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The World Health Organisation (WHO), last week, welcomed initial clinical trial results from the United Kingdom (UK) that showed dexamethasone, a corticosteroid, can help patients who are critically ill with coronavirus (COVID-19).

Scientists are in a race to find a cure or vaccine for the disease. While many drug trials are still ongoing, preliminary study using dexamethasone, has shown potential for treatment of critically ill COVID-19 patients.

The preliminary findings of the study showed that treatment using the drug reduced mortality by about one third for patients on ventilators, and by about one-fifth for patients requiring only oxygen.

According to WHO, the benefit was only seen in patients seriously ill with COVID-19, and was not observed in patients with milder conditions.

WHO on Thursday answered some questions on the drug and its future for COVID-19 treatment.

Excerpts

What is dexamethasone and does it work AGAINST COVID-19?

Dexamethasone is a corticosteroid used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects.

It was tested in hospitalised patients with COVID-19 in the United Kingdom’s national clinical trial RECOVERY and was found to have benefits for critically ill patients.

According to preliminary findings shared with WHO (and now available as a preprint), for patients on ventilators, the treatment was shown to reduce mortality by about one third, and for patients requiring only oxygen, mortality was cut by about one fifth.

Question: Were all patients in recovery given dexamethasone?

Answer: Eligible patients were randomly allocated between several treatment arms. Dexamethasone was administered as an oral (liquid or tablets) or intravenous preparation, at a dose of 6 mg once daily for ten days, in one of the arms.

In pregnancy or breastfeeding women, patients were randomized to prednisolone (a milder corticosteroid) 40 mg administered by mouth.

Question: Does WHO recommend the use of Dexamethasone for COVID-19 patients?

Answer: WHO is in the process of updating treatment guidelines to include dexamethasone or other steroids.

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Question: is dexamethasone on the WHO Essential Medicine List?

Answer: Yes, dexamethasone has been on the WHO Model List of Essential Medicines (EML) since 1977 for several indications in multiple formulations. Since 2013, dexamethasone (Injectable formulation) has been indicated for respiratory distress syndrome in new-borns. Prednisolone is also on the EML and was included in 1984.

Dexamethasone and prednisolone are included on the EML for the following indications:

– allergic or hypersensitivity conditions, without further specifying the type

– pain and oedema due to malignancy in palliative care

– nausea and vomiting,

– as part of treatment protocols for some blood tissue cancers.

These indications are broad and can also include cytokine-related lung injury and as prevention or treatment of acute respiratory distress syndrome (ARDS) associated with severe acute respiratory infections (i.e. viral pneumonia). Both medicines are also recommended in children.

Question: is dexamethasone prequalified by WHO?

Answer : Yes, dexamethasone solution for injection 4mg/ml in 1ml ampoules, manufactured by Kern Pharma SL, Spain, has been prequalified for its use in the management of diseases associated with HIV/AIDS, but not for COVID-19.

Another dexamethasone injection product is currently under assessment.

Manufacturers interested in prequalifying their product can contact the Prequalification Team at prequal@who.int for further information.

Question: what dose was used in the recovery trial?

Answer: Dexamethasone was used in the Recovery Trial in oral (liquid or tablets) or intravenous preparation 6 mg once daily for ten days.

In pregnancy or breastfeeding women, prednisolone 40 mg administered by mouth (or intravenous hydrocortisone 80 mg twice daily) should be used instead of dexamethasone.

Note: It is permitted to switch between the two routes of administration according to clinical circumstances.

Source: Page 9 of 35 RECOVERY [V6.0 2020-05-14] ISRCTN50189673 EudraCT 2020-001113-21

Question: What are the typical side effects of dexamethasone?

Answer: Dexamethasone is generally safe. It presents a favourable benefit-risk profile, particularly in patients with severe forms of pneumonia, while the benefit is less prominent in patients with non-severe pneumonia. As the treatment is short, even at high doses, corticosteroids are not associated with serious side effects. Potentially higher blood glucose levels (hyperglycaemia) are temporary.

Prolonged use (I.e., used for more than two weeks) may be associated with adverse events such as glaucoma, cataract, fluid retention, hypertension, psychological effects (e.g., mood swings, memory issues, confusion or irritation), weight gain, or increased risk of infections and osteoporosis.

To reiterate: All these adverse events are not associated with short term use (with the exception of hyperglycaemia that can worsen diabetes).

Question: How do the dose used in recovery trial compare with those used normally?

Answer: The Recovery trial used dexamethasone 6mg daily oral or intravenous for ten days. Higher daily doses of dexamethasone have been used for other indications for a long time and are known to be safe.

Question: Can steroid be used in elderly/ children and pregnancy?

Answer: They can be used in children and the elderly. In pregnancy, the Recovery trial used prednisolone orally or hydrocortisone by intravenous infusion instead of dexamethasone. Steroids are ubiquitous in terms of geographic use.

Question: is dexamethasone available across the world?

Answer: Yes. Dexamethasone is off-patent and has been marketed in different formulations (e.g., tablets, liquid, solution for injection) for many years. It is generally available in most countries. There are several manufacturers of the product. One manufacturer has already been prequalified by WHO (Kern Pharma in Spain) while another is under assessment.

The most common formulations are:

Tablets: 0.5mg, 0.75mg, 1mg, 1.5mg, 2mg, 4mg and 6mg

Oral Solution: 0.5mg/5ml, 20mg/5ml and 1mg/ml (concentrate)

Injectable suspension: 4mg/ml, 20mg/5ml

In recent years there have been occasional reports of shortages of this product. It is important to quickly understand the projected volumes for COVID-19 utilization and manufacturing capacity to help assess the impact for existing indications and the potential need for substitute therapies, to ensure all patients retain access to a safe, effective, quality, affordable product to meet their therapeutic needs.

Question: How many API (Active Pharmaceutical Ingredients (API)) suppliers are there?

Answer: There are many manufacturers of Active Pharmaceutical Ingredients (API) around the world, ensuring a large and diversified capacity of production for this product. So far, we have identified ten potentially quality approved suppliers from Asia, North America, and Europe.

Question: Is dexamethasone affordable/ what is the price per treatment?

Answer : Dexamethasone is an off-patent, common supportive treatment option and is generally affordable. WHO 2016 and 2019 surveys of different health facilities in low- and middle-income countries indicate that dexamethasone was available to patients at a median price of $0.33 per 4mg/ml injection ampoules (range: US$0.13-$3.5). Major UN procurers may be able to supply dexamethasone for a median price of $0.092 per 4mg/ml injection ampoule.

Question: Are there any import restrictions?

Answer : There are likely no restrictions, as dexamethasone is authorized worldwide.

Question: what are the risk of substandard or falsified (SF) products?

Answer: There are 21 records of falsified dexamethasone in the WHO Global Surveillance and Monitoring System database with the most recent one received from the Eastern Mediterranean in February 2020.

It is expected that, following the high level of publicity given to the medicines, more reports will be received in the future. This is based on experience with chloroquine products when hydroxychloroquine was thought to be a potential treatment for COVID19

Increased vigilance throughout all supply chains and due diligence in any procurement activities are essential. Member States and regulatory authorities are encouraged to promptly report any incidents of substandard or falsified dexamethasone to the WHO global surveillance and monitoring system.

Question: what is the worldwide production capacity?

Answer: Work is ongoing to determine producers of licensed and quality assured products. Further assessments of additional production capacity will be undertaken.

Source : WHO

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