Zuvatan 50 Tablets

Sacubitril and Valsartan Tablets 50 mg / 100 mg / 200 mg

Zuvatan 50

Each film coated tablet contains :

24 mg Sacubitril and 26 mg Valsartan as sodium salt

Excipients q.s.

Colours : Iron Oxide Black, Iron Oxide Red and Titanium Dioxide IP

Zuvatan 100

Each film coated tablet contains :

49 mg Sacubitril and 51 mg Valsartan as sodium salt

Excipients q.s

Colours : Iron Oxide Yellow, Iron Oxide Red and Titanium Dioxide IP

Zuvatan 200

Each film coated tablet contains :

97 mg Sacubitril and 103 mg Valsartan as sodium salt

Excipients q.s.

Colours : Iron Oxide Black, Iron Oxide Red and Titanium Dioxide IP

Tablet, 50 (24 + 26) mg, 100 (49 + 51) mg, 200 (97 + 103) mg

4.1 Therapeutic indication

To reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

4.2 Posology and method of administration

General considerations

Zuvatan is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to Zuvatan allow a washout period of 36 hours between administration of the two drugs

Adult heart failure

The recommended starting dose of Zuvatan is 100 mg orally twice-daily. Double the dose of Zuvatan after 2 to 4 weeks to the target maintenance dose of 200 mg twice daily, as tolerated by the patient.

Dose adjustment for patients not taking an ace inhibitor or arb or previously taking low doses of these agents

In patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents, start Zuvatan at half the usually recommended starting dose. After initiation, increase the dose every 2 to 4 weeks in adults and every 2 weeks in paediatric patients to follow the recommended dose escalation thereafter.

Dose adjustment for severe renal impairment

In adults and paediatric patients with severe renal impairment (eGFR < 30 mL/min/1.73 m ), start Zuvatan at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter.

No starting dose adjustment is needed for mild or moderate renal impairment.

Dose adjustment for hepatic impairment

In adults and paediatric patients with moderate hepatic impairment (Child-Pugh B classication), start Zuvatan at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter.

No starting dose adjustment is needed for mild hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

Method of administration

Oral use

Zuvatan may be administered with or without food. The tablets must be swallowed with a glass of water.

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in the formulation.
• Concomitant use with ACE inhibitors. Zuvatan must not be administered until 36 hours after discontinuing ACE inhibitor 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 <60 ml/min/1.73 m² ).
• Severe hepatic impairment, biliary cirrhosis and cholestasis.
• Second and third trimesters of pregnancy.

4.4 Warning and precautions

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. 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. The combination of Sacubitril / Valsartan with direct renin inhibitors such as Aliskiren is not recommended. The combination of Sacubitril / Valsartan with Aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or 2 in patients with renal impairment (eGFR <60 ml/min/1.73 m ). Zuvatan contains valsartan, and therefore should not be co-administered with another ARB containing medicinal 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 Sacubitril / Valsartan 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 Sacubitril / Valsartan, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of Sacubitril / Valsartan is recommended. Dose adjustment of diuretics, concomitant antihypertensive 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.

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 2 in patients with severe renal impairment (estimated GFR < 30 ml/min/1.73 m ) and these patients may be at greatest risk of hypotension. 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-inammatory agents (NSAIDs). Down-titration should be considered in patients who develop a clinically signicant 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. 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 signicant hyperkalaemia 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 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 must not be re-administered. In cases of confirmed angioedema where swelling has been conned 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. Black patients have an increased susceptibility to develop angioedema.

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 classication 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.

Patients with hepatic impairment

There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classication) 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. Sacubitril / Valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification).

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

4.5 Drug interactions

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.

Aliskiren

The concomitant use of Sacubitril / Valsartan with Aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or 2 in patients with renal impairment (eGFR < 60 ml/min/1.73 m ). The combination of Sacubitril / Valsartan with direct renin inhibitors such as Aliskiren is not recommended. 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).

Interactions resulting in concomitant use not being recommended

Sacubitril / Valsartan contains valsartan, and therefore should not be co-administered with another ARB containing medicinal product.

Interactions requiring precautions

OATP1B1 and OATP1B3 substrates, e.g. statins In vitro data indicate that Sacubitril inhibits OATP1B1 and OATP1B3 transporters. Zuvatan 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 Zuvatan 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

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.

Non-steroidal anti-inflammator y 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 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.

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 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 coadministration. The average daily dose of Furosemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with Sacubitril / Valsartan.

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 Nitroglycerin 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 (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.

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.

4.6 Special populations

Pregnancy

The use of Sacubitril / Valsartan is not recommended during the rst trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. There are no data from the use of Sacubitril / Valsartan in pregnant women. Animal studies with Sacubitril / Valsartan have shown reproductive toxicity.

