Levonorgestrel (Page 2 of 3)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Many studies have found no harmful effects on fetal development associated with long-term use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects.

8.3 Nursing Mothers

In general, no adverse effects of progestin-only pills have been found on breastfeeding performance or on the health, growth or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers taking progestin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma.

8.4 Pediatric Use

Safety and efficacy of progestin-only pills for long-term contraception have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of levonorgestrel tablets, 0.75 mg emergency contraception before menarche is not indicated.

8.5 Geriatric Use

This product is not intended for use in postmenopausal women.

8.6 Race

No formal studies have evaluated the effect of race. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both levonorgestrel tablets, 0.75 mg and the Yuzpe regimen (another form of emergency contraception). The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown.

8.7 Hepatic Impairment

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel tablets, 0.75 mg.

8.8 Renal Impairment

No formal studies were conducted to evaluate the effect of renal disease on the disposition of levonorgestrel tablets, 0.75 mg.

9 DRUG ABUSE AND DEPENDENCE

Levonorgestrel is not a controlled substance. There is no information about dependence associated with the use of levonorgestrel tablets, 0.75 mg.

10 OVERDOSAGE

There are no data on overdosage of levonorgestrel tablets, 0.75 mg, although the common adverse event of nausea and associated vomiting may be anticipated.

11 DESCRIPTION

Each levonorgestrel tablets, 0.75 mg contains 0.75 mg of a single active steroid ingredient, levonorgestrel [18,19-Dinorpregn-4-en-20-yn-3-one-13-ethyl-17-hydroxy-, (17 α)-(-)-], a totally synthetic progestogen. The inactive ingredients present are colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, and povidone.

Levonorgestrel has a molecular weight of 312.45, and the following structural and molecular formulas:

Levonorgestrel USP
(click image for full-size original)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Emergency contraceptive pills are not effective if a woman is already pregnant. Levonorgestrel tablets, 0.75 mg are believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, it may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.

12.3 Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel 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.

After a single dose of levonorgestrel (0.75 mg) administered to 16 women under fasting conditions, the maximum serum concentrations of levonorgestrel were 14.1 + 7.7 ng/mL (mean + SD) at an average of 1.6 + 0.7 hours.

Cmax = maximum concentration

Tmax = time to maximum concentration

CL = clearance

Vd = volume of distribution

t ½ = elimination half life

AUCinf = area under the drug concentration curve from time 0 to infinity

Mean (± SD)
Cmax (ng/mL) Tmax (h) CL (L/h) Vd (L) t ½ (h) AUCinf ( ng/mL.h)
Levonorgestrel 14.1 (7.7) 1.6 (0.7) 7.7 (2.7) 260.0 24.4 (5.3) 123.1 (50.1)

Effect of Food: The effect of food on the rate and the extent of levonorgestrel absorption following single oral administration of levonorgestrel tablets, 0.75 mg have not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. 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.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.

Specific Populations

Pediatric

This product is not intended for use in the pediatric (pre-menarcheal) population, and pharmacokinetic data are not available for this population.

Geriatric

This product is not intended for use in postmenopausal women and pharmacokinetic data are not available for this population.

Race

No formal studies have evaluated the effect of race on pharmacokinetics of levonorgestrel tablets, 0.75 mg. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both levonorgestrel tablets, 0.75 mg and the Yuzpe regimen (another form of emergency contraception). The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown [see USE IN SPECIFIC POPULATIONS (8.6)].

Hepatic Impairment

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel tablets, 0.75 mg.

Renal Impairment

No formal studies were conducted to evaluate the effect of renal disease on the disposition of levonorgestrel tablets, 0.75 mg.

Drug-Drug Interactions

No formal drug-drug interaction studies were conducted with levonorgestrel tablets, 0.75 mg [see DRUG INTERACTIONS (7)].

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