Aptivus

Contraception in males and females

Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe method of contraception should be used during treatment.

Pregnancy

There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Tipranavir should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breastfeeding

Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue breast-feeding if they are receiving Aptivus.

Fertility

Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir showed no adverse effect on fertility.

Dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

Summary of the safety profile

Amongst the most common adverse reactions reported for Aptivus were gastrointestinal complaints such as diarrhoea and nausea as well as hyperlipidaemia. The most serious adverse reactions include hepatic impairment and liver toxicity. Intracranial haemorrhage (ICH) was only observed in post marketing experience.

Tabulated summary of adverse reactions

Assessment of adverse reactions from HIV-1 clinical study data is based on experience in all Phase II and III trials in adults treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily (n=1397) and are listed below by system organ class and frequency according to the following categories:

Very common (> 1/10), common (> 1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000)

Tabulated summary of adverse reactions associated with Aptivus based on clinical studies and post-marketing experience:

* see section Description of selected adverse reactions “Bleeding” for source of information

Description of selected adverse reactions

The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were seen at higher frequency among tipranavir with ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with ritonavir administration. The clinical significance of these observations has not been fully explored.

Hepatotoxicity

After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT abnormalities was higher in tipranavir with ritonavir patients compared with comparator arm patients (10% and 3.4%, respectively). Multivariate analyses showed that baseline ALAT or ASAT above DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most patients were able to continue treatment with tipranavir with ritonavir.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy

Hyperlipidaemia

Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir with ritonavir arm compared with the comparator arm. At 48 weeks these rates were 25.2% of patients in the tipranavir with ritonavir arm and 15.6% in the comparator arm.

Bleeding

This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials (n=6300).

RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between treatment groups in coagulation parameters. The significance of this finding is being further monitored.

Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir, many of whom had other medical conditions or were receiving concomitant medicinal products that may have caused or contributed to these events. However, in some cases the role of tipranavir cannot be excluded. No pattern of abnormal haematological or 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.

An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS such as those treated in the Aptivus clinical trials.

Rash

An interaction study in women between tipranavir, co-administered with low dose ritonavir, and ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash.). No cases of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis have been reported in the clinical development programme of tipranavir.

Laboratory abnormalities

Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of patients in the tipranavir with ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%), increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count (5.7%).

Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Reactivation of herpes simplex and herpes zoster virus infections were observed in the RESIST trials.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

Paediatric population

In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 62 children aged 2 to 12 years received Aptivus oral solution. In general, adverse reactions were similar to those seen in adults, with the exception of vomiting, rash and pyrexia which were reported more frequently in children than in adults. The most frequently reported moderate or severe adverse reactions in the 48 week analyses are noted below.

Most frequently reported moderate or severe adverse reactions in paediatric patients age 2 to < 12 years (reported in 2 or more children, Trial 1182.14, 48 weeks analyses, Full Analysis Set).

¹ Includes abdominal pain (N=1), dysphagia (N=1) and epigastric discomfort (N=1).

² Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash maculo-papular, rash pruritic, and urticaria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Human experience with tipranavir overdose is very limited. No specific signs and symptoms of overdose are known. Generally, an increased frequency and higher severity of adverse reactions may result from overdose.

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 substance. Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE09

Mechanism of action

The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1 protease that inhibits viral replication by preventing the maturation of viral particles.

Antiviral activity in vitro

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% and 90% effective concentrations (EC₅₀ and EC₉₀) ranging from 0.03 to 0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. 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 µM and 0.233-0.522 µM, 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.

Resistance

The development of resistance to tipranavir in vitro is slow and complex. In one particular in vitro resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9 months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T, A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype conferred 69-fold resistance to tipranavir. In vitro, there is an inverse correlation between the degree of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing > 3-fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same conditions. Tipranavir resistant viruses which emerge in vitro from wild-type HIV-1 show decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remain sensitive to saquinavir.

Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or reduced 48-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a > 10-fold decrease in tipranavir susceptibility harboured 8 or more tipranavir-associated mutations. In Phase II and III clinical trials, 276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations with tipranavir treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre-existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.

