Aptivus (Tipranavir) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Drug Interactions

Tipranavir administered with ritonavir can alter plasma exposure of other drugs and other drugs can alter plasma exposure of tipranavir and ritonavir.

Tipranavir co-administered with 200 mg of ritonavir at the recommended dosage is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of tipranavir/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring (see CONTRAINDICATIONS and PRECAUTIONS).

The mechanisms of the potential interactions are described in the CLINICAL PHARMACOLOGY, Drug Interactions section.

Drugs that are contraindicated or not recommended for co-administration with APTIVUS are included in Table 8 below. These recommendations are based on either drug interaction studies or they are predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 8 Drugs that Should Not be Co-administered with APTIVUS Co-administered with 200 mg of Ritonavir

Drug Class/Drug Name	Clinical Comment
Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics.
Antihistamines Astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials Rifampin	May lead to loss of virologic response and possible resistance to tipranavir or to the class of protease inhibitors.
Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agents Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal products St. John's wort	May lead to loss of virologic response and possible resistance to tipranavir or to the class of protease inhibitors.
HMG CoA reductase inhibitors Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptics Pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedatives/hypnotics Midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

Clinically significant drug-drug interactions of APTIVUS co-administered with 200 mg of ritonavir are summarized in Table 9 below.

Table 9 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug name	Effect on Concentration of Tipranavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Nucleoside reverse transcriptase inhibitors:
Abacavir	↓ Abacavir AUC by approximately 40%	Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.
Didanosine (EC)	↓ Didanosine	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.
Amprenavir Lopinavir Saquinavir	↓ Amprenavir, ↓ Lopinavir, ↓ Saquinavir
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.
Fluconazole Itraconazole Ketoconazole Voriconazole	↑ 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 ↑ Desacetyl-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.
Desipramine	Combination with TPV/ritonavir not studied ↑ Desipramine	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.
Fluoxetine Paroxetine Sertraline	↑ Fluoxetine ↑ Paroxetine ↑ Sertraline
Calcium Channel Blockers: Diltiazem Felodipine Nicardipine Nisoldipine Verapamil	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. ↨Diltiazem ↑ Felodipine (CYP 3A substrate but not P-gp substrate) ↨Nicardipine ↨Nisoldipine (CYP 3A substrate but not clear whether it is a P-gp substrate) ↨Verapamil	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 (e.g. metronidazole).
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 Glipizide Glyburide Pioglitazone Repaglinide Tolbutamide	↨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: Cyclosporine Sirolimus Tacrolimus	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. ↨Cyclosporine ↨Sirolimus ↨Tacrolimus	More frequent concentration monitoring of these medicinal products is recommended until blood levels have been stabilized.
Inhaled /nasal steroids: Fluticasone	↑ 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:
Meperidine	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: Sildenafil Tadalafil Vardenafil	Combinations with TPV/ritonavir not studied. ↑ Sildenafil ↑ Tadalafil ↑ Vardenafil	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.

OVERDOSAGE

There is no known antidote for tipranavir overdose. Treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.

CONTRAINDICATIONS

APTIVUS (tipranavir) is contraindicated in patients with known hypersensitivity to any of the ingredients of the product.

APTIVUS is contraindicated in patients with moderate and severe (Child-Pugh Class B and C, respectively) hepatic insufficiency (see WARNINGS).

Co-administration of APTIVUS with 200 mg of ritonavir, with drugs that are highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. These drugs are listed in Tables 7 below. For information regarding clinical recommendations see PRECAUTIONS, Drug Interactions, Tables 8 and 9.

Table 7 Drugs that are Contraindicated with Tipranavir, Co-Administered with 200 mg of Ritonavir

Drug Class	Drugs within Class that are Contraindicated with APTIVUS, Co-administered with 200 mg of ritonavir
Antiarrhythmics	Amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines	Astemizole, terfenadine
Ergot derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI motility agent	Cisapride
Neuroleptic	Pimozide
Sedatives/hypnotics	Midazolam, triazolam

Due to the need for co-administration of APTIVUS with 200 mg of ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.