COMMENTARIES Calculating aluminum content
`
`C O M M E N T A R I E S
`
`Calculating aluminum content in total
`parenteral nutrition admixtures
`
`MARYBETH DRISCOLL AND DAVID F. DRISCOLL
`
`Am J Health-Syst Pharm. 2005; 62:312-5
`
`be included in the software programs
`used for automated compounding
`devices.
`Since Abbott Laboratories is al-
`ready in compliance with FDA’s
`mandate,1 we calculated the theoreti-
`cal aluminum exposure associated
`with its products (except for multivi-
`tamin injections) in clinically rele-
`vant nutrition support scenarios for
`infants and adults.3,4 Table 1 lists the
`products used in these calculations;
`the volumes selected were based on
`components that would typically be
`used with automated compounding
`devices wherever possible. Data on
`the aluminum concentrations of
`
`T he Food and Drug Administra-
`
`tion (FDA) rule for limiting alu-
`minum content
`in
`total
`parenteral nutrition (TPN) prepara-
`tions continues to cause concerns
`among health care professionals, es-
`pecially pharmacists.1 The federal
`regulation applies to drug manufac-
`turers and not pharmacy practition-
`ers and has three main objectives: (1)
`that the labels of all large- and small-
`volume parenterals used to prepare
`TPN formulations state the maxi-
`mum aluminum concentration (in
`micrograms per liter) at expiration,
`(2) that the data submitted to FDA
`supporting the label claim must in-
`clude information that describes a
`validated assay method for alumi-
`num determination, and (3) that
`objectives 1 and 2 allow, but not
`mandate, health care professionals
`to calculate a patient’s exposure to
`aluminum when receiving TPN and
`take actions that limit intake in pa-
`tients susceptible to aluminum toxic-
`ity. The statement on clinical limits
`for aluminum levels required by FDA
`for inclusion in the package insert
`contains this warning: “Levels of alu-
`minum at greater than 4 to 5 µg/kg/
`day accumulate aluminum at levels
`associated with central nervous sys-
`tem and bone toxicity.”2 Although
`the FDA rule does not require phar-
`macists to intervene whenever a TPN
`formulation contains more alumi-
`num than a daily dosage of 5 µg/kg,
`we believe that practicing pharma-
`
`cists have a professional responsibili-
`ty to calculate the daily aluminum
`load of compounded TPN prepara-
`tions and that this information
`should be reported on the label of
`each admixture dispensed. Such cal-
`culations can be performed manual-
`ly, but ideally the total aluminum
`content in a TPN preparation should
`
`Additive
`Aminosyn II 10%a
`Aminosyn PF 10%a
`Dextrose 70%a
`Liposyn III 20%a
`Sterile Water for Injection, USPa
`Sodium Chloride 23.4%, USPa
`Sodium Phosphates, USPa
`Sodium Acetate 16.4%, USPa
`Potassium Chloride Concentrate, USPa
`Potassium Acetate 19.6%, USPa
`Calcium Gluconate 10%, USPa
`Magnesium Sulfate 50%, USPa
`Trace Elements 4, USPa
`Cysteine Hydrochloride, USPa
`MVI-12 Adultb
`MVI-Pediatricb
`aAbbott Laboratories, Chicago, IL.
`baaiPharma, Wilmington, DE.
`
`Table 1.
`Aluminum Concentration in Parenteral Nutrition Additives
`Maximum
`Aluminum
`Concentration
`(µµµµµg/L)
`25
`25
`25
`25
`25
`100
`28,000
`360
`100
`200
`12,000
`280
`570
`15,000
`45
`45
`
`Volume
`(mL)
`2,000
`1,000
`2,000
`500
`2,000
`250
`50
`100
`250
`100
`10
`50
`50
`10
`50
`10
`
`List No.
`7121-07
`1617-05
`7918-15
`9791-03
`7118-07
`1130-02
`3295-51
`3299-06
`1513-02
`3294-06
`1184-01
`2168-03
`4592-50
`8975-18
`1199-71
`1839-31
`
`MARYBETH DRISCOLL, B.S.PHARM., is Staff
`Pharmacist, Parenteral Admixture Com-
`pounding Facility, Department of Pharmacy,
`B. I. Deaconess Medical Center (BIDMC),
`Boston, MA. DAVID F. DRISCOLL, PH.D., is
`Assistant Professor of Medicine, Harvard
`Medical School, and Senior Researcher, Nu-
`trition/Infection Laboratory, Department of
`Medicine, BIDMC.
