Ringer acetate S.A.L.F.: detailed information

Package leaflet: Information for the user

RINGER ACETATO S.A.L.F. infusion solution

Sodium chloride, potassium chloride, calcium chloride dihydrate, sodium acetate trihydrate
Generic medicine
Please read this leaflet carefully before using this medicine as it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

What RINGER ACETATO S.A.L.F. is and what it is used for
What you need to know before using RINGER ACETATO S.A.L.F.
How to use RINGER ACETATO S.A.L.F.
Possible side effects
How to store RINGER ACETATO S.A.L.F.
Contents of the pack and other information

1. What RINGER ACETATO S.A.L.F. is and what it is used for

RINGER ACETATO S.A.L.F. is an infusion solution intended for direct intravenous injection, containing a combination of active substances: sodium chloride, potassium chloride, calcium chloride dihydrate and sodium acetate trihydrate.
This medicinal product is indicated to provide water and electrolytes to the body following losses of extracellular fluids and electrolytes, when correction of mild to moderate acidotic states (i.e. when your blood is too acidic) is required.

2. What you should know before using RINGER ACETATE S.A.L.F.

Do not use RINGER ACETATE S.A.L.F.

if you are allergic to sodium chloride, potassium chloride, calcium chloride dihydrate, sodium acetate trihydrate, or to any of the other ingredients of this medicine (listed in section 6);
if you have severe kidney problems (renal failure);
if you have high levels of calcium in the blood (hypercalcemia) or in the urine (hypercalciuria), or suffer from severe kidney diseases;
if you have high levels of sodium in the blood (hypernatremia) or of other electrolytes (water and electrolyte overload);
if you have high levels of potassium in the blood (hyperkalemia) or reduced ability to excrete potassium (potassium retention);
if you have a heart rhythm disorder called ventricular fibrillation, as calcium chloride may increase the risk of cardiac rhythm disturbances (arrhythmias);
if you have kidney stones, which may worsen with calcium administration;
if you suffer from a chronic systemic disease called sarcoidosis, which may enhance the increase in blood calcium levels (hypercalcemia);
if you have severe liver problems (severe hepatic insufficiency);
if you have blood coagulation disorders (hypercoagulability);
if you are taking medications for heart conditions called cardioactive glycosides (see section "Other medicines and RINGER ACETATE S.A.L.F.");
if you have a disease of the adrenal glands (Addison's disease) and are not receiving treatment for it;
if you experience painful, short-duration muscle cramps (heat cramps);
if the patient is a newborn (<28 days), RINGER ACETATE S.A.L.F. (or other calcium-containing solutions) must not be administered simultaneously with ceftriaxone (an antibiotic), even if separate infusion lines are used. There is a risk of fatal formation of particles in the newborn's bloodstream.

In case of blood transfusions, the solution must not be administered through the same infusion catheter as whole blood due to the possible risk of coagulation.
Warnings and precautions
Talk to your doctor or nurse before using RINGER ACETATE S.A.L.F.
This medicine must be administered by a very slow infusion , as potassium intoxication may occur, which could lead to death due to loss of heart function (cardiac depression), heart rhythm disturbances (arrhythmias), up to cardiac arrest (see section "How to use RINGER ACETATE S.A.L.F.").
Due to the presence of sodium, this medicine must be administered with caution in the following cases:

if you have heart problems (congestive heart failure, cardiac insufficiency) or kidney problems (severe renal failure, reduced renal function);
if you have fluid accumulation (edema with salt retention), either in the lungs (pulmonary edema), or associated with swelling of the ankles and legs (peripheral edema);
if you are taking heart medications (cardiotropic drugs) or anti-inflammatory corticosteroid drugs or hormonal drugs (corticotropics);
if you have high blood pressure (hypertension);
if you have a condition called pre-eclampsia during pregnancy, characterized by high blood pressure, swelling due to fluid accumulation, and presence of proteins in the urine, or other conditions caused by sodium accumulation.

Due to the presence of potassium, this medicine must be administered with caution in the following cases:

if you have severe kidney problems (renal failure), as it may cause potassium retention;
if you have heart problems (cardiac insufficiency) and are taking other heart medications (digitalis);
if you have a disease of the adrenal glands (adrenal insufficiency);
if you have severe liver problems (hepatic insufficiency);
familial periodic paralysis (occasional episodes of muscle weakness);
if you suffer from a condition characterized by muscle stiffness (congenital myotonia);
if you have recently undergone surgery (early postoperative phase).

