Natrovit powder for solution for infusion EFG: detailed information

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Natrovit powder for concentrate for solution for infusion EFG

Retinol (vitamin A), colecalciferol (vitamina D3), α-tocoferol (vitamin E), ácido ascórbico (vitamin C), tiamina (vitamin B1), riboflavina (vitamin B2), piridoxina (vitamin B6), cianocobalamina (vitamin B12), ácido fólico, ácido pantoténico, biotina, nicotinamida (vitamin B3)

For use in adults and children over 11 years of age.

Read this entire leaflet carefully before you start using this medicine, because it contains important information for you.

Keep this leaflet, as you may need to read it again.

If you have any questions, ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for you only, and you should not give it to other people, even if they have the same symptoms as you, because it may harm them.

If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if these are effects not listed in this leaflet. See section 4.

The name of the medicine is «Natrovit powder for concentrate for solution for infusion EFG». In the remainder of this leaflet it will be referred to as «Natrovit».

Contents of the leaflet

What Natrovit is and what it is used for
What you need to know before using Natrovit
How to use Natrovit
Possible side effects
How to store Natrovit
Contents of the pack and other information

1. What Natrovit is and what it is used for

Natrovit is a multivitamin preparation used to provide an appropriate supply of vitamins to meet the daily requirements of adults and children over 11 years of age, whenever oral administration is contraindicated or not possible, and vitamin replacement is required as part of parenteral nutrition.

2. What you need to know before using Natrovit

Contraindications are diseases or circumstances in which certain medications should not be used, or may only be used after careful evaluation by a physician, because the balance between expected benefit and potential risks is generally unfavorable. In order for your doctor to carefully assess whether contraindications exist, you must inform them of all illnesses you have previously had, current medical conditions, other treatments you are receiving, and your personal circumstances and habits. In addition, contraindications may not be present or may not become apparent until after starting treatment with this medication. In such cases, you must also inform your doctor.

Do not use Natrovit:

if you are allergic to the active substances or to any of the other components of this medicine, particularly thiamine (Vitamin B1) or to soy and peanut proteins (listed in section 6).
if you have hypervitaminosis related to any of the vitamins contained in Natrovit
in children under 11 years of age

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before using Natrovit if:

you have kidney disease,
you have liver disease,
you have cancer,
you have short bowel syndrome,
you have cystic fibrosis,
you are taking vitamins from other sources (e.g., supplements),
you have vitamin B12 deficiency,
you have diabetes, as Natrovit may affect blood glucose measurements.

Hypersensitivity reactions

Allergic reactions ranging from mild to severe have been reported in relation to vitamins B1, B2, B12, folic acid, and soy lecithin.

Cross-reactive allergic reactions between soy and peanut proteins have been observed.

Your doctor will monitor you during the infusion to ensure you are receiving the appropriate amount of vitamins. Inform your doctor immediately if you notice signs of allergy such as sweating, fever, chills, headache, skin rash, hives, redness, or difficulty breathing. The infusion will be stopped immediately and necessary emergency measures will be taken.

Due to the content of glycocholic acid, close monitoring of liver function is required when Natrovit is administered repeatedly or long-term to patients with hepatic jaundice or significant biochemical signs of cholestasis.

Interference with laboratory tests

NATROVIT contains 69 μg of biotin per vial. If you are undergoing laboratory tests, you must inform your doctor or laboratory personnel that you are currently receiving or have recently received NATROVIT, as biotin may interfere with test results. Depending on the test, results may show false elevations or false reductions due to biotin. Your doctor may instruct you to discontinue NATROVIT before laboratory testing. You should also be aware that other products you may be taking, such as multivitamin preparations or supplements for hair, skin, and nails, may also contain biotin and affect laboratory test results. Inform your doctor or laboratory personnel if you are taking such products.

Use of Natrovit with other medicines

Inform your doctor if you are taking, have recently taken, or might need to take any other medicines.

