Entresto: composition and dosage form
One film-coated tablet contains 24.3 mg, 48.6 mg or 97.2 mg of sacubitril and, respectively, 25.7 mg, 51.4 mg or 102.8 mg of valsartan, as a complex of the sodium salts of both substances. On the pack the same strengths are given rounded: 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg.
The valsartan in this complex is absorbed better than valsartan from ordinary tablets, so its milligrams cannot be converted directly into a dose of the familiar sartan. The tablet is swallowed whole with a glass of water and the timing does not depend on meals.
How Entresto works
The mechanism is twofold: neprilysin inhibition and angiotensin receptor blockade. Sacubitril is a prodrug and its active metabolite LBQ657 inhibits neprilysin, the neutral endopeptidase that breaks down natriuretic peptides. Valsartan at the same time selectively blocks the type 1 angiotensin II receptor and suppresses angiotensin-dependent aldosterone release.
The natriuretic peptides that accumulate activate membrane receptors coupled to guanylate cyclase, which raises cyclic guanosine monophosphate. The consequences are vasodilatation, urinary sodium loss and diuresis, a higher glomerular filtration rate and renal blood flow, suppressed renin and aldosterone release, lower sympathetic activity and opposition to hypertrophy and fibrosis. The receptor blockade from valsartan stops the renin-angiotensin-aldosterone system from retaining sodium and fluid and from remodelling the heart and vessels.
Indications
In adults the medicine is used in symptomatic chronic heart failure with reduced ejection fraction. In children and adolescents from one year of age, in symptomatic chronic heart failure with left ventricular systolic dysfunction.
Tablets are not suitable for a child weighing under 40 kg: for them there are granules dosed by body weight. In children under one year safety and efficacy have not been established and there are no dosing recommendations.
How to take it and dosage
It is taken twice a day. Adults usually start with the 49 mg/51 mg tablet twice daily and, after 2–4 weeks and if tolerance allows, the dose is doubled to the target of 97 mg/103 mg twice daily. In those not currently on an ACE inhibitor or a sartan, or on low doses of them, experience is limited: start at 24 mg/26 mg twice daily and double every 3–4 weeks. Treatment is not started with a serum potassium above 5.4 mmol/l or a systolic pressure below 100 mm Hg; between 100 and 110 mm Hg half the starting dose is worth considering. A missed dose is not made up — the next one is taken at the usual time.
| Who is taking it | Where treatment starts |
|---|---|
| Adult already on usual doses of an ACE inhibitor or a sartan | 49 mg/51 mg twice daily, doubled after 2–4 weeks |
| Adult without such therapy or on low doses | 24 mg/26 mg twice daily, doubled every 3–4 weeks |
| Moderate renal impairment, eGFR 30–60 | Half the starting dose |
| Severe renal impairment, eGFR below 30 | Half the starting dose and caution, limited experience |
| Child-Pugh class B liver or ALT and AST above twice the upper limit | Half the starting dose and caution |
| Child weighing 40 to 50 kg | 0.8 mg/kg twice daily as granules, increased every 2–4 weeks |
With mild renal impairment (eGFR 60–90) and Child-Pugh class A liver the dose is unchanged; in end-stage renal failure the medicine is not recommended and with class C liver it is contraindicated. In older people the dose is matched to renal function. If signs of intolerance appear — systolic pressure of 95 mm Hg or below, symptoms of hypotension, hyperkalaemia, worsening renal function — the accompanying therapy is reviewed first, then the dose is temporarily reduced, and only after that is the medicine withdrawn. In children the potassium threshold is stricter (5.3 mmol/l) and blood pressure is judged against the fifth percentile for age.
Contraindications
The key contraindication is concurrent use of an ACE inhibitor, and the ban also covers the time around the switch: the medicine is not started until 36 hours after the last dose of the ACE inhibitor. Nor may it be prescribed to anyone who has ever developed angioedema on an ACE inhibitor or a sartan, or in hereditary or idiopathic angioedema.
