Primene

Package leaflet: Information for the patient

PRIMENE – 10% amino acid solution, solution for infusion

10% amino acid solution
Please read all of this leaflet carefully before this medicine is administered to the child
as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If any adverse reaction occurs, including any not listed in this leaflet, inform your doctor or nurse. See section 4.

Contents of this leaflet:

1. What PRIMENE is and what it is used for
2. What you need to know before the child is given PRIMENE
3. How PRIMENE will be given to the child
4. Possible side effects
5. How to store PRIMENE
6. Contents of the pack and other information

1. What PRIMENE is and what it is used for

PRIMENE contains amino acids (substances used by the body for protein production).
PRIMENE is a solution for parenteral nutrition, meaning it is administered through a vein,
in combination with sugar- and fat-rich solutions, and supplemented with salts, vitamins and trace elements, to meet nutritional requirements.
PRIMENE is indicated in children, infants, full-term or premature newborns, with normal or below-normal birth weight,
when oral feeding or feeding via a tube reaching the stomach (enteral nutrition) is impossible, insufficient or contraindicated.
Consult your doctor if the child does not feel better or feels worse.

2. What you need to know before your child is given PRIMENE

PRIMENE must not be administered to your child

• If he/she is allergic to one or more of the amino acids or to any of the other ingredients of this medicine (listed in section 6).
• If he/she has severe liver disease.
• If he/she has high levels of acid in the blood (acidosis).
• If he/she has an inherited disorder that makes amino acid metabolism difficult.

Warnings and precautions
Talk to your doctor or pharmacist before your child is given PRIMENE.
Treatment with PRIMENE must be stopped immediately if any of the following occur:

• Allergic reactions
• Severe breathing difficulties

Your doctor will perform frequent blood tests/monitoring, especially if your child:

• Has liver disease
• Has low levels of albumin in the blood
• Has kidney disease
• Has heart disease
• Has lung disease
• Has a weakened immune system
• Has high blood sugar levels (hyperglycemia)
• Has a condition that may predispose him/her to infections
• Is malnourished
• Has fever/chills
• Has low levels of white blood cells in the blood (leukocytosis)
• Has high levels of ammonia detected in blood tests
• Has a lung disorder called pulmonary edema. This occurs when fluid from blood vessels leaks into the surrounding lung tissue, causing swelling
• Has a weak heart (heart failure)

Children and adolescents
The doctor will perform frequent blood tests on the child to prevent unwanted effects that may occur during prolonged treatment.

Other medicines and PRIMENE
Inform the doctor if your child is taking, has recently taken, or might take or be given any other medicines.
To minimize the risk of possible incompatibilities, no other drugs should be added to the solution.

3. How PRIMENE will be administered to the child

This medicine will be administered to the child strictly according to the doctor's instructions.
The dose will be determined by the doctor based on the child's age, weight, and health status.
The child will receive this medicine by injection into a vein.
If you have any doubts, consult the doctor.
If the child is given more PRIMENE than prescribed
If excessive doses of PRIMENE are administered, the doctor will stop the treatment and decide whether any further therapy is necessary.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If any of the following side effects occur during treatment with PRIMENE, the doctor will stop the infusion and start appropriate therapy:

effects related to the heart

• pulmonary insufficiency, an abnormality of the valve that normally prevents blood pumped by the heart towards the lungs from flowing back into the right ventricle from which it originated. This side effect may manifest as fatigue, difficulty breathing (especially during physical activity), dizziness or fainting, heart rhythm disturbances,
  sensation of feeling one's own heartbeat (palpitations), chest pain, swollen legs and feet,
  and bluish lips or nails.

allergic reactions

Allergic reactions, even severe ones, which may include:

• swelling of the face and eyes
• skin rash
• fever
• chills
• effects affecting mouth, stomach, and intestine
• skin rashes and other allergic manifestations
• low or high blood pressure
• joint and/or muscle pain
• red, itchy skin (urticaria)
• itching
• redness of the skin (erythema)
• headache

Other side effects have been observed in patients receiving parenteral nutrition, but their exact frequency is unknown:

• liver disorders (hepatic insufficiency, hepatic cirrhosis)
• increase in connective tissue (the supporting tissue of the body) in the liver (hepatic fibrosis)
• bile stasis, a substance useful in digestive processes (cholestasis)
• fat accumulation in the liver (hepatic steatosis)
• abnormalities in liver function tests detected in blood examinations
• inflammation of the gallbladder, the organ that aids digestion
• formation of small stones (calculi) in the gallbladder
• formation of particles in blood vessels
• increased levels of nitrogen and ammonia detected in blood tests
• increased acid levels in the blood
• folate deficiency

