Long-acting oral bromocriptine (Parlodel SRO)* in the treatment of hyperprolactinemia†

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Long-acting oral bromocriptine (Parlodel SRO)* in the treatment of hyperprolactinemiat

Cleide O. Weingrill, M.D. Wania Mussio, M.D. Carlines R. S. Moraes, M.D.

Evandro Portes, M.D. Rita C. Castro, M.D. Ana-Maria J. Lengyel, M.D., Ph.D.:j:§

Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Sao Paulo, Brazil

Objectives: To compare the effect of Parlodel SRO (Sandoz, Basel, Switzerland), a long-acting oral bromocriptine, to Parlodel (Sandoz) and to study the chronic effects of Parlodel SRO. Design: The study was twofold: (1) random, double-blind and (2) open. Setting: Patients were studied in an academic environment. Patients: Hyperprolactinemic patients were selected. Sixteen patients were treated during 1 month. Ten patients completed the I-year follow-up. Interventions: Parlodel SRO or Parlodel was administered during 1 month (first 15 days: 5 mg/d; afterwards: 10 mg/d). Parlodel SRO was given during 1 year in variable doses (maximal 20 mg/d). Main Outcome Measures: Prolactin (PRL) levels, clinical improvement, and side effects were evaluated. Results: After 1 month, 63% of the patients in both groups had normal PRL and 43% had menses. Side effects were similar. After 1 year all patients except one had normal PRL levels, and 89% were ovulating. Conclusions: The efficacy, tolerability, and long duration of action of Parlodel SRO make it an excellent alternative for the treatment of hyperprolactinemic patients. Fertil SterilI992;57:331-5 Key Words: Parlodel SRO, hyperprolactinemia

Endocrinology, Escola Paulista de Medicina, CP 20266, Sao Paulo 04034, Brazil. § Ana-Maria J. Lengyel is a Senior Scientist of Conselho Nacional de Desenvolvimento Cientifico e Tecnol6gico (CNPq, Brazil).

ever, these drugs usually have a short duration of action, and although they are well tolerated in the majority of the patients, side effects such as nausea and postural hypotension can occur.16 Therefore, new agonists with longer duration of action and with less adverse effects are being developed. Parlodel SRO (slow-releasing oral; Sandoz, Basel, Switzerland) is a new long-acting oral form ofbromocriptine that is slowly and more uniformly absorbed by the gastrointestinal tract because of a capsule with osmotic properties. In normal subjects it effectively suppresses PRL levels for >24 hours after one single oral doseP The aim of this study was to evaluate the efficacy and tolerability of Parlodel SRO in hyperprolactinemic patients and to compare it with the well-

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Dopamine agonists such as bromocriptine are widely used in the treatment of hyperprolactinemia because they are very effective in decreasing serum prolactin (PRL).1-6 Moreover, these compounds can also decrease tumor size in 60% to 70% of the patients harboring PRL-secreting adenomas. 7- I5 How-

Received April 25, 1991; revised and accepted October 4, 1991.

* Parlodel SRO, Sandoz, Basel, Switzerland.

t Supported in part by Sandoz, Basel, Switzerland. t Reprint requests: Ana-Maria J. Lengyel, M.D., Division of

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established normal formulation of oral bromocriptine (Parlodel; Sandoz). MATERIALS AND METHODS Patients

Sixteen hyperprolactinemic patients were studied (14 females and 2 males). Six patients had PRLsecreting macroadenomas (2 not treated previously), and 5 had microadenomas. Five patients had no evidence of tumor in the computed tomographic (CT) scan, including one female (patient 10) who previously had a grade II adenoma treated with transphenoidal surgery and afterwards with bromocriptine. Clinical data are shown in Table 1. Three patients were on replacement therapy, 2 because of associated primary hypothyroidism (patients 2 and 6) and 1 because of thyrotropin and adrenocorticotropin deficiency (patient 14). All women had menstrual abnormalities (oligomenorrhea in 3, amenorrhea in 11),9 had galactorrhea, and 7 referred to decrease in libido. Both male patients complained of decrease in libido and potency. Table 1 Group

Clinical Data of Patients Patient no.