Cross-resistance

Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1 clinical isolates showing post-treatment decreased susceptibility to the currently approved protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir. Greater than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from highly treatment experienced patients who have received multiple peptidic protease inhibitors.

ECG evaluation

The effect of tipranavir with low dose of ritonavir on the QTcF interval was measured in a study in which 81 healthy subjects received the following treatments twice daily for 2.5 days: tipranavir/ritonavir (500/200 mg), tipranavir/ritonavir at a supra-therapeutic dose (750/200 mg), and placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% Upper CI: 10.8 ms) for the supra-therapeutic 750/200 mg dose. Hence tipranavir at therapeutic dose with low dose of ritonavir did not prolong the QTc interval but may do so at supratherapeutic dose.

Clinical pharmacodynamic data

This indication is based on the results of one phase II study investigating pharmacokinetics, safety and efficacy of Aptivus oral solution in mostly treatment-experienced children aged 2 to 12 years.

The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class experienced patients, evaluating treatment with tipranavir 500 mg co-administered with low dose ritonavir 200 mg (twice daily) plus an optimised background regimen (OBR) individually defined for each patient based on genotypic resistance testing and patient history. The comparator regimen included a ritonavir-boosted PI (also individually defined) plus an OBR. The ritonavir-boosted PI was chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir.

All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based regimen at the time of study entry. 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 on codons 33, 82, 84 or 90.

After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over to tipranavir with ritonavir in a separate roll-over study.

The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were 86% male, 75% white, 13% black and 1% Asian. In the tipranavir and comparator arms median baseline CD4 cell counts were 158 and 166 cells/mm³, respectively, (ranges 1-1893 and 1-1184 cells/mm³); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log₁₀ copies/ml, respectively (ranges 2.34-6.52 and 2.01-6.76 log₁₀ copies/ml).

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of 67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs. A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a median of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. With respect to mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84 and 90 and 53% had at least one key mutation at codon 90. One patient in the tipranavir arm had four mutations. In addition the majority of participants had mutations associated with both NRTI and NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples. There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41-fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.

Combined 48-week treatment response (composite endpoint defined as patients with a confirmed >1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34% in the tipranavir with ritonavir arm and 15% in the comparator arm. Treatment response is presented for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of patients with genotypically resistant strains in the Table below.

Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment-experienced patients)

* Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without evidence of treatment failure

** Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r 600 mg/100 mg twice daily (n=194)

ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv

Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir

Combined 48-week median time to treatment failure for both studies was 115 days in the tipranavir with ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).

Through 48 weeks of treatment, the proportion of patients in the tipranavir with ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14% respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all randomised and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log₁₀ copies/ml in patients receiving tipranavir with ritonavir versus -0.22 log₁₀ copies/ml in the comparator PI/ritonavir arm.

Among all randomised and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm³ in patients receiving tipranavir with ritonavir (N=740) versus +4 cells/mm³ in the comparator PI/ritonavir (N=727) arm.

The superiority of tipranavir co-administered with low dose ritonavir over the comparator protease inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that tipranavir is superior to these boosted comparator protease inhibitors in patients harbouring strains susceptible to these protease inhibitors. RESIST data also demonstrate that tipranavir co-administered with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains genotypically available antiretroviral agents (e.g. enfuvirtide).

At present there are no results from controlled trials evaluating the effect of tipranavir on clinical progression of HIV.

Paediatric population

HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label, multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) and randomized to receive one of two tipranavir with ritonavir dose regimens: 375 mg/m²/150 mg/m² dose, compared to the 290 mg/m²/115 mg/m² dose, plus background therapy of at least two non-protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance testing. All patients initially received Aptivus oral solution. Paediatric patients who were 12 years or older and received the maximum dose of 500 mg/200 mg twice daily could change to Aptivus capsules from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as virologic and immunologic responses through 48 weeks.

The available clinical data do not support the use of Aptivus oral solution in adolescents or adults. Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral solution. Due to this and to the high vitamin E content of the oral solution, the risk of adverse reactions (type, frequency and/or severity) may be higher than with the capsule formulation.

