| Concomitant Drug Class: |
| Effect on Concentration of|
Tipranavir or Concomitant Drug
| Clinical Comment |
| Nucleoside reverse transcriptase inhibitors: |
↓ Abacavir AUC by approximately 40%
|Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.|
|Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from TPV/ritonavir dosing by at least 2 hours.|
|Zidovudine||↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered.||Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.|
| Protease inhibitors (co-administered with 200 mg of ritonavir): ||Combining amprenavir, lopinavir or saquinavir with APTIVUS/ritonavir is not recommended. No formal drug interaction data are currently available for the concomitant use of APTIVUS, co-administered with 200 mg of ritonavir, with protease inhibitors other than those listed above.|
Other Agents for Opportunistic Infections
| Antifungals: ||Fluconazole increases TPV concentrations but dose adjustments are not needed. Fluconazole doses > 200 mg/day are not recommended.|
Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (200 mg/day) are not recommended.
Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction.
|↑ Tipranavir, ↔ Fluconazole|
↑ Itraconazole (not studied)
↑ Ketoconazole (not studied)
↨Voriconazole (not studied)
| Antimycobacterials: |
|Clarithromycin||↑ Tipranavir, ↑ Clarithromycin,|
↓ 14-hydroxy-clarithromycin metabolite
|No dose adjustment of tipranavir or clarithromycin for patients with normal renal function is necessary.|
For patients with renal impairment the following dosage adjustments should be considered:
- For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
- For patients with CLCR< 30 mL/min the dose of clarithromycin should be decreased by 75%.
|Rifabutin||Tipranavir not changed, ↑Rifabutin|
Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g. 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary.
Other Agents Commonly used
| Antidepressants: |
|Trazadone||↑ Trazadone||Concomitant use of trazadone and APTIVUS/ritonavir may increase plasma concentrations of trazadone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazadone and ritonavir. If trazadone is used with a CYP3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazadone should be considered.|
Combination with TPV/ritonavir not studied
Dosage reduction and concentration monitoring of desipramine is recommended.
|Selective Serotonin-Reuptake Inhibitors:||Combination with TPV/ritonavir not studied||Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.|
| Calcium Channel Blockers: |
|Combination with TPV/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP 3A and P-gp due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp.|
↑ Felodipine (CYP 3A substrate but not P-gp substrate)
↨Nisoldipine (CYP 3A substrate but not clear whether it is a P-gp substrate)
|Caution is warranted and clinical monitoring of patients is recommended.|
|Disulfiram/Metronidazole||Combination with TPV/ritonavir not studied||APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction|
| HMG-CoA reductase inhibitors: ||Start with the lowest possible dose of atorvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors.|
Concomitant use of APTIVUS, co-administered with 200 mg of ritonavir, with lovastatin or simvastatin is not recommended.
|Atorvastatin||↑ Tipranavir, ↑ Atorvastatin|
↓ Hydroxy-atorvastatin metabolites
| Hypoglycemics: ||Combination with TPV/ritonavir not studied.||Careful glucose monitoring is warranted.|
↨Glimepiride (CYP 2C9)
↨Glipizide (CYP 2C9)
↨Glyburide (CYP 2C9)
↨Pioglitazone (CYP 2C8 and CYP 3A4)
↨Repaglinide (CYP 2C8 and CYP 3A4)
↨Tolbutamide (CYP 2C9)
The effect of TPV/ritonavir on CYP 2C8 and CYP 2C9 substrates is not known.
| Immunosuppressants: |
|Combination with TPV/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp.|
|More frequent concentration monitoring of these medicinal products is recommended until blood levels have been stabilized.|
| Inhaled /nasal steroids: |
|↑ Fluticasone||Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS).|
| Narcotic analgesics: |
Combinations with TPV/ritonavir not studied
↓ Meperidine, ↑ Normeperidine
|Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g. seizures).|
|Methadone||↓ Methadone by 50%|
Dosage of methadone may need to be increased when co-administered with tipranavir and 200 mg of ritonavir.
| Oral contraceptives/Estrogens: ||Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with tipranavir and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.|
Women using estrogens may have an increased risk of non serious rash.
|Ethinyl estradiol||↓ Ethinyl estradiol concentrations by 50%|
| PDE5 inhibitors: |
|Combinations with TPV/ritonavir not studied.|
|Concomitant use of PDE5 inhibitors with tipranavir and ritonavir should be used with caution and in no case should the starting dose of:|
- sildenafil exceed 25 mg within 48 hours
- tadalafil exceed 10 mg every 72 hours
- vardenafil exceed 2.5 mg every 72 hours
|Warfarin||Combination with TPV/ritonavir not studied.|
Cannot predict the effect of TPV/ritonavir on S-Warfarin due to conflicting effect of TPV and RTV on CYP 2C9
|Frequent INR (international normalized ratio) monitoring upon initiation of tipranavir/ritonavir therapy.|