Sex

Basal PRL

CT scan a

Previous treatment

MIL

Parlodel SRO

Parlodel

1 2 7 9 10 11

F F F F F F

79 60 167 139 102 119

14

M

1,197

16 3 4

F F F

4,100 242 112

5 6 8

F F F

119 75 311

12 13 15

F F M

837 343 487

Hardy's classification. TF, transfrontal surgery. C BC, bromocriptine. d Previous to surgery: macro II e TS, transfenoidal surgery. ! SSE, suprasellar extension. g RTX, radiotherapy.

Normal Macro II Micro Micro Normal d Normal Macro III + SSE! Macro III + SSE Normal Micro Macro II + SSE Micro Normal Macro II + SSE Micro Macro II

TFbjBCc

BC Tse/BC TF/RTX8 BC BC BC RTX/BC BC

BC

a

b

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+ SSE.

Parlodel SRO in hyperprolactinemia

Experimental Protocol

The study was approved by the Ethics Committee of Escola Paulista de Medicina. All subjects gave a written informed consent. Patients who were previously treated with dopamine agonists underwent a washout period of at least 4 weeks before entering the study. Only patients who had PRL ~ 60 J1,g/L, in three samples obtained in different days, were included. All patients were submitted to a randomized double-blind protocol, either with Parlodel in the normal formulation (Parlodel) or with long-acting Parlodel (Parlodel SRO) for 1 month. In the first 15 days, they received 5 mg/d ofbromocriptine and thereafter 10 mg/d to day 31. Parlodel was administered twice a day at 8 A.M. and 8 P.M., and Parlodel SRO in a single dose at 8 A.M., with placebo given at 8 P.M. The tablets were always taken after standardized meals. In the open part of the study (after the 1st month), 12 subjects received Parlodel SRO in variable doses, depending on their PRL levels, up to 15 mg/d, administered once a day in the evening, for 6 months. Ten patients were followed for 1 year (maximal dose of Parlodel SRO = 20 mg/d). Four subjects who failed to participate in the open part of the study were patients with PRL-secreting macroadenomas (patients 5, 12, 14, and 16) who were subsequently treated with long-acting repeatable bromocriptine. Blood samples for PRL determination were taken throughout the day (every 2 hours from 8 A.M. to 4 P.M. and also at 8 P.M.) before starting the medication (day 1) and on days 2,16,17, and 31. Subjects remained supine from 8 A.M. to 1 P.M. Single PRL determinations were performed on days 8 and 23 at 8 A.M. In the open part of the study, blood samples were drawn throughout the day at the end of the 3rd and the 6th month of therapy. Single PRL determinations were performed after 1 year of treatment. Progesterone (P) levels were measured on day 21 after the onset of menses in patients who had a return of regular periods. During the study, the tolerability of the drug was assessed by measurements of the vital signs (blood pressure and pulse rate) and by the adverse effects. Each patient had routine electrocardiogram and laboratory safety tests 7 days before the study, at the end of the 1st month and also at the 6th month of treatment. Prolactin Radioimmunoassay (RIA)

Prolactin was measured by a double antibody RIA.1s The sensitivity of the assay is 1.6 J1,g/L and

Fertility and Sterility

PARLODEL SRO

PARLODEL

Figure 1 Individual PRL levels before and after 1 month of treatment with Parlodel SRO and Parlodel in hyperprolactinemic patients (n = 16).

the intra-assay and interassay coefficients of variation are 7% and 11%. Normal values with this method are :::;;25 f.Lg/L in females and :::;;20 f.Lg/L in males. Results are shown as means ± SE. Statistical Analysis

Student's t-test was used to compare PRL levels between the groups (unpaired) and inside each group (paired). Fisher's exact probability test was used to compare the incidence of side effects.