You should be especially careful if you are taking any of the following types of medicines:

phenobarbital, phenytoin, primidone, carbamazepine, valproate (for epilepsy),
aspirin (for pain and inflammation),
chloramphenicol, trimethoprim, tetracyclines (for bacterial infections),
deferoxamine (for iron poisoning or excess iron in the body),
efavirenz, zidovudine, tipranavir (HIV treatments),
ethionamide, cycloserine, isoniazid (for tuberculosis),
fluoropyrimidines, raltitrexed, bexarotene (cancer treatments),
methotrexate, sulfasalazine, penicillamine (for rheumatoid arthritis),
pyrimethamine (antimalarial drug),
levodopa (used to treat Parkinson's disease),
triamterene, hydralazine (for heart conditions),
phenelzine (for depression),
theophylline (for respiratory diseases and asthma),
warfarin (anticoagulant).

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy

There are no data or data are limited regarding the use of Natrovit in pregnant women. Your doctor will administer this infusion solution only if considered necessary. Overdoses during pregnancy should be avoided due to the risk of congenital malformations.

Breastfeeding

Components/metabolites of Natrovit are excreted in breast milk, but at therapeutic doses of Natrovit, effects on newborns/infants are not expected. Natrovit may be used during breastfeeding.

Fertility

There are insufficient data on the use of NATROVIT with regard to fertility in male or female patients.

Natrovit contains sodium

This medicine contains 25 mg of sodium (main component of table/cooking salt) per vial. This corresponds to 1.25% of the maximum daily recommended sodium intake for an adult.

This should be taken into account by patients on a sodium-controlled diet.

3. How to use Natrovit

Natrovit is a preparation administered by healthcare professionals. Natrovit is usually given as an intravenous infusion.

Dosage and method of administration

Dosage

Unless otherwise prescribed, the following dosage recommendations apply:

Adults and children over 11 years: 1 vial per day.

Method of administration

For intravenous infusion.

Natrovit is intended solely for use as an additive to infusion solutions.

The contents of the vial are dissolved by adding 5 ml of a suitable vehicle solution (water for injections) and gently shaking.

Slow infusion in isotonic sodium chloride or glucose solution, for example.

Natrovit may be added to certain infusion solutions for parenteral nutrition containing carbohydrates, lipids, amino acids, and electrolytes. However, compatibility and stability with the respective solution must first be ensured.

Reconstitution and addition to the infusion solution must take place immediately before administration.

If you have further questions regarding the use of this medicine, consult your doctor or pharmacist.

If you have any further doubts about the use of this medicine, ask your doctor or pharmacist.

If you receive more Natrovit than you should

Overdose cases are not expected within the indicated dose range.

Signs of overdose include, among others, nausea and vomiting, headache, confusion, and skin desquamation.

If you notice any of these signs of overdose, contact your doctor.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

The following adverse effect is common (may affect between 1 and 10 out of 100 patients):

Pain at the infusion site

The following adverse effects are uncommon (may affect between 1 and 10 out of 1,000 patients):

Nausea and vomiting

The following adverse effects have been reported, although their frequency is unknown:

Allergic reactions with difficulty breathing, chest pain, throat tightness, skin rash, sensation of warmth, hot flushes, abdominal pain, and heart problems.
Increased vitamin A and vitamin A-binding protein in the blood
Disturbance of taste sensation (metallic taste)
Rapid heartbeat
Rapid breathing
Diarrhea
Increased liver enzymes and bile acids
Pruritus (itching)
Fever, general malaise, reactions at the infusion site such as burning and sensation of warmth

Soybean lecithin may very rarely cause allergic reactions.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.es.

By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Natrovit

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the vial and outer packaging following EXP. The expiry date refers to the last day of the month indicated.

After reconstitution, any unused solution must be discarded immediately.

Do not store above 25°C.

Keep vials in the outer packaging to protect from light.

Addition to the infusion solution should take place immediately before administration.