Effects at the site of administration:
vein obstruction and inflammation (thrombophlebitis),
vein irritation, skin death (necrosis), blistering, pain, redness, warmth, swelling, hardening

Reporting of side effects
If the child experiences any side effect, including those not listed in this leaflet, please contact the doctor.
You can also report side effects directly via the national reporting system at the website: www.agenziafarmaco.gov.it/it/responsabili.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store PRIMENE

This medicinal product does not require any special storage temperature. Do not freeze.
Keep this medicine out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the bag after EXP. The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What PRIMENE Contains

• Active substances in 1000 ml of 10% amino acid solution:

L-Isoleucine g 6.70 L-Alanine g 8.00
L-Leucine g 10.00 L-Aspartic acid g 6.00
L-Valine g 7.60 L-Cysteine (E 920) g 1.89
L-Lysine g 11.00 L-Glutamic acid (E 620) g 10.00
(as monohydrate lysine) g 12.35 Glycine g 4.00
L-Methionine g 2.40 L-Proline g 3.00
L-Phenylalanine g 4.20 L-Serine g 4.00
L-Threonine g 3.70 L-Tyrosine g 0.45
L-Tryptophan g 2.00 L-Ornithine HCl g 3.18
L-Arginine g 8.40 Taurine g 0.60
L-Histidine g 3.80
pH 5.0–6.5
Density 1.033 g/ml
Calories 400 (equivalent to 1680 kJ/l)
Total nitrogen: 15 g/l;
Amino acids: 100 g/l;
Chlorides: 19.0 mmol/l;
Osmolarity: 790 mOsm/l.

• Other components: Malic acid (E 296), Water for injections.

Description of the Appearance of PRIMENE and Contents of the Package
PRIMENE is supplied as an infusion solution in 100 ml and 250 ml vials.
Available pack sizes: 20 vials of 100 ml and 10 vials of 250 ml of 10% amino acid solution.

Marketing Authorization Holder and Manufacturer
Baxter S.p.A.
Piazzale dell’Industria 20
00144 Rome, Italy

Manufacturer
BIEFFE MEDITAL S.p.A. – Via Nuova Provinciale - 23034 Grosotto (SO)

The following information is intended exclusively for physicians or healthcare professionals:

PRECAUTIONS FOR USE

Allergic Reactions/Hypersensitivity Reactions
Anaphylactic/anaphylactoid reactions and other infusion-related hypersensitivity reactions have been reported with amino acid solutions administered as part of parenteral nutrition. Infusion must be immediately discontinued if any sign or symptom of a reaction occurs.

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 calcium phosphate precipitation. Precipitates have also been reported even in the absence of phosphate salts in solution. Cases of distal filter precipitation and suspected in vivo precipitate formation have also been reported.
In addition to inspecting the solution, the infusion set and catheter should be periodically checked for precipitate formation.

Infectious Complications
Close monitoring of symptoms and laboratory test results in cases of fever/chills, leukocytosis, technical complications with the access device, and hyperglycemia may help detect infections early.
The risk of septic complications can be reduced by careful attention to catheter placement and maintenance, and to the preparation of the nutritional formulation using aseptic techniques.

Refeeding Syndrome in Patients Receiving Parenteral Nutrition
Refeeding severely malnourished patients may lead to refeeding syndrome, characterized by intracellular shifts of potassium, phosphate, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Careful monitoring and gradual increase in nutrient intake can prevent overfeeding and help avoid these complications.

Hypertonic Solutions
Infusion of hypertonic solutions may cause venous irritation, venous damage, and thrombosis when administered into peripheral veins.

General Monitoring
Monitoring should be tailored to the individual patient’s clinical condition and should include assessment of fluid and electrolyte balance, serum osmolarity, acid/base balance, blood glucose levels, blood ammonia levels, and hepatic and renal function.

Metabolic Effects
Metabolic complications may occur if nutrient intake does not match patient requirements or if the patient’s metabolic capacity for a given dietary component has not been adequately assessed. Adverse metabolic effects may result from inadequate or excessive administration of nutrients, or from administration of a solution with inappropriate composition for a patient with specific needs.

