Dipeptiven is indicated as part of a clinical nutrition regimen in patients in hypercatabolic and/or hypermetabolic states. It should be given together with parenteral or enteral nutrition or a combination of both.

Solution for infusion after mixture with a compatible infusion solution.
Solutions of mixtures with an osmolarity above 800 mosmol/l should be infused by the central venous route.
Adults
Dipeptiven is administered parallel with parenteral nutrition or enteral nutrition or a combination of both. Dosage depends on the severity of the catabolic state and on amino acids/protein requirement.
A maximum daily dosage of 2 g amino acids and/or protein per kg body weight should not be exceeded in parenteral/enteral nutrition. The supply of alanine and glutamine via Dipeptiven should be taken into consideration in the calculation. The proportion of the amino acids supplied through Dipeptiven should not exceed approx. 30% of the total amino acids/protein supply.

Daily dose
1.5 - 2.5 ml of Dipeptiven per kg body weight (equivalent to 0.3 - 0.5 g N(2)-L-alanyl-L-glutamine per kg body weight). This equates to 100 to 175 ml Dipeptiven for a patient of 70 kg body weight.
Maximum daily dose: 2.5 ml equivalent to 0.5 g N(2)-L-alanyl-L-glutamine of Dipeptiven per kg body weight.
The maximum daily dose of 0.5 g N(2)–L-alanyl-L-glutamine per kg body weight should be administered in combination with at least 1.0 g amino acids/protein, per kg body weight per day. With the amino acids from Dipeptiven included, this results in a daily dosage of at least 1.5 g amino acids/protein per kg body weight.
The following adjustments are examples for the supply with Dipeptiven and amino acids through the parenteral nutrition solution, and/or protein through enteral nutrition formula:
Amino acids/protein requirement 1.2 g/kg body weight per day:
0.8 g amino acids/protein + 0.4 g N(2)-L-alanyl-L-glutamine per kg body weight.
Amino acids/protein requirement 1.5 g/kg body weight per day:
1.0 g amino acids/protein + 0.5 g N(2)-L-alanyl-L-glutamine per kg body weight.
Amino acids/protein requirement 2 g/kg body weight per day:
1.5 g amino acids/protein + 0.5 g N(2)-L-alanyl-L-glutamine per kg body weight.
Dipeptiven is an infusion solution concentrate which is not designed for direct administration.
Patients with total parenteral nutrition
The rate of infusion depends on that of the carrier solution and should not exceed 0.1 g amino acids/kg body weight per hour.
Dipeptiven should be mixed with a compatible amino acid carrier solution or an amino acid containing infusion regimen prior to administration.
Patients with total enteral nutrition
Dipeptiven is continuously infused over 20-24 hours per day. For peripheral venous infusion, dilute Dipeptiven to an osmolarity ≤ 800 mosmol/l (e.g. 100 ml Dipeptiven + 100 ml saline).
Patients with combined enteral and parenteral nutrition
The full daily dosage of Dipeptiven should be administered with the parenteral nutrition, i.e. mixed with a compatible amino acid solution or an amino acid containing infusion regimen prior to administration.
The rate of infusion depends on that of the carrier solution and should be adjusted according to the proportions of parenteral and enteral nutrition.
Duration of administration
The duration of use should not exceed 3 weeks.
Children
Safety and efficacy in children have not been established.

It is advisable to regularly monitor liver function parameters in patients with compensated hepatic insufficiency.
As there is currently insufficient data on administration of Dipeptiven to pregnant women, nursing mothers and children, administration of the preparation in these patient groups is not recommended.
Serum electrolytes, serum osmolarity, water balance, acid-base status as well as liver function tests (alkaline phospatase, ALT, AST), possible symptoms of hyperammonaemia should be controlled.
The choice of a peripheral or central vein depends on the final osmolarity of the mixture. The general accepted limit for peripheral infusion is about 800 mosmol/l but it varies considerably with the age and general condition of the patient and the characteristics of the peripheral veins.
Experience with the use of Dipeptiven for longer periods than nine days is limited.

No interactions are known to date.

Due to lack of experience, Dipeptiven should not be administered during pregnancy and lactation.

Not applicable

None known when correctly administered.

