Large volume parenterals

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Large Volume Parenterals
Dr. Prashant L. Pingale
Associate Professor,
GES’s Sir Dr. M. S. Gosavi College of Pharm. Edu. and Research,
Nashik-422005

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Contents as per Syllabus…
✓ Types of LVPs,
✓ Concept of formulation,
✓ Influence of physiological factors,
✓ Stabilization of LVPs,
✓ Processing and manufacturing of LVPs,
✓ Parenteral Nutrition,
✓ IV admixture.
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✓ A single-dose injection that is intended for intravenous use and is packaged in
containers labelled as containing more than 100 mL.
✓ LVPs (LVIs) are aqueous solutions usually supplied in volumes of at least 100 ml
with sizes of 250 ml, 500 ml, 1000 ml, 3000 ml, and 5000 ml most common.
✓ Directions usually recommend that large quantities be administered.
✓ Many different LVP solutions are commercially available.
✓ Packaged in glass bottles or in large volume flexible containers.
✓ May contain greater than 100 ml to greater than 1 or 2 L.
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Characteristics of LVP
✓ Sterile,
✓ Pyrogen-Free,
✓ Essentially free of particulate matter,
✓ No anti-microbial agents/ free of preservatives,
✓ Isotonicity,
✓ The LVP is supplied in sizes appropriate to label claims facilitating use of
the contents promptly following initial entry.
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LVP’s Label
✓ contain no preservatives.
✓ intended for use promptly following initial entry.
✓ any portions not used promptly should be discarded.
✓ clearly indicate concentration of individual ingredients and physiological
parameters of the solution.
✓ complies with other applicable labelling requirements in the FD&C Act and
its implementing regulations, including 21 CFR Part 201.
✓ manufactured in accordance with cGMP.
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Commonly used LVPs
✓ Four solutions are commonly used either as primary fluids (infused at 2 - 3 ml
per minute) or as the base of an admixture solution.
✓ The solutions are sodium chloride solution, dextrose solution, Ringer's solution,
and Lactated Ringer's solution.
✓ Various combinations of different strengths of sodium chloride and dextrose
solutions are also available, i.e., 5% dextrose and 0.45% sodium chloride, or 5%
dextrose and 0.2% sodium chloride.
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Examples of LVPs
✓ Calcium solutions
✓ Sodium chloride, Ringer's, sodium bicarbonate and other electrolyte solutions
✓ Dextrose (glucose) and other sugar solutions
✓ Amino acid, peptide and other protein-fraction solutions
✓ Solutions containing a combination of the above, sometimes with vitamins
added
✓ Dextrans, and other plasma expanders
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✓ The usual route of administration is intravenous (IV) but other routes, such as
intraperitoneal (IP) or subcutaneous (SQ or SC), are sometimes recommended.
✓ LVP solutions are typically bags or bottles containing larger volumes of intravenous
solutions.
✓ Common uses of LVP solutions without additives include:
✓ Correction of electrolyte and fluid balance disturbances
✓ Nutrition; and
✓ Vehicle for administering other drugs.
✓ There are three types of containers:
✓ Glass bottle with an air vent tube, glass bottle without an air vent tube, and plastic bags.
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Containers for Large Volume Parenterals
▪ Plastic:
▪ Plastic bags have advantages over glass bottles:
▪ they do not break;
▪ they weigh less;
▪ they take up less storage space, and
▪ they take up much less disposal space.
✓ Plastic bags are available in different sizes.
✓ The most common sizes are 250, 500, and 1,000 ml.
✓ Graduation marks are on the front of the bag to indicate the volume of solution used.
✓ They are marked at 25 ml to 100 ml intervals depending on the overall size of the bag.
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▪ Drawbacks of Plastic:
✓ Some drugs adsorb to the plastic.
✓ Some drugs and solutions leach a plasticizer out of the plastic; the
plasticizer is included to keep the plastic flexible.
✓ There are now newer plastics that minimize some of these problems.
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▪ Glass:
✓ The major advantage of glass bottles is to administer drugs that are
incompatible with plastic bags.
✓ Glass intravenous bottles are packaged with a vacuum, sealed with a solid
rubber closure, and the closure is held in place by an aluminium band.
✓ Graduation marks are along the sides of the bottle and are usually spaced every
20 ml to 50 ml.