Physical and chemical in-use stability of Natrovit powder for solution for infusion EFG has been demonstrated for 24 hours after reconstitution with 5 ml of water for injections, 5 ml of sodium chloride 0.9%, and 5 ml of glucose 5%, when stored at 25 ± 2°C and under refrigerated conditions. From a microbiological standpoint, the medicine should be used immediately. Otherwise, the storage times and conditions prior to use are the responsibility of the user and, in general, should not exceed 24 hours at a temperature between 2°C and 8°C, unless reconstitution/dilution, etc., has been carried out under controlled and validated aseptic conditions.

Natrovit must not be used if the solution is not clear or if the vial is damaged.

Since this product will be administered by healthcare professionals, they are responsible for the proper storage of the product both before and during use, as well as for its appropriate disposal.

6. Contents of the container and additional information

Composition of Natrovit

The active substances are:

Retinol (vitamin A, equivalent to 3500 IU), as Retinyl Palmitate	1.050 mg
Cholecalciferol (vitamin D3, equivalent to 220 IU)	5.500 µg
all-rac-alpha-Tocopherol (vitamin E)	10.20 mg
Ascorbic Acid (vitamin C)	125 mg
Thiamine (vitamin B1) as cocarboxylase tetrahydrate	3.51 mg
Riboflavin (vitamin B2) as sodium riboflavin phosphate dihydrate	4.14 mg
Pyridoxine (vitamin B6) as pyridoxine hydrochloride	4.53 mg
Cyanocobalamin (vitamin B12)	6 micrograms
Folic Acid	414 micrograms
Pantothenic Acid as Dexpanthenol	17.25 mg
Biotin (vitamin B7) as D-Biotin	69 micrograms
Nicotinamide (vitamin B3)	46 mg

Other components are:

glycine, glycocholic acid, soybean lecithin, sodium hydroxide (pH adjuster), and hydrochloric acid (pH adjuster).

Patients on low-sodium diets should be aware that this medicinal product contains 25 mg (approximately 1.09 mmol) of sodium per vial.

Appearance of the product and contents of the container

Natrovit is a powder for concentrate for solution for infusion; it appears orange to red-orange within a brown glass vial, sealed with an elastomeric stopper and an overlaid aluminium seal.

Each pack contains the vial with the lyophilized powder.

Natrovit is supplied in packs containing 1, 10 or 20 vials of lyophilized powder.

Only certain pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Noridem Enterprises Ltd.

Evagorou & Makariou

Mitsi Building 3, Office 115

1065 Nicosia, Cyprus

Manufacturer

DEMO S.A. PHARMACEUTICAL INDUSTRY

21st Km National Road Athens-Lamia.

14568 Greece

T: +30 210 8161802, F: +30 2108161587.

This medicinal product is authorized in the European Economic Area member states under the following names:

Germany: NATROVIT Pulver für ein Konzentrat zur Herstellung einer Infusionslösung

Spain: NATROVIT powder for concentrate for solution for infusion EFG

Date of most recent review of this leaflet: 09/2024

This information is intended for healthcare professionals only:

One vial with 750 mg of powder for concentrate for solution for infusion contains:

Retinol (vitamin A, equivalent to 3500 IU), as Retinyl Palmitate	1.050 mg
Cholecalciferol (vitamin D3, equivalent to 220 IU)	5.500 µg
all-rac-alpha-Tocopherol (vitamin E)	10.20 mg
Ascorbic Acid (vitamin C)	125 mg
Thiamine (vitamin B1) as cocarboxylase tetrahydrate	3.51 mg
Riboflavin (vitamin B2) as sodium riboflavin phosphate dihydrate	4.14 mg
Pyridoxine (vitamin B6) as pyridoxine hydrochloride	4.53 mg
Cyanocobalamin (vitamin B12)	6 micrograms
Folic Acid	414 micrograms
Pantothenic Acid as Dexpanthenol	17.25 mg
Biotin (vitamin B7) as D-Biotin	69 micrograms
Nicotinamide (vitamin B3)	46 mg

Excipients: glycine, glycocholic acid, soybean lecithin (phosphatidylcholine), sodium hydroxide (to adjust pH), hydrochloric acid (to adjust pH)

Description: Concentrated, lyophilized, sterile, orange-red powder. After reconstitution, the resulting solution is clear and orange-red in colour.

