Azmarda 200

Azmarda 200 is a Medicine for Heart failure containing Sacubitril 97 mg+Valsartan 103 mg. It is sold by JB Pharma.

Azmarda 200 is Heart failure medication belonging to the angiotensin II receptor blocker / Neprilysin inhibitor class.

Azmarda 200 is an angiotensin II receptor blocker / Neprilysin inhibitor used to treat Adult and Pediatric Heart failure.

The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5 hours, 2 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril is estimated to be ≥ 60%. The valsartan in Azmarda 200 is more bioavailable than the valsartan in other marketed tablet formulations;103 mg of valsartan in Azmarda 200 is equivalent to 160 mg of valsartan in other marketed tablet formulations, respectively. Azmarda 200 can therefore be administered with or without food. Azmarda 200 is highly bound to plasma proteins (94% to 97%). Based on the comparison of plasma and CSF exposures, Sacubitril [LBQ657] crosses the blood brain barrier to a limited extent (0.28%). The average apparent volumes of distribution of Valsartan and Sacubitril are 75 and 103 L, respectively. Sacubitril is readily converted to LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent. Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (< 10%). Following oral administration, 52% to 68% of sacubitril (primarily as LBQ657) and ~ 13% of valsartan and its metabolites are excreted in urine; 37% to 48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces. Sacubitril, LBQ657, and valsartan are eliminated from plasma with a mean elimination half-life (T1/2) of approximately 1.4 hours, 11.5 hours, and 9.9 hours, respectively.

Azmarda 200 shows common side effects like Cough, extreme tiredness.

Azmarda 200 is available in the form of Oral Tablets.

Sacubitril + Valsartan is available in India, US, South Korea, Singapore, Italy, Canada, China, Japan and Australia.

Azmarda 200 contains Sacubitril 97 mg + Valsartan 103 mg.

Azmarda 200 belonging to the the angiotensin II receptor blocker / Neprilysin inhibitor, acts as a medicine for Heart failure.

Sacubitril: Prodrug that inhibits neprilysin (neutral endopeptidase) through the active metabolite LBQ657, leading to increased levels of peptides, including natriuretic peptides; induces vasodilation and natriuresis.

Valsartan: Produces direct antagonism of the angiotensin II (AT2) receptors. Displaces angiotensin II from the AT1 receptor; antagonizes AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

The Data of onset of action of Sacubitril 97 mg + Valsartan 103 mg is not available.

The Tmax of Sacubitril 97 mg + Valsartan 103 mg is found to be 0.5 hour (Sacubitril) and 1.5 hours (Valsartan).

The Data of duration of Action of Sacubitril 97 mg + Valsartan 103 mg is not available.

Azmarda 200 which contains Sacubitril 97 mg + Valsartan 103 mg and is approved for use in the following clinical indications.

● Adult Heart Failure

Azmarda 200 is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clear in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat.

● Pediatric Heart Failure

Azmarda 200 is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. Azmarda 200 reduces NT-proBNP and is expected to improve cardiovascular outcomes.

Azmarda 200 which contains Sacubitril 97 mg + Valsartan 103 mg and is approved for use in the following clinical indications.

● Adult Heart Failure

❖ Heart failure with reduced ejection fraction:

Patients previously taking a moderate to high dose of an ACE inhibitor (eg, >10 mg/day of enalapril or equivalent) or ARB (eg, >160 mg/day of valsartan or equivalent)

Oral: Recommended target maintenance dose is Sacubitril 97 mg/Valsartan 103 mg twice daily.

Patients previously taking a low dose of an ACE inhibitor (eg, ≤10 mg/day of enalapril or equivalent) or ARB (eg, ≤160 mg/day of valsartan or equivalent)

Oral: Recommended target maintenance dose is Sacubitril 97 mg/Valsartan 103 mg twice daily.

Patients not currently taking an ACE inhibitor or an ARB

Oral: Recommended target maintenance dose is Sacubitril 97 mg/Valsartan 103 mg twice daily.

❖ Heart failure with preserved ejection fraction:

Oral: Recommended target maintenance dose is Sacubitril 97 mg/Valsartan 103 mg twice daily.

● Pediatric Heart Failure

Patients previously taking a moderate to high dose ACE inhibitor (ie, ≥0.2 mg/kg/day or 10 mg/day of enalapril or equivalent) or angiotensin II receptor blocker (ARB)

Tablets

Children and Adolescents:

≥50 kg: Oral: Recommended dose is Sacubitril 97 mg/Valsartan 103 mg twice daily.

