Lolo - Scientific Information
|Condition:||Birth Control (Contraception), Contraception (Birth Control)|
|Ingredients:||norethindrone acetate, ethinyl estradiol, lactose monohydrate, mannitol, microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate and vitamin E, the blue tablets also contain FD&C Blue No. 1 aluminum Lake, acacia, lactose monohydrate, magnesium stearate, corn starch, sugar, talc and colours (FD&C Blue No.1, FD&C Red No.3, FD&C Red No. 40).|
|Proper name:||norethindrone acetate|
|Chemical name:||[19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-][M 2.3.S.1.1]|
|Molecular formula and molecular mass:||C22H28O3 and 340.07|
|Physicochemical properties:||A white solid with a melting point of 157o to 163oC, freely soluble in dioxane, sparingly soluble in ether, and insoluble in water. Norethindrone acetate is a unique progestin synthesized from plant sterols, which may include soy. Soy is not present in the final drug product.|
|Proper name:||ethinyl estradiol|
|Molecular formula and molecular mass:||C20H24O2 and 296.41|
|Physicochemical properties:||A fine white, odorless crystalline powder, insoluble in water but soluble in vegetable oils and organic solvents. Ethinyl estradiol is synthesized from plant sterols, which may include soy. Soy is not present in the final drug product.|
The following table gives reported pregnancy rates for various forms of birth control, including no birth control. The reported rates represent the number of women out of 100 who would become pregnant in one year.
|Reported Pregnancies per 100 Women per Year:|
|Combination pill||less than 1 to 3*|
|Intrauterine device (IUD)||less than 1 to 6|
|Condom with spermicidal foam or gel||1 to 6|
|Mini-pill||3 to 6|
|Condom||2 to 12|
|Diaphragm with spermicidal foam or gel||3 to 18|
|Spermicide||3 to 21|
|Sponge with spermicide||3 to 28|
|Cervical cap with spermicide||5 to 18|
|Periodic abstinence (rhythm), all types||2 to 20|
|No birth control||60 to 85|
*Based on the results of one clinical study, about 3 out of 100 women may get pregnant during the first year they use LOLO.
Study demographics and trial design
In a one year (thirteen 28-day cycles) multicenter open-label clinical trial, 1,582 women 18 to 45 years of age, were studied to assess the safety and efficacy of LOLO, completing the equivalent of 15,591 28-day evaluable cycles of exposure. 1,270 women 18-35 years of age were studied to assess the efficacy of LOLO and completed the equivalent of 12,482 28-day evaluable cycles of exposure. The racial demographic of all enrolled women was: Caucasian (74.9%), African- American (11.8%), Hispanic (9.8%), Asian (1.3%), and Other (2.2%). Women with body mass index (BMI) greater than 35 kg/m2 were excluded from the study. The weight range for those women treated was 89 to 260 lbs., with a mean weight of 150 lbs. Among the women in the trial, 51% had not used hormonal contraception immediately prior to enrolling in this study. Of treated women, 13.7% were lost to follow-up, 10.7% discontinued due to an adverse event, and 8.9% discontinued by withdrawing their consent.
|Study#||Trial design||Dosage, route of administration and duration||No. Study subjects||Mean age (Range)||Mean weight (Range)||Gender|
|RR-03108||Non-comparative, multicentre study||LOLO x 13 cycles||1582||28.6 years
(18 – 45.9 years)
(89 – 260 lb)
The pregnancy rate (Pearl Index [PI]) in women 18 to 35 years of age was 2. 92 (95% confidence interval 1.94-4.21) pregnancies per 100 women-years of use, based on 28 pregnancies that occurred after the onset of treatment and extending through the 7 days following the last dose of LOLO (See Table 2). Cycles in which conception did not occur, but which included the use of backup contraception, were not included in the calculation of the PI. The PI includes women who did not take the drug correctly.
No. 28 day treatment cycles
(95% CI: 1.55,3.37)
(95% CI: 1.94,4.21)
* N= number of women with
The clinical trial that evaluated the efficacy of LOLO also assessed scheduled and unscheduled (intra-cycle) bleeding and/or spotting (IB/S). The participants in this 12-month clinical trial (N=1,582 who had at least one post-treatment evaluation) completed over 15,000 cycles of exposure.
