Vymada 50 mg, 100 mg, & 200 mg FC tablets

Chronic heart failure with reduced ejection fraction (HFrEF) VYMADA is indicated as a second-line therapy, replacing angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) for treatment of symptomatic heart failure (NYHA class II-IV) in patients with reduced ejection fraction. VYMADA has been shown to reduce the rate of cardiovascular death and heart failure hospitalisation. VYMADA is administered in combination with other heart failure therapies as appropriate. Chronic heart failure with preserved ejection fraction (HFpEF) VYMADA is indicated for the treatment of heart failure (NYHA class II-IV) in patients with preserved ejection fraction with left ventricular ejection fraction (LVEF) below normal. VYMADA has been shown to reduce the rate of cardiovascular death and heart failure hospitalisation in these patients.

The target dose of VYMADA is 200 mg twice daily. To avoid hypotension the recommended starting dose of VYMADA 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 u2013 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. VYMADA must not be started until 36 hours after discontinuing ACE inhibitor therapy (see section 4.3). If patients experience tolerability issues (symptomatic hypotension, hyperkalaemia, renal dysfunction), consideration should be given to adjustment of concomitant medications, or to downu2013titration or discontinuation of VYMADA.

Special populations

Renal impairment VYMADA is contraindicated in patients with severe impaired renal function.

Hepatic impairment No dose adjustment is required when administering VYMADA 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 VYMADA in these patients is not recommended (see section 5).

Paediatric patients The safety and efficacy of VYMADA in paediatric patients aged below 18 years has not been established.

Geriatric patients (older than 65 years) Patients over the age of 65 years may have impaired renal function, therefore a lower starting dose is recommended.

Method of administration VYMADA may be administered with or without food (see section 5.2).

• Sensitivity to the active substance, sacubitril, valsartan, or to any of the ingredients of VYMADA.
• Concomitant use with ACE inhibitors (see section 4.2; 4.4 and 4.5). VYMADA 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.
• Hereditary or idiopathic angioedema
• 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 VYMADA may lead to toxic blood concentrations of lithium (see section 4.5).
• Concomitant use of VYMADA with renin antagonists such as aliskiren (see section 4.4).
• Pregnancy and lactation (see section 4.6).
• Severe renal function impairment (creatinine clearance less than 30 ml/min)
• The concomitant use of VYMADA with aliskiren-containing products is contraindicated (see section 4.4)
• Concomitant use of fluoroquinolones with and Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 30 ml/min) and in elderly patients.

Should a woman become pregnant while receiving VYMADA, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6)

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

VYMADA must not be administered with an ACE inhibitor or another ARB. VYMADA must not be initiated until 36 hours after taking the last dose of ACE inhibitor or ARB therapy. If treatment with VYMADA is stopped, ACE inhibitor or ARB therapy must not be initiated until 36 hours after the last dose of VYMADA (see 4.2, 4.3 and 4.5).

Hypotension

Cases of symptomatic hypotension have been reported commonly in patients treated with VYMADA during clinical trials. If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive medicines, and treatment of other causes of hypotension (e.g. hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of VYMADA should be reduced or the product should be discontinued (see section 4.2). 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 VYMADA.

Impaired renal function

The use of VYMADA may be associated with decreased renal function. Down titration or discontinuation of VYMADA should be considered in patients who develop a clinically significant decrease in renal function (see section 4.3).

Hyperkalaemia

The use of VYMADA is associated with an increased risk of hyperkalaemia. Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium supplements) should not be used with VYMADA. If clinically significant hyperkalaemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. Monitoring of serum potassium is recommended especially in patients with risk factors such as diabetes mellitus, hypoaldosteronism or receiving a high potassium diet (see section 4.2 and 4.3).

Angioedema

Angioedema has been reported in patients treated with VYMADA. If angioedema occurs, VYMADA should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. VYMADA must not be re-administered. 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., subcutaneous epinephrine/adrenaline solution 1:1000 (0,3 ml to 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 (see section 4.3). Black patients may have increased susceptibility to develop angioedema.

Patients with renal artery stenosis See section 4.3

Anticipated interactions resulting in a contraindication

ACE inhibitors: The concomitant use of VYMADA with ACE inhibitors and ARBs is contraindicated. VYMADA must not be started until 36 hours after taking the last dose of ACE inhibitor or ARB therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of VYMADA (see sections 4.2 and 4.3).

Fluoroquinolones: Concomitant use of fluoroquinolones and Angiotensin receptor blockers may precipitate acute kidney injury (see section 4.3). The mechanism of the possible interaction between the different classes of medicines referred to, over and above different mechanism of kidney damage, is unknown (see sections 4.3 and 4.4)

Aliskiren: The concomitant use of VYMADA with aliskiren is contraindicated.

Observed interactions to be considered

Statins: In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters. VYMADA may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of VYMADA increased the C max 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 VYMADA with statins as the adverse effects of statins are dose/exposure related.

Sildenafil: Addition of a single dose of sildenafil to VYMADA at steady state in patients with hypertension was associated with greater BP reduction compared to administration of VYMADA alone. Therefore, caution should be exercised when sildenafil or another PDE-5 inhibitor is initiated in patients treated with VYMADA.

