Summary of Product Characteristics

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

NATROVIT Powder for Solution for Infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial with 750mg powder for solution for infusion (lyophilisate) contains: Equivalent to: Retinol palmitate 1.924mg Retinol (Vitamin A) 3500 IU

Cholecalciferol 5.5μg Cholecalciferol (Vitamin D3) 220 IU all-rac-alpha-Tocopherol 10.20 mg α-Tocopherol (Vitamin E) 10.20mg Ascorbic acid 125 mg Ascorbic Acid (Vitamin C) 125 mg

Cocarboxylase tetrahydrate 5.80 mg Thiamine (Vitamin B1) 3.51 mg Riboflavin sodium phosphate dihydrate 5.67 mg Riboflavin (Vitamin B2) 4.14 mg Pyridoxine hydrochloride 5.50 mg Pyridoxine (Vitamin B6) 4.53 mg Cyanocobalamin 6 μg Cyanocobalamin (Vitamin B12) 6 μg Folic acid 414 μg Folic Acid 414 μg Dexpanthenol 16.15 mg Pantothenic acid 17.25 mg D-Biotin 69 μg Biotin 69 μg

Nicotinamide 46 mg Nicotinamide (Vitamin B3) 46 mg pH value: 5.0-6.0 Osmolality almost 1000mOsm/Kg (reconstituted solution)

Excipient(s) with known effect: Soya lecithin. Sodium content: 25 mg (approximately 1.09 mmol) / vial.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion.

Lyophilized orange to red sterile powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Supply of vitamins corresponding to the daily needs of adults and children over 11 years, provided that oral nutrition is contraindicated, or not possible and vitamin replacement as part of parenteral nutrition is required.

4.2 Posology and method of administration

Posology Single and daily doses

Unless otherwise prescribed, the following dosing guidelines apply:

Adults and Children over 11 years: One vial per day reconstituted with Water for Injection (5 mL) or other compatible IV solutions (5 mL) as described under “method of administration”.

Method and duration of administration

For intravenous infusion. NATROVIT is intended exclusively for use as an additive to solutions for infusion.

NATROVIT Powder for Solution for Infusion is a sterile preparation. Thus, aseptic procedure must be applied throughout the administration and reconstitution.

The single dose vial of NATROVIT Powder for Solution for Infusion is reconstituted by adding 5mL of sterile Water for Injection or other intravenous fluids (0.9% Sodium Chloride Injection or 5% Glucose Injection). Five millilitres (5mL) of diluent should be added by means of sterile syringe into the vial and gently mixed to dissolve the lyophilised powder.

The resultant solution should then be added to a solution for infusion (e.g. 0.9% Sodium Chloride or 5% Glucose) and administered by slow Intravenous Infusion (at least over one to two hours).

NATROVIT can be added to certain solutions for infusion for parenteral nutrition containing carbohydrates, fats, amino acids and electrolytes, in order to meet nutritional requirements and to prevent symptoms of deficiency and complications. However, compatibility and stability with the respective solution must firstly be ensured.

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

Total vitamin intake from all sources must be considered, e.g. from foodstuffs, other vitamin preparations or from medicinal products containing vitamins as excipients (see section 4.5).

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

It should be remembered that some vitamins, especially vitamins A, B2 and B6, react sensitively to ultraviolet light (direct or indirect sunlight). Furthermore, the concentration of vitamins A, B1, C and E may decrease with increasing oxygen levels in the solution. These factors must be considered if no adequate vitamin levels are achieved.

The total duration of use (even after intermittent administration) must be restricted to 4 weeks, due to the lack of sufficient long-term studies.

For instructions on reconstitution/dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Hypervitaminosis involving any of the vitamins contained in NATROVIT. Suspected thiamine hypersensitivity. Patients in whom signs of thiamine intolerance have occurred must not be given NATROVIT. Known hypersensitivity to any of the other vitamins or soya proteins/soya products contained in NATROVIT (phospholipids are an excipient and are derived from soya beans). NATROVIT contains soya lecithin and is contraindicated in patients who have peanut or soya allergies.

4.4 Special warnings and precautions for use

Warnings

Hypersensitivity reactions

 Severe systemic hypersensitivity reactions have been described in connection with multivitamin, other multivitamin preparations and individual vitamins (including vitamins B1, B2, B12 and folic acid). In association with multivitamin and other parenteral vitamin preparations, reactions with fatal outcome have been reported (see section 4.8).

 In some cases, manifestation of a hypersensitivity reaction during intravenous multivitamin administration might be linked to the infusion rate. Therefore NATROVIT should be infused slowly.

 In the event of signs or symptoms of a hypersensitivity reaction, discontinue the infusion immediately.

Vitamin toxicity  To avoid overdose and toxicity, the patient’s clinical status and vitamin blood levels must be monitored, particularly with regard to vitamins A, D and E. This particularly applies to patients receiving additional vitamins from other sources or who are using substances that increase the risk for the onset of vitamin toxicity.

 Monitoring is particularly important in long-term replacement.

Hypervitaminosis, vitamin A  There is an increased risk for the onset of vitamin A hypervitaminosis and vitamin A toxicity (e.g. skin and bone changes, diplopia, cirrhosis), for instance, in:  patients with protein malnutrition  patients with impaired renal function (even without vitamin A replacement)  patients with impaired hepatic function  patients of short stature (e.g. children)  patients on long-term treatment  In patients whose hepatic vitamin A storage capacity is exhausted, acute liver disease may lead to the manifestation of vitamin A toxicity.

