Bioavailability Monograph: Ferrous Sulfate

Bioavailability Monograph: Ferrous Sulfate

Bioavailability Monograph As research and study regarding the bioavailability of drug products continue, additional information will be made availabl...

6MB Sizes 0 Downloads 20 Views

Bioavailability Monograph

As research and study regarding the bioavailability of drug products continue, additional information will be made available adding to and! or altering the information and conclusions contained in this monograph. Drug manufacturers and others who conduct bioavailability studies of drug products are encouraged to submit their results immediately to APhA. Monographs will be revised and updated periodically to reflect new information, and when necessary special announcements regarding new data will appear in this Journal.


Ferrous sulfate is considered the drug of choice in treating and / or preventing iron deficiency anemia. 1 Neither dissolution studies nor well-designed comparative bioavailability studies on ferrous sulfate products marketed in this country have been reported. The FDA does not include ferrous sulfate among the 77 drugs recommended for in vitro dissolution tests nor among the 60 drugs recommended for in vivo absorption tests. 2 However, in a joint recommendation of the American Pharmaceutical Association and the APhA Academy of Pharmaceutical Sciences to the Department of Health, Education, and Welfare in 1974, this drug was classified in a category of drugs whose solid oral dosage forms were suspected to have a potential for bioequivalence and / or quality assurance problems that could have serious implications for therapy. 3 The statement further recommended that bioavailability data on ferrous sulfate probably should be required of all manufacturers. After reviewing the limited published data on certain domestic and foreign products and manufacturer-supplied data, it is felt that some ferrous sulfate solid dosage forms may have a clinically significant bioavailability problem and that absorption, or at least dissolution, studies should be conducted for all solid dosage form products. The Drug Entity

General Characteristics-Iron is an essential mineral in the body. There are many chemical sources available, such as metallic (reduced) iron and ferric and ferrous salts. However, ferrous salts are the most commonly used salts because of their reported superior gastrointestinal absorption. Among the ferrous salts-

Vol. NS 17, No.6, June 1977

Ferrous Sulfate

such as the sulfate, fumarate, succinate, glutamate, gluconate and lactate-the sulfate salt is considered the salt otchoice and is the least expensive. The validity of claims of better absorption or less ga$~ trointestinal side effects for more expensive ferrous salts and derivatives has been seriously questioned. 1 Therefore, this monograph deals prImarily with ferrous sulfate preparations, although many principles discussed also could be appJied to other iron preparations. ' There are ~bout 3.5 g of iron present in the body of normal adults. It is almost exclusively complexed to proteins (transferrin and ferritin) and heme (hemoglobin, myoglobin and heme enzymes). Hemoglobin contains approximately 65 percent of the total body iron. Therefore, hemoglobin levels are often used as a measure of iron deficiency. Natural and enriched diets are the iron sources in normal subjects. Iron from ferrous sulfate and other sources is absorbed mainly from the upper part of the small intestine by both active and passive transport processes, although absorption from the colon also has been demohstrated. 1,4 Passive transpOrt is dominant at doses exceeding those in a normal diet. 1 This transport was demonstrated by an approximate proportional increase in serum iron levels with an increasing dose of ferrous sulfate from 96 to 163 mg of equivalent iron. 5 Oral iron abs
or ,complex forms. In one study on human subjects, only 2.9 to 4.4 percent of the dose wasre..; covered in 4 days of urine collec!i~.~~f~er an intravenous dose. 7 The majcir' ~x€)r"e; 1 tory pathway is through epithelial c~lIs sloughed from the skin and gastroJptestinal tract. ' Common side effects of iron therapy include constipation, diarrhea, naUsea and epig~stric pain and are often dose ' dependent. Although other ferro Its' have been claimed to cause fe effects ,than ferrous SUlfate,', t ':st factor and the validity of such claim ., including the degree of absorption, .·should be exafDined carefully by practitioners. Due to the capacity of bone marrow, less than 100 mg of absorbed iron.can be incorporated into hemoglobin .p~e ,' ~ay. Therefor~, administration of mu~h . l~t~~t daily doses has limited hemat9P6ietic value. 1 PhYSical Characteristics-Two official pure forms are available: ferrous sulfate iJsp and dried ferrous sulfate USP. The former contains 7 moles of water and 20 perc~nt by w~.ight of el~~ental •.iron, while the latter cohtainspdmarily FeS ' with varying amounts of FeS04-20. Although both are freely soluble in water, their dissolution rate is not very rapid. This factor is more obvious in the case of dried ferrous sulfate. In moist air, ferrous sulfate rapidly oxidizes to the less absorbable ferric salt. Dosage Forms