Dosage and method of administration

Dosage

Adults and children over 11 years: 1 vial/day.

Method of administration

For intravenous infusion.

Natrovit is intended exclusively for use as an additive to infusion solutions.

The contents of the single-dose vial are dissolved by adding 5 mL of a suitable diluent (water for injections, 0.9% sodium chloride or 5% dextrose) and gently mixing.

Slow infusion (over at least 1 to 2 hours), for example, with sodium chloride or glucose.

Natrovit may be added to certain parenteral nutrition solutions containing carbohydrates, lipids, amino acids and electrolytes in order to meet nutritional requirements and prevent deficiency symptoms and complications. However, compatibility and stability with the respective solution must first be ensured.

Reconstitution and addition to the infusion solution must take place immediately before administration.

The total intake of vitamins from all sources should be taken into account, e.g., from food products, other vitamin preparations or medications containing vitamins as excipients.

To maintain adequate concentrations, the patient's clinical status and vitamin levels should be monitored.

It should be remembered that certain vitamins, especially vitamins A, B2 and B6, are sensitive to ultraviolet light (direct or indirect sunlight). In addition, the concentration of vitamins A, B1, C and E may decrease with increasing oxygen content in the solution. These factors should be considered if adequate vitamin concentrations are not achieved.

Contraindications

Hypersensitivity to the active substances, especially suspected hypersensitivity to thiamine.

Patients who have shown signs of intolerance to thiamine must not receive Natrovit.

Hypersensitivity to any other vitamin or to derivatives/proteins from soy contained in Natrovit (phospholipids are an excipient derived from soybeans), or to peanut proteins or products, or to any of the excipients listed in section 6.1.

Hypervitaminosis of any of the vitamins contained in Natrovit.

Special warnings and precautions for use

Warnings

Hypersensitivity reactions

Severe systemic hypersensitivity reactions have been reported in association with multivitamin preparations and individual vitamins (such as vitamins B1, B2, B12 and folic acid). Fatal reactions have been reported in association with multivitamin preparations and other parenteral vitamin preparations.
Cross-allergic reactions between soybean proteins and peanut have been observed.
In some cases, the manifestation of a hypersensitivity reaction during intravenous administration of multiple vitamins may be related to the rate of infusion. Therefore, Natrovit must be infused slowly.
If signs or symptoms of a hypersensitivity reaction occur, the infusion or injection must be stopped immediately.

Vitamin toxicity

To avoid overdose and toxicity, the patient's clinical status and blood vitamin concentrations should be monitored, especially for vitamins A, D and E. This measure is particularly important for patients receiving additional vitamins from other sources or using substances that increase the risk of vitamin toxicity.
Monitoring is especially important during long-term replacement.

Hypervitaminosis, vitamin A

There is an increased risk of hypervitaminosis and vitamin A toxicity (skin and bone disorders, diplopia, cirrhosis), for example, in the following patients:
patients with protein malnutrition
patients with renal insufficiency (even without vitamin A replacement)
patients with hepatic insufficiency
short-stature patients (e.g., children)
patients receiving long-term treatment
In patients with depleted hepatic storage capacity for vitamin A, acute hepatopathy may lead to the manifestation of vitamin A toxicity.

Refeeding syndrome in patients receiving parenteral nutrition

In patients with extreme malnutrition, the introduction of nutrients may trigger a refeeding syndrome. This syndrome is characterised by the intracellular shift of potassium, phosphate and magnesium as the patient enters an anabolic state. Additionally, thiamine deficiency and fluid retention may occur. These complications can be prevented by close monitoring and gradual increase in nutrient intake, while avoiding overfeeding. In case of dietary deficiency, appropriate replacement therapy may be indicated.

