Azmarda

Azmarda contains a salt complex of the anionic forms of Azmarda, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5 respectively. Following oral administration, Azmarda dissociates into Sacubitril (Azmarda) (which is further metabolized to LBQ657) and Valsartan (Azmarda).

Azmarda film-coated tablets contains 50 mg (Sacubitril (Azmarda) 24.3 mg/Valsartan (Azmarda) 25.7 mg)^*.

Azmarda film-coated tablets contains 100 mg (Sacubitril (Azmarda) 48.6 mg/Valsartan (Azmarda) 51.4 mg)^*.

Azmarda film-coated tablets contains 200 mg (Sacubitril (Azmarda) 97.2 mg/Valsartan (Azmarda) 102.8 mg)^*.

^*Certain dosage strengths may not be available in all countries.

Excipients/Inactive Ingredients: Microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate (vegetable origin), talc and colloidal silicon dioxide.

Excipients of Film-Coating: Hypromellose, titanium dioxide (E171), Macrogol 4000, talc, iron oxide red (E172).

For 50 and 200 mg: Iron oxide black (E172). For 100 mg: Iron oxide yellow (E172).

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

Azmarda is administered in combination with other heart failure therapies (eg, beta blockers, diuretics and mineralocorticoid antagonists) as appropriate, in place of an ACE inhibitor or ARB.

Sacubitril (Azmarda) is a blood pressure medicine. It works by increasing the levels of certain proteins in the body that can dilate (widen) blood vessels. This helps lower blood pressure by reducing sodium levels.

Valsartan (Azmarda) is an angiotensin II receptor blocker (sometimes called an ARB). Valsartan (Azmarda) keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Azmarda is a combination medicine used in certain people with chronic heart failure. This medicine helps lower the risk of needing to be hospitalized when symptoms get worse, and helps lower the risk of death from heart failure.

Azmarda is usually given together with other blood pressure medications.

Azmarda may also be used for purposes not listed in this medication guide.

Dosing

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

The recommended starting dose of Azmarda is 49/51 mg twice-daily.

Double the dose of Azmarda after 2 to 4 weeks to the target maintenance dose of 97/103 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

A starting dose of 24/26 mg twice-daily is recommended for patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents. Double the dose of Azmarda every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.

Dose Adjustment For Severe Renal Impairment

A starting dose of 24/26 mg twice-daily is recommended for patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). Double the dose of Azmarda every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.

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

Dose Adjustment For Hepatic Impairment

A starting dose of 24/26 mg twice-daily is recommended for patients with moderate hepatic impairment (Child-Pugh B classification). Double the dose of Azmarda every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.

No starting dose adjustment is needed for mild hepatic impairment.

Use in patients with severe hepatic impairment is not recommended.

How supplied

Dosage Forms And Strengths

Azmarda is supplied as unscored, ovaloid, film-coated tablets in the following strengths:

Azmarda 24/26 mg, (Sacubitril (Azmarda) 24 mg and Valsartan (Azmarda) 26 mg) are violet white and debossed with “NVR” on one side and “LZ” on the other side.

Azmarda 49/51 mg, (Sacubitril (Azmarda) 49 mg and Valsartan (Azmarda) 51 mg) are pale yellow and debossed with “NVR” on one side and “L1” on the other side.

Azmarda 97/103 mg, (Sacubitril (Azmarda) 97 mg and Valsartan (Azmarda) 103 mg) are light pink and debossed with “NVR” on one side and “L11” on the other side.

Storage And Handling

Azmarda (Azmarda) is available as unscored, ovaloid, biconvex, film-coated tablets, containing 24 mg of Sacubitril (Azmarda) and 26 mg of Valsartan (Azmarda); 49 mg of Sacubitril (Azmarda) and 51 mg of Valsartan (Azmarda); and 97 mg of Sacubitril (Azmarda) and 103 mg of Valsartan (Azmarda). All strengths are packaged in bottles and unit dose blister packages (10 strips of 10 tablets) as described below.

Store at 25°C (77°F) with excursions between 15°C and 30°C (59°F and 86°F) permitted. Protect from moisture.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: Aug 2015

See also:
What is the most important information I should know about Azmarda?

Hypersensitivity to Sacubitril (Azmarda), Valsartan (Azmarda), or any component of the formulation; history of angioedema related to previous ACE inhibitor or ARB therapy; concomitant use or use within 36 hours of ACE inhibitors; concomitant use of aliskiren in patients with diabetes

According to the ACC/AHA/HFSA guidelines, the use of Azmarda is contraindicated in patients with a history of angioedema, regardless of cause (ACC/AHA/HFSA [Yancy 2016]).

Canadian labeling: Additional contraindications (not in US labeling): Recent symptomatic hypotension prior to initiation of treatment with Azmarda; concomitant use of aliskiren in patients with moderate to severe renal impairment (eGFR <60 mL/minute/1.73 m); pregnancy; breastfeeding.

This product is used to treat certain types of heart failure. It may help you live longer and lower your chance of having to go to the hospital for heart failure. This product contains 2 medications: Azmarda. Sacubitril (Azmarda) belongs to a class of drugs called neprilysin inhibitors and Valsartan (Azmarda) belongs to a class of drugs called angiotensin receptor blockers (ARBs). They work by relaxing blood vessels so that blood can flow more easily, which makes it easier for your heart to pump blood to your body.

