|Lamivudine||Nucleoside analogue reverse transcriptase inhibitor|
|Zidovudine||Nucleoside analogue reverse transcriptase inhibitor|
|AHFS/Drugs.com||FDA Professional Drug Information|
|CompTox Dashboard (EPA)|
Lamivudine/zidovudine, sold under the brand name Combivir among others, is a medication used to treat HIV/AIDS. It is a combination of two antiretroviral medications, lamivudine and zidovudine. It is used together with other antiretrovirals. It is taken by mouth twice a day.
Common side effects include headache, feeling tired, nausea, diarrhea, and fever. Severe side effects may include bone marrow suppression, muscle damage, worsening of hepatitis B if previously infected, high blood lactate and liver enlargement. It may be part of a recommended treatment during pregnancy. The medications are both of the nucleoside reverse transcriptase inhibitor (NRTI) class. They work by blocking the action of the enzyme, reverse transcriptase, that the virus requires to reproduce.
Lamivudine/zidovudine was approved for medical use in the United States in 1997. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world is about US$6.90 to $29.64 per month. As of 2015 the cost for a typical month of medication in the United States more than $200.
Lamividine/zidovudine is pregnancy category C in the United States, meaning there are potential risks to the baby during pregnancy, but potential benefits may outweigh the risks. Data supports the safety of this combination during pregnancy and is often preferred over other fixed dose combinations during pregnancy.
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. 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. 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.
Lamividine/zidovudine interacts with Stavudine and Zalcitabine by competing intracellularly for activation and results in inhibiting phosphorylation. 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. Monitoring renal function and hematologic tests can be used to assess these potential 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.
Mechanism of action
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. 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.
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.
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.
Lamivudine and zidovudine are not extensively metabolized by CYP450 liver enzymes.
Lamivudine/Zidovudine (brand name Combivir) was introduced to the market with FDA licensure 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.
Society and culture
Drug formulations: tablets by mouth
- Combivir: lamivudine 150 mg and zidovudine 300 mg (scored). 60 tablets cost $994. It is marketed by ViiV Healthcare.
- Generic: lamivudine 150 mg and zidovudine 300 mg. 60 tablets cost $749.
- WHO Model Formulary 2008 (PDF). World Health Organization. 2009. pp. 157, 161. ISBN 9789241547659. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- "Combivir - FDA prescribing information, side effects and uses". www.drugs.com. Archived from the original on 8 November 2016. Retrieved 10 December 2016.
- Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 59. ISBN 9781284057560.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- "Lamivudine + Zidovudine". International Drug Price Indicator Guide. Archived from the original on 5 March 2017. Retrieved 8 December 2016.
- "Highlight of Prescribing Information: Combivir" (PDF). Nov 2015. Archived (PDF) from the original on 2016-11-09.
- Heather Watts, D.; Covington, Deborah L.; Beckerman, Karen; Garcia, Patricia; Scheuerle, Angela; Dominguez, Kenneth; Ross, Brenda; Sacks, Susan; Chavers, Scott; Tilson, Hugh (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.
- 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 2374941. PMID 18472979.
- 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. PMID 17760894.
- 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): 381–90. doi:10.1001/jama.283.3.381. ISSN 0098-7484. PMID 10647802.
- "Drugs for HIV Infection" (PDF). The Medical Letter, Inc. October 2006. Archived (PDF) from the original on 2017-03-05.
- "Prescribing Information: Combivir (lamivudine/zidovudine)" (PDF). Archived (PDF) from the original on 2016-11-09.
- Breckenridge, Alasdair (June 2005). "Pharmacology of drugs for HIV". Medicine. 33 (6): 30–31. doi:10.1383/medc.188.8.131.52012.
- "Summary of Product Characteristics: Lamivudine, Nevirapine and Zidovudine Tablets" (PDF). May 2011. Archived (PDF) from the original on 2016-11-09.
- "Combivir". www.catie.ca. Archived from the original on 2016-11-08. Retrieved 2016-11-08.
- "Combivir | ViiV Healthcare". www.viivhealthcare.com. Archived from the original on 2016-05-05. Retrieved 2016-11-08.
- "Combivir - FDA prescribing information, side effects and uses". www.drugs.com. Archived from the original on 2016-11-08. Retrieved 2016-11-08.
- Portsmouth, S. D.; Scott, C. J. (2007). "The renaissance of fixed dose combinations: Combivir". Therapeutics and Clinical Risk Management. 3 (4): 579–583. PMC 2374941. PMID 18472979.
- "WHO Model Lists of Essential Medicines". World Health Organization. Archived from the original on 2016-11-02. Retrieved 2016-11-07.
- "The Cost of HIV Treatment". 2015-04-02. Archived from the original on 2016-11-25. Retrieved 2016-11-16.
- Combivir website operated by GlaxoSmithKline