Letrozol Accord
Aromatase Inhibitor for Hormone Receptor-Positive Breast Cancer
Quick Facts About Letrozol Accord
Key Takeaways About Letrozol Accord
- Highly effective hormonal therapy: Letrozole reduces oestrogen levels by approximately 98%, significantly reducing breast cancer recurrence in postmenopausal women with hormone receptor-positive tumours
- Once-daily dosing: Taken as a single 2.5 mg tablet once daily with or without food, making adherence straightforward
- Postmenopausal women only: Letrozol Accord must only be used in women who have completed menopause – it is not suitable for premenopausal women
- Bone health monitoring essential: Letrozole can reduce bone mineral density and increase fracture risk, so bone density should be assessed regularly during treatment
- Long-term treatment: Treatment typically lasts 5 years or longer as adjuvant therapy, or continues as long as the cancer responds in advanced disease
What Is Letrozol Accord and What Is It Used For?
Letrozol Accord contains letrozole, a potent aromatase inhibitor used to treat hormone receptor-positive breast cancer in women who have gone through menopause. It works by blocking the enzyme aromatase, which dramatically reduces oestrogen levels in the body and starves oestrogen-dependent breast cancer cells of the fuel they need to grow.
Letrozole belongs to a class of medicines called aromatase inhibitors, which are a form of hormonal (endocrine) therapy for breast cancer. In postmenopausal women, the main source of oestrogen is the conversion of androgens (male hormones produced by the adrenal glands) into oestrogen by an enzyme called aromatase. This conversion takes place primarily in peripheral tissues such as fat, muscle, and the breast itself. By selectively and potently inhibiting aromatase, letrozole reduces circulating oestrogen levels by approximately 98% compared to baseline, effectively depriving hormone receptor-positive breast cancer cells of the oestrogen signal that stimulates their growth.
Letrozol Accord is a third-generation non-steroidal aromatase inhibitor. The term “third-generation” signifies that it is among the most refined and selective drugs in this class, offering superior oestrogen suppression with fewer side effects compared to earlier agents. Letrozole was first approved for clinical use in the late 1990s and has since become one of the cornerstone treatments in the management of hormone receptor-positive breast cancer, supported by extensive clinical trial data including the landmark BIG 1-98 and MA.17 trials.
Clinical Indications
Letrozol Accord is indicated for the treatment of breast cancer in postmenopausal women in several clinical settings:
- Adjuvant therapy: After breast cancer surgery, letrozole is used to reduce the risk of the cancer coming back. The BIG 1-98 trial demonstrated that letrozole as initial adjuvant therapy was superior to tamoxifen in reducing the risk of recurrence, particularly distant metastases, in postmenopausal women with hormone receptor-positive early breast cancer.
- Extended adjuvant therapy: After completing approximately five years of adjuvant tamoxifen therapy, switching to letrozole for an additional period has been shown to significantly reduce the risk of recurrence. The MA.17 trial showed a 42% relative reduction in the risk of recurrence when women switched to letrozole after five years of tamoxifen.
- First-line treatment of advanced breast cancer: In women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer, letrozole is used as a primary treatment to control disease progression.
- Neoadjuvant therapy: When immediate surgery is not appropriate, letrozole may be used before surgery to shrink the tumour, potentially allowing for less extensive surgery (breast-conserving surgery instead of mastectomy).
Letrozole is included in the World Health Organization’s Model List of Essential Medicines, recognising its importance in global cancer treatment. Multiple generic formulations, including Letrozol Accord, are available worldwide, making this essential cancer treatment accessible and affordable. It is one of the most commonly prescribed endocrine therapies for breast cancer globally.
What Should You Know Before Taking Letrozol Accord?
Before starting Letrozol Accord, it is essential to confirm that you have completed menopause. This medication must not be taken during pregnancy or while breastfeeding. Tell your doctor if you have severe kidney or liver disease, osteoporosis, or a history of bone fractures.
Your oncologist will carefully evaluate whether Letrozol Accord is the right treatment for you based on the characteristics of your breast cancer, your menopausal status, your overall health, and any other medical conditions you may have. The following information will help you understand the important precautions associated with this medication.
