* Clinical use protocol | Heberon® alfa R (interferon alfa-2b) for patients with Coronavirus Disease 2019 (COVID- 19).

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Rationality 

Due to its known mechanism of action, it is common to use interferon (IFN) against viral infections for which specific therapies are not available. IFN alfa-2b is one of the drugs of greatest attention used as experimental biotherapy for patients affected by COVID-19 1,2. Its use is based and justified by the antiviral properties of the interferon molecule, a member of the first line of antiviral defense with activation of the innate immune response against the virus and the mechanism of inhibition of viral replication, mediated by the inducer genes of IFN.

SARS-CoV (coronavirus associated with the 2002 epidemic) has been reported to reduce IFN expression and prevent IFN-inducing STAT1 and MyD88 genes from activating, as well as antiviral defense mechanisms detect the presence of the virus. On the other hand, IFN induction has been shown to protect against infection by MERS-CoV (coronavirus associated with the 2012 epidemic) 3. There are current reports of clinical use of nebulized IFN in pediatric and pregnant populations affected by COVID-19 4,5.

Due to the urgency of COVID-19 pandemic, not only IFN, but various drugs are being used as therapeutic tools, even though their efficacy has not been demonstrated for the treatment of SARSCOV-2. These previous evidences and studies suggest the possible usefulness of IFN as a preventive measure in vulnerable populations and in early stages of infection, in addition to the fact that its use continues to be published in the current pandemic and appears recommended in patient treatment protocols by different countries and organizations.

There are guideline issued by Expert Committees of WHO, Singapore, South Korea and US Institutions who recommend the clinical use of IFN for the treatment and prevention of COVID- 19 6-10. China and Spain have incorporated this drug into their national protocols and clinical guidelines for the care of this type of patient 11,12. For example, the combined use of nebulized Lopinavir / ritonavir + interferon alfa-2b is the recommended treatment in China for the treatment of patients with COVID-19 pneumonia. Similarly, several clinical trials for COVID-19 are being carried out in China, including treatment of mild infections with lopinavir / ritonavir as monotherapy (ChiCTR2000029387, ChiCTR2000029539) and in combination with interferon alfa2b (ChiCTR2000029308) 13.

Drug (active ingredient) 

Heberon® Alfa R (Recombinant Human Interferon alfa-2b)

Commercial presentation 

Liquid injectable solution with 3 or 5 million international units (MIU) of recombinant human interferon alfa-2b, presented in hermetically sealed vial.

Active ingredient 

Recombinant human interferon alpha-2b, produced in Escherichia coli at the Center for Genetic Engineering and Biotechnology, Havana, Cuba.

Other Ingredients 

Benzyl alcohol, sodium chloride, polysorbate 80, disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrated and water for injection.

Pharmacological action 

Antiviral

Therapeutic indication 

Coronavirus disease (COVID-19) patients

Administration route 

Nebulization by vaporization through the respiratory tract

Posology

5 MUI or 6 MUI of Heberon® Alfa R diluted in 2 mL of water for injection or in saline solution (physiological serum).

Schedule (frequency and duration) of treatment 

Twice a day for 5 to 10 days

Nebulization solution preparation method 

  1. Extract the total content of Heberon® Alfa R solution to be used into a nebulizer container, consisting of one 5 MUI bulb or two 3 MUI bulbs, depending on the drug
  2. Add 2 mL of water for injection or saline solution in the nebulizer container (in this step the solution to be nebulized will be ready)
  3. Administer in nebulization

The Heberon® Alfa R solution is designed for immediate use after the bulb has been opened, therefore, the described steps must occur immediately. At the end of step 3 the used Heberon® Alfa R bulbs and any remaining volume of solution in the nebulizer device should be discarded. To prepare the solution to be nebulized in the next dose, new Heberon® Alfa R bulbs must be used.

Cautions

Heberon® Alfa R must be administered under the supervision of a specialist physician. Should be administered cautiously in patients with pre-existing heart disease.

