Category Archives: hivbook 2011 – Download

– Jan Thoden –

With an increasing number of antiretroviral drugs there is an growing risk of adverse drug-drug interactions. These might interfere with therapeutic success. Moreover, antiretroviral drugs are used by an aging patient population with a variety of co-morbidities requiring additional medications. Therefore drug combinations as well as drug concentrations or dosages need to be carefully chosen to avoid toxicity while exceeding sub-therapeutic levels.

By inducing or inhibiting enzyme production, the elimination of a drug and hence its plasma levels are influenced. Especially metabolization by cytochrome-P450 plays a crucial role for drug-drug interactions. As many other drugs, PIs and NNRTIs are mainly metabolized by CYP3A4 in liver and the gastrointestinal tract. Another pathway for the elimination of antiretroviral drugs is the glucuronidation by glucuronosyltransferases, though this usually does not cause clinically relevant interactions. Moreover, there are major inter-individual differences in enzyme activity and drug metabolization rates. Other factors that need to be considered include genetic polymorphisms, ethnicity, age, sex, and co-morbidities.

The tables in this chapter provide a brief overview of drug combinations deemed safe (+) as well as drug combinations that should be avoided (L). However, for many drug combinations the interactions are uncertain, unknown or can only be assumed based on theoretical calculations (K). In these cases, use might still be safe and should be controlled by regular TDM.

The first part of this chapter deals with ART/ART interactions, the second part deals with interactions between ART and selected relevant concomitant medications. Clinically irrelevant drugs, such as delavirdine, as well as drugs which are not yet approved are not included. Except for nelfinavir, all PIs are assumed to be given boosted with ritonavir. T-20 is only mentioned in the first part as there are no known relevant interactions with concomitant medications. Ritonavir is only mentioned in the first part, too, yet interactions between it, used as a booster, and concomitant medications need to be considered.

This chapter is intended as a tool to support rapid decision making in the daily practice, but – when in doubt – should not replace a thorough literature search. On rare occasions, drug combinations with know adverse effects might be unavoidable due to a lack of alternatives. In these cases, close monitoring of the patients and the drug levels is necessary, as well as regular TDM.

Abbreviations:

+            Combination of these drugs possible

K            Potential interactions or unknown, combination of these drugs is often possible, therapeutic drug monitoring suggested

L            Combination of these drugs should be avoided or is contraindicated

↑             up to 50% increased drug levels, ↑↑ up to 100%, ↑↑↑ > 100%

↓             up to 50% decreased drug levels, ↓↓ up to 100%, ↓↓↓ > 100%

BID        Twice daily (TID = Three times daily)

QD          Once daily

TDM      Therapeutic drug monitoring

Part 1: ART + ART

NRTIs + NRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT
3TC		+	+	+	L1	+	+
ABC	+		K	+	+	K	+
DDI	+	K		L2	+	L3	+
D4T	+	+	L2		+	+	L
FTC	L1	+	+	+		+	+
TDF	+	K	L3	+	+		K
AZT	+	+	+	L	+	K

¹ Antagonism   ² Increased mitochondrial toxicity (lactic acidosis, pancreatitis, polyneuropathy)

³ DDI ↑↑ (reduce daily dose to 250 mg), increased toxicity, reduced efficacy

NRTIs + NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT
EFV	+	+	+1	+	+	+	+
ETV	+	+	+	+	+	+	+
NVP	+	+	+	+	+	+	+

¹ Take DDI fasting, ETV with food – if taken apart, no dose adjustment necessary 

NRTIs + PIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT
ATV	+	+	K1	+	+	K2	+
DRV	+	+	+	+	+	+3	+
FPV	+	+	+	+	+	+	+
IDV	+	+	+	+	+	+	+
LPV	+	K4	+	+	+	+3	+
NFV	+	+	+	+	+	+	+
RTV	+	+	+	+	+	K	+
SQV	+	+	+	+	+	+	+
TPV	+	K4	+	+	+	+	K4

¹ ATV ↓↓, ATV to be taken > 2 hrs before DDI       ² ATV ↓, TDF ↑, ATV always boosted

³ TDF ↑, caveat: combination with nephrotoxic drugs, increased nephrotoxicity possible