`
`Address correspondence to Dr. Driscoll at
`the Department of Medicine, B. I. Deaconess
`Medical Center, Baker-605, 185 Pilgrim Road,
`Boston, MA 02215 (ddriscol@bidmc.
`harvard.edu).
`
`Copyright © 2005, American Society of
`Health-System Pharmacists, Inc. All rights re-
`served. 1079-2082/05/0201-0312$06.00.
`
`312
`
`Am J Health-Syst Pharm—Vol 62 Feb 1, 2005
`
`EXELA 2022
`Nexus Pharmaceuticals v. Exela Pharma Sciences
`PGR2024-00016
`
`1
`
`

`

`COMMENTARIES Calculating aluminum content
`
`aNutritional intakes: protein, 1.5 g/kg/day; total energy, ~25 kcal/kg/day (~80% dextrose and ~20% lipid); TPN volume, 25 mL/kg/day; sodium, 100 meq; potassium, 60 meq; calcium, 10 meq; magnesium, 10 meq; phosphorus,
`
`30 mmol.
`
`2.2
`21.5
`10
`20
`10
`10
`10
`17.3
`200
`486
`1200
`
`2000
`10
`
`……
`
`3
`
`80 kg
`
`Aluminum
`
`8.4
`599.7
`
`…
`
`0.5
`1.7
`0.6
`
`258
`
`22
`
`3.6
`
`280
`
`1
`
`0.1
`4.4
`10.7
`26.3
`(µµµµµg)
`
`2.2
`21.5
`10
`20
`10
`10
`10
`2.3
`
`175
`426
`1050
`
`70 kg
`
`1750
`10
`
`……
`
`3
`
`Aluminum
`
`9.8
`593.7
` …
`0.5
`1.7
`0.6
`
`258
`
`22
`
`3.6
`
`280
`
`01
`
`3.8
`9.1
`22.5
`(µµµµµg)
`
`1510.7
`
`……
`
`10
`
`3
`
`2.2
`21.5
`10
`20
`10
`10
`10
`
`150
`364
`900
`
`0
`
`60 kg
`
`Aluminum
`
`11.6
`587.9
`
`…
`
`0.5
`1.7
`0.6
`
`258
`
`22
`
`3.6
`
`280
`
`01
`
`3.1
`7.6
`18.8
`(µµµµµg)
`
`1275.7
`
`……
`
`10
`
`3
`
`2.2
`21.5
`10
`20
`10
`10
`10
`
`125
`304
`750
`
`0
`
`50 kg
`
`Aluminum
`
`14.3
`582
`
`…
`
`0.5
`1.7
`0.6
`
`258
`
`22
`
`3.6
`
`280
`
`01
`
`2.5
`6.1
`15
`(µµµµµg)
`
`1039.7
`
`……
`
`10
`
`3
`
`2.2
`21.5
`10
`20
`10
`10
`10
`
`100
`243
`600
`
`0
`
`MVI-12 (mL)
`Trace-4 (mL)
`Magnesium sulfate (mL)
`Calcium gluconate (mL)
`Potassium acetate (mL)
`Potassium chloride (mL)
`Sodium acetate (mL)
`Sodium phosphates (mL)
`Sodium chloride (mL)
`Sterile water for injection (mL)
`Liposyn III (mL)
`Dextrose (mL)
`Aminosyn II (mL)
`
`Aluminum (µg/kg/day)
`Total aluminum (µg)
`TPN volume (mL)
`
`40 kg
`
`Additive
`
`Am J Health-Syst Pharm—Vol 62 Feb 1, 2005
`
`313
`
`Aluminum
`
`12.2
`30
`(µµµµµg)
`
`501
`
`7.5
`
`606
`
`…
`
`0.5
`1.7
`0.6
`
`258
`
`22
`
`3.6
`
`280
`
`.4
`
`
`
`Calculated Aluminum Exposure Associated with Typical Adult Total Parenteral Nutrition (TPN) Admixtures Based on Body Weighta
`Table 2.
`
`these products were provided by Ab-
`bott Laboratoriesa and aaiPharma.b
`The calculations were based on the
`maximum aluminum concentration
`at expiration reported on the label of
`each product. The desired outcome
`for patients receiving TPN would be
`limiting cumulative aluminum expo-
`sure to no more than 5 µg/kg/day.
