CIPLADOC - AIDS Update - DRUG INTERACTIONS IN HIV THERAPY - DRUGS MOST LIKELY TO BE INVOLVED IN DRUG INTERACTIONS

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DRUG INTERACTIONS IN HIV THERAPY
A Clinician's Guide

DRUGS MOST LIKELY TO BE INVOLVED IN DRUG INTERACTIONS

Certain drugs are most likely to be involved in drug interactions. This 'red flag' list of drugs reads as follows:

1 P450 Inhibitors

HIV protease inhibitors
HIV non-nucleoside reverse transcriptase inhibitors
Macrolide antibiotics
Azole antifungals
H2 antagonists

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2 P450 Inducers

Rifamycin antibiotics
HIV protease inhibitors
HIV non-nucleoside reverse transcriptase inhibitors
Anticonvulsants (that are P450 inducers)

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3 Metabolised drugs with narrow therapeutic indices

Non-sedating antihistamines
Long-acting opiate analgesics
Promotility agents
Antiarrhythmics
Long-acting benzodiazepines
Ergotamines and dihydroergotamine
Illicit drugs
Coumarin anticoagulants
Oral contraceptives

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4 Renally cleared drugs with narrow therapeutic indices

Ganciclovir
Foscarnet
Aminoglycosides

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5 Drugs with specific requirements for absorption

Ketaconazole and itraconazole
Didanosine
Fluoroquinolones

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6 Special case: Sildenafil

Sildenafil is a CYP450 substrate (mainly 3A4), and is a very weak P450 inhibitor (several isoforms). However, sildenafil's concentrations are significantly increased with 3A4 inhibitors. Therefore, caution should be advised when administering sildenafil with protease inhibitors or NNRTIs. All protease inhibitors and delavirdine could decrease sildenafil clearance and increase sildenafil effects. Inducers (ritonavir, nelfinavir and nevirapine) could increase sildenafil clearance and reduce sildenafil effects. However, no data exist on any of these interactions yet.

The package insert also warns against combining the drug with nitrates such as amyl nitrate (also known as 'poppers') because serious hypotension may occur.

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Alternatives to the 'red flag' list

The following information is presented in table format for ease of use. Alternative suggestions have been included whenever possible.

1 Cytochrome P450 inhibitors
2 Cytochrome P450 Inducers
3 Metabolised drugs with narrow therapeutic indexes
4 Renally cleared drugs with narrow therapeutic indices
5 Drugs with specific requirements for absorption

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1 Cytochrome P450 inhibitors

Drug Class	Likelihood of a drug interaction	Alternatives
HIV Protease inhibitors	Ritonavir: strongest Amprenavir: intermediate Indinavir: intermediate Nelfinavir: intermediate Saquinavir: weakest	Saquinavir has less potential to cause drug interactions
Non-nucleoside reverse transcriptase inhibitors	Delavirdine is a potent inhibitor of CYP450 potentially raising concentrations of other drugs Efavirenz is a mixed inhibitor/ inducer, depending on the concomitant drug	While it may be beneficial in some cases to use delavirdine to increase concentrations of other drugs (e.g. protease inhibitors), alternatives in this class would be nevirapine and efavirenz or perhaps nucleoside analogs (i.e. didanosine, zidovudine) if clinically appropriate.
Macrolides	Erythromycin and clarithromycin are both inhibitors of CYP450; however, the inhibition may be greater with erythromycin	Azithromycin is not metabolized by CYP450 and may be substituted if clinically warranted
Antifungals	Listed by strength of inhibition: Ketoconazole > Itraconazole > Fluconazole Ketoconazole and Itraconazole are potent inhibitors of CYP450	Azithromycin is not metabolized by CYP450 and may be substituted if clinically warranted Fluconazole is associated with less drug interactions when dosages of 200 mg or less are used. As dose is increased, there is a greater potential for drug interactions. Topical antifungals such as clotrimazole troches and nystatin may be useful for prophylaxis of thrush or minor infections. For more severe fungal infections, amphotericin B may be used.
H2 antagonists	Cimetidine is a CYP450 inhibitor with a high propensity for causing interactions	Any other H2 antagonist i.e. ranitidine or famotidine.