⁴ NRTI ↓ (unknown relevance) 

NRTIs + Entry-/Integrase inhibitors

	3TC	ABC	DDI	D4T	FTC	TDF	AZT
T-20	+	+	+	+	+	+	+
MVC	+	+	+	+	+	+	+
RAL	+	+	+	+	+	+	+

 

	EFV	ETV	NVP	T20	MVC	RAL
EFV	L, NNRTIs should not be combined			+	K1	K2
ETV				+	K1	K2
NVP				+	+	+
T-20	+	+	+		+	+
MVC	K1	K1	+	+		+3
RAL	K2	K2	+	+	+3
1 MVC ↓↓, increase MVC to 2 x 600 mg/d, if not combined with PI or potent CYP3A4 inhibitor 2 RAL ↓, relevance unclear  3 RAL ↓, MVC↓, probably without clinical relevance   NNRTIs + PIs, Entry-/Integrase-Inhibitors + PIs
	EFV	ETV	NVP	T207	MVC	RAL
ATV	K1	L1	KL	+	K2	K
DRV	K	+	+	+	K2	+
FPV	K	L3	K	+	+	+
IDV	K	L	K	+	K2	+
LPV	K4	+	K4	+	K2	+
NFV	K	L	K	+	K2	+
RTV	K	K	+	+	K2	+
SQV	K	+5	K	+	K2	+
TPV	+	L6	+	K	+	K

¹ ATV ↓↓, ATV always boosted                  ² MVC ↑↑↑, reduce MVC to 2 x 150 mg/d

³ FPV ↑↑, relevance unclear, monitor FPV levels              

⁴ LPV ↓, increase LPV to 2 x 3 tablets (controversial in combination with NVP, use TDM)

⁵ SQV ↓↓, always boosted            ⁶ ETV ↓↓, TPV ↑, combination therefore not recommended

⁷ T-20 can be increased by PIs, PIs by T-20, too, no clinical relevance; TDM if problems

 

PIs + PIs

	ATV	DRV	FPV	IDV	LPV	NFV	SQV	TPV
ATV		+	K	L	K	K	+1	L
DRV	+		K	K	L	K	L	L
FPV	K	K		+	K	+	+2	L
IDV	L	K	+		K	K	K	K
LPV	K	L	K	K		K	+	L
NFV	K	K	+	K	K		+	K
RTV	+	+	+	+	+	+	+	+
SQV	+1	L	+2	K	+	+		L
TPV	L	L	L	K	L	K	L

*¹ ATV ↑, SQV ↑, combination well tolerated  *² FPV with 200 mg RTV, combination possible

Comment: The combination of two PIs is probably not more effective compared to second generation PIs (DRV and TPV), is therefore only recommended for special indications.

Part 2: ART + concomitant medications

Gastrointestinal agents

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Cimetidine	+	+	+	+	+	K	+	+	+	+
Famotidine	+	+	+	+	+	+	+	+	+	+
Loperamide	+	+	+	+	+	+	+	+	+	+
MCP	+	+	+	+	+	+	+	+	+	+
Mesalazine	K	+	+	+	K	K	+	+	+	+
Ondansetrone	+	+	+	+	+	+	+	+1	+1	+1
PPIs	+	+	+	+	+	+	+	+	+	+
Ranitidine	+	+	+	+	+	+	+	+	+	+

¹ NNRTIs are strong enzyme inductors, ondansetrone levels can be decreased

MCP = metoclopramide, PPIs = proton pump inhibitors.

PIs/Entry-/Integrase inhibitors

ATV

DRV

FPV

IDV

LPV

NFV

SQV

TPV

MVC

RAL

Antacids

K1

+

+

K1

+

K

+

K1

+

K

Cimetidine

K

+

K

+

+

+

+2

K

+

K

Famotidine

K

+

K

K

+

+

K

K

+

K

Loperamide

K

K

+

+

K

+

K

K

K

K

MCP

+

+

+

+

+

+

K

+

K

K

Mesalazine

+

+

+

+

+

+

+

+

+

+

Ondansetrone

+

+

+

+

+

+

+

K

K

K

PPIs

L3

+

+

K

+

L

K

K

K4

K5

Ranitidine

K

+

K

+

+

+

+

K

+

K

¹ PIs ↓, take antacids at least 2 hours apart   ² Cimetidine ↑, SQV ↑↑↑   ³ ATV boosted, TDM recommended, avoid this combination. ⁴ Potential interactions with esomeprazole, other PPIs probably without relevant interactions. ⁵ RAL↑↑, relevance unclear