Precipitates in patients receiving parenteral nutrition

In patients receiving parenteral nutrition, precipitates have been observed in the pulmonary vasculature. In some of these cases, the outcome was fatal. Excessive addition of calcium and phosphate increases the risk of calcium phosphate precipitate formation. Precipitates have also been observed with phosphate-free solutions. Furthermore, precipitates distal to the integrated filter have been found, and suspected cases of precipitate formation in the bloodstream have been reported.

The solution, as well as the infusion set and catheter, should be inspected at regular intervals for possible presence of precipitates.

If signs of respiratory difficulty occur, the infusion must be stopped and a medical evaluation performed.

Precautions

Hepatic effects

Monitoring of liver function tests is recommended during the use of Natrovit. Particularly close monitoring is indicated in patients with hepatic jaundice or signs suggestive of cholestasis.

In some cases, an increase in liver function test values has been reported during multivitamin use, for example, isolated elevation of alanine aminotransferase (ALT) in patients with inflammatory bowel disease.

An increase in bile acid concentration (total and individual, such as glycocholic acid) has also been reported with multivitamin use.

It is known that hepatobiliary disorders may occur in some cases with parenteral nutrition (even with additional vitamin supplementation). These disorders include cholestasis, steatosis, fibrosis and cirrhosis, possibly leading to subsequent hepatic failure, as well as cholecystitis and cholelithiasis. These conditions are likely to have an underlying multifactorial cause that may vary from patient to patient. In case of manifest laboratory abnormalities or other signs of hepatobiliary disease, appropriate measures must be taken to ensure immediate diagnostic evaluation by a hepatologist to identify possible causal or contributing factors and initiate prophylaxis and treatment.

Use in patients with hepatic insufficiency

Patients with hepatic insufficiency may require individualised vitamin replacement.

Special attention must be paid to the prevention of vitamin A toxicity, as liver disease is associated with increased sensitivity to it, especially in the presence of excessive and prolonged alcohol consumption (see subsections "Hypervitaminosis, vitamin A" and "Hepatic effects").

Use in patients with renal insufficiency

Patients with renal insufficiency may require individualised vitamin replacement, depending on the degree of renal dysfunction and possible concomitant diseases. In patients with severe renal insufficiency, special attention must be paid to ensure adequate vitamin D levels and to prevent vitamin A toxicity. These patients may experience vitamin A toxicity even when receiving low doses or even without replacement therapy.

In patients on long-term haemodialysis receiving an intravenous multivitamin solution three times a week containing 4 mg of pyridoxine (vitamin B6), pyridoxine hypervitaminosis and toxic effects (peripheral neuropathy, involuntary movements) have been reported.

General monitoring

In patients receiving vitamins for a prolonged period exclusively through parenteral multivitamin solutions, monitoring of clinical status and vitamin concentrations is necessary, while verifying adequate replacement of the following:

vitamin A in patients with pressure sores, wounds, burns, short bowel syndrome or cystic fibrosis
vitamin B1 in patients undergoing dialysis
vitamin B2 in patients with cancer
vitamin B6 in patients with renal insufficiency
vitamins required individually, whose need may increase due to pharmacological interactions

Deficiency of one or more vitamins should be corrected by specific replacement.

If Natrovit is used for more than 3 weeks, haematological counts and liver enzyme analyses should be performed.

Natrovit does not contain vitamin K. If required, it should be administered separately.

Use in patients with vitamin B12 deficiency

If the patient is at risk of vitamin B12 deficiency and/or if several weeks of replacement with Natrovit are planned, vitamin B12 concentration should be determined before starting Natrovit administration.

