Reasanz (Concentrate) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Pharma Stein AG (Switzerland)

ATC Code

C01DX21 (Serelaxin)

Active Substance

Serelaxin (Rec.INN registered by WHO)

Dosage Form

Reasanz

Concentrate for solution for infusion 3.5 mg/3.5 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion from colorless to brownish-yellow, transparent.

Excipients: sodium acetate trihydrate – 9.52 mg, water for injections – up to 3.5 ml, hydrochloric acid solution 1M – to pH 5, sodium hydroxide solution 1M – to pH 5.

3.5 ml – vials of colorless glass (1) – cardboard packs.

Clinical-Pharmacological Group

Peripheral vasodilator

Pharmacotherapeutic Group

Vasodilating agent

Pharmacological Action

Peripheral vasodilator. Serelaxin is a recombinant molecule identical to the native human relaxin-2 peptide hormone. In the renal and systemic circulation, as well as in the kidney epithelium, relaxin-2 binds to the specific G-protein-coupled receptor RXFP1. Binding to this receptor, relaxin-2 stimulates rapid signaling pathways leading to nitric oxide synthase activation, as well as slower signaling pathways leading to stimulation of endothelin type B receptors and expression of angiogenic growth factors and matrix metalloproteinases (gelatinases). These pathways cause relaxation of the systemic and renal blood vessel walls, leading to a decrease in systemic vascular resistance and an increase in cardiac output. Furthermore, according to experimental studies, Serelaxin has a beneficial effect on connective tissue remodeling processes, resulting in reduced myocardial hypertrophy and fibrosis. The cardioprotective effect of the drug is also likely mediated by the prevention of inflammation and oxidative stress.

The vasoactive properties of relaxin-2 are confirmed by studies of vascular adaptation in women during pregnancy. It is believed that the temporary increase in plasma relaxin-2 concentration in the first trimester of pregnancy, reaching 6 ng/ml, causes a decrease in systemic vascular resistance and an increase in cardiac output, ensuring adequate oxygen transport to the fetoplacental unit.

The therapeutic use of serelaxin in heart failure is based on the fact that achieving a serum serelaxin concentration of about 18 ng/ml improves ventriculo-arterial coupling, vasorelaxation processes, blood flow, and organ perfusion. Available data on increased production of cardiac relaxin-2 and its elevated concentration in the bloodstream in patients with chronic heart failure indicate a natural compensatory role of relaxin-2 in heart failure.

In patients with compensated heart failure receiving Serelaxin at doses from 10 to 960 mcg/kg/day in an open-label clinical study, there was a trend towards improvement in hemodynamic parameters (specifically, a decrease in pulmonary artery wedge pressure, a decrease in systemic vascular resistance, and an increase in cardiac index), as well as improvement in renal function parameters (decrease in serum creatinine, blood urea nitrogen, and uric acid).

In a clinical study in patients with acute heart failure (AHF) hospitalized with dyspnea at rest or with minimal exertion, systolic BP above 125 mm Hg, and mild or moderate renal impairment (estimated GFR — 30-75 ml/min/1.73 m²), statistically significant relief of dyspnea was observed with serelaxin use, along with a trend towards reduction in signs and symptoms of heart failure, specifically a decrease in the frequency of worsening heart failure, reduction in manifestations of circulatory disorders in the pulmonary and systemic circulation (including pulmonary edema, pulmonary rales, jugular venous distension and pathological pulsation), and a significant reduction in the length of hospital stay.

The reduction in the severity of signs and symptoms of acute heart failure was accompanied by a significant reduction in the need for standard AHF treatments. The total dose of intravenous diuretics administered within the first 5 days after the start of serelaxin infusion was significantly lower than in the placebo group. The proportion of patients with worsening signs and/or symptoms of heart failure who required intensification of intravenous heart failure therapy or mechanical ventilation or circulatory support measures by day 5 after infusion was significantly lower in the serelaxin group compared to the placebo group.

The study showed that serelaxin use reduced the risk of cardiovascular mortality by 37%, with the difference in cardiovascular mortality evident as early as day 5 after infusion and observed regardless of gender or age.

