Norgestrel

Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials. ... As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Store at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F).

Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Store levonorgestrel tablets at 20 to 25 °C (68 to 77 °F)

The levonorgestrel-releasing intrauterine system should be stored at a temperature of 25 °C but may be exposed to temperatures ranging from 15-30 °C. The system is supplied as a sterile device and should not be resterilized. The device should not be used if the inner package is damaged or has been opened.

Estrogen-progestin combinations generally should be stored at room temperature in a well-closed container, unless otherwise specified by the manufacturer. Commercially available oral contraceptives are provided in mnemonic (memory-aid) dispensing packages which are exempted from the child-safety packaging requirements of the US Poison Prevention Packaging Act of 1970.

Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Wash spill site. Place spillage and all contaminated cleanup materials in a thick plastic hazardous waste disposal bag or leakproof container and label it CAUTION: HAZARDOUS CHEMICAL WASTE.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

This material is assumed to be combustible. As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

Engineering controls such as exhaust ventilation are recommended.

SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. The completeness of the cleaning procedures should be considered before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at the end of shift, but should remain at employee's place of work for cleaning.

For more Preventive Measures (Complete) data for NORGESTREL (6 total), please visit the HSDB record page.

Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible. Eye Protection: Safety goggles or glasses. Protective clothing: Protect exposed skin.

The metabolism of estrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg phenobarbital, phenytoin, carbamazepine), and anti-infectives (eg rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's Wort (Hypericum Perforatum) may induce the metabolism of estrogens and progestagens.

Phenytoin and rifampin increase the serum concentrations of sex hormone-binding globulin (SHBG); this significantly decreases the serum concentration of free drug for some progestins, which is a special concern in patients using progestins for contraception. /Progestins/

Drug interaction data are not available for rifabutin, but because its structure is similar to that of rifampin, similar precautions with its use with progestins may be warranted. ... /Progestins/

Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of coadministration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8,100(SRC), determined from a structure estimation method(2), indicates that norgestrel is expected to be immobile in soil(SRC). Volatilization of norgestrel from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Norgestrel is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8100(SRC), determined from a structure estimation method(2), indicates that norgestrel is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 91(SRC), from an estimated log Kow of 3.48(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2011).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), norgestrel, which has an estimated vapor pressure of 1.0X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase norgestrel may be removed from the air by wet or dry deposition(SRC). Norgestrel contains chromophores that absorb at wavelengths >290 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8,100(SRC), determined from a structure estimation method(2), indicates that levonorgestrel is expected to be immobile in soil(SRC). Volatilization of levonorgestrel from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Levonorgestrel is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.92X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8,100(SRC), determined from a structure estimation method(2), indicates that levonorgestrel is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 92(SRC), from an estimated log Kow of 3.48(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2011).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), levonorgestrel, which has an estimated vapor pressure of 3.9X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase levonorgestrel may be removed from the air by wet or dry deposition(SRC). Levonorgestrel contains chromophores that absorb light at <290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

For the emergency contraceptive, the timing of when patients ingest the drug plays a significant role in its efficacy in preventing pregnancy; this means the adverse effect of pregnancy occurring becomes greater when the patient waits over 48 to 72 hours or longer to take the drug, as well as when taking the medication during an ovulation cycle. Many studies have shown a reduction in efficacy in women with a BMI greater than 30 kg/m², but this difference is not significant enough to restrict the use of levonorgestrel in this subset of patients. This appears to be due to the lower bioavailability of a standard 1.5 mg dose of levonorgestrel, which is free plus albumin-bound, in these patients. The most common adverse effects are menstrual abnormalities, amenorrhea, dysmenorrhea, oligomenorrhea, headaches, and acne. Other adverse effects that can occur are nausea and vomiting. Importantly, this drug does not protect any patient from sexually transmitted infections and diseases, and the advice to patients is to use condoms for protection.

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

EXPERIMENTAL: ... Twelve healthy exclusively breastfeeding volunteers received 1.5 mg levonorgestrel (LNG). Women refrained from nursing for 72 hr after dosing and fed their infants with milk frozen beforehand. Serial blood and milk samples were collected for 120 hr and assayed for LNG and sex hormone binding globulin. LNG concentrations peaked in plasma and in milk 1-4 hr and 2-4 hr after dosing, respectively. Concentrations in milk (M) paralleled those in plasma (P) but were consistently lower (mean M:P ratio 0.28). Estimated infant exposure to LNG is 1.6 ug on the day of dosing (1 ug in the first 8 hr), 0.3 ug on the second day and 0.2 ug on the third day. Nursing mothers may need EC. These results suggest that to limit infant exposure to the period of maximum LNG excretion in milk, mothers should discontinue nursing for at least 8 hr, but not more than 24 hr, after EC.