Due to the presence of calcium, this medicine must be administered with great caution in the following cases:

if you have kidney problems (including chronic renal failure) or heart problems, as it may increase the risk of heart rhythm disturbances (arrhythmias);
if you have received a blood transfusion, as calcium ion concentrations may differ from expected levels;
if you suffer from lung problems that may cause heart enlargement (cor pulmonale);
if you have breathing problems (respiratory failure) or a decrease in blood pH (respiratory acidosis);
if you have low body water levels (dehydration) or an electrolyte imbalance (electrolyte imbalance);
if you have low blood pressure, as administration of calcium chloride may cause vasodilation leading to further lowering of blood pressure;
if you have previously suffered from kidney stones. Calcium chloride solution is irritating and therefore must not be administered by intramuscular injection, subcutaneous injection, or peri-vascular injection, as tissue damage and death (necrosis) may occur.

Due to the presence of acetate, the medicine must be used with caution in individuals who have an increase in pH (metabolic and respiratory alkalosis) or elevated acetate levels in the blood, such as in individuals with liver problems (mild or moderate hepatic insufficiency).
The medicine should not be used unless strictly necessary in the following cases:

if you suffer from a disease of the adrenal glands characterized by excessive production of the hormone aldosterone (primary and secondary hyperaldosteronism) or if you have a condition called pre-eclampsia characterized by high blood pressure, swelling due to fluid accumulation, and presence of proteins in the urine, as it may cause sodium retention, fluid overload, or fluid accumulation (edema);
if you are predisposed to high potassium levels in the blood (hyperkalemia) due to the following conditions: severe kidney damage or a disease of the adrenal glands (adrenocortical insufficiency), severe dehydration, or extensive tissue damage, and if you have heart problems (cardiac insufficiency).

During treatment with this medicine, your doctor should periodically monitor heart function through electrocardiograms and the concentration of electrolytes, particularly sodium, as hospital-acquired hyponatremia (sodium deficiency) may develop, as well as fluid levels, osmolarity, and blood pH.
Frequent monitoring of calcium levels in blood and urine is required to prevent hypercalciuria (elevated calcium levels in urine), as this may lead to increased calcium levels in the blood (hypercalcemia).
This medicine must be administered with caution and under specific monitoring conditions due to the risk of reduced sodium concentration in plasma (hyponatremia) if:

you have heart problems (cardiac insufficiency) or lung problems (pulmonary insufficiency);
you have liver and/or kidney disease (hepatopathies and/or nephropathies);
you have non-osmotic release of antidiuretic hormone (vasopressin), including the syndrome of inappropriate vasopressin secretion (SIADH), or are undergoing treatment with vasopressin agonists. Acute hyponatremia may cause acute hyponatremic encephalopathy (cerebral edema), characterized by headache, nausea, seizures, lethargy, and vomiting. Patients with cerebral edema are particularly at risk of severe, irreversible, and life-threatening brain damage.

Children, women of childbearing age, and patients with reduced cerebral compliance (e.g., meningitis, intracranial hemorrhage, and cerebral contusion) are particularly at risk of severe and life-threatening cerebral fluid accumulation (cerebral edema) caused by acute hyponatremia.
Children
As with other calcium-containing solutions, concomitant treatment with ceftriaxone is contraindicated in neonates (age ≤ 28 days) due to the risk of fatal precipitation of ceftriaxone-calcium salt in the neonate's bloodstream (see section "Other medicines and RINGER ACETATE S.A.L.F." and " Possible side effects").
Other medicines and RINGER ACETATE S.A.L.F.
Inform your doctor if you are currently using, have recently used, or might use any other medicines.
This medicine must not be administered if you are taking:

cardioactive glycosides (digitalis), digoxin and digitoxin, used for heart problems, as concomitant use may increase the risk of heart rhythm disturbances (arrhythmias), considering that inotropic effects and toxic effects are synergistic.

This medicine must be administered with caution if you are taking:

medicines used to lower blood pressure such as: potassium-sparing diuretics, ACE inhibitors that cause a decrease in aldosterone levels, angiotensin II receptor antagonists, and medicines that inhibit the immune system response such as immunosuppressants (e.g., tacrolimus and cyclosporine), as they may lead to increased potassium levels in the blood (hyperkalemia); in such cases, potassium levels in the blood must be closely monitored;
anti-inflammatory steroid medicines (corticosteroids) that may cause sodium and water retention, leading to fluid accumulation (edema) and increased blood pressure (hypertension);
medicines such as thiazide diuretics, used to treat high blood pressure, and vitamin D, as they may lead to increased calcium levels in the blood (hypercalcemia) due to reduced renal excretion of calcium; magnesium-containing medicines, as they may increase the risk of elevated calcium (hypercalcemia) or magnesium (hypermagnesemia) levels, especially in patients with kidney disorders;
medicines that cause increased vasopressin such as: chlorpropamide, clofibrate, carbamazepine, vincristine, selective serotonin reuptake inhibitors, 3,4-methylenedioxy-N-methamphetamine, ifosfamide, antipsychotics, narcotics, NSAIDs, cyclophosphamide, desmopressin, oxytocin, vasopressin, terlipressin;
diuretics in general and antiepileptic drugs (e.g., oxcarbazepine), as they may increase the risk of hyponatremia.

