Lamivudine

Paul A. Pham, Pharm.D., John G. Bartlett, M.D., Alice Jenh Hsu, Pharm.D.

INDICATIONS

FDA

Treatment of HIV infection in combination with other antiretrovirals.
Treatment of HBV (Epivir HB)

NON-FDA APPROVED USES

Treatment of hepatitis in HIV-HBV co-infected pts.

FORMS

brand name	preparation	manufacturer	route	form	dosage^	cost*
Epivir	Lamivudine (3TC)	ViiV Healthcare	oral	tablet	150 mg, 300 mg	$7.63; $15.27
			oral	solution	10 mg/mL (240 mL)	$122.14
Epivir HB (for HBV infection)	Lamivudine (3TC)Route	ViiV Healthcare	oral	tablet	100 mg	$13.66
			oral	solution	5 mg/mL (240 mL)	$163.97
Combivir and generic AZT/3TC	Lamivudine (3TC)/Zidovudine (AZT)	ViiV Healthcare and generic manufacturer (Aurobindo Pharma Limited)	oral	tablet	150 mg 3TC/300 mg AZT	$16.55; generic price (TBA)
Trizivir	Lamivudine (3TC)/Zidovudine (AZT)/Abacavir (ABC)	ViiV Healthcare	oral	tablet	ABC 300 mg + AZT 300 mg + 3TC 150 mg	$26.81
Epzicom	Lamivudine (3TC)/Abacavir (ABC)	ViiV Healthcare	oral	tablet	ABC 600 mg + 3TC 300 mg	$35.78
Kivexa (brand name available in Europe)	ABC + 3TC	ViiV Healthcare	oral	tablet	ABC 600 mg + 3TC 300 mg	variable

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

Pill burden:
- HIV: 1-2 tabs once-daily
- HBV: 100 mg once-daily

As Epivir: 3TC 300 mg PO once-daily or 150 mg PO twice-daily
As Combivir or Trizivir: 1 tab PO twice-daily
As Epzicom: 1 tab PO once-daily

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

Neonate/Infant (< 4 weeks old):
- For prevention of transmission or treatment of HIV: 2 mg/kg/dose twice daily
Pediatrics (≥4 weeks):
- 4 mg/kg/dose (max 150mg/dose) twice daily
Pediatric dosing for scored 150-mg tablet (weight ≥14 kg):
- 14 to 21 kg: 1/2 tablet (75mg) twice daily
- >21 to < 30 kg: 1/2 tablet (75mg) in AM and 1 tablet (150mg) in PM
- ≥ 30 kg: 1 tablet (150mg) twice daily
Adolescent (≥ 16 y/o):
- < 50 kg: 4 mg/kg/dose (max 150 mg) twice daily
- ≥50 kg: 150 mg twice daily OR 300 mg once daily
For combination tablets containing lamivudine for treatment of HIV: see adult dosing
For HBV:
- Children ≥2 years and Adolescents: 3 mg/kg/dose (max 100 mg/dose) once daily

PEDIATRIC RENAL DOSING

Infants/Children: Requires renal dosage adjustment. Insufficient data exists to recommend specific dosing; however, the following has been suggested (Aronoff 2007):
- CrCl 30-50 mL/min: 4 mg/kg/dose once daily
- CrCl 10-29 mL/min: 2 mg/kg/dose once daily
- CrCl < 10 mL/min: 1 mg/kg/dose once daily
- HD: 1 mg/kg/dose once daily, dose after HD on HD days
Children and Adolescents ≥30 kg:
- CrCl ≥50 mL/min: usual dose
- CrCl 30-49 mL/min: 150 mg once daily
- CrCl 15-29 mL/min: 150 mg x 1, then 100 mg once daily
- CrCl 5-14 mL/min: 150 mg x 1, then 50 mg once daily
- CrCl < 5 mL/min: 50 mg x 1, then 25 mg once daily
- HD: 50 mg x 1, then 25 mg once daily, dose after HD on HD days

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

300 mg once-daily or 150 mg PO twice-daily.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Cr Clearance 30-49 mL/min: 150 mg PO once-daily ; Cr Clearance 15-29 mL/min: 150 mg x1 then 100 mg once-daily.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

150 mg x1 then 25-50 mg once-daily.

DOSING IN HEMODIALYSIS

50 mg x1, then 25-50 mg once-daily (post HD).

DOSING IN PERITONEAL DIALYSIS

150 mg x1, then 25-50 mg once-daily (limited data).

DOSING IN HEMOFILTRATION

No data consider 150 mg PO once-daily.

ADVERSE DRUG REACTIONS

GENERAL

One of the best tolerated NRTIs with side effect profile comparable to placebo in hepatitis trials.

OCCASIONAL

Headache
GI: nausea, diarrhea, abdominal pain
Insomnia (association unclear; may be due to co-administered ARVs)
Hepatitis flare or fulminant hepatitis (in HBV co-infected pts if 3TC withdrawn or with development 3TC-resistant HBV)

RARE

Lactic acidosis: listed as NRTI class effect, but unlikely to be caused by 3TC.
- In vitro, 3TC, along with TDF, FTC, and ABC, are not associated with mitochondrial toxicity.
Pancreatitis (reported in pediatric pts)

DRUG INTERACTIONS

No pertinent drug interactions since it is not a substrate, inhibitor, or inducer of CYP450 isoforms.