`Tables 2 and 3 list the calculated
`aluminum loads in TPN admixtures
`prepared from small- and large-
`volume parenteral nutrient additives
`prescribed for a given clinical situa-
`tion. To provide adequate amounts
`of macro- and micronutrients for
`both adults and infants, the total
`aluminum exposure far exceeds the
`clinical limits set forth in the warn-
`ing statement required in the pack-
`age inserts for these commercial
`products. In admixtures for adults,
`most of the aluminum content is at-
`tributable to the concentration of
`aluminum in calcium gluconate in-
`jection and inorganic phosphates
`injection. In TPN admixtures for in-
`fants, another major source of alumi-
`num is the age-essential amino acid
`cysteine hydrochloride.
`The pharmacist has few options
`for reducing the aluminum load in
`TPN formulations. For example,
`switching to products packaged in
`plastic vials may result in lower con-
`centrations of aluminum. An exam-
`ple is Sodium Phosphates Injection,
`USP (Abbott list no. 7391-72), a 10-
`mL plastic vial, which contains only
`180 µg of aluminum per liter, com-
`pared with the example listed in Ta-
`ble 1 (Abbott list no. 3295-51), a 50-
`mL glass vial, which contains 28,000
`µg/L. Although the package size
`makes it inconvenient to prepare
`TPN admixtures with automated
`compounding devices, one could
`meet FDA’s clinical limits for alumi-
`num in adults weighing 70–80 kg by
`switching to the product in the plas-
`tic container. However, the other
`TPN formulations presented in Ta-
`bles 2 and 3 still do not have a rea-
`sonable solution. Therefore, in most
`
`2
`
`

`

`COMMENTARIES Calculating aluminum content
`
`Aluminum
`
`0.03
`78
`
`.1
`
`000
`
`166.4
`
`…
`
`0.1
`72
`
`0
`
`14
`
`.5
`
`
`
`000
`
`0.4
`1.3
`(µµµµµg)
`
`.5
`
`14.2
`50
`A5D10
`
`0
`
`21.2
`
`
`
`00000
`
`2.2
`.8
`
`100
`
`…
`
`04
`
`0.1
`6.5
`.5
`
`0.03
`78
`
`.1
`
`000
`
`148.4
`
`…
`
`0.1
`54
`
`0
`
`14
`
`
`
`10000
`
`.8
`
`.4
`
`
`
`Aluminum
`
`(µµµµµg)
`
`.5
`
`14.2
`40
`A4D10
`
`0
`
`32.4
`
`
`
`00000
`
`2.2
`.6
`
`100
`
`…
`
`03
`
`0.1
`6.5
`.5
`
`Aluminum
`
`0.03
`78
`
`.1
`
`000
`
`130.4
`
`…
`
`0.1
`36
`
`0
`
`14
`
`.1
`
`
`
`010
`
`0.4
`0.8
`(µµµµµg)
`
`2.2
`.4
`
`.5
`
`clinical cases, there are no “appropri-
`ate substitutions if the patient is in
`the high risk group,” as suggested by
`FDA.1
`Providing mineral supplementa-
`tion in TPN formulations on alter-
`nate days or reductions in certain
`nutrient intakes may be considered
`but would result in some compro-
`mise in the effectiveness of TPN
`therapy. We do not recommend that
`pharmacists choose alternative elec-
`trolyte salts solely to reduce aluminum
`exposure, especially when this involves
`calcium and phosphate in TPN ad-
`mixtures.5 For example, a change in
`calcium salts to either acetate or
`chloride could introduce disastrous
`consequences if the phosphate con-
`tent in the same TPN formulation is
`not reduced accordingly. Parenteral
`organic phosphate salts may be an
`alternative, since they, like the organ-
`ic calcium gluconate salt, have limit-
`ed dissociation of free interacting
`ions to form calcium phosphate pre-
`cipitate in TPN admixtures. This is
`not possible at present, since
`parenteral organic phosphate salts
`are not approved for use in the Unit-
`ed States. Hence, efforts to reduce
`aluminum concentrations in these
`products should come from im-
`proved manufacturing techniques
`that have existing FDA approval or
`developing new formulations with
`low aluminum content.