Dosage forms must meet official requirements which include primarilY ide~tification and assay. For ferrous sulfate tablets USP, additional disintegration (30 minute limit) and weight variation tests are required. , Unofficial products include elixirs, controUed-release formulations and dosage forms in which ferrous sulfate is complexed with molybdenum sesquioxide. Also, ferrous sulfate is often included in many vitamin and mineral preparations. Analytical Methods

Although hematological responses such as hemoglobin concentration frequently have been used to study the bioavailability of ferrous products, it is generally agreed that this method is relatively insensitiVe.


Ferrous Sulfate

Many colorimetric and atomic absorption methods have been published for the determination of serum iron levels. 8- 1o The simple, rapid , accurate, semimicro (0.2 ml of serum) colorimetric method of Jung and Parekh 10 appears to be the most useful. This method does not require the deproteinization of serum prior to reacting it with the coloring agent. A recently published flame atomic emission spectrometric method 11 provides the highest sensitivity among published methods. It requires only 10 III of serum and its detection limit is 0.088 ng / ml. Bloavailability

Literature Survey and Evaluation-In a bioavailability evaluation, it is common to compare the plasma level profile of the drug from a particular dosage form to that of a reference product administered orally or intravenously. Ferrous sulfate alone is not available for intravenous use. Since the absorption, distribution and elimination of iron from the body are unusually complicated , it is doubtful whether plasma level data generated directly from intravenous administration of ferrous sulfate or other derivat'lves could be very useful in estimating the absolute bioavailability of ferrous sulfate from various oral dosage forms. Although solution forms of ferrous sulfate that potentially could be used as reference products are commercially available, it appears that no well-designed absorption study comparing a solid product and a reference solution product has been published. To date, studies on the percent of absorption from the enriched diet and other ferrous sulfate preparations have been based on the radioactivity in the plasma, whole blood or whole body after administration of radiolabeled iron. 12- 15 In one study5 employing six normal adult subjects, both serum iron levels and areas under the curves up to 7.5 hours after dosing generally were proportional to the administered doses of ferrous SUlfate in gelatin capsules. These data suggested that plasma or serum levels could be used for bioavailability comparisons among the various ferrous sulfate products. The linear correlation between the in vitro dissolution rate and the area under the serum iron concentration-time curves also suggests that iron absorption could be dissolution rate limited. An appropriate dissolution test may be useful for the

decreases iron absorption. 1, 19 Coadministration of ferrous sulfate with tetracycline, oxytetracycline,' methacycline and doxycycline decreases the absorption of these antibiotics.2o Two to three hours between dosing of ferrous sulfate and tetracyclines is recommended to avoid this drug interaction.21 Although the effect on iron absorption was not reported in these two studies,20,21 it is expected that iron absorption also will be inhibited by the coadministration of tetracyclines. Iron absorption is decreased in patients with diarrhea and malabsorption syndromes.22 Iron absorption could be reduced in patients with achlorhydria and partial or complete gastrectomy. Absorption and utilization of iron generally increase as the degree of iron deficiency or the need for body iron increases. For example, iron absorption from non-heme food increased from less than 1 percent in most women during early pregnancy to about 5 percent in mid-pregnancy and 14 percent at the 36th week of gestation. 15 Orange juice, probably due to its acidity, increases iron absorption. 1 Coadministration of ascorbic acid equivalent to about 30 times the weight of elementary iron is required to significantly enhance iron absorption from ferrous sulfate. 13 Therefore, the effect of a small amount of ascorbic acid, included in many iron preparations to increase the iron absorption, is doubtful. Regulatory and Compendial Activity -A diSintegration test is . required for ferrous sulfate tablets USP. In light of the facts that (1) absorption can be dissolution rate limited, (2) the drug can be slowly released from conventional or controlled-release products and (3) serum iron peaks were obtained 6 to 8 hours after the oral administration of sugar-coated or film-coated tablets, it is suggested that a reliable in vitro dissolution test be established to correlate with the bioavailability of ferrous sulfate and to use as a routine quality control procedure.

