Class	Drug	HIV Drug
Analgesics	Buprenorphine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary No data. Coadministration may decrease buprenorphine concentrations. Patients should be closely monitored and the dose of buprenorphine should be increased appropriately if patients complain of decreased benefit from buprenorphine or if there is re-emergence of craving for illicit drugs. Description The interaction of buprenorphine with CYP 3A4 inducers has not been investigated, therefore it is recommended that patients receiving buprenorphine should be closely monitored if enzyme inducers are co-administered. Use of these medications may increase the metabolism of buprenorphine and the dose of buprenorphine should be increased appropriately if patients complain of decreased benefit from buprenorphine or if there is re-emergence of craving for illicit drugs. Subutex Summary of Product Characteristics, Schering Plough Ltd, January 2006. The interaction of buprenorphine with CYP 3A4 inducers has not been investigated; therefore it is recommended that patients receiving buprenorphine should be closely monitored if inducers of CYP 3A4 are co-administered. Subutex Prescribing Information, Reckitt Benckiser Pharmaceuticals Inc, June 2005.

Class	Drug	HIV Drug
Analgesics	Fentanyl	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease fentanyl concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and fentanyl, which may cause decreased fentanyl plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Analgesics	Methadone	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration decreases methadone AUC by ~40-65%; narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Description In the presence of nevirapine, a 3-fold increase in clearance of oral methadone was observed. Methadone mean AUC and mean Cmax, corrected for the change in methadone dose administered, are decreased by 65% and 50%, respectively. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. In a controlled pharmacokinetic study with 9 patients receiving chronic methadone to whom steady state nevirapine therapy was added, the clearance of methadone was increased by 3-fold resulting in symptoms of withdrawal, requiring dose adjustments in 10 mg segments, in 7 of the 9 patients. Methadone did not have any effect on nevirapine clearance. Increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with methadone (racemic n=11; (R)-methadone n=9) significantly decreased the methadone mean dose-adjusted AUC by 41%. AUC reductions were similar in patients taking the racemic methadone (37%) or the R-enantiomer (44%). 14/20 patients required additional methadone due to withdrawal symptoms. However, the median dose increase (15%) was less than that which would be expected from the PK data. Nevirapine significantly reduces the levels of racemic methadone and (R)-methadone in human immunodeficiency virus-infected patients. Stocker H, Kruse G, Kreckel P, et al., Antimicrob Agents Chemother, 2004, 48: 4148-4153. Administration of nevirapine (200 mg bd) to 8 HIV-infected injection drug users who also received methadone resulted in a significant reduction in methadone exposure after 7-10 days of therapy. There was a 36% reduction in mean methadone Cmax (from 676 to 435 ng/ml) and mean methadone AUC reduced from 12024 to 5713 ng/ml.h. 6/8 patients complained of symptoms of methadone withdrawal and required a mean increase in methadone dose of 16%. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clarke SM, Mulcahy FM, Tjia J, et al. Clin Infect Dis, 2002, 33:1595-1597 Ten HIV+ patients on methadone maintenance commenced nevirapine under dose escalation to a final dose of 400 mg once daily. 9/10 patients developed acute opioid withdrawal symptoms beginning 4-14 days after commencing nevirapine. Methadone AUC decreased by ~50% and a mean methadone increase of 22% was required. Pharmacokinetics of methadone in drug users taking methadone who start HAART with nevirapine once daily. Portilla J, Arroyo E, Climent E, et al. 14th International AIDS Conference, Barcelona, July 2002, abstract MoPeC3408. There are various case reports of patients previously stable on methadone therapy experiencing withdrawal symptoms when nevirapine was added. Altice et al. have shown a decrease in trough plasma methadone concentrations in two patients (patient 1 – trough methadone decreased from 0.72 to 0.08 µg/ml with nevirapine; patient 2 – trough methadone decreased from 0.92 to 0.06 µg/ml with nevirapine). Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Heelon MW, Meade LB. Pharmacotherapy, 1999, 19:471–2. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. Altice FL, Friedland GH, Cooney EL. AIDS, 1999, 13:957–62.

Class	Drug	HIV Drug
Antiarrhythmics	Amiodarone	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease amiodarone concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and amiodarone, which may cause decreased amiodarone plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Antiarrhythmics	Disopyramide	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease disopyramide concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and disopyramide, which may cause decreased disopyramide plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Antiarrhythmics	Lidocaine (Lignocaine)	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease lidocaine concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and lidocaine, which may cause decreased lidocaine plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Antibacterials	Clarithromycin	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine (200 mg twice daily) with clarithromycin (500 mg twice daily) decreased clarithromycin AUC (31%), Cmax (23%) and Cmin (57%), and increased 14-OH-clarithromycin AUC (42%) and Cmax (47%) with no change in Cmin. Compared to historical controls, there were increases in nevirapine Cmin (28%), AUC (26%) and Cmax (24%). No dose adjustment is necessary for either clarithromycin or nevirapine; however, close monitoring of hepatic abnormalities is recommended. As the clarithromycin metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity may be altered and alternatives to clarithromycin, such as azithromycin, should be considered. Description The results of a nevirapine-clarithromycin interaction study (n=15) revealed a reduction in clarithromycin mean AUC by 31% mean Cmin by 56%; the active clarithromycin metabolite 14-OH clarithromycin showed an increase in the mean AUC by 42% and mean Cmax by 47%. There were increases in the nevirapine Cmin by 28%, AUC by 26% and Cmax by 24% compared to historical controls. These results would suggest that no dose adjustment is necessary for either clarithromycin or nevirapine when the two medicinal products are co-administered. Close monitoring of hepatic abnormalities is nevertheless recommended. However, alternative therapy to clarithromycin should be considered when treating a patient for mycobacterium avium-intracellulare complex, as the active metabolite is not effective in this instance. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with clarithromycin (500 mg twice daily), in 15 HIV+ patients, resulted in a 31% ,23% and 57% decrease in clarithromycin AUC, Cmax and Cmin, respectively. 14-OH-clarithromycin AUC and Cmax were increased by 42% and 47%, respectively, and Cmin was unaltered. The effect on nevirapine pharmacokinetics was not significant. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of nevirapine (200 mg twice daily) and clarithromycin (500 mg twice daily) was studied in 18 HIV+ individuals. There was a 30% reduction in clarithromycin AUC, a 21% decrease in Cmax and a 46% decrease in Cmin. AUC of 14-OH clarithromycin increased by 58% and Cmax increased by ~60%. Results suggest that NVP increased the metabolic clearance of clarithromycin to its active metabolite resulting in lower steady-state concentrations of parent drug and higher concentrations of metabolite. Coadministration of clarithromycin resulted in a 26% increase in nevirapine AUC, a 24% increase in Cmax and a 28% increase in Cmin. Effect of the reverse transcriptase inhibitor, nevirapine, on the steady-state pharmacokinetics of clarithromycin in HIV-positive patients. Robinson P, Gigliotti M, Lamson M et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999, abstract 374. LHPG Comment: Monitoring for hepatic abnormalities and activity against Mycobacterium aviium indicates amber.

Class	Drug	HIV Drug
Antibacterials	Dapsone	Nevirapine
No clinically significant interaction expected
Summary In vitro studies showed that dapsone did not affect the formation of nevirapine hydroxylated metabolites. No data on the effect of nevirapine on dapsone. Description Studies using human liver microsomes indicated that dapsone did not affect the formation of nevirapine hydroxylated metabolites. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008.

Class	Drug	HIV Drug
Antibacterials	Erythromycin	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Erythromycin significantly inhibited the formation of nevirapine hydroxylated metabolites. There is the potential for an interaction. Description Erythromycin significantly inhibited the formation of nevirapine hydroxylated metabolites. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008.

Class	Drug	HIV Drug
Antibacterials	Rifabutin	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine (200 mg twice daily) with rifabutin (150 or 300 mg once daily) increased rifabutin AUC (17%) and Cmax (28%) with no change in Cmin, and also increased 25-O-desacetyl-rifabutin AUC (24%), Cmax (29%) and Cmin (22%). The effect on nevirapine pharmacokinetics was not significant. Caution is warranted as due to high intersubject variability, some patients may experience larger increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Description In a pharmacokinetic study (n=19) the concomitant administration of rifabutin following full induction with nevirapine resulted in a mean increase of 17% in the steady state AUC and a 28% increase in mean Cmax of rifabutin. There was also an increase in the 25-O-desacetylrifabutin metabolite mean AUC by 24% and an increase in mean Cmax by 29%. Due to the high intersubject variability some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. A clinically not relevant increase in the apparent clearance of nevirapine (by 9%) compared to historical pharmacokinetic data was reported. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 20082007. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with rifabutin (150 or 300 mg once daily), in 19 HIV+ patients, caused a 17% and 28% increase in rifabutin AUC and Cmax, respectively, but caused no alteration in Cmin. Nevirapine caused a 24%, 29% and 22% increase in 25-O-desacetyl-rifabutin AUC, Cmax and Cmin, respectively. Rifabutin and its metabolite concentrations were moderately increased. The effect on nevirapine pharmacokinetics was not significant. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of rifabutin (150 or 300 mg once daily) and nevirapine (200 mg twice daily) was studied in 21 HIV+ individuals. Nevirapine AUC (54.0 ± 18.7 µg/ml.h) was consistent with historical controls. Nevirapine Cmax values of 5.8 ± 1.9 µg/ml and Cmin values of 3.8 ± 1.3 µg/ml were obtained. Nevirapine and rifabutin can be safely coadministered with no need for dose adjustment. Pharmacokinetic interaction between nevirapine and rifabutin. Maldonad S, Lamso M, Gigliotti M et al. 39th International Conference on Antimicrobial Agents and Chemotherapy, 1999, abstract 341. LHPG Comment: Further data required hence amber.

Class	Drug	HIV Drug
Antibacterials	Rifampicin	Nevirapine
These drugs should not be coadministered
Summary Coadministration is contraindicated due to decreased nevirapine concentrations. Coadministration of nevirapine (200 mg twice daily) with rifampicin (600 mg once daily) increased rifampicin AUC (11%) and had no effect on Cmax. Compared to historical controls, there were clinically significant decreases in nevirapine AUC (58%), Cmax (50%) and Cmin (68%). Consider using rifabutin instead or switching to a triple NRTI combination for a variable period of time, depending on the TB treatment regimen. Preliminary data suggest that adequate nevirapine concentrations may be attained in patients with low body weight. Dose escalation should not be used when starting nevirapine and a dose increase may be necessary. Description LHPG Comment: Important to obtain expert advice from TB and HIV specialists. The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine is not recommended. Therefore, these medicinal products should not be used in combination. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine containing regimen may consider use of rifabutin instead. Rifabutin and nevirapine can be administered concurrently without dose adjustments. Alternatively physicians may consider switching to a triple NRTI combination for a variable period of time, depending on the tuberculosis treatment regimen. An open-label study (n=14) to determine the effects of nevirapine on the steady state pharmacokinetics of rifampicin resulted in no significant change in rifampicin Cmax and AUC. In contrast, rifampicin produced a significant lowering of nevirapine AUC (58% decrease), Cmax (50% decrease) and Cmin (68% decrease) compared to historical data. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with rifampicin (600 mg once daily) in 14 HIV+ patients caused an 11% increase in rifampicin AUC but no alteration in Cmax. Rifampicin Cmin was below the limit of detection for the assay. Administration of rifampicin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Cmax by greater than 50%. Nevirapine and rifampicin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with TB and using a nevirapine containing regimen may use rifabutin instead. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. The pharmacokinetic of nevirapine were determined 30 HIV-infected Thai subjects with active TB and on rifampicin randomized to receive nevirapine 400 mg (arm 1) or nevirapine 600 mg (arm 2). A nevirapine lead in was performed in both arms of 200 and 400 mg/day. Suboptimal nevirapine concentrations (<3.1 mg/L) were found in 77% of patients in the 400 mg arm at week 2 (after lead in period) compared to 13% of patients in the 600 mg arm. However the higher dose was associated with a high rate of hypersensitivity (4 patients). There was no difference in the 12 week efficacy data between the 2 arms (<50 copies; 53% vs 43% in arms 1 and 2 respectively). The authors concluded that nevirapine 400 mg/day may be sufficient in Asian (low body weight) patients receiving rifampicin but the 200 mg lead in should be avoided. Pharmacokinetic and 12 weeks efficacy of nevirapine: 400 mg versus 600 mg per day in HIV infected patients with active tuberculosis receiving rifampicin: a multicenter study. Avihingsanon A, et al. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, February 2007, abstract 576. Coadministration of nevirapine (200 mg twice daily) and rifampicin (450 mg once daily if less than 60 kg; 600 mg once daily if >60 kg) was studied in 13 HIV+ subjects. Rifampicin caused significant reductions in nevirapine Cmax (42%), Cmin (53%) and AUC (46%) with 8/13 subjects having subtherapeutic concentrations (Cmin <3 µg/ml). Nevirapine dose was increased to 300 mg twice daily in 7/8 subjects and resulted in Cmin within the target range (3-12 µg/ml). Further studies to evaluate the long-term safety of the higher nevirapine dose are required. Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration. Ramachandran G, Hemanthkumar AK, Rajasekaran S, et al. J Acquir Immune Defic Syndr, 2006, 42(1): 36-41. A pilot study to measure plasma concentrations of nevirapine was conducted in 27 HIV+ Malawian subjects who commenced Triomune (generic fixed-dose nevirapine, zidovudine and lamivudine) whilst receiving rifampicin based TB therapy. Despite good adherence, subtherapeutic nevirapine levels (<3000 ng/ml) were found in 37% of the 94 samples and in 78% of the patients on at least one occasion. However, 83% of the low levels occurred during the first two weeks of Triomune therapy when the standard nevirapine dose escalation schedule was used (i.e. 200 mg once daily for two weeks, then 200 mg twice daily). Sub-therapeutic nevirapine levels during combined Triomune® (stavudine + lamivudine + nevirapine) and tuberculosis treatment in Malawian adults. van Oosterhout JJG et al. 16th International AIDS Conference, Toronto, August 2006, abstract TUPE0091. NVP pharmacokinetic profiles were determined in 12 HIV- subjects receiving single doses of nevirapine (200 mg) alone and after 7 days of rifampicin (standard weight-related dose). Coadministration resulted in decreases in nevirapine AUC (79%), Cmax (20%) and Cmin (60%). The pharmacokinetics of single-dose nevirapine among healthy Indian volunteers was similar to that reported from other racial populations. Rifampicin induction significantly alters the pharmacokinetic profile of nevirapine in this population, and concurrent use should not be recommended. Effect of rifampin hepatic induction on nevirapine levels in Indian volunteers. Pujari et al. 13th Conference on Retroviruses and Opportunistic Infections, Denver, February, 2006, abstract 574. The effect of rifampicin on NVP pharmacokinetics was investigated in Thai patients receiving a generic fixed dose combination of stavudine/lamivudine/NVP alone (n=74) and in combination with rifampicin (n=70). There were no differences between the groups for age, gender, weight, height or BMI. Median (range) NVP trough concentrations when given alone were 8170 ng/ml (1550-13580; n=45) compared to 4430 ng/ml (650-13760; n=49) when given with rifampicin. Concentrations were below target (3100 ng/ml) in two patients receiving NVP alone, and in 7 patients receiving NVP with rifampicin. Multivariate analysis showed use of rifampicin and time of drug intake to be significantly associated with NVP concentrations. Nevirapine plasma concentrations in the presence of rifampicin (HIV-NAT 025). Autar, R et al. 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, April 2005, abstract 21. Coadministration of nevirapine (200 mg twice daily) and rifampicin was investigated in a cross sectional study in 13 Thai patients. The mean nevirapine plasma concentration was 12690 ng/ml and 12/13 patients had concentrations that exceeded the lower clinical limit (3000 ng/ml). What is the clinical relevance of the drug interaction between nevirapine and rifampicin? Autar R, Mahanontharit A, Anekthananon T, et al., 11th International AIDS Conference, Bangkok, July 2004, abstract B11784. Coadministration of nevirapine and rifampicin was studied in 10 HIV-infected patients with tuberculosis. In the presence of rifampicin, nevirapine AUC was reduced by 31%, Cmax by 36% and Cmin by 21%. Exposure to rifampicin was not significantly different in the presence of nevirapine. Given that the lowest trough nevirapine concentration was 40x the protein binding adjusted median infective dose (IC50) of wild type HIV, the authors suggest that there is no need to increase nevirapine dosage when it is given with rifampicin. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. Ribera E, Pou L, Lopez RM, et al. J Acquir Immune Defic Syndr, 2001, 28:450-453. Coadministration of nevirapine (200 mg twice daily) with rifampicin (600 mg once daily) to 22 HIV+ individuals resulted in no significant change in rifampicin AUC or Cmax compared to baseline levels. Average nevirapine concentration was reduced by 58% and Cmin was reduced by 68% compared to historical controls. There are insufficient data to assess whether dose adjustments are necessary. Consideration should be given to increasing the nevirapine dose by 50% (to 300 mg twice daily) if given concurrently with rifampicin. However, there are no safety data available for the combination at this dose of nevirapine and it should only be used if clearly indicated and with careful monitoring. Pharmacokinetic interaction between nevirapine and rifampin. Robinson P, Lamson M, Gigliotti M et al. 12th World AIDS Conference, 1998, abstract 60623.

