NATROVIT POWDER FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Natrovit Powder for Concentrate for Solution for Infusion EFG

Retinol (Vitamin A), Cholecalciferol (Vitamin D3), α-Tocopherol (Vitamin E), Ascorbic Acid (Vitamin C), Thiamine (Vitamin B1), Riboflavin (Vitamin B2), Pyridoxine (Vitamin B6), Cyanocobalamin (Vitamin B12), Folic Acid, Pantothenic Acid, Biotin, Nicotinamide (Vitamin B3)

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

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

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

- If you have any further questions, ask your doctor, pharmacist, or nurse.

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

• If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

The name of this medicine is «Natrovit Powder for Concentrate for Solution for Infusion EFG». In this leaflet, it will be referred to as «Natrovit».

Contents of the pack and other information

1. What is Natrovit and what is it used for
2. What you need to know before you use Natrovit
3. How to use Natrovit
4. Possible side effects
5. Storage of Natrovit

1. Contents of the pack and other information

1. What is Natrovit and what is it used for

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

2. What you need to know before you use Natrovit

Contraindications are diseases or circumstances in which certain medicines should not be used, or can only be used after careful evaluation by the doctor, because the relationship between the expected benefit and the possible risks is generally not favorable. So that the doctor can carefully check for contraindications, you must inform him of all the diseases you have had, of current diseases, of other treatments you are receiving, and of your particular circumstances and habits. Additionally, contraindications may not be present or may not become apparent until after the start of treatment with this medicine. In these cases, you should also inform your doctor.

Do not useNatrovitif:

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

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use 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 a vitamin B12 deficiency,
• you have diabetes, as Natrovit may affect blood glucose measurements.

Hypersensitivity reactions

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

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

Your doctor will keep you under observation during the infusion to ensure you are receiving the correct amount of vitamins. Inform your doctor immediately if you notice signs of an allergy, such as sweating, fever, chills, headache, skin rash, urticaria, or redness, or if you experience breathing difficulties. The infusion will be stopped immediately and necessary emergency measures will be taken.

Due to the content of glycolic acid, close monitoring of liver function is required with repeated or long-term administration of Natrovit 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 going to have laboratory tests, you must inform your doctor or the laboratory staff that you are receiving or have recently received NATROVIT, as biotin may affect the results of these tests. Depending on the test, the results may show false elevations or false reductions due to biotin. Your doctor may advise you to stop receiving NATROVIT before having laboratory tests. 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 the results of laboratory tests. Inform your doctor or the laboratory staff if you are taking this type of product.

Using Natrovit with other medicines

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

You should be especially careful if you are using 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 iron overload),
• efavirenz, zidovudine, tipranavir (HIV treatments),
• ethionamide, cycloserine, isoniazid (for tuberculosis),
• fluoropyrimidines, raltitrexed, bexarotene (cancer treatments),
• methotrexate, sulfasalazine, penicillamine (for rheumatoid arthritis),
• pyrimethamine (anti-malarial drug),
• levodopa (used to treat Parkinson's disease),
• triamterene, hydralazine (for heart disease),
• phenelzine (for depression),
• theophylline (treatment for respiratory diseases and asthma),
• warfarin (anticoagulant).

Pregnancy, breast-feeding, and fertility

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

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

Breast-feeding

The ingredients/metabolites of Natrovit are excreted in breast milk, but at therapeutic doses of Natrovit, no effects are expected in newborns/children during breast-feeding. Natrovit can be used during breast-feeding.

Fertility

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

Natrovit contains sodium

This medicine contains 25 mg of sodium (a major component of table/cooking salt) in each vial. This is equivalent to 1.25% of the maximum recommended daily intake of sodium for an adult.

To be taken into consideration by patients on a controlled sodium diet.

3. How to use Natrovit

Natrovit is a preparation administered by healthcare professionals. You will normally receive Natrovit as an intravenous infusion.

Dosage and administration

Dosage

Unless otherwise prescribed, the following dosage recommendations apply:

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

Administration

For intravenous infusion.

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

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

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

Natrovit can be added to certain infusion solutions for parenteral nutrition that contain carbohydrates, lipids, amino acids, and electrolytes. However, compatibility and stability with the corresponding solution must first be ensured.

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

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

If you have any other questions 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 dosage range.

