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FIGURE 9.4 Label for a multidose package of Heparin
Sodium Injection, USP, displaying a dual statement of strength
to clarify contents and reduce misinterpretation and medication
errors. (Source:
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?
setid=56dc3074-f1c5-45a3-b923-f1d14858e06d. Courtesy of
Pfizer, Inc.)
Various Expressions of Potency
Biologics are preparations produced from a living source. They include
vaccines, toxoids, and immune sera, used for the development of
immunity or resistance to disease; certain antitoxins and antivenins, used
as treatment against specific antigens; and toxins and skin antigens, used
as diagnostic aids. Biologics are prepared from human serum (e.g.,
immune globulin), horse serum (e.g., tetanus antitoxin), chick cell culture
(e.g., measles virus vaccine), and other such animate media.
The strengths of the various biologic products are expressed in a
number of ways. The strength of a bacterial vaccine commonly is
expressed in terms of micrograms or units of antigen per milliliter. The
strength of a viral vaccine is most commonly expressed in terms of the
tissue culture infectious dose (TCID50), which is the quantity of virus
estimated to infect 50% of inoculated cultures. Viral vaccines may also be
described in terms of units, micrograms of antigen, or number or
organisms per milliliter. The strength of a toxoid is generally expressed in
terms of flocculating units (Lf Unit), with 1 Lf Unit having the capacity to
flocculate or precipitate one unit of standard antitoxin.
Vaccines are available for a large number of diseases, including
cervical cancer (human papillomavirus), hepatitis A and B, influenza,
measles, mumps, pneumococcal pneumonia, shingles (herpes zoster),
smallpox, and tuberculosis. In addition, many additional vaccines are in
various stages of development. The National Institute of Allergy and
Infectious Diseases (NIAID) of the National Institutes of Health (NIH)
lists all vaccines licensed for use in the United States as well as the status
of vaccines in current research and development.3,4 The Centers for
Disease Control and Prevention (CDC) offers current guidelines for
vaccine use in different population groups, such as infants, children,
adults, and pregnant women.
5
Specific examples of the potency of vaccines expressed in terms other
than weight are:
Hepatitis A vaccine, inactivated, 1440 ELISA units per 1-mL dose
M-M-R II: Measles virus ≥1000 TCID50, mumps virus ≥12,500
TCID50, and rubella virus ≥1000 TCID50 per vial
Zoster Vaccine, Live, 19,400 PFU (plaque-forming units) per 0.65-mL
dose
Products of biotechnology
In addition to the biologic types of products just described, the activities
of some products of biotechnology also are expressed in terms of units of
activity (e.g., interferon alfa-2b contains 2.6 × 108 international units per
milligram).
Pharmacy-based immunizations
Pharmacy-based immunization programs are commonplace nowadays.
Many colleges of pharmacy and pharmacy organizations have developed
pharmacy immunization training programs, and states permit pharmacists
to administer immunizations under established guidelines and protocols.
Example calculations of measures of activity or
potency
Determinations of the activity or potency of a biologic material
considered in this chapter may be performed through the use of ratio and
proportion or dimensional analysis, as demonstrated by the following
examples.
Units of Activity
Calculations involving units of activity are exemplified as follows:
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1. How many milliliters of U-100 insulin should be used to obtain 40
units of insulin?
U-100 insulin contains 100 units/mL
Or, solving by dimensional analysis:
2. How many milliliters of a Heparin Sodium Injection containing
200,000 units in 10 mL should be used to obtain 5000 heparin
sodium units that are to be added to an intravenous dextrose
solution?
3. If a 2.5-mL vial contains 100 units of onabotulinumtoxinA (BOTOX),
and 0.1 mL is injected into each of five sites during a procedure, how
many units of drug would remain in the vial?
4. How much insulin lispro would be needed to prepare 50 vials each
containing 10 mL of U-100 insulin lispro? (1 mg insulin lispro = 27
units)
Activity Based on Weight
Calculations involving the determination of activity per unit of weight are
exemplified as follows:
If neomycin sulfate has a potency of 600 mcg of neomycin per
milligram, how many milligrams of neomycin sulfate would be equivalent
in potency to 1 mg of neomycin?