MCP = metoclopramide, PPIs = proton pump inhibitors

PIs/NNRTIs

	ATV	DRV	FPV	IDV	LPV	NFV	SQV	TPV	EFV	ETV	NVP
Amiodarone	K	L	L	L	L	L	L	L	K	K	K
Chinidine	L	L	L	L	K	L	L	L	K	K	K
Flecainide	L	K	L	L	L	K	L	L	K	K	K
Propafenone	L	K	L	L	K	K	L	L	K	K	K

Antibiotics

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Amoxicillin	+	+	+	+	+	+	+	+	+	+
Azithromycin	+	+	+	+	+	+	+	+	K	+
Ciprofloxacin	+	+	+	+	+	+	+	+	+	+
Clarithromycin	+	+	+	+	+	+	K1	K2	K2	K2
Clindamycin6	+	+	+	+	+	K3	+	+	+	+
Cotrimoxazol	K	+	+	K	K	K	K4	+	+	+
Dapson	+	+	K5	K5	+	+	K4	K	K	K
Erythromycin6	+	+	+	+	+	+	+	+	K7	K7
Ethambutol	+	+	K5	K5	+	+	+	+	+	+
Isoniazid	+	+	K5	K5	+	+	+	+	+	+
Meropenem	+	+	K	K	+	K	+	+	+	+
Metronidazol6	+	+	+	+	+	+	+	+	+	+
Pentamidin6	+	+	+	+	+	K3	+	K	+	+
Pyrazinamid6	+	+	+	+	+	K3	+	+	+	+
Pyrimethamin	+	+	+	+	+	K3	K4	+	+	+
Rifabutin	+	+	+	+	+	+	+	K8	L9	K
Rifampicin	+	K	+	+	+	+	K	K10	L11	L
Streptomycin	+	+	+	+	+	K3	+	+	+	+

¹ AZT ↓, take 1-2 h apart    ² active metabolite ↑, consider alternatives e.g. azithromycin.   

³ Caveat: renal function  ⁴ Caveat: hematotoxicity  ⁵ Caveat: neuropathy, avoid; dapsone ↓

⁶ Theoretical data on interactions with NRTIs    ⁷ NNRTI ↑, consider alternatives (azithromycin)

⁸Rifabutin ↓, increase dosage to 450-600 mg/d    ⁹ETV ↓, rifabutin ↓, avoid  this combination

¹⁰ EFV ↓, increase EFV to 800 mg/d    ¹ ETV approved in combination with PI/r – rifampin contraindicated

Comment: No relevant interactions with azithromycin, ciprofloxazin and tetracyclines.

PIs/Entry-/Integrase inhibitors

	ATV	DRV	FPV	IDV	LPV	NFV	SQV	TPV	MVC	RAL
Amoxicillin	+	+	+	+	+	+	+	+	+	+
Azithromycin	+	+	+	+	+	K1	+	+	K	+
Ciprofloxacin	+	K	+	+	K	K	K	K	K	K
Clarithromycin	K2	K	+	+	K	+	+	L3	+4	+
Clindamycin	+	+	+	+	+	+	+	+	+	+
Cotrimoxazol	+	+	+	+	+	+	+	K	+	+
Dapson	+	+	K	+	+	+	K	K	+	+
Erythromycin5	+	+	+	+	+	+	K	K	K	+
Ethambutol	+	+	+	+	+	+	+	+	+	+
Isoniazid	K	K	+	+	K	+	+	K	K	+
Meropenem	+	+	+	+	+	+	+	+	+	+
Metronidazol6	K	K	+	+	K	+	+	K	K	+
Pentamidin6	+	+	+	+	K	+	+	+	+	+
Pyrazinamid6	+	+	+	+	+	+	+	+	+	+
Pyrimethamin6	+	+	+	+	+	+	+	+	+	+
Rifabutin7	K	K	K	+	K	K	K	K	K	+
Rifampicin	L	L	L	L	L	L	L	L	+8	K
Streptomycin6	+	+	+	+	+	+	+	+	+	+
Tetracycline	+	+	+	+	+	+	+	+	K	K