Signs of overdose are, among others, nausea and vomiting, headache, confusion, and skin peeling.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effect is common (may affect up to 1 in 10 people):

• Pain at the infusion site

The following side effects are uncommon (may affect up to 1 in 100 people):

• Feeling sick (nausea) and vomiting

The following side effects have been reported, but their frequency is not known:

• Allergic reactions with difficulty breathing, chest pain, feeling of constriction in the throat, skin rash, feeling of heat, flushing, abdominal pain, and heart problems.
• Increased vitamin A and vitamin A-binding protein in the blood
• Alteration of taste (metallic taste)
• Fast heartbeat
• Rapid breathing
• Diarrhea
• Increased liver enzymes and bile acids
• Itching (pruritus)
• Fever, general malaise, reactions at the infusion site such as burning and feeling of heat

Soy lecithin may rarely cause allergic reactions.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Medicines Monitoring System, www.notificaRAM.es.

By reporting side 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 which is stated on the vial and on the outer packaging after EXP. The expiry date is the last day of the month stated.

After reconstitution, any unused solution must be discarded immediately.

Do not store above 25°C.

Store the vials in the outer packaging to protect them from light.

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

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

Natrovit should not be used if the solution is not clear or the vial is not intact.

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

6. Container Content and Additional Information

Composition ofNatrovit

• The active ingredients are:

• The other components are:

Glycine, glycolic acid, soy lecithin, sodium hydroxide (pH adjuster), and hydrochloric acid (pH adjuster).

Patients with low-sodium diets should note that this medication contains 25 mg (approximately 1.09 mmol) of sodium per vial.

Product Appearance and Container Content

Natrovit is a powder for concentrate for solution for infusion; it is presented as orange to reddish-orange inside a brown glass vial, sealed with an elastomer stopper and an overlaid aluminum cap.

Each container contains the vial with the lyophilized powder.

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

Only some package 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 Member States of the European Economic Area 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 the last revision of this leaflet: 09/2024

This information is intended only for healthcare professionals:

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

Excipients:Glycine,glycolic acid,soy lecithin (phosphatidylcholine),sodium hydroxide (for pH adjustment),hydrochloric acid (for pH adjustment)

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

Posology and Method of Administration

Posology

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 content of the single-dose vial is dissolved by adding 5 mL of a suitable diluent (water for injectable preparations, 0.9% sodium chloride, or 5% dextrose) and gently mixing.

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

Natrovit can be added to certain infusion solutions for parenteral nutrition containing carbohydrates, lipids, amino acids, and electrolytes to meet nutritional needs and prevent deficiency symptoms and complications. However, compatibility and stability with the corresponding solution must first be ensured.

Reconstitution and addition to the infusion solution should 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 condition and vitamin levels should be monitored.

It should be noted that some vitamins, especially vitamins A, B2, and B6, are sensitive to ultraviolet light (direct or indirect sunlight). Additionally, 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 ingredients, especially suspected hypersensitivity to thiamine.

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

Hypersensitivity to any other vitamin or to soy derivatives/proteins contained in Natrovit (phospholipids are an excipient obtained from soybeans), or peanut proteins or products, or 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 described in relation to multivitamin preparations and individual vitamins (such as vitamins B1, B2, B12, and folic acid). Fatal outcomes have been reported in association with multivitamin preparations and other parenteral vitamin preparations.

• Cross-allergic reactions have been observed between soy proteins and peanuts.
• In some cases, the manifestation of a hypersensitivity reaction during intravenous administration of multiple vitamins may be related to the infusion rate. Therefore, Natrovit should be infused slowly.
• If signs or symptoms of a hypersensitivity reaction are detected, the infusion or injection should be discontinued immediately.

Vitamin toxicity

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

Hypervitaminosis, vitamin A

• There is a higher 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 liver insufficiency
• patients of short stature (e.g., children)
• patients receiving long-term treatment

• In patients with depletion of hepatic vitamin A storage capacity, acute liver disease can lead to the manifestation of vitamin A toxicity.

Refeeding syndrome in patients with parenteral nutrition

In patients with extreme malnutrition, the introduction of nutrients can trigger a refeeding syndrome. This syndrome is characterized by the entry of potassium, phosphorus, and magnesium into the intracellular space, while the patient enters anabolism. Additionally, thiamine deficiency and fluid retention may occur. These complications can be prevented by close monitoring and gradual increase in nutrient intake, avoiding overfeeding at the same time. In case of nutritional deficiency, appropriate replacement therapy may be indicated.

Precipitates in patients with parenteral nutrition

In patients with 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 solutions without phosphate salts. Additionally, precipitates have been found distal to the integrated filter, and suspected cases of precipitate formation in the bloodstream have been reported.

The solution, infusion set, and catheter should be inspected at regular intervals to detect possible precipitates.

If signs of respiratory distress occur, the infusion should be discontinued and a medical examination should be performed.

Precautions

Hepatic effects

• It is recommended to monitor liver function tests during the use of Natrovit. Close monitoring is especially indicated in patients with hepatic jaundice or signs indicative of cholestasis.

