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NORGESTIMATE

Norgestimate is a synthetic progestin commonly used in hormonal contraceptives. It’s frequently combined with ethinyl estradiol in various formulations for birth control, acne treatment, and other medical conditions. This article examines how norgestimate has been studied in clinical trials, focusing on its effectiveness, safety profile, and interactions with other medications. Whether used in oral contraceptive pills or transdermal patches, norgestimate plays an important role in women’s healthcare options. Understanding these clinical trials can help patients make informed decisions about their contraceptive choices.

Table of Contents

What is Norgestimate?

Norgestimate (NGM) is a synthetic progestin that is commonly used in combination with ethinyl estradiol (EE) in hormonal contraceptives. This combination is available in various formulations and is marketed under different brand names including Ortho Tri-Cyclen, Ortho Cyclen, and their generic equivalents[1]. Norgestimate works by breaking down into active metabolites in the body, primarily norelgestromin (NGMN) and norgestrel (NG), which are responsible for its contraceptive effects[2].

When combined with ethinyl estradiol, norgestimate is available in different dosages and regimens:

  • A monophasic version where the hormone dose remains constant throughout the cycle (typically 250 mcg NGM/35 mcg EE or 250 mcg NGM/25 mcg EE)
  • A triphasic version where the norgestimate dose varies throughout the cycle (typically 180 mcg/215 mcg/250 mcg NGM with 35 mcg or 25 mcg EE)

Norgestimate for Contraception

The primary use of norgestimate is as a component in combined hormonal contraceptives. When used correctly, NGM/EE combinations are highly effective at preventing pregnancy. The contraceptive effect is achieved through multiple mechanisms[3]:

  • Inhibition of ovulation by suppressing follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
  • Thickening of cervical mucus, making it difficult for sperm to enter the uterus
  • Changes to the endometrial lining that would make implantation less likely

The typical regimen involves taking active hormone tablets for 21 days followed by 7 days of placebo tablets or no tablets, during which time withdrawal bleeding (similar to a period) occurs[4]. However, research has also been conducted on extended regimens where active hormones are taken for longer periods (such as 84 days) followed by a shorter hormone-free interval[4].

Norgestimate for Acne Treatment

Beyond contraception, norgestimate/ethinyl estradiol combinations have been studied and approved for the treatment of moderate acne vulgaris (commonly known as pimples) in females who also desire contraception[5].

Clinical studies have compared the efficacy of norgestimate/ethinyl estradiol with other progestin/estrogen combinations for acne treatment. For example, one study compared the effect of norgestimate/ethinyl estradiol with desogestrel/ethinyl estradiol in female participants with mild to moderate acne vulgaris[5]. The results were measured by examining changes in the total acne lesion count, which includes open and closed comedones, papules, pustules, and nodules.

Another study compared norgestimate/ethinyl estradiol with cyproterone acetate/ethinyl estradiol (marketed as Diane-35) for acne treatment[6]. These studies help determine which hormonal combinations provide the best balance of efficacy and safety for women with acne who also need contraception.

The anti-acne effects are believed to be due to the following mechanisms:

  • Reduction in the production of androgens (male hormones)
  • Decrease in the free testosterone in circulation by increasing sex hormone binding globulin (SHBG)
  • Reduction in sebum production, which is often elevated in acne patients

Norgestimate’s Effects on Bone Health

Research has also explored the potential benefit of norgestimate/ethinyl estradiol on bone health, particularly in populations at risk for decreased bone mineral density (BMD). One study specifically investigated the effect of norgestimate/ethinyl estradiol on lumbar spine and total hip bone mineral density in pediatric subjects with anorexia nervosa[7].

Anorexia nervosa is associated with low estrogen levels, which can lead to decreased bone mineral density and increased risk of osteoporosis. The study aimed to determine if providing hormonal treatment with norgestimate/ethinyl estradiol could help prevent bone loss in these adolescents[7].

This research is important because although oral contraceptives are sometimes prescribed to prevent bone loss in adolescents with anorexia nervosa, there had been limited definitive placebo-controlled studies evaluating their effectiveness for this purpose prior to this research[7].