Or, solving by dimensional analysis:
Dose or Antigen Content of a Biologic Based on Potency
Calculations of the dose or the antigen content of a biologic product are
exemplified as follows:
1. INFANRIX (DTaP) vaccine suspension contains 25 Lf Units of
diphtheria toxoid in each 0.5-mL vial of product. The CDC
immunization guidelines state that a pediatric patient should receive
a total of five 0.5-mL doses of this suspension at 2, 4, 6, 15 to 18
months, and at 4 to 6 years of age. How much total diphtheria toxoid
will a patient receive with this regimen?
Or, solving by dimensional analysis:
2. VIVOTIF is a typhoid vaccine that is available as enteric-coated
capsules to be administered orally. Each capsule contains at least 2
¥ 109 colony-forming units (CFU) of viable Salmonella typhi Ty21a.
To prevent typhoid fever, an adult patient should take one capsule
every other day for four doses. How much total CFU will a patient
receive over the course of therapy?
CASE IN POINT 9.1
A
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A pharmacist is asked to assist in determining the correct dose of
epoetin alfa (PROCRIT) injection for a 76-year-old, 165-lb male
patient suffering from anemia, in part due to chronic renal failure. The
patient’s initial hemoglobin is 9.2 g/dL.
The literature states the starting adult dose of epoetin alfa to be “50
to 100 units/kg SC TIW” to stimulate red blood cell production.
Firstly, (a) what would be the correct interpretation of this dosage
statement?
b
The literature further states that the dose is to be reduced by 25%
when the patient’s hemoglobin reaches a level suitable to avoid
transfusion or increases >1 g/dL in any 2-week period.
Using epoetin alfa injection, 10,000 units/mL, and the minimal
starting dose, calculate (b) the number of milliliters required for the
initial dose and (c) the total number of milliliters to be administered
during the first week of treatment. If the patient’s hemoglobin
increases to 10.5 g/dL after 2 weeks of treatment, what would be the
new dose in (d) units of epoetin alfa and in (e) milliliters of injection?
a
Case in Point courtesy of Flynn Warren, Bishop, GA.
b
If unsure of the abbreviations, refer to Chapter 4 for guidance.
PRACTICE PROBLEMS
Authors’ Note: some abbreviations in this section are as they appear in
certain product literature, and their use here is strictly for instructional
purposes and not an endorsement of style.
Units of Activity Calculations
How many milliliters of U-100 human insulin isophane suspension
(HUMULIN N) should be used to obtain 18 units of insulin?
If a diabetic patient injects 20 units of insulin twice daily, how
many days will a 10-mL vial of the U-100 product last the patient?
The biotechnology-derived product interferon beta-1b contains 32
million international units per milligram. Calculate the number of
international units present in a vial containing 0.3 mg of interferon
beta-1b.
ALFERON N injection contains 5 million international units of
interferon alfa-n3 per milliliter. How many units will an injection
of 0.05 mL deliver?
Insulin glargine (LANTUS) injection is available in 10-mL vials,
containing 100 units/mL. How many milliliters would a patient
administer for (a) a starting dose of 10 units and (b) a maintenance
dose of 4 units?
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
A 5,000,000-unit vial of penicillin G potassium is reconstituted
with 8.2 mL of sterile water for injection to produce a
concentration of 500,000 units/mL. How many milliliters of the
injection are needed to prepare 15 g of an ointment that is to
contain 15,000 units of penicillin G potassium per gram?
HUMALOG contains 100 units of insulin lispro (rDNA origin) per
milliliter. How many complete days will a 3-mL HUMALOG PEN
last a patient whose dose is 35 units b.i.d.?
Using Table 9.1, calculate the range of penicillin V units in
penicillin V potassium 500-mg tablets.
POLYTRIM ophthalmic solution contains polymyxin B at a
concentration of 10,000 units/mL. How many milligrams of
polymyxin B sulfate would be needed to prepare enough solution
to fill 30 bottles each containing 10 mL of POLYTRIM solution? (1
mg polymyxin B sulfate = 6000 units polymyxin B)
FOSAMAX PLUS D contains 70 mg alendronate and 140 mcg of
vitamin D3, the latter equivalent to 5600 international units of
vitamin D. At a once-a-week dose, calculate the daily intake of
vitamin D3 in milligrams and units.
A vial for preparation of 100 mL of injection of the drug alteplase
(ACTIVASE) contains 100 mg of drug equivalent to 58 million
international units to be administered by intravenous infusion.
Calculate (a) the units administered to a 176-lb patient at a dose of
0.9 mg/kg and (b) the milliliters of injection to use.