In the presence of megaloblastic anaemia associated with vitamin B12 deficiency, erythrocyte count, reticulocyte count and haemoglobin concentration may increase in some cases, even after a few days of use, due to the amount of cyanocobalamin (vitamin B12) and folic acid supplied through Natrovit. These may mask an existing vitamin B12 deficiency. The dose of cyanocobalamin contained in Natrovit is not high enough to effectively treat vitamin B12 deficiency.

In case of vitamin B12 deficiency, folic acid replacement alone (without concomitant vitamin B12 intake) is not sufficient to prevent the onset or progression of neurological symptoms associated with this deficiency. It has been suggested that functional neurological deterioration could even be accelerated.

When interpreting vitamin B12 test results, it should be remembered that values after vitamin B12 intake may fall within the normal range and tissue deficiency may still exist.

Interference with laboratory tests

Biotin may interfere with clinical laboratory analyses based on biotin-streptavidin interaction, leading to falsely low or falsely high results, depending on the type of test. The risk of interference is higher in children and patients with renal insufficiency and increases with higher doses. When interpreting laboratory test results, possible biotin interference must be taken into account, especially if there is inconsistency with the clinical presentation (e.g., thyroid test results suggestive of Graves' disease in asymptomatic patients treated with biotin or false negative troponin results in patients with myocardial infarction treated with biotin). In cases where such interference is suspected, alternative tests not susceptible to biotin interference should be used, if available. Laboratory personnel should be consulted when requesting analytical tests in patients receiving biotin.

Depending on the reagents used, the presence of ascorbic acid in blood or urine may lead to falsely high or low glucose values in some systems for blood glucose and glucosuria determination (test strips, glucometers, etc.). To determine possible vitamin interference, the technical information of the respective analytical test should be consulted.

Paediatric use

Natrovit is indicated in paediatric patients over 11 years of age (see also hypervitaminosis A in section 4.4 of the Summary of Product Characteristics).

Use in elderly patients

In general, the possibility of adjusting the dosage regimen to elderly patients (dose reduction and/or prolonged administration intervals) should be evaluated, as hepatic, renal or cardiac insufficiency, as well as concomitant diseases and medications, are more frequent in this population.

Sodium content

This medicinal product contains 25 mg of sodium per vial, equivalent to 1.25% of the maximum daily intake of 2 g of sodium recommended by WHO for an adult.

Do not dissolve directly in concentrated electrolyte and trace element solutions.

Use only clear solutions in intact containers.

Interaction with other medicinal products and other forms of interaction

In case of interactions between specific vitamins contained in Natrovit and other substances, appropriate measures should be taken.

Possible interactions:

Drugs that may cause pseudotumour cerebri (such as some tetracyclines): increased risk of pseudotumour cerebri with concomitant administration of vitamin A
Alcohol (excessive and prolonged consumption): increases the risk of vitamin A hepatotoxicity
Anticonvulsants (phenytoin, fosphenytoin, phenobarbital, primidone): vitamin replacement with folic acid may reduce serum anticonvulsant concentrations and increase the risk of seizures
Antiplatelet agents (e.g., acetylsalicylic acid): vitamin E may potentiate platelet function inhibition
Acetylsalicylic acid (high-dose treatment): may reduce folic acid concentration by increasing urinary excretion
Certain anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, valproate): may cause deficiency of folic acid, pyridoxine and vitamin D
Certain antiretroviral preparations: efavirenz and zidovudine, for example, are associated with decreased vitamin D concentration. Protease inhibitors are associated with reduced formation of the active metabolite of vitamin D
Chloramphenicol: may inhibit the haematological response to vitamin B12 treatment
Deferoxamine: increased risk of iron-induced heart failure due to increased iron mobilisation caused by supraphysiological vitamin C replacement. Specific preventive measures are indicated in the deferoxamine product information.
Ethionamide: may cause pyridoxine deficiency
Fluoropyrimidines (5-fluorouracil, capecitabine, tegafur): increased cytotoxicity with concomitant administration of folic acid
Folic acid antagonists (e.g., methotrexate), sulfasalazine, pyrimethamine, triamterene, trimethoprim and high doses of catechins contained in tea: block the conversion of folic acid into its active metabolites and reduce the efficacy of replacement therapy
Folic acid antimetabolites (methotrexate, raltitrexed): folic acid replacement may attenuate the effects of antimetabolites
Pyridoxine antagonists such as cycloserine, hydralazine, isoniazid, penicillamine, phenelzine: may cause pyridoxine deficiency
Retinoids, such as bexarotene: increased risk of toxicity with concomitant administration of vitamin A (see section "Hypervitaminosis, vitamin A").
Theophylline: may cause pyridoxine deficiency
Oral tipranavir solution: contains 116 IU/mL of vitamin E and therefore exceeds the recommended daily dose
Vitamin K antagonists (e.g., warfarin): increased anticoagulant effect due to vitamin E
Levodopa: pyridoxine accelerates the metabolism of levodopa and reduces its effectiveness. This effect is neutralised by combination with decarboxylase inhibitors (carbidopa and benserazide).

