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 Zambia HIV National Guidelines
 


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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Drugs>Antiretrovirals>
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Nevirapine

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
04-04-2011

Zambia Specific Information

  • Available formulation in Zambia: Oral liquid: 50 mg/5 ml; Tablet: 200 mg. NVP 200 mg/d4T 30 mg/3TC 150 mg combination tab
  • TDF/FTC plus NVP is one preferred first line regimen.
  • Incidence of rash and hepatitis higher than with EFV based regimen.
  • Single-dose NVP for prevention of perinatal transmission not associated with hepatotoxicity. 
  • Two-week lead-in recommended, as it reduces risk of rash and hepatotoxicity.
  • NVP-based regimens not recommended for treatment of HIV-2 infection.
  • To prevent NNRTI resistance with treatment discontinuation, discontinue NVP and continue NRTIs for an additional 7-14 days.
Zambia Information Author: Paul A. Pham, Pharm.D.

INDICATIONS

FDA

  • Treatment of HIV infection in combination with other antiretrovirals.
  • Due to increased risk of hepatitis, avoid starting NVP in women with CD4 >250 and men with CD4 >400.
NON-FDA APPROVED USES

  • Single dose at time of delivery to prevent perinatal transmission (widely used in developing countries, but risk of NNRTI resistance; combination therapy preferred when available). Risk of hepatitis for women with CD4 >250 does not apply to single dose NVP.

FORMS

brand 
name
 
generic 
Mfg 
brand 
forms
 
cost* 
Viramune Nevirapine (NVP)Boehringer Ingleheimoral
tablet
200 mg
$9.12
      oral
suspension
50 mg/5 mL (240 mL)
$118.50 per 240 mL
      oral
sustained-release tablet
400 mg
tba

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

Pill burden: 2 tabs per day

  • NVP 200 mg once-daily x14 days then 200 mg twice-daily or 400 mg sustained-release tablet once-daily
  •  If rash occurs during initial 14-day lead-in period of 200 mg/day, NVP dose should not be increased until the rash has resolved (BUT total duration of once-daily lead-in dosing period should not exceed 28 days).
  • With LPV/r: Consider NVP 200 mg twice-daily + LPV/r 500/125mg twice-daily
  • With IDV: NVP 200 mg twice-daily + either IDV 1000 mg q8h or IDV 800 mg twice-daily + RTV 100 mg twice-daily.
  • With SQV: NVP 200 mg twice-daily + SQV 1000 mg twice-daily + RTV 100 mg twice-daily.
  • With NFV: NVP 200 mg twice-daily + NFV 1250 mg twice-daily.
  • With FPV: Consider FPV 700 mg twice-daily + RTV 100 mg twice-daily (limited data).
  • With ATV: Avoid co-administration
  • With DRV: Consider DRV/r 600/100 mg twice-daily + standard dose NVP (limited data)
  • With TPV: Consider TPV/r 500/200 mg twice-daily + standard dose NVP (limited data)
  • With MVC: Consider MVC 300 mg twice-daily + standard dose NVP (limited data).
  • With ETR or EFV: not recommended.
  • With RAL: standard doses
  • Discontinuation of NVP-based regimen: continue NRTI for 7 days after NVP discontinuation or substitute PI/r for NVP x 1-4 weeks before discontinuation.
  • Switching from EFV to NVP: NVP dose escalation not necessary. Start with NVP 200mg twice-daily on day 1 (Winston A, et al. AIDS 2004;18:572).
  • Switching from NVP (immediate-release) 200 mg twice-daily to NVP (extended-release) 400 mg once-daily.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

200 mg once-daily x 14 days then 200 mg twice-daily.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

200 mg once-daily x 14 days then 200 mg twice-daily.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

200 mg once-daily x 14 days then 200 mg twice-daily.

DOSING IN HEMODIALYSIS

200 mg once-daily x 14 days then 200 mg twice-daily , on days of dialysis dose post dialysis.

DOSING IN PERITONEAL DIALYSIS

No data. Consider standard dose.

DOSING IN HEMOFILTRATION

No data. Consider standard dose.

ADVERSE DRUG REACTIONS

COMMON

  • Maculopapular erythematous rash with or without pruritus in 17%; requires NVP discontinuation in 7%. Steroids not effective. Cross-reaction with EFV unlikely. D/C NVP if rash is blistering, involves mucous membranes, is accompanied by elevated transaminase levels or fever.
OCCASIONAL

  • Hepatitis (2 forms): 1) SEVERE ACUTE HEPATITIS (part of hypersensitivity reaction) reported in up to 11% of treatment-naive women with CD4 >250 (12-fold increase compared to women with CD4 <250) and 6.4% of men with CD4 >400. This form of hepatitis occurs early in the course (6-8 wks) and is presumed to be immune-mediated; may accompany rash and fever; 2) Hepatitis usually occurring after months of therapy in up to 15% of pts, usually asymptomatic, resembling transaminatis seen with PIs and EFV, and may usually be "treated through." Rate is increased with HBV and HCV co-infection. Some recommend NVP discontinuation if ALT >5 or 10x UNL.
  • Hypersensitivity reaction presenting as rash, hepatitis, fever, arthralgias, and myalgias in first 6-8 wks of therapy; can be fatal if not recognized.
  • Rhabdomyolysis observed in some patients with rash and hepatitis.
RARE

  • STEVENS-JOHNSON SYNDROME or TOXIC EPIDERMAL NECROLYSIS with 5 reported deaths.