Patients not currently taking an ACE inhibitor or an ARB or previously taking low doses of an ACE inhibitor (ie, 0.1 mg/kg/day or 5 mg/day of enalapril or equivalent) or ARB

Oral suspension

Children and Adolescents weighing ≤50 kg: Oral: Initial: 0.8 mg/kg/dose twice daily; titrate dose in 2 weeks to 1.6 mg/kg/dose twice daily, then 2 weeks later to 2.3 mg/kg/dose twice daily, then 2 weeks later to 3.1 mg/kg/dose twice daily.

Tablets

Children and Adolescents weighing >50 kg: Oral: Recommended dose is Sacubitril 97 mg/Valsartan 103 mg twice daily.

Azmarda 200 is available in Sacubitril 97 mg and Valsartan 103 mg.

Azmarda 200 is available in the form of Oral Tablets.

Azmarda 200 is contraindicated in patients

• With known sensitivity towards any component [Sacubitril or Valsartan].
• In patients with a history of angioedema related to previous ACE inhibitor or ARB therapy.
• With concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor.
• With concomitant use of aliskiren in patients with diabetes.

Azmarda 200 containing Sacubitril 97 mg and Valsartan 103 mg should be used with certain warnings and precautions

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

● Fetal Toxicity

SACUBITRIL + VALSARTAN can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue SACUBITRIL + VALSARTAN. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.

● Angioedema

SACUBITRIL + VALSARTAN may cause angioedema. In the double-blind period of PARADIGM-HF, 0.5% of patients treated with SACUBITRIL + VALSARTAN and 0.2% of patients treated with enalapril had angioedema. If angioedema occurs, discontinue SACUBITRIL + VALSARTAN immediately, provide appropriate therapy, and monitor for airway compromise. SACUBITRIL + VALSARTAN 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 edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and take measures necessary to ensure maintenance of a patent airway. SACUBITRIL + VALSARTAN has been associated with a higher rate of angioedema in Black than in non-Black patients. Patients with a prior history of angioedema may be at increased risk of angioedema with SACUBITRIL + VALSARTAN. SACUBITRIL + VALSARTAN must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy. SACUBITRIL + VALSARTAN should not be used in patients with hereditary angioedema.

● Hypotension

SACUBITRIL + VALSARTAN lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. In the double-blind period of PARADIGM-HF, 18% of patients treated with SACUBITRIL + VALSARTAN and 12% of patients treated with enalapril reported hypotension as an adverse event, with hypotension reported as a serious adverse event in approximately 1.5% of patients in both treatment arms. Correct volume or salt depletion prior to administration of SACUBITRIL + VALSARTAN or start at a lower dose. If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue SACUBITRIL + VALSARTAN. Permanent discontinuation of therapy is usually not required.

● Impaired Renal Function

Because of inhibiting the renin-angiotensin-aldosterone system (RAAS), decreases in renal function may be anticipated in susceptible individuals treated with SACUBITRIL + VALSARTAN. In the double-blind period of PARADIGM-HF, 5% of patients in both the SACUBITRIL + VALSARTAN and enalapril groups reported renal failure as an adverse event. In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and down-titrate or interrupt SACUBITRIL + VALSARTAN in patients who develop a clinically significant decrease in renal function. As with all drugs that affect the RAAS, SACUBITRIL + VALSARTAN may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function.

● Hyperkalemia

Through its actions on the RAAS, hyperkalemia may occur with SACUBITRIL + VALSARTAN. In the double-blind period of PARADIGM-HF, 12% of patients treated with SACUBITRIL + VALSARTAN and 14% of patients treated with enalapril reported hyperkalemia as an adverse event. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of SACUBITRIL + VALSARTAN may be required.

There is no sufficient scientific evidence traceable regarding the use and safety of Azmarda 200 in concurrent use with alcohol.

There is no information regarding its presence in human milk, the effects on the breastfed infant, or the effects on milk production. Sacubitril/valsartan is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with Azmarda 200.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue Azmarda 200 as soon as possible.

The adverse reactions related to Azmarda 200 can be categorized as

Common Adverse effects

Hypotension, Endocrine & metabolic: Hyperkalemia, Increased serum creatinine, Orthostatic hypotension, decreased hematocrit, decreased hemoglobin, Angioedema, Dizziness, falling, Acute kidney injury, renal failure syndrome, Cough.

Rare Adverse effects

Pruritus, skin rash and Anaphylaxis etc.

The clinically relevant drug interactions of Azmarda 200 is briefly summarized here

● Dual Blockade of The Renin-Angiotensin-Aldosterone System

Concomitant use of SACUBITRIL + VALSARTAN with an ACE inhibitor is contraindicated because of the increased risk of angioedema. Avoid use of SACUBITRIL + VALSARTAN with an ARB, because SACUBITRIL + VALSARTAN contains the angiotensin II receptor blocker valsartan. The concomitant use of SACUBITRIL + VALSARTAN with aliskiren is contraindicated in patients with diabetes. Avoid use with aliskiren in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).

