General Information About APTIVUS

APTIVUS, (co-administered with 200 mg of ritonavir, is indicated for combination antiretroviral treatment of HIV infected adult patients, who are treatment-experienced and infected with HIV strains resistant to more than one protease inhibitor (PI). This indication is based on analyses of plasma HIV RNA levels in two controlled studies of APTIVUS/ritonavir (APTIVUS/r) of 48 weeks duration. Both studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with APTIVUS/r:

• The use of APTIVUS/r in treatment-naïve patients is not recommended
• The use of other active agents with APTIVUS/r is associated with a greater likelihood of treatment response
• Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/r. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/r
• Use caution when prescribing APTIVUS/r to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment
• Liver function tests should be performed at initiation of therapy with APTIVUS/r and monitored frequently throughout the duration of treatment
• The drug-drug interaction potential of APTIVUS/r when co-administered with other drugs must be considered prior to and during APTIVUS/r use
• Use caution when prescribing APTIVUS/r in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding
• APTIVUS should not be used in children under 2 years of age.

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

Mechanism of Action
Tipranavir (TPV) is an HIV protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag‑Pol polyproteins in HIV infected cells, thus preventing formation of mature virions.

Antiviral Activity
Tipranavir inhibits the replication of laboratory strains of HIV and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07 µM (18-42 ng/mL).  Tipranavir demonstrates antiviral activity in cell culture against a broad panel of HIV group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF).  Group O and HIV-2 isolates have reduced susceptibility in cell culture to tipranavir with EC50 values ranging from 0.164 -1 µM and 0.233-0.522 µM, respectively.  When used with other antiretroviral agents in cell culture, the combination of tipranavir was additive to antagonistic with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and generally additive with the NNRTIs (delavirdine, efavirenz, and nevirapine) and the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine).  Tipranavir was synergistic with the HIV fusion inhibitor enfuvirtide.  There was no antagonism of the cell culture combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis.

Pharmacokinetic profile
In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of APTIVUS with ritonavir is essential (see Dosage and Administration [Link to 2.4]) Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pump and possibly intestinal CYP 3A. In a dose-ranging evaluation in 113 HIV negative male and female volunteers, there was a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir following APTIVUS co-administered with low-dose ritonavir (500/200 mg twice daily) compared to APTIVUS 500 mg twice daily without ritonavir. In adults the mean systemic ritonavir concentration when 200 mg of ritonavir was given with 500 mg of APTIVUS was similar to the concentrations observed when 100 mg was given with the other protease inhibitors.

Figure 1 in the full Prescribing Information displays mean plasma concentrations of tipranavir and ritonavir at steady state for 30 HIV infected adult patients dosed with 500/200 mg tipranavir/ritonavir for 14 days.

Special Populations

Renal Impairment
APTIVUS pharmacokinetics have not been studied in patients with renal dysfunction. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Hepatic Impairment
In a study comparing 9 HIV negative patients with mild (Child-Pugh Class A) hepatic impairment to 9 HIV negative controls, the single and multiple dose plasma concentrations of tipranavir and ritonavir were increased in patients with hepatic impairment, but were within the range observed in clinical trials. No dosing adjustment is required in patients with mild hepatic impairment.

The influence of moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C) on the multiple-dose pharmacokinetics of tipranavir administered with ritonavir has not been evaluated (see Dosage and Administration (2), Contraindications (4.1), and Warnings and Precautions (5.1) in the full Prescribing Information).
Gender
Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48  demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of APTIVUS/ritonavir 500/200 mg BID, the median plasma trough concentration of tipranavir was 43.9M for females and 31.1M for males.  The difference in concentrations does not warrant a dose adjustment.
Race
Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races.
Geriatric Patients
Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age.  There were an insufficient number of women greater than age 65 years in the two trials to evaluate the elderly.
Pediatric Patients
Among pediatric patients in clinical trial 1182.14, steady-state plasma tipranavir trough concentrations were obtained 10 to 14 hours following study drug administration. Pharmacokinetic parameters by age group are presented in Table 6 in the full Prescribing Information.

Important Safety Information for APTIVUS
APTIVUS/r has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.
Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/r treatment and seek medical evaluation. APTIVUS/r has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH).

Adverse Events

• In adults the most frequent adverse reactions (incidence > 4%) were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain
• In pediatric patients (age 2 to 18 years) the most frequent adverse reactions were generally similar to those seen in adults.  However, rash was more frequent in pediatric patients than in adults