Refeeding syndrome in patients on parenteral nutrition In severely malnourished patients, the introduction of nutrition may trigger a refeeding syndrome. This is characterised by a shift of potassium, phosphorus and magnesium into the intracellular space, whilst the patient becomes anabolic. Furthermore, thiamine deficiency and fluid retention may occur. Such complications can be prevented by careful monitoring and a slow increase in nutrient intake, whilst avoiding overfeeding. In the event of a nutrient deficiency, appropriate replacement may be indicated.

Precipitates in patients on parenteral nutrition In patients on parenteral nutrition, precipitates have been observed in the pulmonary vessels. Some of these cases had a fatal outcome. Excessive addition of calcium and phosphate increases the risk for the formation of calcium phosphate precipitates. Precipitates have also been observed with solutions free from phosphate salts. Furthermore, precipitates have been found distal to the integrated filter and suspected cases of precipitate formation in the bloodstream have been reported. In addition to the solution, the infusion set and catheter should also be checked for precipitates at regular intervals. If signs of pulmonary respiratory distress occur, discontinue the infusion and arrange for a medical examination.

Precautions

Furthermore, an increase in the concentration of bile acids has been described with NATROVIT (total and individual, including glycocholic acid).  It is known that hepatobiliary disorders may occur with parenteral nutrition in some cases (even with additional vitamin replacement). These include cholestasis, steatosis, fibrosis and cirrhosis possibly resulting in hepatic insufficiency, as well as cases of cholecystitis and cholelithiasis. These diseases probably have an underlying multifactorial aetiology, which can vary from patient to patient. In the event of conspicuous laboratory findings or other signs of hepatobiliary disease, arrangements must be made for a prompt investigation by a physician experienced in hepatopathology, in order to identify potentially causative or contributing factors and to initiate therapeutic and prophylactic measures.

Use in patients with impaired hepatic function Patients with impaired hepatic function may require individually tailored vitamin replacement. Particular attention should be given to the prevention of vitamin A toxicity, as the presence of hepatic disease is associated with increased susceptibility to vitamin A toxicities, especially in the presence of chronic excessive alcohol consumption (see above sections “Hypervitaminosis, vitamin A” and “Hepatic effects”). Due to the glycocholic acid content, careful monitoring of liver function is required with repeated administration or long-term administration of NATROVIT to patients with hepatic jaundice or significant biochemical signs of cholestasis.

Use in patients with impaired renal function Patients with impaired renal function may require individually tailored vitamin replacement, depending on the degree of renal dysfunction and possible comorbidities. In patients with severely impaired renal function, particular attention should be paid to ensure an adequate vitamin D status and to prevent vitamin A toxicity. Vitamin A toxicities may occur in these patients on low-dose vitamin A replacement and even without replacement. In long-term haemodialysis patients receiving a thrice-weekly intravenous multivitamin solution with 4 mg pyridoxine (vitamin B6), pyridoxine hypervitaminosis and toxicities (peripheral neuropathy, involuntary movements) have been described.

General monitoring In patients receiving their vitamins over a prolonged period exclusively via parenteral multivitamin solutions, monitoring of clinical status and vitamin levels is required, whilst in particular ensuring, for example, adequate replacement of:  vitamin A in patients with bedsores, wounds, burns, short bowel syndrome or cystic fibrosis

 vitamin B1 in dialysis patients  vitamin B2 in cancer patients  vitamin B6 in patients with impaired renal function  vitamins required on an individual basis, the need for which may be increased due to drug interactions (see section 4.5) Deficiency of one or more vitamins should be corrected by specific replacement. If NATROVIT is used beyond a 3-week period, blood count monitoring and laboratory monitoring of liver enzyme tests must be performed.

NATROVIT contains no vitamin K. If required, this must be administered separately.

In existing vitamin B12 deficiency, replacement of folic acid alone - without concomitant vitamin B12 intake - is not sufficient to prevent the onset or progression of neurological symptoms associated with vitamin B12 deficiency. There are suggestions that functional neurological impairment may even be accelerated. When interpreting vitamin B12 levels, it should be remembered that values after previous vitamin B12 intake may be within the normal range, although a deficiency is present within tissue.

Influence on laboratory results Depending on the reagents used, the presence of ascorbic acid in the blood or urine may lead to falsely high or falsely low glucose levels in some systems for the determination of urine and blood glucose (test strips, blood glucose meter, etc.). To establish potential interference by vitamins, the technical information for the respective laboratory test must be consulted.

Use in children and adolescents NATROVIT is indicated for paediatric patients over 11 years. Use in elderly patients In general, an adjustment in the dosage regimen must be considered in elderly patients (dose reduction and/or prolongation of dosing intervals), as impaired hepatic, renal or cardiac function, as well as comorbidities and concomitant medications, are more common in this population.

Sodium content

This medicinal product contains 25 mg sodium per vial, equivalent to 1,25% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Do not dissolve directly with electrolyte and trace element concentrates.

Use only clear solutions in intact containers.

4.5 Interaction with other medicinal products and other forms of interaction

In the event of interactions between specific vitamins contained in NATROVIT and other substances, appropriate measures must be taken.

