APTIVUS(r) (tipranavir) is the brand name for tipranavir (TPV), a non-peptidic protease inhibitor (PI) of HIV belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides. APTIVUS soft gelatin capsules are for oral administration. Each capsule contains 250 mg tipranavir. The major inactive ingredients in the capsule are dehydrated alcohol (7% w/w or 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, mono/diglycerides of caprylic/capric acid and gelatin. The chemical name of tipranavir is 2-Pyridinesulfonamide, N-[3-[(1R)-1-[(6R)-5,6-dihydro- 4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5- (trifluoromethyl). It has a molecular formula of C31H33F3N2O5S and a molecular weight of 602.7. Tipranavir has the following structural formula and is a single stereoisomer with the 1R, 6R configuration.

DEPARTMENT OF HEALTH & HUMAN SERVICES

CF3 Tipranavir is a white to off-white to slightly yellow solid. It is freely soluble in dehydrated alcohol and propylene glycol, and insoluble in aqueous buffer at pH 7.5.

CLINICAL PHARMACOLOGY

Microbiology

Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to uM (18-42 ng/mL). Tipranavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 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 vitro to tipranavir with EC50 values ranging from 0.164 -1 uM and 0.233-0.522 uM, respectively. Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-fold in conditions where human serum is present. When used with other antiretroviral agents in vitro, 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 in vitro combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis.

DEPARTMENT OF HEALTH & HUMAN SERVICES

In vitro: HIV-1 isolates with a decreased susceptibility to tipranavir have been selected in vitro and obtained from patients treated with APTIVUS/ritonavir (TPV/ritonavir). HIV-1 isolates that were 87-fold resistant to tipranavir were selected in vitro by 9 months and contained 10 protease mutations that developed in the following order: L33F, I84V, K45I, I13V, V32I, V82L, M36I, A71V, L10F, and I54V/T. Changes in the Gag polyprotein CA/P2 cleavage site were also observed following drug selection. Experiments with site-directed mutants of HIV-1 showed that the presence of 6 mutations in the protease coding sequence (I13V, V32I, L33F, K45I, V82L, I84V) conferred > 10-fold reduced susceptibility to tipranavir. Recombinant viruses showing >= 3-fold reduced susceptibility to tipranavir were growth impaired.

In Phase 3 studies 1182.12 and 1182.48, multiple protease inhibitor-resistant HIV-1 isolates from 59 highly treatment- experienced patients who received APTIVUS/ritonavir and experienced virologic rebound developed amino acid substitutions that were associated with resistance to tipranavir. The most common amino acid substitutions that developed on 500/200 mg APTIVUS/ritonavir in greater than 20% of APTIVUS/ritonavir virologic failure isolates were L33V/I/F, V82T, and I84V. Other substitutions that developed in 10 to 20% of APTIVUS/ritonavir virologic failure isolates included L10V/I/S, I13V, E35D/G/N, I47V, K55R, V82L, and L89V/M. Tipranavir resistance was detected at virologic rebound after an average of 38 weeks of APTIVUS/ritonavir treatment with a median 14-fold decrease in tipranavir susceptibility.

Cross-resistance among protease inhibitors has been observed. Tipranavir had < 4-fold decreased susceptibility against 90% (94/105) of HIV-1 isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir. Tipranavir-resistant viruses which emerged in vitro had decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remained sensitive to saquinavir.

Baseline Genotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining tipranavir susceptibility before initiation of APTIVUS/ritonavir therapy. Several analyses were conducted to evaluate the impact of specific mutations and mutational patterns on virologic outcome. Both the type and number of baseline protease inhibitor mutations as well as use of additional active agents (e.g., enfuvirtide) affected APTIVUS/ritonavir response rates in Phase 3 studies 1182.12 and 1182.48 through Week 24 of treatment.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Regression analyses of baseline and/or on-treatment HIV-1 genotypes from 860 highly treatment-experienced patients in Phase 2 and 3 studies demonstrated that mutations at 16 amino acid codons in the HIV protease coding sequence were associated with reduced virologic responses at 24 weeks and/or reduced tipranavir susceptibility: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V. Analyses were also conducted to assess virologic outcome by the number of primary protease inhibitor mutations present at baseline. Response rates were reduced if five or more protease inhibitor-associated mutations were present at baseline and subjects did not receive concomitant enfuvirtide with APTIVUS/ritonavir. See Table 1.

Table 1 Phase 3 Studies 1182.12 and 1182.48: Proportion of Responders (confirmed

>= 1 log10 decrease at Week 24) by Number of Baseline Primary Protease Inhibitor (PI) Mutations

Primary PI mutations include any amino acid change at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90

The median change from baseline in HIV-1 RNA at weeks 2, 4, 8, 16 and 24 was evaluated by the number of baseline primary protease inhibitor mutations (1-4 or >= 5) in subjects who received APTIVUS/ritonavir with or without enfuvirtide. The following observations were made:

DEPARTMENT OF HEALTH & HUMAN SERVICES

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data.

Baseline Phenotype and Virologic Outcome Analyses

APTIVUS/ritonavir response rates were also assessed by baseline tipranavir phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, mutations at protease amino acid codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to APTIVUS/ritonavir therapy at Week 24 are summarized in Table 2. These baseline phenotype groups are not meant to represent clinical susceptibility breakpoints for APTIVUS/ritonavir because the data are based on the select 1182.12 and 1182.48 patient population. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to APTIVUS/ritonavir in highly protease inhibitor-experienced patients.