¹ NFV ↓ , azithromycin ↑↑  ² QT-prolongation possible, clarithromycin ↑ – 50%, reduce dose 

³ TPV ↑↑   ⁴ MVC ↑↑, reduce MVC to 2×150 mg/d  ⁵ PIs ↑, erythromycin ↑, consider azithromycin  

⁶ Little data, probably no relevant interactions   ⁷ rifabutin ↑↑, reduce to 150 mg every other day    ⁸ Increase MVC to 2 x 600 mg/d, if not combined with PI or potent CYP3A4 inhibitor

Comment: (Probably) no relevant interactions with ciprofloxazin, clindamycin and streptomycin.

Antidepressants

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Amitriptyline	K	K	K	K	K	K	K	+1	+	+
Bupropion	K	K	K	K	K	K	K	K1	K	K
Citalopram	K	K	K	K	K	K	K	K1	K	K
Desipramine	K	K	K	K	K	K	K	+1	+	+
Doxepin	K	K	K	K	K	K	K	+1	+	+
Fluoxetine	K	K	K	K	K	K	K	+1	+	+
St. John´s w.	K	K	K	K	K	K	K	L	L	L
Lithium	+	+	+	+	+	+	+	+	+	+
Mirtazapine	K	K	K	K	K	K	K	K1	K	K
Nortriptyline	K	K	K	K	K	K	K	+	+	+
Paroxetine	K	K	K	K	K	K	K	+1	+	+
Sertraline	K	K	K	K	K	K	K	K1	+	+
Trazodone	+	+	+	+	+	+	+	K1	K	K
Venlafaxine	+	+	+	+	+	+	+	K1	K	K

¹ CNS-effects of EFV can be increased

Comment: No data exists for most antidepressants and their interactions with NRTIs       

PIs/Entry-/Integrase inhibitors

ATV

DRV

FPV

IDV

LPV

NFV

SQV

TPV

MVC

RAL

Amitriptyline1

L

K

L

K

K

+

K

K

K

K

Bupropion

K

K

K

K

K1

K

K

K

K

K

Citalopram4

K

K

K

K

K

K

K

K

K

K

Desipramine1

K

K

K

K

+

+

K

K

K

K

Doxepin4

K

K

K

K

K

K

K

K

K

K

Fluoxetine4

K

K

K

K

K

+

K

K

K

K

St. John´s w.

L

L

L

L

L

L

L

L

L

+

Lithium

K

+

+

+

+

+

+

+

+

+

Mirtazapine

K

K

K

K

K

K

K

K

K

K

Nortriptyline1

K

K

K

K

K

+

K

K

K

K

Paroxetine

K2

K2

K2

K4

L4

+

K4

K4

K

K

Sertraline

K

K3

K

K

L

K

K

K4

K

K

Trazodone

L

L4

L

L4

K

L

L

L

+

+

Venlafaxine5

K

K

K

K

K

K

K

K

K

+

¹ Tricyclic antidepressants and boosted PIs: PI ↑, antidepressant ↑ 

² Paroxetine ↓-↓↓, adjust if applicable                 ³ Sertraline ↓, adjust if applicable 

⁴ Antidepressant↑, titrate dose!  ⁵ Boosted PIs ↑ and venlafaxine ↑, TDM of PIs, careful titration!  ⁶ Tricyclic antidepressants and boosted PIs: PI ↑, antidepressants ↑ 

Antidiabetics (oral)

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Exenatide	+	+	+	+	+	+	+	+	+	+
Glibenclamid	+	+	+	+	+	+	+	+	+	+
Glimepirid	+	+	+	+	+	+	+	K	+	+
Metformin	+	+	+	+	+	+	+	+	+	+
Pioglitazone	+	+	+	+	+	+	+	K	K	K
Repaglinide	+	+	+	+	+	+	+	K1	K1	K1
Rosiglitazone	+	+	+	+	+	+	+	+	+	+
Sitagliptin	+	+	+	+	+	+	+	+	+	+

