Zuvilix Tablets 200mg

Elagolix Tablets 150 mg / 200 mg

Zuvilix 150 mg Each tablet contains :

155.2 mg of Elagolix Sodium

equivalent to Elagolix 150 mg

Colours : Titanium Dioxide IP, FD&C Red #40/, Allura Red AC, Aluminium Lake, FD&C Blue #1/, Brilliant Blue FCF, Aluminium Lake

Zuvilix 200 mg Each tablet contains :

207.0 mg of Elagolix Sodium

equivalent to Elagolix 200 mg

Colours : Titanium Dioxide IP, Ferric Oxide Red USP-NF

Tablet 150 mg/200 mg

4.1 Therapeutic indications

For the management of moderate to severe pain associated with endometriosis.

4.2 Posology and method of administration

Limitations of use

Limit the duration of use based on the dose and coexisting condition.

Important dosing information

• Exclude pregnancy before starting Zuvilix or start Zuvilix within 7 days from the onset of menses.
• Take Zuvilix at approximately the same time each day, with or without food.
• Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives.
• Limit the duration of use because of bone loss (Table 1).

Table 1. Recommended dosage and duration of use

Renal impairment

No dose adjustment of Zuvilix is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis).

Hepatic impairment

No dosage adjustment of Zuvilix is required in women with mild hepatic impairment (Child-Pugh A). Compared to women with normal liver function, those with moderate hepatic impairment had approximately 3-fold higher elagolix exposures and those with severe hepatic impairment had approximately 7-fold higher elagolix exposures. Because of these increased exposures and risk for bone loss :

• Zuvilix 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of Zuvilix 200 mg twice daily is not recommended for women with moderate hepatic impairment.
• Zuvilix is contraindicated in women with severe hepatic impairment (Child-Pugh C).

Missed dose

Instruct the patient to take a missed dose of Zuvilix on the same day as soon as she remembers and then resume the regular dosing schedule.

• 150 mg once daily : take no more than 1 tablet each day.
• 200 mg twice daily : take no more than 2 tablets each day.

4.3 Contraindications 

• Pregnant. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss.
• With known osteoporosis because of the risk of further bone loss.
• Severe hepatic impairment.
• Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake transporter) that are known or expected to significantly increase elagolix plasma concentrations.
• With known hypersensitivity reaction to elagolix or any of its inactive components. Reactions have included anaphylaxis and angioedema.

4.4 Special warnings and precautions for use

Bone loss

Elagolix causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. Elagolix is contraindicated in women with known osteoporosis. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss. Limit the duration of use to reduce the extent of bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

Change in menstrual bleeding pattern and reduced ability to recognize pregnancy

Women who take Elagolix may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected, and discontinue Elagolix if pregnancy is confirmed.

Suicidal ideation, suicidal behaviour, and exacerbation of mood disorders.

Suicidal ideation and behaviour, including one completed suicide, occurred in subjects treated with Elagolix in the endometriosis clinical trials. Elagolix subjects had a higher incidence of depression and mood changes compared to placebo, and Elagolix subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benets. Patients with new or worsening depression, anxiety or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behaviour. Re-evaluate the benets and risks of continuing Elagolix if such events occur.

Hepatic transaminase elevations

In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3- times the upper limit of the reference range occurred with Elagolix. Use the lowest effective dose of Elagolix and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks.

Interactions with hormonal contraceptives

Advise women to use effective non-hormonal contraceptives during treatment with Elagolix and for 28 days after discontinuing Elagolix. Increase in Estrogen Exposure and Potential Associated Increased Risks When Elagolix 200 mg Twice Daily is Taken with Combined Hormonal Contraceptives.

Potential for reduced efficacy of progestin-containing hormonal contraceptives

Co-administration of Elagolix 200 mg twice daily and a COC containing 0.1 mg levonorgestrel decreases the plasma concentrations of levonorgestrel by 27%, potentially affecting contraceptive efficacy. Co-administration of Elagolix with COCs containing norethindrone acetate did not show a reduction in plasma concentrations of norethindrone.

Reduced efficacy of Elagolix

Based on the mechanism of action of Elagolix, estrogen-containing contraceptives are expected to reduce the efficacy of Elagolix. The effect of progestin-only contraceptives on the efficacy of Elagolix is unknown.

4.5 Drugs interactions

Potential for Elagolix to affect other drugs

Elagolix is :

• A weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with Elagolix may decrease plasma concentrations of drugs that are substrates of CYP3A (see Table 2).
• A weak inhibitor of CYP 2C19. Co-administration with Elagolix may increase plasma concentrations of drugs that are substrates of CYP2C19 (see Table 2).
• An inhibitor of efux transporter P-glycoprotein (P-gp). Co-administration with Elagolix may increase plasma concentrations of drugs that are substrates of P-gp (see Table 2).

The effects of co-administration of Elagolix on concentrations of concomitant drugs and the clinical recommendations for these drug interactions are summarized in Table 2.