`Finally, certain drug additives can
`also contribute aluminum, but they
`do not fall under the proposed agen-
`cy mandate. In most cases, however,
`the amounts of aluminum contribut-
`ed from non-TPN drug products,
`with the exception of albumin, are
`very small. Fortunately, the routine
`use of albumin via TPN admixtures
`is of questionable clinical value and
`has been largely abandoned by most
`clinicians.6
`A high aluminum content in TPN
`admixtures is largely the result of
`three parenteral nutrient additives:
`calcium gluconate, inorganic phos-
`phates injection (sodium or potassi-
`
`aNutritional intakes: amino acids (A) and dextrose (D) are listed as final percentages. Cysteine hydrochloride content is based on 40 mg per gram of protein. TPN volume is calculated on the basis of 100 mL/kg/day in which
`
`bA = final amino acid concentration (percent), D = final dextrose concentration (percent). The subscripts denote the concentration of each ingredient.
`
`sodium, 2 meq; potassium, 1 meq; calcium, 3 meq; magnesium, 0.4 meq; phosphorus, 1.5 mmol.
`
`Calculated Aluminum Exposure in a 100-mL Total Parenteral Nutrition (TPN) Admixture for an Infanta
`Table 3.
`
`Total aluminum (µg)
`TPN volume (mL)
`MVI-Pediatric (mL)
`Cysteine hydrochloride (mL)
`Trace-4 (mL)
`Magnesium sulfate (mL)
`Calcium gluconate (mL)
`Potassium acetate (mL)
`Potassium chloride (mL)
`Sodium acetate (mL)
`Sodium phosphates (mL)
`Sodium chloride (mL)
`Sterile water for injection (mL)
`Liposyn III (mL)
`Dextrose (mL)
`Aminosyn PF (mL)
`Additive
`
`314
`
`Am J Health-Syst Pharm—Vol 62 Feb 1, 2005
`
`14.2
`30
`A3D10
`
`0
`
`45.2
`
`
`
`00000
`
`0.1
`6.5
`.5
`
`100
`
`…
`
`02
`
`Aluminum
`
`0.03
`78
`
`.1
`
`000
`
`118.5
`
`…
`
`0.1
`24
`
`0
`
`14
`
`.4
`
`
`
`010
`
`0.4
`0.5
`(µµµµµg)
`
`.5
`
`14.2
`20
`A2D10
`
`0
`
`54.4
`
`
`
`00000
`
`2.2
`.6
`
` …
`100
`
`01
`
`0.1
`6.5
`.5
`
`Aluminum
`
`0.03
`78
`
`.1
`
`000
`
`106.5
`
`…
`
`0.1
`12
`
`0
`
`14
`
`.6
`
`
`
`010
`
`0.4
`0.3
`(µµµµµg)
`
`.5
`
`b
`
`14.2
`10
`A1D10
`
`0
`
`65.2
`
`
`
`2.2
`.8
`
`100
`
`…
`
`00
`
`0.1
`6.5
`.5
`
`00000
`
`3
`
`

`

`COMMENTARIES Calculating aluminum content
`
`um), and cysteine hydrochloride. Al-
`though available products may meet
`the validation and labeling require-
`ments of the FDA mandate, limiting
`aluminum exposure from TPN ther-
`apy to less than 5 µg/kg/day will not
`be possible for most patients.
`
`aBaker M, Abbott Laboratories. Aluminum
`values for HPD products used in total par-
`enteral nutrition. Personal communication.
`2003 Sep 30.
`bCurrier SJ, aaiPharma. Aluminum values
`for MVI-12 and MVI-Pediatric. Personal
`communication. 2003 Oct 6.
`
`References
`1. Young D. FDA aluminum rule poses chal-
`lenges for industry, pharmacists. Am J
`Health-Syst Pharm. 2004; 61:742,744.
`News.
`2. Food and Drug Administration. Alumi-
`num in large and small volume parenterals
`
`used in total parenteral nutrition. Fed Reg-
`ist. 2000; 65:4103-11.
`3. Greene HL, Hambidge KM, Schanler R et
`al. Guidelines for the use of vitamins,
`trace elements, calcium, magnesium, and
`phosphorus in infants and children re-
`ceiving total parenteral nutrition: report
`of the Subcommittee on Pediatric
`Parenteral Nutrition Requirements from
`the Committee on Clinical Practice Issues
`of the American Society for Clinical Nu-
`trition. Am J Clin Nutr. 1988; 48:1324-
`42.
`4. Mirtallo JM, Driscoll DF, Helms R et al.