Possible interactions:  Agents that can cause pseudotumor cerebri (including certain tetracyclines): increased risk for the onset of pseudotumor cerebri with concomitant administration of vitamin A  Alcohol (chronic excessive consumption): increases the risk for the onset of vitamin A hepatotoxicity  Anticonvulsants (phenytoin, fosphenytoin, phenobarbital, primidone): replacement folic acid may reduce anticonvulsant serum levels and increase the risk of seizure  Platelet aggregation inhibitors (e.g. acetylsalicylic acid): vitamin E may potentiate inhibition of platelet function  Acetylsalicylic acid (high-dose treatment): can reduce folic acid levels by increasing urinary excretion  Certain anticonvulsants (e.g. phenytoin, carbamazepine, phenobarbital, valproate): may cause folic acid, pyridoxine and vitamin D deficiency  Certain antiretroviral preparations: efavirenz and zidovudine, for example, are associated with decreased vitamin D levels. Protease inhibitors are associated with decreased formation of the active vitamin D metabolite.

 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 make replacement less effective.  Folic acid antimetabolites (methotrexate, raltitrexed): replacement folic acid can attenuate the effects of the antimetabolites  Pyridoxine antagonists, including cycloserine, hydralazine, isoniazid, penicillamine, phenelzine: may cause pyridoxine deficiency  Retinoids, including bexarotene: increase the risk of toxicity with concomitant administration of vitamin A (see section 4.4: hypervitaminosis A)  Theophylline: may cause pyridoxine deficiency  Tipranavir oral solution: contains 116 IU/mL vitamin E and thus exceeds the recommended daily dose  Vitamin K antagonists (e.g. warfarin): increased anticoagulant effect due to vitamin E

Active substances that bind to alpha-1-acid glycoprotein: In an in vitro study with human serum, at a glycocholic acid concentration approximately 4 times higher than the glycocholic acid serum concentration achieved after a NATROVIT bolus injection in adults, the free fraction of selected active substances known to bind to alpha-1-acid glycoprotein increased by 50-80%. It is not known whether this effect is clinically relevant when the amount of glycocholic acid contained in a standard NATROVIT dose (as a component of the mixed micelles) is administered as a slow intravenous injection, intramuscular injection or infusion over a prolonged period. Patients using medicinal products that bind to alpha-1-acid glycoprotein in addition to NATROVIT must be carefully monitored for increases occurring as a result of concomitant use of these products. This applies to medicinal products such as propranolol, prazosin and various others.

Interaction in case of additional vitamin replacement: With some medicinal products, interactions can occur when certain vitamins are supplied in amounts significantly higher than the doses contained in NATROVIT. This must be considered when vitamins are supplied from several sources. If applicable, monitoring for such interactions and suitable measures are required. Possible interactions:

 Amiodarone: concomitant administration of vitamin B6 may enhance amiodarone-induced photosensitivity  Substances with anticoagulant activity (e.g. abciximab, clopidogrel, heparin, warfarin): increased risk of bleeding due to additional bleeding tendency associated with high vitamin A doses  Carbamazepine: high nicotinamide doses are associated with inhibition of its metabolism  Chemotherapy agents which act by producing reactive oxygen species: potential inhibition of chemotherapeutic activity due to the antioxidant effects of high-dose vitamin E  Insulin, antidiabetics: high nicotinamide doses are associated with a reduction in insulin sensitivity  Iron: high-dose vitamin E replacement may reduce the haematological response to iron therapy in anaemic patients  Oral contraceptives (combined hormonal products): high vitamin C doses are associated with breakthrough bleeding and failure of the contraceptive effect  Phenobarbital: high pyridoxine doses are associated with increased metabolism/lower serum levels and attenuation of the effect  Phenytoin, fosphenytoin: high pyridoxine doses are associated with reduced serum levels  Primidone: high nicotinamide doses are associated with reduced metabolism of phenobarbital and elevated primidone levels

4.6 Fertility, pregnancy and lactation

Pregnant and lactating women may have higher vitamin requirements in some cases.

Before using NATROVIT, doctors must carefully weigh the possible risks and the possible benefit for each patient.

Pregnancy To date, there are no adequate data from the use of NATROVIT in pregnant women. In addition, animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Vitamin A: During pregnancy, the recommended maximum daily dose is 2.4 mg retinol equivalent or 8,000 IU and the maximum single dose is 0.9 mg retinol equivalent or 3,000 IU. If high doses of vitamin A are taken during pregnancy, there is a risk of infant malformations. Vitamin D: Overdose of vitamin D during pregnancy must be prevented, as sustained hypercalcaemia may lead to physical and mental retardation, supravalvular aortic stenosis and retinopathy in the child.

Vitamin B12: The recommended daily vitamin B12 allowance during pregnancy is 4 g. Based on experience to date, higher doses have no adverse effects on the foetus. Folic acid: Controlled studies in pregnant women with daily doses of up to 5 mg folic acid have shown no evidence of harm to the embryo or foetus. Folic acid supplementation may reduce the risk of neural tube defects. As the safety of higher doses is not assured, doses in excess of 5 mg folic acid per day are contraindicated during pregnancy and breastfeeding.

Breastfeeding Ingredients/metabolites of NATROVITare excreted in human milk. At therapeutic doses, no effects on the breastfed infant are to be expected. NATROVIT may be administered during breastfeeding.

The recommended daily vitamin B12 allowance during breastfeeding is 4 g. Based on experience to date, higher doses have no adverse effects on the infant. There are no known risks for doses up to 5 mg folic acid per day. Folic acid must not be used during breastfeeding at doses higher than 5 mg per day.

Fertility No data are available. At therapeutic doses, no effects are to be expected.

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

Adverse reactions that have occurred in association with treatment with multivitamin are listed together with their relative frequencies. This table contains adverse reactions from clinical trials and post-marketing reports. Multivitamin has been investigated in 3 clinical studies on 267 adult patients requiring vitamin supplementation.