Class	Drug	HIV Drug
Antibacterials	Trimethoprim/Sulfamethoxazole	Nevirapine
No clinically significant interaction expected
Summary In vitro studies showed that trimethoprim/sulfamethoxazole did not affect the formation of nevirapine hydroxylated metabolites. Description Studies using human liver microsomes indicated that trimethoprim/sulfamethoxazole did not affect the formation of nevirapine hydroxylated metabolites. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008.

Class	Drug	HIV Drug
Anticonvulsants	Carbamazepine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease carbamazepine concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and carbamazepine, which may cause decreased carbamazepine plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Anticonvulsants	Clonazepam	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease clonazepam concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and clonazepam, which may cause decreased clonazepam plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Anticonvulsants	Ethosuximide	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease ethosuximide concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and ethosuximde, which may cause decreased ethosuximide plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Antidepressants	Citalopram	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary The potential for citalopram affecting the concentrations of other drugs is low. However, citalopram is extensively metabolised by CYP450; since there are no interaction data, caution is required as citalopram concentrations may be altered by other drugs. Description LHPG Comment: Citalopram is a weak inhibitor of CYP1A2 and CYP2D6, and has minimal or no inhibitory effect on CYP2C9, CYP2C19, CYP2E1 and CYP3A4. Therefore the potential for citalopram affecting the concentrations of other drugs is low. However, citalopram is extensively metabolised by CYP450; since there are no interaction data, caution is required as citalopram concentrations may be altered by other drugs.

Class	Drug	HIV Drug
Antidepressants	Mirtazapine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Mirtazapine is extensively metabolised by CYP3A4. Coadministration with NNRTIs is likely to increase its clearance which could decrease mirtazapine concentrations. Description LHPG Comment: Mirtazapine is extensively metabolised by CYP3A4. Its clearance is likely to be increased by coadministration of NNRTIs, which could result in a decrease in mirtazapine plasma concentrations.

Class	Drug	HIV Drug
Antifungals	Caspofungin	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Limited population pharmacokinetic data indicate that coadministration of caspofungin 35, 50 or 70 mg i.v. once daily) with enzyme inducers (including nevirapine) was associated with a 20-40% reduction in caspofungin AUC and Ctrough. An increase in the daily dose of caspofungin to 70 mg, following the 70 mg loading dose should be considered. Description Limited data from population pharmacokinetic studies indicate that concomitant use of caspofungin with the inducers efavirenz or nevirapine may result in a decrease in caspofungin AUC. When coadministered with inducers of metabolic enzymes, an increase in the daily dose of caspofungin to 70 mg, following the 70 mg loading dose should be considered. Cancidas Summary of Product Characteristics,Merck Sharp & Dohme Ltd, October 2004. Results from regression analyses of patient pharmacokinetic data suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine) with caspofungin may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible. When caspofungin is co-administered with inducers of drug clearance, such as efavirenz or nevirapine, use of a daily dose of 70 mg of caspofungin should be considered. Cancidas Prescribing Information, Merck & Co, February 2005. Concomitant use of caspofungin (35, 50 or 70 mg i.v. once daily) with enzyme inducers (including efavirenz) was associated with 20-40% reductions in caspofungin AUC and Ctrough. Population pharmacokinetics of caspofungin in candidiasis patients. Stone JA, Winchell, Li S, Winchell G, et al. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 2003, abstract A-1571.

Class	Drug	HIV Drug
Antifungals	Fluconazole	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine (200 mg twice daily) with fluconazole (200 mg once daily)had no effect on fluconazole AUC, Cmax or Cmin but increased nevirapine exposure by ~100% when compared to historic data. Caution should be used because of the risk of increased exposure to nevirapine and patients should be monitored closely for nevirapine-associated adverse events. Description Co-administration of fluconazole and nevirapine resulted in approximately 100% increase in nevirapine exposure compared with historical data where nevirapine was administered alone. Because of the risk of increased exposure to nevirapine, caution should be exercised if the medicinal products are given concomitantly and patients should be monitored closely. There was no clinically relevant effect of nevirapine on fluconazole. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with fluconazole (200 mg once daily) in 19 HIV+ patients caused no alteration in fluconazole AUC, Cmax or Cmin. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data. Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with fluconazole (200 mg once daily) caused an approximate doubling of nevirapine Cmin, Cmax and AUC compared to historical controls. Furthermore, 95% of drug related adverse events occurred during the period of coadministration of fluconazole and nevirapine. Nevirapine did not significantly influence the plasma levels of fluconazole. The authors suggest that in light of the increased incidence of toxicity the combination of nevirapine and fluconazole should be used with caution. Effect of fluconazole on nevirapine pharmacokinetics. Geel J, Pitt J, Orrell C, et al., 11th International AIDS Conference, Bangkok, July 2004, abstract TuPeB4606.

Class	Drug	HIV Drug
Antifungals	Itraconazole	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine (200 mg once daily for 7 days) and itraconazole (200 mg once daily for 7 days) was studied in 12 HIV- subjects. Itraconazole mean AUC and Cmax were significantly reduced by 38% and 61% respectively. There was no significant difference in the pharmacokinetics of nevirapine. Dose adjustment of itraconazole may be needed due to possible decrease in clinical effect. Description A similar decrease in itraconazole concentrations to that seen with ketoconazole (72% decrease in AUC, 44% decrease in Cmax) cannot be excluded if coadministered with nevirapine. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. There is a potential drug interaction between nevirapine and itraconazole, which may cause decreased itraconazole plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of nevirapine (200 mg once daily for 7 days) and itraconazole (200 mg once daily for 7 days) was studied in 12 HIV- subjects. The mean AUC and Cmax of itraconazole were significantly reduced by 38% and 61% respectively with the half life of itraconazole being reduced by 31%. There was no significant difference in the pharmacokinetics of nevirapine when given alone or with itraconazole. Pharmacokinetic interaction between itraconazole and nevirapine in healthy volunteers. Jaruratanasirikul S, et al. 16th International AIDS Conference, Toronto, August 2006, abstract TUPE0161.

Class	Drug	HIV Drug
Antifungals	Ketoconazole	Nevirapine
These drugs should not be coadministered
Summary Nevirapine and ketoconazole should not be administered concomitantly because decreased ketoconazole concentrations may reduce its efficacy. Coadministration of nevirapine (200 mg twice daily) with ketoconazole (400 mg once daily) decreased ketoconazole AUC (72%) and Cmax (44%) and Cmin was below the limit of detection for the assay. The effect on nevirapine pharmacokinetics was not significant (15-28% increase in exposure compared to historical data). Description Co-administration of ketoconazole (400 mg once daily) following full induction of nevirapine resulted in a reduction of ketoconazole exposure at steady state. Ketoconazole AUC decreased by a mean of 72% and Cmax decreased by a mean of 44%. In the same study (n=21), ketoconazole administration resulted in a 15-28% increase in the plasma levels of nevirapine compared to historical controls. Ketoconazole and nevirapine should not be given concomitantly. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with ketoconazole (400 mg once daily), in 21 HIV+ subjects, caused a 72% and 44% reduction in ketoconazole AUC and Cmax. Ketoconazole Cmin was below the limit of detection for the assay. The effect on nevirapine pharmacokinetics was not significant. Nevirapine and ketoconazole should not be administered concomitantly because decreases in the ketoconazole plasma concentrations may reduce the efficacy of the drug. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of nevirapine (200 mg twice daily) with ketoconazole (400 mg once daily) to 22 HIV+ individuals resulted in a 63% reduction in ketoconazole AUC and a 40% reduction in Cmax. There was a 15–28% increase in plasma concentration of nevirapine. The pharmacokinetic interactions of nevirapine and ketoconazole. Lamson M, Robinson P, Lamson M et al. 12th World AIDS Conference, 1998, abstract 12218.

Class	Drug	HIV Drug
Antifungals	Voriconazole	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Although not studied, the metabolism of voriconazole may be induced by nevirapine. Patients should be carefully monitored for any occurrence of drug toxicity and/or lack of efficacy during the co-administration of voriconazole and NNRTIs. Description Although not studied, the metabolism of voriconazole may be induced by nevirapine. An in-vivo study showed that voriconazole inhibited the metabolism of efavirenz: voriconazole may also inhibit the metabolism of NNRTIs besides efavirenz. Patients should be carefully monitored for any occurrence of drug toxicity and/or lack of efficacy during the co-administration of voriconazole and NNRTIs. Vfend Summary of Product Characteristics, Pfizer Ltd, October 2008. In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by a NNRTI (e.g. delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy volunteers suggest that the metabolism of voriconazole may be induced by an NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI. Efavirenz and voriconazole coadministration is contraindicated. Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g. nevirapine and delavirdine). Vfend Prescribing Information, Pfizer Inc, May 2008.

Class	Drug	HIV Drug
Antimigraine Agents	Ergotamine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease ergotamine concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and ergotamine, which may cause decreased ergotamine plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Antineoplastics	Cyclophosphamide	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease cyclophosphamide concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and cyclophosphamide, which may cause decreased cyclophosphamide plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Antineoplastics	Paclitaxel	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Case report suggesting that paclitaxel AUC and Cmin in patient receiving nevirapine (200 mg twice daily) and paclitaxel (100 mg/m2, 3 h iv infusion) were similar to historical data for paclitaxel alone. The addition of paclitaxel did not appear to affect the pharmacokinetics of nevirapine. Description The pharmacokinetics of nevirapine and paclitaxel were presented in a case report of an HIV+ patient receiving nevirapine (200 mg twice daily) and paclitaxel (100 mg/m2, 3 h iv infusion). Pacitaxel AUC and Cmax (3787 ng/ml.h and 989 ng/ml) obtained when the patient was receiving nevirapine were similar to those obtained from historical controls (n=8) when given alone (AUC 3614 ± 701 ng/ml.h; Cmax 967 ±187 ng/ml). Mean plasma concentrations of nevirapine was similar when given alone (4210 ± 400 ng/ml) or with paclitaxel (4790 ± 560 ng/ml) and were always higher than the target trough concentration (3400 ng/ml). Based on the findings from a single patient, the authors suggest that no dose adjustment of nevirapine is needed. No pharmacokinetic drug-drug interaction between nevirapine and paclitaxel. Kappelhoff BS, Huitema AD, Mairuhu AT, Schellens JH, Beijnen JH. Anticancer Drugs, 2005, 16(6): 627-30.

