PRELIMINARY RESULTS: SERUM CHEMISTRY VALUES BEFORE AND AFTER THE INTRAVAGINAL ADMINISTRATION OF 5% NONOXYNOL-9 CREAM

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1 FERTILITY AND STERILITY Copyright" 1981 The American Fertility Society Vol. 35, No.6, June 1981 Printed in U.8A. PRELIMINARY RESULTS: SERUM CHEMISTRY VALUES BEFORE AND AFTER THE INTRAVAGINAL ADMINISTRATION OF 5% NONOXYNOL-9 CREAM BOHDAN MAL YK, M.D. * Ortho Pharmaceutical Corporation, Raritan, New Jersey Thirty-two healthy premenopausal women between the ages of 18 and 39 were randomly assigned to three study groups as follows: Group I received daily intravaginal administration of2.5 gm of 5% nonoxynol-9.vaginal cream (Conceptrol [Ortho Pharmaceutical Corporation, Raritan, N. J.J cream) for 14 days. Group II received daily intravaginal administration of 2.5 gm of the cream base alone, and group III received no treatment. The numbers of subjects completing the study were 12,11, and 7 for groups I, II, and III, respectively. Fasting blood samples were obtained from each subject prior to treatment and on days 8 and 15 after treatment. Blood samples were analyzed for 20 constituents, including proteins, lipids, triglycerides, and serum enzymes. There were no differences in any of the measured parameters between the pre- and post-treatment periods in any of the groups. On the basis of these findings it may be concluded that there are no apparent systemic effects following daily intravaginal administration of a 125-mg dose of nonoxynol-9 in a cream base for 2 weeks. Fertil Steril 35:647, 1981 Nonoxynol-9, a non-ionic surfactant, is the active spermicidal ingredient in many commercially available va~inal contraceptive products. In the past, the safety of nonoxynol-9 in these products has been its strong point, and nonoxynol-9 has been tentatively classified by the Food and Drug Administration Advisory Review Panel on Vaginal Contraceptives as Category 1,1 generally recognized as safe and effective. There are no known reports of mortality or serious adverse reactions attributable to nonoxynol-9. 2 However, as knowledge of the physiology of the female reproductive system increases, new questions about the possibility of systemic effects from vaginal contraceptives have arisen. No clear evidence is present for this apparent increase in concern, but it probably results from a general concern for safety in all drugs. To date, only local irritation has been reported and only as an occasional side effect of nonox- Received October 1, 1980; revised and accepted December 31,1980. *Reprint requests: Bohdan Malyk, M.D., Director of Clinical Research,Ortho Pharmaceutical Corporation, Raritan, New Jersey ynol-9 use. 2 Even when the Food and Drug Administration Advisory Panel reviewed the drug, no reports of systemic toxic effects to the user were identified. 1 Recent investigations in animals 3 have raised questions about the potential for hepatic toxicity of nonoxynol-9, although the dosages studied were high relative to human-use doses and were given as aqueous solutions. The present study was conducted to evaluate the effects, if any, of a commercially available 5% nonoxynol-9 vaginal contraceptive cream (Conceptrol [Ortho Pharmaceutical Corporation, Raritan, N. J.J cream) on the serum chemistries of healthy premenopausal women, when used intravaginally once daily for a period of 2 weeks. A special effort was made to evaluate hepatic function, using recognized serum enzyme parameters. MATERIALS AND METHODS Thirty-two healthy, nonpregnant, premenopausal women between the ages of 18 and 39 years participated in the study. Criteria for entry into the study were established and subjects were

2 r! 648 MALYK screened carefully before they were included. Any subject with a history of acute or chronic systemic disease was excluded. Current use of any medications, including oral or vaginal contraceptive products, was also an exclusion criterion. All subjects were instructed not to use any other intravaginal products, not to take any oral medications, including over-the-counter drugs, and not to consume any alcoholic beverages at any time during the study period. At the initial study visit, a pretreatment fasting blood sample was obtained. Each subject was then randomly assigned to one of three study regimens; thirteen received the 5% nonoxynol-9 cream, twelve received the cream base alone, and seven received no product at all. The women using cream were instructed to use one standard Ortho 2.5-gm applicatorful daily for 14 consecutive days. All of the women returned on the 8th and 15th days of the study for repeat fasting blood samples. All blood samples were analyzed by an independent commercial clinical laboratory for the following: calcium, phosphorus, blood urea nitrogen (BUN), total protein, albumin (A), globulin (G), A/G ratio, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, lactic acid dehydrogenase (LDH), creatine phosphokinase (CPK), 'Y-glutamyl transpeptidase (GGT), cholesterol, triglycerides, and total lipids. Additionally, isoenzymes ofldh and CPK were analyzed if total LDH or CPK values were elevated. After the study started, bile acid determination was added as another sensitive parameter for the evaluation of hepatic function. Thus measurements of bile acids were not conducted on all subjects at all time intervals. At the conclusion of the study, all subjects were questioned to confirm their adherence to the study protocol. Once assured of their compliance, data from each subject's serum profile were tabulated for analysis, using Fischer's least significant difference method. 4 RESULTS Thirty-two subjects starte~ the protocol; however, study of two volunteers had to be terminated, one in group I and one in group II. The subject in group I developed severe pharyngitis requiring antibiotic treatment; the other subject was excluded because of a nonspecific upper respi- June 1981 ratory infection requiring decongestants. Of the remaining volunteers, all completed the protocol. The results were divided into three groups: group I, receiving 5% nonoxynol-9 cream; group II, receiving base cream alone; and group III, receiving no treatment. The vaues for total LDH, total protein, total bilirubin, direct bilirubin, SGOT, SGPT, alkaline phosphatase, GGT, CPK, bile acid, BUN, creatinine, glucose, albumin, globulin, cholesterol, and triglycerides were statistically analyzed using Fischer's least significant method 4 to test the differences between any two treatment group means. No statistically significant (P < 0.05) differences were detected from these data. Each patient value used in the statistical analysis was based on the difference from its own basal (pretreatment) value. The data for each of the parameters evaluated are listed in Tables 1, 2, and 3. DISCUSSION There is no available analytical method for the determination of nonoxynol-9 in human serum with which to document absorption. Therefore, one must rely on indirect assessments for evaluating any possible physiologic effects of the compound. This is true not only for nonoxynol-9 but for virtually all agents in this category currently available to the physician or consumer. However, toxic manifestations of many materials present environmentally and occupationally were first identified with the use of these indirect biochemical screening studies. Some investigators believe that one can infer that a drug is being metabolized in the liver, primarily by an increase in the transaminase enzymes.5 These isolated increases may occur as part of the metabolic process of the drug without implying hepatic injury.5 Many sensitive methods are available for detection of hepatic dysfunction. Tests for GGT and bile acids are newer additions to the still-valuable SGOT, SGPT, alkaline phosphatase, and serum bilirubin determinations. 6, 7 All constituents that were measured in this group of healthy premenopausal women as listed in Tables 1, 2, and 3 (also included were determinations of serum calcium, phosphorus, total lipids, and magnesium, not listed in the tables) were normal. Isolated instances of nonsignificantly increased concentrations appear (Tables 1, 2, and 3); however, no demonstrable pattern was