¹ TDM of NNRTIs recommended

PIs/Entry-/Integrase inhibitors

ATV

DRV

FPV

IDV

LPV

NFV

SQV

TPV

MVC

RAL

Exenatide

+

+

+

+

+

+

+

+

+

+

Glibenclamid

+

+

+

+

+

+

+

+

+

+

Glimepirid

+

+

+

+

+

+

+

+

+

+

Metformin

+

+

+

+

+

+

+

+

+

+

Pioglitazone

K

K

K

K

K

K

K

K

+

+

Repaglinide

K

K

K

K

K

K

K

+

+

+

Rosiglitazone

K

+

+

+

K

+

+

+

+

+

Sitagliptin

+

K

+

+

K

K

K

K

+

+

Antihistamines

No relevant interactions with NRTIs, MVC and RAL to be expected.

PIs/NNRTIs

	ATV	DRV	FPV	IDV	LPV	NFV	SQV	TPV	EFV	ETV	NVP
Astemizole1	L	L	L	L	L	L	L	L	L	L	K
Cetirizine	+	+	+	+	+	+	+	+	+2	+	+
Fexofenadine	K	K	K	K	K	+	K	K	K2	K	K
Loratadine	K	K	K	K	K	K	K	K	K	K	+
Terfenadine1	L	L	L	L	L	L	L	L	L	L	K

¹ Caveat: Arrhythmia       ² CNS-effects of EFV can be increased

Comment: No relevant interactions with NRTIs

Antihypertensive therapy

Calcium-channel blockers (CCB) can be increased (separate chapter), especially in combination with  PIs. They should be carefully introduced. In combination with NNRTIs variations in drug levels are possible. In general, alternatives should be considered.

The combination of beta blockers and Atazanavir can lead to QT-prolongation.

Anticonvulsants

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Cabamazepine	K	K	K	K	K	K	K	K1,2	L	K1
Gabapentine	+	+	+	+	+	+	+	+2	+	+
Lamotrigine	+	+	+	+	+	+	+	+2	+	+
Levetiracetam	+	+	+	+	+	+	+	+	+	+
Oxcarbazepine	+	+	+	+	+	+	+	+	K	K
Phenobarbital	+	K	+	+	+	+	K	K	L	K
Phenytoin	+	K	+	+	+	+	K	K	L	K
Pregabaline	K	+	+	+	K	K	+	+	+	+
Valproic acid	+	K	+	+	+	+	K3	+	+	K

¹ EFV ↓, NVP ↓, avoid combination or monitor closely (TDM) 

² CNS-effects of EFV can be increased ³ AZT ↑↑, monitor for side effects

PIs/Entry-/Integrase inhibitors

ATV

DRV

FPV

IDV

LPV

NFV

SQV

TPV

MVC

RAL

Carbamazepine

K1

K1

K1

K1

K1

L1

K1

K1

K

K

Gabapentine

+

+

+

+

+

+

+

+

+

+

Lamotrigine

K

+

+

K

+2

+

+

+

+

+

Levetiracetam

+

+

+

+

+

+

+

+

+

+

Oxcarbazepine

K

K

K

K

K

K

K

K

+

+

Phenobarbital

K

L

K

K

K

L

K

K

K

K

Phenytoin

K

L

L

K

K

K

K

K

K

K

Pregabaline

+

+

+

+

+

+

+

+

+

+

Valproic acid

K

+

+

K

K

K

+

K

K

K

¹ PIs ↓, Carbamazepine ↑, avoid if possible or monitor closely (TDM) 

² Lamotrigine ↓, increase if necessary

Antimycotic agents

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Amphotericin B	K	+	K	K	K	L1	K1,2	+	+	+
Caspofungin	K	K	K	K	K	K	K1,2	K9	K9	K9
Fluconazole	+	+	K	+	+	+	K1,2,3	+	+	K4
Flucytosine	K	+	K	K	K	K	K	+	+	+
Itraconazole	+	+	+7	+	+	+	+	K6	K5	L4
Ketoconazole	+	+	+7	+	+	+	+	K6	K5	L8
Posaconazole	+	K	+	+	+	+	K	L11	K5	K4
Terbinafine	K	K	K	K	K	K	K	+	+	+
Voriconazole	K	K	K	K	K	K	K	K6, 10	K5	K4

