Ringer malate

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RINGER MALATE (RINGER MALATE)

Composition:

Active substances: sodium chloride, potassium chloride, magnesium chloride hexahydrate, calcium chloride dihydrate, sodium acetate trihydrate, L-malic acid;

1 ml of solution contains sodium chloride 6.80 mg; potassium chloride 0.30 mg; magnesium chloride hexahydrate 0.20 mg (calculated as magnesium chloride 0.094 mg); calcium chloride dihydrate 0.37 mg; sodium acetate trihydrate 3.27 mg (calculated as sodium acetate 1.971 mg); L-malic acid 0.67 mg;

Electrolyte concentrations: sodium — 145.0 mmol/l; potassium — 4.0 mmol/l; magnesium — 1.0 mmol/l; calcium — 2.5 mmol/l; chlorides — 127.0 mmol/l; acetates — 24.0 mmol/l; malates — 5.0 mmol/l;

Excipients: sodium hydroxide*, water for injections.

* 2 M sodium hydroxide is used to adjust the pH of the preparation to the specified range.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution. Theoretical osmolarity 309 mosmol/l; pH 5.1–5.9.

Pharmacotherapeutic group. Plasma substitutes and perfusion solutions. Solutions for intravenous administration. Solutions used for correction of electrolyte balance disorders. Electrolytes.

ATC code B05B B01.

Pharmacological Properties

Pharmacodynamics

This medicinal product is an isotonic electrolyte solution in which electrolyte concentrations correspond to their plasma concentrations. Ringer Malate is used to correct extracellular fluid losses (i.e., losses of water and electrolytes in proportional amounts). The aim of administering the solution is to restore and maintain normal osmotic conditions in the extracellular and intracellular spaces.

The anion composition of the product represents a balanced combination of chlorides, acetates, and malates, which helps prevent the development of metabolic acidosis.

Pharmacokinetics

Absorption

Since Ringer Malate is administered intravenously, its bioavailability is 100%.

Distribution and Elimination

Sodium and chloride are distributed mainly in the extracellular space, whereas potassium, magnesium, and calcium are distributed predominantly intracellularly. Sodium, potassium, magnesium, and chloride are primarily excreted by the kidneys, but small amounts may also be excreted through the skin and gastrointestinal tract. Calcium is excreted in urine and via intraintestinal secretion in approximately equal amounts.

During infusion of acetates and malates, their plasma levels rise until equilibrium levels are reached. After infusion is discontinued, anion concentrations rapidly decrease. Urinary excretion of acetates and malates increases during infusion; however, their metabolism in body tissues is so rapid that only negligible fractions are detected in urine.

Clinical Characteristics

Indications

The medicinal product Ringer Malate is used for replacement of extracellular fluid losses in isotonic dehydration and in the presence of, or threat of, acidosis.

Contraindications

• Hyperhydration.
• Severe congestive heart failure.
• Renal failure with oliguria or anuria.
• Severe generalized edema.
• Hyperkalemia.
• Hypercalcemia.
• Metabolic alkalosis.

Interaction with other medicinal products and other forms of interactions

Sodium, potassium, calcium, and magnesium in Ringer Malate are present at the same concentrations as in blood plasma. Therefore, when used according to the recommended indications and contraindications, Ringer Malate does not lead to increased plasma concentrations of these electrolytes. However, if plasma concentration of any electrolyte increases for other reasons, the interactions described below should be considered.

Medicinal products causing sodium retention

The use of corticosteroids/steroids and carbenoxolone may lead to sodium and water retention (with edema and arterial hypertension).

Medicinal products interacting with potassium

Suxamethonium, potassium-sparing diuretics (amiloride, spironolactone, triamterene, alone or in combination), tacrolimus, and cyclosporine may increase plasma potassium concentration and lead to potentially fatal hyperkalemia, especially in the presence of renal impairment, which enhances the hyperkalemic effect.

Medicinal products interacting with calcium

The effect of digitalis glycosides (cardiac glycosides) may be enhanced during hypercalcemia, leading to severe or fatal cardiac arrhythmias.

Vitamin D may cause hypercalcemia.