Class	Drug	HIV Drug
Anti-platelet and Anti-coagulant	Warfarin	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may alter warfarin concentrations. The nature and magnitude of any effect may change with time. Frequent monitoring of INR is recommended. Description The interaction between nevirapine and the antithrombotic agent warfarin is complex, with the potential for both increases and decreases in coagulation time when used concomitantly. The net effect of the interaction may change during the first weeks of co-administration or upon discontinuation of nevirapine, and close monitoring of anticoagulation levels is therefore warranted. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. The in vitro interaction between nevirapine and the antithrombotic agent warfarin in complex. As a result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels (INR) should be monitored frequently. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. In case studies of three Italian patients all taking antiretroviral therapy including nevirapine plus warfarin, all experienced increased Quick times. In the first case 5 mg of warfarin per day was able to stabilise anticoagulant activity. In the second case 12 mg of warfarin was required and in the third case only after stopping nevirapine was 7.5 mg of warfarin enough to achieve the therapeutic range needed. Need for increased dose of warfarin in HIV patients taking nevirapine. Dionisio D, Mininni S, Bartolozzi D et al. AIDS, 2001,15:277–78.

Class	Drug	HIV Drug
Antiprotozoals	Artemisinins	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may alter plasma levels of artemisinins. Close monitoring required. Artemisinin and derivatives are rapidly metabolized via CYP3A4 to an active metabolite, dihydroartemisinin which has greater potency than the parent drugs. Induction of CYP3A4 would increase dihydroartemisinin, but decrease concentrations of the parent drug. The effects of PIs and NNRTIs are unclear. Description LHPG Comment: Artemisinin, and its derivatives such as artesunate and artemether, are rapidly metabolized via CYP3A4 to a biologically active metabolite, dihydroartemisinin (the metabolism of artesunate is so rapid that it may be considered a pro-drug for dihydroartemisinin). Although the parent drugs and dihydroartemisinin all have antimalarial activity, dihydroartemisinin has greater potency than the parent drugs. Induction of CYP3A4 would increase dihydroartemisinin, but decrease concentrations of the parent drug. The effects of protease inhibitors and non-nucleoside reverse transcriptase inhibitors are unclear.

Class	Drug	HIV Drug
Antiprotozoals	Halofantrine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Lumefantrine and halofantrine are extensively metabolized by CYP3A4. Inhibition of halofantrine metabolism could potentially prolong the QT interval; given the narrow therapeutic index of this drug, nevirapine should be used with caution. Description LHPG Comment: Lumefantrine and halofantrine are extensively metabolized by CYP3A4. Inhibition of halofantrine metabolism could potentially prolong the QT interval; given the narrow therapeutic index of this drug, nevirapine should be used with caution. Lumefantrine does not seem to prolong the QT interval and is much safer than halofantrine. Nevertheless, interactions with PIs and NNRTIs are likely, and the manufacturer's Summary of Product Characteristics advises that coadministration of CYP 3A4 inhibitors such as PIs are contraindicated. Given the increasing use of lumefantrine–artemether for malaria, caution is recommended when using PI/NNRTIs. The need for interaction data is urgent and studies should be prioritized to address this gap in knowledge.

Class	Drug	HIV Drug
Antiprotozoals	Lumefantrine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Lumefantrine is metabolised predominantly by CYP3A4. Caution is recommended when combining lumefantrine with drugs exhibiting variable patterns of inhibition, induction or competition for CYP3A4 as the therapeutic effects could be altered. Description Lumefantrine is metabolised predominantly by the cytochrome enzyme CYP3A4, and does not inhibit this enzyme at therapeutic concentrations. Caution is recommended when combining Riamet (artemether/lumefantrine) with drugs exhibiting variable patterns of inhibition, induction or competition for CYP3A4 as the therapeutic effects of some drugs could be altered. Riamet Summary of Product Characteristics, Novartis Pharmaceuticals UK Ltd, January 2009.

Class	Drug	HIV Drug
Antiprotozoals	Mefloquine	Nevirapine
No clinically significant interaction expected
Summary Although we have indicated that these drugs can be coadministered, it should be noted that there are no data of an interaction of mefloquine with antiretrovirals apart from decreased ritonavir concentrations. Description LHPG Comment: Although we have indicated that these drugs can be coadministered, it should be noted that there are no data of an interaction of mefloquine with antiretrovirals apart from decreased ritonavir concentrations.

Class	Drug	HIV Drug
Antiprotozoals	Proguanil	Nevirapine
No clinically significant interaction expected
Summary Since proguanil is a prodrug and is partially activated by CYP2C19 to cycloguanil, there is concern that inhibition of metabolism by ritonavir will reduce pharmacological effect. However, synergy with atovaquone is related to proguanil, not cycloguanil. When the drugs are coadministered, CYP2C19 inhibition could potentially enhance this synergistic effect which may offset decreased cycloguanil formation. Description LHPG Opinion: Since proguanil is a prodrug and is partially activated (by CYP2C19) to cycloguanil, there is concern that inhibition of metabolism will reduce pharmacological effect. However, synergy with atovaquone is related to proguanil, not cycloguanil. When the drugs are coadministered, CYP2C19 inhibition could potentially enhance this synergistic effect which may offset decreased cycloguanil formation. Studies with enzyme inducers are required.

Class	Drug	HIV Drug
Antiprotozoals	Quinine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Quinine is extensively metabolized by CYP3A4. Exposure could be decreased due to induction of CYP 3A4 by efavirenz. Description LHPG Comment: Quinine is extensively metabolized by CYP3A4. Exposure could be decreased due to induction of CYP 3A4 by nevirapine.

Class	Drug	HIV Drug
Antiretrovirals (Entry Inhibitors)	Enfuvirtide (T20)	Nevirapine
No clinically significant interaction expected
Summary In vitro and in vivo studies suggest that enfuvirtide is unlikely to have significant drug interactions with drugs metabolised by CYP450 enzymes. No drug interactions with other antiretroviral medications have been identified that would warrant dose alteration of either drug. Description No clinically significant pharmacokinetic interactions are expected between enfuvirtide and concomitantly given medicinal products metabolised by CYP450 enzymes. In an in vivo human metabolism study enfuvirtide, at the recommended dose of 90 mg twice daily, did not inhibit the metabolism of substrates by CYP3A4 (dapsone), CYP2D6 (debrisoquine), CYP1A2 (caffeine), CYP2C19 (mephenytoin), and CYP2E1 (chlorzoxazone). In separate pharmacokinetic interaction studies, co-administration of ritonavir (potent CYP3A4 inhibitor) or saquinavir in combination with a booster dose of ritonavir or rifampicin (potent CYP34A inducer) did not result in clinically significant changes of the pharmacokinetics of enfuvirtide. Fuzeon Summary of Product Characteristics, Roche Products Ltd, July 2008. Results from in vitro and in vivo studies suggest that enfuvirtide is unlikely to have significant drug interactions with concomitantly administered drugs metabolised by CYP450 enzymes. No drug interactions with other antiretroviral medications have been identified that would warrant alteration of either the enfuvirtide dose or the dose of the other antiretroviral medication. Coadministration of ritonavir (200 mg twice daily for 4 days) and enfuvirtide (90 mg twice daily) to 12 HIV+ subjects resulted in increases in enfuvirtide AUC, Cmax and Cmin of 22%, 24% and 14% respectively. Coadministration of saquinavir/ritonavir (1000/100 mg twice daily for 4 days) and enfuvirtide (90 mg twice daily) to 12 HIV+ subjects resulted in increases in enfuvirtide AUC and Cmin of 14% and 26% respectively, with no change in Cmax. Fuzeon Prescribing Information, Roche Laboratories Inc, June 2007.

Class	Drug	HIV Drug
Antiretrovirals (Entry Inhibitors)	Maraviroc	Nevirapine
No clinically significant interaction expected
Summary The recommended dose of maraviroc when coadministered with nevirapine is 300 mg twice daily. When compared to historical data, coadministration of a single dose of maraviroc (300 mg) to HIV+ subjects stable on a nevirapine containing regimen had no effect on maraviroc AUC and increased Cmax by 54%. Nevirapine concentrations were not measured, but no effect is expected. Description Comparison to exposure in historical controls suggests that maraviroc 300 mg twice daily and nevirapine can be co-administered without dose adjustment. When compared to historical controls, coadministration of nevirapine (200 mg twice daily) and maraviroc (300 mg single dose) resulted in no change in maraviroc AUC and an increase in Cmax. Nevirapine concentrations were not measured, but no effect is expected. Celsentri Summary of Product Characteristics, Pfizer Ltd, August 2009. When maraviroc (300 mg single dose) was coadministered with nevirapine (200 mg twice daily) and lamivudine/tenofovir, there was no effect on nevirapine AUC and a 54% increase in Cmax, compared to historical data. The recommended dose of maraviroc when coadministered with nevirapine is 300 mg twice daily. Selzentry Prescribing Information, Pfizer Inc, June 2009. Coadministration of maraviroc (300 mg single dose) to HIV+ subjects stable on a nevirapine containing regimen (200 mg twice daily with 3TC/TDF, n=8) had no effect on maraviroc AUC, but increased Cmax by 54% when compared to historical data. A novel probe drug interaction study to investigate the effect of selected ARV combinations on the pharmacokinetics of a single oral dose of UK-427,857 in HIV+ subjects. Muirhead G, et al. 12th Conference on Retroviruses and Opportunistic Infections, Boston, February 2005, abstract 663.

Class	Drug	HIV Drug
Antiretrovirals (Integrase Inhibitors)	Raltegravir	Nevirapine
No clinically significant interaction expected
Summary No dose modification of raltegravir required. Description Less potent inducers (e.g., nevirapine) may be used with the recommended dose of raltegravir Isentress Summary of Product Characteristics, Merck Sharp & Dohme Ltd, September 2009. Raltegravir is not expected to affect the pharmacokinetics of drugs that are substrates of UDP-glucuronosyltransferases (UGT1A1, UGT2B7) or P-glycoprotein (e.g., NNRTIs). Isentress Prescribing Information, Merck & Co Inc, October 2009.

Class	Drug	HIV Drug
Antiretrovirals (NNRTIs)	Efavirenz	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine (200 mg twice daily) with efavirenz (600 mg once daily) decreased efavirenz AUC (28%), Cmax (12%) and Cmin (32%), with no significant effect on nevirapine pharmacokinetics. Appropriate doses for this combination have not been established. However, this combination is not recommended as it could lead to a higher risk for side effects. Moreover coadministration does not improve efficacy over either NNRTI alone. Description Limited pharmacokinetic data (n=17) are available on the co-administration of nevirapine and efavirenz. No major pharmacokinetic interaction was shown, only a limited decreased exposure of efavirenz was observed. However, this coadministration is not recommended since the co- administration of efavirenz and nevirapine could lead to a higher risk for side effects. Moreover this co-administration does not improve efficacy over either NNRTI alone. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with efavirenz (600 mg once daily) in 17 HIV+ patients caused a 28%, 12% and 32% decrease in efavirenz AUC, Cmax and Cmin, respectively. Appropriate doses for this combination have not been established. The effect on nevirapine pharmacokinetics was not significant. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. No studies have been performed with efavirenz in combination with other NNRTIs and the potential for pharmacokinetic or pharmacodynamic interactions is unknown. Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, August 2008. A sub analysis of the 2NN study investigated the pharmacokinetics of nevirapine and efavirenz. It was found that concomitant use of nevirapine significantly increased efavirenz oral clearance by 43%. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Kappelhoff BS, Huitema ADR, van Leth FCM, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract H-861. In a study efavirenz (600 mg once daily) and nevirapine (400 mg once daily) were coadministered. The result was a significant decrease in efavirenz AUC, Cmin and Cmax by 22%, 36% and 17%, respectively. More studies are needed to find the correct dose of efavirenz to use with nevirapine but a dose increase of efavirenz to 800 mg once daily may be warranted. The pharmacokinetic parameters of nevirapine are not affected by coadministration with efavirenz. The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in human immunodeficiency virus type 1-infected persons. Veldkamp AI, Harris M, Montaner JSG et al. J Infect Dis, 2001, 184:37–42

Class	Drug	HIV Drug
Antiretrovirals (NNRTIs)	Etravirine	Nevirapine
These drugs should not be coadministered
Summary Coadministration decreased etravirine AUC by 55% and Cmax by 36%. Coadministration is contraindicated as it significantly decreases etravirine concentrations. Combining two NNRTIs has not been shown to be beneficial. Description It is not recommended to co administer etravirine with other NNRTIs. Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine with efavirenz or nevirapine may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of etravirine. Intelence Summary of Product Characteristics, Janssen-Cilag Ltd, August 2008. Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine with nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine. Etravirine and other NNRTIs should not be co-administered. Intelence Prescribing Information, Tibotec Pharmaceuticals Ltd, January 2008. Coadministration of nevirapine (200 mg twice daily for 11 days following dose escalation) and etravirine (900 mg phase II formulation, single dose) was studied in 5 HIV- subjects. Nevirapine decreased etravirine AUC and Cmax by 55% and 36% respectively. The use of nevirapine is not recommended in combination with etravirine. Drug interactions with TMC125, a potent next generation NNRTI. Baede P, et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, September 2002, abstract A-1827.