Table 2 Response by Baseline Tipranavir Phenotype in the 1182.12 and 1182.48 Trials

Number of amino acid substitutions in HIV protease among L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V

Pharmacodynamics

The median Inhibitory Quotient (IQ) determined from 301 highly treatment-experienced patients was about 75 (inter-quartile range: 29-189), from pivotal clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral IC50 value, corrected for protein binding. There was a relationship between the proportion of patients with a >= 1 log10 reduction of viral load from baseline at week 24 and their IQ value. Among the 206 patients receiving APTIVUS/ritonavir without enfuvirtide, the response rate was 23% in those with an IQ value < 75 and 55% in those with an IQ value >= 75. Among the 95 patients receiving APTIVUS/ritonavir with enfuvirtide, the response rates in patients with an IQ value < 75 versus those with an IQ value >= 75 were 43% and 84%, respectively. These

DEPARTMENT OF HEALTH & HUMAN SERVICES

IQ groups are derived from a select population and are not meant to represent clinical breakpoints.

Pharmacokinetics in Adult Patients

In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of APTIVUS with 200 mg of ritonavir is essential (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-glycoprotein (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 tipranavir co-administered with low- dose ritonavir (500/200 mg twice daily) compared to tipranavir 500 mg twice daily without ritonavir. Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for the 500/200 mg tipranavir/ritonavir dose.

Figure 1 Mean Steady State Tipranavir Plasma Concentrations (95% CI) with Ritonavir Co-administration (tipranavir/ritonavir 500/200 mg BID)

DEPARTMENT OF HEALTH & HUMAN SERVICES

Absorption and Bioavailability

Absorption of tipranavir in humans is limited, although no absolute quantification of absorption is available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well. In vivo data suggest that the net effect of tipranavir/ritonavir at the proposed dose regimen (500/200 mg) is P-gp induction at steady-state, although ritonavir is a P-gp inhibitor. Tipranavir trough concentrations at steady-state are about 70% lower than those on Day 1, presumably due to intestinal P-gp induction. Steady state is attained in most subjects after 7-10 days of dosing. Dosing with APTIVUS 500 mg concomitant with 200 mg ritonavir twice-daily for greater than 2 weeks and without meal restriction produced the following pharmacokinetic parameters for female and male HIV-positive patients. See Table 3.

Table 3 Pharmacokinetic Parametersa of tipranavir/ritonavir 500/200 mg for HIV+ Patients by Gender

DEPARTMENT OF HEALTH & HUMAN SERVICES

Effects of Food on Oral Absorption

APTIVUS capsules co-administered with ritonavir should be taken with food. Bioavailability is increased with a high fat meal. Tipranavir capsules, administered under high fat meal conditions or with a light snack of toast and skimmed milk, were tested in a multiple dose study. High-fat meals (868 kcal, 53% derived from fat, 31% derived from carbohydrates) enhanced the extent of bioavailability (AUC point estimate 1.31, confidence interval 1.23-1.39), but had minimal effect on peak tipranavir concentrations (Cmax point estimate 1.16, confidence interval 1.09-1.24). When APTIVUS, co-administered with 200 mg ritonavir, was co-administered with 20 mL of aluminum and magnesium-based liquid antacid, tipranavir AUC12h, Cmax and C12h were reduced by 25-29%. Consideration should be given to separating tipranavir/ritonavir dosing from antacid administration to prevent reduced absorption of tipranavir.

Distribution

Tipranavir is extensively bound to plasma proteins (> 99.9%). It binds to both human serum albumin and a-1-acid glycoprotein. The mean fraction of APTIVUS (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers (0.015% +- 0.006%) and HIV-positive patients (0.019% +- 0.076%). Total plasma tipranavir concentrations for these samples ranged from 9 to 82 uM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range. No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.

Metabolism

metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism.

The oral clearance of tipranavir decreased after the addition of ritonavir, which may represent diminished first-pass clearance of the drug at the gastrointestinal tract as well as the liver. The metabolism of tipranavir in the presence of 200 mg ritonavir is minimal. Administration of 14C-tipranavir to subjects that received tipranavir/ritonavir 500/200 mg dosed to steady- state demonstrated that unchanged tipranavir accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity). In feces, unchanged tipranavir represented the majority of fecal radioactivity (79.9% of fecal radioactivity). The most abundant fecal metabolite, at 4.9% of fecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in

DEPARTMENT OF HEALTH & HUMAN SERVICES

trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Elimination

Administration of 14C-tipranavir to subjects (n=8) that received tipranavir/ritonavir 500/200 mg dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in feces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n=67) and HIV-infected adult patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg twice daily with a light meal.

Pharmacokinetics in Special Populations

APTIVUS pharmacokinetics has 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.

In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 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 B) or severe hepatic impairment (Child-Pugh C) on the multiple-dose pharmacokinetics of tipranavir administered with ritonavir has not been evaluated (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS).

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the 1182.12 and 1182.48 studies demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of tipranavir/ritonavir 500/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 uM for females and 31.1 uM for males. The difference in concentrations does not warrant a dose adjustment.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the 1182.12 and 1182.48 studies 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.

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the 1182.12 and 1182.48 studies 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, but the trend of consistent trough tipranavir concentrations with increasing age through 80 years for men was supported.

The pharmacokinetic profile of tipranavir in pediatric patients has not been established.

Drug Interactions

APTIVUS co-administered with 200 mg of ritonavir can alter plasma exposure of other drugs and other drugs may alter plasma exposure of tipranavir.

Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring (see CONTRAINDICATIONS and PRECAUTIONS). Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 2C19 and CYP 2D6. The potential net effect of tipranavir/ritonavir on CYP 2D6 is inhibition, because ritonavir is a CYP 2D6 inhibitor. The in vivo net effect of tipranavir administered with ritonavir on CYP 1A2, CYP 2C9 and CYP 2C19 is not known. Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl transferases and whether tipranavir induces CYP 1A2, CYP 2C9 and CYP 2C19.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well. Data suggest that the net effect of tipranavir co-administered with 200 mg of ritonavir is P-gp induction at steady-state, although ritonavir is a P-gp inhibitor. It is difficult to predict the net effect of APTIVUS administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP 3A and P-gp, and the extent of intestinal first-pass metabolism/efflux.