Breast-feeding

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

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable Effects

The most commonly reported adverse reactions during treatment with Sacubitril / Valsartan were hypotension, hyperkalaemia and renal impairment. Angioedema was reported in patients treated with Sacubitril / Valsartan.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Limited data are available with regard to overdose in humans. A single dose of 583 mg Sacubitril / 617 mg Valsartan and multiple doses of 437 mg Sacubitril / 463 mg Valsartan (14 days) were studied in healthy volunteers and were well tolerated. Hypotension is the most likely symptom of overdose due to the blood pressure lowering effects of Sacubitril / Valsartan. Symptomatic treatment should be provided. The medicinal product is unlikely to be removed by haemodialysis due to high protein binding.

5.1 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 fltration 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 vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodelling.

5.2 Pharmacodynamic Properties

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 Nterminal prohormone brain natriuretic peptide (NTproBNP) compared to valsartan. In a 21-day study in HFrEF patients, Sacubitril / Valsartan signicantly 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. 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- (A ) 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 A 1-38 compared to placebo; there were no changes in concentrations of CSF A 1-40 and 1-42. The clinical relevance of this finding is not known

5.3 Pharmacokinetic properties

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 litres to 103 litres, 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 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 valsar tan 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.

6.1 Animal toxicology or pharmacology

Non-clinical data (including studies with Sacubitril and Valsartan components and/or Sacubitril / Valsartan) reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility.

Zuvatan (Sacubitril and Valsartan) is a combination of a Neprilysin inhibitor and an angiotensin II receptor blocker.

Following oral administration, the complex dissociates into Sacubitril (which is further metabolized to LBQ657) and Valsartan. The complex is chemically described as Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´- biphenyl]-4-ylmethyl)-4-ethoxy-3- methyl-4-oxobutyl]amino}-4-oxobutanoate)hexakis(N-pentanoyl-N-{[2´- (1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)—water (1/15).

Its empirical formula is C₄₈H₅₅N₆O₈Na₃ 2.5 H₂O. Its molecular mass is 957.99 g/mol and its schematic structural formula is

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Zuvatan 50 : Alu-Alu blister strip of 10 tablets.

Zuvatan 100 : Alu-Alu blister strip of 10 tablets.

Zuvatan 200 : Alu-Alu blister strip of 10 tablets.

8.4 Storage and handing instructions

Store below 30°C. Store in an original package in order to protect from moisture.

Keep out of reach of children.

What is Zuvatan ?

Zuvatan is a prescription medicine used to treat adults with long-lasting (chronic) heart failure to help reduce the risk of death and hospitalization. Zuvatan works better when the heart cannot pump a normal amount of blood to the body.

Pregnancy

Advise female patients of childbearing age about the consequences of exposure to Zuvatan during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible

Angioedema

Advise patients to discontinue use of their previous ACE inhibitor or ARB. Advise patients to allow a 36 hour wash-out period if switching from or to an ACE inhibitor.

What is the most important information I should know about Zuvatan ?

Zuvatan can harm or cause death to your unborn baby. Talk to your doctor about other ways to treat heart failure if you plan to become pregnant. If you get pregnant during treatment with Zuvatan, tell your doctor right away.

Do not take Zuvatan if you :

• Are allergic to any of the ingredients in Zuvatan. See the end of this Patient Information leaflet for a complete list of ingredients in Zuvatan.
• Have had an allergic reaction including swelling of your face, lips, tongue, throat, or trouble breathing while taking a type of medicine called an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).
• Take an ACE inhibitor medicine. Do not take Zuvatan for at least 36 hours before or after you take an ACE inhibitor medicine. Talk with your doctor or pharmacist before taking Zuvatan if you are not sure if you take an ACE inhibitor medicine.
• Have diabetes and take a medicine that contains Aliskiren.

Before taking Zuvatan, tell your doctor about all of your medical conditions, including if you :

• Have a history of hereditary angioedema.
• Have kidney or liver problems.
• Are pregnant or plan to become pregnant.
• Are breastfeeding or plan to breastfeed. It is not known if Zuvatan passes into your breast milk. You and your doctor should decide if you will take Zuvatan or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using Zuvatan with certain other medicines may affect each other. Using Zuvatan with other medicines can cause serious side effects.

Especially tell your doctor if you take :

• Potassium supplements or a salt substitute.
• Nonsteroidal anti-inflammatory drugs (NSAIDs).
• Lithium
• Other medicines for high blood pressure or heart problems such as an ACE inhibitor, ARB, or Aliskiren.

How should I take Zuvatan ?

• Take Zuvatan exactly as your doctor tells you to take it.
• Take Zuvatan 2 times each day. Your doctor may change your dose of Zuvatan during treatment.
• If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will prepare Zuvatan as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor will adjust the dose as needed. Shake the bottle of suspension well before measuring the dose of medicine to give to your child.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose,
• Do not take the missed dose. Take the next dose at your regular time.
• If you take too much Zuvatan, call your doctor right away.

15 February 2023