  
blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. This  
prevents sustained activation of the renin-angiotensin- aldosterone system that would result in  
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Product proprietary name: SACUVAN 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
Dosage form and strength: Film coated tablets and 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation,  
and subsequent maladaptive cardiovascular remodeling.  
Pharmacodynamic effects  
The pharmacodynamic effects of sacubitril/valsartan were evaluated after single and multiple dose  
administrations in healthy subjects and in patients with heart failure, and are consistent with  
simultaneous neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study in  
patients with reduced ejection fraction (HFrEF), administration of sacubitril/valsartan resulted in an  
initial increase in natriuresis, increased urine cGMP, and decreased plasma levels of mid- regional  
pro-atrial natriuretic peptide (MR-proANP) and N- terminal prohormone brain natriuretic peptide  
(NT-proBNP) compared to valsartan. In a 21-day study in HFrEF patients, sacubitril/valsartan  
significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-  
proBNP, aldosterone and endothelin-1 compared to baseline. The AT1- receptor was also blocked  
as evidenced by increased plasma renin activity and plasma renin concentrations. In the  
PARADIGM-HF study, sacubitril/valsartan decreased plasma NT- proBNP and increased plasma  
BNP and urine cGMP compared with enalapril. BNP is not a suitable biomarker of heart failure in  
patients treated with sacubitril/valsartan because BNP is a neprilysin substrate (see section 4.4).  
NT-proBNP is not a neprilysin substrate and is therefore a more suitable biomarker.  
In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril/valsartan 194  
mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac  
repolarisation.  
Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain  
and cerebrospinal fluid (CSF). Administration of sacubitril/valsartan 194 mg sacubitril/206 mg  
valsartan once daily for two weeks to healthy subjects was associated with an increase in CSF  
Aβ1-38 compared to placebo; there were no changes in concentrations of CSF Aβ1-40 and 1-42.  
The clinical relevance of this finding is not known.  
May 2025  
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Product proprietary name: SACUVAN 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
Dosage form and strength: Film coated tablets and 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
5.2 Pharmacokinetic properties  
The valsartan contained within sacubitril/valsartan is more bioavailable than the valsartan in other  
marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril/valsartan is  
equivalent to 40 mg, 80 mg and 160 mg of valsartan in other marketed tablet formulations,  
respectively.  
Absorption  
Following oral administration, sacubitril/valsartan dissociates into valsartan and the prodrug  
sacubitril. Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak  
plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute  
bioavailability of sacubitril and valsartan is estimated to be more than 60% and 23%, respectively.  
Following twice daily dosing of sacubitril/valsartan, steady-state levels of sacubitril, LBQ657 and  
valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate  
significantly, while LBQ657 accumulates 1,6-fold. Administration with food has no clinically  
significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan.  
Sacubitril/valsartan can be administered with or without food.  
Distribution  
Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94-97 %). Based on the  
comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited  
extent (0,28 %). The average apparent volume of distribution of valsartan and sacubitril were 75 L  
to 103 L, respectively  
Biotransformation  
Sacubitril is readily converted to LBQ657 by carboxylesterases 1b and 1c; LBQ657 is not further  
metabolised to a significant extent. Valsartan is minimally metabolised, as only about 20% of the  
dose is recovered as metabolites. A hydroxyl metabolite of valsartan has been identified in plasma  
May 2025  
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at low concentrations (<10 %).  
Since CYP450-enzyme-mediated metabolism of sacubitril and valsartan is minimal, co-  
administration with medicinal products that impact CYP450 enzymes is not expected to impact the  
pharmacokinetics.  
In vitro metabolism studies indicate that potential for CYP450 based drug interactions is low since  
there is limited metabolism of sacubitril/valsartan via CYP450 enzymes. Sacubitril/valsartan does  
not induce or inhibit CYP450 enzymes.  
Elimination  
Following oral administration, 52-68 % of sacubitril (primarily as LBQ657) and ~13 % of valsartan  
and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as LBQ657) and 86 % of  
valsartan and its metabolites are excreted in faeces. Sacubitril, LBQ657 and valsartan are  
eliminated from plasma with a mean elimination half-life (T ) of approximately 1,43 hours, 11,48  
½
hours, and 9,90 hours, respectively.  
Linearity/non-linearity  
The pharmacokinetics of sacubitril, LBQ657 and valsartan were approximately linear over a  
sacubitril/valsartan dose range of 24 mg sacubitril/26 mg valsartan to 97 mg sacubitril/103 mg  
valsartan.  
Special population  
Elderly patients  
LBQ657 and valsartan exposure are increased in subjects over 65 years of age by 42 % and 30 %,  
respectively, compared to younger subjects.  
Impaired renal function  
May 2025  
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Product proprietary name: SACUVAN 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
Dosage form and strength: Film coated tablets and 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
A correlation was observed between renal function and systemic exposure to LBQ657 in patients  
with mild to severe renal impairment. The exposure of LBQ657 in patients with moderate (30  
ml/min/1,73 m2 ≤ eGFR <60 ml/min/1,73 m2) and severe renal impairment (15 ml/min/1,73 m2 ≤  
eGFR <30 ml/min/1,73 m2) was 1,4-fold and 2,2-fold higher compared to patients with mild renal  
impairment (60 ml/min/1.73 m2 ≤ eGFR <90 ml/min/1,73 m2), the largest group of patients enrolled  
in PARADIGM- HF. The exposure of valsartan was similar in patients with moderate and severe  
renal impairment compared to patients with mild renal impairment. No studies have been  
performed in patients undergoing dialysis. However, LBQ657 and valsartan are highly bound to  
plasma protein and therefore unlikely to be effectively removed by dialysis.  