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2 Cytochrome P450 Inducers

Drug Class	Likelihood of a drug interaction	Alternatives
HIV Protease inhibitors: Nelfinavir and Ritonavir	Moderate inducers of CYP450, potentially decreasing concentrations of other drugs which are metabolized	In this class, alternatives would be: Amprenavir, indinavir, saquinavir, delavirdine or perhaps nucleoside analogs, i.e. didanosine, zidovudine could be used if clinically
Non-nucleoside reverse transcriptase inhibitors: Nevirapine and Efavirenz	Moderate inducers of CYP450, potentially decreasing concentrations of other drugs	Alternatives in this class would be delavirdine or perhaps nucleoside analogs i.e. didanosine, zidovudine if clinically appropriate.
Rifamycin: Rifabutin and Rifampin	Potent inducers of CYP450 and may decrease concentrations of drugs metabolized by these pathways	For patients receiving protease inhibitors, rifampin should be avoided. However, rifabutin may be used with indinavir, amprenavir and nelfinavir at one-half the normal dose (150 mg/day). For ritonavir, rifabutin can be used on an every-other-day basis or 3 times weekly at one half the normal dose (150 mg q M-W-F). In patients requiring MAC prophylaxis, azithromycin or clarithromycin may be substituted for rifabutin
Anticonvulsants: Phenobarbital, Phenytoin, Carbamazepine	Major/moderate inducers of CYP450, potentially decreasing concentrations of other drugs	If clinically warranted, possible alternative anti-epileptics include: valproic acid, gabapentin, lamotrigine, topiramate, a tiagabine (Investigational)

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3 Metabolised drugs with narrow therapeutic indexes

Warning: All of these agents should be avoided, especially with potential P450 inhibitors, as they may produce serious or life-threatening side effects if their concentrations are increased or decreased.

Drug Class	Likelihood of a drug interaction	Alternatives/Notes
Non-sedating antihistamines	Terfenadine, astemizole	Newer non-sedating antihistamines such as cetirizine, fexofenadine and loratadine can be safely used with P450 inhibitors, as well as most over-the-counter preparations.
Antiarrhythmics	Flecainide, encainide, quinidine	Antiarrhythmic therapy should be closely monitored and used with caution in patients receiving inhibitors of cytochrome P450
Long-acting opiate analgesics	Fentanyl	Alternative analgesics include hydromorphone, codeine, and NSAIDs, particularly in patients receiving ritonavir
Promotility agents	Cisapride	Metoclopramide, Domperidone
Long-acting benzodiazepines	Midazolam, triazolam
Ergotamines and dihydroergotamine
Illicit drugs	Ecstacy/XTC/MDMA
Coumarin anticoagulants	Warfarin
Oral contraceptives		Oral contraceptives should not be given concurrently with P450 inducers, as this can decrease their concentrations and lead to unwanted pregnancy

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4 Renally cleared drugs with narrow therapeutic indices

Drug/Notes		Alternatives
Foscarnet, ganciclovir		Adjust dose for renal function with these agents Cidofovir may be used if clinically appropriate, but this agent can cause irreversible renal insufficiency
Aminoglycosides: Gentamicin, tobramycin, amikacin (Any drugs that are nephrotoxic may decrease aminoglycoside clearance and increase likelihood of aminoglycoside toxicity)		Other antibiotics covering gram-negative bacteria: Aztreonam Broad spectrum penicillins and cephalosporins

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5 Drugs with specific requirements for absorption

Drug	Requirements	Alternatives
Didanosine (enteric-coated formulation)	Must be taken on an empty stomach and separated from indinavir by one hour since the buffer component may impair indinavir absorption	Administer didanosine once daily on empty stomach to lessen inconvenience associated with indinavir. Can use alternative nucleoside analogs if clinically appropriate
Ketoconazole, itraconazole	Require an acidic gastric pH for optimal absorption-avoid in patients with achlorhydria or those receiving H2-antagonists, antacids, or proton pump inhibitors	Fluconazole can be substituted if clinically appropriate. Topical antifungals such as clotrimazole troches and nystatin may be useful for prophylaxis of thrush or minor involvement. For more severe fungal infections, amphotericin B may be used
Fluoroquinolones	Must be separated from di- and trivalent cations (calcium products, antacids, iron preparations, ddI, etc.) to avoid chelation and decreased therapeutic effect	Separate quinolone from cations by 2-4 hours - administer quinolone first. Also, other antimicrobials with appropriate coverage (i.e. cephalosporins) may be used if clinically appropriate

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