Lutein

I N S T R U C T I O N for medical use of the medicinal product LUTEINA (LUTEINA)

Composition:

Active substance: progesterone;

1 tablet contains 100 mg or 200 mg of progesterone;

Excipients: lactose monohydrate, pregelatinized corn starch, sodium croscarmellose, hypromellose, citric acid monohydrate, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Vaginal tablets.

Main physicochemical properties:
100 mg vaginal tablets: round uncoated, biconvex tablets, white or almost white, with the imprint “100” on one side and “22” on the other;

200 mg vaginal tablets: round uncoated, biconvex tablets, white or almost white.

Pharmacotherapeutic group. Sex gland hormones and drugs used in disorders of the genital system. ATC code G03DA04.

Pharmacological properties.

Pharmacodynamics.

Progesterone is a hormone produced by the corpus luteum of the ovary. It promotes the formation of normal secretory endometrium in women. It induces the transition of the uterine mucosa from the proliferative phase to the secretory phase, and after fertilization, facilitates its transformation into a state necessary for the development of the fertilized ovum. It reduces excitability and contractility of the uterine musculature and fallopian tubes, and stimulates development of the terminal elements of the mammary gland. It has no androgenic activity. It exerts a blocking effect on the secretion of hypothalamic releasing factors LH and FSH, suppresses the formation of gonadotropic hormones by the pituitary gland, and inhibits ovulation.

Pharmacokinetics.

After vaginal administration, progesterone is rapidly absorbed through the mucous membrane.

The increase in progesterone levels in plasma begins within the first hour, with peak plasma concentrations achieved within 1–3 hours after administration.

At a dose of 100 mg of progesterone per day, Luteina enables achieving and maintaining a physiological and stable level of plasma progesterone (on average around 9.7 ng/mL), similar to that observed during the luteal phase of a menstrual cycle with normal ovulation. Thus, Luteina promotes adequate maturation of the endometrium and supports embryo implantation.

With higher doses (above 200 mg per day), progressively increased, vaginal administration enables achieving plasma progesterone levels similar to those observed during the first trimester of pregnancy.

Metabolism.

Metabolites in plasma and urine are identical to those observed during physiological secretion by the ovarian corpus luteum: in plasma, these are mainly 20α-hydroxy, δ4α-pregnanolone, and 5α-dihydroprogesterone. Excretion in urine occurs in 95% as glucuronide metabolites, the main component being 3α,5β-pregnanediol (pregnanediol).

Clinical characteristics.

Indications.

Reduced fertility in primary or secondary infertility associated with partial or complete luteal phase deficiency (anovulation, luteal phase support during preparation for in vitro fertilization, oocyte donation programs). Prevention of recurrent miscarriage or threatened spontaneous abortion in luteal phase deficiency. Prevention of preterm birth in women with a short cervix or in women with a history of spontaneous preterm birth. Inability or limitation to administer the drug orally.

Contraindications.

Hypersensitivity to any component of the drug. Severe impairment of liver function. Suspected or confirmed neoplasia of the breast or genital organs. Undiagnosed vaginal bleeding. Failed or incomplete abortion.

Thrombophlebitis. Thromboembolic disorders. Cerebral hemorrhage. Porphyria.

Interaction with other medicinal products and other forms of interaction.

No clinically significant interactions between progesterone and other drugs have been confirmed. In vitro studies have shown that drugs which reduce cytochrome P450 activity (e.g., ketoconazole) may slow down progesterone metabolism. The clinical significance of this effect is unknown.

Antisteroid drugs. Aminoglutethimide markedly reduces plasma concentrations of medroxyprogesterone acetate and megestrol, possibly through a hepatic enzyme-inducing effect.

Anticoagulants. Progesterone may enhance or diminish the anticoagulant effect of coumarins.

Progesterone antagonizes the anticoagulant effect of phenindione.

Emergency contraception. Concomitant use of ulipristal acetate with progesterone may lead to reduced efficacy of progesterone.

Diazepam. Progesterone may increase plasma diazepam concentrations.

Tizanidine. Progesterone may increase plasma tizanidine concentrations.

Terbinafine. There are isolated reports of breakthrough bleeding when terbinafine is used concomitantly with progesterone.

Laboratory tests. Progesterone may affect laboratory test results of liver and/or endocrine function.

Administration of high doses of progesterone may temporarily increase urinary excretion of sodium and chloride.

Progestins reduce glucose tolerance, which may require an increase in daily insulin dose or other antidiabetic agents in patients with diabetes mellitus.