Drug interaction studies were performed with APTIVUS, co-administered with 200 mg of ritonavir, and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of APTIVUS with 200 mg ritonavir, on the AUC, Cmax and Cmin, are summarized in Tables 4 and 5. For information regarding clinical recommendations see PRECAUTIONS, Drug Interactions, Tables 8 and 9.

Table 4 Drug Interactions: Pharmacokinetic Parameters for Tipranavir in the Presence of Co-administered Drugs

Ratio (90% Confidence Interval) of Tipranavir Pharmacokinetic Parameters with/without

DEPARTMENT OF HEALTH & HUMAN SERVICES

Table 5 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Tipranavir/Ritonavir

Ratio (90% Confidence Interval) of Co-administered Drug Pharmacokinetic Parameters with/without TPV/ritonavir;

DEPARTMENT OF HEALTH & HUMAN SERVICES

Table 5 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Tipranavir/Ritonavir (continued)

Food and Drug Administration Rockville, MD 20857
Ethinyl estradiol	0.035 mg	500/100 mg BID	21	\|	0.52 (0.47, 0.57)	0.52 (0.48, 0.56)	-
	(1 dose)	750/200 mg BID (21 doses)	13	\|	0.48 (0.42, 0.57)	0.57 (0.54, 0.60)	-
Fluconazole	200 mg (Day 1)	500/200 mg BID	19	-	0.97 (0.94, 1.01)	0.99 (0.97, 1.02)	0.98 (0.94, 1.02)
	then 100 mg QD	(2 or 14 doses)	19	-	0.94 (0.91, 0.98)	0.92 (0.88, 0.95)	0.89 (0.85, 0.92)
	(6 or 12 doses)
Lopinavir/RTV a	400/100 mg BID	500/200 mg BID	21	\|	0.53 (0.40, 0.69) d	0.45 (0.32, 0.63) d	0.30 (0.17, 0.51) d
	(27 doses)	(28 doses)	69	\|	-	-	0.48 (0.40, 0.58) e
Loperamide	16 mg (1 dose)	750/200 mg BID (21 doses)	24	\|	0.39 (0.31, 0.48)	0.49 (0.40, 0.61)	-

Ratio (90% Confidence Interval) of Co-administered Drug Pharmacokinetic Parameters with/without TPV/ritonavir; No Effect = 1.00

25-O-desacetyl-rifabutin 20 | 3.20 (2.78, 3.68) 20.71 (17.66, 24.28) 7.83 (6.70, 9.14)

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Rockville, MD 20857
Zidovudine b	300 mg BID	250/200 mg BID	48	\|	0.54 (0.47, 0.62)	0.58 (0.51, 0.66)	-
	300 mg BID	750/100 mg BID	31	\|	0.51 (0.44, 0.60)	0.64 (0.55, 0.75)	-
	300 mg BID (43 doses)	1250/100 mg BID (42 doses)	23	\|	0.49 (0.40, 0.59)	0.69 (0.49, 0.97)	-
	300 mg	500/100 mg BID	29	\|	0.39 (0.33, 0.45)	0.57 (0.52, 0.63)	0.89 (0.81, 0.99)
	(1 dose)	750/200 mg BID	25	\|	0.44 (0.36, 0.54)	0.67 (0.62, 0.73)	1.25 (1.08, 1.44)
		(23 doses)
Zidovudine	glucuronide	500/100 mg BID	29	\|	0.82 (0.74, 0.90)	1.02 (0.97, 1.06)	1.52 (1.34, 1.71)
		750/200 mg BID	25	\|	0.82 (0.73, 0.92)	1.09 (1.05, 1.14)	1.94 (1.62, 2.31)

HIV+ patients (TPV/ritonavir 250 mg/200 mg, 750 mg/200 mg and 1250 mg/100 mg) and healthy volunteers (TPV/ritonavir 500 mg/100 mg and 750 mg/200 mg)

Normalized sum of parent drug (rifabutin) and active metabolite (25-O-desacetyl-rifabutin)

DEPARTMENT OF HEALTH & HUMAN SERVICES

INDICATIONS AND USAGE

APTIVUS (tipranavir), co-administered with 200 mg of ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors. This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 24 weeks duration. Both 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 other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response (see CLINICAL PHARMACOLOGY, Microbiology and INDICATIONS AND USAGE, Description of Clinical Studies).
Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir (see CLINICAL PHARMACOLOGY, Microbiology). The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir (see CLINICAL PHARMACOLOGY, Microbiology).
Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk of increased bleeding or who are receiving medications known to increase the risk of bleeding (see WARNINGS).
Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment (see WARNINGS).
Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or other underlying hepatic impairment (see WARNINGS).
The extensive drug-drug interaction potential of APTIVUS/ritonavir when co- administered with multiple classes of drugs must be considered prior to and during APTIVUS/ritonavir use (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).
The risk-benefit of APTIVUS/ritonavir has not been established in treatment-naive adult patients or pediatric patients.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration Rockville, MD 20857

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

Description of Clinical Studies

The following clinical data is derived from analyses of 24-week data from ongoing studies measuring effects on plasma HIV-1 RNA levels and CD4+ cell counts. At present there are no results from controlled studies evaluating the effect of APTIVUS/ritonavir on clinical progression of HIV.