± 2%, respectively). Lack of normalization was mainly observed in those with the highest PRL levels (n = 6). Four of these patients had large tumors (patients 12, 14, 15, and 16), whereas one had a microadenoma (patient 13). The other patient had a normal CT scan when entering the study, although she had previously a grade II adenoma treated with transphenoidal surgery (patient 10). Even in the patients who did not normalize their PRL levels, a marked and stable suppression throughout the day was seen both with Parlodel SRO and Parlodel. In the Parlodel SRO group (patients 10, 14, and 16) basal PRL levels of the partial responders were 1,798 ± 1,193 f.Lg/L and decreased to 353 ± 161 f.Lg/L (mean 70%, range 54% to 89%), whereas in the Parlodel group (patients 12, 13, and 15) basal levels were 556 ± 147 f.Lg/L and decreased to 35 ± 3 f.Lg/L (mean 93%, range 90% to 95%). Figure 2 shows the pattern of PRL suppression throughout the day during different phases of the treatment in five patients of the Parlodel SRO group who normalized their PRL levels. At the end of the 6th month of treatment with Parlodel SRO, 92% of the patients had normal PRL levels (Fig. 3). Only one patient remained with hyperprolactinemia (patient 10; PRL = 37 f.Lg/L ) , with 15 mg/d of Parlodel SRO. Prolactin levels remained suppressed in all patients who were followed up to 1 year. Before entering the study, all women had menstrual abnormalities. At the end of the 1st month 200 PARLODEL SRO

RESULTS

150

Mean basal PRL levels were 745 ± 498 f.Lg/L in the Parlodel SRO group and 316 ± 89 f.Lg/L in the Parlodel group (not significant). At the end of the first 15 days of treatment (with 5 mg/d of bromocriptine) 63% (5/8) of the patients using Parlodel SRO had normal PRL levels, whereas 50% (4/8) of the patients in the Parlodel group had normal PRL levels. However, in the Parlodel group, one patient did not take adequately the medication on day 15. At the end of the 1st month, 63 % of the patients in both groups had normal PRL levels (Fig. I). In these patients, mean PRL levels were significantly lower than pretreatment values in both groups (Parlodel SRO: 113 ± 19 versus 9 ± 2 f.Lg/L, P < 0.01; Parlodel: 172 ± 45 versus 9 ± 2 f.Lg/L, P < 0.02), and mean percentual decrease was similar (91 % ± 2% and 94%

Figure 2 Mean PRL levels before (baseline) and after the first dose of Parlodel SRO (5 mg), after 15 days of treatment (5 mg/ d), and after 30 days (10 mg/d) in five hyperprolactinemic patients.

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50

o

10

12

14

16

io TIME (ho.".)

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! 300

:-- --!-

-lll-- - - --'---1--

o~~----------~--------~------PATIENTS

Figure 3 Individual PRL levels before and after 6 months of treatment with Parlodel SRO (n = 12).

(Parlodel SRO: 5; Parlodel: 4), nasal congestion (Parlodel SRO: 5; Parlodel: 2), constipation (Parlodel SRO: 4; Parlodel: 3), asthenia (Parlodel SRO: 4; Parlodel: 2), and epigastric pain (Parlodel SRO: 1; Parlodel: 4). However, no significant differences were found between the tolerability of Parlodel SRO and Parlodel. During follow-up, the most common side effects were nausea and asthenia (n = 4), headaches (n = 3), dizziness (n = 2), and epigastric pain (n = 1). None of the patients had to interrupt the treatment because ofthe side effects. Electrocardiogram and laboratory evaluation (safety tests) were normal throughout the study in all patients, except in three who had a slight decrease in hemoglobin values. Two of them had primary hypothyroidism and were on replacement therapy. DISCUSSION

