HYPERTENSION

SACUBITRIL/ VALSARTAN Tablets

VYMADA

Vymada 50 mg film- coated tablets (sacubitril/ valsartan)

Vymada 100 mg film- coated tablets (sacubitril/ valsartan)

Vymada 200 mg film-coated tablets (sacubitril/ valsartan).

DESCRIPTION AND COMPOSITION

Pharmaceutical form

Film-coated tablets.

50 mg: violet white ovaloid biconvex film-coated tablet with beveled edges, unscored, debossed with “NVR” on one side and “LZ” on the other side.

100 mg: pale yellow ovaloid biconvex film-coated tablet with beveled edges, unscored, debossed with “NVR” on one side and “L1” on the other side.

200 mg: light pink ovaloid biconvex  film-coated tablet with beveled edges, unscored, debossed with “NVR” on one side and “L11” on the other side.

Active substances

sacubitril/ valsartan

vymada contains a salt complex of the anionic form of sacubitril and valsartan, sodium cation, and water molecules in the molar ratio of 1:1:3:2.5 respectively. Following oral administration ,vymada dissociates into sacubitril (which is further metabolized to LBQ657 [SACUBITRILAT] and valsartan.

Excipents

Microcrystalline cellulose, low substituted hydoxypropylcellulose, crospovidone ,mg stearate (vegetable origin), talc and colloidal silicon dioxide.

Excipents of Film-coating:

Hypromellose, TiO₂ ,macrogol 4000, talc, iron oxide red for 50 and 200 mg: iron oxide black. For 100 mg : iron oxide yellow.

INDICATIONS

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.

DOSAGE AND ADMINISTRATION

The target dose of vymada is 200 mg twice daily.

The recommended starting dose of vymada is 100mg twice daily. A starting dose of 50 mg twice daily is recommended for patients not currently taking an angiotensin-converting enzyme(ACE) inhibitor or an angiotensin II receptor blocker(ARB), and should be considered for patients previously taking low dose of these agents (see section CLINICAL STUDIES).

• The dose of vymada should be doubled every 2-4 weeks to the target dose of 200 mg twice daily, as tolerated by the patient.

Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, Vymada must not be started until 36 hours after discontinuing ACE inhibitor therapy (see section CONTRAINDICATIONS).

Vymada should not be co-administered  with an ARB due to the angiotensin II receptor blocking activity of vymada (see section WARNINGS AND PRECAUTIONS and INTERACTIONS).

If patients experience tolerability issue (symptomatic hypotension, hyperkalemia, renal dysfunction),consideration should be given to adjustment of concomitant medications, or to temporary down –titration of vymada.

Special populations

Renal impairment

A starting dose of 50 mg twice daily is recommended in patients with severe Renal impairment

(eGFR <30 ml/min/1.73 m²). Caution is recommended when using vymada in these patients due to limited data (see sections CLINICAL PHARMACOLOGY).

No dose adjustment is required in patients with mild (eGFR 60-90 ml/min/1.73 m²) to moderate (eGFR 30-60 ml/min/1.73 m²) renal impairment.

Hepatic impairment

A starting dose of 50 mg twice daily is recommended in patients with moderate hepatic impairment (child-pugh B classification).

No dose adjustment is required when administering vymada to patients with mild hepatic impairment (child-pugh A 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 sections CLINICAL PHARMACOLOGY).

Pediatric patients

The safety and efficacy of vymada in pediatric patients aged below 18 years has not been established.

Geriatric patients (older than 65 years)

No dosage adjustment is required in patients over 65 years.

Method of administration

For oral use. Vymada may be administered with or without food recommended  (see sections CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS

•   Hypersensitivity to the active substance, sacubitril, valsartan, or to any of the excipients.
•   Concomitant use with ACE inhibitor (see section WARNINGS AND PRECAUTIONS,   DOSAGE AND ADMINISTRATION and INTERACTIONS). Vymada must not be started   until 36 hours after discontinuing ACE inhibitor therapy.
•  Known history of angioedema related to previous ACE inhibitor or ARB therapy.
•  Hereditary angioedema 
•  Concomitant use with aliskiren in patients with type 2 diabetes (see section WARNINGS AND PRECAUTIONS and INTERACTIONS).
•  Pregnancy (see section FEMALES OF CHILD-BEARING POTENTIAL, PREGNANCY, BREAST-FEEDING AND FERTILITY).

WARNINGS AND PRECAUTIONS

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

•   Vymada must not be administered with an ACE inhibitor due to the risk of angioedema. Vymada must not be initiated until 36 hours after taking the last dose of  ACE inhibitor therapy. If treatment with Vymada is stopped,  ACE inhibitor therapy must not be initiated until 36 hours after taking the last dose of vymada (see section CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION and INTERACTIONS).
•  Caution is required while co-administering vymada with direct renin inhibitors such as aliskiren (see section CONTRAINDICATIONS and INTERACTIONS). Vymada must not be administered with aliskiren in patients with type 2 diabetes (see section CONTRAINDICATIONS).
• Vymada should not be co-administered with an ARB due to angiotensin II receptor blocking activity of vymada (see section DOSAGE AND ADMINISTRATION and INTERACTIONS).

Hypotension

Cases of symptomatic hypotension have been reported in patients treated with vymada during clinical trials. If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other cause of hypotension (eg. Hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of vymada should be reduced or the product should be temporarily discontinued (see section DOSAGE AND ADMINISTRATION). Permanent discontinuation of therapy is usully not required. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with vymada.

Impaired renal function

As for any drug that acts on the renin-angiotensin-aldosterone system, use of vymada may be associated with decreased renal function. In PARADIGM-HF,the incidence of clinically relevant renal impairment was low and associated treatment discontinuation was observed less frequently in patients receiving vymda compared to enalapril. Down titration of vymada should be considered in patients who develop a clinically significant decrease in renal function. (see section DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY).

Hyperkalemia

As for any drug that acts on the renin-angiotensin-aldosterone system, use of vymada may be associated with an increased risk of hyperkalemia. In PARADIGM-HF,the incidence of clinically relevant hyperkalemia was low, resulting in  treatment discontinuation in 0.26% of vymada treated patients compared to 0.35% of enalapril treated patients. Medications known to raise potassium level (e.g. potassium-sparing diuretics, potassium supplements) should be used with caution when co-administered with vymada. Monitoring of serum potassium is recommended especially in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism or receiving a high potassium diet (see section DOSAGE AND ADMINISTRATION).

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. In case 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.

As they may be at higher risk for angioedema, caution is recommended if vymada is used in these patients. Vymada must not be used in patients with a known history of angioedema related to previous ACE  inhibitor or ARB therapy, or in patients with hereditary angioedema (see section CONTRAINDICATIONS).

 Patients with renal artery stenosis

Similar to othe drugs that affect the renin-angiotensin-aldosterone system, vymada 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.

Adverse drug reactions	Vymada 200 mg twice daily(%)	Enalapril 10 mg twice daily(%)	Frequency category
Metabolism &	nutrition disorder
Hyperkalemia	11.61	14.00	Very common
Hypokalemia	3.31	2.53	common
Nervous system	disorder
Dizziness	6.33	4.87	common
Dizziness postural	0.57	0.28	uncommon
Headache	2.45	2.51	common
Ear and	Labyrinth disorder
Vertigo	1.45	1.40	Common
vascular	disorder
Hypotension	17.61	11.97	Very common
Syncope	2.24	2.70	common
Orthostatic hypotension	1.52	0.80	common