Studies 1182.12 and 1182.48: APTIVUS/ritonavir 500/200 mg BID + optimized background regimen (OBR) vs. Comparator Protease Inhibitor/ritonavir BID + OBR

Studies 1182.12 and 1182.48 are ongoing, randomized, controlled, open-label, multicenter studies in HIV-positive, triple antiretroviral class experienced patients. All patients were required to have previously received at least two protease inhibitor-based antiretroviral regimens and were failing a protease inhibitor-based regimen at the time of study entry with baseline HIV-1 RNA at least 1000 copies/mL and any CD4+ cell count. At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations at codons 33, 82, 84 or 90. These studies evaluated treatment response at 24 weeks in a total of 1159 patients receiving either APTIVUS co-administered with 200 mg of ritonavir plus OBR versus a control group receiving a ritonavir-boosted protease inhibitor (lopinavir, amprenavir, saquinavir or indinavir) plus OBR. Prior to randomization, OBR was individually defined for each patient based on genotypic resistance testing and patient history. The investigator had to declare OBR, comparator protease inhibitor, and use of enfuvirtide prior to randomization. Randomization was stratified by choice of comparator protease inhibitor and use of enfuvirtide. After Week 8, patients in the control group who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over to APTIVUS/ritonavir in a separate roll-over study. Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir arm and control arm. In both studies combined, the 1159 patients had a median age of 43 years (range 17-80), were 88% male, 73% white, 14% black and 1% Asian. The median baseline plasma HIV-1 RNA was 4.82 (range 2 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 155 (range 1 to 1893) cells/mm3. Forty percent (40%) of the patients had baseline HIV-1 RNA of >= 100,000 copies/mL, 61% had a baseline CD4+ cell count < 200 cells/mm3, and 57% had experienced an AIDS defining Class C event at baseline.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 12% of patients had previously used enfuvirtide. In baseline patient samples (n=454), 97% of the isolates were resistant to at least one protease inhibitor, 95% of the isolates were resistant to at least one NRTI, and > 75% of the isolates were resistant to at least one NNRTI. The individually pre-selected protease inhibitor based on genotypic testing and the patient's medical history was lopinavir in 50%, amprenavir in 26%, saquinavir in 20% and indinavir in 4% of patients. A total of 86% were possibly resistant or resistant to the pre-selected comparator protease inhibitors. Approximately 25% of patients used enfuvirtide during study. There were differences between Studies 1182.12 and 1182.48 in the use of the protease inhibitors and in the use of enfuvirtide. Treatment response and efficacy outcomes of randomized treatment through Week 24 of Studies 1182.12 and 1182.48 are shown in Table 6.

Table 6 Outcomes of Randomized Treatment Through Week 24 (Pooled Studies 1182.12 and 1182.48)

Comparator protease inhibitors were lopinavir, amprenavir, saquinavir or indinavir and 86% of patients were possibly resistant or resistant to the chosen protease inhibitors.

a Patients achieved and maintained a confirmed >= 1 log10 HIV-1 RNA drop from baseline through Week 24 without prior evidence of treatment failure.

b Patients did not achieve a 0.5 log10 HIV-1 RNA drop from baseline and did not have viral load < 100,000 copies/mL by Week 8.

Includes patients who were lost to-follow-up, withdrawn consent, non-adherent, protocol violations, added/changed background antiretroviral drugs for reasons other than tolerability or toxicity, or discontinued while suppressed.

Through 24 weeks of treatment, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 34% and 16% respectively, and with HIV-1 RNA < 50 copies/mL was 23% and 9% respectively. Among all randomized and treated patients, the median change from baseline in HIV-1 RNA

DEPARTMENT OF HEALTH & HUMAN SERVICES

at the last measurement up to Week 24 was -0.80 log10 copies/mL in patients receiving APTIVUS/ritonavir versus -0.25 log10 copies/mL in the comparator PI/ritonavir arm. Among all randomized and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 24 was +34 cells/mm3 in patients receiving tipranavir/ritonavir (N=582) versus +4 cells/mm3 in the comparator PI/ritonavir (N=577) arm. Patients in the APTIVUS/ritonavir arm achieved a significantly better virologic outcome when APTIVUS/ritonavir was combined with enfuvirtide (see CLINICAL PHARMACOLOGY, Microbiology).

DEPARTMENT OF HEALTH & HUMAN SERVICES

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 Table 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

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

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.

WARNINGS

ALERT: Find out about medicines that should NOT be taken with APTIVUS(r).

APTIVUS (tipranavir) must be co-administered with 200 mg of ritonavir to exert its therapeutic effect (see DOSAGE AND ADMINISTRATION). Failure to correctly co- administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions (effect of tipranavir and ritonavir on other drugs).

DEPARTMENT OF HEALTH & HUMAN SERVICES

Please refer to ritonavir prescribing information for additional information on precautionary measures.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Intracranial Hemorrhage

APTIVUS, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS.

Platelet Aggregation Inhibition

In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir. APTIVUS/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents or anticoagulants.

Hepatic Impairment and Toxicity

APTIVUS co-administered with 200 mg of ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment. Patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2.5-fold risk for developing further transaminase elevations or hepatic decompensation. Additionally, Grade 3 and 4 increases in hepatic transaminases were observed in 6% of healthy volunteers in Phase 1 studies and 6% of subjects receiving APTIVUS/ritonavir in Phase 3 studies. Tipranavir is principally metabolized by the liver. Therefore caution should be exercised when administering APTIVUS/ritonavir to patients with hepatic impairment because tipranavir concentrations may be increased. APTIVUS/ritonavir is contraindicated in patients with moderate to severe (Child-Pugh Class B and Child-Pugh Class C) hepatic insufficiency. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools,

DEPARTMENT OF HEALTH & HUMAN SERVICES

liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. For information on the multi-dose pharmacokinetics of tipranavir in hepatically impaired patients see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Hepatic Impairment.

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Drug Interactions

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of APTIVUS/ritonavir and fluticasone propionate may produce the same effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, 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 PRECAUTIONS, Drug Interactions). Particular caution should be used when prescribing phosphodiesterase (PDE5) inhibitors for erectile dysfunction (e.g., sildefafil, tadalafil, or vardenafil) in patients receiving protease inhibitors, including APTIVUS. Co-administration of a protease inhibitor with PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS, Drug Interactions and Information for Patients, and the complete specific PDE5 inhibitor prescribing information).

PRECAUTIONS

Sulfa Allergy

DEPARTMENT OF HEALTH & HUMAN SERVICES

APTIVUS (tipranavir) should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir is unknown.