Frequency is stated as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); or not known (cannot be estimated from the available data). System organ class Preferred MedDRA Term Frequencya Immune system disorders: Systemic hypersensitivity reactions with Not known manifestations such as dyspnoea, chest discomfort, throat tightness, urticaria, rash, erythema, epigastric discomfort, cardiac arrest with fatal outcome Anaphylactic reaction Metabolism and nutrition Vitamin A levels increased a,b Not knownc disorders Retinol-binding protein increasedb Not knownc

Nervous system disorders Dysgeusia (metallic taste) Not known

Cardiac disorders Tachycardia Not known

Respiratory, thoracic and Tachypnoea Not known mediastinal disorders Gastrointestinal disorders Vomiting Uncommon Nausea Uncommon Diarrhoea Not known Hepatobiliary disorders Transaminases increased Not knownc Alanine aminotransferase increased (isolated) Not knownc Glutamate dehydrogenase increased Not knownc Blood alkaline phosphatase increased Not knownc Bile acid concentration increasede Not known Gamma-glutamyltransferase increased Not known Skin and subcutaneous tissue Pruritus Not known disorders General disorders and Injection/infusion site pain Common administration site conditions Pyrexia Not known Generalised pain Not known Infusion site reactions (burning, rash) Not known a No symptoms of vitamin A hypervitaminosis have been described b On day 45 of administration, increased vitamin A plasma levels were described in 8 of 20 patients receiving multivitamin as part of parenteral nutrition. Between days 45 and 90 of administration, increased vitamin A levels remained stable (reported peak value: 3.6 µmol/L on day 90; normal value: 1 - 2.6 µmol/L). Furthermore, an average increase in retinol-binding protein levels (RBP) has been described. The reported peak RBP value was 60 mg/L on day 90 (normal values: 30 – 50 mg/L). c Either the frequency could not be determined or the total number of patients in the individual studies was too small for any robust estimation of frequency. d In the presence of inflammatory bowel disease, an isolated increase in alanine aminotransferase levels has been described multivitamin was administered as an intravenous injection without parenteral nutrition. e With multivitamin use, an increase in bile acid concentrations (total and individual), including glycocholic acid, occurred early in the course of parenteral nutrition.

Soya lecithin can very rarely cause allergic reactions.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.*

4.9 Overdose

Overdose is not to be expected within the stated dose range.

An acute or chronic overdose of vitamins (especially vitamins A, B6, D and E) may lead to symptomatic hypervitaminosis. The risk of overdose is particularly high if vitamins are supplied from several sources and the total replacement of any vitamin does not meet the patient’s individual needs or if the patient is particularly susceptible to hypervitaminosis (see section 4.4). a) Symptoms of intoxication

Symptoms of vitamin A hypervitaminosis: Acute increase in cerebrospinal fluid pressure with headache, vomiting, dizziness, loss of consciousness. In infants, bulging fontanelles.

Symptoms of chronic overdose:

Intracranial pressure symptoms, skin desquamation and dryness, alopecia, bone and joint pain, radiological evidence of transformation zones.

Symptoms of vitamin D hypervitaminosis: Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) increase calcium and phosphate absorption from the intestinal lumen and mobilise calcium from bone, whereby vitamin D has more of an anti-rachitic effect, whilst its reduction product DHT (dihydrotachysterol) is more effective in calcium mobilisation from bones. All these substances have a relatively narrow therapeutic index. The toxic threshold in adults is > 0.5 mg/d for vitamin D and > 0.25 mg/d for DHT. However, single acute doses generally have no toxic effect.

In the event of overdose, in addition to a rise in serum and urinary phosphorus, hypercalcaemia syndrome may occur, subsequently leading to calcium deposits within tissues and especially the kidneys (nephrolithiasis, nephrocalcinosis) and blood vessels (hypertension). The clinical picture of hypercalcaemia syndrome is uncharacteristic: weakness, fatigue, exhaustion, headache, nausea, vomiting and diarrhoea, as well as polyuria, polydipsia, nocturia and proteinuria in patients with impaired renal concentrating ability. Particularly in cases where a psychosyndrome with confusion predominates, symptoms of intoxication are easily overlooked (e.g. diabetes mellitus, malignant neoplasm, psychosis). Diagnostically, this is characterised by an increase in calcium, phosphorus and NPN in plasma or serum, as well as possible osteoporosis and tissue or renal calcifications, which are identifiable radiographically. NB: repeated serum calcium monitoring and bone histology are required. b) Treatment of intoxication Immediate discontinuation of the product.

1. Vitamin A overdose: Pressure relief and continuous monitoring of cardiac, hepatic and renal function, blood counts and ocular fundus examination. 2. Hypercalcaemia: In patients with adequate renal function, infusions with isotonic NaCl solution (3 – 6 L in 24 hours) with the addition of furosemide, together with continuous calcium and ECG monitoring, have a very reliable calcium-lowering effect. However, haemodialysis therapy is indicated in cases of oligo-anuria. Glucocorticoids and calcitonin may be attempted. Warning: fatalities often occur even after normalisation of serum calcium levels.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Multivitamin preparation, ATC code: B05XC

The active substances contained therein are physiological substances and exert no pharmacological effect at the dosages stated.

5.2 Pharmacokinetic properties

The active substances contained therein are physiological substances and exert no pharmacological effect at the dosages stated.

5.3 Preclinical safety data

At physiological concentrations, there are no expected toxic effects on humans.