Class	Drug	HIV Drug
Antiretrovirals (Nucleoside/tide Analogues)	Didanosine (ddI)	Nevirapine
No clinically significant interaction expected
Summary No dosage adjustments are required when nevirapine is taken with didanosine as the absorption of nevirapine is not affected by the alkaline buffering agent in some formulations of didanosine. Coadministration of nevirapine (200 mg twice daily) with didanosine (100-150 mg twice daily) caused no alteration in didanosine AUC or Cmax and the effect on nevirapine pharmacokinetics was not significant. Description LHPG Comment: Unlike the Videx chewable/dispersible tablets, the new formulation of ddI (Videx EC) does not contain antacids. Interactions with the old formulation that were due to the presence of antacid should not apply to the new formulation. Timing of administration of Videx EC with other medications will still be dependent on food requirements, but no longer on gastric pH requirements. No dosage adjustments are required when nevirapine is taken in combination with zidovudine, didanosine, or zalcitabine. The absorption of nevirapine is not affected by food, antacids or medicinal products which are formulated with an alkaline buffering agent (e.g., didanosine). In one crossover study, nevirapine had no effect on the steady-state pharmacokinetics of either didanosine (n=18) or zalcitabine (n=6). Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Nevirapine may be administered with or without food, antacid or didanosine. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with didanosine (100-150 mg twice daily) in 18 HIV+ patients caused no alteration in didanosine AUC or Cmax, Cmin was below the limits of detection for the assay. The effect on nevirapine pharmacokinetics was not significant. In a separate study in HIV-1 infected patients (n=6), nevirapine steady-state systemic exposure (AUC) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Addition of nevirapine (200 mg twice daily) to a regimen of didanosine (125 or 200 mg twice daily) and zidovudine in 80 HIV+ individuals showed that nevirapine did not interfere with the bioavailability of ddI. Combination of didanosine and nevirapine allows the full impact of their respective pharmacodynamic properties; drugs were taken simultaneously. Population pharmacokinetics of nevirapine, zidovudine and didanosine in human immunodeficiency virus-infected patients. Zhou XJ, Sheiner LB, D'Aquila RT et al. Antimicrob Agents Chemother, 1999, 43:121–8.

Class	Drug	HIV Drug
Antiretrovirals (Nucleoside/tide Analogues)	Emtricitabine (FTC)	Nevirapine
No clinically significant interaction expected
Summary Based on the results of in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low. Description In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low. Emtriva Summary of Product Characteristics, Gilead Sciences International Ltd, August 2008. At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP 2C9, CYP2C19, CYP2D6 and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low. Emtriva Presrcibing Information, Gilead Sciences Inc, May 2008. The effect of tenofovir/emtricitabine on the pharmacokinetics of nevirapine (200 mg twice daily) was studied in 7 HIV+, African-American subjects. The mean ± sd steady state nevirapine Cmin was 4971 ± 1985 ng/ml and was comparable to historical values. The mean nevirapine Cmin after the 200 mg once daily 2 week lead-in phase was also determined and was 2876 ng/ml. Lack of pharmacokinetic interaction of tenofovir and emtricitabine on nevirapine. Davis JrC, Gillam B, Amoroso A, et al. 11th European AIDS Conference, Madrid, October 2007, abstract P4.1/03

Class	Drug	HIV Drug
Antiretrovirals (Nucleoside/tide Analogues)	Lamivudine (3TC)	Nevirapine
No clinically significant interaction expected
Summary Data from a population pharmacokinetic study of 90 patients receiving lamivudine with nevirapine or placebo revealed no changes to lamivudine apparent clearance and volume of distribution, suggesting no induction effect of nevirapine on lamivudine clearance. Description A population pharmacokinetic study of 90 patients assigned to receive lamivudine with nevirapine or placebo revealed no changes to lamivudine apparent clearance and volume of distribution, suggesting no induction effect of nevirapine on lamivudine clearance. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. The pharmacokinetics of lamivudine (150 mg twice daily) were determined using non-linear mixed effects modelling on samples from HIV-infected subjects receiving lamivudine alone (n=47) or with nevirapine (200 mg twice daily, n=43). The results of the modelling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. The pharmacokinetics of nevirapine were consistent with those of several earlier trials. Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection. Sabo JP et al. AAPS Pharm Sci, 2002, 2: E1.

Class	Drug	HIV Drug
Antiretrovirals (Nucleoside/tide Analogues)	Stavudine (d4T)	Nevirapine
No clinically significant interaction expected
Summary Coadministration of nevirapine (200 mg twice daily) with stavudine (30-40 mg twice daily) caused no alteration in stavudine AUC or Cmax, and the effect on nevirapine pharmacokinetics was not significant. Description Results from a 28 day study in HIV infected patients (n=22) administered nevirapine, nelfinavir (750 mg three times daily) and stavudine (30-40 mg twice daily) showed no clinically relevant changes in the AUC or Cmax of stavudine. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with stavudine (30-40 mg twice daily), in 22 HIV+ patients, caused no alteration in stavudine AUC or Cmax. Stavudine Cmin was below the limit of detection for that assay. The effect on nevirapine pharmacokinetics was not significant. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. The effect of nevirapine (200 mg twice daily) on the pharmacokinetics of stavudine (30-40 mg twice daily) in the presence of nelfinavir was studied in 25 HIV-infected subjects. No statistically significant changes in stavudine AUC or Cmax were observed. The effect of nevirapine on stavudine Cmin could not be determined as Cmin was below the limit of quantification in 77% of subjects (this was as expected because although the intracellular half-life is long, the plasma half life is short). Nevirapine AUC, Cmax and Cmin values were consistent with historical data. Pharmacokinetic evaluation and short-term activity of stavudine, nevirapine and nelfinavir therapy in HIV-1-infected adults. Skowron G, et al. J Acquir Immune Defic Syndr, 2004, 35:351-358.

Class	Drug	HIV Drug
Antiretrovirals (Nucleoside/tide Analogues)	Tenofovir	Nevirapine
No clinically significant interaction expected
Summary Tenofovir appeared to have no significant effect on nevirapine concentrations determined in TDM samples from groups of HIV+ patients receiving nevirapine (200 mg twice daily or 400 mg once daily) alone or with tenofovir (300 mg once daily). Description The effect of tenofovir/emtricitabine on the pharmacokinetics of nevirapine (200 mg twice daily) was studied in 7 HIV+, African-American subjects. The mean ± sd steady state nevirapine Cmin was 4971 ± 1985 ng/ml and was comparable to historical values. The mean nevirapine Cmin after the 200 mg once daily 2 week lead-in phase was also determined and was 2876 ng/ml. Lack of pharmacokinetic interaction of tenofovir and emtricitabine on nevirapine. Davis JrC, Gillam B, Amoroso A, et al. 11th European AIDS Conference, Madrid, October 2007, abstract P4.1/03 The interaction between tenofovir and nevirapine was assessed in TDM samples from groups of HIV+ patients receiving nevirapine (200 mg twice daily or 400 mg once daily) alone or with tenofovir (300 mg once daily). For twice daily dosing, although nevirapine samples were collected at various times post dose (0.2-14.3 h), there was no significant difference in the times post dose between the control group (n=272) and the tenofovir group (n=39). Nevirapine concentrations were not significantly different between the groups (5.68 µg/ml vs 6.48 µg/ml, control vs tenofovir). For once daily dosing, samples were collected 0-24.4 h post dose in the control group (n=18) and the tenofovir group (n=94). There was no significant difference between the groups for the time post dose or nevirapine concentrations (5.25 µg/ml vs 4.85 µg/ml, control vs plus tenofovir). Assessment of drug-drug interactions between tenofovir disoproxil fumarate and the nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz in HIV-infected patients. Droste JA, Kearney BP, Hekster YA, Burger DM. J Acquir Immune Defic Syndr, 2006, 41(1): 37-43. Trough nevirapine concentrations (23-25 h post dose) were obtained from patients undergoing routine TDM whilst receiving nevirapine (400 mg once daily). Geometric mean (CI) nevirapine troughs in 171 patients receiving nevirapine and tenofovir were 3420 (3170-3670) ng/ml. Values for patients receiving nevirapine without tenofovir (n=87) were 3260 (2980-3540) ng/ml, suggesting that tenofovir does not affect nevirapine plasma concentrations. Nevirapine trough concentrations in HIV-infected patients treated with or without tenofovir. Breske A, et al. 10th European AIDS Conference, Dublin, November 2005, abstract PE4.3/10.