Impaired hepatic function  
In patients with mild to moderate hepatic impairment, the exposure of sacubitril increased by 1,5  
and 3,4-fold, LB0657 increased by 1,5-and 1,9-fold, and valsartan increased by 1,2-fold and 2,1-  
fold, respectively, compared to matching healthy subjects. No dosage adjustments are  
recommended when administering sacubitril valsartan sodium hydrate to patients with mild to  
moderate hepatic impairment (Child- Pugh A and B classification) including patients with biliary  
obstructive disorders. Sacubitril valsartan sodium hydrate has not been studied in patients with  
severe hepatic impairment, biliary cirrhosis or cholestasis (see sections 4.3 and 4.4). Therefore, its  
use is not recommended in patients with severe hepatic impairment.  
Effect of gender  
The pharmacokinetics of sacubitril/valsartan (sacubitril, LBQ657 and valsartan) are similar between  
male and female subjects.  
Paediatric population  
Sacubitril valsartan sodium hydrate has not been studied in paediatric patients.  
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6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
•
•
•
•
Micro crystalline cellulose  
Low substituted Hydroxypropyl cellulose-  
Povidone  
Crospovidone  
Silicon dioxide,  
Magnesium stearate  
Composition of Opadry White 06A580019  
•
•
•
Hypromellose E464  
Di-acetylated monoglycerides E472a  
Titanium dioxide E171  
Composition of Opadry Brown 06A565000  
•
•
•
•
Hypromellose E464  
Di-acetylated monoglycerides E472a  
Titanium dioxide E171  
Iron oxide red E172  
Composition of Opadry Blue 06A505000  
•
•
•
•
Hypromellose E464  
Di-acetylated monoglycerides E472a  
Titanium dioxide E171  
FD&C Blue #2/indigo carmine aluminum lake E132  
6.2 Incompatibilities  
Not applicable.  
6.3 Shelf life  
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Dosage form and strength: Film coated tablets and 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
24 months  
6.4 Special precautions for storage  
Store at or below 25 °C  
Protect from moisture.  
Keep the tablets in the original container until required for use  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
SACUVAN tablets 24 mg / 26 mg  
60’s count  
High Density Polyethylene Container with a child resistant plastic cap with pulp liner and a silica gel  
sachet.  
180’s count  
High Density Polyethylene Container with a child resistant plastic cap with pulp liner and a silica gel  
sachet.  
10 x 10’s Alu-Alu Blister pack  
Formpack film with Desiccant, with a plain Alu lidding foil.  
3 x 10’s Alu-Alu Blister pack  
Formpack film with Desiccant, with a plain Alu lidding foil.  
SACUVAN tablets 49 mg / 51 mg  
60’s count  
High Density Polyethylene Container with a child resistant plastic cap with pulp liner and a silica gel  
sachet.  
May 2025  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: SACUVAN 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
Dosage form and strength: Film coated tablets and 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
180’s count  
High Density Polyethylene Container with a child resistant plastic cap with pulp liner and a silica gel  
sachet.  
8 x 10’s Alu-Alu Blister pack  
Formpack film with Desiccant, with a plain Alu lidding foil.  
3 x 10’s Alu-Alu Blister pack  
Formpack film with Desiccant, with a plain Alu lidding foil.  
SACUVAN tablets 97 mg / 103 mg  
60’s count  
High Density Polyethylene Container with a child resistant plastic cap with pulp liner and a silica gel  
sachet.  
180’s count  
High Density Polyethylene Container with a child resistant plastic cap with pulp liner and a silica gel  
sachet.  
6 x 10’s Alu-Alu Blister pack  
Formpack film with Desiccant, with a plain Alu lidding foil.  
3 x 10’s Alu-Alu Blister pack  
Formpack film with Desiccant, with a plain Alu lidding foil.  
6.6 Special precautions for disposal and other handling  
‘No special requirements’  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: SACUVAN 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
Dosage form and strength: Film coated tablets and 24 mg / 26 mg, 49 mg / 51 mg & 97 mg / 103 mg  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus  
Building No.2, First Floor  
74 Waterfall Drive  
Midrand, 2066  
Telephone number: 012 644 1220  
e-mail address: nokuthula.n@hetero.com  
8 REGISTRATION NUMBER(S)  
SACUVAN 24 mg / 26 mg: 56/7.6/1116.1113  
SACUVAN 49 mg / 51 mg: 56/7.6/1117.1114  
SACUVAN 97 mg / 103 mg: 56/7.6/1118.1115  
9 DATE OF FIRST AUTHORISATION/ RENEWAL OF AUTHORISATION  
29 April 2025  
10 DATE OF REVISION OF THE TEXT  
02 June 2025  
May 2025  
Initial…MU…….  
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