Contraindications
You must not take Letrozol Accord if any of the following apply to you:
- Allergy to letrozole or any of the other ingredients in the tablet (lactose monohydrate, maize starch, hypromellose, sodium starch glycolate, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, titanium dioxide, yellow iron oxide, macrogol 400, talc)
- Premenopausal status: If you still have menstrual periods, even irregular ones, you must not use this medication. Letrozole is designed only for women who have completed menopause
- Pregnancy: Letrozole can cause serious harm to an unborn baby and must not be used during pregnancy
- Breastfeeding: It is not known whether letrozole passes into breast milk. You must not breastfeed while taking this medication
Warnings and Precautions
Talk to your doctor or pharmacist before taking Letrozol Accord if you have any of the following conditions, as they may require special monitoring or dose adjustments:
- Severe kidney disease: Although letrozole is primarily metabolised by the liver, patients with severe renal impairment (creatinine clearance less than 10 mL/min) have not been studied extensively and require careful monitoring
- Severe liver disease: Letrozole is metabolised by the liver enzymes CYP3A4 and CYP2A6. Severe hepatic impairment can significantly increase blood levels of the drug, potentially increasing the risk of side effects
- Osteoporosis or history of fractures: Letrozole reduces oestrogen levels, which can accelerate bone loss. If you already have osteoporosis or a history of fractures, your doctor will assess your bone health before starting treatment and monitor it regularly throughout
- Tendon disorders: Letrozole may cause inflammation of tendons (tendinitis) or, rarely, tendon rupture. If you experience tendon pain, swelling, or stiffness, rest the affected area and contact your doctor promptly
Although Letrozol Accord is intended for postmenopausal women, your doctor should discuss the use of effective contraception with you, as some women may still be able to conceive during treatment. If you think you may have become pregnant, stop taking the medication immediately and contact your doctor.
Children, Adolescents, and Elderly Patients
Children and adolescents (under 18 years): Letrozol Accord must not be used in children or adolescents. It has not been shown to be safe or effective in this age group, and it is not indicated for any condition in paediatric patients.
Elderly patients (65 years and older): No dose adjustment is required for elderly patients. Letrozol Accord can be used at the same 2.5 mg daily dose as in younger postmenopausal adults. Clinical trials have included substantial numbers of elderly patients, and no overall differences in safety or efficacy have been observed compared to younger adults.
Pregnancy and Breastfeeding
Letrozol Accord is strictly contraindicated during pregnancy. Animal studies have shown that letrozole can cause foetal harm, including malformations and embryo-foetal death at therapeutic doses. Although Letrozol Accord is intended for postmenopausal women who are unlikely to become pregnant, your doctor may recommend using a reliable form of contraception during treatment as a precautionary measure, because in rare cases ovarian function may not be completely absent.
If you discover that you are pregnant while taking Letrozol Accord, stop the medication immediately and contact your oncologist. You should also inform your doctor if you are breastfeeding, as it is not known whether letrozole is excreted in human breast milk, and breastfeeding is therefore not recommended during treatment.
Driving and Operating Machinery
Letrozole can occasionally cause dizziness, fatigue, drowsiness, or a general feeling of being unwell. If you experience any of these effects, you should not drive or operate machinery until the symptoms have resolved. You are responsible for assessing whether you are fit to drive or perform tasks requiring alertness. Read all the information in this guide for guidance, and discuss with your doctor or pharmacist if you are uncertain.
Important Information About Ingredients
Lactose: Letrozol Accord tablets contain lactose monohydrate. If you have been told by your doctor that you have an intolerance to certain sugars, contact your doctor before taking this medicine.
Sodium: This medicine contains less than 1 mmol (23 mg) of sodium per tablet, meaning it is essentially sodium-free.
How Does Letrozol Accord Interact with Other Drugs?
Letrozole has relatively few clinically significant drug interactions compared to many other cancer treatments. However, it should not be taken with tamoxifen or oestrogen-containing preparations, as these can reduce its effectiveness. Always inform your doctor about all medications you are taking, including over-the-counter products and herbal supplements.