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

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

• It is known that hepatobiliary disorders can occur with parenteral nutrition (even with additional vitamin replacement). These disorders are cholestasis, steatosis, fibrosis, and cirrhosis, possibly with subsequent liver failure, as well as cholecystitis and cholelithiasis. These diseases probably have a multifactorial underlying cause that can vary from patient to patient. In case of manifest analytical results or other signs of hepatobiliary disease, the necessary measures should be taken for a hepatologist to perform a diagnostic study as soon as possible, in order to identify possible causal or contributing factors and initiate prophylaxis and treatment.

Use in patients with liver insufficiency

Patients with liver insufficiency may require personalized vitamin replacement.

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

Due to the content of glycolic acid, close monitoring of liver function is required with repeated or long-term administration of Natrovit to patients with hepatic jaundice or significant biochemical signs of cholestasis.

Use in patients with renal insufficiency

Patients with renal insufficiency may require personalized vitamin replacement, depending on the degree of renal dysfunction and possible concomitant diseases. In patients with severe renal insufficiency, special attention should be paid to ensuring sufficient vitamin D concentration and preventing vitamin A toxicity. These patients may suffer from vitamin A toxicity even with low doses or without replacement therapy.

In patients undergoing long-term hemodialysis who received an intravenous multivitamin solution three times a week with 4 mg of pyridoxine (vitamin B6), pyridoxine hypervitaminosis and toxicity (peripheral neuropathy, involuntary movements) have been described.

General monitoring

In patients receiving vitamins for a prolonged period exclusively through parenteral multivitamin solutions, it is necessary to monitor the clinical condition and vitamin concentrations, while ensuring adequate replacement of:

• vitamin A in patients with scars, 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 necessary on an individual basis, whose need may increase due to pharmacological interactions

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

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

Natrovit does not contain vitamin K. If necessary, 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, the vitamin B12 concentration should be determined before starting Natrovit administration.

In the presence of megaloblastic anemia associated with vitamin B12 deficiency, it is possible that the erythrocyte count, reticulocyte count, and hemoglobin 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 could 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, replacement of folic acid alone (without concurrent consumption of vitamin B12) is not sufficient to prevent the appearance 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 results, it should be remembered that values after vitamin B12 consumption may be within the normal range, and yet, there may be a tissue deficiency.

Interference with laboratory tests

Biotin can interfere with clinical laboratory tests based on the interaction between biotin and streptavidin, which can result in falsely reduced or elevated results, depending on the type of test. The risk of interference is higher in children and in patients with renal insufficiency and increases with higher doses. When interpreting laboratory test results, possible biotin interference should be taken into account, particularly if there is an inconsistency with the clinical presentation (e.g., thyroid test results reminiscent 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 this interference is suspected, alternative tests that are not susceptible to biotin interference should be used, if available. Laboratory personnel should be consulted when requesting analytical tests for patients receiving biotin.

Depending on the reagents used, the presence of ascorbic acid in blood or urine can result in a falsely high or low glucose value in some systems for determining blood glucose and glucosuria (test strips, glucometers, etc.). To determine possible vitamin interference, the technical information of the corresponding analytical test should be consulted.

Pediatric use

Natrovit is indicated in pediatric 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 should be evaluated for elderly patients (dose reduction and/or prolongation of administration intervals), as liver, kidney, or heart 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 the WHO for an adult.

Do not dissolve directly in electrolyte and oligoelement concentrates.

Use only transparent solutions in intact containers.

Interaction with Other Medicinal Products and Other Forms of Interaction

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

Possible interactions:

• Drugs that can cause pseudotumor cerebri (such as some tetracyclines): increased risk of pseudotumor cerebri with concomitant administration of vitamin A
• Alcohol (excessive and prolonged consumption): increases the risk of hepatotoxicity due to vitamin A
• Anticonvulsants (phenytoin, fosphenytoin, phenobarbital, primidone): folic acid replacement may reduce the serum concentration of anticonvulsants and increase the risk of seizures
• Antiplatelet agents (e.g., acetylsalicylic acid): vitamin E may potentiate the inhibition of platelet function
• Acetylsalicylic acid (high-dose treatment): may reduce folic acid concentration, increasing the risk of deficiency

• Urinary excretion
• Certain anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, valproate): may cause folate, pyridoxine, and vitamin D deficiency
• Certain antiretroviral preparations: efavirenz and zidovudine, for example, are associated with a decrease in vitamin D concentration. Protease inhibitors are associated with decreased formation of the active metabolite of vitamin D
• Chloramphenicol: may inhibit the hematologic response to vitamin B12 treatment
• Deferoxamine: increased risk of iron-induced heart failure due to increased iron mobilization caused by supraphysiological replacement of vitamin C. The deferoxamine datasheet lists specific preventive measures.
• 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 treatment
• Folic acid antimetabolites (methotrexate, raltitrexed): folic acid replacement may attenuate the effects of antimetabolites
• Pyridoxine antagonists, such as cycloserine, hydralazine, isoniazid, penicillamine, and phenelzine: may cause pyridoxine deficiency

• Retinoids, such as bexarotene: increase the risk of toxicity with concomitant administration of vitamin A (see section on Hypervitaminosis, vitamin A).
• Theophylline: may cause pyridoxine deficiency
• Tipranavir oral 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 neutralized by combining it with decarboxylase inhibitors (carbidopa and benserazide).