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▪ The solution bottle is hung on an administration pole in an inverted position using
the aluminium or plastic band on the bottom of the bottle.
▪ Solutions in either the plastic bag or glass bottle flow from the containers to the
patient through an administration set.
▪ A solution to flow out of a glass container, air must be able to enter the container to
relieve the vacuum as the solution leaves.
▪ Some bottles have air tubes built into the rubber closure for this purpose.
▪ Some bottles do not, in which case an administration set with a filtered airway in
the spike must be used.
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Preservative in LVP
▪ LVPs should be free of preservatives, unless the LVP is the subject of an approved
new animal drug application that specifically establishes the safety of and
permits use of the preservative in that particular product.
▪ LVPs should be supplied in container sizes appropriate for their intended use or
uses so that the majority of the contents would ordinarily be used promptly
following initial entry.
▪ Too large a container size relative to intended use would encourage retention of
unused contents which could result in microbial contamination of a product
containing no preservatives.
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Labelling of LVP
▪ Labelling of LVPs should clearly indicate the lack of preservatives and should promote
use of contents promptly following initial entry and disposal of unused contents.
▪ The concentration of individual ingredients should be clearly expressed.
▪ If the product is not a compendial item or the physiologic parameters are not
otherwise clearly defined, the label should bear an indication of the pH and
osmolarity (tonicity) of the solution.
▪ Labelling should in all other respects bear adequate directions for use and not be false
or misleading in any particular.
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Types of LVPs
▪ General uses of LVP:
▪ Electrolytes
▪ Carbohydrates
▪ Nutritional Solutions
▪ Proteins
▪ Lipid Emulsions
▪ Peritoneal Dialysis
▪ Irrigating Solutions
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▪ Types of LVP:
▪ Hyper alimentation Solutions
▪ Cardioplegic Solutions
▪ Peritoneal Dialysis Solution
▪ Irrigating Solutions

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Methods of Delivery for LVPs
▪ Peripheral Vein –if solution with low osmolality
▪ Hyper or Hypotonicity can irritate the vein–phlebitis
▪ Central Vein –Subclavian Vein
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Hyperalimentation Solution (TPN)
✓ Total Parenteral Nutrition (TPN) may be defined as provision of nutrition for
metabolic requirements and growth through the parenteral route.
✓ This is a complete form of nutrition, containing protein, sugar, fat and added vitamins
and minerals as needed for each individual.
✓ TPN refers to the provision of all required nutrients, exclusively by the IV route.
✓ Parenteral Nutrition (PN)can be used to supplement ordinary or tube feeding.
✓ Commonly consist of mixtures of dextrose, amino acids & lipids, added electrolytes,
trace metals & vitamins.
✓ Administration of life-saving or life-sustaining nutrients to comatose patients or to
patients undergoing treatment for esophageal obstruction, GI diseases (including
cancer), ulcer.
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Nomenclature of TPN
✓ TPN: Total Parenteral Nutrition
✓ IVH: Intravenous Hyperalimentation
✓ TNA: Total Nutrient Admixture
✓ 3-In-1 Admixture
✓ All-In-One Admixture
✓ PPN: Peripheral Parenteral Admixture
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z Components of TPN solutions
✓ Protein as crystalline amino acids.
✓ Fats as lipids.
✓ Carbohydrate as glucose.
✓ Electrolytes–Sodium, potassium, chloride, calcium and magnesium.
✓ Metals/Trace elements–Zinc, copper, manganese, chromium, selenium.
✓ Vitamins A, C, D, E, K, thiamine, riboflavin, niacin, pantothenic acid, pyridoxine,
biotin, choline and folic acid.
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When TPN is necessary?
✓ TPN is normally used following surgery, when feeding by mouth or using the gut
is not possible,
✓ When a person's digestive system cannot absorb nutrients due to chronic
disease, or, alternatively, if a person's nutrient requirement cannot be met by
enteral feeding (tube feeding) and supplementation.
✓ General Indications
✓ Patient who can’t eat
✓ Patient who won’t eat
✓ Patient who shouldn’t eat
✓ Patient who can’t eat enough
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Why TPN is necessary?
✓ a patient is severely undernourished, and needs
to have surgery, radiotherapy or chemotherapy;
✓ a patient suffers from chronic diarrhea and
vomiting;
✓ a baby's gut is too immature;
✓ a patient's (their "gastrointestinal tract") is
paralyzed, for example after major surgery.
