Valsartan and Sacubitril

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.

In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Sacubitril/valsartan may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of sacubitril/valsartan increased the C_max 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 sacubitril/valsartan were co-administered.

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 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or 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 medicinal products.

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.

Half of the starting dose should be considered in patients with moderate renal impairment (eGFR 30-60 ml/min/1.73 m²).

As there is very limited clinical experience in patients with severe renal impairment (eGFR <30 ml/min/1.73 m²), sacubitril/valsartan should be used with caution and half of the starting dose is recommended. In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended. After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks.

Caution should be exercised when initiating sacubitril/valsartan in patients with NYHA functional classification IV due to limited clinical experience in this population.

There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classification) or with aspartate transaminase (AST)/alanine transaminase (ALT) values more than twice the upper limit of the normal range. Sacubitril/valsartan should be used with caution in these patients and half of the starting dose is recommended. In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended. After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks.

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.

Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, salt substitutes containing potassium or other agents (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 agents.

Co-administration of sacubitril/valsartan with metformin reduced both C_max 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.

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.

The use of sacubitril/valsartan is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.

Valsartan

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with ARBs, similar risks may exist for this class of medicinal product. Unless continued ARB 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 ARBs should be stopped immediately and, if appropriate, alternative therapy should be started. Exposure to ARBs therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to ARBs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ARBs should be closely observed for hypotension.

Sacubitril

There are no data from the use of sacubitril in pregnant women. Studies in animals have shown reproductive toxicity.

Sacubitril/valsartan

There are no data from the use of sacubitril/valsartan in pregnant women. Animal studies with sacubitril/valsartan have shown reproductive toxicity.

It is not known whether sacubitril/valsartan is excreted in human milk. Sacubitril and valsartan were excreted in the milk of lactating rats. Because of the potential risk for adverse reactions in breast-fed newborns/infants, it is not recommended during breast-feeding. A decision should be made whether to abstain from breast-feeding or to discontinue sacubitril/valsartan while breast-feeding, taking into account its importance to the mother.

Fertility

There are no available data on the effect of sacubitril/valsartan on human fertility. No impairment of fertility was demonstrated in studies with it in male and female rats.

Sacubitril/valsartan 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 occasionally dizziness or fatigue may occur.

Summary of the safety profile

The most commonly reported adverse reactions in adults during treatment with sacubitril/valsartan were hypotension (17.6%), hyperkalaemia (11.6%) and renal impairment (10.1%). Angioedema was reported in patients treated with sacubitril/valsartan (0.5%) (see description of selected adverse reactions).

Tabulated list of adverse reactions

Adverse reactions are ranked by System organ class and then by frequency with the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

List of adverse reactions:

^* See description of selected adverse reactions.
^** Including auditory and visual hallucinations

Description of selected adverse reactions

Angioedema

Angioedema has been reported in patients treated with sacubitril/valsartan. In PARADIGM-HF, angioedema was reported in 0.5% of patients treated with sacubitril/valsartan, compared with 0.2% of patients treated with enalapril. A higher incidence of angioedema was observed in Black patients treated with sacubitril/valsartan (2.4%) and enalapril (0.5%).

Hyperkalaemia and serum potassium

In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/l were reported in 11.6% and 19.7% of sacubitril/valsartan-treated patients and 14.0% and 21.1% of 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 17.6% and 4.76% of sacubitril/valsartantreated patients compared with 11.9% and 2.67% of enalapril-treated patients, respectively.

Renal impairment

In PARADIGM-HF, renal impairment was reported in 10.1% of sacubitril/valsartan-treated patients and 11.5% of enalapril-treated patients.

Paediatric population

In the PANORAMA-HF study, the safety of sacubitril/valsartan was assessed in a randomised, active-controlled, 52-week study of 375 paediatric heart failure (HF) patients aged 1 month to <18 years compared to enalapril. The safety profile observed in paediatric patients aged 1 month to <18 years who received treatment with sacubitril/valsartan was similar to that observed in adult patients. Safety data in patients aged 1 month to <1 year was limited.

Limited safety data are available in paediatric patients with moderate hepatic impairment or moderate to severe renal impairment.