Active ingredients that bind to alpha-1-acid glycoprotein

In an in vitro study with human serum, at a concentration of glycolic acid approximately 4 times higher than the serum concentration of glycolic acid achieved after a bolus injection of multivitamins in adults, the free fraction of selected active ingredients that bind to alpha-1-acid glycoprotein increased by between 50% and 80%.

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

Patient monitoring is recommended for patients receiving medications that bind to alpha-1-acid glycoprotein in addition to Natrovit, in order to detect increases due to the concomitant use of these products, such as propranolol, prazosin, and others.

Interaction in case of additional vitamin replacement

With some medications, interactions may occur when administering certain vitamins in quantities significantly higher than the doses contained in Natrovit. This possibility should be taken into account when the intake of vitamins comes from several sources. If necessary, patient monitoring is required to detect such interactions and take appropriate measures.

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 the bleeding tendency associated with high doses of vitamin A

• Carbamazepine: high doses of nicotinamide are associated with inhibition of its metabolism

• Antineoplastics that produce reactive oxygen species: possible inhibition of antineoplastic activity due to the antioxidant effects of high doses of vitamin E

• Insulin, antidiabetics: high doses of nicotinamide are associated with reduced insulin sensitivity

• Iron: replacement treatment with high doses of vitamin E could reduce the hematologic response to iron therapy in patients with anemia

• Oral contraceptives (combined hormonal products): high doses of vitamin C are associated with intermenstrual metrorrhagia and contraceptive ineffectiveness
• Phenobarbital: high doses of pyridoxine are associated with increased metabolism/lower serum concentration and attenuation of the effect
• Phenytoin, fosphenytoin: high doses of pyridoxine are associated with decreased serum concentration
• Primidone: high doses of nicotinamide are associated with reduced metabolism of phenobarbital and increased primidone concentration

Overdose

No cases of overdose are 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 several sources and the total replacement of a vitamin does not meet the individual needs of the patient or if the patient is particularly prone to hypervitaminosis (see section on 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 fontanelles.

Symptoms of overdose after multiple-dose treatment:

Symptoms of chronic overdose:

Symptoms of increased intracranial pressure, skin scaling 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 the absorption of calcium and phosphate from the intestinal lumen and mobilize calcium from bones, so vitamin D has a more anti-rachitic effect, while the product of its reduction, DHT (dihydroxytachysterol), is more effective in mobilizing 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 phosphorus, hypercalcemic syndrome may occur, which in turn causes calcium deposits in tissues, especially in the kidneys (nephrolithiasis, nephrocalcinosis) and blood vessels (hypertension). The clinical picture of hypercalcemia syndrome is not characteristic: weakness, fatigue, exhaustion, headache, nausea, vomiting, and diarrhea, as well as polyuria, polydipsia, nocturia, and proteinuria in patients with decreased renal concentrating capacity. Especially in cases where a psychosyndrome with confusion predominates, it is easy to overlook the symptoms of intoxication (e.g., diabetes mellitus, malignant neoplasia, psychosis). From a diagnostic point of view, it is characterized by increased calcium, phosphorus, 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 product administration.

1. Vitamin A overdose

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

1. Hypercalcemia

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

Pharmaceutical data

Shelf life

Unopened: 2 years.

Physical and chemical stability of Natrovit powder for solution for infusion has been demonstrated for 24 hours after reconstitution with 5 mL of water for injectable preparations, 5 mL of 0.9% sodium chloride, or 5 mL of 5% dextrose, and storage at 25 ± 2°C and under refrigeration conditions. From a microbiological point of view, the product should be used immediately. Otherwise, the times and conditions of storage prior to use are the responsibility of the user and should not generally 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 storage precautions

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.) with a brown color, with an elastomeric stopper, containing sterile orange-red powder.

Box of 1, 10, or 20 vials of lyophilized powder.

Only certain pack sizes may be marketed.

Incompatibilities

Compatibility with infusion solutions: no incompatibilities are known to date. The use of mixed infusion is decided by the responsible physician. Visible indicators of incompatibility are, for example, flocculation, clouding, 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 injectable preparations, 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 color.

Disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.