Hepatic Function
Patients receiving parenteral nutrition may develop hepatic complications (including cholestasis, hepatic steatosis, fibrosis, and cirrhosis, which may lead to liver failure, as well as cholecystitis and cholelithiasis), and should therefore be monitored accordingly. The etiology of these disorders is thought to be multifactorial and may vary between patients.
Patients who develop abnormal laboratory parameters or other symptoms of hepatobiliary dysfunction should be evaluated by a hepatologist to identify potential causative or contributing factors, and appropriate therapy or prophylaxis should be prescribed if necessary.
Amino acid solutions should be used with caution in patients with pre-existing liver disease or renal insufficiency.
Liver function parameters should be closely monitored in these patients, who should also be monitored for possible signs of hyperammonemia.
Elevated blood ammonia levels and hyperammonemia may develop in patients receiving amino acid solutions. In some patients, this may indicate a congenital amino acid metabolism disorder or hepatic insufficiency.
Blood ammonia levels should be frequently measured in neonates and children up to 2 years of age to detect hyperammonemia.
Potential symptoms (e.g., lethargy, irritability, poor feeding, hyperventilation, chills, and seizures) that may lead to complications including developmental delay and mental disability can be difficult to identify in this age group. Depending on severity and etiology, hyperammonemia may require immediate intervention.

Renal Effects
Elevated blood urea nitrogen levels have been reported in patients receiving amino acid-containing solutions, particularly in those with renal insufficiency.
Use with caution in patients with renal insufficiency (e.g., uremia). Nitrogen tolerance may be altered, and dosage adjustments may be necessary. Fluid and electrolyte status must be closely monitored in these patients.

Additional Precautions

• Injection site reactions have been reported with parenteral nutrition, including thrombophlebitis at the infusion site, venous irritation, and severe reactions (e.g., necrosis and blistering) when extravasation occurs. Patients should be monitored accordingly.
• Severe fluid and electrolyte imbalances, severe fluid overload, and severe metabolic disturbances should be corrected before initiating infusion.
• Use with caution in patients with pulmonary edema or heart failure. Fluid status must be closely monitored.
• Do not connect containers in series to avoid gas embolism due to possible residual air in the primary container.

Infusion of amino acid solutions for parenteral nutrition must be performed with great care, with continuous monitoring of blood glucose, protein levels, liver and kidney function tests, ionogram, serum osmolarity, blood ammonia levels, pH, and CO₂ content.
The use of amino acid solutions for parenteral nutrition must be supplemented with an adequate amount of physiologically usable substrates for energy production to support protein synthesis reactions.
Glucose at an appropriate concentration may serve as a suitable caloric source; however, concomitant use of glucose-containing solutions may lead to hyperglycemia, glycosuria, and hyperosmolar syndrome.
Furthermore, discontinuation of treatment should be gradual to avoid effects related to insulin hypersecretion induced by glucose load.
Concomitant use of electrolyte solutions should be evaluated and monitored based on serum levels of sodium, potassium, and other electrolytes to avoid undesirable accumulation effects or dangerous interference with cardiac, renal, pulmonary, or central nervous system function.
Amino acid solutions may worsen folate deficiency, which should be corrected with appropriate supplementation.

SPECIAL WARNINGS
Careful monitoring of the infusion, as well as the clinical and biological status of the child, is required.
Due to its osmolarity, Primene 10% must not be infused alone into a peripheral vein.
Use the vial only if the solution is perfectly clear, free from visible particles in suspension, not discolored, and if vacuum is present.

INTERACTIONS
Do not use Primene to administer other drugs.
Do not mix with other solutions before verifying compatibility of the final mixture (for data on compatibility and stability of Primene with other solutions, contact the Marketing Authorization Holder).

DOSAGE, METHOD, AND DURATION OF ADMINISTRATION

Dosage
The initiation, duration, and dosage (dose and rate of administration) of parenteral nutrition depend on the following patient characteristics:

• Age, weight, and clinical condition
• Nitrogen requirement
• Ability to metabolize the components of Primene
• Additional nutritional intake that may be provided via parenteral/enteral routes

The flow rate should be adjusted according to dosage, characteristics of the solution to be infused, total volume over 24 hours, and duration of infusion. The flow rate should be gradually increased during the first hour.

