Plan b (levonorgestrel)

Overdose

There are no data on overdosage of Plan B, although the common adverse event of nausea and associated vomiting may be anticipated.

Contraindications

Plan B is contraindicated for use in the case of known or suspected pregnancy.

Undesirable effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A double-blind, controlled clinical trial in 1,955 evaluable women compared the efficacy and safety of Plan B (one 0.75 mg tablet of levonorgestrel taken within 72 hours of unprotected intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets each containing 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two tablets taken 12 hours later).

The most common adverse events (>10%) in the clinical trial for women receiving Plan B included menstrual changes (26%), nausea (23%), abdominal pain (18%), fatigue (17%), headache (17%), dizziness (11%), and breast tenderness (11%). Table 1 lists those adverse events that were reported in ≥5% of Plan B users.

Table 1: Adverse Events in ≥5% of Women, by % Frequency

The following adverse reactions have been identified during post-approval use of Plan B. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abdominal Pain, Nausea, Vomiting

Fatigue

Dizziness, Headache

Dysmenorrhea, Irregular Menstruation, Oligomenorrhea, Pelvic Pain

Therapeutic indications

Plan B® is a progestin-only emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. To obtain optimal efficacy, the first tablet should be taken as soon as possible within 72 hours of intercourse. The second tablet should be taken 12 hours later.

Plan B is available only by prescription for women younger than age 17 years, and available over the counter for women 17 years and older.

Plan B is not indicated for routine use as a contraceptive.

Pharmacokinetic properties

No specific investigation of the absolute bioavailability of Plan B 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 Plan B (0.75 mg) administered to 16 women under fasting conditions, maximum serum concentrations of levonorgestrel were 14.1 + 7.7 ng/mL (mean + SD) at an average of 1.6 + 0.7 hours.

Table 2: Pharmacokinetic Parameter Values Following Single Dose Administration of Plan B (Levonorgestrel) Tablets 0.75 mg to Healthy Female Volunteers under Fasting Conditions

Effect of Food: The effect of food on the rate and the extent of levonorgestrel absorption following single oral administration of Plan B has not been evaluated.

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.

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.

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

Date of revision of the text

Name of the medicinal product

Plan B (levonorgestrel) price

Fertility, pregnancy and lactation

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.

Qualitative and quantitative composition

Each Plan B tablet is supplied as a white, round tablet containing 0.75 mg of levonorgestrel and is marked with INOR on one side.

Plan B (levonorgestrel) tablets, 0.75 mg, are available for a single course of treatment in PVC/aluminum foil blister packages of two tablets each. The tablet is white, round and marked INOR on one side.

Available as: Unit-of-use NDC 51285-769-93

Store Plan B tablets at controlled room temperature, 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).

Manufacturer by: Gedeon Richter, Ltd., Budapest, Hungary for Teva Women’s Health, Inc. Revised: Sep 2017.

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

Ectopic pregnancies account for approximately 2% of all reported pregnancies. Up to 10% of pregnancies reported in clinical studies of routine use of progestin-only contraceptives are ectopic.

A history of ectopic pregnancy is not a contraindication to use of this emergency contraceptive method. Healthcare providers, however, should consider the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain after taking Plan B. A follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking Plan B.

Plan B is not effective in terminating an existing pregnancy.

Some women may experience spotting a few days after taking Plan B. Menstrual bleeding patterns are often irregular among women using progestin-only oral contraceptives and women using levonorgestrel for postcoital and emergency contraception.

If there is a delay in the onset of expected menses beyond 1 week, consider the possibility of pregnancy.

lan B does not protect against HIV infection (AIDS) or other sexually transmitted infections (STIs).

A physical examination is not required prior to prescribing Plan B. A follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking Plan B.

A rapid return of fertility is likely following treatment with Plan B for emergency contraception; therefore, routine contraception should be continued or initiated as soon as possible following use of Plan B to ensure ongoing prevention of pregnancy.

• Take Plan B as soon as possible and not more than 72 hours after unprotected intercourse or a known or suspected contraceptive failure.
• If you vomit within two hours of taking either tablet, immediately contact your healthcare provider to discuss whether to take another tablet.
• Seek medical attention if you experience severe lower abdominal pain 3 to 5 weeks after taking Plan B, in order to be evaluated for an ectopic pregnancy.
• After taking Plan B, consider the possibility of pregnancy if your period is delayed more than one week beyond the date you expected your period.
• Do not use Plan B as routine contraception.
• Plan B is not effective in terminating an existing pregnancy.
• Plan B does not protect against HIV-infection (AIDS) and other sexually transmitted diseases/infections.
• or women younger than age 17 years, Plan B is available only by prescription.

There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorgenicity following administration of levonorgestrel to rats for 2 years at approximately 5 μg/day, to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 μg/kg/day. In another 7 year dog study, administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies.

Levonorgestrel was not found to be mutagenic or genotoxic in the Ames Assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice.

There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.

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.

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.

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 Plan B emergency contraception before menarche is not indicated.

This product is not intended for use in postmenopausal women.

No formal studies have evaluated the effect of race. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both Plan B 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.

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Plan B.

No formal studies were conducted to evaluate the effect of renal disease on the disposition of Plan B.

Dosage (Posology) and method of administration

Take one tablet of Plan B orally as soon as possible within 72 hours after unprotected intercourse or a known or suspected contraceptive failure. Efficacy is better if the tablet is taken as soon as possible after unprotected intercourse. The second tablet should be taken 12 hours after the first dose. Plan B can be used at any time during the menstrual cycle.

If vomiting occurs within two hours of taking either dose of medication, consideration should be given to repeating the dose.

Interaction with other medicinal products and other forms of interaction

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A double-blind, controlled clinical trial in 1,955 evaluable women compared the efficacy and safety of Plan B (one 0.75 mg tablet of levonorgestrel taken within 72 hours of unprotected intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets each containing 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two tablets taken 12 hours later).

The most common adverse events (>10%) in the clinical trial for women receiving Plan B included menstrual changes (26%), nausea (23%), abdominal pain (18%), fatigue (17%), headache (17%), dizziness (11%), and breast tenderness (11%). Table 1 lists those adverse events that were reported in ≥5% of Plan B users.

Table 1: Adverse Events in ≥5% of Women, by % Frequency

The following adverse reactions have been identified during post-approval use of Plan B. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abdominal Pain, Nausea, Vomiting

Fatigue

Dizziness, Headache

Dysmenorrhea, Irregular Menstruation, Oligomenorrhea, Pelvic Pain

Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of progestin-only pills. Some drugs or herbal products that may decrease the effectiveness of progestin-only pills include:

• barbiturates (including primidone)
• bosentan
• carbamazepine
• felbamate
• griseofulvin
• oxcarbazepine
• phenytoin
• rifampin
• St. John’s wort
• topiramate

Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Concomitant administration of efavirenz has been found to reduce plasma levels of levonorgestrel (AUC) by around 50%, which may reduce the effectiveness of Plan B.

Consult the labeling of all concurrently used drugs to obtain further information about interactions with progestin-only pills or the potential for enzyme alterations.

Levonorgestrel is not a controlled substance. There is no information about dependence associated with the use of Plan B.