Duosav 50/100/200

DUOSAV

Sacubitril/ Valsartan Tablets

Composition:

DUOSAV 50 (Sacubitril/ Valsartan Tablets 50 mg)

Each film coated tablet contains:

Sacubitril 24.3 mg & Valsartan 25.7 mg

(as sacubitril valsartan sodium salt complex)

Excipients: q.s.

Color: Iron oxide red, Iron oxide black, Titanium dioxide BP

 

DUOSAV 100 (Sacubitril/Valsartan Tablets 100 mg)

Each film coated tablet contains:

Sacubitril 48.6 mg & Valsartan 51.4 mg

(as sacubitril valsartan sodium salt complex)

Excipients: q.s.

Color: Iron oxide yellow

 

DUOSAV 200 (Sacubitril/ Valsartan Tablets 200 mg)

Each film coated tablet contains:

Sacubitril 97.2 mg & Valsartan 102.8 mg

(as sacubitril valsartan sodium salt complex)

Excipients: q.s.

Color: Erythrosine

 

Therapeutic Indications:

DUOSAV is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.

 

 

Dosage & Administration:

The recommended starting dose of DUOSAV is one tablet of Sacubitril/ Valsartan Tablets 100 mg twice daily, except in the situations described below. The dose should be doubled at 2-4 weeks to the target dose of one tablet of Sacubitril/ Valsartan Tablets 200 mg twice daily, as tolerated by the patient. If patients experience tolerability issues (systolic blood pressure [SP] ≤95 mmHg, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down-titration or discontinuation of DUOSAV is recommended.

There is limited experience in patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, therefore a starting dose of Sacubitril/Valsartan Tablets 50 mg twice daily and slow dose titration (doubling every 3-4 weeks) are recommended in these patients.

Treatment should not be initiated in patients with serum potassium level >5.4 mmol/L or with SBP<100 mmHg. A starting dose of Sacubitril/Valsartan Tablets 50 mg twice daily is considered for patients with SBP≥ 100 to 110 mmHg.

DUOSAV should not be co-administered with an ACE inhibitor or an ARB. Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor. it must not be started for at least 36 hours after discontinuing ACE inhibitor therapy. If a dose is missed, the patient should take the next dose at the scheduled time.

Special populations

Elderly population: The dose should be in line with the renal function of the elderly patient.

Renal impairment: No dose adjustment is required in patients with mild (Estimated Glomerular Filtration Rate [eGFR] 60-90 ml/min/1.73 m2) renal impairment. A starting dose of Sacubitril/ Valsartan Tablets 50 mg twice daily 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), DUOSAV should be used with caution and a starting dose of Sacubitril/ Valsartan Tablets 50 mg twice daily is recommended. There is no experience in patients with end-stage renal disease and use of DUOSAV is not recommended.

Hepatic impairment: No dose adjustment is required when administering DUOSAV to patients with mild hepatic impairment (Child-Pugh A classification). 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. DUOSAV should be used with caution in these patients and the recommended starting dose is Sacubitril/ Valsartan Tablets 50 mg twice daily. DUOSAV is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification).

 

 

Paediatric population: The safety and efficacy of DUOSAV in children and adolescents aged below 18 years have not been established. No data are available.

Method of administration: For Oral use, DUOSAV may be administered with or without food. The tablets must be swallowed with a glass of water.

Contraindications:

• Hypersensitivity to the active substances or to any of the excipients
• Concomitant use with ACE inhibitors. DUOSAV must not be administered until 36 hours after discontinuing ACE inhibitors therapy
• Known history of angioedema related to previous ACE inhibitor or ARB therapy
• Hereditary or idiopathic angioedema
• Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR < 60ml/min/1.73 m2)
• Severe hepatic impairment, biliary cirrhosis and cholestasis
• Second and third trimester of pregnancy

Warnings & Precautions:

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

• The combination of DUOSAV with an ACE inhibitor is contraindicated due to the increased risk of angioedema. DUOSAV must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with DUOSAV is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of DUOSAV.
• The combination of DUOSAV with direct renin inhibitors such as aliskiren is not recommended. The combination of DUOSAV with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2)
• DUOSAV contains valsartan, and therefore should not be co-administered with another ARB containing product.

Hypotension

Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with DUOSAV during clinical studies, 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 DUOSAV, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of DUOSAV is recommended. Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolemia) 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 DUOSAV: however, such corrective action must be carefully weighed against the risk of volume overload.

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. 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. There is no experience in patients with end-stage renal disease and use of DUOSAV is not recommended.

Worsening renal function

Use of DUOSAV may be associated with decreased renal function. The risk may be further increased by dehydration or concomitant use of non-steroidal anti-inflammatory agents (NSAIDs). 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/. Use of DUOSAV may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur. 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. If patients experience clinically significant nyperkalaemia adjustment of concomitant medicinal products, 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 DUOSAV. If angioedema occurs, DUOSAV should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. It 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 DUOSAV is used in these patients. DUOSAV is contraindicated in patients with a known history of angioedema related to a previous ACE inhibitor or ARB therapy or with hereditary or idiopathic angioedema

Black patients have an increased susceptibility to develop angioedema.

 

 

Patients with renal artery stenosis

DUOSAV 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 DUOSAV 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 DUOSAV because it is a neprilysin substrate.

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 patients, exposure may be increased, and safety is not established. Caution is therefore recommended when using it in these patients. DUOSAV is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification).

Drug-Interactions:

Interactions resulting in a contraindication

ACE inhibitors

The concomitant use of DUOSAV with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. DUOSAV 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 DUOSAV.