Rash

Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in subjects receiving APTIVUS/ritonavir. In Phase 2 and 3 trials rash was observed in 14% of females and in 8-10% of males receiving APTIVUS/ritonavir. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by APTIVUS/ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving APTIVUS/ritonavir (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS).

Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established.

Lipid Elevations

Treatment with APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides (see ADVERSE REACTIONS, Table 11). Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate (see PRECAUTIONS, Drug Interactions, Table 9: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with APTIVUS/ritonavir and HMG- CoA reductase inhibitors).

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome

DEPARTMENT OF HEALTH & HUMAN SERVICES

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tipranavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jeroveci pneumonia, tuberculosis, or reactivation of herpes simplex and herpes zoster), which may necessitate further evaluation and treatment.

Information for Patients

Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage.

Patients should report any unusual or unexplained bleeding to their physician. Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir,

has been associated with severe liver disease, including some deaths. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. Symptoms of hepatitis include fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Extra vigilance is needed for patients with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity.

Liver function tests should be performed prior to initiating therapy with tipranavir and 200 mg of ritonavir, and frequently throughout the duration of treatment. Patients with chronic hepatitis B or C co-infection or elevations in liver enzymes prior to treatment are at increased risk (approximately 2.5-fold) for developing further liver enzyme elevations or severe liver disease. Caution should be exercised when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients. APTIVUS should not be given to patients with moderate to severe liver disease. Mild to moderate rash has been reported in HIV-infected men and women receiving APTIVUS/ritonavir. Women receiving estrogen-based hormonal contraceptives should be instructed that additional or alternative contraceptive measures should be used during therapy with APTIVUS/ritonavir. There may be an increased risk of rash when APTIVUS is given with hormonal contraceptives. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Patients should be informed that APTIVUS must be co-administered with 200 mg ritonavir to ensure its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using APTIVUS. Patients should be advised to take APTIVUS and other concomitant antiretroviral therapy every day as prescribed. APTIVUS, co-administered with ritonavir, must be given in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of APTIVUS is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose. Patients should be informed that APTIVUS is not a cure for HIV-1 infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of APTIVUS are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with APTIVUS can reduce the risk of transmitting HIV to others through sexual contact. APTIVUS may interact with some drugs; therefore, patients should be advised to report to their health care provider the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort. APTIVUS should be taken with food to enhance absorption. The Patient Package Insert provides written information for the patients, and should be dispensed with each new prescription and refill.

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.

DEPARTMENT OF HEALTH & HUMAN SERVICES

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

due to potential for serious and/or life- threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics.

due to potential for serious and/or life- threatening reactions such as cardiac arrhythmias.

May lead to loss of virologic response and possible resistance to tipranavir or to the class of protease inhibitors.

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

due to potential for serious and/or life- threatening reactions such as cardiac arrhythmias.

May lead to loss of virologic response and possible resistance to tipranavir or to the class of protease inhibitors.

Potential for serious reactions such as risk of myopathy including rhabdomyolysis.

due to potential for serious and/or life- threatening reactions such as cardiac arrhythmias.

due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or

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

DEPARTMENT OF HEALTH & HUMAN SERVICES

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

Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered.

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.

Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.

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

Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (200 mg/day) are not recommended.

DEPARTMENT OF HEALTH & HUMAN SERVICES

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 (continued)

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%.

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.

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-

DEPARTMENT OF HEALTH & HUMAN SERVICES

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 (continued)

APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazadone should be considered.

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.

Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.

APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction

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

DEPARTMENT OF HEALTH & HUMAN SERVICES

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 (continued)

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.

| 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).

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).

DEPARTMENT OF HEALTH & HUMAN SERVICES

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 (continued)

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.

Concomitant use of PDE5 inhibitors with tipranavir and ritonavir should be used with caution and in no case should the starting dose of:

Cannot predict the effect of TPV/ritonavir on S-Warfarin due to conflicting effect of TPV and

Frequent INR (international normalized ratio) monitoring upon initiation of tipranavir/ritonavir therapy.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term animal carcinogenicity bioassays with tipranavir and tipranavir/ritonavir are currently in progress. However, tipranavir showed no evidence of mutagenicity or clastogenicity in a battery of five in vitro and in vivo tests including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, unscheduled DNA synthesis in rat hepatocytes, induction of gene mutation in Chinese hamster ovary cells, a chromosome aberration assay in human peripheral lymphocytes, and a micronucleus assay in mice. Tipranavir had no effect on fertility or early embryonic development in rats at dose levels up to 1000 mg/kg/day, equivalent to a Cmax of 258 uM in females. Based on Cmax levels in these rats, as well as an exposure (AUC) of 1670 uM *h in pregnant rats from another study, this exposure was approximately equivalent to the anticipated exposure in humans at the recommended dose level of 500/200 mg tipranavir/ritonavir BID.

Pregnancy

Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats. No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 uM *h or approximately 0.8-fold human exposure at the recommended dose. In rats and rabbits, fetal toxicity was not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, corresponding accordingly to Cmax/AUC0-24h levels of 30.4 uM/340 uM *h and 8.4 uM/120 uM *h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose. In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day (~0.8-fold human exposure). No post- weaning functions were affected at any dose level. There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. APTIVUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to APTIVUS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and any possible adverse effects of tipranavir, mothers should be instructed not to breastfeed if they are receiving APTIVUS.

Pediatric Use

Geriatric Use

Clinical studies of APTIVUS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of APTIVUS in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

APTIVUS (tipranavir), co-administered with 200 mg of ritonavir, has been studied in a total of 1854 HIV-positive adults as combination therapy in clinical studies. Of these, 1397 patients received the dose of 500/200 mg BID. Seven hundred sixty one (761) adults, including 385 in the 1182.12 and 1182.48 Phase 3 pivotal studies, have been treated for at least 24 weeks. In 1182.12 and 1182.48 in the APTIVUS/ritonavir arm, the most frequent AEs were diarrhea, nausea, fatigue, headache and vomiting. Adverse events leading to discontinuation were reported by 7.8% of the tipranavir-treated patients and 4.9% of the comparator arm patients. Due to the need for co-administration of APTIVUS with 200 mg of ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration Rockville, MD 20857

The most frequent clinical treatment-emergent adverse events reported in Phase 3 clinical studies (1182.12 and 1182.48) in adults are summarized in Table 10 below. Events of moderate to severe intensity (Grades 2-4) reported in at least 2% of highly treatment- experienced subjects in either treatment group are included.