Calcitonin is available as an injection containing 200 international
units per milliliter. Adult doses of up to 32 units per kilogram have
produced no adverse effects. On this basis, if a 120-lb patient were
administered 0.75 mL of injection, would adverse effects be
anticipated?
A physician’s hospital medication order calls for a patient to
receive 1 unit of insulin injection subcutaneously for every 10
mg/dL of blood glucose over 175 mg/dL, with blood glucose levels
and injections performed twice daily in the morning and evening.
The patient’s blood glucose was 200 mg/dL in the morning and 320
mg/dL in the evening. How many total units of insulin injection
were administered?
A physician’s hospital medication order calls for isophane insulin
suspension to be administered to a 136-lb patient on the basis of 1
unit/kg per 24 hours. How many units of isophane insulin
suspension should be administered daily?
Somatropin (NUTROPIN AQ) contains 5 mg of drug equivalent to
approximately 15 IU of drug in 2 mL of injection. If the starting
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adult dose is 0.006 mg/kg, calculate the dose (a) in units and (b) in
milliliters for a 132-lb patient.
Cod liver oil is available in capsules containing 0.6 mL per capsule.
Using Table 9.1, calculate the amounts, in units, each of vitamins A
and D in each capsule. The specific gravity of cod liver oil is 0.92.
A hepatitis B immune globulin contains 312 IU/mL. If the dose is
0.06 mL/kg for certain at-risk persons, calculate the dose (a) in
units and (b) in milliliters for a 188-lb person.
Using Table 9.1, determine the amount of gentamicin sulfate
needed to prepare 60 g of a cream containing 0.05% w/w
gentamicin.
EPOGEN injection is available containing in each milliliter, 2000,
3000, 4000, or 10,000 units of epoetin alfa. If the starting dose for a
160-lb patient is prescribed at 50 units/kg, which of the following
would provide that dose?
a. 4 mL of 2000 units/mL
b. 1 mL of 3000 units/mL
c. 0.9 mL of 4000 units/mL
d. 0.8 mL of 10,000 units/mL
Tetanus immune globulin is used off-label to treat tetanus by
administering 3000 to 6000 units intramuscularly. How much of a
250-units/mL solution should be injected to achieve this dosage
range?
Additional Calculations of Potency
The product CREON (pancrelipase) contains 3000 units of lipase,
9500 units of protease, and 15,000 units of amylase in delayedrelease capsules. The capsules are to be swallowed whole or the
contents added uncrushed to food immediately prior to
administration. The dose should not exceed 2500 lipase units/kg of
body weight. If a child weighing 24 pounds ingests five CREON
capsules, has he exceeded the maximum dose?
What is the numerical difference between “1 mIU” and “1 MIU?”
During cholecystography to determine gallbladder function, the
contents of one bottle of cholecystokinin containing 75 units is
dissolved in physiological saline solution to make 7.5 mL. Then, 1
unit per kilogram of body weight is administered by slow
intravenous injection. Calculate the dose, in units, and the volume,
in milliliters, to be administered to a patient weighing 154 pounds.
24.
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27.
Using Table 9.1, calculate the clindamycin potency equivalence, in
milligrams per milliliter, of a solution containing 1 g of
clindamycin hydrochloride in 10 mL of solution.
Each 1-mL adult dose of hepatitis A vaccine (HAVRIX) contains
1440 EL.U. of viral antigen. What would be the pediatric dose of
this vaccine if 720 EL.U. of viral antigen are to be administered?
a. 1.6 mL
b. 0.5 mL
c. 8 mL
d. 0.8 mL
A patient weighing 70 kg should receive a dose of 1400 units of
rabies immune globulin after exposure to rabies. How much of a
solution containing 900 units per 3 mL should be injected for this
dose?
Zoster Vaccine Live (ZOSTAVAX) contains 19,400 plaque-forming
units (PFU) of attenuated virus per 0.65 mL. What is the
concentration expressed as PFU/mL?
CALCQUIZ
9.A. If a 5-mL quantity of a nystatin oral suspension is prepared to
contain 500,000 USP Nystatin Units, using Table 9.1, calculate (a) the
concentration of nystatin in the suspension in mg/mL. If a child's dose
is 2 mL four times a day, how many (b) nystatin units and (c)
milligrams of nystatin would be administered daily?