¹ Caveat: additive nephrotoxicity possible    ² Increased hematotoxicity  ³ AZT ↑↑, Fluconazole ↓

⁴ NVP ↑↑, monitor liver function tests; in combination with azoles Fluconazole still preferred

⁵ azoles increase ETR levels, relevance unclear              

⁶ NNRTIs ↑, azoles ↓  ⁷ Itraconazole ↓ (take 2 h apart)  ⁸ NVP ↑, Ketoconazole ↓↓

⁹ Caspofungin ↓, dose 70mg/d recommended. ¹⁰ Efavirenz ↑ (reduce or TDM), Vorivconazol ↓↓, dose  400mg BID recommended. ¹¹ Posaconazol ↓↓.

PIs/Entry-/Integrase inhibitors

ATV

DRV

FPV

IDV

LPV

NFV

SQV

TPV

MVC

RAL

Amphoter. B

+

+

+

+

+

+

+

+

K

K

Caspofungin

K

K

K

+

K

+

+

K

K

K

Fluconazole

+

+

+

+

+

+

+

K1

+

+

Flucytosine

+

+

+

+

+

+

+

+

K

K

Itraconazole2

K

K

K

+

K3

+

+

K

K4

+

Ketoconazole2

K

K

+

K

K

+

+

K

K4

+

Posaconazole

L7

K

K

K

K

K

K

K

K6

+

Terbinafine

+

+

+

+

+

+

+

+

K

K

Voriconazole5

K

L

K

K

L

K

K

K

K6

+

¹ Fluconazole ↑↑, do not excess 200 mg/d  ² PIs ↑, Itra-/Ketoconazole↑, avoid doses >200 mg/d   ³ LPV ↑, Itraconazole ↑; avoid doses > 200 mg Itrac./d  ⁴ Keto-/Itraconazole: MVC 150 mg BID   ⁵ Voriconazole ↓ by RTV, avoid boosted PIs if possible ⁶TDM recommended, if necessary decrease.MVC to 150 mg BID    ⁷ ATV-Clearance ↓, TDM!

Calcium channel antagonists (CCB)

The serum levels of CCB can be increased, especially if combined with PIs. In combination with NNRTIs serum levels might be fluctuating. Start CCB at low dose and titrate to full effect, monitor BP or discuss alternatives.

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Amlodipine	+	+	+	+	+	+	+	K	K	K
Diltiazem	+	+	+	+	+	+	+	K	K	K
Felodipine	+	+	+	+	+	+	+	K	K	K
Nifedipine	+	+	+	+	+	+	+	K	K	K
Verapamil	+	+	+	+	+	+	+	K	K	K

PIs/Entry-/Integrasehemmer

ATV

DRV

FPV

IDV

LPV

NFV

SQV

TPV

MVC

RAL

Amlodipine

K

K

K

K

K

K

K

K

K

K

Diltiazem

K

K

K

K

K

K

K

K

K

K

Felodipine

K

K

K

K

K

K

K

K

+

+

Nifedipine

K

K

K

K

K

K

K

K

K

K

Verapamil

K

K

K

K

K

K

K

K

K

K

Immunosupressants/Chemotherapeutic agents

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Azathioprine	+	+	K	+	+	+	K2	+	+	+
Cyclophosph.	K	K	K	K	K	K	K2	K	K	K
Cyclosporine	K	K	K	K	K	K3	K	K4	K4	K4
Cytarabine	+	+	+	+	+	+	K2	+	+	+
Docetaxel	+	+	+	+	+	+	+	K	K	K
Doxorubicine	+	+	+	K	+	+	K2	K	K	K
Etoposide	+	+	+	+	+	+	K2	K	K	K
Interferons	+	+	+	+	+	+	L2	+	+	+
Irinotecan	+	+	+	+	+	+	K2	K	K	K
Mycophenol.	+	+	+	+	+	+	+	+	+	+
Paclitaxel	K	K	K	K	K	K	K2	+5	+5	+5
Sirolimus	+	+	+	+	+	+	+	K4	K4	K4
Tacrolimus	K	+	+	+	K	K3	+	K4	K4	K4
Tamoxifen	+	+	+	+	+	+	+	K	K	K
Vinblastine	K	+	K1	K1	K	K	K	K	K	K
Vincristine	K	++	L1	L1	K	K	K	K	K	K

