Anhydrous theophylline equivalence of commercial theophylline formulations

Anhydrous theophylline equivalence of commercial theophylline formulations

CORRESPONDENCE Anhydrous theophylline To the In became content theophylline formulations equivalence of commercial Editor: the course of studies ...

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Anhydrous theophylline To the In became content

theophylline formulations


of commercial

Editor: the course of studies on the hioavaila.bility of several theophylline preparations, it evident that there were substantial differences in terms of anhydrous theophylline among the various formulations. For example, label claims for Tedral and Quadrinal

TABLE I. Theophylline-containing



of drug



for oral


Aminophylline (85 % anhydrous theophyllittel

and manufacturer

Oxtriphylline (64.4 % anhydrous theopkylline)


256 mg 128 mg

Junior Asbron Asbron

elixir (Dorsey) tablets (Dorsey)

Aminophylline Brondecon

tablets elixir

Bronkolixir Bronkotabs

elixir (Mallinckrodt) tablets (Mallinckrodt)

100 mg/5 cc 100 mg 200 mg

80 mg/15 cc


32.5 mg/5 cc 130 mg

syrup (Roerig) tablets (Roerig)

Quadrinal Quadrinal Quibron Quibron

suspension (Knoll) tablets (Knoll) 50 mg/5 cc 150 mg

elixir (Mead Johnson) capsules (Mead Johnson)


Theokin Theokin

15 mg/5 cc 100 mg

(Breon) (Breon)

Lufyllin Lufyllin

Tedral Tedral Tedral

100 mg


elixir (Warner-Chilcott) tablets (Warner-Chilcott)


100 mg


Choledyl Choledyl

Marax Marax

Theophylkbse (~W=eei


80 mg/15 cc


elixir ( Warner-Chilcott) suspension ( Warner-Chileott tablets (Warner-Chilcott)


130 mg

elixir (Knoll) tablets (Knoll)

Verequad suspension (Knoll) Verequad tablets (Knoll) *This percentage is approximate only. Manufacturer uses basic calcium salicylate in tableda kZld so that content of anhydrous theophylline is as labeled. tin contrast to the other formulations listed, dihydroxypropyltheophylline (DHPT) is not trans mine its anhydrous theophylline equivalency as was done with the other preparations. Vol. 59, No. 8, pp. 116-119




indicate that each contains 130 mg. of theophylline per tablet. However, the theophylline in Quadrinal is in the form of the calcium salicylate salt, while Tedral contains anhydrour Quadrinal contains only 48% theophylline. In terms of theophylline content, therefore, of the amount in Tedral. Another widely prescribed preparation, Choledyl, the choline salt of theophylline, contains only 64 mg. of anhydrous theophylline per 100 mg. tablet. Anhydrour theophylline is a relatively water-insoluble alkaloid alleged to be erratically absorbed from the gastrointestinal tract.1 For this reason, numerous combinations of theophylline usually in the form of a salt have been devised in an attempt to improve the bioavailability of the drug. There is no evidence that this has been accomplished, and, in fact, a recent bioavailability study2 indicates very similar bioavailability of various theophylline formulations when given in equivalent amounts in terms of anhydrous theophylline. Because these differences among theophylline-containing medications are not widely appreciated, we have prepared a tab16 indicating the composition of various theophylline formulations and their anhydrous theophyl,

Theophylline sodium glycinate (50 % anhydrous theophylline)

Theophylline calcium salicylate 148 % anhydrous theophylline)*

Theophylline NF (91 %I (monohydrate)


Anhydrous theophylllne equivalent


mg mg

150 150

mg mg





15 100

mg mg

64 64

mg mg mg

256 300 mg/15 cc 300 mg

128 100 mg mg/15 cc 200 mg

i t mg


32.5 mg 130 mg 32.5 mg 65.0 mg

65 mg/5 cc 130 mg


mg mg




59 130

mg mg mg

225 225

mg mg


38.5 Big/b e3 lug/5

cc cc 448.5 mg/15 cc 448.5, mg

325 mg 65.0 mg

65 mg/5 cc 130 mg




in liquids.


in the body to theophylline



but exerts


its activity


as DHPT.



is added’

one cannot





line equivalent. These differences in anhydrous theophylline equivaleneies may have important therapeutic implications leading to under- or overdosage, particularly when a patient is switched from one theophylline-containing preparation to another. Therefore, we propose that theophylline be prescribed in a dosage based upon the content of anhydrous theophylline in the formulation. Esther D. Eddy Department of Pharmaq Services Children’s Hospital of Buffalo Buffalo, Neul Pork

Elliot F. Ellis, M.D. Pediatric Allergy Department National Jewish Hospital Denver, Colorado REFERENCES

in Goodman, L. S., and Gelman, A., editors: The phar1 Ritehie, 5. M.: (‘The Xanthines,” macological basis of therapeutics, ed. 4, New York, 1970, Macmillan Publishing Co., Inc., p. 365. 2 Basso, J. A., Jr., and Ellis, E. F.: Bioavailability of theophylline-containing preparations. In preparation.


to tetanus


To the Editor: In reference to the article “Hypersensitivity to Tetanus Toxoid,” which appeared in the July, 1973, issue of the JOURNAL, we would like to offer additional data to keep the subject of tetanus toxoid “allergy” in perspective. At this United States Air Force base we have administered an average of approximately 850,000 doses of alum-precipitated tetanus-diphtheria toxoid each year for the past ten years. The men are first questioned about any prior reactions. Five-tenths ml. of toxoid is given by “gun” twice during basic training. The recipients are observed at 20 to 30 minutes; then the arm is examined again in 48 or 72 hours. Any man who cannot perform duty is admitted to the hospital. No diagnosis of allergy to any immunization is accepted nor is any man excused from any question for the immunization without being evaluated by our service. This is an important Air Force since allergy to a required vaccine may be cause for separation from service. “tetanus toxoid,” “tetanus boosters,” All patients with a history of allergy to “tetanus,” were skin-tested to a fluid extract of tetanus toxoid according to the or “tetanus antitoxin” following schedule : 1. If 2. 3. 4. 5. 6. 7. 8.

0.02 ml. 1.D. of l:lOO,OOO (read in Xi-20 min.) no reaction then 0.02 ml. I.D. of 1 :lO,OOO (read in 15-20 min.) 0.02 ml. I.D. of l:l,OOO (read in 15-20 min.) 0.02 ml. I.D. of 1: 100 (read in 15-20 min.) 0.02 ml. I.D. of 1: 10 (read in 15-20 min.) 0.1 ml. sub.-cut. 1 :lO (read in 30 min.) 0.1 ml. sub.-cut. full strength (read in 30 min.) 0.4 ml. sub.-cut. full strength (read in 30 min.)

This schedule was modified for all patients reporting reactions that began more than two hours after the suspected dose as follows. Following injection of dose No. 6, the testing was deferred for 24 or 48 hours, to detect any “Arthus” or “delayed reaction.” We average two referrals per duty day to rule out “tetanus allergy.” In the past ten years we have: 1. Not been able to document a single case of anaphylaetic reactivity to tetanus toxoid. 2. Recognized 3 patients who were mercury-sensitive and were reacting to the preservative in the vaccine. 3. All patients who were teeted were able to receive at least 0.1 ml. of the full strength alum-precipitated tetanus-diphtheria toxoid.