routine quality control of these products. Different results have been reported on the absorption, efficacy and side effects of controlled-release ferrous sulfate products. For example, plastic matrix products (e.g., Fero-Gradumet, Abbott) are as effective as the conventional form of ferrous sulfate in treating iron deficiency anemia and exhibit no more side effects than a placebo. 16 The Gradumet product also produced an equal or better hematological response than that observed following a higher divided dose of conventional tablets. 17 Patient compliance and the retarding effect of meals on iron absorption may contribute to the results obtained with conventional tablets. However, in another study conducted in anemic patients, the Gradumet product produced a less predictable clinical response than did a fast-release ferrous sulfate capsule. 18 Interestingly, no side effects from either product were reported in the 57 patients studied. Extremely variable and generally less satisfactory absorption also was reported for an unspecified slow-release tablet. 12 In addition to formulation factors that may affect the bioavailability of iron preparations, several conditions may influence the absorption of iron from ferrous sulfate or other chemical sources. These factors are important in the design of a protocol for bioavailability evaluation and also to clinicians adviSing patients on the uses of iron preparations. It has been shown repeated ly that administration of ferrous sulfate or other iron preparations with a meal or immediately after a meal can Significantly reduce iron absorption; in one study, a reduction of about 50 percent was reported.6 Therefore, for maximum absorption, the drug should be administered on an empty stomach, either at bedtime or between meals, provided this regimen can be tolerated. Phosphate, phytate and calcium in food are thought to be responsible for reduced absorption. 1 Tea, coffee and milk inhibit iron absorption. In one study, tea decreased iron absorption by approximately 70 percent compared to water. 13 The formation of a water-insoluble iron-tannin complex was proposed as the probable cause for the observed decrease in iron absorption. Coadministration of ferrous sulfate with antacid preparations, especially those containing magnesium trisilicate, also

Data on the bioavailability of solid oral dosage forms of ferrous sulfate are scarce; consequently, a solid oral reference product cannot be recommended at this time. It appears reasonable to conclude that an oral ferrous su lfate so-


Journal of the American Pharmaceutical Association

Criteria for Bioavailability Tests

lution should serve as a reference even though well-designed studies comparing solid ~nd solution oral dosage forms have not been conducted. 1. Tests should be conducted in a crossover design using 10 to 12 normal subjects each weighing 50 to 80 kg. Hepatic and hematological tests should be within normal limits. Subjects should not be menstruating or have any condition resulting in blood loss. 2. Solution dosage forms of ferrous sulfate can be used as a reference product for comparison. 3. Ferrous sulfate should be administered (swallowed intact) on an empty stomach, using about 200 ml of lukewarm water, in the morning after an overnight fast. Food, water or other liquids should be withheld for 2 hours. 4. Blood samples for plasma or serum iron level determinations should be obtained at 0, 1, 2, 3, 4, 6, 8, and 10 hours after dosing. Because of the diurnal fluctuation of serum iron levels, baseline iron levels should be determined at the corresponding 0, 2, 4, 6, 8 and 10 hours 1 day prior to the ferrous sulfate study. 5. Plasma or serum iron levels above the baseline values and the area under the curve up to 10 hours can be calculated. 6. Studies on the same individual should be separated by at least 1 week. Plasma or serum baseline iron levels also should be determined in the second study. 7.To minimize data variation, plasma or serum iron level data from each individual subject should be corrected based on the average 70 kg of body weight prior to being subjected to statistical analysis. 8. The bioavailability of the test product should average at least 70 percent of that of the reference product based on analysis of the 0-10 hour area under the curve. Appropriate allowance for variation in individual rates and extents of absorption also should be established. Information Available From Suppliers

Bioavailability information was requested by letter from 78 manufacturers and / or suppliers of ferrous sulfate tablets. The following 56 companies did not respond:

Vol. NS 17, No.6, June 1977

American Laboratories American Pharmaceutical Approved Pharmaceutical Barry-Martin Pharmaceuticals Blue Cross (Halsey) Burgin-Arden C. R. Canfield Carr Drug H. R. Cenci Cord Laboratories Corvit Pharmaceutical$ Paul B. Elder Faraday Laboratories Fellows Medical Manufacturing Fielding First Texas Pharmaceuticals Geneva Drugs Gotham Pharmaceutical Don Hall Laboratories Harvey 'Laboratories Horton & Converse Laboratories ICN Pharmaceuticals Inwood Laboratories Jenkins Laboratories Kenyon Drug Kirkman Laboratories Lannett Len-Tag Eli Lilly Mallinckrodt Merit Pharmaceutical Midway Medical Mylan Pharmaceutical .National Lead Neo-Vadrin P. J. Noyes Parke-Davis Pharmecon Premo Pharmaceutical Purepac Pharmaceutical Richlyn Laboratories William H. Rorer Royal International Vitamins Scrip Stan Laboratories Tablicaps Truxton Ulmer Pharmaceuticals Vita-Fore Products Weeks and Leo West-ward Winsale Drug Wolins Pharmacal Zemmer Zenith Laboratories

The following 12 companies indicated that they were only distributors of ferrous sulfate products manufactured by another company and, therefore, could not provide any bioavailability information: Distributor Manufacturer Arcum Lannett Pharmaceutical J. T. Baker Mallinckrodt National Lead Coast Laboratories Wm. T. Thompson Columbia Medical Tablicaps Cord Laboratories Geneva Generics Mallinckrodt Humco Laboratories Kay Pharmacal Cord Laboratories Mylan Lederle Pharmaceutical Laboratories H. L. Moore Drug Mylan Pharmaceutical Exchange Tablicaps Robinson Tablicaps Laboratories Sheraton ICN Pharmaceuticals Laboratories Wm. T. Thompson Upsher-Smith ICN Laboratories Pharmaceuticals The following four companies indicated that their products meet compendial requirements including the disintegration test: Bell Pharmaceutical-sugar-coated tablets, 45 minutes or less (USP limit, 30 minutes) Geneva Generics Philips Roxane Laboratories-disintegration in 4-7 minutes Towne-Paulsen Pharmaceuticals-enteric-coated products disintegrate in 20-30 minutes in artificial intestinal fluid; no aging effect observed. Consolidated Midland, Century Pharmaceuticals and Stayner Pharmaceutical indicated that no bioavailability data were available for their products. Abbott Laboratories responded that it markets ferrous sulfate syrup and controlled-release tablets (Fero-Gradumet) . However, Abbott believed (also supported by the Steering Committee on this Bioavailability Project) that the purpose of this project was to evaluate only ferrous sulfate tablets USP. Therefore, no information was forwarded by Abbott Laboratories. Schering Corporation provided a reprint of an article 23 on oral absorption


Ferrous Sulfate

studies of its iron-molybdenum preparation (Mol-Iron) . Serum iron level data at 2 and 4 hours after dosing in normal female subjects failed to show the enhancing effect of molybdenum oxide on iron absorption in spite of the fact that the product produced a better therapeutic effect in other studies. The company also provided a reprint of an article 24 on comparative absorption studies of its sustained-release capsules (Mol-Iron Chronosule) and a sirrlilar product (Feosol Spansule, Smith Kline & French) conducted in 63 normal subjects. Smith Kline & French Laboratories provided pharmacological response data obtained after administration in a noncrossover design of its Feosol Spansule and plain ferrous sulfate solution to anemic piglets. There were no clinically significant differences between the two dosage forms in terms of hematological response. Companies Providing Bioavailability Information

The Upjohn Company provided average serum iron levels obtained from 26 normal subjects afte administration of 325 mg of ferrous sulfate sugar-coated or film-coated tablets. A control study without iron administration also was

Table 1. Average Serum Iron Concentrations (#1g/ml) Obtained from Oral Ferrous Sulfate Studies in 26 Subjects


0.67 0 1.16 1 1.82 2 2.02 3 4 2. 13 2.24 6 0.95 8 1.07 12 0.66 16 0.69 24 Area under curve 29.81 (0- 24 hours), J.Lg X hour/ml Average individual 6.1 peak times, hours

0.64 0.91 1. 18 1.46 1.69 1.89 2. 11 1.00 0.71 0.72 27.66

0.74 0.86 1. 07 0.98 1.06 1.23 1.26 0.93 0.62 0.66 21 . 19



performed to show the diurnal yariation of serum iron levels. These data are summarized in Table 1. There was no statistically significant difference between the two formulat ions in terms of the peak level, peak time and area under the curve. The company fur-