Pharmacokinetics

Distribution

Steady-state serum concentration (C_ss) was achieved within 4-6 hours after the start of IV infusion. In healthy volunteers and patients with heart failure receiving Serelaxin as an IV infusion, the AUC and total clearance of serelaxin at steady state were approximately the same.

In healthy volunteers, the steady-state volume of distribution (V_d) after IV infusion of serelaxin was 0.267-0.339 L/kg, and in patients with acute heart failure — 0.593 L/kg.

The AUC and C_ss of serelaxin increased proportionally with the dose. The values of total clearance and steady-state V_d remained constant over the dose range of 10-960 mcg/kg/day.

Metabolism

Specific studies on the metabolism of serelaxin have not been conducted. Its primary metabolic pathway is presumably catabolism by peptidases and proteases in various body tissues, including the liver and kidneys. It is assumed that in vivo, Serelaxin breaks down into small peptides and amino acids and is utilized via the same pathways as endogenous human relaxin-2.

Elimination

Serelaxin is rapidly eliminated from the body. The half-life (T_1/2) after the end of IV administration ranges from 7 to 15.9 hours. According to clinical studies, the plasma clearance of serelaxin ranges from 82 to 229 ml/kg/h.

Pharmacokinetics in special patient groups

Patient age does not affect the pharmacokinetics of serelaxin.

The influence of hepatic impairment on the pharmacokinetics of serelaxin was studied in patients with mild, moderate, and severe hepatic impairment, assessed by Child-Pugh score (from 5 to 15 points), compared to healthy volunteers with normal liver function. Hepatic impairment did not affect the pharmacokinetics of serelaxin.

No data were obtained indicating that mild or moderate renal impairment affects the clearance of serelaxin. Studies of serelaxin in patients with severe renal impairment have not been conducted.

No differences in serelaxin clearance between men and women were found.

No differences in serelaxin clearance between ethnic subgroups were found.

According to population pharmacokinetic analysis, no dependence of serelaxin clearance on body mass index was identified.

Indications

• Acute heart failure in patients with normal or elevated BP concomitantly with standard therapy for acute heart failure, including "loop" diuretics.

ICD codes

Dosage Regimen

Reasanz is intended for use in a hospital setting, for intravenous administration only.

The drug should be diluted immediately before use.

The contents of the vial are for single use only.

Before using Reasanz, systolic BP should be stabilized at a level above 125 mm Hg.

The dose of Reasanz should be selected based on the patient’s body weight (see Table 1). The drug should be administered as a continuous IV infusion over 48 hours. The recommended dose is 30 mcg/kg/day. Two consecutive IV infusions (24 hours each) should be administered at a constant infusion rate of 10 ml/h.

Table 1. Volume of Reasanz, concentrate for solution for infusion, to be diluted in 250 ml of 5% sterile dextrose (glucose) solution for the preparation of one 24-hour IV infusion

Dose adjustment

BP should be monitored regularly during Reasanz administration. If the systolic BP level decreases by more than 40 mm Hg from baseline but remains above 100 mm Hg, or if systolic BP decreases below 100 mm Hg, the following measures should be taken (see Table 2).

Table 2.

* These BP values must be confirmed by two measurements taken 15 minutes apart.

Use in patients with severe renal impairment (GFR <30 ml/min/1.73 m²) has not been studied. The drug may be used only if the expected benefit outweighs the potential risk. In patients with mild and moderate renal impairment (GFR ≥30 and ≤75 ml/min/1.73 m²), no dose adjustment is required when using the drug.

In patients with hepatic impairment, no dose adjustment is required.

No change in dosage regimen based on gender, age, or ethnicity is required.

The safety and efficacy of Reasanz in children and adolescents under 18 years of age have not been established.

Instructions for use

Preparation of the infusion solution should be performed under aseptic conditions.

Reasanz should not be mixed with any other medicinal products.

1. Using a sterile syringe, draw up the required amount of concentrate for solution for infusion, based on the patient’s body weight (see Table 3), and inject it into an infusion container containing 250 ml of 5% sterile dextrose (glucose) solution.