In patients less than 12 years of age, however, the oral solution is the only available option for treatment with tipranavir, as no data are available on the efficacy and safety of Aptivus capsules in children less than 12 years of age.). Moreover, in patients with a body surface area of less than 1.33 m² appropriate dose adjustments cannot be achieved with the capsule formulation. These factors lead to the conclusion that the benefits outweigh the risks of Aptivus oral solution only in children between 2 and 12 years of age without any other therapeutic option.

The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients receiving Aptivus oral solution are displayed in the tables below.

Baseline characteristics for patients 2 - <12 years treated with Aptivus oral solution

* AIDS defining illness

Key efficacy results at 48 weeks for patients 2 - <12 years treated with Aptivus oral solution

Analyses of tipranavir resistance in treatment experienced patients

Tipranavir with ritonavir response rates in the RESIST studies were assessed by baseline tipranavir genotype and phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to tipranavir with ritonavir therapy were assessed.

Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M, and no more than two mutations on codons 33, 82, 84 or 90.

The following observations were made:

- Primary PI mutations

Analyses were conducted to assess virological outcome by the number of primary PI mutations (any change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline. Response rates were higher in tipranavir with ritonavir patients than comparator PI boosted with ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.

- Mutations at protease codons 33, 82, 84 and 90

A reduced virological response was observed in patients with viral strains harbouring two or more mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.

- Tipranavir resistance-associated mutations

Virological response to tipranavir with ritonavir therapy has been evaluated using a tipranavir-associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score (counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation between the tipranavir mutation score and response to tipranavir with ritonavir therapy at week 48 has been established.

This score has been determined from the selected RESIST patient population having specific mutation inclusion criteria and therefore extrapolation to a wider population mandates caution.

At 48-weeks, a higher proportion of patients receiving tipranavir with ritonavir achieved a treatment response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible combinations of genotypic resistance mutations (see table below).

Proportion of patients achieving treatment response at Week 48 (confirmed > 1 log₁₀ copies/ml decrease in viral load compared to baseline), according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

* Includes patients who did not receive ENF and those who were previously treated with and continued ENF

**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received tipranavir with ritonavir and new enfuvirtide. If patients did not receive tipranavir with ritonavir with new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide use (see Table below).

Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation score and enfuvirtide use in RESIST patients

* Includes patients who did not receive ENF and those who were previously treated with and continued ENF

** Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V

ENF Enfuvirtide; TPV/r Tipranavir with ritonavir

- Tipranavir phenotypic resistance

Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing virological response. Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen, coadministration of tipranavir with low dose ritonavir twice daily is essential. Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (P-gp) efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose-ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC_0-12h, C_max and C_min and decreases the clearance of tipranavir. 500 mg tipranavir co-administered with low dose ritonavir (200 mg; twice daily) was associated with a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without ritonavir.

Absorption

Absorption of tipranavir in humans is limited, though 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. Data suggest that, although ritonavir is a P-gp inhibitor, the net effect of Aptivus, co-administered with low dose ritonavir, at the proposed dose regimen at steady-state, is P-gp induction. Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from single dose data, presumably due to hepatic enzyme induction. Steady-state is attained in most subjects after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear pharmacokinetics at steady state.

Dosing with Aptivus capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (C_max) of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106), occurring approximately 3 hours after administration. The mean steady-state trough concentration prior to the morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM-h (CL=1.15 l/h) for female patients and 710 ± 207 µM-h (CL=1.27 l/h) for male patients. The mean half-life was 5.5 (females) or 6.0 hours (males).

Effects of food on oral absorption

Food improves the tolerability of tipranavir with ritonavir. Therefore Aptivus, co-administered with low dose ritonavir, should be given with food.

Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of antacids.

Distribution

Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015% ± 0.006%; HIV-positive subjects 0.019% ± 0.076%). Total plasma tipranavir concentrations for these samples ranged from 9 to 82 μM. The unbound fraction of tipranavir appeared to be independent of total concentration over this concentration range.

No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.

Biotransformation

In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism.

The oral clearance of tipranavir decreased after the addition of ritonavir which may represent diminished first-pass clearance of the substance at the gastrointestinal tract as well as the liver.