Total Bleeding/Spotting (scheduled and unscheduled):
The mean number of total bleeding/spotting days (scheduled and unscheduled) was 3.8 days per cycle and tended to decrease throughout the study from Cycle 2 through Cycle 12 (See Figure 1).
Figure 1: Mean Number of Bleeding Days per Cycle (N=1582)
Scheduled (withdrawal) Bleeding/Spotting:
Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year study, with an average of less than 2 days per cycle when including all women and all cycles. The incidence of withdrawal bleeding decreased over the course of the study, from 43% of subjects during Cycle 1 to 22% during Cycle 13. Incidence and duration of withdrawal bleeds tended to be greater in new users than in switchers.
Intensity of a bleeding/spotting episode was defined by a score of 0-3 where 0 = none, 1=light; 2 = normal; and 3 = heavy. The overall mean median intensity of withdrawal bleeding / spotting was 1.53 for Cycle 2 through Cycle 13.
Unscheduled (intra-cycle) Bleeding and or Spotting (IB/S):
The mean number of days per cycle of IB/S decreased over the course of the study from 3.2 days during Cycle 2 to 1.8 days during Cycle 13. The mean duration throughout the study was 2.6 days/cycle.
A total of 1,257 women (85.9%) experienced IB/S at some time during Cycles 2-13 of this study. The incidence of IB/S was highest during Cycle 2 (53%) and lowest at Cycle 13 (36%).
Subjects in the study reported an average of 0.53 episodes per cycle of IB/S during the study. The mean maximum intensity score for IB/S episodes was 1.6 for Cycles 2 through Cycle 13. In all subgroups (new users, switchers, 18-35 and 36-45) the numbers of IB/S, spotting only and bleeding-only days per cycle decreased over the course of the study. The incidence of IB/S, the mean number of episodes and the mean intensity for IB/S were higher in younger patients 18-35 than those 36 to 45. Measures of IB/S such as incidence and number of episodes, and maximum intensity tended to be higher in new users than in switchers, and decreased over the course of the study.
The incidence of amenorrhea (absence of bleeding throughout the cycle) during Cycles 1 to 3 was approximately 30% to 32%, and increased to 49% for Cycle 13. In general the incidence of absence of bleeding was higher in older subjects (age 36-45), and in switchers vs. new users.
See ACTION AND CLINCIAL PHARMACOLOGY, Mechanism of Action for additional information.
Both norethindrone (NE) and ethinyl estradiol (EE) have been subject to extensive biological examination over the past four decades. Norethindrone, using the Clauberg assay with rabbits, has been variously estimated to possess an oral progestational activity at least 10 times that of injected progesterone. Only slight estrogenic activity along with some androgenic activity (9% that of methyl testosterone) has been evident. Ethinyl estradiol has been demonstrated to be slightly more active than 17R-estradiol using the vaginal cornification test in rats.
Norethindrone/ethinyl estradiol, in the ratio of 1.0/0.035, fed to female rats for 22 days at a daily dose of 0.15 mg/kg was effective in reducing the littering activity during a period of 15 days cohabitation with fertile males. Subsequent to the dosing period, these females regained their fertility.
Estrogenic, progestational and antigonadotropic characteristics are revealed for the endocrine profile of this combination. In female rats, a uterotropic effect is clearly demonstrated for a range of 0.1-0.4 mcg, total oral dose. In rabbits a McPhail index of 2.6 is recorded at a total oral dose of 0.8 mg of this progestin/estrogen combination. At a total dose of 450 mcg (based on EE content) compensatory ovarian hypertrophy is completely inhibited in hemicastrate female rats.
Toxicity Studies of Norethindrone Acetate (NA) in Animals
The LD50 value of NA (on intraperitoneal administration to rats was greater than 1000 mg per kg body weight. The drug produced no toxic effects or abnormalities when administered orally to dogs in a single 30 mg dose. Administration of NA by the drug-diet method in rats over a period of 41 weeks produced depression in food intake and weight gain comparable to that following the use of norethindrone. Animals received average daily doses of 6, 14, and 27 mg per kg body weight.
Hematocrit, hemoglobin and leukocyte counts were not noticeably affected. Cholesterol values were low in all drug-fed animals, but all other microchemical determinations (minerals, transaminase, proteins, bilirubin, glucose and urea nitrogen) revealed normal values. Histologic examination of tissues showed functional depression of testes and seminal vesicles and atrophy of pituitary and adrenal glands at the two higher dosage levels. Liver cell atrophy and several deviations of a minor nature were also noted.