Special Precautions for Use

Large-volume infusions may be administered to patients with mild to moderate cardiac or respiratory insufficiency under careful monitoring of the patient's condition (for use in more severe conditions, see section "Contraindications").

Ringer Malate should be prescribed with special caution in patients with the following conditions:

• Hypernatremia;
• Hyperchloremia;
• Renal insufficiency;
• Hyperkalemia or conditions that may lead to hyperkalemia;
• Hypertonic dehydration, arterial hypertension, eclampsia or risk of its occurrence, aldosteronism, or other conditions in patients undergoing therapy (e.g., corticosteroids/steroids) associated with sodium retention (see section "Interaction with other medicinal products and other forms of interaction");
• Conditions requiring restriction of sodium intake, such as mild to moderate heart failure, peripheral edema, pulmonary edema, or extracellular hyperhydration (for use in more severe conditions, see section "Contraindications");
• Conditions requiring restriction of calcium intake, such as sarcoidosis.

Solutions containing potassium salts should be administered cautiously to patients with heart disease or conditions that may lead to hyperkalemia, such as renal insufficiency or adrenal cortical insufficiency, acute dehydration, or extensive tissue destruction in severe burns.

Due to the presence of calcium:

• Caution should be exercised during intravenous administration to avoid extravasation;
• When blood transfusion is performed simultaneously, this solution must not be administered through the same infusion system as blood components.

Solutions containing anions that are metabolized should be administered cautiously to patients with respiratory disorders.

Clinical monitoring should include serum ionogram, fluid balance, and pH.

In case of prolonged parenteral therapy, appropriate nutritional support should be provided to the patient.

Sodium and Potassium Content

Ringer Malate contains 72.5 mmol (or 1666.8 mg) of sodium and 2 mmol (or 78.2 mg) of potassium per 500 ml of solution.

Use during Pregnancy or Breastfeeding

There are no data on the use of Ringer Malate in pregnant or breastfeeding women. Within the framework of recommended indications, risk is not expected if the volume of infused solution, electrolyte levels, and acid-base parameters are carefully monitored.

Ringer Malate should be used cautiously in pregnant women with toxemia.

It should be used with caution in pregnancy-induced hypertension (preeclampsia).

Ability to Influence Reaction Rate when Operating Vehicles or Other Machinery

Ringer Malate does not affect the ability to drive vehicles or operate other machinery.

Method of Administration and Dosage

Dosage

The dosage depends on the patient's age, body weight, laboratory parameters, clinical condition, and concomitant therapy.

Children over 12 years of age, adults and elderly patients

Volume of infused solution: from 500 ml to 3 l per day (corresponding to 1 mmol to 6 mmol of sodium per kg of body weight per day and 0.03 mmol to 0.17 mmol of potassium per kg of body weight per day).

Children aged 28 days to 12 years

Volume of infused solution: from 20 ml to 100 ml per day (corresponding to 3 mmol to 14 mmol of sodium per kg of body weight per day and 0.08 mmol to 0.40 mmol of potassium per kg of body weight per day).

Infusion Rate

The maximum infusion rate depends on the patient's fluid and electrolyte requirements, body weight, laboratory parameters and clinical condition.

The average infusion rate for children is 5 ml/kg/hour, but varies depending on age:

infants (children aged 28 days to 1 year) — 6–8 ml/kg/hour;

children aged 1 to 2 years — 4–6 ml/kg/hour;

children aged 2 to 12 years — 2–4 ml/kg/hour.

Method of Administration

Ringer Malate is intended only for intravenous infusion.

Ringer Malate can be administered into peripheral veins (for pH and theoretical osmolarity, see section "Basic physicochemical properties").

When administering under pressure or rapid infusion from a bottle and infusion set, all air must be removed prior to infusion, otherwise there is a risk of air embolism during infusion.

During administration, fluid balance, plasma electrolyte concentrations and pH must be monitored.

Ringer Malate may be administered as long as there are indications for fluid replacement.

Children

The safety and efficacy of the medicinal product in neonates (children under 28 days of age) have not been established.

Overdose

Excessive or too rapid administration of the solution may lead to water or sodium overload, resulting in edema, particularly in cases of impaired renal sodium excretion. In such cases, additional hemodialysis may be required.