DRUG INTERACTIONS

CYP3A4 substrate and inhibitor. May significantly decrease serum levels of other CYP3A4 substrates. CYP3A4 inducers may decrease NVP levels.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
Clarithromycin Clarithromycin AUC decreased by 29% but 14-hydroxy clarithromycin AUC increased by 27%. NVP AUC increased by 26%No dose modification needed. Consider azithromycin for treatment or prophylaxis of MAC
EFV EFV AUC: decreased by 22%; Cmin: decreased by 36%Co-administration not recommended due to overlapping resistance profile and potential for increased toxicity.
FPV May decrease APV levels.Clinical significance unknown. Dose: FPV with RTV (FPV 700 mg + RTV100 mg twice-daily) with co-administration (limited data)
IDV IDV AUC: decreased by 28%.Clinical trials demonstrated good efficacy with standard dose. Consider increasing the dose of IDV to 1000 mg q8h (or IDV 800 mg + RTV 100 mg twice-daily) with NVP co-administration.
Lopinavir/ritonavir LPV AUC: decreased by 22%; Cmin: decreased by 55%.Consider increasing dose of LPV to 600/150 mg (3 tabs) twice-daily or 6.5 mL twice-daily , especially in pts with PI resistance. Standard doses may be adequate in PI-naive pts..
Rifampin NVP Cmin: decreased by 37-68%; NVP AUC: decreased by 37-58%. RIF AUC increased 11%(NS).Co-administration not recommended. Rifabutin with NVP OR rifampin with EFV can be considered . NVP dose escalation not needed if RIF at steady-state. Case series of favorable outcome with NVP 200 mg twice-daily with rifampin 600 mg once-daily has been published (Oliva et al. AIDS 2003;17:637), but higher rates of virologic failure reported in large cohorts (Boulle A. JAMA 2008;300:530). Although NVP 300 mg twice-daily may result in better PK, a randomized trial comparing standard dose NVP (200 mg twice-daily) to a higher dose (300 mg twice-daily) among patients on rifampin demonstrated increased risk of NVP hypersensitivity among pts receiving high-dose NVP.  
RTV RTV AUC decreased by 11%.Not clinically significant. Use standard dose.
SQV SQV AUC: decreased by 38%.boost SQV with RTV (SQV 1000 mg + RTV 1000 mg twice-daily ).
Fluconazole Nevirapine clearance decreased by 2-fold; no significant effect on fluconazole levels. Data limited to an interaction study with 24 HIV+ pts; 25% developed elevated transaminates (5 x UNL). Recommend monitoring for liver toxicity and NVP levels.
Atazanavir ATV mean Cmin was lower with NVP co-administration.Avoid unboosted ATV with NVP co-administration. Consider ATV 300 mg once-daily + RTV 100 mg once-daily (limited data)
Tipranavir May decrease TPV serum concentrations. No change in NVP concentrations (observational data) Dose: TPV/r 500/200 mg twice-daily plus standard dose NVP.
NFV No significant drug interaction. Dose: NVP 200 mg twice-daily + NFV 1250 mg twice-daily
Atazanavir (ATV) ATV decreased 41%. NVP increased by 46% (compared with historical control) Co-administration not recommended.
Maraviroc  MVC serum concentration was not significantly affected compared to historical controls in a single dose study; however, MVC AUC may be decreased at steady state. Consider MVC 300 mg twice-daily plus NVP 200 mg twice-daily.
DRV/r Based on observational data, NVP AUC decreased by 27%. No change in DRV AUC. Dose: DRV/r 600/100 mg twice-daily plus standard dose NVP.
AmiodaroneSerum levels of amiodarone may be decreased.Clinical significance unknown. Dose adjustment of co-administered drug may be needed with titration to effect.
APV May decrease APV levels.Clinical significance unknown. Boosting APV with RTV (APV liquid 700 mg + RTV 100 mg twice-daily) with co-administration will likely overcome potential interaction. FPV/r 700/100 mg twice-daily with NVP co-administration preferred.
Artemether (artemisinin)May decrease serum levels of artemether.Applies to EFV and NVP.Co-administration of artesunate and amodiaquine may result in significant LFT elevations. Close monitoring of artemether therapeutic efficacy recommended (i.e. parasite count on blood smear and clinical signs and symptoms of clinical improvement).
AzathioprineInteraction unlikely.Applies to all PIs and NNRTIs: Use standard dose.
CarbamazepineMay decrease serum levels of NVP and carbamazepine.Consider alternative anticonvulsants (i.e. valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants level and consider TDM of NNRTIs.
CaspofunginMay decrease caspofungin serum levelsMonitor for caspofungin for therapeutic failure, may need to increase dose to 70 mg/day.
CimetidineNVP Cmin increased by 21%.No significant interaction. Use standard dose.
Clonazepam May decrease serum levels of clonazepam.Consider alternative anticonvulsants (i.e. valproic acid, levetiracetam, or topiramate).
CocaineMay theoretically increase serum levels of hepatotoxic metabolite.Avoid illicit drug use for obvious reasons.
CyclophosphamideSerum concentrations of co-administered drug may be decreased.Clinical significance unknown. Monitor serum concentrations of immunosuppressant with dose adjustment if needed.
CyclosporineSerum concentrations of cyclosporine drug may be significantly decreased.Clinical significance unknown. Monitor serum concentrations of immunosuppressant with dose adjustment if needed.
Diltiazem
NVP may decrease diltiazem serum concentrations. Titrate diltiazem to therapeutic effect with NVP co-administration.
DisopyramideSerum concentrations of disopyramide may be decreased.No data. Clinical significance unknown. Monitor disopyramide serum concentrations (target: 2 to 7.5 mcg/mL).
DocetaxelMay decrease serum concentrations of docetaxel.Applies to EFV and NVP: No data. Docetaxel dose may need to be increased.
Echinacea May decrease NVP serum level. Echinacea (400 mg 4x/d) decreased CYP3A4 substrate (midazolam) by 23%.Clinical significance unknown but should be avoided until the safety of this combination is further evaluated.
Ergot AlkaloidSerum levels of co-administered drug may be decreased.Clinical significance unknown. Consider sumatriptan.
Ethinyl Estradiol/NorethindroneEthinyl estradiol: AUC decreased by 23%; Norethindrone: AUC decreased by 18%.Pts should use alternative form of birth control methods (i.e. barrier contraceptive method).
EthosuximideMay decrease serum levels of ethosuximide.Consider switching to valproic acid for treatment of absence seizure.
EtoposideMay decrease serum concentrations of etoposide.Applies to EFV and NVP: No data. Etoposide dose may need to be increased.
Fentanyl Serum concentrations of co-administered drug may be decreased.Clinical significance unknown. Dose adjustment of co-administered drug may be needed. Consider other opiates (i.e. morphine or oxycodone).
FoodNVP AUC not affected.Administer NVP with or without food.
Garlic Supplement No data.Studies only done with SQV resulting in reduction of SQV levels. Avoid co-administration.
Heroin (Diamorphine)Drug interaction unlikely.Applies to PIs and NNRTIs: Interaction unlikely but illicit drug use should be avoided for obvious reasons.
IfosphamideMay decrease serum concentrations of ifosphamide.Applies to EFV and NVP: No data. Ifosphamide dose may need to be increased.
Itraconazole Serum concentrations of itraconazole may be decreased.Clinical significance unknown. Dose adjustment of co-administered drug may be needed.
Ketoconazole Ketoconazole AUC decreased by 72%; NVP levels increased by 15-30%.Co-administration not recommended. Consider alternative antifungal (i.e. fluconazole).
Lidocaine (systemic)Serum concentrations of lidocaine may be decreased.No data. Clinical significance unknown. Dose adjustment of co-administered drug may be needed. Monitor serum levels (target: 1.5 to 6 mcg/mL) with co-administration.
Medroxyprogesterone (DMPA)NVP AUC slightly increased with DMPA co-administration. DMPA levels were not reported. No evidence of ovulation based on progesterone levels through week 12. Small increase in NVP AUC not likely to be significant.
Mefloquine May decrease serum concentrations of mefloquine.Monitor mefloquine serum concentrations. Close monitoring of mefloquine therapeutic efficacy (i.e. parasite count on blood smear and clinical signs and Sx of clinical improvement).
Methadone Methadone AUC: decreased by 46%-51%.Monitor for signs and Sx of methadone withdrawal (methadone withdrawal observed one wk into therapy); some pts may need an increase in the methadone dose.
Milk Thistle No data.Data limited to an interaction study with milk thistle and IDV. IDV AUC unchanged; IDV Cmin decreased by 47%. Clinical significance unknown. Avoid co-administration.
Mycophenolate (MMF)NVP clearance increased by 27%.Clinical significance unknown. Unlikely to be significant.
Nifedipine NVP may decrease nifedipine serum concentrations. Titrate nifedipine to therapeutic effect with NVP co-administration.
Paclitaxel Case report states no dose adjustments necessary if KS treated with paclitaxel dose of 100 mg/m2.Monitor for chemotherapeutic response.
PhenobarbitalMay decrease serum concentrations of NVP and phenobarbital.Consider alternative anticonvulsants (i.e. valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants levels.
PhenytoinMay decrease serum levels of NVP and phenytoin.Consider alternative anticonvulsants (i.e. valproic acid, lamotrigine, levetiracetam, or topiramate).With co-administration, monitor anticonvulsants level and consider TDM of NVP.
Rifabutin RFB AUC increased by 16% (NS) NVP AUC unchanged.Unlikely to be clinically significant. Monitor for RFB associated ADRs. Standard dose: RFB 300 mg/day or 300 mg 3x/wk.
Rifapentine NVP serum levels may be significantly decreased.Avoid co-administration. Consider using rifabutin.
RosiglitazoneNVP AUC decreased by 31%, Cmin decreased by 36% (p=0.032) (n=4).Clinical significance unknown. Consider alternative agent EFV (no interaction).
Rosuvastatin  Interaction unlikely.Data limited to one drug interaction study with LPV and TPV showing that rosuvastatin were increased . LPV and RTV PK parameters were not significantly affected. Effect on NVP PK unknown. Close monitoring recommended due to limited clinical data.
SirolimusMay significantly decrease serum concentrations of sirolimus.Applies to EFV and NVP: Dose sirolimus based on serum concentrations. May need to increase sirolimus dose.
St. John's wortNVP Clearance : increased by 35%.Do not co-administer.
TacrolimusMay significantly decrease serum concentrations of tacrolimus.Applies to EFV and NVP: Dose tacrolimus based on serum concentrations. May need to increase tacrolimus dose.
TeniposideMay decrease serum concentrations of teniposide.Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Teniposide dose may need to be increased.
THCBased on data with NFV and IDV interactions are unlikely.Applies to PIs and NNRTIs: Interactions are unlikely but illicit drug use should be avoided for obvious reasons.
Verapamil NVP may decrease verapamil serum concentrations. Titrate verapamil to therapeutic effect with NVP co-administration.
VinblastineMay decrease serum concentrations of vinblastine.Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Vinblastine dose may need to be increased.
VincristineMay decrease serum concentrations of vincristine.Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Vincristine dose may need to be increased.
Voriconazole Serum concentrations of voriconazole may be significantly decreased. Voriconazole may increase NVP serum concentrations.Avoid or use with voriconazole TDM. D (Target Cmin >2mcg/mL. Dose adjustment of voriconazole may be needed.
WarfarinWarfarin plasma concentrations may be increased (per manufacturer), but case reports of need for increased dose of warfarin in pts taking NVP have been published.Clinical significance unknown. Monitor INR closely with NVP co-administration.

RESISTANCE

  • K103N: High level resistance (seen more when NVP is used with AZT); causes high-level cross-resistance to all available NNRTIs.
  • 181C/I: High-level resistance to NVP, DLV; low-level resistance to EFV, though clinical data do not support use of EFV after NVP failure. 181C partially reverses TAM-mediated AZT and TDF resistance.
  • 106A/M: 106A causes high-level NVP resistance, intermediate DLV resistance, and low-level EFV resistance; 106M causes high-level NVP and EFV resistance and intermediate DLV resistance; 106I is a polymorphism that does not cause NNRTI resistance.
  • 188C/L/H: 188C causes high-level resistance to NVP and low-level resistance to EFV and DLV; 188H causes low-level resistance to NVP, DLV, EFV; 188L causes high-level resistance to NVP, EFV and low to intermediate resistance to DLV.
  • 190A/S: 190A causes high-level resistance to NVP, intermediate resistance to EFV; susceptibility or hypersusceptibility to DLV (clinical significance unknown); 190S same as above, but high-level EFV resistance.
  • 230L: High-level NVP resistance, intermediate EFV resistance, low-level DLV resistance.
  • 108I: Potential low-level resistance to NVP, EFV, and DLV.
  • 100I: Intermediate resistance to NVP, DLV, EFV.

PHARMACOLOGY

Pharmacology

COMMENTS

  • Pros: Efficacy comparable to EFV at 1 yr in 2NN trial (though non-inferiority not established); more favorable lipid profiles than EFV; no neuropsychiatric toxicity; safety and efficacy of single dose to prevent perinatal transmission established.
  • Cons: Less clinical data than for EFV; potential for severe hepatoxicity and sometimes lethal rash reaction; CD4 count restrictions; single dose NVP used to prevent perinatal transmission associated with development of high level resistance to NNRTIs; considered alternative in current U.S. treatment guidelines. Inconclusive data on efficacy when combined with TDF + either FTC or 3TC.

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