Results indicated that the acetate is as well tolerated as norethindrone in continuous long-term use.
Long-Term Use of Norethindrone in Monkeys
Long-term oral administration of norethindrone to female rhesus monkeys produced only temporary changes in ovarian function. Six monkeys were treated for two years and 12 monkeys for one year at a dosage of 2.5 mg daily for 21 days of each cycle. This is comparable to a dosage of 25 mg daily for eight-and four-year periods in humans. Extensive studies were conducted on the blood, bone marrow, and on the various other tissues and organs, particularly the ovaries. The only noteworthy differences between control and treated animals were found in the genital organs and the pituitary. The treated monkeys could not be differentiated from control on the basis of general health, alertness, and behaviour. Bleeding usually started on the third or fourth day after discontinuation of drug administration each month, lasted three or four days, and was never heavy.
Ovaries from animals treated for one or two years were small, whitish with only small follicles visible, and no sign of recent rupture or of corpora lutea. Germinal epithelium was intact, and the layer of primordial ovocytes and young follicles appeared normal. Inside this cortical layer were small and medium-sized vesicular follicles and many corpora atretica, remnants of old follicles. Follicles had developed normally until the vesicular stage and then degenerated before attaining their full preovulatory growth.
Ovocytes appeared normal in all stages of development until the last pre-ovulatory step when maturation was inhibited. Uteri of treated monkeys had proliferative endometria with no decidual changes in the stroma. The vaginal tracts exhibited moderate to considerable epithelial cornification. Mammary glands were in the resting stage. Pituitaries of treated monkeys showed a decrease of basophilic cells.
Normal ovulatory cycles resumed shortly after medication was stopped. The sexual skin increased in redness, the vaginal epithelium became highly carnified during ovulation, and corpora lutea developed in the ovaries. The number and appearance of ova were normal, as was the rate of atresia. Endometria were proliferative or secretory. The ability to conceive also returned. The conception rate in the treated group compared favourably with that in the control group. Babies of treated animals were all normal at birth, and the females developed normally.
In summary, it was concluded from these studies that continuous administration of norethindrone for periods of one and two years suppressed ovulation without permanent effects on ovarian function and fertility of monkeys.
Chronic Oral Toxicities in Monkeys
Chronic oral toxicity studies were conducted in 8 immature rhesus monkeys - 4 males and 4 females. Norethindrone was administered in the amount of 2.5 mg per kg daily, five days a week for 183 days. No gross or microscopic signs of drug toxicity were found from blood studies, biopsies or at autopsy. As might be anticipated, testicular atrophy occurred in the males. There was also evidence of hormonal stimulation of the sexual skin and mammary glands of both sexes and of the uterine mucosa in females.
Long-Term Oral Studies of the Combination
A combination of 50 parts NA to one part ethinyl estradiol was administered orally for 7 years at dosage levels of 0.051, 0.51, and 1.275 mg/kg/day (equivalent to 1, 10 and 25 times the human dose) in 28-day cycles (21 days of drug administration followed by 7 days of drug withdrawal). Sixteen dogs were initiated as controls and at each dosage level.
All dogs were observed daily. Body weights were recorded weekly. Mammary examinations were conducted once each month. Ophthalmoscopic examinations (indirect technique) were done every six months. Clotting studies were conducted for all dogs twice during the control period, six times during the first year, and semiannually thereafter. Urinary steroid outputs were done once during the control period and annually thereafter.
One control dog and 9 treated dogs died or were sacrificed in extremis during the study. At the end of 7 years of study, the number of dogs surviving in each group was 15, 15, 14 and 10 at the control, 0.051, 0.51, and 1.275 mg/kg/day dosage levels, respectively. One dog at the 0.051 and 0.51 mg/kg/day dosage levels, and 2 dogs at the 1.275 mg/kg/day dose levels were hysterectomized during the study. At the end of 7 years of study, nodules were palpated in the mammary tissue of 5 control dogs, 5 dogs at the 0.051 mg/kg/day dosage level, 6 dogs at the 0.51 mg/kg/day level and 6 dogs at the 1.275 mg/kg/day level. Frequently, nodules disappeared after variable periods of time. Only rarely did nodules reach or exceed 10 mm in diameter, and commonly the behaviour of these indicated that they were cystic in nature.