Drug-to-Drug Interactions
Drug	Effect of Interaction	Recommendations/Comments
Abacavir	3TC AUC decreased by 15%; Cmax decreased by 35%.	Not clinically significant. Use standard dose.
Methadone	3TC: No reported interaction. Methadone: No change.	Not clinically significant. Use standard dose.
Nelfinavir	No effect on 3TC AUC.	Not clinically significant. Use standard doses of both.
Trimethoprim/Sulfamethoxazole	3TC AUC increased by 44%.	Not clinically significant. Use standard dose.

SPECTRUM

HIV and HBV

RESISTANCE

184V: selected by 3TC, resulting in high-level resistance to 3TC and FTC, slight decrease in susceptibility to ddI and ABC, and enhanced susceptibility to AZT, d4T, and TDF.
TAMs (41L, 210W, 215Y/F, 219Q/E, 67N, 70R): resistance likely with multiple TAMs.
T69S: high-level resistance.
Q151M complex: high-level resistance.
K65R: intermediate resistance.
44D and 119I: increase 3TC resistance in combination with TAMs.

PHARMACOLOGY

MECHANISM

Intracellular phosphorylation to active lamivudine triphosphate, which competitively inhibits HIV DNA polymerase.

PHARMACOKINETIC PARAMETERS

Absorption

86%

Metabolism and Excretion

Renal excretion accounts for 71%.

Protein Binding

36%

Cmax, Cmin, and AUC

Cmax = 3mcg/mL; Intracellular carbovir triphosphate 100 FM/million cells.

T1/2

Serum: 5-7 hrs; Intracellular:12 hrs.

Distribution

Widely distributed. Vd = 1.3 L/kg.

DOSING FOR DECREASED HEPATIC FUNCTION

Usual dose.

PREGNANCY RISK

Category C: Negative carcinogenicity and teratogenicity studies in rodents. Placental passage ratio of 1.0 (newborn:mother). Well tolerated in pregnant pts.

BREAST FEEDING COMPATIBILITY

No human data, breast milk excretion in animal studies. Breast feeding is not recommended in the U.S. in order to avoid post-natal transmission of HIV to the child, who may not yet be infected.

COMMENTS

Pros: very well tolerated; active against HBV.
- Convenient coformulations available; once-daily dosing with low pill burden (1 tab once-daily).
- Resistance (184V mutation) increases susceptibility to AZT, d4T, and TDF, and delays accumulation of TAMs.
- 3TC or FTC are essential components of all recommended initial regimens; coformulated with AZT (Combivir), ABC (Epzicom), and AZT + ABC (Trizivir).
- Decreased fitness with 184V mutation, which may result in partial antiviral activity.
Cons: high-level resistance with single point mutation (184V).
- Risk of hepatitis flare or fulminant hepatitis if 3TC withdrawn or if resistance develops in co-infected pts.
- High rate of HBV resistance with prolonged therapy if not used in combination with other anti-HBV agent (typically TDF).
- Shorter intracellular half-life compared to FTC.
- More frequent emergence of 184V with AZT/3TC than TDF/FTC in GS934 study.

References

Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006;20(6):795-803. [PMID:16549962]
Comment: This open-label pilot study determined whether there was clinical or immunological benefit to continuing 3TC in pts harboring M184V mutation. Pts randomly assigned to monotherapy with 3TC 300 mg once -daily or discontinuation of all ARV drugs (TI group). By wk 48, 20 of 29 (69%) pts in TI group (69%) and 12 of 29 (41%) in the 3TC group had discontinued study because of immunological (CD4 <350) or clinical failure, which was significantly delayed in 3TC group (p = 0.018).
Fox Z, Dragsted UB, Gerstoft J, et al. A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial. Antivir Ther. 2006;11(6):761-70. [PMID:17310820]
Comment: In vitro data suggest benefit of continuing 3TC after virological failure due to a decrease in viral fitness. This prospective randomized trial did not support this theory. At wk 48 the average decline in VL (AAUCMB) was comparable between the 2 groups (p=0.65). However, continuing 3TC despite M184V mutation may be beneficial for resistance reasons, especially in pts taking AZT, d4T, or TDF. In pts who continued 3TC, 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M184V (p<0.0001) were observed.
Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341(17):1256-63. [PMID:10528035]
Comment: Randomized, placebo-controlled trial in 34 centers in U.S. with 66 untreated pts with HBV given 3TC 100 mg/day for 52 wks. Statistically significant histologic improvement with 3TC treatment (52% vs. 23%), decreased levels of HBeAg(undetectable in 32% vs. 11%), and suppression of HBV DNA (44% vs. 16%). Rate of AEs same in both groups. Limitation of 3TC monotherapy is development of resistance, which occurred at rate of 15-20% per yr.
Perry CM, Faulds D. Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection. Drugs. 1997;53(4):657-80. [PMID:9098665]
Comment: Review article outlining therapeutic efficacy, pharmacokinetic properties, and antiviral activity.
Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed (04/23/14) [pages O-16 to O-21]
Comment: DHHS dosing recommendations for lamivudine in pediatric patients.

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