Zambian HIV Guidelines:: Nevirapine

	Zambia HIV National Guidelines
	Introduction HIV Counseling and Testing Sexually Transmitted Infections (STIs) General Principles of Antiretroviral Therapy for Chronic HIV Infection in Adults and Adolescents When to Start ARV Therapy for Chronic HIV Infection in Adults and Adolescents Initial Regimen for ARV Therapy Adherence Baseline evaluation and Monitoring Calculations: Ideal Body Weight, Body Mass Index and Creatinine Clearance ARV Therapy for Individuals with Tuberculosis Co-Infection Adverse Effects and Toxicity Immune Reconstitution Inflammatory Syndrome (IRIS) Changing or Stopping ART Treatment Failure Stopping ARV Therapy Post Exposure Prophylaxis Cotrimoxazole Prophylaxis WHO Staging in Adults and Adolescents Nutrition Care and Support Palliative Care in HIV and AIDS
	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>

Nevirapine

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
03-24-2008

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 days.

Zambia Information Author: Paul A. Pham, Pharm.D.

INDICATIONS

FDA

Treatment of HIV infection in combination with other antiretrovirals.
Due to the 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 Ingleheim	oral tablet 200 mg	$8.05
			oral suspension 50 mg/5 mL (240 mL)	$104.63 per 240 mL

*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 qd x14 days then 200 mg bid or 400 mg qd (qd dosing not FDA approved; may increase risk if hepatotoxicity, especially during early mos of therapy).
Switching from EFV to NVP. NVP dose escalation not necessary. Start with NVP 200mg bid on day 1 (Winston A, et al. AIDS 2004;18:572).
With LPV/r: Consider NVP 200 mg bid + LPV/r 600/150mg (3 tabs) bid in PI-experienced pts. Standard doses of both drugs may be adequate in PI-naive pts
With IDV: NVP 200 mg bid + either IDV 1000 mg q8h or IDV 800 mg bid + RTV 100 mg bid.
With SQV: NVP 200 mg bid + SQV 1000 mg bid + RTV 100 mg bid.
With NFV: NVP 200 mg bid + NFV 1250 mg bid.
With FPV: Consider FPV 700 mg bid + RTV 100 mg bid (limited data).
With ATV: Consider ATV 300 mg qd + RTV 100 mg qd (limited data).
With DRV: Consider DRV/r 600/100 mg bid + standard dose NVP (limited data)
With TPV: Consider TPV/r 500/200 mg bid + standard dose NVP (limited data)

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

200 mg qd x 14 days then 200 mg bid.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

200 mg qd x 14 days then 200 mg bid.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

200 mg qd x 14 days then 200 mg bid.

DOSING IN HEMODIALYSIS

200 mg qd x 14 days then 200 mg bid, 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; TEN 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

Drug	Effect of Interaction	Recommendations/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.
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 bid) 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 bid) with NVP co-administration.
Rifampin	NVP Cmin: decreased by 37-68%; NVP AUC: decreased by 37-58%. RFA AUC increased 11%(NS).	The manufacturer does not recommend co-administration. Consider RFB with NVP co-administration. Case series of favorable outcome with NVP 200 mg bid with RIF600 mg qd has been published (Oliva et al. AIDS 2003;17:637). No data but CDC recommends considering NVP 300 mg bid with RIF co-administration (with close monitoring).
RTV	RTV AUC decreased by 11%.	Not clinically significant.
SQV	SQV AUC: decreased by 38%.	boost SQV with RTV (SQV 1000 mg + RTV 1000 mg bid).
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 qd + RTV 100 mg qd (limited data)
NFV		Dose: NVP 200 mg bid + NFV 1250 mg bid
DRV/r	Based on observational data, NVP AUC decreased by 27%. No change in DRV AUC.	Dose: DRV/r 600/100 mg bid plus standard dose NVP.
Amiodarone	Serum 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 bid) with co-administration will likely overcome potential interaction.
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).
Azathioprine	Interaction unlikely.	Applies to all PIs and NNRTIs: Use standard dose.
Carbamazepine	May 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.
Caspofungin	May decrease caspofungin serum levels	Monitor for caspofungin for therapeutic failure, may need to increase dose to 70 mg/day.
Cimetidine	NVP 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).
Cocaine	May theoretically increase serum levels of hepatotoxic metabolite.	Avoid illicit drug use for obvious reasons.
Cyclophosphamide	Serum levels of co-administered drug may be decreased.	Clinical significance unknown. Monitor serum levels of immunosuppressant with dose adjustment if needed.
Cyclosporine	Serum levels of cyclosporine drug may be significantly decreased.	Clinical significance unknown. Monitor serum levels of immunosuppressant with dose adjustment if needed.
Disopyramide	Serum levels of disopyramide may be decreased.	No data. Clinical significance unknown. Monitor disopyramide serum levels (target: 2 to 7.5 mcg/mL).
Docetaxel	May decrease serum levels 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 Alkaloid	Serum levels of co-administered drug may be decreased.	Clinical significance unknown. Consider sumatriptan.
Ethinyl Estradiol/Norethindrone	Ethinyl estradiol: AUC decreased by 23%; Norethindrone: AUC decreased by 18%.	Pts should use alternative form of birth control methods (i.e. barrier contraceptive method).
Ethosuximide	May decrease serum levels of ethosuximide.	Consider switching to valproic acid for treatment of absence seizure.
Etoposide	May decrease serum levels of etoposide.	Applies to EFV and NVP: No data. Etoposide dose may need to be increased.
Fentanyl	Serum levels 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).
Food	NVP 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.
Ifosphamide	May decrease serum levels of ifosphamide.	Applies to EFV and NVP: No data. Ifosphamide dose may need to be increased.
Itraconazole	Serum levels 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 levels 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.
LPV	LPV AUC: decreased by 22%; Cmin: decreased by 55%.	Consider increasing dose of LPV to 600 mg/150 mg (3 tabs) bid or 6.5 mL bid, especially in pts with PI resistance. Standard doses may be adequate in PI-naive pts..
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 levels of mefloquine.	Monitor mefloquine serum levels. 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.
Paclitaxel	Case report states no dose adjustments necessary if KS treated with paclitaxel dose of 100 mg/m².	Monitor for chemotherapeutic response.
Phenobarbital	May decrease serum levels of NVP and phenobarbital.	Consider alternative anticonvulsants (i.e. valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants levels.
Phenytoin	May 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.
Rosiglitazone	NVP AUC decreased by 31%, Cmin decreased by 36% (p=0.032) (n=4).	Clinical significance unknown. Consider alternative agent EFV (no interaction).
Rosuvastatin	Other CYP3A4 inhibitor (i.e. erythromycin) did not affect rosuvastatin serum levels. Rosuvastatin AUC and Cmax were increased 2.1 to 4.7-fold, respectively when coadministered with LPV. LPV and RTV PK parameters were not significantly affected.	Data limited to one drug interaction study with LPV showing that rosuvastatin AUC and Cmax were increased 2.1 to 4.7-fold, respectively. LPV and RTV PK parameters were not significantly affected. Effect on NVP PK unknown. Close monitoring recommended due to limited clinical data.
Sirolimus	May significantly decrease serum levels of sirolimus.	Applies to EFV and NVP: Dose sirolimus based on serum levels. May need to increase sirolimus dose.
St. John's wort	NVP Clearance : increased by 35%.	Do not co-administer.
Tacrolimus	May significantly decrease serum levels of tacrolimus.	Applies to EFV and NVP: Dose tacrolimus based on serum levels. May need to increase tacrolimus dose.
Teniposide	May decrease serum levels of teniposide.	Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Teniposide dose may need to be increased.
THC	Based 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.
TPV/r	May decrease TPV serum concentrations. No change in NVP concentrations (observational data)	Dose: TPV/r 500/200 mg bid plus standard dose NVP.
Vinblastine	May decrease serum levels of vinblastine.	Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Vinblastine dose may need to be increased.
Vincristine	May decrease serum level of vincristine.	Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Vincristine dose may need to be increased.
Voriconazole	Serum levels of voriconazole may be significantly decreased. Voriconazole may increase NVP serum levels.	Avoid or use with voriconazole TDM. Dose adjustment of voriconazole may be needed.
Warfarin	Warfarin 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/I: 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 treatment guidelines

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