Dosage depends on the child’s age, weight, and protein catabolism.
The usual range is:

• 1.5 – 3.5 g of amino acids/kg/24 hours
• 0.23 – 0.53 g of nitrogen/kg/24 hours
• 15 – 35 ml of Primene 10%/kg/24 hours

Method of Administration
Primene 10% must be administered at an infusion rate not exceeding 0.05 ml/kg/minute.

Recommended Infusion Rate:

• Neonates and infants: continuous infusion (over 24 hours)
• Children: continuous infusion (over 24 hours) or cyclic infusion (at least 12 hours over 24 hours)

Route of Administration
Primene is for intravenous use only.
Primene is not indicated for fluid or volume replacement.
Primene 10% administered alone must be given via a central vein.
Primene 10% administered concomitantly or in mixture should be administered via central or peripheral vein depending on the osmolarity of the infused solution.
Highly hypertonic parenteral nutrition solutions (>900 mOsm/L) must be administered through a central venous catheter with the tip positioned in a large central vein.
If deemed appropriate by healthcare professionals, parenteral nutrition solutions may be administered via peripheral vein in patients of all ages if the formulation osmolarity is ≤ 900 mOsm/L.

Administration Method
Primene 10% is generally administered with an appropriate energy source meeting the child’s needs, either concomitantly or in mixture.
Primene 10% may be included in the composition of nutritional mixtures combining carbohydrates, lipids, trace elements, and vitamins when compatibility and stability are known (for data on compatibility and stability of Primene with other solutions, contact the Marketing Authorization Holder).
When Primene is mixed with other substances, the following instructions must be followed:
Mix formulations containing Primene and trace elements (all types, including those containing copper) according to established hospital practice procedures.
Use of a final filter is required during administration of formulations containing Primene and trace elements (including copper, iron, or zinc) to remove visible particles observed in the infusion line with certain formulations.
1- For 2-in-1 parenteral nutrition solutions (amino acids and carbohydrates), use a 0.22 micron filter to remove particulate matter. For 3-in-1 parenteral nutrition solutions (lipids, amino acids, and carbohydrates), use a 1.2 micron filter to remove particulate matter, as the addition of lipids requires a larger pore size filter.
2- Perform visual inspection to verify whether the solution has become cloudy or if precipitates have formed in the solution or filter, both after mixing and before administration, and periodically during infusion.
3- If discoloration or precipitate formation is observed in the solution or filter before administration to the patient, the solution must not be used. If discoloration or precipitate formation is noticed after administration to the patient, blood tests for copper (or other trace elements) must be performed.
Additives may be incompatible.
Excessive addition of calcium and phosphate increases the risk of calcium phosphate precipitate formation (see section “Precautions for Use”).
Visually inspect the container to verify the integrity of the vial.
Use the vial only if the solution is perfectly clear, free from visible suspended particles, not discolored, and if vacuum is present.
Use aseptic conditions. Discard any unused portion of Primene and do not use for subsequent administrations.

When additives are added to the container:

• Ensure compatibility and stability of the resulting preparation (contact the Marketing Authorization Holder).
• Use aseptic conditions. Appropriately prepare the container’s injection site.
• Pierce the stopper and add substances using a syringe or a transfer/reconstitution set as described.
• Mix the container contents and added substances thoroughly.
• Inspect the container for possible discoloration and presence of particles.
• Confirm container integrity. Use only if the container is undamaged and the solution is clear.
• Ensure that storage requirements for added substances are met.

Administration of the Infusion Solution:
The solution should be at room temperature before use.
Use aseptic conditions.
For single use only.
Confirm container integrity. Use only if the container is undamaged and the solution is clear.
Do not reconnect partially used containers.
Use of a final filter is recommended during administration of all parenteral nutrition solutions (see section “Administration Method”).
Inspect the container for discoloration and presence of particles.
Do not connect containers in series to avoid possible gas embolism due to residual air in the primary container.
Primene must not be infused through the same tubing used for blood or blood components.

OVERDOSE
Inappropriate administration (overdose and/or infusion rate higher than recommended) may result in hypervolemia, electrolyte imbalances, acidosis, and/or azotemia. In such cases, infusion must be immediately stopped. If medically appropriate, further intervention may be required to prevent clinical complications.
There is no specific antidote for overdose. Emergency procedures should include appropriate corrective measures.
The same measures should be taken in case of hyperazotemia: in such cases, monitor renal function and reassess caloric and electrolyte intake.
In case of excessive administration, metabolic acidosis and increased azotemia may occur in children with renal insufficiency.