Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2018 Publisher: Pfizer New Zealand Limited, P O Box 3998, Auckland, New Zealand, 1140, Toll Free Number: 0800 736 363
LOETTE is a combined oral contraceptive tablet containing the synthetic progestogen, levonorgestrel, and the synthetic estrogen, ethinylestradiol.
The hormonal components of LOETTE suppress gonadotropins in a manner that inhibits ovulation, which leads to contraception.
The following non-contraceptive health benefits related to the use of combination oral contraceptives are supported by epidemiological studies, which largely utilised oral contraceptive formulations containing doses exceeding 0.035 mg of ethinylestradiol or 0.05mg mestranol.
Increased menstrual cycle regularity.
Decreased blood loss and decreased incidence of iron deficiency anaemia.
Decreased incidence of dysmenorrhoea.
Decreased incidence of ectopic pregnancies.
Decreased incidence of functional ovarian cysts.
Decreased incidence and severity of acne.
Decreased incidence of fibroadenomas and fibrocystic disease of the breast.
Decreased incidence of acute pelvic inflammatory disease.
Decreased incidence of endometrial carcinoma.
Decreased incidence of ovarian carcinoma.
An open-label multicentre phase III clinical study was conducted in 1,447 women receiving LOETTE. Of 7,720 cycles of exposure evaluable for efficacy, a total of 5 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 0.84 per 100 woman-years (over 99% effective). This rate includes patients who did not take the medicine correctly.
No specific investigation of the absolute bioavailability of LOETTE in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first-pass metabolism. Ethinylestradiol is rapidly and almost completely absorbed from the gastrointestinal tract but due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinylestradiol is between 38% and 48%.
After a single dose of LOETTE to 22 women under fasting conditions, maximum serum concentrations of levonorgestrel are 2.8 ± 0.9 ng/mL (mean ± SD) at 1.6 ± 0.9 hours. At steady state, attained from day 19 onwards, maximum levonorgestrel concentrations of 6.0 ± 2.7 ng/mL are reached at 1.5 ± 0.5 hours after the daily dose. The minimum serum levels of levonorgestrel at steady state are 1.9 ± 1.0 ng/mL. Observed levonorgestrel concentrations increased from day 1 (single dose) to days 6 and 21 (multiple doses) by 34% and 96%, respectively. Unbound levonorgestrel concentrations increased from day 1 to days 6 and 21 by 25% and 83%, respectively. The kinetics of total levonorgestrel are nonlinear due to an increase in binding of levonorgestrel to sex hormone binding globulin (SHBG), which is attributed to increased SHBG levels that are induced by the daily administration of ethinylestradiol. Levonorgestrel in serum is primarily bound to SHBG.
Following a single dose, maximum serum concentrations of ethinylestradiol of 62 ± 21 pg/mL are reached at 1.5 ± 0.5 hours. At steady state, attained from at least day 6 onwards, maximum concentrations of ethinylestradiol were 77 ± 30 pg/mL and were reached at 1.3 ± 0.7 hours after the daily dose. The minimum serum levels of ethinylestradiol at steady state are 10.5 ± 5.1 pg/mL. Ethinylestradiol concentrations accumulated by 19% from days 1 to 21. Ethinylestradiol is about 97% bound to plasma albumin. Ethinylestradiol does not bind to SHBG, but induces SHBG synthesis.
The most important metabolic pathway occurs in the reduction of the ∆4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2- hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and faecal excretion. Levels of Cytochrome P450 (CYP3A) vary widely among individuals and can explain the variation in rates of ethinylestradiol 2-hydroxylation. Ethinylestradiol is excreted in the urine and faeces as glucuronide and sulfate conjugates, and undergoes enterohepatic circulation.
The elimination half-life for levonorgestrel is approximately 36 ± 13 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40% to 68%) and about 16% to 48% are excreted in faeces. The elimination half-life of ethinylestradiol is 18 ± 4.7 hours at steady state.
No effects that might indicate an unexpected risk to humans were observed during systemic tolerance studies after repeated administration of combined oral contraceptives.
Long-term repeated dose toxicity studies for evaluation of a possible tumourigenic activity did not indicate a tumourigenic potential in case of therapeutic use of the preparation in humans. However, it must be borne in mind that sex steroids can promote the growth of certain hormonedependent tissues and tumours.
In vitro and in vivo studies performed with ethinylestradiol and levonorgestrel gave no indication of a mutagenic potential.
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