Excessive potassium administration may lead to hyperkalemia, especially in patients with renal insufficiency. Symptoms of hyperkalemia include limb paresthesia, muscle weakness, paralysis, cardiac arrhythmia, heart block, cardiac arrest and confusion. Treatment of hyperkalemia includes administration of calcium, insulin (with glucose), sodium bicarbonate, ion-exchange resins or dialysis.

Excessive parenteral administration of magnesium salts leads to hypermagnesemia. Important signs include loss of deep tendon reflexes and respiratory depression, both resulting from neuromuscular blockade. Other symptoms of hypermagnesemia may include nausea, vomiting, skin flushing, thirst, arterial hypotension due to peripheral vasodilation, drowsiness, confusion, muscle weakness, bradycardia, coma and cardiac arrest.

Excessive chloride administration may cause bicarbonate loss, leading to acidosis.

Excessive use of compounds metabolized to bicarbonate anion, such as acetates and malates, may lead to metabolic alkalosis, particularly in patients with impaired renal function. Symptoms may include mood changes, fatigue, dyspnea, muscle weakness and cardiac arrhythmia (disturbances in heart rhythm). In patients with concomitant hypocalcemia, muscle hypertonia, muscle twitching and tetany may develop. Treatment of metabolic alkalosis associated with increased bicarbonate levels primarily involves appropriate correction of fluid and electrolyte balance.

Excessive administration of calcium salts may lead to hypercalcemia. Symptoms of hypercalcemia may include anorexia, nausea, vomiting, constipation, abdominal pain, muscle weakness, psychiatric disorders, polydipsia, polyuria, nephrocalcinosis, kidney stone formation, and in severe cases, cardiac arrhythmia and coma. Very rapid intravenous administration of calcium salts may also cause numerous symptoms of hypercalcemia, as well as a chalky taste in the mouth, hot flushes and peripheral vasodilation. Mild asymptomatic hypercalcemia usually resolves after discontinuation of calcium and other agents promoting its development, such as vitamin D. In cases of severe hypercalcemia, emergency treatment is required (e.g., loop diuretics, hemodialysis, calcitonin, bisphosphonates, or sodium edetate).

If overdose is related to medicinal products added to the solution, signs and symptoms of their excessive administration will also depend on the nature of the added substances. In case of accidental overdose, treatment should be discontinued and the patient should be examined for relevant signs and symptoms related to the substance. If necessary, appropriate symptomatic and supportive measures should be taken.

Side effects

Symptoms of overdose may occur (see section "Overdose").

The frequency of adverse reactions listed in this section is classified as follows: rare (≥ 1/10,000, < 1/1,000), unknown (frequency cannot be estimated from the available data).

Immune system disorders

Unknown: isolated cases of hypersensitivity reactions such as urticaria have been reported following intravenous administration of magnesium salts.

Gastrointestinal disorders

Rare cases of paralytic ileus have been reported after intravenous administration of magnesium sulfate, although oral administration of magnesium salts stimulates intestinal peristalsis.

General disorders and administration site reactions

Adverse reactions may be related to the administration technique, including febrile response, infections at the injection site, local pain or local reactions, venous irritation, venous thrombosis or phlebitis extending from the injection site, and extravasation.

Adverse reactions may also be related to medications added to the solution; the nature of the added substances will determine the type of any additional adverse effects.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Shelf life after first opening of the bottle

From a microbiological standpoint, the product should be used immediately after opening. If the solution is not administered immediately, the person using the product is responsible for ensuring appropriate storage prior to use, which generally should not exceed 24 hours at 2–8 °C, unless the solution has been reconstituted/diluted under controlled and validated aseptic conditions.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities

Mixing with other medicinal products containing carbonates, phosphates, sulfates, or tartrates may result in precipitate formation.

Packaging

500 mL in polymer bottles.

Prescription status. Prescription only.

Manufacturer

LLC "Yuria-Pharm".

Manufacturer's address

108, Kobzarska Street, Cherkasy, Cherkasy region, Ukraine.

Tel.: (044) 281-01-01.