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Normal Diet TPN
Protein …… Amino Acids
Carbohydrates …… Dextrose
Fat …… Lipid Emulsion
Vitamins …… Multivitamin Infusion
Minerals …… Electrolytes &
Trace Elements

z TPN Electrolytes
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Short term use of TPN Long term use of TPN
✓ Bowel injury /surgery,
✓ Bowel disease,
✓ Severe malnutrition,
✓ Nutritional preparation prior to surgery,
✓ Malabsorption - bowel cancer.
✓ Prolonged Intestinal Failure
✓ Crohn’s Disease
✓ Bowel resection

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Use of Hyperalimentation
(TPN)
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Complications of TPN✓ GI disease,
✓ Major trauma, Septicaemia,
✓ Major Abdominal Surgery,
✓ Malignancy of Small Bowel,
✓ Radiation Enteritis,
✓ Chemotherapy & Radiotherapy,
✓ Bone Marrow Transplantation,
✓ Prolonged Coma.
✓ Sepsis
✓ Air embolism
✓ Clotted catheter line
✓ Catheter displacement
✓ Fluid overload
✓ Hyperglycaemia
✓ Rebound Hypoglycaemia

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Cardioplegia Solution
✓ The word cardioplegia combines the roots cardio- meaning the heart, and plegia means
paralysis.
✓ Technically this means arresting or stopping the heart so that surgical procedures can be
done in a still and bloodless field.
✓ The four main goals of hypothermic cardioplegia are:
✓ Immediate and sustained electromechanical quiescence,
✓ Rapid and sustained homogenous myocardial cooling,
✓ Maintenance of therapeutic additives in effective concentrations,
✓ Periodic washout of metabolic inhibitors.
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Composition of Cardioplegia Solution
✓ Each 100 mL of solution contains:
✓ Calcium Chloride Dihydrate USP 17.6 mg,
✓ Magnesium Chloride (Hexahydrate) USP 325.3 mg,
✓ Potassium Chloride USP 119.3 mg,
✓ Sodium Chloride USP 643 mg, in Water for Injection, USP.
✓ May contain HCl and/or NaOH for pH adjustment.
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Cardioplegia Solution
✓ Electrolyte content per liter (not including ions for pH adjustment):
✓ Sodium (Na+) 110 mEq;
✓ Magnesium (Mg++) 32 mEq;
✓ Potassium (K+) 16 mEq;
✓ Calcium (Ca++) 2.4 mEq;
✓ Chloride (Cl-) 160 mEq.
✓ Osmolar concentration, 304 mOsmol/liter (calc.);
✓ pH 3.8 (3.5 - 3.9)
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Peritoneal Dialysis Solution
✓ Peritoneal dialysis (PD) is a treatment for patients with severe chronic
kidney disease.
✓ Although the ancient Egyptians were the first to describe the
peritoneal cavity in approximately 3000 BC, the concept of peritoneal
dialysis (PD) is relatively new.
✓ In the late 19th century, Wegner, a German investigator, was the first to
use peritoneal solutions in animals; he reported that hypertonic
solutions increased in volume when injected into the peritoneal cavity.
✓ Additional investigations found that hypertonic solutions increased
and hypotonic solutions decreased peritoneal fluid volume.
✓ Infused continuously into abdominal cavity, bathing peritoneum & are
then continuously withdrawn.
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Components of PD fluid
✓ Contains electrolytes sodium, chloride, calcium, and magnesium,
dextrose (D-glucose) as an osmolyte, and lactate as a buffer.
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✓ Removal of toxic substances from body.
✓ To aid & accelerate excretion normal.
✓ To treat acute renal insufficiency.
Use of PD fluid

z Irrigating Solutions
✓ Irrigating solutions are sterile or non-pyrogenic isotonic solutions, made under sterile conditions.
✓ They are generally used for washing, irrigation and rinsing purposes.
✓ Irrigating solutions for medical applications.
✓ Available in a variety of sizes including 120mL, 250mL, 500mL, 1000mL, 2000mL and 3000mL.
✓ Irrigating solutions come in Excel containers, flexible containers, Aqualite bottles and plastic sterile
bottles designed to minimize waste and maximize convenience.
