Cernevit

Cernevit is a multivitamin preparation. One vial (5 mL) contains: See Table 1.

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Excipients/Inactive Ingredients: See Table 2.

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Cernevit is a multivitamin preparation of both water soluble and fat soluble vitamins (except Vitamin K) combined with mixed micelles (glycocholic acid and lecithin). It is presented as an odourless orange-yellow lyophilised cake of sterile powder to be reconstituted with 5 ml of Water for injection Ph Eur or other intravenous fluids such as 0.9% Sodium Chloride, 5% Glucose or nutrition mixtures prior to parenteral administration. When reconstituted with Water for Injections the solution has a pH of approximately 5.9.

Cernevit is indicated when the daily requirements of vitamins are required to be given to the patient by the parenteral route because oral administration is either contraindicated, impossible or insufficient (eg due to malnutrition, gastrointestinal malabsorption, etc).

Adults and children over 11 years of age should receive the contents of one vial per day. 5 ml of Water for injections should first be added by syringe into the vial and gently mixed to dissolve the lyophilized powder. If infused intravenously, Cernevit should be administered slowly. If injected intravenously, the injection must be administered slowly (over at least 10 minutes).
Cernevit may be included in the composition of parenteral nutrition mixtures combining carbohydrates, lipids, amino acids, electrolytes and trace elements, provided that compatibility and stability have been confirmed. The patient's clinical status and vitamin levels should be monitored to ensure maintenance of adequate levels.
It should be taken into account that some vitamins, especially A, B2, and B6 are sensitive to ultraviolet light (e.g., direct or indirect sun light). In addition, loss of vitamins A, B1, C, and E may increase with higher levels of oxygen in the solution. These factors should be considered if adequate vitamin levels are not achieved.

Acute or chronic overdose of vitamins (in particular A, B6, D, and E) can cause symptomatic hypervitaminosis.
The risk of overdose is particularly high if a patient receives vitamins from multiple sources and overall supplementation of a vitamin does not match the patient's individual requirements, and in patients with increased susceptibility to hypervitaminosis.
Treatment of vitamin overdose usually consists of withdrawal of the vitamin and other measures as clinically indicated.

Known hypersensitivity to Cernevit or soy proteins/products.
Hypervitaminosis from any vitamin contained in this formulation.

Hypersensitivity Reactions: Severe systemic hypersensitivity reactions have been reported with Cernevit, other multivitamin preparations, and individual vitamins (including B1, B2, B12 and folic acid). Reactions with fatal outcome have been reported with Cernevit and other parenteral vitamin products.
In some cases, the manifestations of a hypersensitivity reaction during intravenous administration of multivitamins may be rate related.
The infusion or injection must be stopped immediately if signs or symptoms of a hypersensitivity reaction develop.
Cernevit contains soy-derived lecithin and should be used with caution in patients with peanut allergies due to potential cross-reactivity.
Vitamin Toxicity: The patient's clinical status and blood vitamin concentrations should be monitored to avoid overdose and toxic effects, especially with vitamins A, D and E, and in particular in patients who receive additional vitamins from other sources or use other agents that increase the risk of vitamin toxicity.
Monitoring is particularly important in patients receiving long-term supplementation.
Hypervitaminosis A: The risk for hypervitaminosis A and vitamin A toxicity (e.g., skin and bone abnormalities, diplopia, cirrhosis) is increased in, for example: patients with protein malnutrition,
patients with renal impairment (even in the absence of vitamin A supplementation),
patients with hepatic impairment,
patients with small body size (e.g., pediatric patients), and
patients on chronic therapy.
Acute hepatic disease in patients with saturated hepatic vitamin A stores can lead to the manifestation of vitamin A toxicity.
Refeeding Syndrome in Patients Receiving Parenteral Nutrition: Refeeding severely undernourished patients may result in refeeding syndrome that is characterized by the shift of potassium, phosphorus, and magnesium intracellularly as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Careful monitoring and slowly increasing nutrient intakes while avoiding overfeeding can prevent these complications. Should nutrient deficiencies occur, appropriate supplementation may be warranted.
Precipitates in Patients Receiving Parenteral Nutrition: Pulmonary vascular precipitates have been reported in patients receiving parenteral nutrition. In some cases, fatal outcomes have occurred. Excessive addition of calcium and phosphate increases the risk of the formation of calcium phosphate precipitates. Precipitates have been reported even in the absence of phosphate salt in the solution. Precipitation distal to the in-line filter and suspected precipitate formation in the blood stream have also been reported.
In addition to inspection of the solution, the infusion set and catheter should also periodically be checked for precipitates.
If signs of pulmonary distress occur, the infusion should be stopped and medical evaluation initiated.