¹Neuropathy! Avoid combination if possible  ² AZT: Hematotoxicity, avoid if possible  ³ Additive nephrotoxicity possible ⁴Immunosuppressants ↑-↓, always TDM and dose adjustments!  ⁵ Paclitaxel ↓

PIs/Entry-/Integrase inhibitors

ATV

DRV

FPV

IDV

LPV

NFV

SQV

TPV

MVC

RAL

Azathioprin

+

+

+

+

+

+

+

+

+

+

Cyclophosph.

+

+

+

+

+

+

+

+

K

K

Cyclosporine1

K

K

L

K

K

K

K

K

K

K

Cytarabine

+

+

+

+

+

+

+

+

K

K

Docetaxel

K

K

K

K

K

+

K

K

+

+

Doxorubicine

K3

K3

K3

K3

K3

K3

K3

+

K

K

Etoposide

K3

K3

K3

K3

K3

K3

K3

K3

K

K

Interferon α

+

+

+

+

+

+

+

+

+

+

Interleukin 2

+

+

+

+

+

+

+

+

+

+

Irinotecan

L2

K2

K2

K2

K2

K2

K2

K4

+

+

Mycophenol.

+

+

+

+

+

+

+

+

+

+

Paclitaxel

K5

K5

K5

K5

K5

K5

K5

K5

K

K

Sirolimus1

K

K

K

K

K

K

K

K

+

+

Tacrolimus1

K

K

K

K

K

K

K

K

+

+

Tamoxifen

K

K

K

K

K

+

K

K

+

+

Vinblastine

K

K

K

K

K

K

K

K

K

K

Vincristine

K

K

K

K

K

K

K

K

K

K

¹ Cyclosporine, Sirolimus and Tacrolimus ↑-↑↑↑ in combination with PIs, always TDM, dose adjustments if necessary! ² Irinotecan toxicity may be increased ³ PIs-drug levels variable in this combinations, TDM! ⁴ Irinotecan ↓             ⁵ Paclitaxel ↓

Contraception

The serum levels of both ethinylestradiol and norethindrone can be very fluctuation especially in combination with (boosted) PIs. Therefore the use of oral contraceptives containing these hormones might be unsafe. Furthermore their levels can be fluctuating if combined with EFV and NVP. Combination with ETV is usually safe. For these reasons as well as for STD and HIV transmission prophylaxis oral contraceptives should always be combined with an additional method of contraception, preferably a condom.

Little data exist on combination with entry inhibitors or integrase inhibitors.  The data presented here is based on theoretical interactions.

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Artemisins	+	+	+	+	+	+	K1	K	K	K
Atovaquone	+	+	+	+	+	+	K1	K	+	+
Qinine	+	+	+	+	+	+	+	K	K	K
Choroquine	+	+	+	+	+	+	+	+	+	+
Halofantrine	+	+	+	+	+	+	+	K	K	K
Lumefantrine	K	K	K	K	K	K	K	+	+	+
Mefloquine	+	+	+	+	+	+	+	+	+	+
Pentamidine i.v.	+	+	+	+	+	K2	+	K	+	+
Primaquine	+	+	+	+	+	+	+	K	K	K
Proguanil	+	+	+	+	+	+	+	+	+	+
Pyrimethamin	K	+	K	K	K	K	K3	+	+	+

¹ AZT ↑, monitor for toxicity   ² Caveat: Nephrotocicity   ³ Caveat: Hematotoxicity

PIs/Entry-/Integrase inhibitors

	ATV	DRV	FPV	IDV	LPV	NFV	SQV	TPV	MVC	RAL
Artemisin	K	K	K	K	+	K	K	K	+	+
Atovaquon	K	+	+	K	K	+	+	K	+	+
Chinin	K	K	K	K	K	K	K	K	+	+
Chloroquin	+	+	+	+	+	+	+	+	+	+
Halofantrin	L	L	L	L	L	L	L	L	+	+
Lumefantrin	K	K	K	K	K	K	L	L	+	+
Mefloquin	+	+	+	+	+	+	+	+	+	+
Pentamidin	+	+	+	+	+	+	+	+	+	+
Primaquin	+	+	+	+	+	+	+	+	+	+
Proguanil	+	+	+	+	+	+	+	+	+	+
Pyrimethamin	+	+	+	+	+	+	+	+	+	+