9.B. The drug dalteparin sodium (FRAGMIN) is administered by
subcutaneous injection in patients with unstable angina or myocardial
infarction at doses of 120 units/kg but not to exceed 10,000 units.
Prefilled calibrated syringes are available with the following strengths
(units/mL): 2500/0.2 mL, 5000/0.2 mL, 7500/0.3 mL, 10,000/0.4 mL,
12,500/0.5 mL, and 15,000/0.6 mL. Calculate (a) the most efficient
product strength to use to dose a patient weighing 148 lb, (b) the
volume of that injection to administer, and (c) the weight of a
hypothetical patient, in pounds, to reach the maximum dose of 10,000
units.
9.C. An injection contains 5 million international units (5 MIU) of
interferon alfa-n3 (ALFERON N) proteins per milliliter. The
recommended dose is 0.05 mL. The literature states that the activity of
interferon alfa-n3 is approximately equal to 2.6 × 108 international
units/mg of protein. Calculate (a) the number of international units
and (b) the micrograms of interferon alfa-n3 proteins administered per
dose.
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9.D. One general guideline for the maintenance dosing of heparin in
pediatric patients is 100 units/kg every 4 hours, or 20,000 units/m2/24
hours administered continuously. The available injection for use by
intravenous infusion contains 1000 USP Heparin Units/mL. For a 44lb child, measuring 42 inches in height, calculate the difference
between the quantities of heparin administered over a 24-hour period
in (a) heparin units, (b) in milligrams of heparin (sodium), and (c) in
milliliters of heparin injection.
ANSWERS TO “CASE IN POINT” AND
PRACTICE PROBLEMS
Case in Point 9.1
a. TIW = three times a week (It should be noted that although this
abbreviation appears in the literature, it is considered error
prone and thus its use is not approved by the Institute of Safe
Medication Practices.)
b. 165 lb ÷ 2.2 lb/kg = 75 kg, weight of patient
Minimal starting dose = 50 units/kg; thus, 50 units × 75 (kg) =
3750 units
3750 units ÷ 10,000 units/mL = 0.375 mL of epoetin alfa
injection
c. 0.375 mL/dose × 3 (times per week) = 1.125 mL epoetin alfa
injection
d. Dose reduced by 25% or 937.5 units; thus, 3750–937.5 = 2812.5
units epoetin alfa
e. 2812.5 units ÷ 10,000 units/mL = 0.28 mL epoetin alfa injection
Practice Problems
0.18 mL U-100 insulin isophane suspension
25 days
9,600,000 units interferon beta 1-b
250,000 international units
a. 0.1 mL insulin glargine
b. 0.04 mL insulin glargine
0.45 mL penicillin G potassium
4 days
690,000 – 805,000 units/tablet
500 mg polymyxin B sulfate
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27.
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5.
800 units and 0.02 mg/day
a. 41.76 million units alteplase
b. 72 mL alteplase injection
No
17 units insulin
61.82 units isophane insulin
a. 1.08 units somatropin
b. 0.14 mL somatropin injection
331.2 to 1380 units of vitamin A and 33.12 to 138 units of vitamin
D
a. 1599.71 IU hepatitis B immune globulin
b. 5.13 mL hepatitis B immune globulin
50.85 mg gentamicin sulfate
c. 0.9 mL of 4000 units/mL
12 to 24 mL tetanus immune globulin injection
No
1 billion international units
70 units/dose and 7 mL/dose
80 mg/mL clindamycin
b. 0.5 mL
4.67 mL rabies immune globulin
29,846.15 PFU/mL
References
US Pharmacopeial Convention, Inc. General Chapters. <1041> Biologics. United States
Pharmacopeia 42 National Formulary 37 [book online]. Rockville, MD: US
Pharmacopeial Convention, Inc.; 2019.
World Health Organization (WHO). Available at:
https://www.who.int/biologicals/reference_preparations/en/. Accessed June 12, 2020.
National Institute of Allergy and Infectious Diseases. Vaccine Research Center. Available
at: https://www.niaid.nih.gov/about/vrc. Accessed June 12, 2020.
National Institute of Allergy and Infectious Diseases. Disease-specific vaccines. Available
at: https://www.niaid.nih.gov/research/disease-specific-vaccines. Accessed June 12, 2020.
Centers for Disease Control and Prevention. Vaccines and immunizations. Available at:
https://www.cdc.gov/vaccines/. Accessed June 12, 2020.
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