Aliskiren

The concomitant use of DUOSAV with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). The combination of DUOSAV with direct renin inhibitors such as aliskiren is not recommended. Combination of DUOSAV with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure).

Interactions resulting in concomitant use not being recommended

DUOSAV contains valsartan, and therefore should not be co-administered with another ARB containing product.

 

Interactions requiring precautions

OATP1B1 and OATP1B3 substrates, e.g. statins

In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. DUOSAV may, therefore, increase the systemic exposure of OATP1B1 and OATP 183 substrates such as statins. Co-administration of DUOSAV 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 DUOSAV with statins. No clinically relevant drug-drug interaction was observed when simvastatin and DUOSAV were co-administered.

PDE5 inhibitors including sildenafil

Addition of a single dose of sildenafil to DUOSAV at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of DUOSAV alone. Therefore, caution should be exercised when sildenafil or another PDE5 inhibitor is initiated in patients treated with DUOSAV.

Potassium

Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, and 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 DUOSAV is co-administered with these agents.

Non-steroidal anti-inflammatory agents (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 DUOSAV and NSAIDs may lead to an increased risk of worsening renal function. Therefore, monitoring of renal function is recommended when initiating or modifying treatment in patients on DUOSAV who are taking NSAIDs concomitantly.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin Il receptor antagonists. Interactions between DUOSAV and lithium have not been investigated. 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 DUOSAV and furosemide had no effect on the pharmacokinetics of DUOSAV 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 DUOSAV.

Nitrates, e.g. nitroglycerine

There was no drug-drug interaction between DUOSAV and intravenously administered nitroglycerin regarding blood pressure reduction. Co-administration of nitroglycerin and DUOSAV 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 DUOSAV 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 OAT substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of DUOSAV with inhibitors of OATP 1B1, OATP1B3, OAT3 (e.g. rifampicin, cyclosporine), 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.

Metformin

Co-administration of DUOSAV with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with DUOSAV 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 DUOSAV was co-administered with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of levonorgestrel/ethinyl estradiol.

CYP 450 interactions

In vitro metabolism studies indicate that potential for CYP 450-based drug interactions is low since there is limited metabolism of DUOSAV via CYP450 enzymes. DUOSAV does not induce or inhibit CYP450 enzymes,

Pregnancy and Lactation:

Pregnancy

The use of DUOSAV 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, and 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

DUOSAV

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

Breastfeeding

It is not known whether DUOSAV is excreted in human milk. The components of DUOSAV, 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 breastfeeding. A decision should be made whether to abstain from breastfeeding or to discontinue DUOSAV while breastfeeding, considering the importance of DUOSAV to the mother.

Fertility

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

Effects on Ability to Drive and Use Machines

DUOSAV has a minor influence on the ability to drive and use machines. When driving vehicles or operating machines it should be considered that occasionally dizziness or fatigue may occur.

Undesirable Effects:

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some side effects may be serious.

• Stop taking DUOSAV and seek immediate medical attention if you notice any swelling of the face, lips, tongue and/or throat, which may cause difficulties in breathing or swallowing. These may be signs of angioedema.

Other possible side effects: If any of the side effects listed below become severe, tell your doctor or pharmacist. Very common (may affect more than 1 in 10 people):

• Low blood pressure (dizziness, light-headedness)
• High level of potassium in the blood (shown in a blood test)
• Decreased renal function (renal impairment) Common (may affect up to 1 in 10 people)
• Cough, dizziness, diarrhoea, low level of red blood cells (shown in a blood test), and tiredness
• (Acute) renal failure (severe kidney disorder)
• Low level of potassium in the blood (shown in a blood test)
• Headache, fainting, weakness, feeling sick (nausea),
• Low blood pressure (dizziness, light-headedness) when switching from sitting or lying to standing position
• Gastritis (stomach pain, nausea)
• Spinning sensation
• Low level of sugar in the blood Uncommon (may affect up to 1 in 100 people)
• Allergic reaction with rash and itching
• Dizziness when switching from sitting to standing position Reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse.

This includes any possible side effects not listed in this leaflet.

Pharmacological Action:

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; angiotensin II antagonists, other combinations.

DUOSAV 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 Il type-1a(AT1) receptor via valsartan. The complementary cardiovascular benefits of DUOSAV 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 AT receptor, and also inhibits angiotensin II-dependent aldosterone release. This prevents sustained activation of the renin-angiotensin-aldosterone system that would result in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodeling.

 

Pharmacokinetics:

The valsartan contained within DUOSAV is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in DUOSAV is equivalent to 40 mg, 80 mg and 160 mg of valsartan in other marketed tablet formulations, respectively.

Absorption

Following oral administration, DUOSAV dissociates into valsartan and the prodrug sacubitril. Sacubitril is further metabolized 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 DUOSAV, 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. DUOSAV 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 CS 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 litres to 103 litres, respectively.

Biotransformation

Sacubitril is readily converted to LBQ657 by carboxylesterases 1b and 1c; LBQ657 is not further metabolized to a significant extent. Valsartan is minimally metabolized, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite of valsartan has been identified in plasma 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 pharmacokinetics.

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 (T½) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.

Storage: Store in a cool and dry place below 30°C. Protected from light and moisture. Keep the medicine away from children.

Presentation: 1 blister containing 10 tablets is packed in a primary carton along with the Pack Insert.

Carefully read the accompanying instructions before use.

Updated on : 05.08.2024