Alopecia was seen more frequently for treated dogs than for control dogs. Red or brown vaginal discharge was seen most frequently for control dogs and dogs at the 0.051 mg/kg/day dosage level. It was rarely noted for dogs at the 0.51 and 1.275 mg/kg/day dosage levels following 18 months of study. Treated dogs showed greater body weight gains than control dogs. No changes considered to be related to treatment were seen in the mammary development, behaviour or in urinary steroid output. Fibrinogen concentrations were somewhat greater for treated dogs than for control dogs during the 6th and 7th years of study. No other unusual changes were noted in clotting studies.
Ophthalmologic examinations revealed eye changes for several dogs in each group. No drug relationship was noted with respect to the occurrence of these changes. Drug related gross lesions consisting of alopecia and enlarged and/or cystic uteri were observed in a number of dogs at terminal sacrifice. Organ weight effects were limited to increase in uterine weights of individuals in most experimental groups. Microscopically, drug related changes included absence of ovulation in all dogs in the high-dose group and most dogs in the mid-dose group, and increased incidence and severity of cystic endometrial hyperplasia and uterine adenomyosis in dogs in the high dose group.
The occurrence of benign tumours in vaginas and uteri of several dogs in the high dose group was considered drug related. Hyperplastic nodules and benign tumours occurred in mammary glands of dogs both in control and treated groups, but the incidence at the high-dose level was somewhat greater. No malignant mammary neoplasm occurred in any of the dogs in this study.
A combination of 50 parts of NA to one part ethinyl estradiol was administered orally to mature female rhesus monkeys in a long-term study for a period of 10 years at dosage levels of 0.051,0.51, and 2.55 mg/kg/day (1, 10, and 50 times the human dose). The dosing regimen consisted of consecutive cycles of 21 days of drug administration followed by 7 days of drug withdrawal. Sixteen monkeys were assigned to each treatment group; while an additional 16 animals received the food vehicle only. Daily observations of general health revealed no evidence of overt effects of drug treatment or significant changes in behaviour. The percent body weight gain of surviving animals was comparable, although the body weights of the treated groups were less than controls at some intervals.
Red vaginal discharge occurred with greater frequency in control and low-dose groups and was usually observed in the withdrawal phase of the mid-and high-dose groups, reflecting the pharmacologic action of the drug combination. No drug related alterations were noted in vaginal cytology or mammary development.
A retinal macular granularity, with and without foci of altered reflectivity, was noted in both control and treated animals beginning at 6 years. Although the incidence and severity of these alterations appeared to be greater in treated animals, no definite relationship to drug administration was considered to have been established.
Reduced total platelet count and increased fibrinogen concentrations were noted more frequently for treated monkeys during the initial 90 months and 48 months of study, respectively. An occasional animal showed an elevated postprandial glucose concentration, but no treatment or dosage relationship was apparent. No drug related alteration in urinary steroid output was observed.
Small nodules were palpable in or near the mammary tissue of five, four, three, and two monkeys in the control, 0.051, 0.51, and 2.55 mg/kg/day dosage groups, respectively, at least at one examination. Detailed physical examinations also revealed an abdominal mass in 2 control monkeys, slight curvature of the spine in 2 low-dose animals, and a pulsating saphenous vein in a high-dose animal. No drug related gross lesions were seen in animals that died, were sacrificed in extremi during the study or were terminally sacrificed. A frequent cause of death in this study, which is a common occurrence in non-human primates, was acute gastric dilatation. The lesions observed at necropsy appeared spontaneous and unrelated to drug administration.
A statistically significant decrease (p<0.05) in the mean absolute uterine weight at the high-dose level was drug related. Microscopically, drug related lesions included uterine atrophy, slightly increased incidence of occurrence of mucus and inflammatory cells in the cervical canal, and dilatation of acini and ducts in mammary glands of monkeys from the high-dose group, were considered to be related to the pharmacologic effect of the test combination.
No drug related neoplasms were observed in the study. A low overall incidence of neoplasms was seen in all organs and tissues examined. A total of 6 neoplastic microscopic lesions were noted during this entire study; an adenoma (pancreatic duct origin) in a low-dose animal; a granulosa cell carcinoma (ovary) in a control animal with metastasis to liver, lymph node, and lung; and a leiomyoma (uterus) and 2 papillomas (skin) in high-dose animals. With the exception of the granulosa cell carcinoma, no malignant neoplasms were identified.