Letrozole is primarily metabolised by the liver enzymes CYP3A4 and CYP2A6. In principle, drugs that significantly inhibit or induce these enzymes could alter letrozole blood levels. However, in clinical practice, the most important interactions are pharmacodynamic rather than pharmacokinetic – meaning they relate to conflicting mechanisms of action rather than changes in drug metabolism.
Major Interactions
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Tamoxifen | SERM (anti-oestrogen) | Tamoxifen can reduce letrozole blood levels and may counteract its oestrogen-lowering effect | Do not use concurrently; sequential use is acceptable (e.g., tamoxifen followed by letrozole) |
| Oestrogen-containing preparations | Hormone replacement therapy (HRT), oral contraceptives | Directly opposes the mechanism of action of letrozole by reintroducing oestrogen | Strictly avoid all oestrogen-containing products during letrozole treatment |
Other Interactions to Be Aware Of
| Drug | Category | Effect | Recommendation |
|---|---|---|---|
| Strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) | Antifungals, HIV treatment | May potentially increase letrozole blood levels, although clinical significance appears limited | Monitor for increased side effects; inform your oncologist |
| Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine) | Antibiotics, anti-epileptics | May decrease letrozole blood levels, potentially reducing efficacy | Inform your oncologist; alternative treatments may be considered |
| NSAIDs (ibuprofen, naproxen) | Pain relievers | No direct pharmacokinetic interaction, but may be used to manage letrozole-related joint pain | Can be used as needed; discuss with your doctor if using regularly |
| Bisphosphonates (alendronate, zoledronic acid) | Bone-protective agents | No interaction; often co-prescribed to counteract letrozole-induced bone loss | Commonly recommended alongside letrozole to protect bone health |
It is important to tell your doctor or pharmacist about all medicines you are taking, have recently taken, or might take in the future. This includes prescription medicines, over-the-counter preparations, vitamins, and herbal products. Your oncologist can then assess whether any adjustments to your treatment plan are necessary.
What Is the Correct Dosage of Letrozol Accord?
The standard dose of Letrozol Accord is one 2.5 mg tablet taken by mouth once daily. The tablet can be taken with or without food and should be swallowed whole with a glass of water. Take it at the same time each day to maintain consistent blood levels.
Always take this medicine exactly as your doctor or pharmacist has told you. Do not change the dose or stop taking the medication without consulting your oncologist, even if you feel well. Letrozole works by maintaining continuously suppressed oestrogen levels, so consistent daily dosing is essential for optimal effectiveness.
Adults (Postmenopausal Women)
Standard Dosing
Dose: 2.5 mg once daily
Administration: Oral, with or without food
How to take: Swallow the tablet whole with a glass of water or another drink. Try to take it at the same time each day.
Duration of Treatment
The duration of treatment with Letrozol Accord varies depending on the clinical setting and your individual response to therapy:
- Adjuvant therapy (after surgery): Typically 5 years. Some patients may benefit from extended treatment beyond 5 years, as determined by the oncologist based on individual risk factors and tolerance
- Extended adjuvant therapy (after tamoxifen): Usually continued for an additional 5 years after completing tamoxifen, for a total of approximately 10 years of endocrine therapy
- Advanced or metastatic breast cancer: Treatment continues for as long as the tumour responds and the patient tolerates the medication. Disease progression is monitored regularly through clinical assessments and imaging
- Neoadjuvant therapy (before surgery): Typically 4 to 8 months, until maximum tumour shrinkage is achieved as assessed by your surgical team
Children
Letrozol Accord is not indicated for use in children or adolescents under 18 years of age. There is no relevant use of letrozole in the paediatric population for the approved indications.
Elderly Patients
No dose adjustment is required for patients aged 65 years and older. The same 2.5 mg once-daily dose is recommended. In clinical trials, elderly patients were well-represented and showed comparable efficacy and safety profiles to younger patients.