Due to the alkalinizing action of acetate (bicarbonate formation), the medicine may interfere with the elimination of acidic drugs such as salicylates, barbiturates, and lithium (increased renal clearance) and alkaline drugs such as sympathomimetics (e.g., ephedrine, pseudoephedrine), dextroamphetamine sulfate, and phenfluramine hydrochloride (decreased renal clearance).
Due to the presence of calcium chloride, RINGER ACETATE S.A.L.F. may interact with the following medicines:

verapamil (and other calcium channel blockers), used to treat high blood pressure, as concomitant use may reduce the antihypertensive effect of verapamil;
neuromuscular blockers, as calcium salts may neutralize the action of non-depolarizing blockers; in some cases, an increase and prolongation of the action of tubocurarine has also been observed;
ceftriaxone (an antibiotic) due to the risk of particle formation.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before this medicine is administered to you.
This medicine must not be used during pregnancy and breastfeeding unless absolutely necessary.
RINGER ACETATE S.A.L.F. must be administered with caution to pregnant women during labor, particularly regarding serum sodium levels, if administered in association with oxytocin.
Driving and using machines
This medicine does not affect the ability to drive vehicles or operate machinery.

3. How to use RINGER ACETATO S.A.L.F.

This medicinal product will be prepared by a doctor, pharmacist, or nurse and must not be mixed or administered simultaneously with injections containing ceftriaxone.
Monitoring of electrolyte balance, serum electrolytes, and acid-base balance may be required before and during administration, with particular attention to serum sodium levels if you have the syndrome of inappropriate antidiuretic hormone secretion (SIADH), or if you are receiving concomitant treatment with vasopressin agonists, due to the risk of hospital-acquired hyponatremia.
Monitoring of serum sodium is particularly important when hypotonic solutions are used.
This medicinal product must be administered directly into a vein (intravenous infusion) by trained medical personnel.
It must not be injected via other routes of administration (intramuscular, subcutaneous, or into perivascular tissues).
This medicinal product must be administered only if your kidney function is intact and at a rate not exceeding 10 mEq of potassium per hour.
After administration of the medicinal product, remain lying down for a short period.
The dose will be adjusted by the doctor according to your age, body weight, and health condition (only if your kidney function is intact).
The recommended dose in adults is approximately 20–30 ml of solution per kg of body weight per day, which may be increased up to a maximum of 40 ml of solution per kg of body weight per day.
Infusions that are too rapid may cause local pain; administration must be stopped if you experience pain or redness at the injection site, as this may be due to leakage of the medicinal product from the vein (drug extravasation).

If you use more RINGER ACETATO S.A.L.F. than you should
This medicinal product will be administered by a doctor or trained healthcare professional; therefore, it is unlikely that you will receive an excessive dose. However, if you think that you have been given an excessive dose of RINGER ACETATO S.A.L.F., inform your doctor or another healthcare professional immediately.
Following administration of an excessive dose of this medicinal product, the following may occur:

increase in potassium levels in the blood (hyperkalemia), which may lead to death due to heart damage (cardiac depression, arrhythmias, or arrest);
increase in sodium levels (hypernatremia) and in blood volume (hypervolemia). If sodium levels in the blood rise too much, loss of fluids from internal organs (dehydration) may occur, especially in the brain, and fluid accumulation may affect the cerebral, pulmonary, and peripheral circulation, leading to fluid buildup around the lungs (pulmonary edema) or swelling in the legs and ankles (peripheral edema);
increase in chloride levels, resulting in a reduction of blood pH (acidosis) due to decreased concentration of bicarbonate ions;
increase in calcium levels in the blood (hypercalcemia), leading to symptoms such as thirst, nausea, vomiting, constipation, increased urine production (polyuria), abdominal pain, muscle weakness, mental disturbances, and in severe cases, heart problems (cardiac arrhythmia) and coma.