The remaining bans: hypersensitivity to the active substances or excipients; combination with aliskiren-containing products in people with diabetes or with renal function below 60 ml/min/1.73 m²; severe hepatic impairment, biliary cirrhosis and cholestasis; the second and third trimesters of pregnancy.
Special warnings and precautions
The 36-hour rule works both ways: after Entresto is stopped, an ACE inhibitor likewise is not started for 36 hours. The reason is angioedema: inhibiting neprilysin and ACE at once raises its likelihood. In the PARADIGM-HF study angioedema was reported in 0.5% of those on the medicine against 0.2% on enalapril, and in Black patients in 2.4% against 0.5%. If it occurs, the medicine is withdrawn immediately and permanently and is never restarted. Swelling of the face and lips usually settles on its own and antihistamines ease the symptoms, but swelling of the tongue, glottis or larynx is life-threatening and calls for immediate action — adrenaline solution 1 mg/ml in a volume of 0.3–0.5 ml and measures to keep the airway open.
- Blood pressure: treatment is not started until systolic pressure reaches 100 mm Hg, and below that figure the medicine has not been studied. Symptomatic hypotension is commoner after 65, in kidney disease and with a baseline pressure below 112 mm Hg.
- Dehydration: a deficit of sodium and fluid from diuretics, a salt-free diet, diarrhoea or vomiting is corrected before starting, bearing in mind the risk of fluid overload.
- Kidneys: function is always assessed; with mild and moderate impairment the risk of hypotension is higher, with severe impairment it is highest, and in end-stage failure there is no experience. The medicine itself can worsen renal function, especially with dehydration and with non-steroidal anti-inflammatory drugs.
- Potassium: starting is forbidden above 5.4 mmol/l, and it needs watching particularly in kidney disease, diabetes, hypoaldosteronism, a potassium-rich diet and treatment with spironolactone. Hypokalaemia is also possible.
- Renal artery stenosis, one- or two-sided: urea and creatinine may rise and monitoring is needed.
- NYHA functional class IV: clinical experience is scarce and treatment should be started cautiously.
Separately, about tests: BNP stops being a valid marker of heart failure on this treatment, because it is itself a neprilysin substrate and rises because of the medicine rather than because of deterioration. With moderate hepatic impairment or enzymes above twice the upper limit exposure may be increased and safety is not established. The effect on driving is small, but dizziness and tiredness do occur.
Drug interactions
Combining it with an ACE inhibitor is contraindicated; with another sartan it is not allowed, because valsartan is already part of the product; and with direct renin inhibitors such as aliskiren it is not recommended: in people with diabetes and with impaired renal function that combination is forbidden, and in everyone else it increases the frequency of hypotension, hyperkalaemia and acute renal failure.
- Statins: sacubitril inhibits the OATP1B1 and OATP1B3 transporters, and the peak concentration of atorvastatin and its metabolites doubled, with the area under the curve 1.3 times higher. Caution is needed.
- Sildenafil and other PDE5 inhibitors: a single dose on steady treatment lowered blood pressure appreciably more than the medicine alone.
- Potassium-sparing diuretics (triamterene, amiloride), spironolactone and eplerenone, potassium supplements, potassium-containing salt substitutes and heparin raise potassium and creatinine — monitoring is needed.
- Non-steroidal anti-inflammatory drugs in older, dehydrated patients and those with kidney disease increase the risk of worsening renal function.
- Lithium: with ACE inhibitors and sartans a reversible rise in its concentration and toxicity has been described; with this medicine the combination has not been studied and is not recommended, and if it is unavoidable it requires monitoring of lithium levels, the more so if a diuretic is added.
- Transporter inhibitors — rifampicin, ciclosporin, tenofovir, cidofovir, ritonavir — may increase exposure to the active metabolite of sacubitril or to valsartan.