Contraindications

The use of Heberon® Alfa R is contraindicated in patients with hemoglobinopathies, autoimmune diseases, severe liver failure or decompensated liver cirrhosis. It should also not be used in patients with hypersensitivity to interferon alfa or to any of the salts present in the preparation.

Heberon® Alfa R is contraindicated in children less than three years of age, especially in premature newborns, because it uses benzyl alcohol as a preservative in its formulation.

Main side effects 

Most of the adverse events associated with the use of Heberon® Alfa R occur with mild intensity; however, it can cause adverse reactions of moderate or severe intensity that require reducing the dose, temporarily withdrawing the treatment or discontinuing it permanently.

The main adverse events that may occur are anorexia, depression, insomnia, anxiety, emotional lability, dizziness, headache, nausea, vomiting, diarrhea, abdominal pain, alopecia, rash, myalgia, arthralgia, musculoskeletal pain, fatigue, stiffness, pyrexia, flu-like symptoms, malaise, and irritability.

Storage conditions 

Heberon® Alfa R vials must be kept, until the moment of their use, inside pharmaceutical refrigerators with permanently temperatures between 2 and 8 degrees Celsius and located in rooms with controlled temperature and humidity conditions.

Heberon® Alfa R must not be frozen.

Estimated required product 

In the proposed dosage, each patient requires two daily doses of 5 MIU or 6 MIU of Heberon® Alfa R.

In case of prescribing 5 MUI dose, each individual will require the use of a Heberon® Alfa R 5 MUI vial in each administration; therefore two vials will be used for daily treatment. Up to TEN days, would require 20 vials per patient.

In case of prescribing 6 MUI dose, each individual will require the use of two vials of Heberon® Alfa R 3 MIU in each administration; therefore four units will be used for daily treatment and, up to TEN days, would require 40 vials per patient.

References:

  1. Shen L, Niu J, Wang C, et al. High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses. J Virol. 2019;93(12):e00023-00019.
  2. Cohen J. Can an anti-HIV combination or other existing drugs outwit the new coronavirus? Science (New York, NY).
  3. J. Cameron, et al. PLoS ONE 2012; 7(9): e45842.
  4. Novel corona virus disease (COVID-19) in pregnancy: What clinical recommendations to follow? Acta Obstet Gynecol Scand. 2020; 00:1–4.
  5. Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement” and “Pharmaceutical care recommendations for antiviral treatments in children with coronavirus disease 2019”. World Journal of Pediatrics, febrero
  6. Expert Consensus of the Chinese Society of Pharmacology, Published on February 6, 2020.
  7. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). National Health Commission & State Administration of Traditional Chinese Medicine. Published on March 3, 2020
  8. Guides for Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia from John Hopkins Medical Center in Baltimore.
  9. Committee of Experts for the treatment and prevention of COVID-19, integrated by Group of Respirology, Chinese Pediatric Society, Chinese Medical Association, Chinese Medical Doctor Association Committee on Respirology Pediatrics, China Medicine Education Association Committee on Pediatrics, Chinese Research Hospital Association, Committee on Pediatrics · Chinese Non-government Medical Institutions Association Committee on Pediatrics, China Association of Traditional Chinese Medicine, Committee on Children’s Health and Medicine Research, China News of Drug Information Association, Committee on Children’s Safety Medication, Global Pediatric Pulmonology Alliance,
  10. World Journal of Pediatrics del 29 de Enero, https://doi.org/10.1007/s12519-020-00343- 7.
  11. Manejo clínico de pacientes con enfermedad por el nuevo coronavirus (COVID-19); Acceso 18 de febrero de Documento técnico emitido por el Gobierno de España y el Ministerio de Sanidad de España.
  12. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19); Acceso16-24 February
  13. Randomized, open-label, blank-controlled trial for the efficacy and safety of lopinavir- ritonavir and interferon-alpha 2b in hospitalization patients with 2019-nCoV pneumonia (novel coronavirus              pneumonia,             NCP)              http://www.chictr.org.cn/showproj.aspx?proj=48684 Acceso 9 de febrero 2020.