Patients with Kidney or Liver Impairment
No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance above 30 mL/min). For patients with severe renal impairment, data are limited, and close monitoring is advised. Patients with severe liver impairment require careful monitoring as letrozole plasma levels may be increased, though specific dose adjustments have not been formally established.
Missed Dose
If you forget to take a dose and it is close to the time of your next scheduled dose (within 2–3 hours), skip the missed dose and take your next dose at the usual time. If there are more than a few hours until your next dose, take the missed dose as soon as you remember, then resume your normal schedule. Do not take a double dose to make up for a forgotten dose.
Overdose
If you have taken more Letrozol Accord tablets than prescribed, or if someone else has accidentally taken your tablets, contact your doctor, hospital emergency department, or poison control centre immediately. Show them the tablet packaging. An overdose may require medical monitoring and supportive treatment. There is no specific antidote for letrozole overdose.
Your doctor will schedule regular check-ups to monitor the effectiveness of your treatment and watch for potential side effects. Letrozol Accord can cause bone loss (osteoporosis) due to the reduction of oestrogen in the body. Your doctor may measure your bone mineral density before, during, and after treatment. If significant bone loss is detected, treatment with bone-protective medications such as bisphosphonates, calcium, and vitamin D supplements may be recommended.
Stopping Treatment
Do not stop taking Letrozol Accord unless your doctor tells you to do so. Even if you feel well, the medication is working to prevent cancer recurrence by continuously suppressing oestrogen levels. Stopping treatment prematurely may increase the risk of cancer recurrence. If you have concerns about side effects or the duration of treatment, discuss these openly with your oncologist, who can help you weigh the benefits and risks of continuing therapy.
What Are the Side Effects of Letrozol Accord?
Like all medicines, Letrozol Accord can cause side effects, although not everyone experiences them. Most side effects are mild to moderate and are largely caused by the reduction in oestrogen levels. The most common effects include hot flushes, increased cholesterol, fatigue, sweating, and joint pain.
The following side effects have been reported with letrozole. They are organised by frequency to help you understand how likely each one is. If you experience any severe or persistent side effects, or any symptoms not listed here, contact your doctor immediately.
Very Common
May affect more than 1 in 10 patients
- Hot flushes (vasomotor symptoms)
- Increased cholesterol levels (hypercholesterolaemia)
- Fatigue and tiredness
- Increased sweating (hyperhidrosis)
- Bone and joint pain (arthralgia)
Common
May affect up to 1 in 10 patients
- Skin rash
- Headache
- Dizziness
- General feeling of being unwell (malaise)
- Gastrointestinal complaints: nausea, vomiting, indigestion, constipation, diarrhoea
- Increased or decreased appetite
- Muscle pain (myalgia)
- Osteoporosis, sometimes leading to fractures
- Swelling of arms, hands, feet, or ankles (oedema)
- Depression
- Weight gain
- Hair loss (alopecia)
- High blood pressure (hypertension)
- Abdominal pain
- Dry skin
- Vaginal bleeding
- Palpitations, rapid heart rate
- Joint stiffness (arthritis)
- Chest pain (non-cardiac)
Uncommon
May affect up to 1 in 100 patients
- Nervous conditions: anxiety, irritability, drowsiness, memory problems, insomnia
- Pain or burning sensation in hands or wrists (carpal tunnel syndrome)
- Reduced sensation, especially sensitivity to touch
- Eye complaints: blurred vision, eye irritation
- Skin problems such as itching (urticaria)
- Vaginal discharge and dryness
- Breast pain
- Fever
- Thirst, taste changes, dry mouth
- Dry mucous membranes
- Weight loss
- Urinary tract infection, increased frequency of urination
- Cough
- Elevated liver enzymes
- Yellowing of skin or eyes (jaundice)
- Elevated blood bilirubin levels
- Tendon inflammation (tendinitis)
- Stroke (weakness, paralysis, loss of sensation, speech or breathing difficulties)
- Sudden chest pain (signs of cardiac events)
- Swelling and redness along a vein (thrombophlebitis)
- Severe, persistent blurred vision
Rare
May affect up to 1 in 1,000 patients
- Breathing difficulties, chest pain, fainting, increased heart rate, bluish skin discoloration, or sudden pain in arm, leg, or foot (signs of blood clot / pulmonary embolism)
- Tendon rupture
- Severe allergic reactions: swelling of face and throat
- Hepatitis: yellowed skin, nausea, decreased appetite, dark urine
- Severe skin reactions: rash, blisters on lips, eyes, or mouth, skin peeling, fever
- Trigger finger (a condition where a finger locks in a bent position)
Contact your doctor or go to the emergency department immediately if you experience: sudden weakness or numbness in one side of the body; difficulty speaking or understanding speech; sudden severe headache; sudden chest pain or difficulty breathing; swelling of the face, lips, tongue, or throat; severe skin reactions with blistering; or signs of a blood clot (sudden pain, swelling, or discoloration in a limb).