Progesterone use may increase plasma cyclosporine concentrations. Some antibiotics (e.g., ampicillins, tetracyclines) may alter intestinal microflora, resulting in changes to the enterohepatic steroid cycle.

Potent hepatic enzyme inducers—namely barbiturates, antiepileptic drugs (phenytoin, carbamazepine), rifampicin, phenylbutazone, bromocriptine, spironolactone, griseofulvin, nevirapine, efavirenz, certain antibiotics (ampicillins, tetracyclines), as well as herbal preparations containing St. John’s wort (Hypericum perforatum)—may enhance the metabolism and elimination of progesterone. Ritonavir and nelfinavir, known as potent cytochrome enzyme inhibitors, have been shown to exhibit enzyme-inducing properties when used concomitantly with steroid hormones.

Special precautions for use

Administration in the recommended doses does not demonstrate contraceptive effect.

If treatment is initiated very early in the menstrual cycle, particularly before day 15 of the cycle, shortening of the cycle or breakthrough bleeding may occur.

In cases of uterine bleeding, the drug should not be prescribed without first determining the underlying cause, including evaluation of the endometrium.

The drug should be used with caution in patients with fluid retention (e.g., in cases of hypertension, cardiovascular disease, renal disorders), in patients with epilepsy, migraine, bronchial asthma, history of depression, diabetes mellitus, hepatic dysfunction, or photosensitivity.

Prior to initiating treatment, patients with a family history of neoplasms, or with a history of recurrent cholestasis, persistent pruritus during pregnancy, hepatic dysfunction, cardiac or renal insufficiency, fibrocystic mastopathy, epilepsy, asthma, otosclerosis, diabetes mellitus, multiple sclerosis, or systemic lupus erythematosus should be thoroughly examined.

Due to the thromboembolic and metabolic risks, which cannot be completely excluded, treatment should be discontinued if any of the following occur:

• Visual disturbances such as loss of vision, diplopia, retinal vascular lesions, proptosis, or optic disc edema;
• Venous thromboembolic or arterial thrombotic complications, regardless of the site;
• Severe headache or migraine.

In case amenorrhea occurs during treatment, pregnancy should be confirmed or excluded, as it may be the cause of amenorrhea.

More than half of early spontaneous abortions are due to genetic complications. In addition, early abortions may be caused by infectious conditions or mechanical disturbances. The only justified indication for progesterone administration in such cases is delayed expulsion of a nonviable embryo. Therefore, progesterone should be prescribed only when there is evidence of insufficient progesterone secretion, as determined by a physician.

Before initiating treatment, the patient should undergo a thorough medical and gynecological examination, including vaginal and mammological examination and a Papanicolaou smear, taking into account the patient's medical history, contraindications, and precautions. Regular medical check-ups are recommended during treatment. Women receiving hormone replacement therapy should be carefully informed about all potential risks and benefits associated with the therapy.

The physician should discuss with patients the increased risk of developing breast cancer associated with long-term hormone therapy.

Use during pregnancy or breastfeeding

Progesterone use is not contraindicated during pregnancy, including the first weeks (see section "Indications").

No adverse effects of the drug on the fetus have been observed during its use.

When the drug is used during the second and third trimesters of pregnancy, liver function should be monitored.

Excretion of progesterone into breast milk has not been thoroughly studied. Therefore, its use should be avoided during breastfeeding.

There is evidence of a possible risk of hypospadias following the use of progestogens during pregnancy for prevention of habitual abortion or threatened miscarriage due to luteal phase deficiency. Patients should be informed about this potential risk.

Ability to affect reaction rate when driving or operating machinery. Due to the possible occurrence of drowsiness and impaired concentration and attention, patients should refrain from driving or operating machinery. Dizziness, drowsiness, and impaired concentration and attention may occur in individual cases with progesterone use, and patients should be warned accordingly. Taking tablets before bedtime may help avoid these undesirable effects.

Method of Administration and Dosage.

The dosage of Lutein should be individually determined for each patient depending on the indications and therapeutic response. For patient convenience and easier dosage adjustment, Lutein vaginal tablets are available in the following strengths: 50 mg, 100 mg, and 200 mg.

Vaginal tablets should be inserted into the vagina using the applicator provided in the package. For packages without an applicator: tablets should be inserted deeply into the vagina.

Hands must be thoroughly washed before each administration to ensure no residue of soap or cleaning agent remains on the hands.