In a chronic toxicity study on dogs over 30 days, an approximately 3-fold therapeutic dose was tolerated without symptoms. After an approximately 10-fold therapeutic dose, initial toxic signs appeared (bone

marrow lipomatosis, slight increase in ALT) and after a 40-fold therapeutic dose, increased cholesterol and phospholipid levels, as well as a slight increase in alkaline phosphatase, also occurred.

Local tolerance after intravenous administration in rabbits can be considered good. However, following intradermal and intramuscular injection, tissue damage occurred in animals.

No studies on the mutagenic and carcinogenic potential of NATROVIT are available.

Toxicity to reproduction

No embryotoxicity studies with NATROVIT are available. However, the carrier system - known as mixed micelles (glycocholic acid + lecithin) - has been investigated. Embryotoxicity studies in rats and rabbits showed no evidence of a teratogenic potential. In rabbits, an approximately 10-fold therapeutic dose resulted in abortions. Use of an approximately 10 to 20-fold therapeutic dose in the peri/postnatal period in rats resulted in increased mortality of the offspring.

In animal experiments, both vitamin A deficiency and vitamin A overdose had a teratogenic effect. In animal reproductive toxicity studies, malformations (skeletal defects, microcephaly, cardiac malformations) were induced in cases of overdose with cholecalciferol during pregnancy in rats, mice and rabbits. No animal studies are available to establish the reproductive toxicological properties of folic acid.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Glycine Glycocholic acid Soya lecithin (phosphatidylcholine) Sodium hydroxide (pH adjuster) Hydrochloric acid (pH adjuster)

6.2 Incompatibilities

There are no known incompatibilities to date.

Compatibility with solutions for infusion: Solutions for infusion are deemed compatible if no cloudiness, flocculation or precipitation forms within 24 hours at room temperature.

The use of mixed infusions is decided by the physician in charge.

6.3 Shelf life

Unopened: 2 years.

Chemical and Physical in-use stability has been demonstrated for NATROVIT Powder for Solution for Injection or Infusion for 24 hours when reconstituted with 5ml of Water for Injections and stored under refrigeration. From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution etc has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25ºC.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Any unused solution must be discarded.

6.5 Nature and contents of container

Type I Ph.Eur. brown glass vial with an elastomer stopper, containing orange to red sterile powder.

Box of 1, 10 or 20 vials of lyophilised powder

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

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

Mix gently to dissolve the powder.

The obtained solution is clear and orange to red in colour.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

<[To be completed nationally]> {Name and address} <{tel}> <{fax}> <{e-mail}>

8. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY}>

<[To be completed nationally]>

10. DATE OF REVISION OF THE TEXT

<{MM/YYYY}> <{DD month YYYY}>

<[To be completed nationally]>

LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

NATROVIT Powder for solution for infusion

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial of powder contains:

Retinol (Vitamin A) 3500 IU Cholecalciferol (Vitamin D3) 220 IU α-Tocopherol (Vitamin E) 10.20mg Ascorbic Acid (Vitamin C) 125 mg Thiamine (Vitamin B1) 3.51 mg Riboflavin (Vitamin B2) 4.14 mg Pyridoxine (Vitamin B6) 4.53 mg Cyanocobalamin (Vitamin B12) 6 μg Folic Acid 414 μg Pantothenic acid 17.25 mg Biotin 69 μg Nicotinamide (Vitamin B3) 46 mg

3. LIST OF EXCIPIENTS

Excipients: glycine, glycocholic acid, soya lecithin, sodium hydroxide, hydrochloric acid

4. PHARMACEUTICAL FORM AND CONTENTS

Powder for Solution for Infusion

1 vial 10 vials 20 vials

5. METHOD AND ROUTE(S) OF ADMINISTRATION

For single intravenous use only.Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Sodium content is 25 mg / vial. Contains soya lecithin.

8. EXPIRY DATE

EXP:

9. SPECIAL STORAGE CONDITIONS

Store below 25C. Keep the vials in the outer carton in order to protect from light.

After opening, use immediately.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

Discard the remaining contents of the vial after use.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

12. MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

13. BATCH NUMBER

LOT:

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

Use only clear solutions. Do not use if cloudiness or precipitation is observed.

16. INFORMATION IN BRAILLE

[Not applicable. For hospital use only.]

17. UNIQUE IDENTIFIER – 2D BARCODE

<2D barcode carrying the unique identifier included.>

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

< PC: {number} [product code] SN: {number} [serial number] NN: {number} [national reimbursement number or other national number identifying the medicinal product]>

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

GLASS VIAL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

NATROVIT Powder for solution for infusion

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)

2. METHOD OF ADMINISTRATION

For single intravenous use only. 3. EXPIRY DATE

EXP:

4. BATCH NUMBER

LOT:

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

Sodium content is 25 mg / vial. Contains soya lecithin.

PACKAGE LEAFLET

Package leaflet: Information for the user

NATROVIT Powder for Solution for Infusion

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)

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 get 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 your medicine is NATROVIT : Powder for Solution for Infusion’. In the rest of this leaflet this medicine will be called ‘NATROVIT’.