Phosphodiesterase type 5 inhibitors

Combinations of most PDE5 inhibitors (e.g. Sildenafil, Tadalafil and Vardenafil) with PIs can cause severe increase in PDE5 serum levels. Thus they should be started carefully with a reduced (usually half) dose every 48 to 72 hours. In combination with NNRTIs the levels of PDE 5 inhibitors are fluctuating strongly, TDM and individual dosing are recommended (ETV and Sildenafil can be combined, sometimes Sildenafil needs to be increased). There are no known relevant interactions of PDE5 inhibitors with NRTIs, T-20, MVC and RAL. If PDE5 inhibitors are prescribed for pulmonary arterial hypertension alternatives such as endothelin receptors inhibitors should be evaluated.

Due to an FDA warning Sildenafil is now contraindicated for treatment of PAH in combination with a PI. Tadalafil and Bosentan need to be adjusted if prescribed as treatment for PAH in combination with a PI. Coadministration of Bosentan and ATV (without Ritonavir booster) is not recommended.

Statins / Lipid lowering drugs

The combination of NRTIs, Entry- and Integrase inhibitors with statins is generally possible, but the combination with PIs can cause problems.

PIs/NNRTIs

	ATV	DRV	FPV	IDV	LPV	NFV	SQV	TPV	EFV	ETV	NVP
Atorvastatin	K1	K1	K1	L1	L1	K1	K1	L1	K2	K2	K2
Clofibrat	+	+	+	+	+	+	+	+	+	+	+
Ezetimibe	K	+	+	+	+	+	+	+	+	+	+
Fenofibrate	+	+	+	+	+	+	+	+	+	+	+
Fish oils	+	+	+	+	+	+	+	+	+	+	+
Fluvastatin	+	+	+	K	+	+	+	+	+	K	+
Gemfibrozil	+	+	+	+	K	+	+	+	+	+	+
Lovastatin3	L	L	L	L	L	L	L	L	K	K	K
Pravastatin	+	L3	+	K	+	K	K	+	K	K	+
Rosuvastatin	K	K	K	K	K	K	K	K	+	K	+
Simvastatin3	L	L	L	L	L	L	L	L	K	K	K

¹ Atorvastatin ↑ if combined with PIs, low dosing! Consider alternatives: e.g. Pravastatin

² Atorvastatin↓, increase dose if applicable or chose alternatives: e.g. Fluvastatin / Pravastatin 

³ Statin levels severely increased, avoid these combinations!

Comment: All statins should be started low-dose if combined with PIs!

Anti-addictive drugs

NRTIs/NNRTIs

	3TC	ABC	DDI	D4T	FTC	TDF	AZT	EFV	ETV	NVP
Buprenorphin	+	+	+	+	+	+	+	K1	K	K
Naloxone	+	+	+	+	+	+	+	+	+	+
Methadone	+	K2	K3	K	+	+	K4	K2	+	K2

¹ Buprenorphine ↓, increase dose if necessary                 ² Methadone ↓, increase dose if necessary  

³ DDI ↓, relevance unclear  ⁴ AZT ↑, relevance unclear

PIs/Entry-/Integrase inhibitors

	ATV	DRV	FPV	IDV	LPV	NFV	SQV	TPV	MVC	RAL
Buprenorphine	K1	+3	K	K	K	K	K	K	+	+
Naloxon	+	+	+	+	+	+	+	+	+	+
Methadon	K2	K2	K2	K	K2	K2	+2	+2	+	+

¹ Buprenorphine ↑-↑↑, reduce dose if necessary              ² Methadone (↓), adjust dose if necessary

³ Buprenorphine ↓, adjust dose if necessary

Antiviral drugs

There are no known relevant interactions between PIs/NNRTIs and antiviral drugs. No data exists on interactions with CCR5- and Integrase inhibitors.

NRTIs/ NNRTIs

3TC

ABC

DDI

D4T

FTC

TDF