Aptivus Information
Aptivus (Tipranavir) indications And Usage
Aptivus (Tipranavir) , co-administered with ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor (PI).
This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of Aptivus (Tipranavir) /ritonavir of 48 weeks duration in treatment-experienced adults and one open-label 48-week study in pediatric patients age 2 to 18 years. The adult studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with Aptivus (Tipranavir) /ritonavir:
There are no study results demonstrating the effect of Aptivus (Tipranavir) /ritonavir on clinical progression of HIV-1.
Aptivus (Tipranavir) dosage Forms And Strengths
Capsules: 250 mg, pink, oblong capsules imprinted with TPV 250
Oral solution: 100 mg/mL, yellow, viscous clear liquid with a buttermint-butter toffee flavor
Aptivus (Tipranavir) contraindications
Co-administration of Aptivus (Tipranavir) /ritonavir with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers are contraindicated (see Table 1). 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. For information regarding clinical recommendations [].
Due to the need for co-administration of Aptivus (Tipranavir) with ritonavir, please refer to the ritonavir prescribing information for a description of ritonavir contraindications.
Aptivus (Tipranavir) warnings And Precautions
Please refer to the ritonavir prescribing information for additional information on precautionary measures.
Clinical hepatitis and hepatic decompensation, including some fatalities, were reported with Aptivus (Tipranavir) co-administered with 200 mg of ritonavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications. A causal relationship to Aptivus (Tipranavir) /ritonavir could not be established. 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, liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue Aptivus (Tipranavir) /ritonavir treatment and seek medical evaluation.
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 (Tipranavir) /ritonavir, and frequently throughout the duration of treatment.
If asymptomatic elevations in AST or ALT greater than 10 times the upper limit of normal occur, Aptivus (Tipranavir) /ritonavir therapy should be discontinued. If asymptomatic elevations in AST or ALT between 5 – 10 times the upper limit of normal and increases in total bilirubin greater than 2.5 times the upper limit of normal occur, Aptivus (Tipranavir) /ritonavir therapy should be discontinued.
Treatment-experienced patients with chronic hepatitis B or hepatitis C co-infection or elevated transaminases are at approximately 2-fold risk for developing Grade 3 or 4 transaminase elevations or hepatic decompensation. In two large, randomized, open-label, controlled clinical trials with an active comparator (1182.12 and 1182.48) of treatment-experienced patients, Grade 3 and 4 increases in hepatic transaminases were observed in 10.3% (10.9/100 PEY) receiving Aptivus (Tipranavir) /ritonavir through week 48. In a study of treatment-naïve patients, 20.3% (21/100 PEY) experienced Grade 3 or 4 hepatic transaminase elevations while receiving Aptivus (Tipranavir) /ritonavir 500 mg/200 mg through week 48.
Tipranavir is principally metabolized by the liver. Caution should be exercised when administering Aptivus (Tipranavir) /ritonavir to patients with mild hepatic impairment (Child-Pugh Class A) because tipranavir concentrations may be increased [].
Aptivus (Tipranavir) /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 and anticoagulants, or who are taking supplemental high doses of vitamin E.
In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding events and death. Co-administration with vitamin E significantly increased these effects []. However, analyses of stored plasma from adult patients treated with Aptivus (Tipranavir) capsules and pediatric patients treated with Aptivus (Tipranavir) oral solution (which contains a vitamin E derivative) showed no effect of Aptivus (Tipranavir) /ritonavir on vitamin K-dependent coagulation factors (Factor II and Factor VII), Factor V, or on prothrombin or activated partial thromboplastin times.
In experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving Aptivus (Tipranavir) /ritonavir.
Aptivus (Tipranavir) adverse Reactions
The following adverse reactions are described, in greater detail, in other sections:
Due to the need for co-administration of Aptivus (Tipranavir) with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Aptivus (Tipranavir) drug Interactions
See also .
Aptivus (Tipranavir) co-administered with ritonavir at the recommended dose 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 Aptivus (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 [].
Clinically significant drug-drug interactions of Aptivus (Tipranavir) co-administered with ritonavir are summarized in Table 4 below.
A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of Aptivus (Tipranavir) /ritonavir capsule administration on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP 3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). This study determined the first-dose and steady-state effects of 500 mg of Aptivus (Tipranavir) co-administered with 200 mg of ritonavir twice daily in capsule form. Aptivus (Tipranavir) oral solution co-administered with ritonavir capsules demonstrated similar effects as Aptivus (Tipranavir) capsules co-administrated with ritonavir.