If you have any doubts about the use of RINGER ACETATO S.A.L.F., consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
The following side effects may occur, especially in case of inadequate administration or administration that is too rapid (see section “Warnings and precautions”):
Not known (frequency cannot be estimated from the available data):

gastrointestinal disturbances and irritation, nausea, vomiting, diarrhoea, abdominal pain, constipation;
thirst, reduced salivation, metallic taste, chalky taste;
neuromuscular and nervous system disturbances, muscle stiffness, altered limb sensation (paraesthesiae), loss of muscle tone (flaccid paralysis), weakness;
mental confusion, headache, dizziness, restlessness, irritability;
seizures, coma, death;
drowsiness, confusion, mental disorders, cerebral oedema (hyponatraemic encephalopathy)*;
irregular heartbeat (arrhythmias, tachycardia, bradycardia, conduction disorders, disappearance of the P wave, widening of the QRS complex on the electrocardiogram, syncope, ventricular fibrillation, cardiac arrest);
decrease or increase in blood pressure (hypotension, hypertension), swelling of limbs (peripheral oedema), vasodilation, hot flushes;
increased levels of sodium (hypernatraemia), chloride (hyperchloraemia), and blood volume (hypervolaemia);
breathing difficulties (dyspnoea, respiratory arrest);
fluid accumulation in the lungs (pulmonary oedema) and air around the lung (pneumothorax);
chest pain;
chest tightness;
reduced tear production;
kidney problems (renal failure), increased urine production (polyuria);
increased calcium levels in the blood (hypercalcaemia);
Burnett’s syndrome (also known as milk-alkali syndrome), a condition caused by excessive intake of milk or alkaline compounds, characterised by symptoms such as nausea, vomiting, headache, and muscle weakness;
overhydration;
electrolyte imbalances;
decreased sodium levels in the blood (hospital-acquired hyponatraemia)*;
muscle weakness;
fever, infection at the infusion site, pain or local reaction, redness, rash;
abscess formation;
circulatory problems due to blood clot formation in the veins (thrombosis);
inflammation of the vein at the infusion site (phlebitis);
venous irritation;
leakage of the medicine into surrounding tissues at the injection site (extravasation);
tissue damage and tissue death (tissue necrosis);
abscess formation and calcium deposits in the skin (cutaneous calcification);
hypersensitivity reactions to the infusion, including anaphylactic/anaphylactoid reactions;
kidney problems caused by calcium-ceftriaxone deposits. This may cause pain during urination or reduced urine output.

* Hospital-acquired hyponatraemia can cause irreversible brain damage and death due to the development of acute hyponatraemic encephalopathy.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor or pharmacist. You may also report side effects directly via the national reporting system at the following address:
http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store RINGER ACETATO S.A.L.F.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp.".
The expiry date refers to the last day of that month.
Store in the original packaging and in a tightly closed container. Do not freeze.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What RINGER ACETATO S.A.L.F. contains

The active substances are: sodium chloride, potassium chloride, calcium chloride dihydrate, sodium acetate trihydrate. 1000 ml of solution contain 6.0 g of sodium chloride, 0.3 g of potassium chloride, 0.22 g of calcium chloride dihydrate, 4.0 g of sodium acetate trihydrate (Each litre of solution contains 132 mEq of sodium, 4 mEq of potassium, 3 mEq of calcium, 110 mEq of chloride and 29 mEq of acetate). pH: 6.0 - 7.0
The other components are water for injections and hydrochloric acid for pH adjustment.

Description of the appearance of RINGER ACETATO S.A.L.F. and contents of the pack
Infusion solution, sterile and pyrogen-free.
500 ml glass vial
500 ml PP vial
1000 ml PVC bag
15 PVC-free 500 ml bags
10 PVC-free 1000 ml bags

Marketing Authorisation Holder and Manufacturer
S.A.L.F. S.p.A. Laboratorio Farmacologico – Via Marconi, 2 - Cenate Sotto (BG) – Italy.

The following information is intended exclusively for physicians or healthcare professionals

CLINICAL INFORMATION
Dosage and administration
The solution is isotonic with blood and must be administered only with caution in patients with intact renal function by intravenous infusion at a controlled infusion rate (not exceeding 10 mEq potassium/hour).
The dose depends on the patient's age, weight, and clinical condition, and will be determined by the physician.
Due to its potassium content, administration must be guided by serial electrocardiograms; serum potassium levels do not reflect intracellular potassium concentrations. Monitor fluid balance, electrolytes, and acid-base equilibrium.
Use the solution immediately after opening the container. The container is intended for single, uninterrupted administration, and any residual solution must not be reused.
Monitoring of serum sodium is particularly important with physiologically hypotonic solutions.
Ringer Acetate S.A.L.F. infusion solution may become markedly hypotonic after administration.
Patients with non-osmotic vasopressin release (e.g., during acute illness, pain, postoperative stress, infections, burns, and central nervous system disorders), patients with cardiac, hepatic, or renal diseases, and patients treated with vasopressin agonists are particularly at risk of acute hyponatremia following infusion of hypotonic solutions. Acute hyponatremia may cause acute hyponatremic encephalopathy (cerebral edema), characterized by headache, nausea, seizures, lethargy, and vomiting. Patients with cerebral edema are at particular risk of severe, irreversible, and life-threatening brain injury.
Shake well before administration. Do not use the medicinal product if the solution is not clear and colorless or if it contains particles.
Ensure all precautions are taken to maintain sterility before and during intravenous infusion.