Anticipated interactions to be considered

Potassium: Concomitant use of potassium-sparing diuretics (e.g, triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if VYMADA is co-administered with these agents (see section 4.4).

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 Inhibitors): In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of VYMADA and NSAIDs may lead to an increased risk of worsening of renal function and increase in blood pressure. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on VYMADA who are taking NSAIDs concomitantly.

Lithium: The potential for an interaction between VYMADA and lithium has not been investigated. 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).

Transporters: The active metabolite of sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of VYMADA with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin) or MPR2 (e.g. ritonavir) may increase the systemic exposure to LBQ657 or valsartan, respectively. Exercise appropriate care when initiating or ending concomitant treatment with such medicines.

No significant interactions No clinically meaningful drug-drug interaction was observed upon co-administration of VYMADA and furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, metformin, omeprazole, carvedilol, intravenous nitroglycerin or a combination of levonorgestrel/ethinyl estradiol. No interaction is expected with atenolol, indomethacin, glyburide, or cimetidine.

CYP450 Interactions: In vitro metabolism studies indicate that the potential for CYP450 based interactions is low since there is limited metabolism of VYMADA via the CYP450 enzymes. VYMADA does not induce or inhibit CYP450 enzymes.

Pregnancy VYMADA is contraindicated in pregnancy. Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed VYMADA should be discontinued. Medicines affecting the renin-angiotensin system, such as VYMADA, can cause embryonal toxicity, foetal and neonatal morbidity and mortality, when administered to pregnant women.

Breast feeding VYMADA is contraindicated during breastfeeding.

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

VYMADA may influence the ability to drive and use machines. Dizziness and fatigue have been reported in patients taking VYMADA and should be considered when assessing a patientu2019s ability to drive or use machines.

Summary of the safety profile A total of 6 622 heart failure patients were treated with VYMADA in the PARADIGM-HF (vs. enalapril) and PARAGON-HF (vs. valsartan) clinical trials. Of these, 5 085 were exposed for at least 1 year. PARADIGM-HF The safety of VYMADA in patients with chronic heart failure with LVEF u226440% (reduced ejection fraction) was evaluated in a study, in which patients treated twice daily with VYMADA 200 mg (n = 4 203). Patients treated with VYMADA received treatment for up to 4,3 years, with a median duration of exposure of 24 months; 3 271 patients were treated for more than one year. Discontinuation of therapy due to an AE in the double-blind period of the PARADIGM-HF trial occurred in 450 (10,71 %) of patients treated with VYMADA. The events most commonly associated with dosage adjustment or treatment interruption were hypotension, hyperkalaemia and renal impairment.

Tabulated list of adverse reactions Adverse drug reactions are ranked by System Organ Class and then by frequency with the most frequent first, using the following convention: very common (u22651/10); common (u22651/100 to <1/10); uncommon (u22651/1,000 to <1/100); rare (u22651/10,000 to <1/1,000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1. List of adverse reactions System organ class Preferred term Frequency category Blood and lymphatic system disorders Anaemia Common Immune system disorders Hypersensitivity Uncommon Metabolism and nutrition disorders Hyperkalaemia* Very common Hypokalaemia Common Hypoglycaemia Common Nervous system disorders Dizziness Common Postural dizziness Uncommon Headache Common Ear and labyrinth disorders Vertigo Common Vascular disorders Hypotension* Very common Syncope Common Orthostatic hypotension Common Respiratory, thoracic and mediastinal disorders Cough Common Gastrointestinal disorders Diarrhoea Common Nausea Common Gastritis Common Skin and subcutaneous tissue disorders Pruritus Uncommon Rash Uncommon Angioedema* Uncommon Renal and urinary disorders Renal impairment* Very common Renal failure (renal failure, acute renal failure) Common General disorders and administration site conditions Fatigue Common Asthenia Common *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%) (see section 4.4). 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 (20 mmHg) were reported in 17.6% and 4.76% of sacubitril/valsartan -treated 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. PARAGON-HF The safety of VYMADA in patients with chronic heart failure and LVEF u2265 45% (preserved ejection fraction) was evaluated in the pivotal phase 3 study PARAGON-HF, which compared patients treated twice daily with VYMADA 200 mg (n = 2 419) or valsartan 160 mg (n = 2 402). The safety profile of VYMADA was consistent with the safety profile in patients with heart failure with reduced ejection fraction. Other AEs that were commonly reported with VYMADA in >1 % of patients during the double-blind period of PARADIGM-HF include: gynaecomastia, fall, back pain, influenza, nasopharyngitis. These events were reported more frequently with VYMADA but the causal relationship to VYMADA cannot be determined. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorization of VYMADA is important. It allows continued monitoring of the benefit / risk balance of VYMADA. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Hypotension is the most likely symptom of overdosage due to the blood pressure lowering effects of VYMADA. Symptomatic treatment should be provided. VYMADA is unlikely to be removed by haemodialysis due to high protein binding.