The metabolism of tipranavir in the presence of low dose ritonavir is minimal. In a ¹⁴C-tipranavir human study (500 mg ¹⁴C-tipranavir with 200 mg ritonavir, twice daily), unchanged tipranavir was predominant and 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 faeces, unchanged tipranavir represented the majority of faecal radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in 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 500 mg tipranavir with 200 mg ritonavir twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in faeces, 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 with 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 mg/200 mg twice daily with a light meal.

Special populations

Although data available at this stage are currently limited to allow a definitive analysis, they suggest that the pharmacokinetic profile is unchanged in older people and comparable between races. By contrast, evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir concentrations than males. After four weeks of Aptivus 500 mg with 200 mg ritonavir (twice daily) the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males. This difference in concentrations does not warrant a dose adjustment.

Renal impairment

Tipranavir pharmacokinetics have not been studied in patients with renal impairment. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic impairment

In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single and multiple dose exposure of tipranavir and ritonavir were increased in patients with hepatic impairment but still within the range observed in clinical studies. No dosing adjustment is required in patients with mild hepatic impairment but patients should be closely monitored.

The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated. Tipranavir is contraindicated in moderate or severe hepatic impairment.

Paediatric population

The oral solution has been shown to have greater bioavailability than the soft capsule formulation.

Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co-administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. Studies with co-administration of tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those seen in the tipranavir single agent toxicological studies.

The predominant effects of repeated administration of tipranavir across all species toxicologically tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The effects were reversible with termination of treatment. Additional changes included bleeding in rats at high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs.

The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which are equivalent to or even below the human exposure levels at the recommended clinical dose.

In in vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure observed in patients receiving Aptivus with ritonavir. The clinical implications of these findings are not known.

In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At maternal doses producing systemic exposure levels similar to or below those at the recommended clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure.

Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of genetic toxicity in a battery of in vitro and in vivo tests.

Macrogol

Vitamin E polyethylene glycol succinate

Purified water

Propylene glycol

Mono/diglycerides of caprylic/capric acid

Sucralose

Butter mint (flavouring)

Butter toffee (flavouring)

Ascorbic acid

Not applicable.

30 months.

In use storage: 60 days, after first opening of the bottle. It is advisable that the patient writes the date of opening the bottle on the label and/or carton.

Do not store below 15°C. Do not refrigerate or freeze.

Amber glass bottle, with two-piece plastic child-resistant closure (outer shell high density polyethylene (HDPE), inner shell polypropylene resin with a foamed laminated polyethylene liner. Each pack contains 1 bottle of 95 ml oral solution and is supplied with a clear polypropylene 5 ml oral syringe, HDPE syringe tip cap and clear LDPE bottle-syringe adaptor.

Before taking Aptivus it should be checked that the oral solution is clear and whether there are crystals or other particles at the bottom of the bottle. A small amount of crystals may be observed in the bottle, which does not affect the potency or safety of the product. If observed, crystals are typically seen as a paper-thin layer on the bottom when the bottle is stored upright. Dosing by means of the measuring device remains accurate even when crystals are observed. If there is more than a thin layer of crystals at the bottom of the bottle or uncertainty about the amount of crystals observed, the bottle should be returned for a replacement as soon as possible. Until the bottle is exchanged the patient should continue to take the usual doses of the oral solution. Patients should be instructed to observe closely for crystals.

The exact dose should be measured using the supplied measuring syringe and adapter, as follows:

1. Open the bottle by pressing down on the cap and turning in an anti-clockwise direction.

2. Remove the syringe cap covering the tip of the oral syringe (the cap will not be attached if this is the first time the oral syringe has been used) and insert the oral syringe into the adapter located in the neck of the bottle. Make sure the oral syringe is tightly inserted.

3. Turn the bottle upside down and gently withdraw the required amount of Aptivus oral solution.

4. Administer Aptivus oral solution immediately. The maximum volume which can be withdrawn at one time is 5 ml (equivalent to 500 mg tipranavir), which is the maximum single dose for a child with BSA > 1.33 m².

5. After use of the oral syringe, reapply the syringe cap.

No special requirements for disposal.

Boehringer Ingelheim International GmbH

Binger Strasse 173

D-55216 Ingelheim am Rhein

Germany

EU/1/05/315/002

Date of first authorisation: 25 October 2005

Date of latest renewal: 19 June 2015

10 November 2017