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Irrigating Solutions
✓ Are intended to irrigate, flush, & aid in cleansing body cavities & wounds.
✓ Although certain IV solutions, such as normal saline, may be used as irrigating solutions
should not be used parenterally.
✓ They must be sterile, pyrogen-free, & made & handled with the same care as parenteral
solutions.
✓ Examples are:
✓ Sterile water for irrigation, Sodium chloride, Lactated ringers irrigating solution, Ophthalmic
solution eye stream irrigating solution.
✓ Sterile Irrigating Solution is a sterile balanced salt solution.
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Composition of Irrigating solution
✓ Each mL containing
✓ Sodium chloride (NaCl) 0.64%,
✓ Potassium chloride (KCl) 0.075%,
✓ Calcium chloride dihydrate (CaCl2 2H2O) 0.048%,
✓ Magnesium chloride hexahydrate (MgCl26H2O) 0.03%,
✓ Sodium acetate trihydrate (C2H3NaO2 3H2O) 0.39%,
✓ Sodium citrate dihydrate (C6H5Na3O72H2O) 0.17%,
✓ Sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection.
✓ The pH is approximately 7.5.
✓ The osmolality is approximately 300 mOsm/kg.
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Concept of formulation &
Formulation considerations
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✓ Drug-Excipient Compatibility:
✓ The main challenge of all the different parenteral dosage forms is to achieve a
good compatibility of the drug substances with the excipients (no formation of
new impurities either by degradation of the drug substance or formation of
new chemical entity between the drug substance and the excipients).
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✓ Selection of suitable containers:
✓ The compatibility of the preparations with the primary container (no
leachable or adsorption to container) is always a prime concern.
✓ Plasticizers used to keep plastic flexible may leads to leaching as it may
interact with some drugs and solutions.
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✓ Solubility of drug solvent/vehicle:
✓ When drug substances are not soluble, dissolution can be
achieved by the use of co-solvents, surfactants, or a soluble pro-
drug, or eventually the use of solubility enhancers such as
cyclodextrins to the formation of inclusion complex.
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✓ pH:
✓ The pH is one of the critical aspects of parenteral preparations which should
have a pH close to the physiological one.
✓ In certain cases, a compromise should be found between the pH ensuring
stability of the drug substance (such for peptides requiring alkaline pH or
proteins at pH close to the isoelectric point) and the physiological one.
✓ In all cases, large volume preparations (LVP, i.e. more than 100 ml as defined
in pharmacopeia) should not contain a pH buffer as the blood has already a
buffer effect property that could enter into competition with the injected
drug product.
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✓ Drug stability:
✓ The stability of the drug substance is another critical point that a
formulator can face during the development of the formulation.
✓ Unstable drug substances will lead to the formation of new impurities
jeopardizing the safety of use of the preparations.
✓ When the use of a stabilizer is justified (for instance the use of
mannitol as free-radical scavenger or cysteine in paracetamol solution
for injection), it should be included at the minimum concentration
demonstrated to be efficient at release and during the entire shelf-life
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✓ Suitable sterilization method:
✓ Finally the process of the sterilization should be selected according to the
characteristics of the parenteral preparations (for instance, heat steam
sterilization for aqueous solutions and dry heat for non-aqueous
solutions), but in any case it can be justified by the nature of the primary
containers.
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Substances added for stabilization
✓ Buffering agents, Chelating agents, Antimicrobial preservatives, Anti-oxidants
commonly added in parenteral products are rarely used in LVPs.
✓ Buffering agents generally not added such as, acids and bases, which are used to
adjust pH, can raise or lower the buffering capacity of the solution.
✓ By the nature and use, LVPs introduce large amounts of fluid and chemicals into
the body.
✓ The API are present for therapeutics effect, although present in only very low
percentages, added substances might, in total have an effect on the patient who
receives many bottles of solution during the course of treatment.
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✓ Very minute quantities of metals like iron, copper or calcium may be introduced
into LVPs because of ingredients used and hence the quality of the incoming raw
materials must be ensured.
✓ When drugs are administered orally, the GI tract prevents aluminium from being
absorbed into patient tissues; however, when the drugs are administered
parenterally the aluminium can be deposited in tissues, potentially at toxic
amount.