Class	Drug	HIV Drug
Antiretrovirals (Nucleoside/tide Analogues)	Zidovudine (AZT/ZDV)	Nevirapine
No clinically significant interaction expected
Summary Coadministration of nevirapine (200 mg twice daily) with zidovudine (100-200 mg three times daily) decreased zidovudine AUC (28%) and Cmax (30%). There was no significant effect on nevirapine pharmacokinetics. The clinical relevance of the decrease in zidovudine concentrations is currently unknown, but no dosage adjustments are recommended. Description No dosage adjustments are required when nevirapine is taken in combination with zidovudine, didanosine, or zalcitabine. When the zidovudine data were analyzed from a study (n=11) in which HIV-1 infected patients received nevirapine 400 mg/day in combination with zidovudine (100-200 mg three times daily), nevirapine resulted in a mean decrease of 24% in zidovudine AUC and a mean decrease of 26% in zidovudine Cmax. The clinical relevance of the decrease in zidovudine plasma levels is currently unknown. Paired data suggest that zidovudine had no effect on the pharmacokinetics of nevirapine. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with zidovudine (100-200 mg three times daily) in 11 patients caused a 28% and 30% decrease in zidovudine AUC and Cmax, respectively. Zidovudine Cmin was below the limit of detection for the assay. The effect on nevirapine pharmacokinetics was not significant. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Addition of nevirapine (200 mg twice daily) to a regimen of zidovudine (200 mg three times daily) and didanosine in 80 HIV+ individuals showed nevirapine reduced the bioavailability of ZDV by ~30%. The interaction is unlikely to be clinically significant, but could have an impact on the selection of resistant mutants. Zidovudine had no effect on the pharmacokinetics of nevirapine. No dosage adjustments are required. Population pharmacokinetics of nevirapine, zidovudine and didanosine in human immunodeficiency virus-infected patients. Zhou XJ, Sheiner LB, D'Aquila RT et al. Antimicrob Agents Chemother, 1999, 43:121–8.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Atazanavir	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine with atazanavir/ritonavir is not recommended as it increases nevirapine exposure and decreases atazanavir Cmin. The decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. Description Co-administration of nevirapine with atazanavir/ritonavir is not recommended. Coadministration of nevirapine (200 mg twice daily) and atazanavir/ritonavir (400/100 mg once daily) was studied in HIV+ subjects. Nevirapine AUC, Cmax and Cmin increased by 26%, 21% and 25%. When compared to atazanavir/ritonavir 300/100 mg without nevirapine, atazanavir AUC decreased by 19%, Cmax increased by 2% and Cmin decreased by 59%. This decrease in atazanavir Cmin might negatively impact the efficacy of atazanavir. The mechanism of nevirapine/atazanavir interaction is CYP3A4 induction. Reyataz Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, July 2009. Do not coadminister atazanavir with nevirapine because nevirapine substantially decreases atazanavir exposure and there is potential risk for nevirapine associated toxicity due to increased nevirapine exposures. Coadministration of nevirapine (200 mg twice daily) and atazanavir/ritonavir (300/100 mg or 400/100 mg once daily) was studied in 23 HIV+ subjects. With doses of 300/100 mg, atazanavir AUC, Cmax and Cmin decreased by 42%, 28% and 72%, respectively. Increasing the dose to 400/100 mg (and compared to 300/100 mg alone) decreased atazanavir AUC by 19%, increased Cmax by 2% and decreased Cmin by 59%. Nevirapine AUC, Cmax and Cmin increased by 25%, 17% and 32%, respectively with the 300/100 mg regimen and by 26%, 21% and 35% with the 400/100 mg regimen. Reyataz Prescribing Information, Bristol-Myers Squibb Co, November 2009. The effect of nevirapine (200 mg twice daily) on trough concentrations of atazanavir following coadministration of atazanavir/ritonavir (300/100 mg once daily) was studied in 11 HIV+ subjects. Nevirapine decreased atazanavir trough concentrations by 41% (from 631 to 316 ng/ml), but this was still significantly higher that historical data obtained in 54 subjects receiving atazanavir alone (400 mg once daily). When compared to historical data obtained from 18 subjects receiving nevirapine alone, nevirapine trough concentrations in the presence of atazanavir/ritonavir were slightly increased. The effect of nevirapine on the steady-state trough concentrations of atazanavir/ritonavir. Molto J, Lilbre, JM, Valle M, et al. 9th International Workshop on Clinical Pharmacology of HIV Therapy, New Orleans, April 2008, abstract P20. Trough concentrations were obtained from 16 patients receiving nevirapine once daily (400 mg) with atazanavir/ritonavir (300/100 mg, n=7; 400/100 mg n=9). Median atazanavir trough concentrations were 340 ng/ml and 520 ng/ml for the 300 mg and 400 mg groups, respectively; values obtained from historical controls receiving 300/100 mg were 610 ng/ml. Nevirapine trough concentrations were 3900 ng/ml and 4000 ng/ml for the two groups and were comparable to literature values for patients treated with nevirapine alone (3700 ng/ml). Given the decrease in atazanavir trough concentrations, relative to historical controls, therapeutic drug monitoring of atazanavir may be appropriate for patients (especially if treatment experienced) receiving this combination. Plasma concentrations of atazanavir in HIV patients treated with regimens including nevirapine. Kurowski M, et al. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2006, abstract 276. Steady state atazanavir concentrations were assessed in HIV+ patients taking atazananavir/ritonavir (300/100 mg once daily) with and without tenofovir and/or nevirapine. No significant difference was observed in atazanavir concentrations for patients taking atazanavir/ritonavir alone and those taking tenofovir. There was a trend towards decreased atazanavir concentrations for patients co-dosed with nevirapine (with or without tenofovir). These results from a clinical setting suggest that ritonavir boosting of atazanavir reduces the interaction with tenofovir; however, it may not overcome interactions with nevirapine. Interaction between atazanavir/ritonavir and nevirapine is observed in a clinical setting. Alexander CS, Montaner JG, Langridge S, et al. 7th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2004, abstract P275.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Darunavir	Nevirapine
No clinically significant interaction expected
Summary Note: this interaction was studied using a darunavir/ritonavir dose lower than that licensed. Coadministration of nevirapine (200 mg twice daily) and darunavir/ritonavir (400/100 mg twice daily) increased nevirapine AUC (27%), Cmax (18%) and Cmin (47%). Based on between study comparison, darunavir Cmax, AUC and Cmin increased by 40%, 24% and 2%, respectively. These differences are not considered to be clinically relevant and no adjustments to the licensed doses are required. Description Coadministration of nevirapine (200 mg twice daily) and darunavir/ritonavir (at a dose lower than recommended or with a different dosing regimen) increased nevirapine AUC, Cmax and Cmin by 27%, 18% and 47%, respectively. Darunavir concentrations were consistent with historical data. Darunavir/ritonavir increases the plasma concentrations of nevirapine as a result of CYP3A4 inhibition. Darunavir coadministered with low dose ritonavir and nevirapine can be used without dose adjustments. Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, October 2009. The interaction between darunavir/ritonavir and nevirapine was evaluated in clinical studies and no dose adjustment is needed for either drug. Coadministration of nevirapine (200 mg twice daily) and darunavir/ritonavir (400/100 mg twice daily) was studied in 8 subjects. Darunavir and nevirapine exposure both increased. Based on between study comparison, darunavir Cmax, AUC and Cmin increased by 40%, 24% and 2%, respectively. Nevirapine Cmax, AUC and Cmin increased by 18%, 27% and 47%, respectively. Prezista Prescribing Information, Tibotec Inc, June 2009.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Fosamprenavir	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary No clinically relevant interaction was observed when fosamprenavir/ritonavir (700/100 mg twice daily) was used concurrently with nevirapine (200 mg twice daily). Coadministration had no effect on amprenavir Cmax, but decreased AUC and Cmin by 11% and 19%. Nevirapine Cmax, AUC and Cmin were increased by 13%, 14% and 22% respectively. Coadministration with fosamprenavir/ritonavir once-daily has not been studied. Description There was no clinically relevant interaction when fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily was used concurrently with nevirapine (200 mg twice daily). Telzir Summary of Product Characteristics, GlaxoSmithKline UK, October 2008. Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended. Coadministration of nevirapine (200 mg twice daily for at least 12 weeks) and fosamprenavir (1400 mg twice daily for 2 weeks) to 17 patients resulted in decreases in amprenavir Cmax, AUC and Cmin of 25%, 33% and 35%, respectively. Nevirapine Cmax, AUC and Cmin increased by 25%, 29% and 34% respectively. No dosage adjustment required when nevirapine is administered with fosamprenavir/ritonavir twice daily. Coadministration of nevirapine (200 mg twice daily for at least 12 weeks) to 17 patients with fosamprenavir/ritonavir (700/100 mg twice daily for 2 weeks) had no effect on amprenavir Cmax, but decreased AUC and Cmin by 11% and 19%. Nevirapine Cmax, AUC and Cmin were increased by 13%, 14% and 22% respectively. The combination of nevirapine administered with fosamprenavir/ritonavir once-daily regimen has not been studied. Lexiva Prescribing Information, GlaxoSmithKline, March 2008. The interaction between fosamprenavir/ritonavir and nevirapine was investigated in 17 HIV+ patients and data compared to historical controls. Coadministration of fosamprenavir (1400 mg twice daily) with nevirapine (200 mg twice daily) resulted in decreases in amprenavir Cmin (39%), Cmax (25%) and AUC (37%); increases were observed in nevirapine Cmin (34%), Cmax (25%) and AUC (29%). Coadministration of fosamprenavir/ritonavir (700/100 mg twice daily) and nevirapine (200 mg twice daily) resulted in decreases in amprenavir Cmin (19%), Cmax (3%) and AUC (11%); increases were observed in nevirapine Cmin (21%), Cmax (13%) and AUC (14%). Due to significantly lower amprenavir exposure, unboosted fosamprenavir is not recommended with nevirapine. When nevirapine is coadministered with fosamprenavir and ritonavir, no change in dose of any drug is required and this should be considered instead of an unboosted regimen. Evaluation of the pharmacokinetic drug interaction between fosamprenavir, fosamprenavir plus ritonavir and nevirapine in HIV-infected patients (APV10014). Dejesus E, Piliero P, Summers K, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract A-447. Five HIV+ patients receiving nevirapine (200 mg bd), amprenavir (600 mg bd) and lopinavir/ritonavir (400/100 mg bd) were studied. Amprenavir concentrations were in the expected ranges (Cmin 560-3090 ng/ml; Cmax 1760-8040 ng/ml; AUC0-12h 13230-75170 ng/ml.h). However, lopinavir concentrations were quite variable (Cmin 620-5980 ng/ml; Cmax 2710-12600 ng/ml; AUC0-12h 998-175140 ng/ml.h) and 40-60% lower than reported by the manufacturer. The combination of amprenavir, lopinavir and nevirapine may result in unpredictable lopinavir concentrations and pharmacological monitoring is advisable in patients treated with such combinations. Pharmacokinetics of amprenavir and lopinavir in combination with nevirapine in highly pretreated HIV-infected patients. Fatkenheuer G, Romer K, Kamps R, et al. AIDS, 2001, 15:2334-2335.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Indinavir	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine with indinavir alone or indinavir/ritonavir decreases indinavir concentrations. The appropriate doses for these combinations with respect to efficacy and safety have not been established. When given alone, dose increase of indinavir to 1000 mg three times daily could be considered. When given with ritonavir, in treatment-experienced patients or when viral susceptibility to indinavir may be decreased, dose increase of indinavir to 1000 mg or ritonavir to 200 mg could be considered. Description Results from a clinical trial (n=19) with HIV infected patients administered nevirapine and indinavir (800 mg three times daily) indicated that their co-administration leads to a mean decrease of 31% in indinavir AUC, a mean decrease of 15% in Cmax, and a mean decrease of 44% in Cmin. No clinically relevant change in nevirapine plasma levels was found. No definitive clinical conclusions have been reached regarding the potential impact of co-administration of nevirapine and indinavir. A dose increase of indinavir to 1000 mg three time daily should be considered when indinavir is given with nevirapine 200 mg twice daily; however, there are no data currently available to establish that the short term or long term antiviral activity of indinavir 1000 mg three times daily with nevirapine 200 mg twice daily will differ from that of indinavir 800 mg three time daily with nevirapine 200 mg twice daily. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with indinavir (800 mg every 8 hours) in 19 HIV+ patients caused a 31%, 15% and 44% decrease in indinavir AUC, Cmax and Cmin respectively. The effect on nevirapine pharmacokinetics was not significant. Appropriate doses for this combination have not been established, but an increase in the dose of indinavir may be required. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of nevirapine (200 mg twice daily) and indinavir (800 mg three times daily) decreased indinavir AUC by 28% and had no effect on nevirapine concentrations. A dose increase of indinavir to 1000 mg every 8 hours should be considered if given with nevirapine. Crixivan Summary of Product Characteristics, Merck Sharp & Dohme Ltd, October 2008. Indinavir concentrations may be decreased in the presence of nevirapine. The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Crixivan Prescribing Information, Merck & Co Inc, October 2009. Coadministration of indinavir (1000 mg three times daily) and nevirapine (200 mg twice daily) was assessed in HIV+ patients as part of the Tianon-ANRS081 study. Indinavir median Cmin were lower in the nevirapine group at week 8 (72 vs 96 ng/ml, P=0.05, n=134) and at week 24 (72 vs 87 ng/ml, P=0.11, n=103); indinavir median Cmax did not differ between the two groups at week 8 or week 24. Nevirapine median Cmin values were 4650 and 4300 ng/ml at weeks 8 and 24 respectively. Efficacy and safety related to indinavir and nevirapine plasma concentrations in a randomised controlled trial comparing indinavir and nevirapine versus indinavir containing regimen in hiv-1 infected patients (TRIANON-ANRS 081 study). Peytavin G, Flandre P, Morand-Joubert L, et al. 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, July 2003, abstract 842. Antiviral Ther, 2003, 8 (suppl 1): S421. Coadministration of nevirapine (200 mg twice daily) and indinavir (1000 mg every 8 h) was studied in 54 HIV+ individuals receiving nevirapine, indinavir and stavudine and compared to indinavir (800 mg every 8 h) in 70 HIV+ individuals receiving indinavir, stavudine and lamivudine. Indinavir had no significant effect on nevirapine concentrations, however the pharmacokinetics of indinavir suggest that a dose increase to at least 1000 mg every 8 h may be required when coadministered with nevirapine. Cmin and Cmax following indinavir 800 mg were 266 ± 91 and 8402 ± 444 ng/ml, respectively. Following coadministration of indinavir 1000 mg every 8 h with nevirapine, indinavir Cmin and Cmax were 105 ± 21 and 8354 ± 535 ng/ml, respectively (mean ± sem). Launay O, Peytavin G, Landre P, et al. 40th ICAAC, Toronto, September 2000, presentation 1632. Coadministration of nevirapine (200 mg twice daily) and indinavir (800 mg every 8 h) was studied in 19 HIV+ individuals. There was a ~27% reduction in indinavir AUC, a ~11% reduction in Cmax and a 47.5% reduction in Cmin. The data in this study do not support changing the indinavir dose on the basis of pharmacokinetic changes alone. Despite significant pharmacokinetic interactions, the combination of these drugs at the standard doses is associated with sustained and potent antiviral activity. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. Murphy RL, Sommadossi JP, Lamson M, et al. J Infect Dis, 1999, 179:1116–23. Coadministration of nevirapine (200 mg twice daily) and indinavir (800 mg every 8 h) was studied in 17 HIV+ individuals. Indinavir Cmax decreased by 26% following the afternoon dose and by 51% following the morning dose when compared to historical controls. There was a 43% decrease in indinavir Cmin. Nevirapine Cmax and Cmin did not differ significantly from historical controls. The clinical implication of this pharmacokinetic interaction and the role of dosage adjustment for indinavir merit further study. A pilot study of nevirapine, indinavir and lamivudine among patients with advanced human immunodeficiency virus disease who have had failure of combination therapy. Harris M, Durakovic C, Rae S, et al. J Infect Dis, 1998, 177:1514–20. Indinavir + Ritonavir A retrospective analysis was performed on all samples in the Dutch TDM programme to identify those HIV+ subjects receiving indinavir/ritonavir (800/100 mg twice daily) alone (n=139) or in combination with nevirapine (200 mg twice daily; n=21). Indinavir geometric mean Cmin was 0.49 mg/L (95% CI, 0.35-0.6 8mg/L) in the nevirapine group versus 1.14 mg/L (95% CI, 1.00-1.29 mg/L) in the control group (57% difference, P<0.001). No subject in either group had an indinavir Cmin below the proposed minimum effective level (0.10 mg/L). Ritonavir Cmin values were also lower in the nevirapine group than in the control group; 0.22 (0.15-0.31) mg/L vs 0.52 (0.46-0.60) mg/ml; nevirapine vs alone, 58% difference, P<0.001. The effect of nevirapine may be either directly on indinavir or indirectly through the effect on ritonavir. In treatment-naïve patients there appears to be no need to modify the dose. In treatment-experienced patients, or when viral susceptibility to indinavir may be decreased, dose increase of indinavir to 1000 mg or ritonavir to 200 mg could be considered. The effect of nevirapine on the pharmacokinetics of indinavir/ritonavir 800/100 mg bid. Burger DM, Prins JM, van der Ende ME, Aarnoutse RE. J Acquir Immune Defic Syndr, 2004, 35: 97-98. The effect of nevirapine (200 mg bd) on the pharmacokinetics of indinavir when given in combination with low dose ritonavir (800/100 mg bd) were studied in two groups of patients and revealed a 57% decrease in indinavir trough concentrations in the presence of nevirapine. Trough concentrations were 490 ng/ml (250-680 ng/ml) in the nevirapine group (n = 21) and 1140 ng/ml (1000-1290 ng/ml) in the control group (n=139). No patient in either group had indinavir trough concentrations below the target value of 100 ng/ml. The influence of nevirapine on the pharmacokinetics of indinavir and ritonavir 800/100 mg q12h. Burger DM, Prins JM, van der Ende ME, Aarnoutse RE. 3rd International Workshop on Clinical Pharmacology of HIV Therapy, Washington, 2002, abstract 7.9 Coadministration of nevirapine and indinavir (800 mg twice daily) in combination with ritonavir (100 mg twice daily) was studied in HIV+ individuals. Cmin of indinavir when given with ritonavir was reduced by the presence of nevirapine (Cmin with nevirapine = 0.37 µg/ml; without nevirapine = 1.25 µg/ml; Cmin 800 mg indinavir three times daily alone = 0.13 µg/ml). Pharmacokinetics of an indinavir/ritonavir 800/100 mg twice daily regimen. Burger DM, Hugen PWH, Prins JM et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999, astract 363. LHPG Opinion: Potential dose modifications required hence amber.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Lopinavir	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Lopinavir AUC decreased by 27%. Nevirapine should not be coadministered with once daily Kaletra. Lopinavir tablets should be increased to 500/125 mg twice daily; lopinavir oral solution should be increased to 533/133 mg twice daily. Monitor closely. TDM may be useful. Description KALETRA TABLETS: In a study performed in healthy volunteers to explore the interaction between Kaletra tablets (400/100 mg twice daily) and efavirenz (600 mg once daily), efavirenz has been shown to decrease the lopinavir concentrations by 30-40%. Similar pharmacokinetic interactions are expected for the co-administration of Kaletra tablets with the NNRTI nevirapine. When Kaletra tablet dosages were increased to 500/125 mg twice daily during coadministration of efavirenz 600 mg once daily in healthy volunteers, lopinavir pharmacokinetic parameters were similar to those obtained with Kaletra tablets 400/100 mg twice daily administered alone. Therefore, the Kaletra tablets dosage should be increased to 500/125 mg twice daily when coadministered with efavirenz. The same recommendations for monitoring apply for nevirapine co-administration. Kaletra must not be administered once daily in combination with nevirapine. KALETRA ORAL SOLUTION: No change in the pharmacokinetics of lopinavir was apparent in healthy volunteers during nevirapine and Kaletra co-administration. Results from a study in HIV-positive paediatric patients revealed a decrease in lopinavir concentrations during nevirapine co-administration. The effect of nevirapine in HIV-positive adults is expected to be similar to that in paediatric patients and lopinavir concentrations may be decreased. The clinical significance of the pharmacokinetic interaction is unknown. No formal recommendation could be drawn on dosage adjustment when Kaletra is used in combination with nevirapine. However, based on clinical experience, Kaletra dose increase to 533/133 mg twice daily may be considered when co-administered with nevirapine, particularly for patients in whom reduced lopinavir susceptibility is likely. Kaletra Summary of Product Characteristics, Abbott Laboratories Ltd, August 2009. Kaletra tablets and oral solution should not be administered as a ONCE DAILY regimen in combination with nevirapine. A dose increase is recommended for all patients who use Kaletra tablets or oral solution in combination with nevirapine. The recommended dose of Kaletra tablets is 500/125 mg twice daily (such as two 200/50 tablets and one 100/25 tablet). The recommended dose of Kaletra oral solution is 533/133 mg twice daily taken with food. Coadministration of nevirapine (200 mg twice daily, >1 year) and lopinavir/ritonavir (400/100 mg twice daily, >1 year) to 22 HIV+ subjects resulted in decreases in lopinavir Cmax, AUC and Cmin of 19%, 27% and 51% respectively, when compared to data from 19 subjects receiving lopinavir/ritonavir alone. Coadministration of nevirapine (200 once daily for 14 days, escalating to 200 mg twice daily for 6 days) and lopinavir/ritonavir (400/100 mg for 20 days) to 5 HIV- subjects resulted in increases in nevirapine Cmax, AUC and Cmin of 5%, 8% and 15% respectively, when compared to data from 6 subjects receiving nevirapine alone. Kaletra Prescribing Information, Abbott Laboratories, April 2009. Kaletra tablets and oral solution should not be administered as a ONCE DAILY regimen in combination with nevirapine. Kaletra tablets (400/100 mg) can be used twice daily with no dose adjustments in antiretroviral-naïve patients. A dose increase of Kaletra tablets to 600/150 mg twice daily may considered in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history of laboratory evidence) A dose increase is recommended for all patients who use Kaletra oral solution. The recommended dose of Kaletra oral solution is 533/133 mg twice daily taken with food. Coadministration of nevirapine (200 mg twice daily, >1 year) and lopinavir/ritonavir (400/100 mg twice daily, >1 year) to 22 HIV+ subjects resulted in decreases in lopinavir Cmax, AUC and Cmin of 19%, 27% and 51% respectively, when compared to data from 19 subjects receiving lopinavir/ritonavir alone. Coadministration of nevirapine (200 once daily for 14 days, escalating to 200 mg twice daily for 6 days) and lopinavir/ritonavir (400/100 mg for 20 days) to 5 HIV- subjects resulted in increases in nevirapine Cmax, AUC and Cmin of 5%, 8% and 15% respectively, when compared to data from 6 subjects receiving nevirapine alone. Kaletra Prescribing Information, Abbott Laboratories, June 2008. In HIV positive adults, nevirapine used in combination with lopinavir/ritonavir 400/100 mg (3 capsules) twice daily has been reported to result in a decline in the lopinavir AUC of 27% compared with historical data. Although the clinical relevance of this observation has not been fully established, an increase in the dose of lopinavir/ritonavir to 533/133 mg (4 capsules) twice daily with food is recommended in combination with nevirapine. Results from a pharmacokinetic study in paediatric patients were consistent with the findings in adults. During nevirapine co-administration, lopinavir AUC decreased by 22% (AUC ratio 0.78; 0.56-1.09) and lopinavir Cmin by 55% (Cmin ratio 0.45; 0.25-0.82). For children, increase of the dose of lopinavir/ritonavir to 300/75 mg/m2 should be considered when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with Kaletra(400/100 mg lopinavir/ritonavir twice daily) in 22 patients was compared to lopinavir/ritonavir alone in 19 patients. Patients taking nevirapine had 27%, 19% and 51% lower lopinavir AUC, Cmax and Cmin, respectively. The effect on nevirapine pharmacokinetics was not significant. Kaletra 400/100 mg tablets can be used twice-daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients. A dose increase of Kaletra tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. The aim of this study was to assess the influence of nevirapine on lopinavir pharmacokinetics in order to optimise dosing regimens. The study included 15 HIV+ subjects, who received LPV/r (533/133 mg twice daily) and NVP (200 mg once daily for 2 weeks followed by NVP 200 mg twice daily). Steady state pharmacokinetic parameters were measured at week 4 and compared with data from patients (n=23) receiving LPV/r (400/100 mg twice daily) + 2 NRTIs. Following an increase in the LPV/r dosage, the mean ± sd LPV Ctrough was 5240 ± 4029 ng/ml, which was not significantly different from the mean Ctrough for LPV 400/100 mg bid + 2NRTI (4272 ± 3114 ng/ml, P=0.637). No statistically significant difference was observed in the mean AUC for LPV 400/100 mg bid + 2NRTI or with LPV/r 533/133 mg bid + NVP 200 mg bid (82746 ± 41019 vs 100940 ± 48871 ng.h/ml, P=0.3286). The findings suggest that an increase in LPV/r dose to 533/133 mg (4 capsules twice daily) is appropriate when co-administered with NVP. Data is awaited on the new tablet formulation of lopinavir in the presence of nevirapine. The steady state pharmacokinetics (PK) of lopinavir/ritonavir 533/133 mg bid plus nevirapine (200 mg bid) in adult HIV-1-infected individuals (the NRTI sparing study). Youle M, et al. 16th International AIDS Conference, Toronto, August 2006, abstract TUPE0094. Coadministration of an NNRTI (n=25; nevirapine n=9, efavirenz n=16) with lopinavir/ritonavir (400/100 mg twice daily) resulted in a 39% decrease in lopinavir Ctrough but no change in Cmax, compared in patients taking lopinavir/ritonavir (400/100 mg twice daily alone n=125). There was no difference in lopinavir Ctrough between patients taking efavirenz and nevirapine. There was no difference in lopinavir Ctrough between patients taking lopinavir (400/100 mg twice daily, n=125) and those taking lopinavir/ritonavir (533/133 mg twice daily, n=32) with an NNRTI (NVP n=3, EFV n=29). There was no statistically significant difference in ritonavir Ctrough or Cmax in patients taking lopinavir/ritonavir 400/100 mg twice daily with or without an NNRTI but patients taking lopinavir ritonavir 533/133 mg twice daily with an NNRTI had higher ritonavir Ctrough and Cmax. The number of patients with lopinavir concentrations below the 3000 ng/ml threshold was higher in those taking lopinavir/ritonavir 400/100 with an NNRTI compared to those without an NNRTI. However, the number of patients with suboptimal levels was comparable between those taking lopinavir/ritonavir 400/100 mg alone to those taking lopinavir/ritonavir 533/133 mg plus an NNRTI. Similar results were observed when a lower threshold (1500 ng/ml) was used. Therapeutic drug monitoring of lopinavir/ritonavir given alone or with an non-nucleoside reverse transcriptase inhibitor. Solas C, Poizot-Martin I, Drogoul M, et al., Br J Pharmacol, 2003, 57: 436-440. The coadministration of nevirapine to 2 patients receiving lopinavir/ritonavir resulted in lopinavir Cmin values of 1420 and 5240 ng/ml and Cmax values of 3920 and 12300 ng/ml. Mean lopinavir concentrations in a group of patients (n=4) receiving lopinavir/ritonavir alone were 5690 (1420-11120) ng/ml for Cmin and 12400 (3920-17300) ng/ml for Cmax. Nevirapine concentrations were 769 and 1610 ng/ml for Cmin and 2290 and 2490 ng/ml for Cmax. Steady state pharmacokinetics of lopinavir in combination with nevirapine or efavirenz. Degen O, Kurowski M, van Lunzen J, et al. 14th International AIDS Conference, Barcelona, July 2002, abstract TuPeB4573. Five HIV+ patients receiving nevirapine (200 mg bd), amprenavir (600 mg bd) and lopinavir/ritonavir (400/100 mg bd) were studied. Amprenavir concentrations were in the expected ranges (Cmin 560-3090 ng/ml; Cmax 1760-8040 ng/ml; AUC0-12h 13230-75170 ng/ml.h). However, lopinavir concentrations were quite variable (Cmin 620-5980 ng/ml; Cmax 2710-12600 ng/ml; AUC0-12h 998-175140 ng/ml.h) and 40-60% lower than reported by the manufacturer. The combination of amprenavir, lopinavir and nevirapine may result in unpredictable lopinavir concentrations and pharmacological monitoring is advisable in patients treated with such combinations. Pharmacokinetics of amprenavir and lopinavir in combination with nevirapine in highly pretreated HIV-infected patients. Fatkenheuer G, Romer K, Kamps R, et al. AIDS, 2001, 15:2334-2335.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Nelfinavir	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary No data with nelfinavir 1250 mg twice daily. Coadministration of nelfinavir (750 mg three times daily) and nevirapine (200 mg twice daily) had no effect on nelfinavir AUC, but decreased Cmin by 32%. In another study, nelfinavir had no effect on nevirapine pharmacokinetics when compared to historical controls. Although no dose modification is recommended, it may be required in some patients. Therapeutic concentration monitoring may be of use. Description LHPG Comment: Although it is indicated in the SPC that there is no significant interaction, studies from our own group have shown both a marked autoinduction effect of nelfinavir (Merry C, Barry M, Ryan M et al. 7th European Conference on Clinical Aspects and Treatment of HIV Infection, 1999, abstract 831) and a potential additional inductive effect of nevirapine (Merry C, Barry MG, Mulcahy F et al. AIDS 1998, 12:1163–7 and Mulcahy F, Barry M, Merry C, Back D. AIDS 1998;12:2361). It is possible that some patients on this combination will require dosage modification. Results from a 28 day study in HIV infected patients (n=23) administered nevirapine, stavudine (30-40 mg twice daily) and nelfinavir (750 mg three times daily) showed no clinically relevant changes in nelfinavir pharmacokinetic parameters after the addition of nevirapine. Compared to historical controls nevirapine levels appeared to be unchanged. The major metabolite of nelfinavir (AG1402) decreased when administered with nevirapine. The overall effect of nevirapine on the total exposure of nelfinavir plus the AG1402 metabolite was a mean decrease in AUC by 20%, a mean decrease of 12% in Cmax and a mean decrease of 35% in Cmin. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with nelfinavir (750 mg three times a day) was studied in 23 HIV+ patients. Nevirapine caused no alteration in nelfinavir AUC or Cmax but reduced nelfinavir Cmin by 32% and M8 AUC, Cmax and Cmin by 62%, 59% and 66%, respectively. The effect on nevirapine pharmacokinetics was not significant. The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Dose adjustment is not needed when nevirapine is administered with nelfinavir. Viracept Summary of Product Characteristics, Roche Products Ltd, July 2008. Coadministration of nelfinavir (750 mg three times daily for 36 days) with nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks), in 23 subjects, caused no alteration in nelfinavir AUC or Cmax but caused a 32% decrease in Cmin. Based on non-definitive cross-study comparison, nelfinavir plasma concentrations appeared unaffected by coadministration with nevirapine. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. Viracept Prescribing Information, Agouron Pharmaceuticals Inc, August 2007. The pharmacokinetics of nelfinavir (750 mg three times daily) and nevirapine (200 mg bd) were evaluated in 13 HIV+, antiretroviral-experienced patients. The mean trough concentrations of nelfinavir remained above the minimum target concentration and there was no significant difference in AUC when administered with nevirapine. Based on these results, an increase in standard nelfinavir dose was not recommended to maintain antiviral efficacy. The pharmacokinetics of combination therapy with nelfinavir plus nevirapine in HIV positive patients. Vilaro J, Mascaro J, Colomer J, et al. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, December 2001, abstract A-497. Coadministration of nevirapine (200 mg twice daily) and nelfinavir (750 mg three times daily) was studied in 12 HIV+ individuals. Addition of nevirapine resulted in an 8% increase in nelfinavir AUC, a 14% increase in Cmax and a 2% increase in Cmin. No statistically significant changes in nelfinavir levels after the addition of nevirapine. Compared to historical controls, nevirapine levels were unchanged by nelfinavir. Preliminary pharmacokinetic analysis suggests no dose adjustment is necessary for this combination. Stavudine (d4T), nelfinavir (NFV) and nevirapine (NVP): preliminary safety, activity and pharmacokinetic (PK) interactions. Skowron G, Leoung G, Dusek A, et al. 5th Conference on Retroviruses and Opportunistic Infections, 1998, abstract 350. Coadministration of nevirapine (200 mg twice daily) and nelfinavir (750 mg three times daily) was studied in 23 healthy volunteers. There was no significant difference in nelfinavir AUC, Cmax or Cmin when given with nevirapine. No increase in nelfinavir dosage is warranted when coadministered with nevirapine. Lack of pharmacokinetic interaction between nelfinavir and nevirapine. Skowron G, Leoung G, Kerr B, et al. AIDS, 1998, 12:1243–4. Nelfinavir + Ritonavir The influence of nevirapine on the pharmacokinetics on nelfinavir given with low dose ritonavir in once daily regimens was evaluated in healthy volunteers. Pharmacokinetic parameters were assessed after the addition of nevirapine (400 mg od) to three nelfinavir/ritonavir regimens (2000/200, 2000/400 and 2500/200 mg). Since ritonavir strongly increases the ratio of active metabolite (M8) to parent nelfinavir, nelfinavir and M8 concentrations were combined. AUC and Cmin values for combined nelfinavir and M8 after addition of nevirapine were at least equivalent to the same parameters without nevirapine. An increase in combined nelfinavir+M8 concentrations was seen in the arm containing 400 mg ritonavir and this was caused by a significant increase in nelfinavir, but not M8 levels. In both arms containing 200 mg ritonavir, nevirapine cause a significant reduction in ritonavir exposure along with decrease formation of M8. Nevirapine AUC0-24h values were 146-171 mg/L.h and appeared to be higher than reported in sparse literature data. Influence of once daily nevirapine on the pharmacokinetics of once daily nelfinavir/ritonavir combinations in healthy volunteers. Aarnoutse R, Droste J, van Oosterhout J, et al. 3rd International Workshop on Clinical Pharmacology of HIV Therapy, Washington, 2002, abstract 7.5.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Ritonavir	Nevirapine
No clinically significant interaction expected
Summary Coadministration of nevirapine (200 mg twice daily) with ritonavir (600 mg twice daily) caused no alteration in ritonavir AUC, Cmax or Cmin. The effect on nevirapine pharmacokinetics was not significant. Description Results from a clinical trial (n=18) with HIV infected patients administered nevirapine and ritonavir (600 mg twice daily) indicated that their coadministration leads to no clinically relevant change in ritonavir or nevirapine plasma levels. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with ritonavir (600 mg twice daily), in 18 HIV+ patients, caused no alteration in ritonavir AUC, Cmax or Cmin. The effect on nevirapine pharmacokinetics was not significant. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Coadministration of nevirapine (200 mg twice daily) and ritonavir (600 mg twice daily) does not lead to clinically relevant changes in the pharmacokinetics of either nevirapine or ritonavir (i.e., no change in the AUC or Cmin of nevirapine or ritonavir). Norvir Summary of Product Characteristics, Abbott Laboratories Ltd, June 2008.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Saquinavir	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary No data with the 500 mg formulation. No significant interaction with boosted saquinavir (soft gel). Dose modification not recommended, but TDM should be used if available. Description The limited data available with saquinavir soft gel capsule boosted with ritonavir do not suggest any clinically relevant interaction between saquinavir boosted with ritonavir and nevirapine. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 3 weeks) with saquinavir (600 mg three times daily), in 23 HIV+ patients, caused 38% and 32% decrease in saquinavir AUC and Cmax, respectively. Saquinavir Cmin was below the limit of detection of the assay. The effect on nevirapine pharmacokinetics was not significant. Appropriate doses for this combination are not established, but an increase in the dose of saquinavir may be required. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. The interaction between saquinavir/ritonavir and nevirapine has not been evaluated. Co-administration of nevirapine and saquinavir resulted in a 24% decrease in saquinavir AUC and no change to nevirapine AUC. No dose adjustment required. Invirase Summary of Product Characteristics, Roche Products Ltd, July 2008. The interaction between saquinavir/ritonavir and nevirapine has not been evaluated. Appropriate doses for the combination of saquinavir/ritonavir with nevirapine with respect to safety and efficacy have not been established. Invirase Prescribing Information, Roche Pharmaceuticals, July 2007.