Hepatic Effects: Monitoring of liver function parameters is recommended in patients receiving Cernevit. Particularly close monitoring is recommended in patients with hepatic jaundice or other evidence of cholestasis.
In patients receiving Cernevit, instances of liver enzyme increases have been reported, including isolated alanine aminotransferase (ALT) increases in patients with inflammatory bowel disease.
In addition, an increase in bile acid levels have been reported in patients receiving Cernevit.
Hepatobiliary disorders including cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure, as well as cholecystitis and cholelithiasis are known to develop in some patients on parenteral nutrition (including vitamin supplemented parenteral nutrition). The etiology of these disorders is thought to be multifactorial and may differ between patients. Patients developing abnormal laboratory parameters or other signs of hepatobiliary disorders should be assessed early by a clinician knowledgeable in liver diseases in order to identify possible causative and contributory factors, and possible therapeutic and prophylactic interventions.
Use in Patients with Impaired Hepatic Function: Patients with hepatic impairment may need individualized vitamin supplementation. Particular attention should be placed on preventing vitamin A toxicity, because the presence of liver disease is associated with increased susceptibility to vitamin A toxicity, in particular in combination with chronic excessive alcohol consumption (See also Hypervitaminosis A under Warnings and Hepatic Effects as previously mentioned).
Use in Patients with Impaired Renal Function: Patients with renal impairment may need individualized vitamin supplementation, depending on the degree of renal impairment and the presence of concomitant medical conditions. In patients with severe renal impairment, particular attention should be placed on maintaining adequate vitamin D status and preventing vitamin A toxicity, which may develop in such patients with low-dose vitamin A supplementation or even without supplementation.
Pyridoxine (vitamin B6) hypervitaminosis and toxicity (peripheral neuropathy, involuntary movements) have been reported in patients on chronic hemodialysis receiving intravenous multivitamins containing 4 mg pyridoxine administered three times a week.
General Monitoring: Clinical status and vitamin levels should be monitored in patients receiving parenteral multivitamins as the only source of vitamins for extended periods of time. It is particularly important to monitor for adequate supplementation of, for example: Vitamin A in patients with pressure ulcers, wounds, burns, short bowel syndrome or cystic fibrosis;
Vitamin B1 in dialysis patients;
Vitamin B2 in cancer patients;
Vitamin B6 in patients with renal impairment;
Individual vitamins whose requirements may be increased due to interactions with other medicines.
Deficiency of one or more vitamins must be corrected by specific supplementation.
Vitamin K: Cernevit does not contain vitamin K, which should be administered separately if necessary.
Use in Patients with Vitamin B12 Deficiency: Evaluation of vitamin B12 status is recommended before starting supplementation with Cernevit in patients at risk for vitamin B12 deficiency and/or when supplementation with Cernevit over several weeks is planned.
After several days of administration, both the individual amounts of cyanocobalamin (vitamin B12) and folic acid in Cernevit may be sufficient to result in an increase in red blood cell count, reticulocyte count, and hemoglobin values in some patients with vitamin B12 deficiency-associated megaloblastic anemia. This may be masking an existing vitamin B12 deficiency. Effective treatment of vitamin B12 deficiency requires higher doses of cyanocobalamin than provided in Cernevit.
Folic acid supplementation in patients with vitamin B12 deficiency, who do not also receive vitamin B12, does not prevent the development or progression of neurologic manifestations associated with the vitamin B12 deficiency. It has been suggested that neurologic deterioration may even be accelerated.
When interpreting levels of vitamin B12, it should be taken into account that recent intake of vitamin B12 may result in normal levels despite a tissue deficiency.
Laboratory Test Interferences: Depending on the reagents used, the presence of ascorbic acid in blood and urine may cause false high or low glucose readings in some urine and blood glucose testing systems, including test strips and handheld glucose meters. The technical information for any laboratory test should be consulted to determine the potential interference from vitamins.
Biotin may interfere with laboratory tests that are based on a biotin/streptavidin interaction including tests used in emergency situations. The interference may result in either falsely decreased or falsely increased test results, depending on the assay. The risk of interference is higher in children and patients with renal impairment and increases with higher doses. Cases of interference with laboratory tests based on a biotin/streptavidin interaction have been reported in adults receiving high daily biotin oral doses of 5 to 300 mg. The recommended daily dose of Cernevit contains a dose of 69 μg biotin and thus, there is minimal risk for laboratory interference when Cernevit is administered as part of a parenteral nutrition infusion over 12-24 hours. However, biotin plasma concentrations that interfere with certain assays may be reached in some patients e.g. when the daily dose is administered as a bolus injection over 10 minutes (see Dosage & Administration), in patients of low weight, and when Cernevit is administered over 12 to 24 hours to children or to patients with renal impairment.
When interpreting results of laboratory tests, possible biotin interference must be taken into consideration, especially if lack of coherence with the clinical presentation is observed (e.g. inaccurate thyroid test results mimicking Grave's disease in asymptomatic patients or falsely low troponin T test results in patients with myocardial infarction). Consult laboratory personnel for alternative tests in cases where biotin interference is suspected.
Effects on Ability to Drive and Use Machines: There is no information on the effects of CERNEVIT on the ability to operate an automobile or other heavy machinery.
Use in Pregnancy & Lactation: The use of Cernevit has not been studied in human pregnancy. Experimental animal studies are insufficient to assess the safety with respect to the development of the embryo or foetus, the course of gestation, and peri and post-natal development. It is recommended, therefore, that this product should not be used in pregnancy. Since vitamins are known to be excreted in breast milk, this product should also not be used in women who are breast feeding.