✓ Therefore, according to the latest FDP guidelines, the aluminium content of LVP
drug products used in TPN therapy must not exceed 25 ɱg/L.
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✓ Antioxidants such as sodium bisulfite and sodium metabisulfite are part of some LVPs.
✓ They are added to protect the active ingredient from action of oxygen in the solution or
headspace of the container.
✓ The presence of oxygen, even very small amount, can speed up the color formation or
degradation of such product as 5% Dextrose in lactated ringer’s or amino acid solutions.
✓ In lieu of the addition of an antioxidants, which might be added in concentration of up to
0.1%, processing to displace the oxygen with an inert gas, usually nitrogen, may be done
during mixing and filling operation.
✓ If both nitrogen and an antioxidant are used, the used of nitrogen will reduce the amount
of bisulfite needed to protect the product during its shelf life.
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IV Admixture
✓ It is combination of one or more sterile products added to an IV fluid for
administration.
✓ Pharmaceutical mixture of two or more drugs into a Large bag or bottle of I.V
fluid.
✓ It must be sterile and pyrogen free Aseptic techniques are used to mixed the
products.
✓ Types of iv admixtures: There are three types of IV admixtures
✓ Infusions,
✓ Intermittent,
✓ Pre-mixed IV admixtures
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IV infusions / Continuous Infusions
✓ More effective and less toxic than when given intermittently.
✓ Continuous administration is possible.
✓ Basic fluid and electrolyte therapy.
✓ Intravenous therapy is frequently used with hospitalized patients to prevent , or
treat fluid and electrolyte imbalances.
✓ It is introduction of fluids into the patient using an intravenous route.
✓ The nurse is responsible for initiating, monitoring and discontinuing the
intravenous infusion.
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IV infusions / Continuous Infusions
✓ Some drugs are administered as a continuous infusion because they are more
effective and less toxic than when given intermittently.
✓ Continuous infusions include basic fluid and electrolyte therapy, blood
products, and drugs that require tight administration control to minimize
adverse effects.
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Intermittent infusion
✓ Periodic administration,
✓ Increased efficacy,
✓ Reduced toxicity.
✓ Intermittent injection systems are used to administer medications that
work better when infused at defined time intervals rather than when
infused continuously. The reason may be that periodic administration of
the drug increases efficacy or reduces toxicity.
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Intermittent infusion
✓ Examples of drugs commonly given intermittently are antibiotics and
drugs used to treat or prevent gastrointestinal ulcers (e.g., proton pump
inhibitors, such as pantoprazole).
✓ Several types of systems are available for intermittent injections.
✓ Each system has advantages and disadvantages related to cost, flexibility,
waste, and so on.
✓ Intravenous medications may be given in small volumes of sterile IV
solution (25 to 250 ml) and infused over a desired amount of time (given
for 30 minutes every 4 hours) or as a single dose.
✓ Many medications must be given slowly to prevent harm to the patient,
and this method of administration reduces the risk of rapid infusion.
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Pre-mixed admixture
✓ Manufactured LPVs with additives,
✓ Availability in many sizes.
✓ LVPs with additives manufactured in standard concentrations are stable in solution for
longer periods of time than those compounded in the pharmacy and are available in a
variety of sizes (250 mL, 500 mL, 1000 mL) and containers (glass or plastic) depending
on the product and its use.
✓ Examples include lidocaine, potassium, nitroglycerin, dopamine, and aminophylline.
Ready-to-use products are advantageous because they reduce handling by the pharmacy
and therefore, the potential for contamination.
✓ In some cases, these agents are used for emergency situations and may be stocked in the
patient care area for immediate access.
✓ Standard concentrations of IV medications can decrease potential medication errors in
compounding and administration.
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Pre-mixed admixture
✓ Bags/Bottles Containing Powder for Reconstitution: Some drugs are available in
powdered form in final containers of plastic or glass. This system requires that 20 to
100 mL of sterile diluting fluid, such as 0.9% sodium chloride or sterile water for
injection, are added to the bottle to reconstitute the drug. Once reconstituted and
labeled by the pharmacy, these products are administered via piggyback systems.
✓ Basic Continuous Intravenous Therapy: In the basic setup, the IV fluid is a large-
volume parenteral (LVP) that is hung on an IV pole or other device approximately 36
inches higher than the patient’s bed or head.
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