Zoely

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Zoely on Prescriptsy

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Zoely is a combined oral contraceptive pill (COCP) containing nomegestrol acetate 2.5 mg and estradiol 1.5 mg, manufactured by Theramex.

It is the first monophasic COCP to use estradiol (17-beta-estradiol, identical to the oestrogen produced naturally by the ovaries) instead of the synthetic ethinylestradiol found in most other combined pills.

Nomegestrol acetate is a highly selective progestogen derived from 19-norprogesterone with strong anti-gonadotrophic activity and no androgenic, oestrogenic, glucocorticoid, or mineralocorticoid effects.

Zoely uses a 24/4 regimen (24 active tablets followed by 4 placebo tablets) and is a prescription-only medicine (POM) in the United Kingdom.

Combined oral contraceptives are used by millions of women in the UK and remain one of the most effective reversible methods of contraception.

The development of estradiol-based COCPs represents a significant pharmaceutical advance, as estradiol has a more physiological metabolic profile than ethinylestradiol, with reduced effects on hepatic synthesis of coagulation factors, binding proteins, and lipoproteins.

This page provides a comprehensive clinical guide to Zoely, covering its mechanism of action, how it differs from traditional COCPs, dosage instructions, side effects, safety warnings, and how to obtain it in the United Kingdom.

Important safety information about Zoely

Before reading further, note these essential safety points about Zoely.

• All combined hormonal contraceptives carry a small increased risk of venous and arterial thromboembolism. Know the warning signs of blood clots.
• Do not take Zoely if you have a history of blood clots, stroke, heart attack, migraine with aura, or severe liver disease.
• Smoking while using Zoely significantly increases cardiovascular risk, especially in women aged 35 or over.
• Absent withdrawal bleeding is common with Zoely (approximately 20 to 25% of cycles) and does not indicate pregnancy if tablets are taken correctly.
• Acne may develop or worsen with Zoely due to its progestogen profile.

Understanding estradiol-based oral contraception

All COCPs contain an oestrogenic and a progestogenic component. The oestrogen component in most COCPs is ethinylestradiol (EE), a potent synthetic oestrogen introduced in the 1960s.

Ethinylestradiol is resistant to first-pass hepatic metabolism due to its 17-alpha-ethinyl group, resulting in high oral bioavailability and a prolonged half-life.

However, this metabolic resistance also means that ethinylestradiol has disproportionately strong effects on hepatic protein synthesis compared with endogenous estradiol.

It increases the production of coagulation factors (fibrinogen, factors II, VII, VIII, X), sex hormone-binding globulin (SHBG), cortisol-binding globulin, thyroxine-binding globulin, and angiotensinogen, and it modifies hepatic lipid metabolism.

These hepatic effects contribute to the increased risk of VTE and other metabolic effects associated with traditional COCPs.

Estradiol (17-beta-estradiol) is the principal oestrogen produced by the ovaries during reproductive life.

When administered orally, it undergoes extensive first-pass hepatic metabolism, converting primarily to the less active estrone and estrone sulphate.

This means oral estradiol has a much lower impact on hepatic protein synthesis per unit of oestrogenic activity compared with ethinylestradiol.

The challenge in using estradiol in a COCP has been achieving adequate suppression of ovulation and endometrial stability with a natural oestrogen that is rapidly metabolised.

Zoely achieves this through the combination of a potent, highly selective progestogen (nomegestrol acetate) with estradiol 1.5 mg in a 24/4 regimen (the shorter hormone-free interval further suppresses follicular development).

How Zoely works

Nomegestrol acetate 2.5 mg is the primary driver of ovulation suppression in Zoely.

It is a 19-norprogesterone derivative with the highest progestogenic selectivity of any synthetic progestogen currently available.

It binds potently to the progesterone receptor and has negligible affinity for androgen, oestrogen, glucocorticoid, or mineralocorticoid receptors.

Its strong anti-gonadotrophic effect suppresses the LH surge, preventing ovulation in virtually all cycles. Additional contraceptive mechanisms include thickening of cervical mucus and suppression of endometrial receptivity.

Estradiol 1.5 mg contributes to contraceptive efficacy by suppressing FSH and preventing follicular development. It also stabilises the endometrium, preventing unscheduled breakthrough bleeding.

The 24/4 regimen (24 active pills, 4 placebos) shortens the hormone-free interval compared with the traditional 21/7 regimen, further reducing follicular escape and improving contraceptive reliability.

The pharmacokinetic profile of nomegestrol acetate includes rapid oral absorption with peak plasma levels at approximately 2 hours, extensive protein binding (97 to 98%, primarily to albumin, not to SHBG), hepatic metabolism (by CYP3A4 and CYP3A5, and by reduction and conjugation), and a long elimination half-life of approximately 46 hours.

The long half-life contributes to a more forgiving missed-pill window (12 hours, identical to traditional COCPs).

Estradiol 1.5 mg reaches peak levels at 1 to 2 hours, is extensively metabolised on first pass, and has a half-life of approximately 3 hours for estradiol itself, though the active metabolite estrone sulphate has a much longer half-life.

Clinical evidence for Zoely

Zoely's contraceptive efficacy was demonstrated in two large phase III trials involving over 3,200 women across 13 countries.

The Pearl Index (pregnancies per 100 woman-years) was 0.38 with perfect use in women aged 18 to 35, confirming high contraceptive reliability.

In a comparative trial against drospirenone/ethinylestradiol 3 mg/0.03 mg (Yasmin), Zoely demonstrated comparable contraceptive efficacy with a more favourable metabolic profile (less increase in SHBG, less effect on coagulation parameters, and more neutral effects on lipids).

