What Drugs Are Most Likely To Be Involved In Drug Interactions?

1. P450 inhibitors

HIV Protease inhibitors
HIV Non-nucleoside reverse transcriptase inhibitors
Macrolide antibiotics
Azole antifungals
Non-nucleoside reverse transcriptase inhibitors
H₂Antagonists

2. P450 inducers

Rifamycin antibiotics
HIV Protease inhibitors
HIV Non-nucleoside reverse transcriptase inhibitors
Anticonvulsants (that are P450 inducers)

3. Metabolized 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

4. Renally cleared drugs with narrow therapeutic indices

Ganciclovir (Cytovene^®)
Foscarnet (Foscavir^®)
Aminoglycosides

5. Drugs with specific requirements for absorption

Ketoconazole (Nizoral^®) and itraconazole (Sporanox^®)
Didanosine (Videx^®)
Fluoroquinolones

Sildenafil is a CYP 450 substrate (mainly 3A4), and is a very weak P450 inhibitor (several isoforms). Its inhibition is likely to be clinically insignificant, because clinical drug concentrations are far below those required to inhibit microsomal enzymes in vitro.

However, sildenafil's concentrations are significantly increased with 3A4 inhibitors (AUC +182% with erythromycin, and +56% with cimetidine). 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 of serious hypotension.

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

1. Cytochrome P-450 inhibitors:

Warning - Agents that impair drug metabolism of other drugs which share the same pathway increase concentrations of the co-administered drug.

DRUG CLASS	LIKELIHOOD OF A DRUG INTERACTION	ALTERNATIVES
HIV Protease inhibitors	Ritonavir (Norvir®) strongest Amprenavir (Agenerase®) intermed Indinavir (Crixivan®) intermed Nelfinavir (Viracept®)intermed Saquinavir (Fortovase®/ Invirase®) - weakest	Saquinavir (Invirase®/Fortovase®) has less potential to cause drug interactions
Macrolides	Erythromycin and clarithromycin (Biaxin®) are both inhibitors of CYP450, however, the inhibition may be greater with erythromycin	Azithromycin (Zithromax®) is not metabolized by CYP450 and may be substituted if clinically warranted
Antifungals	Listed by strength of inhibition: Ketoconazole (Nizoral®) > Itraconazole (Sporanox®) > Fluconazole (Diflucan®) Ketoconazole (Nizoral®) and Itraconazole (Sporanox®) are potent inhibitors of CYP450	Fluconazole (Diflucan®) 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 (Mycelex®) troches and nystatin may be useful for prophylaxis of thrush or minor infections. For more severe fungal infections, amphotericin B (Fungizone®, Abelcet®, AmBisome®, Amphotec®) may be used
Non-nucleoside reverse transcriptase inhibitors	Delavirdine (Rescriptor®) is a potent inhibitor of CYP450 potentially raising concentrations of other drugs Efavirenz (Sustiva®) 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 (Sustiva®) or perhaps nucleoside analogs (i.e., didanosine [Videx®], zidovudine [Retrovir®]) if clinically appropriate
H2 Antagonists	Cimetidine (Tagamet®) is a CYP450 inhibitor with a high propensity for causing interactions	Any other H2antagonist i.e. Ranitidine (Zantac®) or Famotidine (Pepcid®)

2. Cytochrome P-450 Inducers:

INDUCING DRUG	STRENGTH	ALTERNATIVES
Rifamycins: Rifabutin (Mycobutin®) and Rifampin (Rifadin®, Rimactane®)	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 (Mycobutin®) may be used with indinavir (Crixivan®), amprenavir (Agenerase®) and nelfinavir (Viracept®) at one-half the normal dose (150 mg/day). For ritonavir (Norvir®), rifabutin (Mycobutin®) 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 (Zithromax®) or clarithromycin (Biaxin®) may be substituted for rifabutin
HIV Protease inhibitors: Nelfinavir (Viracept®) and Ritonavir (Norvir®)	Moderate inducers of CYP450, potentially decreasing concentrations of other drugs which are metabolized	In this class Alternatives would be: amprenavir (Agenerase®) indinavir (Crixivan®) saquinavir (Fortovase®) delavirdine (Rescriptor®) or perhaps nucleoside analogs, i.e. didanosin e (Videx®) zidovudine (Retrovir®) could be used if clinically appropriate
Non-nucleoside reverse transcriptase inhibitors: Nevirapine (Viramune®) and Efavirenz (Sustiva®)	Moderate inducers of CYP450, potentially decreasing concentrations of other drugs	Alternatives in this class would be delavirdine or perhaps nucleoside analogs i.e. didanosine (Videx®) zidovudine (Retrovir®) if clinically appropriate
Anticonvulsants: Phenobarbital Phenytoin (Dilantin®) Carbamazepine (Tegretol®)	Major / moderate inducers of CYP450, potentially decreasing concentrations of other drugs.	If clinically warranted, possible alternative anti-epileptics include: valproic acid (Depakene®, Depakote®) gabapentin (Neurontin®) lamotrigine (Lamictal®) topiramate (Topamax®) tigabine (Investigational Tabitril®)

3. Metabolized 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.

CATEGORY	DRUGS	ALTERNATIVES / NOTES
Non-sedating antihistamines	Terfenadine (Seldane®) Astemizole (Hismanal®) *although removed from US market, patients may still have supplies	Newer non-sedating antihistamines such as fexofenadine (Allegra®) and loratadine (Claritin®) can be safely used with P450 inhibitors, as well as most over-the counter preparations
Antiarrythmics	Flecainide (Tambocor®) Encainide (Enkaid®) Quinidine	Antiarrhythmic therapy should be closely monitored and used with caution in patients receiving inhibitors of cytochrome P-450
Long-acting opiate analgesics	Fentanyl (Sublimaze®, Duragesic®)	Alternative analgesics include hydromorphone, codeine, and NSAIDs , particularly in patients receiving ritonavir (Norvir®)
Promotility agents	Cisapride (Propulsid®)	Metoclopramide (Reglan®)
Long-acting benzodiazepines	Midazolam (Versed®) Triazolam (Halcion®)
Ergotamines and dihydroergotamine	Cafergot® Hydergine®D.H.E. 45®
Illicit drugs	Ecstacy/XTC/MDMA
Coumarin anticoagulants	Warfarin (Coumadin®)
Oral contraceptives		Oral contraceptives should not be given concurrently with P450 inducers, as this can decrease their concentrations and lead to unwanted pregnancy

4. Renally cleared drugs with narrow therapeutic indices:

DRUG / NOTES	ALTERNATIVES
Foscarnet (Foscavir®) Ganciclovir (Cytovene®)	Adjust dose for renal function with these agents Cidofovir (Vistide) may be used if clinically appropriate, but this agent can cause irreversible renal insufficiency
Aminoglycosides: Gentamycin Tobramycin Amikacin (Any drugs that are nephrotoxic may decrease aminoglycoside clearance and increase likelihood of aminoglycoside toxicity)	Other antibiotics covering gram – bacteria: Aztreonam (Azactram®) Broad Spectrum penicillins and cephalosporins

5. Drugs with specific requirements for absorption:

DRUGS	REQUIREMENTS	ALTERNATIVES
Ketoconazole (Nizoral®) Itraconazole (Sporanox®)	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 (Mycelex®) troches and nystatin may be useful for prophylaxis of thrush or minor involvement. For more severe fungal infections, amphotericin B (Fungizone®, Abelcet®, AmBisome®, Amphotec®) may be used
Didanosine (Videx®)	Must be taken on an empty stomach and separated from indinavir by one hour since the buffer component may impair indinavir (Crixivan®) absorption	Administer didanosine (Videx®) once daily on empty stomach to lessen inconvenience associated with indinavir. Can use alternative nucleoside analogs if clinically appropriate
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