Aptivus

APTIVUS- tipranavir capsule, liquid filled
APTIVUS- tipranavir solution
Boehringer Ingelheim Pharmaceuticals, Inc.

Intracranial Hemorrhage:

Both fatal and non-fatal intracranial hemorrhage have been reported [see Warnings and Precautions (5.2) ].

1 INDICATIONS AND USAGE

APTIVUS, co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor (PI).

This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 48 weeks duration in treatment-experienced adults and one open-label 48-week study in pediatric patients age 2 to 18 years. The adult studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with APTIVUS/ritonavir:

• The use of APTIVUS/ritonavir in treatment-naïve patients is not recommended [see Warnings and Precautions (5.1) ].
• The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response [see Microbiology (12.4) and Clinical Studies (14)].
• Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir [see Microbiology (12.4) ]. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir [see Microbiology (12.4) ].
• Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment [see Warnings and Precautions (5.1) ].
• Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment [see Warnings and Precautions (5.1) ].
• The drug-drug interaction potential of APTIVUS/ritonavir when co-administered with other drugs must be considered prior to and during APTIVUS/ritonavir use [see Contraindications (4) and Drug Interactions (7)].
• Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding [see Warnings and Precautions (5.4) ].
• The risk-benefit of APTIVUS/ritonavir has not been established in pediatric patients <2 years of age.

There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.

2 DOSAGE AND ADMINISTRATION

APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

• APTIVUS co-administered with ritonavir capsules or solution can be taken with or without meals
• APTIVUS co-administered with ritonavir tablets must only be taken with meals

[see Clinical Pharmacology (12.3) ]

APTIVUS may be administered as either capsules or oral solution to either pediatric or adult patients. APTIVUS capsules must be swallowed whole and must not be opened or chewed.

Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information.

2.1 Adults

The recommended adult dose of APTIVUS is 500 mg (two 250 mg capsules or 5 mL oral solution) co-administered with 200 mg of ritonavir, twice daily.

2.2 Pediatric Patients (age 2 to 18 years)

Healthcare professionals should pay special attention to accurate calculation of the dose of APTIVUS, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.

Prescribers should calculate the appropriate dose of APTIVUS for each individual child based on body weight (kg) or body surface area (BSA, m²) and should not exceed the recommended adult dose.

Before prescribing APTIVUS 250 mg capsules, children should be assessed for the ability to swallow capsules. If a child is unable to reliably swallow an APTIVUS capsule, the APTIVUS oral solution formulation should be prescribed.

The recommended pediatric dose of APTIVUS is 14 mg/kg with 6 mg/kg ritonavir (or 375 mg/m² co-administered with ritonavir 150 mg/m²) taken twice daily not to exceed a maximum dose of APTIVUS 500 mg co-administered with ritonavir 200 mg twice daily. For children who develop intolerance or toxicity and cannot continue with APTIVUS 14 mg/kg with 6 mg/kg ritonavir, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with 5 mg/kg ritonavir (or APTIVUS 290 mg/m² co-administered with 115 mg/m² ritonavir) taken twice daily provided their virus is not resistant to multiple protease inhibitors [see Adverse Reactions (6.2), Use in Specific Populations (8.4), and Clinical Studies (14.2) ].

Body surface area can be calculated as follows:

Mosteller Formula:

BSA (m2) =

3 DOSAGE FORMS AND STRENGTHS

Capsules: 250 mg, pink, oblong capsules imprinted with TPV 250

Oral solution: 100 mg/mL, yellow, viscous clear liquid with a buttermint-butter toffee flavor

4 CONTRAINDICATIONS

• APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and Precautions (5.1) ].
• APTIVUS/ritonavir is contraindicated when co-administered with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers (see Table 1) [see Drug Interactions (7.2) ].

Table 1 Drugs that are Contraindicated with APTIVUS Co-Administered with Ritonavir

Drug Class	Drugs within Class that are Contraindicated with APTIVUS Co-administered with Ritonavir	Clinical Comments:
Alpha 1-adrenoreceptor antagonist	Alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics	Amiodarone, bepridil, flecainide, propafenone, quinidine	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics.
Antimycobacterials	Rifampin	May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors or other co-administered antiretroviral agents.
Ergot derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine	Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent	Cisapride	Potential for cardiac arrhythmias.
Herbal products	St. John’s wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors.
HMG CoA reductase inhibitors	Lovastatin, simvastatin	Potential for myopathy including rhabdomyolysis.
Antipsychotics	Pimozide	Potential for cardiac arrhythmias.
	Lurasidone	Potential for serious and/or life-threatening reactions.
PDE-5 inhibitors	Sildenafil (Revatio) [for treatment of pulmonary arterial hypertension]	A safe and effective dose has not been established when used with APTIVUS/ritonavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Sedatives/hypnotics	Oral midazolam, triazolam	Prolonged or increased sedation or respiratory depression.

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