The PRO-E2 (PROgress with E2) post-authorisation safety study was a large, prospective, observational study comparing the cardiovascular safety of Zoely with established COCPs.

Preliminary data suggest that the VTE risk with Zoely is comparable to that of levonorgestrel-containing COCPs.

The reduced impact on coagulation markers (lower increases in factors VII, VIII, and fibrinogen, and smaller reductions in natural anticoagulants protein S and antithrombin) observed with estradiol-based COCPs compared with ethinylestradiol-based COCPs provides a mechanistic rationale for a potentially lower thrombotic risk, although definitive comparative outcome data are still being collected.

Zoely and bleeding patterns

Withdrawal bleeding with Zoely is typically lighter and shorter than with ethinylestradiol-containing COCPs.

In clinical trials, mean withdrawal bleeding duration was 3 to 4 days (versus 4 to 5 days with drospirenone/ethinylestradiol), and the volume was reduced.

Approximately 20 to 25% of cycles result in no withdrawal bleeding at all.

Unscheduled breakthrough bleeding or spotting during the active tablet phase occurred in approximately 15 to 20% of cycles in the first 3 months, decreasing to below 10% by cycle 6.

These patterns differ from traditional COCPs and should be discussed with patients before starting to reduce anxiety about absent periods.

Dosage and administration

Take 1 white active tablet daily for 24 days, then 1 yellow placebo tablet daily for 4 days (total 28 tablets per blister).

Start the next blister immediately after the last placebo tablet. Take at the same time each day. Start on day 1 of the menstrual period for immediate protection.

If starting on days 2 to 5, use additional barrier contraception for 7 days.

Missed pills: less than 12 hours late, take immediately, no additional contraception.

12 hours or more late: take the missed tablet immediately, use condoms for 7 days, and if fewer than 7 active tablets remain before the placebo phase, skip the placebos and start a new pack.

Missed placebo tablets can be discarded.

Side effects of Zoely

Common side effects

Acne (reported more frequently than with ethinylestradiol-containing COCPs), absent or irregular withdrawal bleeding, breast tenderness, mood changes, headache, weight gain, and decreased libido. These typically improve within the first 3 to 6 cycles.

Thromboembolism

The VTE risk with Zoely is estimated to be in the range of levonorgestrel-containing COCPs (approximately 5 to 7 per 10,000 women per year), based on available data.

Warning signs: leg swelling and pain (DVT), sudden breathlessness or chest pain (PE), sudden severe headache or visual disturbance (stroke). Call 999 immediately. Arterial events are very rare.

Other side effects

Nausea, abdominal pain, hot flushes, vaginal dryness, and migraine are uncommon.

Cholestatic jaundice, gallstones, hepatic adenoma, and changes in breast cancer risk are consistent with the COCP class as a whole.

Report suspected adverse reactions to the MHRA at yellowcard.mhra.gov.uk .

Warnings and precautions

Zoely shares all contraindications of the COCP class: current or past VTE or ATE, known thrombophilia, migraine with aura, smoking aged 35 or over, severe hepatic disease, hepatic tumours, breast cancer, and undiagnosed vaginal bleeding.

Assess VTE and ATE risk using UKMEC before prescribing. Review at least annually with blood pressure and BMI. Stop at least 4 weeks before major surgery.

Enzyme-inducing drugs reduce efficacy. Pregnancy is contraindicated. Not recommended during breastfeeding until feeding is well established.

Switching to or from Zoely

Switching from another COCP to Zoely: take the first Zoely tablet the day after taking the last active tablet from the previous pack.

No pill-free interval is needed and no additional contraception is required. Switching from a progestogen-only pill (POP): stop the POP and start Zoely the next day.

Use additional barrier contraception for the first 7 days.

Switching from an implant, injection, or intrauterine system: start Zoely on the day the implant or IUS is removed, or the day the next injection would be due.

Use additional barrier contraception for 7 days.

Switching from Zoely to another COCP: after the last active (white) Zoely tablet, skip the placebo (yellow) tablets and start the new COCP immediately.

If switching to a POP, start the POP on the day after the last active Zoely tablet and use barrier contraception for the first 2 days.

Your prescriber or sexual health clinic can provide individualised switching advice based on your specific contraceptive history and circumstances.

Zoely and common clinical scenarios

Surgery and immobilisation: stop Zoely at least 4 weeks before planned major surgery or any surgery involving prolonged immobilisation of the lower limbs.

Restart no earlier than 2 weeks after full remobilisation. If emergency surgery is needed while taking Zoely, discuss thromboprophylaxis (low-molecular-weight heparin) with the surgical team.

Air travel lasting more than 4 hours is associated with a small increased VTE risk; ensure adequate hydration and leg movement during long flights.

Gastrointestinal disturbance: if severe vomiting occurs within 3 to 4 hours of taking an active tablet, or if severe diarrhoea persists for more than 24 hours, absorption may be incomplete.

Follow the missed pill guidance (treat as a missed tablet). Consider additional barrier contraception during the illness and for 7 days after recovery.

How to get Zoely in the UK

Zoely is available on NHS prescription from your GP, sexual health clinic, or an authorised online prescriber registered with the General Pharmaceutical Council (GPhC).

All contraceptive prescriptions are free of charge on the NHS regardless of age or exemption status. Zoely is not available over the counter and requires a prescription.

Sources

• Zoely, Summary of Product Characteristics (EMC)
• Nomegestrol acetate with estradiol, British National Formulary (BNF)
• FSRH Guideline: Combined Hormonal Contraception
• UK Medical Eligibility Criteria for Contraceptive Use (UKMEC)
• Combined oral contraceptive pill, NHS
• MHRA Yellow Card Scheme