3 TABLE 1. Serum Chemistry Values of 5% Nonoxynol-9 Cream Users: Group I Test Total Creat- Glu- Total Albu- Glob- Total Direct Alkaline Cho- Triglyc- Bile LDH BUN inine case protein min nlin bilirubin bilirubin SOOT SGPT phosphatase lesterol GGT erides CPK acid IUlliter mgldl mgldl mgldl gmldl gmldl gmldl mgldl mgldl IUlliter IUlliter IUlliter mgldl unitslliter mgldl IUlliter fj.ijldl b b 49b b b b b ~ b b b b od obtained pretreatment; sample 2, blood obtained after 1 week; sample 3, blood obtained after 2 weeks. ue.

4 TABLE 2. Serum Chemistry Value of Placebo Cream Users: Group II Test Total Creat- Glu- Total Albu Glob Total Direct Alkaline Cho- Triglyc- Bile LDH BUN inine cose protein min ulin bilirubin bilirubin SGOT SGPT phosphatase lesterol GGT erides CPK acid luiliter mgldl mgldl mgldl gmldl gmldl gmldl mgldl mgldl lulliter lulliter lulliter mgldl unitslliter mgldl lulliter fjol!ldl b b b b b b b b b d obtained pretreatment; sample 2, blood obtained after 1 week; sample 3, blood obtained after 2 weeks. e.

5 TABLE 3. Serum Chemistry Values of No-Treatment Group: Group III Test Total Creat Glu- Total Albu Glob- Total Direct Alkaline LDH BUN inine case protein min ulin bilirubin bilirubin SGOT SGPT phosphatase Cho- Triglyclesterol GGT erides CPK Bile acid IUIIi~r mgldl mgldl mgldl gmldl gmidl gmldl mgldl mgldl IUIli~r IUlli~r IUIli~r mgldl unitslli~r mgldl IUlliter WIldl b b b b b b b b b 0.36b b b 77b b d obtained pretreatment; sample 2, blood obtained after 1 week; sample 3, blood obtained after 2 weeks. e.

6 r 652 MALYK present. More of these isolated elevations occurred in the untreated controls (Table 3) than in the active or placebo groups when calculated on a percentage basis. There is no evidence in this study to indicate that the use of a 125~mg dose of nonoxynol-9 as Conceptrol cream produces alterations of hepatic function, nor is there evidence of increased metabolic activity in hepatic cells. It is reassuring to note that the toxic effects of nonoxynol-9 implied in other studies 3 do not appear here. On the basis of these findings, it may be concluded that there are no apparent systemic effects following daily intravaginal administration of a 125-mg dose ofnonoxynol-9 in a cream base for 2 weeks. REFERENCES 1. United States Food and Drug Administration (USFDA) Advisory Panel on OTC Contraceptives and Other Vaginal Drug Products: OTC Contraceptives and Other Vaginal Products (Information Copy). Rockville Md, USFDA, November 1978 June Spermicides-Simplicity and Safety Are Major Assets. Population Rep (Barrier Methods), Series H, Vol VII, No 5, September 1979, pp H77-H Chvapil M, Eskelson CD, Droegemueller W, Ulreich JB, Owen JA, Ludwig JC, Stiffel VM: New data on the pharmacokinetics ofnonoxynol-9: vaginal contraceptives, new developments. In Proceedings of an International Workshop on New Developments in Vaginal Contraception, Guatemala City, 1979, Edited by GI Zatuchni, AJ Sobrero, JJ Speidel, JJ Sciarra. Hagerstown, Md, Harper & Row, 1979, pp Miller RG Jr: Simultaneous Statistical Inference. New York, McGraw-Hill Book Co, 1966, pp Popper H: Evaluation of Agents Effecting Liver Toxicity, Vol II: Drug Induced Clinical Toxicity, Edited by FG McMahon. New York, Futura Publishing Co, 1974, pp Rollason JG, Pincherle G, Robinson D: Serum gamma glutamyl transpeptidase in relation to alcohol consumption. Clin Chim Acta 39:75, Skrede S, Solberg HE, Blomhoff JP, Gjone E: Bile acids measured in serum during fasting as a test for liver disease. Clin Chern 24:1095, 1978