Lamivudine/zidovudine

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Lamivudine/zidovudine
Lamivudine and zidovudine.svg
Combination of
Lamivudine Nucleoside analogue reverse transcriptase inhibitor
Zidovudine Nucleoside analogue reverse transcriptase inhibitor
Clinical data
Trade names Combivir
AHFS/Drugs.com Professional Drug Facts
MedlinePlus a601066
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: WARNING [1] Rx-only
  • EU:Rx-only
  • In general: ℞ (Prescription only)
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Lamivudine/zidovudine, sold under the brand name Combivir among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. [2] It contains two antiretroviral medications, lamivudine and zidovudine. [2] It is used together with other antiretrovirals. [2] It is taken by mouth twice a day. [2] [3]

Contents

Common side effects include headache, feeling tired, nausea, diarrhea, and fever. [3] Severe side effects may include bone marrow suppression, muscle damage, worsening of hepatitis B if previously infected, high blood lactate and liver enlargement. [2] [4] It may be part of a recommended treatment during pregnancy. [2] The medications are both of the nucleoside reverse transcriptase inhibitor (NRTI) class. [2] They work by blocking the action of the enzyme, reverse transcriptase, that the virus requires to reproduce. [3]

Lamivudine/zidovudine was approved for medical use in the United States in 1997, and in the European Union in 1998. [3] [5] It is on the World Health Organization's List of Essential Medicines. [6] It is available as a generic medication. [4]

Medical uses

It is indicated for use in combination with an additional antiretroviral agent for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. [3] [5]

Pregnancy

Lamividine/zidovudine is categorized pregnancy category C in the United States, meaning there are potential risks to the baby during pregnancy, but potential benefits may outweigh the risks. [7] Data supports the safety of this combination during pregnancy and is often preferred over other fixed dose combinations during pregnancy. [8]

Side effects

The most common adverse effects of Lamividine/zidovudine are similar to other NRTI's and includes headache, neutropenia, anemia, nausea, vomiting, myopathy and nail pigmentation. [9] [10] More serious and potentially life-threatening adverse effects reported include lactic acidosis with hepatic steatosis, but this rare adverse event is mostly associated with Zidovudine. [10] HIV-positive patients with chronic hepatitis B virus (HBV) infections are at risk for potential flares of hepatitis that can occur with abrupt discontinuation of Lamividine/zidovudine because Lamivudine is also used in low doses for treatment against active HBV. [11]

Interactions

Drug-drug interactions

Lamividine/zidovudine interacts with stavudine and zalcitabine by competing intracellularly for activation and results in inhibiting phosphorylation. [3] [12] There is also a known interaction with nephrotoxic or bone marrow suppressive agents (e.g. doxorubicin) which increases the risk of hematologic toxicity of zidovudine. [13] Monitoring renal function and hematologic tests can be used to assess these potential interactions. [13]

Drug-food interactions

Half lives of lamivudine and Zidovudine are not affected by food and absorption rates were slowed when taken with food but were not clinically significant, therefore, lamivudine/zidovudine may be taken with or without food. [13]

Mechanism of action

The combination of lamivudine and zidovudine is composed of two nucleotide reverse transcriptase inhibitors (NRTIs). [3]

Lamivudine and zidovudine both competitively inhibit and reduce the activity of reverse transcriptase (RT) causing HIV infected cells to decrease the number of viruses in the body. [14] Lamivudine and zidovudine act as nucleoside analogs, which are substrates for the human nucleoside kinases. The initial phosphorylation step is crucial for the drug's activity, then converted into the active 5’-triphosphate form by host kinases. The drug is then incorporated to the end of the growing chain of the viral DNA causing the chain to be terminated, where nucleotides can no longer be added to the growing viral DNA.[ citation needed ]

Lamividuine and zidovudine combination therapy is believed to work synergistically together to prevent mutations in the HIV virus, which can contribute to drug resistance. [15]

Pharmacokinetics

Lamivudine is well absorbed in the body and distributes widely into the extravascular space. Oral bioavailability is >80% and overall metabolism is insignificant where approximately 95% of the drug is found unchanged in the urine. The only known metabolite found in humans is trans-sulfoxide. The half-life of lamivudine is 10 to 15 hours and binds poorly to plasma proteins. [3]

Zidovudine is also well absorbed in the body and penetrates into the cerebrospinal fluid. Oral bioavailability is 75% and primarily metabolized by the liver by glucuronidation. The primary metabolite is GZDV, an inactive metabolite produced after first pass metabolism. The half-life of zidovudine is 0.5 to 3 hours and binds poorly to plasma proteins. [3]

Lamivudine and zidovudine are not extensively metabolized by CYP450 liver enzymes.[ citation needed ]

History

Lamivudine/zidovudine (brand name Combivir) was introduced to the market with FDA approval in 1997. Its impact in history is significant as it was the first combination therapy with a fixed dose for HIV-positive people, and soon solidified its title as a gold standard as it was the most prescribed NRTI in initial HIV treatment for newly diagnosed patients. The arrival of Combivir was seen as a new revolution in HIV therapy, with its improved toxicity profile and tolerability, especially compared to the undesirable side effects of lone AZT therapy or the unfavorable facial and lipoatrophy seen in Stavudine monotherapy at that time. [16]

Society and culture

Lamivudine/zidovudine is on the World Health Organization's List of Essential Medicines. [6]

Drug formulations

Drug formulations: tablets by mouth

  1. Combivir: lamivudine 150 mg and zidovudine 300 mg (scored). It is marketed by ViiV Healthcare.
  2. Generic: lamivudine 150 mg and zidovudine 300 mg.