Active substances binding to α-1-acid glycoprotein

In an in vitro study with human serum, at a glycocholic acid concentration approximately 4 times higher than the serum glycocholic acid concentration achieved after a bolus injection of multivitamin in adults, the free fraction of selected active substances binding to α-1-acid glycoprotein increased by 50% to 80%.

It is unknown whether this effect is clinically relevant when the amount of glycocholic acid contained in a standard dose of Natrovit (as a component of mixed micelles) is administered as a slow infusion over a prolonged period.

Patients receiving medications that bind to α-1-acid glycoprotein in addition to Natrovit should be closely monitored to detect increases resulting from concomitant use of these products, such as propranolol, prazosin and others.

Interaction in case of additional vitamin replacement

Interactions may occur with some medications when certain vitamins are administered in amounts significantly higher than those contained in Natrovit. This possibility should be considered when vitamin intake comes from multiple sources. If appropriate, patients should be monitored for such interactions and appropriate measures taken.

Possible interactions:

Amiodarone: concomitant administration of vitamin B6 may increase amiodarone-induced photosensitivity
Substances with anticoagulant activity (e.g., abciximab, clopidogrel, heparin, warfarin): increased risk of bleeding due to bleeding tendency associated with high doses of vitamin A
Carbamazepine: high doses of nicotinamide are associated with inhibition of its metabolism
Antineoplastic agents acting by producing reactive oxygen species: possible inhibition of antineoplastic activity due to antioxidant effects of high doses of vitamin E
Insulin, antidiabetics: high doses of nicotinamide are associated with reduced insulin sensitivity
Iron: high-dose vitamin E replacement therapy may reduce the haematological response to iron therapy in patients with anaemia
Oral contraceptives (combined hormonal products): high doses of vitamin C are associated with intermenstrual metrorrhagia and contraceptive inefficacy
Phenobarbital: high doses of pyridoxine are associated with increased metabolism/reduced serum concentration and attenuation of effect
Phenytoin, fosphenytoin: high doses of pyridoxine are associated with decreased serum concentration
Primidone: high doses of nicotinamide are associated with reduced phenobarbital metabolism and increased primidone concentration

Overdose

Overdose cases are not expected within the indicated dose range.

Acute or chronic overdose of vitamins (especially vitamins A, B6, D and E) may cause symptomatic hypervitaminosis.

The risk of overdose is particularly high if vitamins are administered from multiple sources and total replacement of any vitamin does not meet the individual patient's needs or if the patient is especially prone to hypervitaminosis (see section "Hypervitaminosis, vitamin A").

Symptoms of intoxication

Symptoms of hypervitaminosis due to vitamin A:

Acute increase in cerebrospinal fluid pressure with headache, vomiting, dizziness and loss of consciousness. In infants, bulging of fontanelles.