`Safe practices for parenteral nutrition for-
`mulations. National Advisory Group on
`Standards and Practice Guidelines for
`Parenteral Nutrition. JPEN J Parenter En-
`teral Nutr. 1998; 22:49-66.
`5. Driscoll DF, Newton DW, Bistrian BR.
`Precipitation of calcium phosphate from
`parenteral nutrient fluids. Am J Hosp
`Pharm. 1994; 51:2834-6.
`6. Blackburn GL, Driscoll DF. Time to aban-
`don routine albumin supplementation.
`Crit Care Med. 1992; 20:157-8. Editorial.
`
`Aluminum exposure through parenteral
`nutrition formulations: Mathematical
`versus clinical relevance
`
`TODD W. CANADA
`
`Am J Health-Syst Pharm. 2005; 62:315-8
`
`A luminum
`
`from
`exposure
`parenteral nutrition (PN) for-
`mulations was first associated
`with osteomalacia some 25 years
`ago.1,2 Aluminum contamination in
`these formulations impaired normal
`osteoblast proliferation and calcium
`uptake by bone, thereby contributing
`to adynamic bone disease. Subse-
`quently, in a study by Bishop et al.,3
`preterm infants (mean age, 29 weeks
`of gestation) who were administered
`PN formulations providing a mean ±
`S.D. of 19 ± 8 µg of aluminum per
`kilogram per day for approximately
`10 days had impaired neurologic de-
`velopment at 18 months of life com-
`pared with another group receiving 3
`± 1 µg/kg/day. The concentrations of
`
`tions, because a safe lower limit for
`aluminum content (or maximum)
`had not been established.5
`Now the clinical dilemma re-
`mains, since most of the aluminum
`contamination in PN formulations
`is from the small-volume parenter-
`al injections. The preterm infants
`who were administered the reduced-
`aluminum PN formulation in the
`study by Bishop et al.3 had the clini-
`cal advantage of an organic phos-
`phate source that contains much less
`aluminum contamination than inor-
`ganic phosphates but is not currently
`available in the United States. Organ-
`ic phosphate products are compati-
`ble when combined with calcium
`chloride solution, which has a lower
`aluminum content than calcium glu-
`conate solution. In the United States,
`calcium chloride is usually not used
`with inorganic phosphates because of
`the risk of calcium phosphate precipi-
`tation. Instead, calcium gluco-
`nate is preferentially used with the in-
`organic phosphates available, which
`results in a high aluminum content.
`Bishop et al.3 did not examine pa-
`tients’ serum or urine aluminum
`concentrations to ascertain if toxicity
`was a function of either of these, nor
`did they report aluminum intake
`from other sources (e.g., colloids,
`heparin, infant formulas, other med-
`ications).6 Most clinicians would as-
`sume that an increased aluminum
`intake would lead to an increased se-
`rum aluminum concentration, but
`this may be offset by an increase in
`urinary aluminum excretion.7 Bish-
`op et al.3 measured the aluminum
`concentrations in the phosphate and
`calcium products (primary sources
`of aluminum contamination) they
`used and found 2154 µg/L for potas-
`sium acid phosphate solution, 21 µg/
`L for mixed sodium–potassium
`
`aluminum in the preterm infants’ PN
`formulations were 250 and 22 µg/L,
`respectively—the latter being similar
`to the FDA regulation setting the up-
`per limit for large-volume parenteral
`injections (e.g., dextrose, amino ac-
`ids, fat emulsion, sterile water for in-
`jection) at 25 µg/L.4 However, FDA
`chose not to set a limit for the small-
`volume parenteral injections such as
`sodium, potassium, magnesium, cal-
`cium, multivitamins, and trace ele-
`ments solutions used in PN formula-
`
`TODD W. CANADA, PHARM.D., BCNSP, is
`Clinical Pharmacy Specialist, Critical Care/
`Nutrition Support, Division of Pharmacy,
`The University of Texas M. D. Anderson Can-
`cer Center, 1515 Holcombe Boulevard, Unit
`
`90, Houston, TX 77030-4009 (tcanada@
`mdanderson.org).
`Copyright © 2005, American Society of
`Health-System Pharmacists, Inc. All rights re-
`served. 1079-2082/05/0201-0315$06.00.
`
`Am J Health-Syst Pharm—Vol 62 Feb 1, 2005
`
`315
`
`4
`
`

`

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