● Potassium-Sparing Diuretics

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

● Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of NSAIDs, including COX-2 inhibitors, with SACUBITRIL + VALSARTAN may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically.

● Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with SACUBITRIL + VALSARTAN.

The common side effects of Azmarda 200 which contains Sacubitril 97 mg+ Valsartan 103 mg includes the following

Common

●Cough, extreme tiredness.

Rare

●Rash, itching, swelling of the lips, tongue, face, or throat, difficulty breathing.

Pregnancy

SACUBITRIL + VALSARTAN can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. In animal reproduction studies, SACUBITRIL + VALSARTAN treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits. When pregnancy is detected, consider alternative drug treatment, and discontinue SACUBITRIL + VALSARTAN. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Nursing Mothers

There is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. Sacubitril/valsartan is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with SACUBITRIL + VALSARTAN.

Pediatric Use

The safety and effectiveness of SACUBITRIL + VALSARTAN in pediatric heart failure patients 1 to < 18 years old are supported by the reduction from baseline to 12 weeks in NT-proBNP in a randomized, double-blind clinical study. The analysis of NT-proBNP included 90 patients aged 6 to 18 years and 20 patients aged 1 to 6 years. Safety and effectiveness have not been established in pediatric patients less than 1 year of age.

Geriatric Use

No relevant pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Azmarda 200

Limited data are available about overdosage in human subjects with SACUBITRIL + VALSARTAN. In healthy volunteers, a single dose of SACUBITRIL + VALSARTAN 583 mg sacubitril/617 mg valsartan and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of SACUBITRIL + VALSARTAN. Symptomatic treatment should be provided. SACUBITRIL + VALSARTAN is unlikely to be removed by hemodialysis because of high protein binding.

Azmarda 200 contains Sacubitril 97 mg+ Valsartan 103 mg

Pharmacodynamics

The pharmacodynamic effects of SACUBITRIL + VALSARTAN was evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of SACUBITRIL + VALSARTAN resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, SACUBITRIL + VALSARTAN significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. SACUBITRIL + VALSARTAN also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, SACUBITRIL + VALSARTAN decreased plasma NTproBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril. In PARAMOUNT, a randomized, double-blind, 36-week study in patients with heart failure with LVEF ≥ 45% comparing 97/103 mg of SACUBITRIL + VALSARTAN (n=149) to 160 mg of valsartan (n =152) twice-daily, SACUBITRIL + VALSARTAN decreased NT-proBNP by 17% while valsartan increased NT-proBNP by 8% at Week 12 (p = 0.005). In PARAGON-HF, SACUBITRIL + VALSARTAN decreased NT-proBNP by 24% (Week 16) and 19% (Week 48) compared to 6% and 3% reductions on valsartan, respectively.

QT Prolongation: 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 repolarization.

Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of SACUBITRIL + VALSARTAN 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ1-38 compared to placebo; there were no changes in concentrations of CSF Aβ1-40 or CSF Aβ1-42. The clinical relevance of this finding is unknown.

Blood Pressure: Addition of a 50 mg single dose of sildenafil to SACUBITRIL + VALSARTAN at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (~ 5/4 mmHg, systolic/diastolic BP) compared to administration of SACUBITRIL + VALSARTAN alone. Co-administration of SACUBITRIL + VALSARTAN did not significantly alter the BP effect of intravenous nitroglycerin.

Pharmacokinetics

Absorption

Following oral administration, SACUBITRIL + VALSARTAN dissociates into sacubitril and valsartan. Sacubitril is further metabolized to LBQ657. The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5 hours, 2 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril is estimated to be ≥ 60%. The valsartan in SACUBITRIL + VALSARTAN is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in SACUBITRIL + VALSARTAN is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively. Following twice-daily dosing of SACUBITRIL + VALSARTAN, steady state levels of sacubitril, LBQ657, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold. SACUBITRIL + VALSARTAN administration with food has no clinically significant effect on the systemic exposures of sacubitril, LBQ657, or valsartan. Although there is a decrease in exposure to valsartan when SACUBITRIL + VALSARTAN is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect. SACUBITRIL + VALSARTAN can therefore be administered with or without food.

Distribution

Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94% to 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 volumes of distribution of valsartan and sacubitril are 75 and 103 L, respectively.

Metabolism

Sacubitril is readily converted to LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent. Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (< 10%).

Excretion

Following oral administration, 52% to 68% of sacubitril (primarily as LBQ657) and ~ 13% of valsartan and its metabolites are excreted in urine; 37% to 48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces. Sacubitril, LBQ657, and valsartan are eliminated from plasma with a mean elimination half-life (T1/2) of approximately 1.4 hours, 11.5 hours, and 9.9 hours, respectively.