oftreatment, 43% (3/7) ofthe women in both groups (Parlodel SRO and Parlodel) had menses. Two patients who remained in amenorrhea despite normalization of PRL levels were found to be gonadotropin deficient (1 in each group). At the end ofthe 6th month of treatment, all women (n = 9), except the gonadotropin deficient, had regular menses. Ovulatory cycles were present in 89% ofthe patients, according to P levels (measured between the 5th and 9th month of treatment). Two patients became pregnant, after the 6th and 12th month of treatment, respectively, when medication was interrupted. One ofthem is being followed, and the other had a spontaneous abortion. Galactorrhea was initially present in 9 patients, and in both groups it improved in 33% ofthe cases at the end ofthe 1st month of treatment. After 6 months 50% of the patients had no galactorrhea, and this number increased to 80% after 12 months of treatment. Both male patients (treated during 1 and 6 months) reported improvement of libido and potency. Only one patient of each group had a decrease in sistolic blood pressure of 30 mm Hg during the 1st day of treatment (8 hours after drug administration). Afterwards, no significant changes in blood pressure were seen. In both groups, side effects were mainly noticed in the beginning of the study and decreased considerably during treatment. They were generally mild and short lasting. The most frequent initial complaints were dizziness (Parlodel SRO: 6 patients; Parlodel: 5 patients), headache (Parlodel SRO: 6; Parlodel: 3), nausea

Since 1972, bromocriptine has been the most used dopamine agonist in the treatment of hyperprolactinemia. 1,3,6,15 However, the incidence of side effects and the need of multiple daily doses are issues to be considered in the long-term management of these patients. In this study, we demonstrate that a single daily dose of Parlodel SRO, a long-acting oral modified release formulation, is effective in suppressing serum PRL levels in hyperprolactinemic patients. In normal subjects, a single oral dose of this new formulation is able to suppress PRL levels for up to 24 hours. 17 Because the pharmacokinetic profile of Parlodel SRO is virtually unchanged by food, different from bromocriptine in the normal formulation, this could explain the lower incidence of side effects in normal subjects taking this preparation, compared with Parlodel. 17 In hyperprolactinemic patients, Parlodel SRO administered for 1 to 2 months effectively suppresses PRL levels and decreases tumor size. 19 In our study, the oral administration of Parlodel SRO once a day was able to decrease PRL levels in hyperprolactinemic patients similar to the twice daily administration of Parlodel. Prolactin remained suppressed for at least 12 hours, which was our sampling period. The degree of PRL suppression and the number of patients who normalized their PRL levels were also comparable with the two formulations of Parlodel used in this study. At the end of the 1st month of treatment (with 10 mg/d of bromocriptine), normal PRL levels were observed in 63% of the patients in both groups. In a previous report,19 71 % of the patients normalized their PRL

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levels after 1 month of treatment with either 2.5 or 5 mg/d of Parlodel SRO. Basal PRL values in these patients were, however, lower than those of our study group, which could explain their slightly higher normalization rate. 6 Moreover, the design of our study did not allow determination ofthe minimal effective dose of Parlodel SRO. We found in both groups that lack of normalization was mainly observed in the patients who had the highest pretreatment values, as reported previously.6 The majority of these patients had PRL-secreting macroadenomas. However, even in these subjects, a marked and stable suppression of PRL levels throughout the day was seen. Long-term treatment with a single oral dose of Parlodel SRO normalized PRL levels in all patients, except in one. However, in this patient the maximal dose used during the study period was 15 mg/d. It is possible that higher doses would decrease PRL values to the normal range. After 1 year of treatment with Parlodel SRO, all females had regular menses, and 89% were ovulating. These results are similar to those obtained by other authors using multiple daily doses of Parlodel,2,16 indicating the clinical efficacy of this new formulation. In our study, no significant differences between the tolerability of Parlodel SRO and Parlodel were found after 1 month of treatment. All patients were able to tolerate effective Parlodel SRO doses. Although initial side effects were present, they were mild and decreased considerably during chronic treatment, confirming an earlier report. 19 In conclusion, Parlodel SRO given once daily decreases serum PRL levels and restores gonadal function. Its efficacy, tolerability, and long duration of action make it an excellent alternative for the treatment of hyperprolactinemic patients. Acknowledgments. We thank Walkiria L. Miranda, Uda Kunii, and Amaryllis Salzano (Escola Paulista de Medicina, Sao Paulo) for the excellent technical and secretarial assistance. We are indebted to Ioana Lancranjan, M.D., (Sandoz, Basel) for supplying Parlodel SRO and for the generous support. We also thank Marilla Ferraz, M.D., (Sandoz, Sao Paulo), and Antonio R. Chacra, M.D., and Jose G. H. Vieira, M.D., (Escola Paulista de Medicina, Sao Paulo) for their assistance throughout the study.