Table 3. Volume of Reasanz, concentrate for solution for infusion, to be drawn up using a sterile syringe

2. Mix the contents of the infusion container by gently rocking it from side to side. Do not shake the infusion container.

3. To avoid microbiological contamination, the prepared solution should be used no later than 4 hours after preparation (when stored at room temperature (20-25°C (68-77°F))).

4. Prepare an infusion set with a separate IV catheter (a multi-lumen catheter may be used).

5. The use of infusion filters with 0.2 micron pores is recommended.

6. Flush the infusion set and infusion filter with the prepared Reasanz solution (15 ml) from the IV infusion container.

7. Start the IV infusion of the drug by setting the infusion rate to 10 ml/h for 24 hours.

8. Prepare the second IV infusion container for use in the same manner shortly before the end of the first IV infusion.

9. Start the second 24-hour IV infusion immediately after the end of the first one

• If no dose adjustment of the drug was made during the first IV infusion, start the second IV infusion by setting the infusion rate to 10 ml/h for 24 hours;
• If during the first IV infusion the infusion rate was reduced from 10 ml/h to 5 ml/h, start the second IV infusion by setting the infusion rate to 5 ml/h for 24 hours.

Unused solution in the vial or infusion system should be discarded after 24 hours.

Exposure of the prepared solution to direct sunlight should be avoided.

Unused drug or waste should be disposed of in accordance with local requirements.

Adverse Reactions

The most frequent adverse reaction with the drug was decreased BP (3.3%).

Predominantly adverse events of mild and moderate severity were noted. In a small number of patients receiving Reasanz (5.4%), the IV infusion of the drug was discontinued due to the development of adverse events.

Below are the adverse events observed with the use of the drug in clinical studies. Adverse events are distributed according to frequency of occurrence. The following criteria were used to assess frequency (according to WHO classification): very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), including isolated reports.

Cardiovascular system common – marked decrease in BP.

Changes in laboratory parameters

In controlled clinical studies, no clinically significant changes in laboratory parameters (serum electrolytes, biochemical parameters, liver function impairment, plasma glucose concentration) associated with the use of Reasanz were observed. Hypokalemia developed in 7% of patients in the serelaxin group and in 6% of patients in the placebo group, but no differences in serum potassium levels were identified.

In clinical studies with the drug, a decrease in hemoglobin, red blood cell count, and hematocrit by more than 20% at 2 weeks after the start of treatment was observed in the Reasanz group in 1.5%, 1.1%, and 1.6% of patients, respectively, and in the placebo group in 0.6%, 0.6%, and 0.6% of patients, respectively.

Episodes of decreased systolic BP requiring dose adjustment

In clinical studies with the drug, episodes of confirmed decreased systolic BP (by more than 40 mm Hg from baseline or to a level below 100 mm Hg) were observed in 29.4% of patients treated with Reasanz, compared to 18.1% of patients receiving placebo. Most of these adverse events occurred between 13 and 17 hours after the start of infusion. In 84.4% of cases, these adverse events resolved either after adjustment of the infusion rate or after discontinuation of the drug. Only 12% of such adverse events noted in the Reasanz group required additional treatment: in most cases, infusion therapy was used, and in some cases, the use of cardiotonic drugs or mechanical circulatory support measures was required.

Contraindications

• Shock of various etiologies;
• Left ventricular outflow tract obstruction (including severe aortic stenosis, hypertrophic obstructive cardiomyopathy);
• Childhood and adolescence under 18 years of age (due to lack of efficacy and safety data);
• Hypersensitivity to serelaxin or any other components included in the drug.

With caution, the drug should be used concomitantly with vasodilating and/or antihypertensive agents.

In patients with severe renal impairment (estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m²), use is possible only if the expected benefit outweighs the potential risk.

Use in Pregnancy and Lactation

In terms of amino acid sequence and structure, Serelaxin is identical to the human peptide hormone relaxin-2, the concentration of which in the systemic circulation increases significantly during pregnancy compared to its concentration during the menstrual cycle, reaches a maximum in the first trimester of pregnancy, and remains elevated in the second and third trimesters of pregnancy. Furthermore, the hormone relaxin-2 is present in breast milk during breastfeeding.