What is in this leaflet 1. What NATROVIT is and what it is used for 2. What you need to know before you use NATROVIT 3. How to use NATROVIT 4. Possible side effects 5. How to store NATROVIT 6. Contents of the pack and other information

1. What NATROVIT is and what it is used for

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

2. What you need to know before you use NATROVIT

Contraindications are diseases or circumstances where certain medicines must not be used, or they may be used only after careful consideration by a doctor, in cases where the ratio between the expected benefit and possible risks is generally not favourable. So that the doctor can carefully check whether contraindications exist, he/she must be told about any previous illnesses, existing illnesses, other ongoing treatments and about your particular circumstances and habits. Furthermore, contraindications may not occur or become evident until after the start of treatment with this medicine. In such cases, you should also tell your doctor.

Do not use NATROVIT in the following cases:

 hypervitaminosis involving any of the vitamins contained in NATROVIT

 allergies (hypersensitivity) to any of the ingredients in NATROVIT, especially vitamin B1 and soya protein (see section 6)  children under 11 years

Warnings and precautions Talk to your doctor, pharmacist or nurse before using NATROVIT :

- if you suffer from kidney disease, - if you have liver disease - if you have cancer, - if you have short bowel syndrome, - if you have cystic fibrosis, - if you are taking vitamins from other sources (e.g. vitamin supplements), - if you know that you have vitamin B12 deficiency, - if you are diabetic NATROVIT can affect blood sugar level measurements).

Your doctor will monitor you during the infusion to ensure that you get the right amount of vitamins. Tell your doctor if you notice signs of an allergy or develop breathing difficulties.

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

Children Do not use this medicine in newborns, infants and children under 11 years of age.

Other medicines and NATROVIT

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

You must be especially careful if you are taking any of the following types of medicines: - Phenobarbital, phenytoin, primidone, carbamazepine, phenobarbital, valproate (used to treat epilepsy), - Aspirin (used to treat pain and inflammation), - Chloramphenicol, trimethoprim, tetracycline (used to treat bacterial infections), - Deferoxamine (used to treat iron poisoning or excessively high concentrations of iron in the body), - Efavirenz, zidovudine, tipranavir (used to treat HIV) - Ethionamide, cycloserine, isoniazid (used to treat tuberculosis), - Fluoropyrimidines, raltitrexed, bexarotene (used to treat cancer), - Methotrexate, sulphasalazine, penicillamine (used to treat rheumatoid arthritis), - Pyrimethamine (used to treat malaria), - Triamterene, hydralazine (used to treat heart disease), - Phenelzine (used to treat depression), - Theophylline (used to treat 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 for advice before taking this medicine.

Pregnancy There is no adequate experience with the use of NATROVIT in pregnant women. Your doctor will administer this solution for infusion only if he/she considers it necessary. Overdoses are to be avoided during pregnancy due to the risk of infant deformities.

Breast-feeding Ingredients/metabolites of NATROVIT are excreted in human milk. At therapeutic doses, no effects on the breast-fed infant are to be expected. NATROVIT can be used during breast-feeding.

Driving and using machines NATROVIT does not affect the ability to drive and use machines.

NATROVIT contains glycine, glycocholic acid, soya lecithin (phosphatidylcholine), sodium hydroxide (pH adjuster), hydrochloric acid (pH adjuster). This medicine contains 25 mg sodium (main component of cooking/table salt) in each vial. This is equivalent to 1.25 % of the recommended maximum daily dietary intake of sodium for an adult. This medicine contains soya lecithin. If you are allergic to peanut or soya, do not take this medicinal product.

3. How to use NATROVIT

NATROVIT is administered by healthcare professionals. Normally, you will be given NATROVIT as an infusion into a vein.

Dosing instructions and method of administration

Dosing instructions

Unless otherwise prescribed, the following dosing guidelines apply:

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

Method of administration

For intravenous infusion.

NATROVIT is intended exclusively for use as an additive to solutions for infusion. The contents of the injection vial are dissolved by injecting and gently shaking 5 mL of a suitable carrier solution (water for injections). Slow infusion in, for example, isotonic sodium chloride or glucose solution. NATROVIT can be added to certain solutions for infusion for parenteral nutrition containing carbohydrates, fats, amino acids and electrolytes. However, compatibility and stability with the respective solution must firstly be ensured. Reconstitution and addition to the solution for infusion must take place immediately prior to administration.

Duration of use

The total duration of use (even after intermittent administration) must be restricted to 4 weeks, due to the lack of sufficient long-term studies.

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

If you are given more NATROVIT than you should

Overdose is not to be expected within the stated dose range. Signs of overdose may be nausea and vomiting, headache, confusion and flaking skin.

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 patients treated):  Pain at the infusion site

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

 Feeling sick (nausea), vomiting

The following side effects have been reported; their frequency is not known:  Allergic reactions with breathing difficulties, chest pain, throat tightness, rash, sensation of warmth, flushing, abdominal pain and heart problems  Severe allergic reaction (anaphylactic reaction)  Increase in vitamin A and vitamin A-binding protein in the blood  Altered taste (metallic taste)  Rapid heartbeat  Rapid breathing  Diarrhoea  Increased levels of liver enzymes and bile acid  Pruritus (itching)  Fever, malaise (generally feeling unwell), reactions at the infusion site such as burning, sensation of warmth

Soya lecithin can very rarely cause allergic reactions.

Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V*. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store NATROVIT

Keep this medicine out of the sight and reach of children. Do not store above 25ºC Keep the vials in the outer carton in order to protect from light.

Do not use this medicine after the expiry date (EXP) which is stated on the vial and carton. The expiry date refers to the last day of that month.

Addition to the solution for infusion must be performed immediately prior to administration.

NATROVIT should not be used if the solution is not clear or if the vial is damaged in any way.