Extended Regimen Usage

Traditional hormonal contraceptive regimens involve 21 days of active hormones followed by 7 days without hormones, resulting in monthly withdrawal bleeding. However, there has been interest in extended regimens that reduce the frequency of withdrawal bleeding[4].

An open-label study evaluated the bleeding profile of norgestimate/ethinyl estradiol administered as an extended regimen (84 consecutive days of active tablets followed by seven days medication-free)[4]. The study was designed to assess whether a triphasic extended regimen, where the progestin dose changes throughout the cycle, would result in breakthrough bleeding and spotting when the progestin dose changes[4].

Extended regimens may offer advantages for women who experience menstrual-related symptoms such as headaches, mood changes, or heavy bleeding, or for those who simply prefer fewer periods per year[4].

Drug Interactions with Norgestimate

Several studies have investigated potential drug interactions between norgestimate/ethinyl estradiol and other medications. These studies are important because certain drugs can affect the metabolism of hormonal contraceptives, potentially reducing their effectiveness[8][9].

For example, one study evaluated the effect of ethinyl estradiol/norgestimate, a weak CYP3A4 inhibitor, on the pharmacokinetics of lomitapide in healthy female subjects[8]. The study aimed to determine if taking these medications together would affect the blood levels of either drug.

Another study examined the potential interaction between sofosbuvir/velpatasvir/voxilaprevir (a treatment for hepatitis C) and norgestimate/ethinyl estradiol[9]. The study assessed whether the hepatitis C medication affected the pharmacokinetics of the hormonal contraceptive components.

A separate study investigated the effect of erenumab (a medication for migraine prevention) on the pharmacokinetics of a norgestimate/ethinyl estradiol oral contraceptive[10]. This is particularly relevant as migraines and contraceptive use can both be concerns for women of reproductive age.

Another area of research has been the potential interaction between folic acid and norgestimate/ethinyl estradiol. Folic acid is important for reducing the risk of neural tube defects in developing fetuses, so understanding how it interacts with contraceptives is valuable for women who may become pregnant after discontinuing contraception[11].

Norgestimate in Special Populations

Research has also looked at the use of norgestimate/ethinyl estradiol in specific populations with unique health considerations.

One study explored the use of norgestimate/ethinyl estradiol in women with cystic fibrosis who experience cyclic exacerbations of their disease related to their menstrual cycles[12]. The research aimed to evaluate satisfaction with hormonal contraception in this population and to assess the impact of hormonal contraceptives on cystic fibrosis disease progression[12].

The study hypothesized that women with cystic fibrosis who have cyclic exacerbations might experience decreased Pseudomonas aeruginosa mucoidy conversion (a marker of disease progression), improved quality of life, and improvement in pulmonary function tests while on hormonal contraception[12].

Safety Profile

The safety of norgestimate/ethinyl estradiol has been evaluated in various studies, including those comparing it to other hormonal contraceptive methods[13].

One study compared the risk of venous thromboembolism (VTE), myocardial infarction (heart attack), and ischemic stroke among women using the transdermal contraceptive system (ORTHO EVRA, which contains norelgestromin, the active metabolite of norgestimate) compared with women using norgestimate-containing oral contraceptives with 35 mcg ethinyl estradiol[13].

Another study investigated the effects of oral contraceptive pills versus a hormonal patch on coagulation parameters, which are relevant to the risk of blood clots[14]. The oral contraceptive in this study contained 35 micrograms ethinyl estradiol and 250 micrograms norgestimate, while the patch contained ethinyl estradiol and norelgestromin[14].

Other safety aspects that have been studied include cycle control (bleeding patterns), effects on weight, blood pressure, and other physical parameters[15]. One study specifically compared cycle control with norgestimate/ethinyl estradiol versus drospirenone/ethinyl estradiol in healthy sexually active females[15].

Understanding the safety profile of norgestimate/ethinyl estradiol helps healthcare providers and patients make informed decisions about contraceptive choices based on individual health histories and risk factors.

