Qlaira

Qlaira Uses, Dosage, Side Effects, Food Interaction and all others data.

Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately 1/3 of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.

Dienogest acts on endometriosis by reducing the endogenous production of estradiol and thereby suppressing the trophic effects of estradiol on both the eutopic and ectopic endometrium. When given continuously, dienogest leads to a hypoestrogenic, hypergestagenic endocrine environment causing initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions. Additional properties eg, immunologic and antiangiogenic effects, seem to contribute to the inhibitory action of dienogest on cell proliferation.

Dienogest exhibits a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use . It also mediates an antiandrogenic effect that is equivalent to approximately one third that of cyproterone acetate . A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. 1mg/kg of dienogest also directly inhibits ovulation . In clinical trials composing of patients with endometriosis, dienogest therapy effectively reduced painful symptoms and endometriotic lesions associated with the disorder .Dienogest displays no antiestrogenic activity as it activate neither estrogen receptor (ER) α nor ERβ [A16570], and causes hypoestrogenic effects instead as it is shown to decrease the relative expressions of ERβ and ERα . It has no glucocorticoid or mineralocorticoid effects. In combined oral contraceptive pills (COCP) with ethinyloestradiol, dienogest conjuction therapy effectively reduces the symptoms of acne and hirsutism, as well as improving excessively heavy or prolonged menstrual bleeding .

Estradiol Valerate (also known as E2V) is a pro-drug ester of Estradiol, a naturally occurring hormone that circulates endogenously within the human body. Estradiol is the most potent form of all mammalian estrogenic steroids and acts as the major female sex hormone. As a pro-drug of estradiol, estradiol acetate therefore has the same downstream effects within the body through binding to the Estrogen Receptor (ER) including ERα and ERβ subtypes, which are located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain.

Estradiol is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter systemic circulation and exert its estrogenic effects . Esterification of estradiol aims to improves absorption and bioavailability after oral administration (such as with Estradiol valerate) or to sustain release from depot intramuscular injections (such as with Estradiol Cypionate) through improved lipophilicity. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Ester pro-drugs of estradiol are therefore considered to be bioidentical forms of estrogen .

Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.

Qlaira
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Qlaira
Generic	estradiol valerate + dienogest
Type
Therapeutic Class
Manufacturer	Bayer plc
Available Country	United Kingdom
Last Updated:	September 19, 2023 at 7:00 am

Uses

Dienoaest is used for the treatment of endometriosis.

Estradiol valerate is an estradiol prodrug used to treat some effects of menopause, hypoestrogenism, androgen dependant carcinoma of the prostate, and in combination products for endometriosis and contraception.

Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.

Qlaira is also used to associated treatment for these conditions: Hypermenorrhea, Pain, Contraception, Oral ContraceptivesHeavy Menstrual Bleeding, Hypogonadism, Menopausal Symptoms, Menopause, Menstrual Irregularities, Postmenopausal Osteoporosis, Primary Amenorrhoea, Secondary Amenorrhea, Advanced Hormone-dependent prostate cancer, Hypoestrogenism, Moderate Menopausal Vasomotor Symptoms, Moderate menopausal vulvovaginal atrophy, Severe Vasomotor Symptoms Associated With Menopause, Severe menopausal vulvovaginal atrophy, Hormone Replacement Therapy, Oral Contraceptives

How Qlaira works

Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use . It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium . Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue . It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism [A16570].

Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.

Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity.

Dosage

Qlaira dosage

Tablet-taking can be started on any day of the menstrual cycle.

The dosage of Dienogest is 2 mg daily without any break, taken preferably at the same time each day with some liquid as needed. Tablet must be taken continuously without regard to vaginal bleeding. When a pack is finished, the next one should be started without interruption.

In the event of missed tablet(s), the woman should take 2 mg only, as soon as she remembers, and should then continue the next day to take the tablet at her usual time. A tablet not absorbed due to vomiting or diarrhea should likewise be replaced by 2 mg.

Side Effects

Increased weight; depressed mood, sleep disorder, nervousness, loss of libido, altered mood; headache, migraine; nausea, abdominal pain or distension, flatulence, vomiting; acne; alopecia; back pain; breast discomfort, ovarian cyst, hot flush, uterine/vaginal bleeding including spotting; asthenic conditions, irritability.