The use of Cernevit has not been studied in human pregnancy. Experimental animal studies are insufficient to assess the safety with respect to the development of the embryo or foetus, the course of gestation, and peri and post-natal development. It is recommended, therefore, that this product should not be used in pregnancy. Since vitamins are known to be excreted in breast milk, this product should also not be used in women who are breast feeding.

Adverse Reactions from Clinical Trials: See Tables 3 and 4.

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Post-marketing Adverse Reactions: The following adverse reactions have been reported in the post-marketing experience.
IMMUNE SYSTEM DISORDERS: Systemic hypersensitivity reactions with manifestations such as Respiratory distress, Chest discomfort, Throat tightness, Urticaria, Rash, Erythema, Epigastric discomfort, as well as Cardiac arrest with fatal outcome.
NERVOUS SYSTEM DISORDERS: Dysgeusia (metallic taste).
CARDIAC DISORDERS: Tachycardia.
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Tachypnea.
GASTROINTESTINAL DISORDERS: Diarrhea.
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Pruritus.
HEPATOBILIARY DISORDERS: Gamma-glutamyltransferase increased.
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Pyrexia, Generalized aching, Infusion site reactions, i.e., Burning sensation, Rash.

Interactions between specific vitamins in Cernevit and other agents should be managed accordingly.
Such interactions include: Agents that can cause pseudotumor cerebri (including certain tetracyclines): Increased risk for pseudotumor cerebri (benign/idiopathic intracranial hypertension) by concomitant administration of Vitamin A.
Alcohol (chronic excessive consumption): Increases the risk of vitamin A hepatotoxicity.
Anticonvulsants (phenytoin, fosphenytoin, phenobarbital, primidone): Folic acid supplementation can decrease the anticonvulsant serum concentration and increase seizure risk.
Antiplatelet agents (e.g., aspirin): Vitamin E can add to the inhibition of platelet function.
Aspirin (high dose therapy): Can reduce folic acid levels by increasing urinary excretion.
Certain anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, valproate): Can cause folate, pyridoxine and vitamin D deficiencies.
Certain antiretroviral agents: Decreased vitamin D levels have been associated with, e.g., efavirenz and zidovudine. Decreased formation of the active vitamin D metabolite has been associated with protease inhibitors.
Chloramphenicol: Can inhibit the hematological response to vitamin B12 therapy.
Deferoxamine: Increased risk of iron-induced cardiac failure due to increased iron mobilization by supraphysiologic vitamin C supplementation. For specific precautions, refer to deferoxamine product information.
Ethionamide: Can cause pyridoxine deficiency.
Fluoropyrimidines (5-fluorouracil, capecitabine, tegafur): Increased cytotoxicity when combined with folic acid.
Folate antagonists, e.g., methotrexate, sulfasalazine, pyrimethamine, triamterene, trimethoprim, and high doses of tea catechins: Block the conversion of folate to its active metabolites and reduce the effectiveness of supplementation.
Folate antimetabolites (methotrexate, raltitrexed): Folic acid supplementation can decrease the antimetabolite effects.
Pyridoxine antagonists, including cycloserine, hydralazine, isoniazid, penicillamine, phenelzine: Can cause pyridoxine deficiency.
Retinoids, including bexarotene: Increase the risk of toxicity when used concomitantly with vitamin A.
Theophylline: Can cause pyridoxine deficiency.
Tipranavir oral solution: Contains 116 IU/mL of vitamin E, which is in excess of the daily recommended intake.
Vitamin K antagonists (e.g., warfarin): Enhanced anticoagulant effect by vitamin E.
Drugs that Bind to alpha1-Acid Glycoprotein (AAG): In an in vitro study using human serum, concentrations of glycocholic acid approximately 4 times higher than the glycocholic acid serum concentration that would result from a bolus injection of Cernevit in adults, increased the unbound fraction of selected drugs known to bind to alpha1-acid glycoprotein (AAG) by 50-80%.
It is not known whether this effect is clinically relevant if the amount of glycocholic acid contained in a standard Cernevit dose (as a component of the mixed micelles) is administered by slow intravenous injection, intramuscular injection, or infused over a longer period of time.