As with other infusion solutions, chills, nausea and vomiting can occur, when the infusion rate of Dipeptiven is exceeded.
Infusion shall be stopped immediately in this case.

B05X B02 – amino acids - concentrate for solution for infusion
The dipeptide N(2)-L-alanyl-L-glutamine is endogenously split into the amino acids glutamine and alanine hereby supplying glutamine with infusion solutions for parenteral nutrition. The released amino acids flow as nutrients into their respective body pools and are metabolised according to the needs of the organism. Many disease conditions, in which parenteral nutrition is indicated, are accompanied by a glutamine depletion, which glutamine containing infusion regimens counteract.

N(2)-L-alanyl-L-glutamine is rapidly split into alanine and glutamine after infusion. In man, half-lives of between 2.4 and 3.8 min (in terminal renal insufficiency 4.2 min) and a plasma clearance of between 1.6 and 2.7 l/min were determined. The disappearance of the dipeptide was accompanied by an equimolar increase of the corresponding free amino acids. Hydrolysis probably takes place exclusively in the extracellular space. Renal elimination of N(2)-L-alanyl-L-glutamine under constant infusion is below 5% and thus the same as that of infused amino acids.

Acute and subchronic toxicity: A matrix of dosage finding tests were conducted on rats and dogs over 1 to 7 days. In the rats, infusion of 50 ml/kg b.w. of a 10%, 15%, 20% and 30% solution of N(2)-L-alanyl-L-glutamine over 4h/day led to tonic spasms, increased respiratory rate and exitus. Infusion of 50 ml/kg b.w. of a 10% solution (5 g N(2)-L-alanyl-L-glutamine/kg b.w.)
resulted in necrotic areas at the infusion site, reduced body weight and yellowing of the kidneys in the rats (6 h/day), and a temporary increase in heart rate in the dog (8 h/day).
Investigations were carried out in dogs (8h/day) and in rats (6h/day) with 0.5 and 1.5 g N(2)-L-alanyl-L-glutamine/kg b.w. per day i.v. over 13 weeks and with 4.5 g N(2)-L-alanyl-L-glutamine/kg b.w. per day i.v. over 6 weeks.
In the dogs, vomiting occurred. With the high dose tonic or tonic-clonic cramps, increased salivation, ataxia, sedation, and lateral position were observed.
Mutagenic and tumorigenic potential: In vitro and in vivo test gave no indications of mutagenic potential.
Studies investigating the tumorigenic potential were not carried out. Carcinogenic effects are not to be expected.
Reproduction toxicity: In animal trials, no indications of teratogenic or other embryotoxic and peripostnatal injuries could be observed up to a dosage of 1.6 g N(2)-L-alanyl-L-glutamine/kg b.w. per day.
Local tolerance: Following repeated i.v. infusion of N(2)-L-alanine-L-glutamine (5 and 10% solution) over 13 weeks, intolerance reactions occurred at the infusion sites (swellings, discolourations, necroses) in the rats and dogs from 0.5 g/kg b.w. onwards. Histopathologically, substance-induced inflammatory reactions with mild to fully developed dermatitis purulenta necroticans and osteomalacia of the tail vertebrae, thrombophlebitis and
SPC 11-391, 2011-05-05 5
periphlebitis, were observed in the rats. In the dog, perivascular inflammatory reactions and, occasionally, vessel blockage were observed.
The tests conducted on the dog on local tolerance after a single, intraarterial, paravenous and intramuscular administration gave no indications of unusual intolerance reactions with incorrect administration.

Water for injection.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Do not store above 25C.
Store in the original package.

Glass bottles
1 x 50 ml, 10 x 50 ml
1 x 100 ml, 10 x100 ml
Type II, colourless glass
Rubber closure.
Not all pack sizes may be marketed.

Dipeptiven is an infusion solution concentrate which is not designed for direct administration.
The container and the solution should be inspected visually prior to use. Use only clear, particle-free solution and undamaged container. For single use only.
The addition of the concentrate to the carrier solution prior to application should take place under aseptic conditions.
Thorough mixing and compatibility must be ensured. Unused solution should be disposed of.
Dipeptiven is infused with the carrier solution. For details see section 4.2.