Since this product will be administered by medical professionals they will be responsible for the correct storage of the product before and during its use, as well as for the correct disposal

6. Contents of the pack and other information

What NATROVIT contains - The active substances are: Retinol/Vitamin A (3500 IU), Cholecalciferol/Vitamin D3 (220 IU), α-tocopherol /Vitamin E (10.20mg) Ascorbic acid/Vitamin C (125 mg), Thiamine/Vitamin B1 (3.51 mg), Riboflavin/Vitamin B2 (4.14 mg), Pyridoxine/Vitamin B6 (4.53 mg), Cyanocobalamin/Vitamin B12 (6 μg),

Folic acid (414 μg), Pantothenic acid (17.25 mg), Biotin (69 μg), Nicotinamide/Vitamin B3 (46 mg)

- The other ingredients are: glycine, glycocholic acid, soya lecithin, sodium hydroxide, hydrochloric acid.

NATROVIT contains 25 mg (approximately1.09 mmol) sodium per injection vial. To be taken into consideration by patients on a controlled sodium diet.

What NATROVIT looks like and contents of the pack NATROVIT is presented as orange to red sterile powder in a brown glass vial, sealed with elastomer closures and crimped by an aluminium cap. Each pack contains the vial with lyophilized powder. NATROVIT is supplied as packs containing 1, 10 or 20 vials. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer {Name and address} <{tel}> <{fax}> <{e-mail}>

This medicinal product is authorised in the Member States of the EEA under the following names: <{Name of the Member State}> <{Name of the medicinal product}>

This leaflet was last revised in MM/YYYY

The following information is intended for healthcare professionals only:

One vial with 750mg powder for solution for infusion (lyophilisate) contains: Equivalent to: Retinol palmitate 1.924mg Retinol (Vitamin A) 3500 IU

Cholecalciferol 5.5μg Cholecalciferol (Vitamin D3) 220 IU all-rac-alpha-Tocopherol 10.20 mg α-Tocopherol (Vitamin E) 10.20mg Ascorbic acid 125 mg Ascorbic Acid (Vitamin C) 125 mg

Nicotinamide 46 mg Nicotinamide (Vitamin B3) 46 mg

Excipients: Glycine, Glycocholic acid, Soya lecithin (phosphatidylcholine), Sodium hydroxide (pH adjuster), Hydrochloric acid (pH adjuster) Description: Lyophilized orange to red sterile powder. After, reconstitution, the obtained solution is clear and orange to redin colour.

Posology and method of administration Posology Single and daily doses Unless otherwise prescribed, the following dosing guidelines apply: Adults and Children over 11 years: One vial per day reconstituted with Water for Injection (5 mL) or other compatible IV solutions (5 mL) as described under “method of administration”.

Method and duration of administration For intravenous infusion. NATROVIT is intended exclusively for use as an additive to solutions for infusion. NATROVIT Powder for Solution for Infusion is a sterile preparation. Thus, aseptic procedure must be applied throughout the administration and reconstitution. The single dose vial of NATROVIT Powder for Solution for Infusion is reconstituted by adding 5mL of sterile Water for Injection or other intravenous fluids (0.9% Sodium Chloride Injection or 5% Glucose Injection). Five millilitres (5mL) of diluent should be added by means of sterile syringe into the vial and gently mixed to dissolve the lyophilised powder. The resultant solution should then be added to a solution for infusion (e.g. 0.9% Sodium Chloride or 5% Glucose) and administered by slow Intravenous Infusion (at least over one to two hours). NATROVIT can be added to certain solutions for infusion for parenteral nutrition containing carbohydrates, fats, amino acids and electrolytes, in order to meet nutritional requirements and to prevent symptoms of deficiency and complications. However, compatibility and stability with the respective solution must firstly be ensured. Reconstitution and addition to the solution for infusion must take place immediately prior to administration. Total vitamin intake from all sources must be considered, e.g. from foodstuffs, other vitamin preparations or from medicinal products containing vitamins as excipients. To maintain adequate concentrations, the patient’s clinical status and vitamin levels must be monitored. It should be remembered that some vitamins, especially vitamins A, B2 and B6, react sensitively to ultraviolet light (direct or indirect sunlight). Furthermore, the concentration of vitamins A, B 1, C and E may decrease with increasing oxygen levels in the solution. These factors must be considered if no adequate vitamin levels are achieved. The total duration of use (even after intermittent administration) must be restricted to 4 weeks, due to the lack of sufficient long-term studies.

Contraindications Hypervitaminosis involving any of the vitamins contained in NATROVIT. Suspected thiamine hypersensitivity. Patients in whom signs of thiamine intolerance have occurred must not be given NATROVIT. Known hypersensitivity to any of the other vitamins or soya proteins/soya products contained in NATROVIT (phospholipids are an excipient and are derived from soya beans). NATROVIT contains soya lecithin and is contraindicated in patients who have peanut or soya allergies.

Special warnings and precautions for use Warnings

Hypersensitivity reactions

 In some cases, manifestation of a hypersensitivity reaction during intravenous multivitamin administration might be linked to the infusion rate. Therefore NATROVIT should be infused slowly.

 In the event of signs or symptoms of a hypersensitivity reaction, discontinue the infusion immediately.

 Monitoring is particularly important in long-term replacement.

