Lamivudine/zidovudine: Difference between revisions

{{Short description|Combination drug for HIV}}

{{Use dmy dates|date=March 2024}}

| verifiedrevid = 399728371

| type = combo

| image = Lamivudine and zidovudine.svg

| width = 150

| alt =

<!--Combo data-->

| component1 = Lamivudine

| class1 = Nucleoside analogue [[reverse transcriptase inhibitor]]

| component2 = Zidovudine

| class2 = Nucleoside analogue [[reverse transcriptase inhibitor]]

<!--Clinical data-->

| tradename = Combivir

| Drugs.com = {{Drugs.com|ppa|lamivudine-and-zidovudine}}

| MedlinePlus = a601066

| DailyMedID = Lamivudine and zidovudine

| pregnancy_AU = B3

| pregnancy_category =

| ATC_prefix = J05

| ATC_suffix = AR01

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = POM

| legal_US = Rx-only

| legal_EU = Rx-only

| legal_status = Rx-only

| routes_of_administration = [[Oral administration|By mouth]]

<!--Identifiers-->

| CAS_number = 165456-81-5

| PubChem = 160352

| DrugBank =

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| KEGG = D07507

| NIAID_ChemDB = 031479

<!--Chemical data-->

<!-- Definition and medical uses -->

'''Lamivudine/zidovudine''', sold under the brand name '''Combivir''' among others, is a [[fixed-dose combination]] [[antiretroviral medication]] used to treat [[HIV/AIDS]].<ref name=WHO2008/> It contains two [[antiretroviral medications]], [[lamivudine]] and [[zidovudine]].<ref name=WHO2008/> It is used together with other antiretrovirals.<ref name=WHO2008/> It is taken by mouth twice a day.<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | pages=157, 161 }}</ref><ref name="Combivir FDA label">{{cite web | title=Combivir- lamivudine and zidovudine tablet, film coated | website=DailyMed | date=10 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16da660b-9981-4d24-a14a-94c7744fce4f | access-date=29 May 2020}}</ref>

<!-- Side effects and mechanism -->

Common side effects include headache, feeling tired, nausea, diarrhea, and fever.<ref name="Combivir FDA label"/> Severe side effects may include [[bone marrow suppression]], [[muscle damage]], worsening of [[hepatitis B]] if previously infected, [[Lactic acidosis|high blood lactate]] and [[liver enlargement]].<ref name=WHO2008/><ref name=Ric2015>{{cite book|last1=Hamilton|first1=Richart|title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=59}}</ref> It may be part of a recommended treatment during [[pregnancy]].<ref name=WHO2008/> The medications are both of the [[nucleoside reverse transcriptase inhibitor]] (NRTI) class.<ref name=WHO2008/> They work by blocking the action of the [[enzyme]], [[reverse transcriptase]], that the virus requires to reproduce.<ref name="Combivir FDA label"/>

<!-- History and culture -->

Lamivudine/zidovudine was approved for medical use in the United States in 1997, and in the European Union in 1998.<ref name="Combivir FDA label"/><ref name="Combivir EPAR" /> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=Ric2015/>

== Medical uses ==

It is indicated for use in combination with an additional [[Management of HIV/AIDS|antiretroviral]] agent for the treatment of [[HIV|human immunodeficiency virus]] type 1 (HIV-1) infection.<ref name="Combivir FDA label"/><ref name="Combivir EPAR">{{cite web | title=Combivir EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/combivir | access-date=29 May 2020}}</ref>

=== 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.<ref>{{cite journal | vauthors = Watts DH, Covington DL, Beckerman K, Garcia P, Scheuerle A, Dominguez K, Ross B, Sacks S, Chavers S, Tilson H | display-authors = 6 | title = Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy | journal = American Journal of Obstetrics and Gynecology | volume = 191 | issue = 3 | pages = 985–992 | date = September 2004 | pmid = 15467577 | doi = 10.1016/j.ajog.2004.05.061 }}</ref> Data supports the safety of this combination during pregnancy and is often preferred over other fixed dose combinations during pregnancy.<ref>{{cite journal | vauthors = Portsmouth SD, Scott CJ | title = The renaissance of fixed dose combinations: Combivir | journal = Therapeutics and Clinical Risk Management | volume = 3 | issue = 4 | pages = 579–583 | date = August 2007 | pmid = 18472979 | pmc = 2374941 }}</ref>

