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 50 mg of progesterone;

Excipients: lactose monohydrate; corn starch; citric acid monohydrate; hydroxypropylmethylcellulose; magnesium stearate.

Pharmaceutical form. Vaginal tablets.

Main physicochemical characteristics: white, biconvex, uncoated tablets, 9 mm in diameter, with a dividing line on one side.

Pharmacotherapeutic group. Sex hormones and drugs used in pathologies of the reproductive system. ATC code G03DA04.

Pharmacological Properties

Pharmacodynamics

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

Pharmacokinetics

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

Plasma progesterone levels begin to rise within the first hour, with peak concentrations in blood plasma achieved within 1–3 hours after administration.

With a daily dose of 100 mg of progesterone, Luteina enables achieving and maintaining a physiological and stable plasma progesterone level (averaging 9.7 ng/mL), similar to levels observed during the luteal phase of a menstrual cycle with normal ovulation. Thus, Luteina promotes adequate endometrial maturation and supports embryo implantation.

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

Metabolism

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

Clinical characteristics.

Indications.

Reduction of fertility in primary or secondary infertility due to partial or complete luteal phase deficiency (anovulation, luteal phase support during preparation for in vitro fertilization, oocyte donation programs). Prevention of habitual or threatened miscarriage in luteal phase deficiency. Prevention of preterm birth in women with a short cervix or with a history of spontaneous preterm birth. Inability or limitation of oral administration of the drug.

Contraindications.

Hypersensitivity to the components 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. Intracerebral 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 the metabolism of progesterone. The clinical significance of this effect is unknown.

Antisteroid drugs. Aminoglutethimide markedly reduces plasma concentrations of medroxyprogesterone acetate and megesterol, possibly due to hepatic enzyme-inducing effects.

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

Progesterone antagonizes the anticoagulant effect of phenindione.

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

Diazepam. Progesterone may increase the plasma concentration of diazepam.

Tizanidine. Progesterone may increase the plasma concentration of tizanidine.

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

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

Administration of high doses of progesterone may temporarily increase the excretion of sodium and chloride from the body.

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

The use of progesterone may increase the plasma concentration of cyclosporine. Some antibiotics (e.g., ampicillins, tetracyclines) may cause changes in intestinal microflora, resulting in alterations of the enterohepatic steroid cycle.

Potent inducers of liver enzymes, 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 strong inhibitors of cytochrome enzymes, exhibit enzyme-inducing properties when used concomitantly with steroid hormones.

Special precautions.

Use within 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.

Do not administer the drug in cases of uterine bleeding until the cause has been established, including endometrial examination.

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

Prior to prescribing the drug, carefully examine patients with a family history of neoplasms, recurrent cholestasis or persistent pruritus during pregnancy, hepatic dysfunction, cardiac or renal failure, fibrocystic mastopathy, epilepsy, asthma, otosclerosis, diabetes mellitus, multiple sclerosis, or systemic lupus erythematosus.

Due to the thromboembolic and metabolic risks, which cannot be completely excluded, discontinue the drug if any of the following occur:

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

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

More than half of early spontaneous abortions are caused by genetic abnormalities. In addition, early abortions may also result from infectious manifestations 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 by a physician only when progesterone secretion is insufficient.

Prior to initiating treatment, the patient should undergo a thorough medical and gynecological examination, including vaginal and mammographic examination and Pap smear, taking into account the patient's history, contraindications, and precautions. Regular physician check-ups are recommended during treatment. Women receiving hormone replacement therapy should carefully consider all associated risks and benefits of 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").

During the period of drug use, no adverse effects of the drug on the fetus have been observed.

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 with the use of progestogens during pregnancy for the prevention of habitual or threatened miscarriage due to luteal phase deficiency; patients should be informed of this potential risk.

Ability to affect reaction speed when driving or operating machinery.
Due to the possible occurrence of drowsiness and impaired concentration and attention, patients should refrain from driving vehicles or operating machinery. When progesterone is used, dizziness, drowsiness, and impaired concentration and attention may occur in isolated cases, about which the patient should be warned. Administering the tablets before bedtime may help avoid these adverse effects.

Method of Administration and Dosage

The dosage of Lutein should be individually determined in each case depending on the indications and therapeutic response. For patient convenience and ease of dose 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, the 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 (usually 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 per day, divided into two 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, administered in three divided doses, up to a maximum of 600 mg per day. This dosage should be maintained until day 60.
• Luteal phase support during in vitro fertilization (IVF) cycles: treatment should begin 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 recurrent miscarriage or threatened spontaneous abortion due to luteal insufficiency: 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: 200 mg per day administered in the evening before bedtime from week 22 to week 36 of gestation.

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.

In 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 concomitant serum estradiol levels.

In such cases, the following measures should be taken:

• reduce the progesterone dose or administer progesterone in the evening before bedtime for 10 days per cycle in cases of drowsiness or transient dizziness;
• 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.

Side effects

When using Lutein, vaginal tablets containing progesterone identical to the endogenous hormone, adverse effects were observed sporadically.

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

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

Skin and subcutaneous tissue disorders: skin redness, acne; hypersensitivity reactions including urticaria, rash, itching; 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 eliminates these symptoms without reducing the therapeutic effect.

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

Other possible adverse reactions include: urticaria, pyrexia, irregular menstruation, breast pain, weight changes, gallbladder disorders, and skin and subcutaneous tissue disorders such as erythema multiforme, nodular erythema, and vasculitic purpura.

Shelf life: 2 years.

Storage conditions: Store at a temperature not exceeding +25 °C, in a dry, light-protected place, out of reach of children.

Packaging: 15 tablets per blister pack, 2 blisters per cardboard box.

Prescription category: Prescription only.

Manufacturer: Adamed Pharma S.A., Poland.

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