Many of these side effects are directly related to the reduction in oestrogen caused by letrozole. Hot flushes, joint pain, and bone loss are among the most commonly reported effects and are typically manageable with supportive measures. Your oncologist can recommend strategies to help you cope with these effects, including exercise programmes for joint stiffness, calcium and vitamin D supplementation for bone health, and lifestyle modifications for hot flushes.
If you experience any side effects not listed in this guide, or if any of the listed side effects become severe, talk to your doctor, pharmacist, or nurse. Reporting side effects helps to continuously monitor the benefit-risk balance of this medication.
How Should You Store Letrozol Accord?
Store Letrozol Accord out of the sight and reach of children. Do not use the tablets after the expiry date printed on the packaging. No special storage conditions are required – store at room temperature in the original packaging.
Keep the following storage guidelines in mind to ensure your medication remains safe and effective:
- Keep out of reach of children: Store the medication in a safe place where children cannot access it
- Check the expiry date: Do not use Letrozol Accord after the expiry date (marked “EXP”) on the carton or blister pack. The expiry date refers to the last day of that month
- Do not use damaged packaging: If the packaging appears damaged or tampered with, do not use the tablets and return them to your pharmacy
- Disposal: Do not throw unused tablets into household waste or flush them down the toilet. Ask your pharmacist about proper disposal methods for medicines you no longer need. These measures help protect the environment
What Does Letrozol Accord Contain?
Each Letrozol Accord 2.5 mg film-coated tablet contains 2.5 mg of letrozole as the active substance, along with several inactive ingredients that form the tablet core and film coating.
Active Substance
Each film-coated tablet contains 2.5 mg letrozole. Letrozole is a non-steroidal aromatase inhibitor with the chemical formula C17H11N5 and a molecular weight of 285.31 g/mol.
Inactive Ingredients (Excipients)
Tablet core: Lactose monohydrate, maize starch, hypromellos (E464), sodium starch glycolate, microcrystalline cellulose (E460), colloidal anhydrous silica (E551), magnesium stearate (E572).
Film coating: Hypromellos (E464), titanium dioxide (E171), yellow iron oxide (E172), macrogol 400, talc (E553b).
Appearance and Pack Sizes
Letrozol Accord 2.5 mg tablets are yellow, round, biconvex, film-coated tablets, unmarked on both sides. They are available in blister packs of 10, 14, 28, 30, 50, 60, 84, 90, 98, and 100 tablets. Not all pack sizes may be marketed in your country.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder: Accord Healthcare B.V., Winthontlaan 200, 3526 KV Utrecht, Netherlands.
Manufacturers: Accord Healthcare B.V. (Utrecht, Netherlands); Accord Healthcare Polska Sp.z o.o. (Pabianice, Poland); Accord Healthcare Single Member S.A. (Greece).
Frequently Asked Questions About Letrozol Accord
Letrozol Accord is a generic formulation of letrozole that contains the same active substance (letrozole 2.5 mg) in the same dose as the original brand-name product. Generic medicines are required to demonstrate bioequivalence to the originator product, meaning they are absorbed into the body at the same rate and to the same extent. The European Medicines Agency (EMA) applies strict standards to approve generic medicines, so you can be confident that Letrozol Accord provides the same therapeutic effect as brand-name letrozole.