Class	Drug	HIV Drug
Antiretrovirals (Protease Inhibitors)	Tipranavir	Nevirapine
No clinically significant interaction expected
Summary No data with tipranavir/ritonavir 500/200 mg twice daily. Formal interaction studies performed with different doses of tipranavir/ritonavir (250/200, 500/100, 750/100, 750/200 mg)showed nevirapine AUC decreased by 0-25%, but there was no change in tipranavir AUC. Limited data from a phase IIa study in HIV+ patients suggest that no significant interaction is expected and therefore no dose adjustments are necessary. Description No specific drug-drug interaction study has been performed between tipranavir and low-dose ritonavir (500/200 mg twice daily) with nevirapine. However, the limited data available from a phase IIa study in HIV-infected patients suggest that no significant interaction is expected between nevirapine and tipranavir co-administered with low dose ritonavir. Moreover a study with tipranavirand low dose ritonavir and another NNRTI (efavirenz) did not show any clinically relevant interaction. Therefore no dose adjustments are necessary. Aptivus Summary of Product Characteristics, Boehringer Ingelheim International GmbH, July 2008. Coadministration of nevirapine (200 mg twice daily) and tipranavir/ritonavir (250/200 mg twice daily) to 26 HIV+ subjects resulted in no significant changes in nevirapine Cmax, AUC or Cmin (decreases of 3-4%). When coadministered with tipranavir/ritonavir (750/100 mg) to 22 HIV+ subjects, nevirapine Cmax, AUC and Cmin decreased by 14%, 11% and 7% respectively. Aptivus Prescribing Information, Boehringer Ingelheim, June 2008. No specific drug-drug interaction study has been performed between tipranavir and low-dose ritonavir (500/200 mg bid) with nevirapine. However, the limited data available from a phase IIa study in HIV-infected patients suggest that no significant interaction is expected between nevirapine and tipranavir co-administered with low dose ritonavir. Moreover a study with tipranavir and low-dose ritonavir and another NNRTI (efavirenz) did not show any clinically relevant interaction. Therefore no dose adjustments are necessary. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. No significant interaction was observed when tipranavir was co-administered with low dose ritonavir and nevirapine. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. The addition of tipranavir/ritonavir (1250/100 mg, n=17; 750/100 mg, n=22; 250/100 mg, n=26) was studied in HIV+ subjects on stable HAART regimens containing nevirapine. No clinically significant changes in nevirapine Cmin were observed. Pharmacokinetic drug interaction screen of three doses of tipranavir/ritonavir in HIV-infected patients on stable highly active antiretroviral therapy. Goebel FD, Sabo JP, MacGregor TR, et al. HIV DART, Naples (Florida), December 2002. Coadministration of tipranavir (1250 mg bd), ritonavir (200 mg bd oral solution) and nevirapine (200 mg bd) was studied in 4 subjects. There was no significant effect of nevirapine on the pharmacokinetics of tipranavir (decreases of 15%, 19% and 3% for AUC, Cmax and Cmin respectively). Tipranavir/ritonavir resulted in non-significant decreases in nevirapine AUC, Cmax and Cmin of 20%, 25% and 14% respectively. Tipranavir appeared to increase the total clearance of ritonavir by ~6.5-fold (compared to historical data) and when nevirapine was included, a further 62% increase in total clearance of ritonavir was observed. Pharmacokinetics of tipranavir and nevirapine. Sabo J, MacGregor T, Lamson M, et al. 10th Annual Canadian Conference on HIV/AIDS Research, Toronto, June 2001, abstract 249P.