Precautions

Hepatic effects  Monitoring of liver function tests is recommended during the use of NATROVIT. Particularly close monitoring is recommended in patients with hepatic jaundice or signs indicative of cholestasis. In some cases, elevation of liver function tests has been described during the use of NATROVIT; including an isolated rise in alanine aminotransferase (ALT) in patients with inflammatory bowel disease. Furthermore, an increase in the concentration of bile acids has been described with NATROVIT (total and individual, including glycocholic acid).  It is known that hepatobiliary disorders may occur with parenteral nutrition in some cases (even with additional vitamin replacement). These include cholestasis, steatosis, fibrosis and cirrhosis possibly resulting in hepatic insufficiency, as well as cases of cholecystitis and cholelithiasis. These diseases probably have an underlying multifactorial aetiology, which can vary from patient to patient. In the event of conspicuous laboratory findings or other signs of hepatobiliary disease, arrangements must be made for a prompt investigation by a physician experienced in hepatopathology, in order to identify potentially causative or contributing factors and to initiate therapeutic and prophylactic measures.

 vitamin B1 in dialysis patients  vitamin B2 in cancer patients  vitamin B6 in patients with impaired renal function  vitamins required on an individual basis, the need for which may be increased due to drug interactions Deficiency of one or more vitamins should be corrected by specific replacement. If NATROVIT is used beyond a 3-week period, blood count monitoring and laboratory monitoring of liver enzyme tests must be performed.

NATROVIT contains no vitamin K. If required, this must be administered separately.

Use in patients with vitamin B12 deficiency If the patient is at risk of developing vitamin B12 deficiency and/or if several weeks of replacement with NATROVIT is scheduled, determination of vitamin B12 status is recommended prior to the start of replacement with NATROVIT. In the presence of vitamin B12 deficiency-associated megaloblastic anaemia, the erythrocyte count, reticulocyte count and haemoglobin levels may rise in some cases even after a few days of use, due to the amounts of cyanocobalamin (vitamin B12) and folic acid supplied via NATROVIT. This could mask an existing vitamin B12 deficiency. The cyanocobalamin dose contained in NATROVIT is not high enough to effectively treat vitamin B12 deficiency. In existing vitamin B12 deficiency, replacement of folic acid alone - without concomitant vitamin B12 intake - is not sufficient to prevent the onset or progression of neurological symptoms associated with vitamin B12 deficiency. There are suggestions that functional neurological impairment may even be accelerated. When interpreting vitamin B12 levels, it should be remembered that values after previous vitamin B12 intake may be within the normal range, although a deficiency is present within tissue.

blood glucose meter, etc.). To establish potential interference by vitamins, the technical information for the respective laboratory test must be consulted.

Use in children and adolescents NATROVIT is indicated for paediatric patients over 11 years.

Use in elderly patients In general, an adjustment in the dosage regimen must be considered in elderly patients (dose reduction and/or prolongation of dosing intervals), as impaired hepatic, renal or cardiac function, as well as comorbidities and concomitant medications, are more common in this population.

Sodium content

This medicinal product contains 25 mg sodium per vial, equivalent to 1,25% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Do not dissolve directly with electrolyte and trace element concentrates.

Use only clear solutions in intact containers.

Interaction with other medicinal products and other forms of interaction

In the event of interactions between specific vitamins contained in NATROVIT and other substances, appropriate measures must be taken.

 Chloramphenicol: may inhibit the haematological response to vitamin B12 treatment  Deferoxamine: increased risk for the onset of iron-induced heart failure due to an increase in the mobilisation of iron caused by supraphysiological vitamin C replacement. Specific precautionary measures can be found in the prescribing information for deferoxamine.  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 make replacement less effective.  Folic acid antimetabolites (methotrexate, raltitrexed): replacement folic acid can attenuate the effects of the antimetabolites  Pyridoxine antagonists, including cycloserine, hydralazine, isoniazid, penicillamine, phenelzine: may cause pyridoxine deficiency

 Retinoids, including bexarotene: increase the risk of toxicity with concomitant administration of vitamin A (see section Hypervitaminosis, vitamin A)  Theophylline: may cause pyridoxine deficiency  Tipranavir oral solution: contains 116 IU/mL vitamin E and thus exceeds the recommended daily dose  Vitamin K antagonists (e.g. warfarin): increased anticoagulant effect due to vitamin E

Overdose

Overdose is not to be expected within the stated dose range.

Symptoms of vitamin A hypervitaminosis: Acute increase in cerebrospinal fluid pressure with headache, vomiting, dizziness, loss of consciousness. In infants, bulging fontanelles.

Symptoms of chronic overdose:

Intracranial pressure symptoms, skin desquamation and dryness, alopecia, bone and joint pain, radiological evidence of transformation zones.

Pharmaceutical particulars

Shelf life Unopened: 2 years.

Special precautions for storage Do not store above 25ºC. Keep the vial in the outer carton in order to protect from light. For storage conditions after reconstitution of the medicinal product, see section “Shelf life”. Any unused solution must be discarded.

Nature and contents of container Type I Ph. Eur. brown glass vial with an elastomer stopper, containing a orange to red sterile powder; Box of 1, 10 or 20 vials of lyophilised powder. Not all pack sizes may be marketed.

Incompatibilities There are no known incompatibilities to date. Compatibility with solutions for infusion: Solutions for infusion are deemed compatible if no cloudiness, flocculation or precipitation forms within 24 hours at room temperature. The use of mixed infusions is decided by the physician in charge.

Special precautions for disposal and other handling Do not use unless solution is clear and the container is undamaged. Using a syringe, inject 5 ml of water for injections, or 5% glucose solution or 0.9% sodium chloride solution into the vial. Mix gently to dissolve the powder. The obtained solution is clear and orange to red in colour. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.