Symptoms of overdose after multiple-dose treatment:

Symptoms of chronic overdose:

Symptoms of increased intracranial pressure, skin peeling and dryness, alopecia, osteodynia and arthralgia, and radiological signs of transformation zones.

Symptoms of hypervitaminosis due to vitamin D:

Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) increase calcium and phosphate absorption from the intestinal lumen and mobilise calcium from bones, so vitamin D has a more antirachitic effect while its reduction product, DHT (dihydrotachysterol), is more effective in mobilising calcium from bones. All these substances have a relatively narrow therapeutic index. The toxic threshold in adults is >0.5 mg/day for vitamin D and >0.25 mg/day for DHT. However, single doses generally have no toxic effect.

In case of overdose, in addition to increased serum and urinary phosphate, hypercalcaemic syndrome may occur, which in turn causes calcium deposition in tissues and especially in the kidneys (nephrolithiasis, nephrocalcinosis) and blood vessels (hypertension). The clinical picture of hypercalcaemia syndrome is not characteristic: weakness, fatigue, exhaustion, headache, nausea, vomiting and diarrhoea, as well as polyuria, polydipsia, nocturia and proteinuria in patients with reduced renal concentrating capacity. Especially in cases where a psychosyndrome with confusion predominates, intoxication symptoms may be easily overlooked (e.g., diabetes mellitus, malignant neoplasia, psychosis). Diagnostically, it is characterised by increased calcium, phosphate and non-protein nitrogen in plasma or serum, as well as possible osteoporosis and tissue or renal calcifications, which are identifiable by radiology.

N.B.: repeated monitoring of serum calcium and bone histology are required.

Treatment of intoxication

Immediate discontinuation of the product.

Vitamin A overdose

Relief of pressure and continuous monitoring of cardiac, hepatic and renal function, haematological counts and ophthalmoscopy.

Hypercalcaemia

In patients with adequate renal function, infusions of isotonic NaCl solution (3 - 6 L in 24 hours) plus furosemide, together with continuous monitoring of calcium and ECG, have a very reliable hypocalcaemic effect. However, in cases of oligoanuria, haemodialysis is indicated. Administration of glucocorticoids and calcitonin may be attempted. Warning: fatal outcomes often occur even after normalization of serum calcium.

Pharmaceutical data

Shelf life

Unopened: 2 years.

Physical and chemical in-use stability of Natrovit powder for solution for infusion has been demonstrated for 24 hours after reconstitution with 5 mL of water for injections, 5 mL of 0.9% sodium chloride or 5 mL of 5% dextrose and storage at 25 ± 2°C and under refrigerated conditions. From a microbiological standpoint, the medicinal product should be used immediately. Otherwise, the times and conditions of storage prior to use are the responsibility of the user and, in general, should not exceed 24 hours at a temperature between 2°C and 8°C, unless reconstitution/dilution etc. has been carried out under controlled and validated aseptic conditions.

Special precautions for storage

Do not store above 25°C.

Keep the vial in the outer packaging to protect it from light.

For storage conditions after reconstitution of the medicinal product, see section "Shelf life".

Any unused solution should be discarded.

Nature and contents of container

Type I glass vial (Ph. Eur.) of brown colour, with elastomeric stopper, containing sterile orange-red concentrated powder.

Pack of 1, 10 or 20 vials of lyophilised powder.

Only some pack sizes may be marketed.

Incompatibilities

Compatibility with infusion solutions: no incompatibilities are currently known. The use of mixed infusion is decided by the responsible physician. Visible indicators of incompatibility include, for example, flocculation, cloudiness and discoloration.

Special precautions for disposal and other handling

Do not use unless the solution is clear and the container is intact.

Using a syringe, inject 5 mL of water for injections, 5% glucose solution or 0.9% sodium chloride solution into the vial.

Gently mix to dissolve the powder.

The resulting solution is clear and orange-red in colour.

Disposal of unused medicinal product and all materials that have been in contact with it must be carried out in accordance with local regulations.