How to use Azmarda

Read the Patient Information Leaflet if available from your pharmacist before you start taking this product and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this product by mouth with or without food as directed by your doctor, usually twice daily. The dosage is based on your medical condition and response to treatment.

To reduce your risk of side effects, your doctor may direct you to start this product at a low dose and gradually increase your dose. Follow your doctor's instructions carefully.

This product should not be taken with ACE inhibitors (such as captopril, enalapril) since your risk of serious side effects may increase. Do not take this product for at least 36 hours before or after taking an ACE inhibitor. Consult your doctor or pharmacist for more details.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

Tell your doctor if you do not get better or if you get worse.

See also:
What other drugs will affect Azmarda?

Interactions Resulting in a Contraindication: ACE Inhibitors: The concomitant use of Azmarda with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. Azmarda 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 Azmarda.

Aliskiren: The concomitant use of Azmarda 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 Azmarda with direct renin inhibitors such as aliskiren is not recommended. Combination of Azmarda 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: Azmarda contains Valsartan (Azmarda), and therefore should not be co-administered with another ARB containing product.

Interactions Requiring Precautions: OATP1B1 and OATP1B3 Substrates eg, Statins: In vitro data indicate that Sacubitril (Azmarda) inhibits OATP1B1 and OATP1B3 transporters. Azmarda may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of Azmarda 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 when coadministering Azmarda with statins.

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

Potassium: Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (eg, 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 Azmarda is co-administered with these agents.

Nonsteroidal 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 Azmarda 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 Azmarda 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. Interactions between Azmarda 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 Azmarda and furosemide had no effect on the pharmacokinetics of Azmarda but reduced C_max 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 Azmarda.

Nitrates, e.g. Nitroglycerin: There was no drug-drug interaction between Azmarda and intravenously administered nitroglycerin with regard to blood pressure reduction. Co-administration of nitroglycerin and Azmarda 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 Azmarda 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 (Azmarda) (LBQ657) and Valsartan (Azmarda) are OATP1B1, OATP1B3, OAT1 and OAT3 substrates; Valsartan (Azmarda) is also a MRP2 substrate. Therefore, co-administration of Azmarda with inhibitors of OATP1B1, OATP1B3, OAT3 (eg, rifampicin, ciclosporin), OAT1 (eg, tenofovir, cidofovir) or MRP2 (eg, ritonavir) may increase the systemic exposure of LBQ657 or Valsartan (Azmarda). Appropriate care should be exercised when initiating or ending concomitant treatment with such medicinal products.

Metformin: Co-administration of Azmarda with metformin reduced both C_max and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with Azmarda 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 Azmarda was coadministered 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 Azmarda via CYP450 enzymes. Azmarda does not induce or inhibit CYP450 enzymes.

See also:
What are the possible side effects of Azmarda?

Clinically significant adverse reactions that appear in other sections of the labeling include:

• Angioedema
• Hypotension
• Impaired Renal Function
• Hyperkalemia

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the PARADIGM-HF trial, subjects were required to complete sequential enalapril and Azmarda run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing Azmarda and enalapril. During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%). During the Azmarda run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%). Because of this run-in design, the adverse reaction rates described below are lower than expected in practice.

In the double-blind period, safety was evaluated in 4,203 patients treated with Azmarda and 4,229 treated with enalapril. In PARADIGM-HF, patients randomized to Azmarda 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 because of an adverse event during the double-blind period occurred in 450 (10.7%) of Azmarda treated patients and 516 (12.2%) of patients receiving enalapril.

Adverse reactions occurring at an incidence of ≥ 5% in patients who were treated with Azmarda in the double-blind period are shown in Table 1.

Table 1: Adverse Reactions Reported in ≥ 5% of Patients Treated with Azmarda in the Double-Blind Period

In the PARADIGM-HF trial, the incidence of angioedema was 0.1% in both the enalapril and Azmarda run-in periods. In the double-blind period, the incidence of angioedema was higher in patients treated with Azmarda than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patients was 2.4% with Azmarda and 0.5% with enalapril.

Orthostasis was reported in 2.1% of patients treated with Azmarda compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF. Falls were reported in 1.9% of patients treated with Azmarda compared to 1.3% of patients treated with enalapril.

Laboratory Abnormalities

Hemoglobin and Hematocrit

Decreases in hemoglobin/hematocrit of > 20% were observed in approximately 5% of both Azmarda- and enalapril-treated patients in the double-blind period in PARADIGM-HF.

Serum Creatinine

Increases in serum creatinine of > 50% were observed in 1.4% of patients in the enalapril run-in period and 2.2% of patients in the Azmarda run-in period. During the double-blind period, approximately 16% of both Azmarda- and enalapril-treated patients had increases in serum creatinine of > 50%.

Serum Potassium

Potassium concentrations > 5.5 mEq/L were observed in approximately 4% of patients in both the enalapril and Azmarda run-in periods. During the double-blind period, approximately 16% of both Azmarda- and enalapril-treated patients had potassium concentrations > 5.5 mEq/L.