Table 2. Drug interactions : Effects of Elagolix on other drugs

Potential for other drugs to affect Elagolix

Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Concomitant use of Elagolix 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of Elagolix 150 mg once daily and strong CYP3A inhibitors to 6 months. Co-administration of Elagolix with strong CYP3A inducers may decrease Elagolix plasma concentrations and may result in a decrease of the therapeutic effects of Elagolix. Concomitant use of Elagolix 200 mg twice daily and rifampin is not recommended. Limit concomitant use of Elagolix 150 mg once daily and rifampin to 6 months. The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of Elagolix is unknown. OATP1B1 inhibitors that are known or expected to signicantly increase Elagolix plasma concentrations are contraindicated due to increased risk of Elagolix associated adverse reactions.

4.6 Use in special populations (such as pregnant women, lactating women, paediatric patients, geriatric patients etc.)

Pregnancy

Use of Elagolix is contraindicated in pregnant women. Exposure to Elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue Zuvilix if pregnancy occurs during treatment.

Lactation

There is no information on the presence of Elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. There are no adequate animal data on the excretion of Elagolix in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Elagolix and any potential adverse effects on the breastfed child from Elagolix.

Females and males of reproductive potential

Based on the mechanism of action, there is a risk of early pregnancy loss if Elagolix is administered to a pregnant woman.

Pregnancy Testing

Elagolix may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding. Exclude pregnancy before initiating treatment with Elagolix. Perform pregnancy testing if pregnancy is suspected during treatment with Elagolix and discontinue treatment if pregnancy is confirmed.

Contraception

Advise women to use effective non-hormonal contraception during treatment with Elagolix and for 28 days after discontinuing Elagolix.

Pediatric use

Safety and effectiveness of Elagolix in pediatric patients have not been established.

4.7 Effects on ability to drive and use machines

Zuvilix is unlikely to affect the ability to drive and use machines as it is not distributed in the central nervous system.

4.8 Undesirable effects

The following serious adverse reactions are reported Bone loss, change in menstrual bleeding pattern and reduced ability to recognize pregnancy, suicidal ideation, suicidal behaviour, and exacerbation of mood disorders, hepatic transaminase elevations, hot flush, headache, nausea, insomnia, anxiety, mood altered, mood swings, amenorrhea, depressed mood, depression, depressive symptoms and/or tearfulness, appendicitis, abdominal pain, back pain, arthralgia, libido, diarrhoea, abdominal pain, weight gain, dizziness, constipation, irritability

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.

5.1 Mechanism of action

Elagolix is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of Elagolix results in dosedependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

5.2 Pharmacodynamic properties

Effect on Ovulation and Estradiol In a 3-menstrual cycle study in healthy women, Elagolix 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, Elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen.

Cardiac Electrophysiology

The effect of Elagolix on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given Elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

5.3 Pharmacokinetic properties

The pharmacokinetic properties of Elagolix in healthy subjects are summarized in Table 3. Table 3. Pharmacokinetic Properties of Elagolix in Healthy Subjects

6.1 Animal toxicology or pharmacology

Carcinogenesis, mutagenesis, impairment of fertility

Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered Elagolix by the dietary route revealed no increase in tumors in mice at up to 19-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (12 to 13-fold the MRHD). The rat tumors were likely species-specic and of negligible relevance to humans. Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay. In a fertility study conducted in the rat, there was no effect of Elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 5-fold. However, because Elagolix has low afnity for the GnRH receptor in the rat and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.

Zuvilix tablets for oral administration contain elagolix sodium, the sodium salt of the active moiety elagolix. Elagolix sodium is a non-peptide small molecule GnRH receptor antagonist.

Elagolix sodium is chemically described as sodium 4-({(1R)-2-[5-(2-fluoro-3- methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6- dihydropyrimidin-1(2H)-yl]-1- phenylethyl}amino)butanoate.

Elagolix sodium has a molecular formula of C32H29F5N3O5Na and a molecular weight of 653.58

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

PVC-Alu blister strip of 10 tablets.

8.4 Storage and handling instructions

Do not store above 30°C. Protect from moisture.

Keep out of reach of children.

Bone Loss

Inform patients about the risk of bone loss. Advise patients that supplementary calcium and vitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate.

Change in Menstrual Bleeding Pattern, Contraception and Pregnancy

Advise women that Zuvilix may delay the recognition of pregnancy because it may reduce the amount, intensity, or duration of menstrual bleeding. Advise patients to use effective non-hormonal contraception while taking Zuvilix and to discontinue Zuvilix if pregnancy is confirmed. Advise pregnant women that there is a pregnancy registry that monitors outcomes in women who become pregnant while treated with Zuvilix.

Suicidal ideation, suicidal behaviour, and exacerbation of mood disorders

Advise patients that suicidal ideation and exacerbation of mood disorders may occur with Zuvilix use. Instruct patients to seek immediate medical attention for suicidal ideation and behaviour and for new onset or worsening depression, anxiety, or other mood changes.

Liver injury

Advise patients to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice.

Zuvilix missed dose instructions

Instruct a patient who miss a dose of Zuvilix to take the missed dose on the same day as soon as she remembers and then resume the regular dosing schedule :

• 150 mg once daily : no more than 1 tablet each day should be taken.
• 200 mg twice daily : no more than 2 tablets each day should be taken.

5/MN/TS/2014/F/G dated 16 November 2024

16 January 2025