Table 10 Percentage of Patients with Treatment Emergent Adverse Events of at Least Moderate Intensity (Grades 2-4) in >= 2% of Patients in Either Treatment Groupa

Phase 3 Studies 1182.12 and 1182.48 (24-weeks)

Gastrointestinal Disorders

Diarrhea Nausea Vomiting

Abdominal painc

General Disorders

Pyrexia Fatigue Asthenia

Infections and Infestations

Tipranavir/ritonavir (500/200 mg BID) + OBR (n=746)

10.9%

6.7%

3.4%

2.8%

4.6%

4.0%

1.5%

Comparator PI/ritonavirb + OBR

(n=737)

9.4%

4.6%

3.0%

3.7%

4.3%

3.9%

2.3%

Bronchitis 2.9% 1.1%

Nervous System Disorders

Headache 3.1% 3.1%

Psychiatric Disorders

Depression Insomnia

Respiratory, Thoracic and Mediastinal Disorders

2.0%

1.2%

3.0%

2.6%

Cough 0.8% 2.2%

Skin and Subcutaneous Tissue Disorders

Rash 2.0% 2.0%

Excludes laboratory abnormalities that were Adverse Events

Comparator PI/RTV: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID

Abdominal pain includes Preferred Terms "Abdominal pain" and "Abdominal pain upper"

Clinically meaningful adverse reactions in < 2% of adult patients (n=1397) treated with APTIVUS/ritonavir 500/200 mg in Phase 2 and 3 trials listed below by body system:

Blood and Lymphatic System Disorders:

anemia, neutropenia, thrombocytopenia

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration Rockville, MD 20857

Gastrointestinal Disorders:

abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis

General Disorders: influenza like illness, malaise, pyrexia Hepatobiliary Disorders: hepatitis, hepatic failure Immune System Disorders: hypersensitivity

Infections and infestations:

reactivation of herpes simplex and varicella zoster

Investigations:

hepatic enzymes increased, liver function test abnormal, lipase increased, weight decreased

Metabolism and Nutrition Disorders:

anorexia, decreased appetite, dehydration, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia

Musculoskeletal and Connective Tissue Disorders:

muscle cramp, myalgia

Nervous System Disorders:

dizziness, intracranial hemorrhage, neuropathy peripheral, somnolence

Psychiatric Disorders:

insomnia, sleep disorder

Renal and Urinary Disorders:

renal insufficiency

Respiratory, Thoracic and Mediastinal Disorders:

dyspnea

Skin and Subcutaneous System Disorders:

exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus

Laboratory Abnormalities

Treatment emergent clinical laboratory abnormalities reported at 24 weeks in Phase 3 clinical studies (1182.12 and 1182.48) in adults are summarized in Table 11 below.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration Rockville, MD 20857

Table 11 Treatment Emergent Laboratory Abnormalities Reported in >= 2% of Adult Patients

Studies 1182.12 and 1182.48 (24-weeks) APTIVUS/ritonavir

Hematology

WBC count decrease

Limit

(500/200 mg BID) + OBR

(n=732)

Comparator PI/ritonavir

+ OBR * (n=726)

Grade 3-4 < 2.0 x 103/uL 3.6% 5.4%

Chemistry

Amylase Grade 3-4	> 2 x ULN	2.9%	4.8%
ALT Grade 2	> 2.5-5 x ULN	10.7%	5.4%
Grade 3	> 5-10 x ULN	3.1%	1.4%
Grade 4	> 10 x ULN	2.7%	0.4%
AST Grade 2	> 2.5-5 x ULN	6.0%	5.8%
Grade 3	> 5-10 x ULN	3.3%	1.0%
Grade 4	> 10 x ULN	0.7%	0.4%
ALT and/or AST Grade 2-4	> 2.5 x ULN	17.5%	9.9%
Cholesterol Grade 2	> 300 - 400 mg/dL	11.3%	4.3%
Grade 3	> 400 - 500 mg/dL	2.5%	0.3%
Grade 4	> 500 mg/dL	0.8%	0%
Triglycerides Grade 2	400 - 750 mg/dL	26.2%	14.7%
Grade 3	> 750 - 1200 mg/dL	12.8%	5.6%
Grade 4	> 1200 mg/dL	6.1%	3.4%

* Comparator PI/RTV: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir

1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID

In clinical trials extending up to 48 weeks, the proportion of patients who developed Grade 2-4 ALT and/or AST elevations increased to 24.4% with APTIVUS/ritonavir and to 12.8% with CPI/ritonavir.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration Rockville, MD 20857

ANIMAL PHARMACOLOGY AND TOXICOLOGY

In preclinical studies, tipranavir treatment induced changes in coagulation parameters (increased prothrombin and activated partial thromboplastin times) in rodents. At higher doses and in extreme cases, these changes led to bleeding in multiple organs and death. The mechanism for this effect is unknown. This effect was not seen in preclinical studies with dogs.

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.

DOSAGE AND ADMINISTRATION

General

The recommended dose of APTIVUS (tipranavir) Capsules is 500 mg (two 250 mg capsules), co-administered with 200 mg of ritonavir, twice daily. APTIVUS Capsules, co-administered with 200 mg of ritonavir should be taken with food. Bioavailability is increased with a high fat meal.