Aspect Details
Common Formulations – Oral contraceptive pills (0.180/0.215/0.250 mg norgestimate with 25-35 mcg ethinyl estradiol)
– Transdermal patch (delivers norelgestromin, the active metabolite of norgestimate)
Primary Uses in Clinical Trials – Contraception (pregnancy prevention)
– Treatment of moderate acne vulgaris
– Management of bone mineral density in anorexia nervosa
– Control of abnormal uterine bleeding
Dosing Regimens Studied – Traditional: 21 days active hormones, 7 days hormone-free
– Triphasic: Increasing norgestimate doses (0.180→0.215→0.250 mg) over 21 days
– Extended: 84 days active hormones, 7 days hormone-free
Drug Interaction Studies – Lomitapide (cholesterol medication)
– Hepatitis C treatments (sofosbuvir/velpatasvir/voxilaprevir)
– HIV treatments (atazanavir/ritonavir)
– Migraine medications (erenumab)
– Folic acid supplements
Pharmacokinetic Properties – Metabolized to active components norelgestromin and norgestrel
– Transdermal delivery results in 55% higher ethinyl estradiol exposure than oral route
– Peak concentration (Cmax) and total exposure (AUC) were primary measurements in trials
Safety Considerations – Effects on coagulation parameters (potential VTE risk)
– Breakthrough bleeding patterns
– Comparison between patch and pill formulations
– Bioequivalence studies for different manufacturing processes

FAQ

  • What is norgestimate and how is it used in contraceptives? Norgestimate is a synthetic progestin that's commonly combined with ethinyl estradiol (an estrogen) in hormonal contraceptives. It works by preventing ovulation, thickening cervical mucus to prevent sperm entry, and changing the uterine lining to prevent implantation. In clinical trials, norgestimate has been studied in both oral pill forms (like Ortho Tri-Cyclen and Ortho-Cyclen) and in transdermal patches. It's typically administered in varying doses throughout a 21-day or 28-day cycle, with different formulations containing between 0.180-0.250 mg of norgestimate.
  • What conditions besides contraception has norgestimate been studied for? Clinical trials have studied norgestimate not only for contraception but also for treating acne vulgaris, managing symptoms in women with anorexia nervosa (particularly for bone density improvement), and controlling abnormal bleeding patterns. In some studies, norgestimate-containing contraceptives were shown to be effective for treating moderate acne. It has also been studied for potential effects on bone mineral density in adolescents with anorexia nervosa, though the effectiveness for this use required further research.
  • How does the norgestimate patch compare to oral pills containing norgestimate? In clinical trials comparing the norgestimate patch (which releases norelgestromin, the active metabolite of norgestimate) to oral contraceptive pills, researchers found some differences in hormone levels and effects. The transdermal patch typically results in about 55% higher overall exposure to ethinyl estradiol compared to oral contraceptives. This difference is due to the steady release of hormones through the skin, bypassing the digestive system. Studies have also examined differences in bleeding patterns, coagulation parameters, and user satisfaction between the two delivery methods.
  • What are the known drug interactions with norgestimate-containing contraceptives? Clinical trials have investigated several important drug interactions with norgestimate-containing contraceptives. Studies have examined interactions with medications like lomitapide (for cholesterol management), hepatitis C treatments (sofosbuvir/velpatasvir/voxilaprevir), migraine medications (erenumab), HIV treatments (atazanavir/ritonavir), and folic acid supplements. The timing of taking these medications relative to norgestimate can affect hormone levels. For example, some antiretroviral medications may decrease the effectiveness of hormonal contraceptives, which could potentially reduce contraceptive efficacy.
  • What are the common dosing regimens for norgestimate in contraceptives? Norgestimate is commonly used in different dosing regimens. In traditional regimens, it's taken for 21 days followed by 7 days of placebo or no medication. Triphasic regimens (like Ortho Tri-Cyclen) use increasing doses throughout the cycle: typically 0.180 mg for days 1-7, 0.215 mg for days 8-14, and 0.250 mg for days 15-21, all combined with ethinyl estradiol. Extended regimens have also been studied, where active hormones are taken for 84 consecutive days followed by 7 hormone-free days, which reduces the frequency of withdrawal bleeding to four times per year instead of monthly.