Related Research Articles

<span class="mw-page-title-main">Zidovudine</span> Antiretroviral medication

Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Zalcitabine</span> Chemical compound

Zalcitabine, also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It is used as part of a combination regimen.

<span class="mw-page-title-main">Stavudine</span> Chemical compound

Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. However, it is not a first-line treatment. It is given by mouth.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Abacavir</span> Chemical compound

Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.

<span class="mw-page-title-main">Emtricitabine</span> Antiretroviral drug used to treat HIV infection

Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

<span class="mw-page-title-main">Entecavir</span> Chemical compound

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection. In those with both HIV/AIDS and HBV antiretroviral medication should also be used. Entecavir is taken by mouth as a tablet or solution.

<span class="mw-page-title-main">Efavirenz</span> Antiretroviral medication

Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is sold both by itself and in combination as efavirenz/emtricitabine/tenofovir. It is taken by mouth.

<span class="mw-page-title-main">Abacavir/lamivudine/zidovudine</span> Mixture of chemical compounds

Abacavir/lamivudine/zidovudine, sold under the brand name Trizivir, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains three reverse transcriptase inhibitors patented by GlaxoSmithKline and marketed by a joint venture with Pfizer, ViiV Healthcare:

<span class="mw-page-title-main">Efavirenz/emtricitabine/tenofovir</span> Combination drug for HIV

Efavirenz/emtricitabine/tenofovir, sold under the brand name Atripla among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains efavirenz, emtricitabine, and tenofovir disoproxil. It can be used by itself or together with other antiretroviral medications. It is taken by mouth.

<span class="mw-page-title-main">Abacavir/lamivudine</span> Combination drug for HIV

Abacavir/lamivudine, sold under the brand name Kivexa among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains abacavir and lamivudine. It is generally recommended for use with other antiretrovirals. It is commonly used as part of the preferred treatment in children. It is taken by mouth as a tablet.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

Lamivudine/nevirapine/stavudine (3TC/NVP/d4T) is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains lamivudine, nevirapine, and stavudine. It is either used by itself or along with other antiretrovirals. It is taken by mouth twice a day.

Lamivudine/nevirapine/zidovudine (3TC/NVP/AZT) is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains lamivudine, nevirapine, and zidovudine. It is either used by itself or along with other antiretrovirals. It is a recommended treatment in those who are pregnant. It is taken by mouth twice a day.

<span class="mw-page-title-main">Bictegravir/emtricitabine/tenofovir alafenamide</span> Fixed dose combination HIV drug

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide. It was approved for use in the United States in February 2018, and for use in the European Union in June 2018.

Dolutegravir/lamivudine, sold under the brand name Dovato, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains dolutegravir, as the salt, an integrase strand transfer inhibitor (INSTI), and lamivudine, a nucleoside analogue reverse transcriptase inhibitor (NRTI). It is taken by mouth.

Dolutegravir/lamivudine/tenofovir (DTG/3TC/TDF) is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It is a combination of dolutegravir, lamivudine, and tenofovir disoproxil. As of 2019, it is listed by the World Health Organization (WHO) as the first line treatment for adults, with tenofovir/lamivudine/efavirenz as an alternative. It is taken by mouth.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  2. 1 2 3 4 5 6 7 World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 157, 161. hdl: 10665/44053 . ISBN   9789241547659.
  3. 1 2 3 4 5 6 7 8 9 "Combivir- lamivudine and zidovudine tablet, film coated". DailyMed. 10 May 2019. Retrieved 29 May 2020.
  4. 1 2 Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 59. ISBN   9781284057560.
  5. 1 2 "Combivir EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 May 2020.
  6. 1 2 World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ↑ Watts DH, Covington DL, Beckerman K, Garcia P, Scheuerle A, Dominguez K, et al. (September 2004). "Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy". American Journal of Obstetrics and Gynecology. 191 (3): 985–992. doi:10.1016/j.ajog.2004.05.061. PMID   15467577.
  8. ↑ Portsmouth SD, Scott CJ (August 2007). "The renaissance of fixed dose combinations: Combivir". Therapeutics and Clinical Risk Management. 3 (4): 579–583. PMC   2374941 . PMID   18472979.
  9. ↑ Esser S, Helbig D, Hillen U, Dissemond J, Grabbe S (September 2007). "Side effects of HIV therapy". Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology. 5 (9): 745–754. doi:10.1111/j.1610-0387.2007.06322.x. PMID   17760894. S2CID   10271162.
  10. 1 2 Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hammer SM, et al. (January 2000). "Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel". JAMA. 283 (3): 381–390. doi:10.1001/jama.283.3.381. PMID   10647802.
  11. ↑ "Drugs for HIV Infection" (PDF). The Medical Letter, Inc. October 2006. Archived from the original (PDF) on 5 March 2017. Retrieved 9 November 2016.
  12. ↑ Breckenridge, Alasdair (June 2005). "Pharmacology of drugs for HIV". Medicine. 33 (6): 30–31. doi:10.1383/medc.33.6.30.66012.
  13. 1 2 3 "Summary of Product Characteristics: Lamivudine, Nevirapine and Zidovudine Tablets" (PDF). May 2011. Archived from the original (PDF) on 9 November 2016.
  14. ↑ "Combivir". www.catie.ca. Archived from the original on 8 November 2016. Retrieved 8 November 2016.
  15. ↑ "Combivir | ViiV Healthcare". www.viivhealthcare.com. Archived from the original on 5 May 2016. Retrieved 8 November 2016.
  16. ↑ Portsmouth SD, Scott CJ (August 2007). "The renaissance of fixed dose combinations: Combivir". Therapeutics and Clinical Risk Management. 3 (4): 579–583. PMC   2374941 . PMID   18472979.
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