Signs and Symptoms of Overdose

Binds to the progesterone and estrogen receptors. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins like levonorgestrel will slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge.

/AQUATIC SPECIES/ ...The effects of two progestins currently marketed in contraceptive formulations, levonorgestrel (LNG) and drospirenone (DRSP), were investigated in adult fathead minnows (Pimephales promelas) following an OECD 21-day fish reproduction screening assay draft protocol with additional end points. Levonorgestrel was tested at measured concentrations of 0.8, 3.3, and 29.6 ng/L, and DRSP at concentrations of 0.66, 6.5, and 70 uL. Both tested progestins caused an inhibition of reproduction. For LNG, this occurred at concentrations of 2:0.8 ng/L, no no-observed-effect concentration (NOEC) could be defined. Higher concentrations resulted in masculinization of females with de novo synthesis of nuptial tubercles. Drospirenone treatment, however, affected the reproductive success of fathead minnow at concentrations of 6.5 uL and higher with a clear dose-response relationship and a NOEC of 0.66 uL, which is above environmentally relevant concentrations.

Levonorgestrel was detected in effluent from the Eysines Sewage Treatment Plant (northern suburbs, Bordeaux, France) at mean concentrations of <5.0, <2.0, and <2.0 ng/L in July 2003, September 2003, and February 2004, respectively (detection limit = 5.0, 2.0, and 2.0, respectively)(1). The compound was tested for but not detected (detection limit = 2-100 ng/L) in effluent samples from sewage treatment plants in the vicinity of Barcelona, Spain, sampled from April to June, 1999(2).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of norgestrel can be estimated to be 8,100(SRC). According to a classification scheme(2), this estimated Koc value suggests that norgestrel is expected to be immobile in soil.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of levonorgestrel can be estimated to be 8,100(SRC). According to a classification scheme(2), this estimated Koc value suggests that levonorgestrel is expected to be immobile in soil.

/HUMAN EXPOSURE STUDIES/ The growth hormone, insulin, and blood glucose values were measured during a glucose tolerance test in 12 women before and after 3 months' use of a sequential contraceptive (11 pills containing .05 mg D-norgestrel and .05 mg ethinyl estradiol and 10 pills containing .05 mg D-norgestrel and .05 mg ethinyl estradiol). Neither fasting blood glucose nor glucose tolerance are altered during administration of the contraceptive steroids. Conversely, the reactive insulin level is significantly increased in comparison to the basal value, thus showing the signs of hyperinsulinemia. Both the gestagens and the estrogens appear to contribute to this disturbance of insulin secretion. Presumably the hyperinsulinemia is an expression of decreased sensitivity of the peripheral tissue to insulin. The growth hormone, a so-called insulin antagonist, is not responsible for the insulin resistance observed. The values measured after administration of the contraceptive do not significantly differ from the basal values.

/SIGNS AND SYMPTOMS/ Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

/CASE REPORTS/ ... Presented is the case of a 45-year-old US woman with right lower quadrant pain and a 5-year history of use of a combined oral contraceptive (OC) containing 0.35 ug ethinyl estradiol and 0.35 ug norgestrel. At presentation, the uterus was enlarged to a size corresponding to 12-14 gestational weeks, with a mass at the right fundal margin. Pelvic ultrasonography revealed a large dominant leiomyoma 7.2 x 5.8 x 5.5 cm and several smaller tumors. OC use was discontinued and, 4 months later, the uterus was a size of 8-10 gestational weeks and a single serosal leiomyoma 5.9 x 4.6 x 4.4 cm remained. The leiomyoma volume had decreased by 47% after OC discontinuation, to 63 cu cm. Pelvic sonography 12 months after OC discontinuation revealed no further changes in myoma volume. In OC users with clinically significant uterine leiomyomas, discontinuation of combined OCs should be considered as a low-risk intervention with the potential to decrease uterine volume.

/CASE REPORTS/ /Investigators/ report a 41-year-old Caucasian woman with polycystic liver and kidney disease, and a 9-year history of severe cyclical urticaria related to her menses. The urticaria was not adequately controlled by antihistamines or Prempak-C (conjugated oestrogens and norgestrel). Intradermal testing with progesterone was strongly positive at 30 min and 18 hr. Buserelin, administered intranasally at doses of up to 800 ug daily, controlled the urticaria within 4 weeks, and she was completely symptom-free thereafter. She had therapy-induced amenorrhea and occasional hot flushes. Unfortunately, her liver cysts progressively enlarged, and a right hepatectomy was performed in June 1992, but she died after complications 3 weeks later. Prior to this she had been free of urticaria for 6 months after starting buserelin. Buserelin, a gonadotrophin-releasing hormone analogue, may be useful in the management of progesterone-induced urticaria, in patients in whom conjugated estrogens are contraindicated or unhelpful.