Pregnancy
Ringer Acetate S.A.L.F. infusion solution must be administered with particular caution in pregnant women during labor, especially when administered concomitantly with oxytocin, due to the risk of hyponatremia.

Overdose
Treatment
Immediately discontinue the infusion and initiate corrective therapy to reduce plasma levels of the excess ions and restore, if necessary, acid-base balance (see section 4.4).
The patient should be closely monitored for the appearance of any signs and symptoms related to the administered drug, with appropriate symptomatic and supportive measures provided as needed.
In case of marked hypernatremia, loop diuretics may be used.
In case of hyperkalemia, intravenous glucose (with or without insulin) or sodium bicarbonate may be administered.
In case of mild calcium chloride overdose, treatment includes immediate discontinuation of the infusion and any other calcium-containing medications. In case of severe overdose (plasma concentrations >2.9 mmol/l), the following measures should be taken:

Rehydration with 0.9% sodium chloride solution;
Use of non-thiazide diuretics to enhance calcium excretion;
Monitoring of plasma potassium and calcium levels, with immediate correction to normal values;
Monitoring of cardiac function; use of beta-blockers to reduce the risk of cardiac arrhythmias;
Hemodialysis if necessary. Elevated plasma electrolyte levels may require dialysis.

Incompatibilities
Due to the presence of calcium chloride, the medicinal product is incompatible with:

Magnesium sulfate: formation of a precipitate;
Medicinal products containing phosphate: formation of calcium phosphate precipitate;
Medicinal products containing carbonate: formation of calcium carbonate precipitate;
Medicinal products containing tartrate: formation of calcium tartrate precipitate.

Incompatibilities of calcium chloride have been observed with:

Aminophylline: due to precipitate formation;
Amphotericin B: due to development of turbidity;
Cefamandole: due to presence of sodium carbonate in cefamandole formulation;
Ceftriaxone sodium: due to precipitate formation; therefore, administration of calcium-containing solutions must not occur within 48 hours following ceftriaxone administration;
Cephalothin: due to physical incompatibility;
Cefradine: due to presence of sodium carbonate in cefradine formulation;
Chlorpheniramine: due to physical incompatibility;
Dobutamine: due to development of turbidity;
Fat emulsion: due to presence of flocculation;
Sodium heparin;
Indomethacin: due to precipitate formation;
Sodium nitrofurantoin;
Promethazine: due to precipitate formation;
Propofol: due to precipitate formation;
Streptomycin: calcium may inhibit streptomycin activity;
Tetracyclines: calcium salts may complex with tetracyclines. Calcium salts can form complexes with many drugs, potentially leading to precipitate formation. Physical incompatibility has been reported with ceftriaxone sodium:

As with other calcium-containing solutions, concomitant use with ceftriaxone is contraindicated in neonates (≤28 days of age), even when separate infusion lines are used (risk of fatal precipitation of ceftriaxone-calcium salt in the neonate’s bloodstream). In patients older than 28 days (including adults), ceftriaxone must not be administered concomitantly with intravenous calcium-containing solutions, including Ringer Acetato S.A.L.F., through the same infusion line (e.g., via a Y-connector).
If the same infusion line is used for sequential administration, the line must be flushed with a compatible fluid between infusions.

Interactions
Medicinal products that may increase the risk of hospital-acquired hyponatremia due to inadequately balanced intravenous fluid therapy include:

Medicinal products stimulating vasopressin release, e.g.: chlorpropamide, clofibrate, carbamazepine, vincristine, selective serotonin reuptake inhibitors, 3,4-methylenedioxy-N-methamphetamine (MDMA), ifosfamide, antipsychotics, narcotics;
Medicinal products enhancing vasopressin action, e.g.: chlorpropamide, NSAIDs, cyclophosphamide;
Vasopressin analogs: desmopressin, oxytocin, vasopressin, terlipressin. Other medicinal products increasing the risk of hyponatremia include diuretics in general and antiepileptic drugs such as oxcarbazepine.

For further information, please refer to the Summary of Product Characteristics.