• In partial luteal phase deficiency (anovulation, menstrual cycle disorders): the daily dose is 200 mg for 10 days (typically from day 17 to day 26 of the cycle).
• In complete luteal phase deficiency [complete absence of progesterone in women with non-functioning (absent) ovaries (oocyte donation)]: the progesterone dose is 100 mg on days 13 and 14 of the transfer cycle. From day 15 to day 25 of the cycle, the progesterone dose is 200 mg, divided into two daily doses (morning and evening). Starting from day 26, in case of early pregnancy diagnosis, the dose should be gradually increased by 100 mg of progesterone per day each week, up to a maximum of 600 mg of progesterone per day in three divided doses. This dosage should be maintained until day 60.
• Luteal phase support during in vitro fertilization (IVF) cycles: treatment begins on the evening of embryo transfer, at a dosage of 600 mg per day in three divided doses (200 mg every 8 hours).
• Prevention of habitual or threatened miscarriage in luteal phase deficiency: 200–400 mg per day (100–200 mg per dose every 12 hours) up to 12 weeks of gestation.
• Prevention of preterm birth in women with a short cervix or a history of spontaneous preterm birth: the dosage is 200 mg per day, administered in the evening before bedtime from week 22 to week 36 of pregnancy.

Children. Clinical data on the use of the drug in children are lacking.

Overdose.

Overdose may manifest as symptoms of adverse reactions, including drowsiness, dizziness, euphoria, dysmenorrhea, shortened cycle duration, and metrorrhagia.

For some individuals, the standard dose may be excessive due to existing or secondary instability in endogenous progesterone secretion, increased sensitivity to the drug, or very low concurrent serum estradiol levels.

In such cases, the following measures should be taken:

• Reduce the progesterone dose or administer the dose in the evening before bedtime for 10 days of the cycle if drowsiness or transient dizziness occurs;
• Delay the start of treatment to a later point in the cycle (e.g., day 19 instead of day 17) if cycle shortening or bleeding occurs.

Adverse reactions.

During the use of Luteini, vaginal tablets containing progesterone identical to the endogenous hormone, adverse effects were observed sporadically.

In individual cases, somnolence, concentration and attention disturbances, feelings of anxiety, depressive states, headache and transient dizziness, insomnia, and increased fatigue were reported.

Reproductive system disorders: menstrual cycle changes, amenorrhea, premenstrual symptoms, intermenstrual bleeding, mastodynia, changes in libido, breast discomfort; hypersensitivity reactions including vaginal burning, hyperemia, and pruritus may occur.

Skin and subcutaneous tissue disorders: skin redness, acne; hypersensitivity reactions including urticaria, rash, pruritus; alopecia, hirsutism, anaphylactic reactions, chloasma.

Gastrointestinal disorders: nausea, gastrointestinal disturbances, vomiting, diarrhea, constipation.

Hepatobiliary disorders: cholestatic jaundice.

Vascular disorders: thrombosis, venous thromboembolism, pulmonary artery embolism.

Other disorders: fluid retention, hyperthermia.

Somnolence and/or transient dizziness are particularly observed in cases of concomitant hypoestrogenism. Reducing the dose of the drug or increasing the estrogen dose promptly resolves these symptoms without diminishing the therapeutic effect.

If treatment is initiated very early in the menstrual cycle, especially before day 15, menstrual cycle shortening or breakthrough bleeding may occur.

Other possible adverse reactions include:

urticaria, pyrexia, irregular menstruation, breast pain, body weight changes, gallbladder disorders, skin and subcutaneous disorders such as erythema multiforme, nodular erythema, and vasculitic purpura.

Shelf life. 36 months.

Storage conditions. Store below 30 °C. Keep out of reach of children.

Packaging. Vaginal tablets 100 mg: 2 blisters of 15 tablets in a cardboard box with an applicator labeled "vaginal applicator 100".

Vaginal tablets 100 mg: 2 blisters of 15 tablets in a cardboard box without an applicator.

Vaginal tablets 200 mg: 3 blisters of 10 tablets in a cardboard box with an applicator labeled "vaginal applicator 200"; 2 blisters of 10 tablets in a cardboard box with an applicator labeled "vaginal applicator 200".

Vaginal tablets 200 mg: 3 blisters of 10 tablets in a cardboard box without an applicator;
2 blisters of 10 tablets in a cardboard box without an applicator.

Prescription category. Prescription only.

Manufacturer. Adamed Pharma S.A., Poland.

Manufacturer's address and place of business.
5 Józefa Piłsudskiego Marshal Street, 95-200 Pabianice, Poland.