HOW SUPPLIED

APTIVUS (tipranavir) Capsules 250 mg are pink, oblong soft gelatin capsules imprinted in black with "TPV 250". They are packaged in HDPE unit-of-use bottles with a child resistant closure and 120 capsules. (NDC 0597-0003-02) APTIVUS capsules should be stored in a refrigerator 2deg-8degC (36deg-46degF) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25degC (77degF); excursions permitted to 15deg-30degC (59deg-86degF) and must be used within 60 days. Store in a safe place out of the reach of children. Address medical inquiries to: http://us.boehringer-ingelheim.com, (800) 542-6257 or (800) 459-9906 TTY.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA APTIVUS(r) is a registered trademark used under license from Boehringer Ingelheim International GmbH (c)Copyright Boehringer Ingelheim International GmbH, 2006 ALL RIGHTS RESERVED APTIVUS Capsules are covered by U.S. Patents 5,852,195; 6,147,095; 6,169,181 and 6,231,887 OT2000B 10003515/US/3 10003515/03

Atorvastatin	(Schedule) 10 mg	(Schedule) 500/200 mg	22	-	C max 0.96 (0.86, 1.07)	AUC 1.08 (1.00, 1.15)	C min 1.04 (0.89, 1.22)
	(1 dose)	BID
		(14 doses)
Clarithromycin	500 mg BID (25 doses)	500/200 mg BID *	24 (68)	\|	1.40 (1.24, 1.47)	1.66 (1.43, 1.73)	2.00 (1.58, 2.47)
Didanosine	400 mg (1 dose)	500/100 mg BID	5	\|	1.32 (1.09, 1.60)	1.08 (0.82, 1.42)	0.66 (0.31, 1.43)
		(27 doses)
Efavirenz	600 mg QD (8 doses)	500/100 mg BID *	21 (89)	\|	0.79 (0.69, 0.89)	0.69 (0.57 , 0.83)	0.58 (0.36, 0.86)
		750/200 mg	25 (100)	-	0.97 (0.85, 1.09)	1.01 (0.85, 1.18)	0.97 (0.69 , 1.28)
		BID *
Ethinyl	0.035/1.0 mg	500/100 mg	21	\|	1.10 (0.98, 1.24)	0.98 (0.88, 1.11)	0.73 (0.59, 0.90)
				14

		750/200 mg BID	13	-	1.01 (0.96, 1.06)	0.98 (0.90, 1.07)	0.91 (0.69, 1.20)
		(21 doses)
Fluconazole	100 mg QD (12 dose)	500/200 mg BID *	20 (68)	\|	1.32 (1.18, 1.47)	1.50 (1.29 , 1.73)	1.69 (1.33, 2.09)
Loperamide	16 mg (1 dose)	750/200 mg BID	24	\|	1.03 (0.92, 1.17)	0.98 (0.86, 1.12)	0.74 (0.62, 0.88)
		(21 doses)
Rifabutin	150 mg (1 dose)	500/200 mg BID	21	-	0.99 (0.93, 1.07)	1.00 (0.96, 1.04)	1.16 (1.07, 1.27)
		(15 doses)
Tenofovir	300 mg (1 dose)	500/100 mg BID	22	\|	0.83 (0.74, 0.94)	0.82 (0.75, 0.91)	0.79 (0.70, 0.90)
		750/200 mg BID	20	-	0.89 (0.84, 0.96)	0.91 (0.85, 0.97)	0.88 (0.78, 1.00)
		(23 doses)
Zidovudine	300 mg (1 dose)	500/100 mg BID	29	\|	0.87 (0.80, 0.94)	0.82 (0.76, 0.89)	0.77 (0.68, 0.87)
		750/200 mg BID	25	-	1.02 (0.94, 1.10)	1.02 (0.92, 1.13)	1.07 (0.86, 1.34)

Amprenavir/RTV a	(Schedule) 600/100 mg BID	(Schedule) 500/200 mg BID	16	\|	C max 0.61 (0.51, 0.73) d	AUC C min 0.56 (0.49, 0.64) d 0.45 (0.38, 0.53) d
	(27 doses)	(28 doses)	74	\|	-	- 0.44 (0.39, 0.49) e
Abacavir a	300 mg BID	250/200 mg BID	28	\|	0.56 (0.48, 0.66)	0.56 (0.49, 0.63) -
	(43 doses)	750/100 mg BID	14	\|	0.54 (0.47, 0.63)	0.64 (0.55, 0.74) -
		1250/100 mg BID (42 doses)	11	\|	0.48 (0.42, 0.53)	0.65 (0.55, 0.76) -
Atorvastatin	10 mg (1 dose)	500/200 mg BID (17 doses)	22	\|	8.61 (7.25, 10.21)	9.36 (8.02, 10.94) 5.19 (4.21, 6.40)
Orthohydroxy-atorvastatin			21,	\|	0.02 (0.02, 0.03)	0.11 (0.08, 0.17)	0.07 (0.06, 0.08)
			12,
			17
Parahydroxy-atorvastatin			13,	\|	1.04 (0.87, 1.25)	0.18 (0.14, 0.24)	0.33 (NA)
			22,
			1
Clarithromycin 500 mg BID (25 doses)		500/200 mg BID (15 doses)	21	\|	0.95 (0.83, 1.09)	1.19 (1.04, 1.37)	1.68 (1.42, 1.98)
14-OH-clarithromycin			21	\|	0.03 (0.02, 0.04)	0.03 (0.02, 0.04)	0.05 (0.04, 0.07)
Didanosine b	200 mg BID,	250/200 mg BID	10	\|	0.57 (0.42, 0.79)	0.67 (0.51, 0.88)	-
	>= 60 kg	750/100 mg BID	8	-	0.76 (0.49, 1.17)	0.97 (0.64, 1.47)	-
	125 mg BID, < 60 kg	1250/100 mg BID (42 doses)	9	-	0.77 (0.47, 1.26)	0.87 (0.47, 1.65)	-
	(43 doses)
	400 mg (1 dose)	500/100 mg BID (27 doses)	5	-	0.80 (0.63, 1.02)	0.90 (0.72, 1.11)	1.17 (0.62, 2.20)
Efavirenz b	600 mg QD	500/100 mg BID	24	-	1.09 (0.99, 1.19)	1.04 (0.97, 1.12)	1.02 (0.92, 1.12)
	(15 doses)	750/200 mg BID (15 doses)	22	-	1.12 (0.98, 1.28)	1.00 (0.93, 1.09)	0.94 (0.84, 1.04)