References 1. Goodman, L. S., and Gilman, A. (eds.) : The pharmacological basis of therapeutics, The Macmillan Company, New York, New York, 1975, p. 1309. 2. Am. Druggist 172: 26 (Aug.) 1975. 3. J. Am. Pharm. Assn. NS 14: 556, 1974. 4. Ohkawara, Y., Bamba, M., Nakai, I., Kinka, S., and Masuda, M.: Gastroenterology 44: 611 , 1963. 5. Middleton, E.J., Nagy, E. , and Morrison, A.B.: N. Engl. J. Med. 274: 136, 1966. 6. Gaitonde, B.B., Vakil, B.J. , Samuel, M.R. , Chabria, N. L. , and Kamath, R.A.: Indian J. Med. Res. 60: 1674, 1972. 7. Crawley, J.: Edinburgh Med. J. 59: 478, 1952. 8. Davidsohn, I., and Henry, J.B.: Todd-Sanford clinical

Film Sugar Coated Coated Control

9. 10. 11. 12. 13.

14. 15.

diagnosis by laboratory methods, W.B. Saunders Company, Philadelphia, Pennsylvania, 1974, p. 652. Caraway, W.T.: Clin. Chem. 9: 188, 1963. Jung, D.H., and Parekh, AC.: Am. J. Clin. Pathol. 54: 813, 1970. McCullough, M.R. , and Vickers, T.J.: A nal. Chem. 48: 1006, 1976. Crosland-Taylor, P., Keeling, D.H., and Cromie, B.W.: Curro Ther. Res. 7: 244, 1965. Disler, P.B., Lynch, S.R. , Charlton, R.W., Torrance, J.D., Bothwell, T.H., Walker, R.B., and Mayet, F.: Gut 16: 193, 1975. Grebe, G., Marlinez-Torees, C., and Layrisse. M.: Curro Ther. Res. 17: 382, 1975. Svanberg , 8.: Absorption of iron in pregnancy. Goteborg, Sweden, 1976.

ther stated that the film-coated product would be marketed. In light of the unusual delay in the attainment of peak levels, it would have been interesting and valuable if a solution dosage form also had been included in the study. The company also provided data on the percent saturation of the total serum binding capacity after the treatments and suggested the potentjal value of these data in the bioavailability evaluation . This monograph contains information supplied to APhA as of May 31 , 1976.

Monograph AuthorWin L. Chiou, PhD, Professor of Pharmacy and Director of the Clinical Pharmacokinetics Laboratory, College of Pharmacy, University of Illinois Medical Center, Chicago, Illinois Monograph CollaboratorsSteven R. Kayser, PharmD, Assistant Clinical Professor of Pharmacy, School of Pharmacy, University of California, San Francisco, California James M. Orr, PhD, Head, Biopharmaceutics Section, Bio-Research Laboratory, Pointe Clair, Quebec, Canada Valentino J. Stella, PhD, Associate Professor of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas

16. Webster, J.J.: Curro Ther. Res. 4: 130, 1962. 17. Gomez, G., and Gomez, J.: Br. J. Clin. Pract. 21: 31 , 1967 . 18. Luntz, G.RW .N., and Bogie. w.: Curro Med. Res. Opin. 3: 145, 1975. 19. Hall, G.J.L., and Davis, A E. : Med. J. Aust. 2: 95, 1969. 20. Neuvonen, P.J.. Gothoni, G., Hackman, R. , and Bjorksten, K.: Br. Med. J. 4: 532, 1970. 21 . Gothoni, G., Neuvonen. P . J~, Mattila, M., and Hackman, R. : A c ta Med. Scand. 19 1: 409, 1972. 22. Gross, S.J .. Stuart, M.J., Swender, P. T., and Oski , F. A : J. Pediat. 88: 795, 1976. 23. Gull berg, S., and Vahlquist, B.: Blood 5: 871 , 1950. 24. Mourat off. G.J. , and Batterman. R.C.: J. New Drugs 1: 157,196 1.

Published b y American Pharm aceutical Association 22 15 Con st itutio n Ave ., NW Wa sh ington , DC 20037


Journal of the American Pharmaceutical Association