Ongoing Clinical Trials on NORGESTIMATE

  • Study on Menstrual Bleeding and Tolerability of Norgestimate and Ethinylestradiol for Women Using Contraceptives in Italy

    Not yet recruiting

    1 1 1 1
    Investigated drugs:
    Italy

Glossary

  • Norgestimate (NGM): A synthetic progestin (female hormone) used in birth control pills and patches, typically combined with ethinyl estradiol. It works by preventing ovulation, thickening cervical mucus, and changing the uterine lining.
  • Ethinyl Estradiol (EE): A synthetic form of estrogen commonly used in combination with progestins in hormonal contraceptives. Doses typically range from 20-35 micrograms in contraceptive formulations.
  • Norelgestromin (NGMN): The active metabolite (breakdown product) of norgestimate that provides the primary contraceptive effect. It's also the active component in the transdermal contraceptive patch.
  • Norgestrel (NG): Another active metabolite of norgestimate that contributes to its contraceptive effects.
  • Transdermal Contraceptive System: A birth control method that delivers hormones through the skin via an adhesive patch. In trials, patches contained 6 mg of norelgestromin and 0.75 mg of ethinyl estradiol.
  • Pharmacokinetics (PK): The study of how drugs move through the body, including absorption, distribution, metabolism, and excretion. PK parameters help determine proper drug dosing.
  • Bioequivalence: When two drug formulations produce the same biological effects and have similar absorption, distribution, metabolism, and excretion. This concept is important when comparing generic and brand-name drugs.
  • AUC (Area Under the Curve): A measurement of the total exposure to a drug over time. Higher AUC values indicate greater overall exposure to the medication.
  • Cmax: The maximum concentration of a drug in the blood after administration. This helps determine how much of a drug is available in the body at its peak.
  • Tmax: The time it takes for a drug to reach its maximum concentration in the blood after administration.
  • Half-life (t1/2): The time it takes for the concentration of a drug in the body to decrease by half. This helps determine how often a medication needs to be taken.
  • CYP3A4: An enzyme in the liver responsible for metabolizing many drugs, including hormonal contraceptives. Drug interactions can occur when two medications are processed by this same enzyme.
  • Breakthrough bleeding: Unexpected vaginal bleeding that occurs between menstrual periods while taking hormonal contraceptives. This is a common side effect, especially in the first few months.
  • Extended regimen: A contraceptive dosing schedule where active hormones are taken for a longer period (typically 84 days) followed by a short hormone-free interval, resulting in fewer withdrawal bleeds per year.
  • Triphasic regimen: A contraceptive dosing schedule where hormone doses change three times throughout the menstrual cycle, mimicking natural hormone fluctuations.
  • Bone Mineral Density (BMD): A measurement of calcium and other minerals in bones. Some studies examined whether hormonal contraceptives affected BMD in women with anorexia nervosa.
  • Venous Thromboembolism (VTE): A blood clot that forms in a vein, which can include deep vein thrombosis (DVT) or pulmonary embolism (PE). This is a rare but serious potential side effect of hormonal contraceptives.

References

  1. https://clinicaltrials.gov/study/NCT02127593
  2. https://clinicaltrials.gov/study/NCT00709189
  3. https://clinicaltrials.gov/study/NCT04828824
  4. https://clinicaltrials.gov/study/NCT00344383
  5. https://clinicaltrials.gov/study/NCT01466673
  6. https://clinicaltrials.gov/study/NCT00752635
  7. https://clinicaltrials.gov/study/NCT00320567
  8. https://clinicaltrials.gov/study/NCT02080468
  9. https://clinicaltrials.gov/study/NCT02533427
  10. https://clinicaltrials.gov/study/NCT02792517
  11. https://clinicaltrials.gov/study/NCT00301587
  12. https://clinicaltrials.gov/study/NCT02144246
  13. https://clinicaltrials.gov/study/NCT00377988
  14. https://clinicaltrials.gov/study/NCT00554632
  15. https://clinicaltrials.gov/study/NCT00745901