Class	Drug	HIV Drug
Antivirals	Adefovir	Nevirapine
No clinically significant interaction expected
Summary No interaction observed at doses of adefovir 6- to 12-fold higher than that recommended for the treatment of chronic hepatitis B. Description At doses of adefovir dipivoxil 6- to 12-fold higher than the 10 mg dose recommended for the treatment of chronic hepatitis B, there was no interaction with nevirapine. Hepsera Summary of Product Characteristic, Gilead Sciences Ltd, October 2007.

Class	Drug	HIV Drug
Calcium Channel Antagonists	Diltiazem	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease diltiazem concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and diltiazem, which may cause decreased diltiazem plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Calcium Channel Antagonists	Nifedipine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease nifedipine concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and nifedipine, which may cause decreased nifedipine plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Calcium Channel Antagonists	Verapamil	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease verapamil concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and verapamil, which may cause decreased verapamil plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Erectile Dysfunctional Agents	Apomorphine	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Apomorphine is not metabolised by CYP450 isoforms. However, since it is metabolised by glucuronidation there is the potential for some NNRTIs to induce. In the absence of data we would suggest caution. Description LHPG Comment: Apomorphine is not metabolised by CYP450 isoforms. However, since it is metabolised by glucuronidation there is the potential for some NNRTIs to induce. In the absence of data we would suggest caution.

Class	Drug	HIV Drug
Erectile Dysfunctional Agents	Sildenafil	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary No data. Coadministration may decrease concentrations of sildenafil. Description LHPG Comment: Induction of CYP enzymes may be anticipated resulting in decreased concentrations of sildenafil.

Class	Drug	HIV Drug
Erectile Dysfunctional Agents	Tadalafil	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary No data. Coadministration may decrease concentrations of tadalafil. Description LHPG Comment: Induction of CYP enzymes may be anticipated resulting in decreased concentrations of tadalafil.

Class	Drug	HIV Drug
Erectile Dysfunctional Agents	Vardenafil	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary No data. Coadministration may decrease concentrations of vardenafil. Description LHPG Comment: Induction of CYP enzymes may be anticipated resulting in decreased concentrations of vardenafil.

Class	Drug	HIV Drug
Gastrointestinal Agents	Antacids	Nevirapine
No clinically significant interaction expected
Summary Nevirapine may be administered with or without antacid. When nevirapine (200 mg) was administered with antacid (Maalox 30 ml), nevirapine AUC was comparable to that observed under fasting conditions. Description The absorption of nevirapine is not affected by food, antacids or medicinal products which are formulated with an alkaline buffering agent. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. When nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with antacid (Maalox 30 ml), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. Nevirapine may be administered with or without antacid. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Gastrointestinal Agents	Cimetidine	Nevirapine
No clinically significant interaction expected
Summary Monitoring of steady-state nevirapine trough concentrations in 13 patients receiving long-term nevirapine revealed a 7% increase in nevirapine trough concentrations in patients who received cimetidine. Description Monitoring of steady-state nevirapine trough plasma concentrations in patients who received long-term nevirapine treatment revealed that nevirapine trough concentrations were elevated in patients who received cimetidine (7% increase, n=13). Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008.

Class	Drug	HIV Drug
Gastrointestinal Agents	Cisapride	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease cisapride concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and cisapride, which may cause decreased cisapride plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Herbals/Nutraceuticals/Vitamins	Garlic	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary In vitro data show that garlic components can affect CYP2C, 2D and 3A mediated metabolism. However, it is difficult to extrapolate in vitro data to the clinical situation. Caution is recommended. Description The effects of garlic and garlic products were assessed in vitro using cDNA expressed human P450 enzymes associated with the metabolism of antiretroviral drugs and P-glycoprotein (P-gp) purified cell membranes. It was shown that CYP2D6 metabolism was generally unaffected. Extracts of fresh garlic stimulated CYP2C9 mediated metabolism. The extracts tested had very low to moderate P-gp interaction compared with verapamil (a positive control). In vitro, garlic components can affect CYP2C, 2D and 3A mediated metabolism; there may be the potential for interactions and further studies need to be carried out in vivo. An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. Foster BC, Foster MS, Vanderhoek S, et al. J Pharm Pharmaceut Sci, 2001,4:176–84. LHPG Comment: Caution is needed when trying to extrapolate in-vitro data to the clinical situation.

Class	Drug	HIV Drug
Herbals/Nutraceuticals/Vitamins	St John's Wort	Nevirapine
These drugs should not be coadministered
Summary Coadministration is contraindicated as St John wort is expected to substantially decrease nevirapine concentrations and may result in sub-optimal levels. If patient is already taking St John's Wort check nevirapine and if possible viral levels and stop St John's Wort. Nevirapine levels may increase on stopping St John's Wort. The dose of nevirapine may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's Wort. Description Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking nevirapine due to the risk of decreased plasma concentrations and reduced clinical effects of nevirapine. Serum levels of nevirapine can be reduced by concomitant use of the herbal preparation St John's Wort (Hypericum perforatum). This is due to induction of drug metabolism enzymes and/or transport proteins by St Johns Wort. If patient is already taking St John's Wort check nevirapine and if possible viral levels and stop St John's Wort. Nevirapine levels may increase on stopping St John's Wort. The dose of nevirapine may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's Wort. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Concomitant use of St John's wort (Hypericum perforatum) or St John's wort containing products and nevirapine is not recommended. Co-administration of nevirapine with St John's wort is expected to substantially decrease nevirapine concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. A study was conducted with 176 HIV+ outpatients who were using nevirapine as part of their antiretroviral drug regimen. Five of these patients also used St John's Wort concomitantly for several months. It was shown that the clearance of nevirapine was significantly increased by 35% thus lowering exposure to nevirapine. Drug inetaction between St John's wort and nevirapine. de Maat MMR, Hoetelmans RMW, Mathôt RAA, et al. AIDS, 2001, 15:420-421.

Class	Drug	HIV Drug
Herbals/Nutraceuticals/Vitamins	Valerian	Nevirapine
No clinically significant interaction expected
Summary Coadministration of valerian with probe substrates for CYP3A4 (alprazolam) and CYP2D6 (dextromethorphan) modestly increased alprazolam Cmax and AUC (~20%) and had no effect on dextromethorphan. A clinically significant interaction is unlikely with drugs metabolised by CYP3A4 or CYP2D6. Description Coadministration of valerian (1000 mg nightly for 14 nights) with probes for CYP3A4 (alprazolam, 2 mg single dose) and CYP2D6 (dextromethorphan, 30 mg single dose) was studied in 12 subjects. Alprazolam Cmax and AUC increased by ~20%, but only the increase in Cmax was statistically significant. There was no significant effect of valerian on dextromethorphan metabolism. Typical doses of valerian are unlikely to produce clinically significant effects on drugs metabolised by CYP3A4 or CYP2D6. Multiple night time doses of valerian (Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Donovan JL, DeVane CL, Chavin KD, et al. Drug Met Dis, 2004, 32: 1333-1336.