Toxicity

Oral LD50 in mouse is 4 mg/kg . In a long-term carcinogenicity study involving rats and mice, exposure of 10 times the dose of maximum recommended clinical dose of dienogest resulted in increased incidences of pituitary adenomas, fibroepithelial mammary tumours, stromal polyps of the uterus and malignant lymphoma . These tumors are thought to arise from marked species differences in the optimal oestrogen:progestogen ratio for reproductive function. In rat liver foci assay, dienogest did not induce tumor promotion activity . Dienogest does not display genotoxic potential.

Precaution

Before starting Dienogest treatment, pregnancy must be excluded. During treatment, patients are advised to use nonhormonal methods of contraception (e.g, barrier method) if contraception is required.

As Dienogest is a progestogen-only preparation, it can be assumed that special warnings and special precautions for use of other progestogen-only preparations are also valid for the use of Dienogest .

Changes in Bleeding Pattern: Dienogest treatment affects the menstrual bleeding pattern in the majority of women.

Hepatic Impairment: Dienogest is contraindicated in patients with present or past severe hepatic disease.

Impairment of Fertility: Based on available data, ovulation is inhibited in the majority of patients during treatment with Dienogest. However, Dienogest is not a contraceptive.

If contraception is required, a nonhormonal method should be used.

Interaction

Progestogens including Dienogest are metabolized mainly by the cytochrome P450 3A4 system . Therefore, inducers or inhibitors of CYP3A4 may affect the progestogen drug metabolism. Known CYP3A4 inhibitors like azole antifungals (e.g, ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g, erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (e.g, ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g, nefazodone, fluvoxamine, fluoxetine) may increase plasma levels of progestogens and result in adverse reactions.

Volume of Distribution

The apparent volume of distribution (Vd/F) of dienogest is 40 L .

Elimination Route

Dienogest is rapidly absorbed following oral administration, with 91% bioavailability. The peak plasma concentration of 47 ng/mL is reached at about 1.5 hours after single ingestion of 2 mg . The stable concentrations of the drug are reached after two days of initial treatment .

IM Injection: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks .

Natazia: After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen.

Half Life

Elimination half-life of dienogest is around 9-10 hours. The half-life of urinary metabolites excretion is 14 hours .

Clearance

The metabolic clearance rate from serum (Cl/F) is 64 mL/min .

Elimination Route

The ratio of renal elimination to fecal elimination of dienogest is 3:1, where dienogest is predominantly excreted in the form of inactive metabolites. Most of orally administered drug is excreted in the urine within the first 24 hours of ingestion .

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Pregnancy & Breastfeeding use

Use in Pregnancy: There are limited data from the use of Dienogest in pregnant women. Animal studies and data from women exposed to Dienogest during pregnancy reveal no special risks on pregnancy, embryonic/fetal development, birth or development after birth for humans. However, Dienogest should not be administered to pregnant women because there is no need to treat endometriosis during pregnancy.

Use in Lactation: Treatment with Dienogest during lactation is not recommended. Physiochemical properties and animal data indicate excretion of Dienogest in breast milk. A decision must be made whether to discontinue breastfeeding or to abstain from Dienogest therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Contraindication

Hypersensitivity to dienogest or to any of the excipients of Dienogest. Dienogest should not be used in the presence of any of the conditions such as, Active venous thromboembolic disorder; arterial and cardiovascular disease, (e.g, myocardial infarction, cerebrovascular accident, ischemic heart disease); diabetes mellitus with vascular involvement; presence or history of severe hepatic disease as long as liver function values have not returned to normal; presence or history of liver tumors (benign or malignant); known or suspected sex hormone-dependent malignancies and undiagnosed vaginal bleeding.

Special Warning

Use in Children: Dienogest is not indicated in children prior to menarche. The safety and efficacy of Dienogest in adolescents (menarche to 18 years) has not yet been established.

Use in the Elderly: There is no relevant indication for the use of Dienogest in the geriatric population.

Acute Overdose

Acute toxicity studies performed with Dienogest did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. There is no specific antidote. Dienogest 20-30 mg/day (10-15 times higher dose than in Dinogest) over 24 weeks of use were very well tolerated.