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
MedlinePlus a601066
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code J05AR01 (WHO)
Legal status
Legal status
Identifiers
PubChem (CID) 160352
ChemSpider 21106283 YesY
NIAID ChemDB 031479
  (verify)

Lamivudine/zidovudine (trade name Combivir) is a medication used to treat HIV/AIDS. It is a fixed dose combination of two antiretroviral drugs, lamivudine (also called 3TC, with the brand name Epivir) and zidovudine (also called AZT or ZDV, with the brand name Retrovir). The drug is a part of the class of medicines called Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Combining of the two drugs has a stronger and more sustained effect than using either drug alone, and assists in reducing pill burden and in aiding compliance with the antiretroviral drug therapy.

Both lamivudine and zidovudine are reverse transcriptase inhibitors, which block the action of an enzyme, reverse transcriptase, that the virus requires for reproduction. It reduces the viral load in the body and raises CD4 cell count.

It was approved for use in the United States by the Food and Drug Administration on September 26, 1997, making it the thirteenth approved antiretroviral. It is marketed by ViiV Healthcare. As of 2015 the cost for a typical month of medication in the United States more than 200 USD.[1]

This fixed dose combination antiretroviral is listed on the core list of the World Health Organization Model List of Essential Medicines as a efficacious, safe and cost-effective medicine that should be available in a basic health-care system.[2]

History[edit]

Lamivudine/Zidovudine (Brand name Combivir) was introduced to the market with FDA licensure in 1997. It's 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.[3]

Medical Uses[edit]

The combination of Lamivudine and Zidovudine is composed of two nucleotide reverse transcriptase inhibitors (NRTIs).[4] It is marketed as a fixed dose combo formulation under the brand name Combivir, which is FDA approved for use in combination with an additional antiretroviral agent for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.[5]

Pregnancy[edit]

Lamividine/zidovudine is pregnancy category C in the United States, meaning there are potential risks to the fetus during pregnancy, but potential benefits may outweigh the risks.[6] Data supports the safety of this combination during pregnancy and is often preferred over other fixed dose combinations during pregnancy.[7]

Drug formulations[edit]

Drug Formulations: Oral tablets

  1. Combivir: Lamivudine 150mg and Zidovudine 300mg (scored). 60 tablets cost $994.[8]
  2. Generic: Lamivudine 150mg and Zidovudine 300mg. 60 tablets cost $749.[8]

Adverse Effects[edit]

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[edit]

Drug-Drug Interactions[edit]

Lamividine/zidovudine interacts with Stavudine and Zalcitabine by competing intraceullarly for activation and results in inhibiting phosphorylation.[4][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[edit]

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[edit]

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.

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/pharmacodynamics[edit]

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. [16]

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.[16]

Lamivudine and zidovudine are not extensively metabolized by CYP450 liver enzymes.

Society/culture[edit]

Lamivudine/Zidovudine (Brand name Combivir) is on the World Health Organization's List of Essential Medicines, the 2015 list of necessary medications.[17]

References[edit]

  1. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 59. ISBN 9781284057560. 
  2. ^ "WHO Model List of Essential Medicines" (PDF). WHO. Nov 2015. 
  3. ^ "The renaissance of fixed dose combinations: Combivir". Therapeutics and Clinical Risk Management 2007. 3(4) 579-583. 
  4. ^ a b "Prescribing Information: Combivir (lamivudine/zidovudine)" (PDF). 
  5. ^ "Highlight of Prescribing Information: Combivir" (PDF). Nov 2015. 
  6. ^ "Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy". www.sciencedirect.com. Retrieved 2016-11-09. 
  7. ^ Portsmouth, Simon D; Scott, Christopher J (2016-11-09). "The renaissance of fixed dose combinations: Combivir". Therapeutics and Clinical Risk Management. 3 (4): 579–583. ISSN 1176-6336. PMC 2374941Freely accessible. PMID 18472979. 
  8. ^ a b "The Cost of HIV Treatment". Retrieved 2016-11-16. 
  9. ^ Esser, Stefan; Helbig, Doris; Hillen, Uwe; Dissemond, Joachim; Grabbe, Stephan (2007-09-01). "Side effects of HIV therapy". JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 5 (9): 745–754. doi:10.1111/j.1610-0387.2007.06322.x. ISSN 1610-0387. 
  10. ^ a b Carpenter, Charles C. J.; Cooper, David A.; Fischl, Margaret A.; Gatell, Jose M.; Gazzard, Brian G.; Hammer, Scott M.; Hirsch, Martin S.; Jacobsen, Donna M.; Katzenstein, David A. (2000-01-19). "Antiretroviral Therapy in Adults". JAMA. 283 (3). doi:10.1001/jama.283.3.381. ISSN 0098-7484. 
  11. ^ "Drugs for HIV Infection" (PDF). The Medical Letter, Inc. October 2006. 
  12. ^ Breckenridge, Alasdair. "Pharmacology of drugs for HIV". Medicine. 33 (6): 30–31. doi:10.1383/medc.33.6.30.66012. 
  13. ^ a b c "Summary of Product Characteristics: Lamivudine, Nevirapine and Zidovudine Tablets" (PDF). May 2011. 
  14. ^ "Combivir". www.catie.ca. Retrieved 2016-11-08. 
  15. ^ "Combivir | ViiV Healthcare". www.viivhealthcare.com. Retrieved 2016-11-08. 
  16. ^ a b "Combivir - FDA prescribing information, side effects and uses". www.drugs.com. Retrieved 2016-11-08. 
  17. ^ "WHO Model Lists of Essential Medicines". World Health Organization. Retrieved 2016-11-07. 

External links[edit]