Patients receiving Cernevit as well as drugs that bind to AAG should be closely monitored for increases in response of these drugs. These include propranolol, prazosin, and numerous others.
Interactions with Additional Vitamin Supplementation: Some medications can interact with certain vitamins at doses markedly higher than those provided with Cernevit. This should be taken into consideration in patients receiving vitamins from multiple sources, and when applicable, patients should be monitored for such interactions and managed accordingly.
Such interactions include: Amiodarone: Concomitant use of vitamin B6 can enhance amiodarone-induced photosensitivity.
Agents with anticoagulant effects (e.g., such as abciximab, clopidogrel, heparin, warfarin): Increased bleeding risk due to additional risk of bleeding associated with high vitamin A doses.
Carbamazepine: Inhibition of metabolism associated with large nicotinamide doses.
Chemotherapeutic agents that rely on the production of reactive oxygen species for their activity: Possible inhibition of chemotherapy activity by the antioxidant effects of high doses of vitamin E.
Insulin, antidiabetic agents: Decreased insulin sensitivity associated with large nicotinamide doses.
Iron: High dose supplementation with vitamin E may reduce the hematological response to iron in anemic patients.
Oral contraceptives (combination hormone types): High doses of vitamin C have been associated with breakthrough bleeding and contraceptive failure.
Phenobarbital: Increased metabolism/lower serum levels and reduced effect associated with large pyridoxine doses.
Phenytoin, fosphenytoin: Lower serum levels associated with large pyridoxine doses.
Primidone: Decreased metabolism to phenobarbital and increased primidone levels associated with large nicotinamide doses.

Pharmaceutical precautions: The product after reconstitution with Water for Injections should be used immediately, or failing this, be stored under refrigeration for no more than 24 hours.
Incompatibilities: Additives may be incompatible with parenteral nutrition containing Cernevit.
Do not add other medicinal products or substances without first confirming their compatibility and the stability of the resulting preparation.
If co-administration of drugs that are incompatible at the Y-site is necessary, administer via separate IV lines. Vitamin A and thiamine in Cernevit may react with bisulfites in parenteral nutrition solutions (e.g., as a result of admixtures) leading to degradation of vitamin A and thiamine.
An increase in pH of a solution may increase the degradation of some vitamins. This should be considered when adding alkaline solutions to the admixture containing Cernevit.
Folic acid stability can be impaired with increased calcium concentrations in an admixture.
Numerous other incompatibilities between vitamins and other medicinal products, including certain antibiotics, and trace elements have been described.
Refer to appropriate compatibility references and guidelines as needed.
Instructions for Use and Handling, and Disposal: Aseptic conditions must be followed during reconstitution and when used as part of an admixture in parenteral nutrition.
Mix gently to dissolve the lyophilized powder.
Before transfer from the vial, Cernevit must be completely dissolved.
Do not use product unless the reconstituted solution is clear and the original seal is intact.
After addition of Cernevit to a parenteral nutrition solution, check for any abnormal color change and/or the appearance of precipitates, insoluble complexes, or crystals.
Mix the final solution thoroughly when Cernevit is used as an admixture in parenteral nutrition.
Any unused portion of reconstituted Cernevit should be discarded and should not be stored for subsequent admixing.
Parenteral drug products should be inspected visually for particulate matter and abnormal discoloration prior to administration, whenever solution and container permit.
Use of a final filter is recommended during administration of all parenteral nutrition solutions.

Protect from light and heat.

Parenteral Nutritional Products / Vitamins &/or Minerals

A11BA - Multivitamins, plain ; Used as dietary supplements.

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