== 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.<ref>{{cite journal | vauthors = Esser S, Helbig D, Hillen U, Dissemond J, Grabbe S | title = Side effects of HIV therapy | journal = Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology | volume = 5 | issue = 9 | pages = 745–754 | date = September 2007 | pmid = 17760894 | doi = 10.1111/j.1610-0387.2007.06322.x | s2cid = 10271162 }}</ref><ref name=":0">{{cite journal | vauthors = Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Saag MS, Schechter M, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA | display-authors = 6 | title = Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel | journal = JAMA | volume = 283 | issue = 3 | pages = 381–390 | date = January 2000 | pmid = 10647802 | doi = 10.1001/jama.283.3.381 }}</ref> 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.<ref name=":0" /> 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.<ref>{{Cite web|url=https://medicine.yale.edu/intmed/infdis/HIV-medications-review_tcm319-31407_tcm319-284-32.pdf|title=Drugs for HIV Infection|date=October 2006|publisher=The Medical Letter, Inc|url-status=dead|archive-url=https://web.archive.org/web/20170305043405/https://medicine.yale.edu/intmed/infdis/HIV-medications-review_tcm319-31407_tcm319-284-32.pdf|archive-date=5 March 2017|access-date=9 November 2016}}</ref>

== Interactions ==

=== Drug-drug interactions ===

Lamividine/zidovudine interacts with [[stavudine]] and [[zalcitabine]] by competing intracellularly for activation and results in inhibiting [[phosphorylation]].<ref name="Combivir FDA label" /><ref>{{Cite journal|last=Breckenridge|first=Alasdair|title=Pharmacology of drugs for HIV|journal=Medicine|volume=33|issue=6|pages=30–31|doi=10.1383/medc.33.6.30.66012|date=June 2005}}</ref> There is also a known interaction with [[Nephrotoxicity|nephrotoxic]] or bone marrow suppressive agents (e.g. [[doxorubicin]]) which increases the risk of hematologic toxicity of zidovudine.<ref name=":1">{{Cite web|url=http://apps.who.int/prequal/whopar/whoparproducts/HA323part4v1.pdf|title=Summary of Product Characteristics: Lamivudine, Nevirapine and Zidovudine Tablets|date=May 2011|url-status=dead|archive-url=https://web.archive.org/web/20161109153457/http://apps.who.int/prequal/whopar/whoparproducts/HA323part4v1.pdf|archive-date=9 November 2016}}</ref> Monitoring renal function and hematologic tests can be used to assess these potential interactions.<ref name=":1" />

=== 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.<ref name=":1" />

== Mechanism of action ==

The combination of [[lamivudine]] and [[zidovudine]] is composed of two nucleotide [[Reverse-transcriptase inhibitor|reverse transcriptase inhibitors]] (NRTIs).<ref name="Combivir FDA label"/>

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.<ref>{{Cite web|url=http://www.catie.ca/fact-sheets/co-formulations/combivir|title=Combivir|website=www.catie.ca|access-date=8 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161108133321/http://www.catie.ca/fact-sheets/co-formulations/combivir|archive-date=8 November 2016}}</ref> Lamivudine and zidovudine act as nucleoside analogs, which are substrates for the human nucleoside [[kinase]]s. 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.{{cn|date=May 2021}}

Lamividuine and zidovudine combination therapy is believed to work synergistically together to prevent mutations in the HIV virus, which can contribute to drug resistance.<ref>{{Cite web|url=https://www.viivhealthcare.com/our-medicines/combivir.aspx|title=Combivir {{!}} ViiV Healthcare|website=www.viivhealthcare.com|access-date=8 November 2016|url-status=dead|archive-url=https://web.archive.org/web/20160505131525/https://www.viivhealthcare.com/our-medicines/combivir.aspx|archive-date=5 May 2016}}</ref>

== 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.<ref name="Combivir FDA label" />

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 effect|first pass metabolism]]. The half-life of zidovudine is 0.5 to 3 hours and binds poorly to plasma proteins.<ref name="Combivir FDA label" />

Lamivudine and zidovudine are not extensively metabolized by [[Cytochrome P450|CYP450]] liver enzymes.{{cn|date=September 2022}}

== 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.<ref>{{cite journal | vauthors = Portsmouth SD, Scott CJ | title = The renaissance of fixed dose combinations: Combivir | journal = Therapeutics and Clinical Risk Management | volume = 3 | issue = 4 | pages = 579–583 | date = August 2007 | pmid = 18472979 | pmc = 2374941 }}</ref>

== Society and culture ==

Lamivudine/zidovudine is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st" />

=== Drug formulations ===

Drug formulations: tablets by mouth

# Combivir: lamivudine 150&nbsp;mg and zidovudine 300&nbsp;mg (scored). It is marketed by [[ViiV Healthcare]].

# Generic: lamivudine 150&nbsp;mg and zidovudine 300&nbsp;mg.

== References ==

{{Reflist}}

{{Antiretroviral drug}}

{{GlaxoSmithKline}}

{{Portal bar | Medicine | Viruses }}

{{DEFAULTSORT:Lamivudine Zidovudine}}

[[Category:Fixed dose combination (antiretroviral)]]

[[Category:Hepatotoxins]]

[[Category:Drugs developed by GSK plc]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]