Furosemide did not affect the pharmacokinetics of the medicine, but its own peak concentration and area under the curve fell by 50% and 28% and urinary sodium excretion decreased; even so, the mean daily furosemide dose in PARADIGM-HF did not change. With metformin the area under the curve and peak concentration fell by 23%; the significance is unknown, but the patient's condition is worth assessing at the start. No clinically relevant interactions were seen with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole or carvedilol; cytochrome P450 plays little part and the medicine neither induces nor inhibits it.
Pregnancy and breastfeeding
In the first trimester the medicine is not recommended and in the second and third it is contraindicated. Data on the teratogenicity of ACE inhibitors in the first trimester are inconclusive, a small increase in risk cannot be ruled out, and a similar risk is assumed for sartans, although there are no controlled studies. A woman planning a pregnancy is switched to another treatment with a known safety profile unless continuing the sartan is essential, and once pregnancy is confirmed the medicine is stopped at once.
The effect of sartans from the second trimester onwards is known: in the fetus, impaired renal function, oligohydramnios and delayed skull ossification; in the newborn, renal failure, hypotension and hyperkalaemia. Ultrasound monitoring of the kidneys and skull is then recommended, and the baby is watched after birth for hypotension. Whether the medicine passes into human milk is unknown; in rats both substances did, so it is not recommended while breastfeeding, and the choice between stopping feeding and stopping treatment depends on how important the treatment is for the mother.
Adverse reactions
The commonest are hypotension, hyperkalaemia and worsening renal function. The profile was studied in PARADIGM-HF, where 4,203 patients received 97 mg/103 mg twice daily and 4,229 received enalapril 10 mg twice daily, with a median treatment duration of 24 months. Hypotension was reported in 17.6% against 11.9% on enalapril, a clinically relevant fall in systolic pressure in 4.76% against 2.67%, hyperkalaemia in 11.6% against 14.0% and worsening renal function in 10.1% against 11.5%. Treatment was stopped because of adverse reactions by 10.7% against 12.2%.
- Very common: hyperkalaemia, lowered blood pressure, impaired renal function.
- Common: hypokalaemia, hypoglycaemia, anaemia, dizziness, headache, syncope, orthostatic hypotension, cough, diarrhoea, nausea, gastritis, renal failure including acute, tiredness and weakness.
- Uncommon: hypersensitivity, orthostatic dizziness, itching, rash and angioedema.
These frequencies are lower than everyday practice would give, and the reason lies in the design of the study: before randomisation the participants went through run-in periods on enalapril and on the medicine, and those who did not tolerate them never reached the main phase. During the run-in 10.4% of patients dropped out, 5.9% of them because of adverse reactions — most often worsening renal function, hypotension and hyperkalaemia.
Overdose
Data on overdose in humans are scarce. Healthy volunteers were given a single dose of 583 mg of sacubitril with 617 mg of valsartan and repeated doses of 437 mg with 463 mg over 14 days, and these were well tolerated.
The most likely feature is a fall in blood pressure, since that is the medicine's own effect. Treatment is symptomatic. Haemodialysis is unlikely to help: the substances bind strongly to plasma proteins.
How to get a prescription for Entresto online
Entresto is almost never the first medicine: it is given instead of an ACE inhibitor or another sartan to a patient already being treated for heart failure, and that is why the previous regimen and the 36-hour rule have to be known before starting. The dose is matched to blood pressure, potassium and renal function and then doubled at intervals of weeks, so the decision belongs to a doctor who can see recent results.
An online consultation is above all suited to continuing a regimen that has already been worked out. The questionnaire covers the diagnosis and functional class, current doses of all cardiac medicines, especially the ACE inhibitor or sartan and the diuretics, the latest systolic pressure, potassium and creatinine with the estimated filtration rate, any past angioedema, pregnancy or plans for one, and also statins, non-steroidal anti-inflammatory drugs and lithium preparations. The doctor studies the answers and, where there are sufficient grounds, issues an electronic prescription that arrives as a code for a Polish pharmacy.