Norgestrel's production and use as in oral contraceptive formulations(1) may result in its release to the environment through various waste streams(SRC).

Levonorgestrel's production and use as an oral contraceptive component(1) may result in its release to the environment through various waste streams(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including norgestrel, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /In combination with Ethinylestradiol/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including levonorgestrel, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Used as a combined oral contraceptive with ethinylestradiol in monophasic, biphasic, and triphasic regimens. It is also used as a 'progestin-only' contraceptive pill and subdermal implant.

MEDICATION

Use (kg; approx.) in Germany (2009): >50

For the treatment of menopausal and postmenopausal disorders and alone or in combination with other hormones as an oral contraceptive.

Reported impurities include: 13-ethyl-3,4-diethynyl-18,19-dinor-17alpha-pregn-5-en-20- yn-3beta,4alpha,17-triol, 13-ethyl-3,4-diethynyl-18,19-dinor-17alpha-pregn-5-en-20-yn-3alpha,4alpha,17- triol 13-ethyl-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol, 13-ethyl-3-ethynyl-18,19-dinor-17alpha-pregna-3,5-dien-20-yn-17-ol, 13-ethyl-17-hydroxy-18,19-dinor-17alpha-pregna-4,8(14)- dien-20-yn-3-one and 13-ethyl-17-hydroxy-18,19-dinor-17alpha-pregn-5(10)-en-20-yn-3-one.

In a representative chemical synthesis, 6-methoxy-alpha-tetralone is reacted with vinylmagnesium bromide, and the resulting 1,2,3,4-tetrahydro-6-methoxy-1-vinyl-1-naphthol is condensed with 2-ethyl-1,3-cyclopentanedione to form initially a tricyclic intermediate (secosteroid) containing all of the gonane skeleton carbon atoms. Cyclization of the secosteroid via dehydration yields a 13-ethylgona-1,3,5(10)-8,14-pentaene structure which is then successively reduced and ethynylated.

Prepn: H. Smith, Belg. pat. 623,844 (1963), C.A. 61, 4427c (1964); G.A. Hughes, H. Smith, U.S. pat. 3,959,322 (1976 to Herchel Smith)

The activity of norgestrel is found in the levorotatory form D-l-norgestrel or levonorgestrel. Synthesis of the levorotatory form involves meta-cresol methyl ether, dimethyl malonate and trans-1,4-dibromo-2-butene as starting materials. The steroid skeleton was constructed by using an intramolecular Diels-Alder reaction of an ortho-quinodimethane derivative, preceded by photo-enolization of an appropriate methyl-substituted acetophenone derivative. Chirality was introduced at an early stage during a nucleophilic substitution reaction. It is not known if this synthesis is used commercially.

Mixture of levonorgestrel with ethinyl estradiol. Levlen, Logynon, Microgynon, Nordette, Ovran, Ovranette, Tetre-gynon, Tri-Levlen, Trinordiol, Triphasil. Clinical trial in acne treatment.

Mixture with ethinyl estradiol. Lo/Ovral, Ovral, Stediril. Clinical efficiacy as oral contraceptive.

Norgestrel is available commercially as a single-ingredient tablet and as a component of combination tablets with ethinylestradiol, estradiol valerate or as combined injectable solution with ethinylestradiol.

Oral: Tablets: Norgestrel and Ethinyl Estradiol 0.3 mg/0.03 mg, Low-ogestrel (Watson Pharma).

Oral: Tablets: 2 mg estradiol valerate (white tablets taken day 1-11), 500 ug norgestrel + 2 mg estradiol valerate (pale brown tablets taken day 12-21), Cyclo-Progynova (Meda Pharmaceuticals).

Levonorgestrel is available commercially as a single-ingredient tablet and in combined tablets with estradiol, estradiol valerate, estriol and ethinylestradiol ... It is also available as an intrauterine system and as a flexible, closed-capsule implant made of silicone rubber tubing.

A synthetic steroid hormone used as an ingredient of oral contraceptives

The activity of norgestrel is found in the levorotatory form D-l-norgestrel or levonorgestrel.

...was manufactured or formulated in Augentina, Australia, Austria, Belgium, Brazil, Canada, Finland, France, German, India, Mexico, the Netherlands, New Zealand, Portugal, South Africa, Spain, Switzerland, the United Kingdom and the U.S.