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2. Thorner MO, McNeilly AS, Hagen C, Besser GM: Long term treatment of galactorrhea and hypogonadism with bromocriptine. Br Med J 2:419, 1974 3. Thorner MO, Besser GM: Bromocriptine treatment of hyperprolactinaemic hypogtmadism. Acta Endocrinol (Copenh) 88(Suppl 216):131, 1978 4. Grossman A, Besser GM: Prolactinomas. Br Med J 290:182, 1985 5. Molitch ME, Elton RL, Blackwell RE, Caldwell B, Chang RJ, Jaffe R, Joplin G, Robbins RJ, Tyson J, Thorner MO: Bromocriptine as primary therapy for prolactin-secreting macroadenoma: results of a prospective multicenter study. J Clin Endocrinol Metab 60:698, 1985 6. Vance ML, Thorner MO: Prolactinomas. Endocrinol Metab Clin North Am 16:731, 1987 7. Nillius SJ, Bergh T, Lundberg PO, Stahle J, Wide L: Regression of a prolactin-secreting pituitary tumor during long-term treatment with bromocriptine. Fertil Steril 30:710, 1978 8. Bergh T, Bergstrom K, Larsson SG, Lundberg PO, Nillius SJ, Wide L: Bromocriptine-induced tumour regression in two women with prolactin-secreting pituitary tumours. Acta Endocrinol (Copenh) 225(Suppl):180, 1979 9. McGregor AM, Scanlon MF, Hall R, Hall K: Effects ofbromocriptine on pituitary tumour size. Br Med J 2:700, 1979 10. Wass JAH, Moult PJA, Thorner MO, Dacie JE, Charlesworth M, Jones AE, Besser GM: Reduction of pituitary tumour size in patients with prolactinomas and acromegaly treated with bromocriptine with or without radiotherapy. Lancet 2:66, 1979 11. George SR, Burrow GN, Zinman B, Ezrin C: Regression of pituitary tumors, a possible effect of bromoergocriptine. Am J Med 66:697, 1979 12. Chiodini P, Liuzzi A, Cozzi R, Verde G, Oppizzi G, Dallabonanza D, Spelta B, Silvestrini F, Borghi G, Lucarelli G, Rainer E, Horowski R: Size reduction of macroprolactinomas by bromocriptine or lisuride treatment. J Clin Endocrinol Metab 53:737, 1981 13. Corenblum B, Hanley DA: Bromocriptine reduction of prolactinoma size. Fertil Steril 36:716, 1981 14. Sobrinho LG, Nunes MC, Calhaz-Jorge C, Mauricio JC, Santos M: Effect of treatment with bromocriptine on the size and activity of prolactin-producing pituitary tumours. Acta Endocrinol (Copenh) 96:24, 1981 15. Franks S, Jacobs H: Hyperprolactinaemia. Clin Endocrinol Metab 12:641, 1983 16. Vance ML, Evans WS, Thorner MO: Drugs five years later: bromocriptine. Ann Intern Med 100:778, 1984 17. Drewe J, Abisch E, Neeter R: Parlodel SRO: an oral modified release formulation of bromocriptine with improved tolerability. In New Activities in the Dopamine Agonist Field, Edited by GM Besser. Carnforth, Parthenon Publishing, 1988, p 59 18. Lengyel AMJ, Vieira JGH, Chacra AR, Abucham-Filho JZ, Lima MPC, Ribeiro AB, Ramos OL: Dynamic evaluation of prolactin secretion in essential hypertension: evidence against hypothalamic pituitary dopaminergic disfunction. J Clin Endocrinol Metab 54:849, 1982 19. Ayalon D, Wachsman Y, Eshel A, Eckstein N, Vagman I, Lancranjan I: Parlodel SRO and prolactinomas: clinical and therapeutic aspects. In New Activities in the Dopamine Agonist Field, Edited by GM Besser. Carnforth, Parthenon Publishing, 1988, p 71

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