Saquinavir/RTV a	600/100 mg	500/200 mg BID	20	\|	0.30 (0.23, 0.40) d	0.24 (0.19, 0.32) d	0.18 (0.13, 0.26) d
	BID (27 doses)	(28 doses)	68	\|	-	-	0.20 (0.16, 0.25) e
Stavudine a	40 mg BID,	250/200 mg BID	26	-	0.90 (0.81, 1.02)	1.00 (0.91, 1.11)	-
	>= 60 kg	750/100 mg BID	22	-	0.76 (0.66, 0.89)	0.84 (0.74, 0.96)	-
	30 mg BID, < 60 kg	1250/100 mg BID (42 doses)	19	-	0.74 (0.69, 0.80)	0.93 (0.83, 1.05)	-
	(43 doses)
Tenofovir	300 mg	500/100 mg BID	22	\|	0.77 (0.68, 0.87)	0.98 (0.91, 1.05)	1.07 (0.98, 1.17)
	(1 dose)	750/200 mg BID (23 doses)	20	\|	0.62 (0.54, 0.71)	1.02 (0.94, 1.10)	1.14 (1.01, 1.27)

Rx only

Prescribing Information

WARNING

APTIVUS CO-ADMINISTERED WITH 200 MG RITONAVIR HAS BEEN ASSOCIATED WITH REPORTS OF BOTH FATAL AND NON-FATAL INTRACRANIAL HEMORRHAGE. (SEE WARNINGS)

DESCRIPTION

DEPARTMENT OF HEALTH & HUMAN SERVICES

CLINICAL PHARMACOLOGY

Microbiology

DEPARTMENT OF HEALTH & HUMAN SERVICES

Baseline Genotype and Virologic Outcome Analyses

DEPARTMENT OF HEALTH & HUMAN SERVICES

Table 1 Phase 3 Studies 1182.12 and 1182.48: Proportion of Responders (confirmed

>= 1 log10 decrease at Week 24) by Number of Baseline Primary Protease Inhibitor (PI) Mutations

DEPARTMENT OF HEALTH & HUMAN SERVICES

Baseline Phenotype and Virologic Outcome Analyses

Table 2 Response by Baseline Tipranavir Phenotype in the 1182.12 and 1182.48 Trials

Pharmacodynamics

DEPARTMENT OF HEALTH & HUMAN SERVICES

Pharmacokinetics in Adult Patients

Figure 1 Mean Steady State Tipranavir Plasma Concentrations (95% CI) with Ritonavir Co-administration (tipranavir/ritonavir 500/200 mg BID)

DEPARTMENT OF HEALTH & HUMAN SERVICES

Absorption and Bioavailability

Table 3 Pharmacokinetic Parametersa of tipranavir/ritonavir 500/200 mg for HIV+ Patients by Gender

DEPARTMENT OF HEALTH & HUMAN SERVICES

Effects of Food on Oral Absorption

Distribution

Metabolism

DEPARTMENT OF HEALTH & HUMAN SERVICES

Elimination

Pharmacokinetics in Special Populations

DEPARTMENT OF HEALTH & HUMAN SERVICES

Drug Interactions

Drug Interactions

DEPARTMENT OF HEALTH & HUMAN SERVICES

Table 4 Drug Interactions: Pharmacokinetic Parameters for Tipranavir in the Presence of Co-administered Drugs

DEPARTMENT OF HEALTH & HUMAN SERVICES

Table 5 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Tipranavir/Ritonavir

DEPARTMENT OF HEALTH & HUMAN SERVICES

Table 5 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Tipranavir/Ritonavir (continued)

DEPARTMENT OF HEALTH & HUMAN SERVICES

DEPARTMENT OF HEALTH & HUMAN SERVICES

INDICATIONS AND USAGE

DEPARTMENT OF HEALTH & HUMAN SERVICES

Description of Clinical Studies

DEPARTMENT OF HEALTH & HUMAN SERVICES

Table 6 Outcomes of Randomized Treatment Through Week 24 (Pooled Studies 1182.12 and 1182.48)

DEPARTMENT OF HEALTH & HUMAN SERVICES

DEPARTMENT OF HEALTH & HUMAN SERVICES

CONTRAINDICATIONS

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

WARNINGS

ALERT: Find out about medicines that should NOT be taken with APTIVUS(r).

DEPARTMENT OF HEALTH & HUMAN SERVICES

DEPARTMENT OF HEALTH & HUMAN SERVICES

Intracranial Hemorrhage

Platelet Aggregation Inhibition

Hepatic Impairment and Toxicity

DEPARTMENT OF HEALTH & HUMAN SERVICES

Diabetes Mellitus/Hyperglycemia

Drug Interactions

PRECAUTIONS

Sulfa Allergy

DEPARTMENT OF HEALTH & HUMAN SERVICES

Rash

Patients with Hemophilia

Lipid Elevations

Fat Redistribution

Immune Reconstitution Syndrome

DEPARTMENT OF HEALTH & HUMAN SERVICES

Information for Patients

Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage.

Patients should report any unusual or unexplained bleeding to their physician. Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir,

DEPARTMENT OF HEALTH & HUMAN SERVICES

Drug Interactions

DEPARTMENT OF HEALTH & HUMAN SERVICES

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

DEPARTMENT OF HEALTH & HUMAN SERVICES

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

DEPARTMENT OF HEALTH & HUMAN SERVICES

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 (continued)