Due to the lack of clinical data on the use of Reasanz in pregnant women with acute heart failure, as well as in women during lactation, the drug can be used during pregnancy and breastfeeding only if the intended benefit to the mother outweighs the potential risk to the fetus and child.

Fertility

There are no data on the effect of Reasanz on fertility.

Use in Hepatic Impairment

In patients with hepatic impairment, no dose adjustment is required.

Use in Renal Impairment

Use in patients with severe renal impairment (GFR <30 ml/min/1.73 m²) has not been studied. The drug may be used only if the expected benefit outweighs the potential risk.

In patients with mild and moderate renal impairment (GFR ≥30 and ≤75 ml/min/1.73 m²) no dose adjustment is required when using the drug.

Pediatric Use

The drug Reasanz is not recommended for use in children and adolescents under 18 years of age (due to the lack of data on efficacy and safety).

Geriatric Use

No dose adjustment based on age is required.

Special Precautions

Episodes of decreased blood pressure

Due to the risk of a marked decrease in blood pressure during the administration of Reasanz, blood pressure should be regularly monitored.

In clinical studies, cases of decreased blood pressure were observed during intravenous administration of Reasanz, some of which were recorded as cases of marked blood pressure decrease. In most cases, these phenomena were not accompanied by clinical manifestations.

If systolic blood pressure decreases by more than 40 mm Hg from the baseline value but remains above 100 mm Hg, the rate of intravenous infusion of Reasanz should be reduced by 50%.

Treatment with Reasanz should be discontinued if the patient’s systolic blood pressure decreases to a level below 100 mm Hg.

In accordance with clinical guidelines, caution should be exercised when using Reasanz concomitantly with vasodilating and/or antihypertensive agents.

Renal impairment

Due to the lack of clinical data on the use of Reasanz in patients with severe renal impairment (estimated GFR <30 ml/min/1.73 m²), the use of the drug should be considered only if the anticipated benefit of treatment outweighs the potential risk.

Repeated intravenous administration

Repeated intravenous administration of Reasanz to patients with acute heart failure has not been studied.

Immunogenicity

Antibodies to serelaxin were detected in only 1 patient with acute heart failure who received Serelaxin as a continuous intravenous infusion for up to 48 hours; the antibodies did not have neutralizing activity.

In clinical studies in other patient populations where Serelaxin was administered as a continuous subcutaneous infusion for at least 2 weeks, antibodies to serelaxin were detected in 43% of patients. In patients with antibodies to serelaxin, the C_ss of serelaxin was higher than in patients without antibodies (by 1.8-3.7 times), but this was not reflected in the safety profile of serelaxin. According to in vitro studies, the antibodies did not have neutralizing activity.

Effect on the ability to drive vehicles and operate machinery

There are no data on the effect of the drug on the ability to drive vehicles and perform other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

No cases of overdose have been reported.

Symptoms the most likely manifestation of overdose is an excessive decrease in systolic blood pressure.

Treatment symptomatic and supportive therapy should be administered (infusion therapy, and in some cases, the use of cardiotonic drugs or mechanical methods of circulatory support).

Drug Interactions

No specific studies on the interaction of serelaxin with other drugs have been conducted.

In clinical studies, no clinically significant effect on the clearance of serelaxin was observed when serelaxin was used concomitantly with other drugs. These drugs include digoxin, ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, potassium-sparing diuretic drugs (aldosterone antagonists), slow calcium channel blockers, vasodilating drugs, non-glycoside cardiotonic agents (inodilators).

No separate studies evaluating the effect of serelaxin on the pharmacokinetics of other drugs have been conducted. There are no data indicating an interaction of serelaxin with cytochrome P450 isoenzymes, therefore the potential for serelaxin to be involved in drug interactions appears to be low.

Incompatibility

Due to the lack of specific compatibility studies, this drug should not be mixed with other drugs in the same infusion system and/or container and should not be administered through the same intravenous catheter with other drugs.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.