Class	Drug	HIV Drug
Immunosuppressants	Ciclosporin	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease ciclosporin concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and ciclosporin, which may cause decreased ciclosporin plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Immunosuppressants	Mycophenolate	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration of nevirapine (200 mg twice daily) and mycophenolate (500 mg twice daily) reduced nevirapine AUC (13%), Cmax (22%) and Cmin (17%). The mechanism and clinical significance of this interaction is unknown. Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA). MPA undergoes glucuronidation; coadministration of inducers or inhibitors of glucuronidation, such as some PIs and NNRTIs, could alter mycophenolate levels. Concentration monitoring of mycophenolate is recommended. Description Antiretroviral-naive men starting treatment with ddI (400 mg once daily), 3TC (150 mg twice daily), ABC (300 mg twice daily), IDV (800 mg twice daily), RTV (100 mg twice daily) and NVP (200 mg twice daily) were randomised to a group with (n=9) or without (n=10) mycophenolate mofetil (500 mg twice daily). After 8 weeks of therapy, there was no difference in plasma clearance of IDV or ABC between the two groups. The clearance of NVP was higher in patients using mycophenolate mofetil (3.25 vs 2.83 L/h, p=0.04). In 12 patients, of whom five also received mycophenolate mofetil, intracellular triphosphates were measured. There was no significant difference in intracellular dCTP, dGTP or 3TCTP concentrations between the two groups. In this small study, mycophenolate mofetil therapy reduced the plasma concentration of NVP (mechanism unknown) but had no effect on plasma concentrations of IDV and ABC. Effect of mycophenolate mofetil on the pharmacokinetics of antiretroviral drugs and on intracellular nucleoside triphosphate pools. Sankatsing SU, Hoggard PG, Huitema AD et al., Clin Pharmacokinet. 2004;43:823-32. LHPG Comment: The clinical significance of this finding is unknown. Further studies are needed.

Class	Drug	HIV Drug
Immunosuppressants	Sirolimus	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease sirolimus concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and sirolimus, which may cause decreased sirolimus plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Immunosuppressants	Tacrolimus	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Coadministration may decrease tacrolimus concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Description There is a potential drug interaction between nevirapine and tacrolimus, which may cause decreased tacrolimus plasma concentrations. Dose adjustment may be needed due to possible decrease in clinical effect. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008.

Class	Drug	HIV Drug
Lipid Lowering Agents	Fish oils	Nevirapine
No clinically significant interaction expected
Summary No data in humans, but inhibited CYP3A-mediated metabolism of saquinavir in rat liver microsomes. Simultaneous coadministration with saquinavir in rats increased saquinavir exposure by ~3-fold. Separating the doses by 2 h overcame the interaction. Description (See Summary)

Class	Drug	HIV Drug
Lipid Lowering Agents	Rosuvastatin	Nevirapine
No clinically significant interaction expected
Summary Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Drug interactions resulting from cytochrome P450-mediated metabolism are not expected. Description Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. Crestor Summary of Product Characteristics, AstraZeneca UK Ltd, February 2006. In vitro and in vivo data indicate that rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole). Crestor Prescribing Information, AstraZeneca, December 2005.

Class	Drug	HIV Drug
Oral Anti-diabetic	Rosiglitazone	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Nevirapine concentrations were determined before and after 28 days of treatment with rosiglitazone (4 mg). There was a consistent trend to reductions in nevirapine Cmax (5%), Cmin (11%) and AUC (4%). Description Therapeutic drug monitoring (TDM) of antiretroviral drugs was performed in a prospective study before and at day 28 after start of treatment with 4 mg of rosiglitazone for combined lipodystrophy syndrome. Drug levels were measured in the morning fasting, and 0.5, 1, 2, 4, 6 and 8 h after standardized drug intake. Mean Cmax of nevirapine (n=4) was reduced significantly [-0.44; 95% CI -0.86 to -0.01]. Furthermore, there was a consistent trend to a reduction in the geometric mean ratio (GMR) of Cmax (5%), Cmin (11%) and AUC (4%). Routine TDM is recommended for patients treated with rosiglitazone and nevirapine. Further studies on the interaction of rosiglitazone with ARV drugs are necessary. Impact of rosiglitazone treatment on the bioavailability of antiretroviral compounds in HIV-positive patients. Oette M, Kurowski M, Feldt T, et al. J Antimicrob Chemother, 2005, 56(2):416-419.

Class	Drug	HIV Drug
Other	Alendronic Acid	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary If taken at the same time, it is likely that food and beverages (including mineral water), calcium supplements, antacids, and some oral medicinal products will interfere with absorption of alendronate. Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product. Description (See Summary)

Class	Drug	HIV Drug
Other	Ibandronic acid	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid. Description (See Summary)

Class	Drug	HIV Drug
Smoking Cessation	Varenicline	Nevirapine
No clinically significant interaction expected
Summary No interactions due to cytochrome P450 metabolism or renal secretion expected. Description Based on varenicline characteristics and clinical experience to date, varenicline has no clinically meaningful drug interactions. No dosage adjustment of varneicline or co-administered medicinal products listed below is recommended. In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes. Furthermore since metabolism of varenicline represents less than 10% of its clearance, active substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline and therefore a dose adjustment of varenicline would not be required. In vitro studies demonstrate that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, active substances that are cleared by renal secretion are unlikely to be affected by varenicline. Champix Summary of Product Characteristics, Pfizer Ltd, August 2008. No clinically meaningful pharmacokinetic drug-drug interactions have been identified. In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4. In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter, OCT2. Co-administration with inhibitors of OCT2 may not require a dose adjustment of varenicline as the increase in systemic exposure to varenicline is not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline and therefore a dose adjustment of varenicline would not be required. Chantix Prescribing Information, Pfizer Inc, May 2008.

Class	Drug	HIV Drug
Steroids	Ethinylestradiol	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception. Coadministration of nevirapine (200 mg twice daily) with an oral contraceptive containing ethinylestradiol/norethindrone (0.035 mg/1 mg once daily) decreased ethinylestradiol AUC (20%) and had no effect on Cmax; norethindrone AUC and Cmax decreased by 19% and 16%, respectively. The effect on nevirapine pharmacokinetics was not significant. An alternative or additional method of contraceptive is recommended. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored. Description Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine might lower the plasma concentrations of these medications. Nevirapine (200 mg twice daily) was co-administered with a single dose of an oral contraceptive containing ethinyl estradiol (0.035 mg) and norethindrone (1.0 mg). Nevirapine following 28 days of exposure (full induction) decreased the mean ethinyl estradiol AUC by 20%. Nevirapine also decreased the mean norethindrone AUC by 19% and the Cmax by 16%. Appropriate doses for hormonal contraceptives (oral and other forms of application) other than DMPA in combination with nevirapine have not been established with respect to safety and efficacy. Additionally, when post menopausal hormonal therapy is used during administration of nevirapine, its therapeutic effect should be monitored. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with ethinylestradiol/norethindrone (0.035 mg/1 mg, as Ortho-Novum, once daily) in 10 HIV+ patients resulted in a 20% decrease in ethinylestradiol AUC, no change in ethinylestradiol Cmax, and a 19% and 16% decrease in norethindrone AUC and Cmax, respectively. The Cmin for ethinylestradiol and norethindrone were below the limit of detection for the assays. The effect on nevirapine pharmacokinetics was not significant. Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraceptive is recommended. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. Nevirapine (200 mg twice daily) was coadministered with a single dose of an oral contraceptive containing ethinylestradiol (0.035 mg) and norethindrone (1.0 mg). Compared to plasma concentrations observed prior to nevirapine administration, the median AUC for 17-alpha-ethinylestradiol was significantly decreased by 29% after 28 days of nevirapine dosing. There was a significant reduction in ethinylestradiol mean resident time and half-life. There was a significant reduction (18%) in median AUC for norethindrone, without changes in mean resident time or half-life. Pharmacokinetic interaction between nevirapine and ethinylestradiol/norethindrone when administered concurrently to HIV-infected women. Mildvan D, Yarrish R, Marshak A, et al. J Acquir Immune Defic Syndr, 2002, 29:471-477.
Further details of the different types of hormonal contraceptives and their potential for interactions can be found by clicking here (file in pdf format).

Class	Drug	HIV Drug
Steroids	Medroxyprogesterone (IM depot injection)	Nevirapine
No clinically significant interaction expected
Summary Coadministration of the progesterone-base depot (IM injection) contraceptive medroxyprogesterone acetate (DMPA) with nevirapine was investigated in HIV+ women and was found to increase nevirapine AUC by 17%, but the increase was not thought to be clinically significant. The efficacy of DMPA in the women studied did not appear to be altered in the presence of nevirapine. Description In a 12 week, parallel group steady state study in HIV-infected women comparing the pharmacokinetic and pharmacodynamic effect of depo-medroxyprogesterone acetate (DMPA) alone (n=16) to DMPA added to a stable nevirapine regimen group (n=16), AUC, Cmax, Cmin, and half-life of DMPA did not change in the presence of nevirapine. Nevirapine co-administration did not alter the ovulation suppression effects of DMPA. Nevirapine pharmacokinetic parameters AUC and Cmax increased by 20% in the presence of DMPA; while statistically significant, this change is not considered clinically relevant. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of depomedroxy-progesterone acetate (DMPA, 150 mg every 3 months) and steady state nevirapine was studied in 32 subjects. The AUC, Cmax and Cmin of DMPA were unaltered by nevirapine. The effect on DMPA on nevirapine pharmacokinetics was not significant. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. The interaction between nevirapine and MPA (given intramuscularly as DMPA) was evaluated in 16 HIV+ women. When compared to a control group of subjects (n=16), there were no significant changes in the Cmin or AUC of MPA when given with nevirapine, with suppression of ovulation being maintained. The pharmacokinetics of nevirapine were determined prior to and 4 weeks after DMPA administration. Coadministration increased nevirapine AUC by 17% with both Cmax and Cmin increasing by 19%. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Cohn SE, Park JG, Watts DH, et al. Clin Pharmacol Ther, 2007, 81(2): 222-227.

Class	Drug	HIV Drug
Steroids	Progesterone/Progestogen	Nevirapine
Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration
Summary Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception. An alternative or additional method of contraceptive is recommended. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored. Coadministration of nevirapine (200 mg twice daily) with an ORAL contraceptive containing ethinylestradiol/norethindrone (0.035 mg/1 mg once daily) decreased ethinylestradiol AUC (20%) and had no effect on Cmax; norethindrone AUC and Cmax decreased by 19% and 16%, respectively. The effect on nevirapine pharmacokinetics was not significant. Coadministration of the progesterone-base DEPOT contraceptive medroxyprogesterone acetate (DMPA) with nevirapine was investigated in HIV+ women and was found to increase nevirapine AUC by 17%, but the increase was not thought to be clinically significant. The efficacy of DMPA in the women studied did not appear to be altered in the presence of nevirapine. Description Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine might lower the plasma concentrations of these medications. Nevirapine (200 mg twice daily) was co-administered with a single dose of an oral contraceptive containing ethinyl estradiol (0.035 mg) and norethindrone (1.0 mg). Nevirapine following 28 days of exposure (full induction) decreased the mean ethinyl estradiol AUC by 20%. Nevirapine also decreased the mean norethindrone AUC by 19% and the Cmax by 16%. In a 12 week, parallel group steady state study in HIV-infected women comparing the pharmacokinetic and pharmacodynamic effect of depo-medroxyprogesterone acetate (DMPA) alone (n=16) to DMPA added to a stable nevirapine regimen group (n=16), AUC, Cmax, Cmin, and half-life of DMPA did not change in the presence of nevirapine. Nevirapine co-administration did not alter the ovulation suppression effects of DMPA. Nevirapine pharmacokinetic parameters AUC and Cmax increased by 20% in the presence of DMPA; while statistically significant, this change is not considered clinically relevant. Appropriate doses for hormonal contraceptives (oral and other forms of application) other than DMPA in combination with nevirapine have not been established with respect to safety and efficacy. Additionally, when post menopausal hormonal therapy is used during administration of nevirapine, its therapeutic effect should be monitored. Viramune Summary of Product Characteristics, Boehringer Ingelheim International GmbH, September 2008. Coadministration of nevirapine (200 mg once daily for 2 weeks then 200 mg twice daily for 2 weeks) with ethinylestradiol/norethindrone (0.035 mg/1 mg, as Ortho-Novum, once daily) in 10 HIV+ patients resulted in a 20% decrease in ethinylestradiol AUC, no change in ethinylestradiol Cmax, and a 19% and 16% decrease in norethindrone AUC and Cmax, respectively. The Cmin for ethinylestradiol and norethindrone were below the limit of detection for the assays. The effect on nevirapine pharmacokinetics was not significant. Coadministration of depomedroxy-progesterone acetate (DMPA, 150 mg every 3 months) and steady state nevirapine was studied in 32 subjects. The AUC, Cmax and Cmin of DMPA were unaltered by nevirapine. The effect on DMPA on nevirapine pharmacokinetics was not significant. Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraceptive is recommended. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored. Viramune Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc, June 2008. This study evaluated the interaction between nevirapine and MPA (given intramuscularly as DMPA) in 16 HIV+ women. When compared to a control group of subjects (n=16), there were no significant changes in the Cmin or AUC of MPA when given with nevirapine, with suppression of ovulation being maintained. The pharmacokinetics of nevirapine were determined prior to and 4 weeks after DMPA administration. Coadministration increased nevirapine AUC by 17% with both Cmax and Cmin increasing by 19%. Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions. Cohn SE, Park JG, Watts DH, et al. Clin Pharmacol Ther, 2007, 81(2): 222-227. Nevirapine (200 mg twice daily) was coadministered with a single dose of an oral contraceptive containing ethinylestradiol (0.035 mg) and norethindrone (1.0 mg). Compared to plasma concentrations observed prior to nevirapine administration, the median AUC for 17-alpha-ethinylestradiol was significantly decreased by 29% after 28 days of nevirapine dosing. There was a significant reduction in ethinylestradiol mean resident time and half-life. There was a significant reduction (18%) in median AUC for norethindrone, without changes in mean resident time or half-life. Pharmacokinetic interaction between nevirapine and ethinylestradiol/norethindrone when administered concurrently to HIV-infected women. Mildvan D, Yarrish R, Marshak A, et al. J Acquir Immune Defic Syndr, 2002, 29:471-477.
Further details of the different types of hormonal contraceptives and their potential for interactions can be found by clicking here (file in pdf format).