Yes, Letrozol Accord can be taken with or without food. Food does not significantly affect the absorption of letrozole. The most important thing is to take the tablet at the same time each day to maintain consistent blood levels of the medication. Swallow the tablet whole with a glass of water or another drink.
The duration of treatment depends on your specific clinical situation. As adjuvant therapy after breast cancer surgery, letrozole is typically taken for 5 years. If you have previously taken tamoxifen for 5 years, your doctor may recommend switching to letrozole for an additional period (extended adjuvant therapy). For advanced or metastatic breast cancer, treatment continues for as long as the cancer responds and you tolerate the medication. Your oncologist will determine the optimal treatment duration based on your individual circumstances.
Letrozole can reduce bone mineral density because it significantly lowers oestrogen levels, which play an important role in maintaining bone strength. This can increase the risk of osteoporosis and fractures over time. However, this risk can be managed effectively. Your doctor should monitor your bone density before, during, and after treatment. Calcium and vitamin D supplements are commonly recommended, and if significant bone loss is detected, your doctor may prescribe bisphosphonates or other bone-protective medications. Regular weight-bearing exercise also helps maintain bone health.
Joint pain (arthralgia) and stiffness are among the most common side effects of letrozole, affecting many patients. Several strategies can help manage this: regular physical activity, including both aerobic exercise and strength training, has been shown in clinical studies to significantly reduce letrozole-related joint symptoms. Over-the-counter pain relievers such as paracetamol or ibuprofen may help. Maintaining a healthy weight also reduces stress on the joints. If joint pain becomes severe or significantly affects your quality of life, speak with your oncologist – they may adjust your treatment plan or refer you for specialist management.
In postmenopausal women with hormone receptor-positive breast cancer, clinical trials (notably the BIG 1-98 trial) have shown that letrozole as initial adjuvant therapy is superior to tamoxifen in reducing the risk of cancer recurrence, particularly distant metastases. However, both medications have different side effect profiles. Tamoxifen remains the preferred choice for premenopausal women. The choice between letrozole and tamoxifen depends on your menopausal status, individual risk factors, and other medical conditions. Your oncologist will recommend the best option for you based on the latest clinical evidence and guidelines from organisations such as ESMO and ASCO.
References
This article is based on the following peer-reviewed sources and international clinical guidelines:
- European Medicines Agency (EMA). Letrozole Summary of Product Characteristics. Available at: www.ema.europa.eu
- BIG 1-98 Collaborative Group. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. New England Journal of Medicine. 2009;361(8):766-776. DOI: 10.1056/NEJMoa0810818
- Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. Journal of the National Cancer Institute. 2005;97(17):1262-1271.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis. Lancet Oncology. 2022;23(3):382-392.
- ESMO Clinical Practice Guidelines. Early Breast Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2024.
- ASCO (American Society of Clinical Oncology). Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. Journal of Clinical Oncology. 2024.
- World Health Organization. WHO Model List of Essential Medicines – 23rd List (2023). Geneva: World Health Organization; 2023.
- National Institute for Health and Care Excellence (NICE). Early and locally advanced breast cancer: diagnosis and management (NG101). Updated 2023.
- Coleman RE, et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Annals of Oncology. 2020;31(12):1650-1663.
- British National Formulary (BNF). Letrozole. Available at: bnf.nice.org.uk
About the Medical Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, which includes board-certified specialists in oncology, clinical pharmacology, and internal medicine. Our content follows the GRADE evidence framework and adheres to international guidelines from ESMO, ASCO, NICE, and WHO.
Every article undergoes rigorous peer review by licensed physicians. Medical claims are verified against current clinical guidelines and peer-reviewed literature. Content is updated when new evidence or guideline changes emerge.
iMedic operates with complete editorial independence and no commercial funding. We accept no pharmaceutical company sponsorship or advertising. Our sole commitment is to provide accurate, evidence-based medical information to patients and caregivers.
Last reviewed: | Evidence level: 1A (systematic reviews and meta-analyses of RCTs) | Next review due: