Drug interactions

Fosamprenavir (Telzir) is metabolised by the cytochrome P450 enzymes in the liver, particularly the CYP3A4 enzyme. Consequently, its levels are affected by other drugs that use the same pathway.

Many other drugs using the CYP3A4 enzyme should not be given with fosamprenavir, as their levels may be altered. These include:

  • Alfuzosin
  • Astemizole
  • Cisapride
  • Colchicine in patients with renal or hepatic impairment
  • Diazepam
  • Ergotamine tartrate (Cafergot / Migril)
  • Flecainide acetate (Tambocor)
  • Flurazepam (Dalmane)
  • Fluticasone propionate (Flixotide): taking this with fosamprenavir can cause symptoms of Cushing’s syndrome and suppression of the adrenal glands, including weight gain, weakening of the skin, sweating, facial hair growth and psychological disturbances.
  • Halofantrine
  • Hypericin (St John’s wort)
  • Lovastatin
  • Lumefantrine
  • Midazolam (Hyponovel)
  • Pimozide (Orap)
  • Propafenone (Arythmol)
  • Rifampicin (Rifadin / Rimactane)
  • Simvastatin (Zocor)
  • Terfenadine
  • Triazolam.

Efavirenz (Sustiva) reduces amprenavir levels in the blood by 45%, even when combined with 200mg ritonavir (Norvir) in a once-a-day regimen. Increasing the ritonavir dose to 300mg once a day can overcome this effect. However, the co-administration of efavirenz with twice-daily ritonavir-boosted fosamprenavir causes no significant drug interactions.1 Taking unboosted fosamprenavir with nevirapine (Viramune) can also lead to reductions in blood levels of amprenavir.2 This is overcome by using standard ritonavir boosting.

Taking fosamprenavir with ritonavir-boosted lopinavir (Kaletra) can lead to large reductions in exposure to both amprenavir and lopinavir.3 This is not overcome by increasing the dose of fosamprenavir, ritonavir or Kaletra, or by separating the doses of the drugs, so an appropriate dose of this drug combination cannot be recommended.4 Unboosted fosamprenavir may also decrease saquinavir (Invirase) levels, but this is overcome by using 200mg ritonavir twice a day, at least in patients taking the now discontinued soft-gel version of saquinavir (Fortovase).5 Combining ritonavir-boosted fosamprenavir with atazanavir (Reyataz) may result in adequate levels of the drugs.6

If ritonavir-boosted fosamprenavir and rifabutin (Mycobutin) are taken together, rifabutin should be reduced by 75%, to avoid rifabutin-related side-effects.

Garlic supplements have been shown to reduce saquinavir (Invirase) levels, but it is not known if fosamprenavir is affected in the same way. It may be best to avoid garlic supplements when taking fosamprenavir, especially if fosamprenavir is not boosted with ritonavir.

Caution is advised when taking any protease inhibitor with the impotence drugs sildenafil (Viagra), tadalafil (Cialis) or vardenafil (Levitra). When taken with fosamprenavir, levels of these drugs may increase making side-effects more likely. Commencing the drugs at a reduced dose is advised. Sildenafil is contraindicated if used for treatment of pulmonary arterial hypertension.

Levels of the lipid-lowering drug atorvastatin (Lipitor) are increased by ritonavir-boosted fosamprenavir. A low dose of atorvastatin is recommended.

Fosamprenavir’s solubility is affected by pH in the stomach. Some studies indicate that acid-reducing agents do not significantly affect the minimum levels of the active drug in the blood when it is boosted with low-dose ritonavir. However, patients taking unboosted fosamprenavir should take proton-pump inhibitors and histamine2-receptor antagonists such as ranitidine (Zantac) with care, as these may reduce exposure to the active drug. Patients using antacids or buffered formulations of ddI should take fosamprenavir one hour before or after their use.

Other drugs that should be used cautiously or whose levels should be checked in people taking fosamprenavir include:

  • Amiodarone hydrochloride (Cordarone X).
  • Amitriptyline hydrochloride.
  • Amlodipine (Istin).
  • Bepidril.
  • Carbamazepine (Tegretol / Carbagen SR / Tegretol Retard).
  • Ciclosporin (Neoral / Sandimmun).7
  • Dexamethasone hydrochloride.
  • Diltiazem (Tildiem / Adizem-SR / Adizem-XL / Angitil SR / Angitil XL / Calcicard CR / Dilcardia SR / Dilzem SR / Dilzem XL / Slozem / Tildiem LA / Tildiem Retard / Viazem XL / Zemtard).
  • Felodipine (Plendil).
  • Imipramine hydrochloride.
  • Isradipine (Prescal).
  • Itraconazole (Sporanox).
  • Ketoconazole (Nizoral).
  • Lidocaine hydrochloride (Minijet Lignocaine / Xylocaine).
  • Nicardipine hydrochloride (Cardene / Cardene SR).
  • Nifedipine (Adalat / Adalat LA / Adalat Retard / Adipine MR / Adipine XL / Cardilate MR / Coracten SR / Coracten XL / Fortipine LA 40 / Hypolar Retard 20 / Nifedipress MR / Nifopress Retard / Slofedipine / Slofedipine XL / Tensipine MR).
  • Nimodipine (Nimotop).
  • Nisoldipine (Syscor MR).
  • Phenobarbital.
  • Phenytoin (Epanutin).
  • Quinidine (Kindin Dureles).
  • Rapamycin.
  • Tacrolimus (Prograf / Protopic).
  • Verapamil hydrochloride (Cordilox / Securon / Half Securon SR / Securon SR / Univer / Verapress MR / Vertab SR 240).
  • Warfarin sodium.

References

  1. Wire MB et al. An assessment of plasma amprenavir pharmacokinetics following administration of GW433908 and ritonavir QD regimens in combination with efavirenz in healthy adult subjects (APV10009). 41st Interscience Conference on Antimicrobial and Antiviral Chemotherapy, Chicago, abstract I-1737, 2001
  2. de Jesus E et al. Evaluation of the pharmacokinetic drug interaction between fosamprenavir, fosamprenavir plus ritonavir and nevirapine in HIV-infected patients (APV10014). 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract A-447, 2004
  3. Kashuba ADM et al. Combining fosamprenavir with lopinavir / ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results. AIDS 19: 145-152, 2005
  4. Corbett AH et al. Dose separation does not overcome the pharmacokinetic interaction between fosamprenavir and lopinavir / ritonavir. Antimicrob Agents Chemother 50: 2756-2761, 2006
  5. Boffito M et al. Steady-state pharmacokinetics of saquinavir hard-gel / ritonavir / fosamprenavir in HIV-1-infected patients. J Acquir Immune Defic Syndr 37: 1376-1384, 2004
  6. Khanlou H et al. Favourable interaction between atazanavir and fosamprenavir with and without ritonavir in the treatment of HIV-infected patients. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P288, 2004
  7. Guaraldi G et al. Pharmacokinetic interaction between amprenavir / ritonavir and fosamprenavir on cyclosporine in two patients with human immunodeficiency virus infection undergoing orthotopic liver transplantation. Transplant Proc 38: 1138-1140, 2006
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