There was no net effect on CYP 2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP 1A2, but there was moderate induction at steady state. There was modest inhibition of CYP 2C19 at the first dose, but there was marked induction at steady state. Potent inhibition of CYP 2D6 and both hepatic and intestinal CYP 3A4/5 activities were observed after first dose and steady state.
Intestinal and hepatic P-gp activity was assessed by administering oral and intravenous digoxin, respectively. The digoxin results indicate P-gp was inhibited after the first dose of Aptivus (Tipranavir) /ritonavir followed by induction of P-gp over time. Thus, it is difficult to predict the net effect of Aptivus (Tipranavir) 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. An induction study in human hepatocytes showed an increase in UGT1A1 by tipranavir similar to that evoked by rifampin. The clinical consequences of this finding have not been established.
Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of Aptivus (Tipranavir) /ritonavir and drugs that induce CYP 3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of Aptivus (Tipranavir) /ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations. Co-administration of Aptivus (Tipranavir) /ritonavir with drugs that inhibit CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of Aptivus (Tipranavir) /ritonavir 500/200 mg twice daily.
Clinically significant drug-drug interactions of Aptivus (Tipranavir) co-administered with ritonavir are summarized in Table 4 below.
Aptivus (Tipranavir) use In Specific Populations
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 μM•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 C/AUC levels of 30.4 μM/340 μM•h and 8.4 μM/120 μM•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 (Tipranavir) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The safety, pharmacokinetic profile, and virologic and immunologic responses of Aptivus (Tipranavir) oral solution and capsules were evaluated in HIV-1 infected pediatric patients age 2 to 18 years [].
The most frequent adverse reactions (grades 2-4) were similar to those described in adults. However, rash was reported more frequently in pediatric patients than in adults [].
The risk-benefit has not been established in pediatric patients
Aptivus (Tipranavir) overdosage
There is no known antidote for Aptivus (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 provide significant removal of the drug.
Aptivus (Tipranavir) description
Aptivus (Tipranavir) is a protease inhibitor of HIV-1 belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides.
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 CHFNOS and a molecular weight of 602.7. Tipranavir has the following structural formula and is a single stereoisomer with the 1R, 6R configuration.
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.
Aptivus (Tipranavir) 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.
Aptivus (Tipranavir) oral solution is available in a strength of 100 mg/mL of tipranavir. Aptivus (Tipranavir) oral solution is a yellow, viscous clear liquid with a buttermint-butter toffee flavor. The major inactive ingredients in the oral solution are polyethylene glycol 400, vitamin E polyethylene glycol succinate (TPGS), purified water, and propylene glycol. Each milliliter of Aptivus (Tipranavir) oral solution contains 116 IU of vitamin E, and when taken at the recommended maximum dose of 500 mg/200 mg tipranavir/ritonavir BID results in a daily dose of 1160 IU.
Aptivus (Tipranavir) clinical Pharmacology
In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of Aptivus (Tipranavir) with ritonavir is essential []. Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pump and possibly intestinal CYP 3A. In a dose-ranging evaluation in 113 HIV-1 negative male and female volunteers, there was a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir following Aptivus (Tipranavir) co-administered with low-dose ritonavir (500/200 mg twice daily) compared to Aptivus (Tipranavir) 500 mg twice daily without ritonavir. In adults the mean systemic ritonavir concentration when 200 mg of ritonavir was given with 500 mg of Aptivus (Tipranavir) was similar to the concentrations observed when 100 mg was given with the other protease inhibitors.
Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for 30 HIV-1 infected adult patients dosed with 500/200 mg tipranavir/ritonavir for 14 days.
In clinical trials 1182.12 and 1182.48 tipranavir resistance was detected at virologic rebound after an average of 38 weeks of Aptivus (Tipranavir) /ritonavir treatment with a median 14-fold decrease in tipranavir susceptibility. Similarly, reduced tipranavir susceptibility was associated with emergent mutations in pediatric patient isolates.
Regression analyses of baseline and/or on-treatment HIV-1 genotypes from 860 treatment-experienced patients in Phase 2 and 3 trials demonstrated that amino acid substitutions at 16 codons in the HIV-1 protease coding sequence were associated with reduced virologic responses 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.
As-treated analyses were also conducted to assess virologic outcome by the number of primary protease inhibitor substitutions present at baseline. Response rates were reduced if five or more protease inhibitor-associated substitutions were present at baseline and subjects did not receive concomitant new enfuvirtide with Aptivus (Tipranavir) /ritonavir. See Table 9.
The median change from baseline in plasma HIV-1 RNA at weeks 2, 4, 8, 16, 24 and 48 was evaluated by the number of baseline primary protease inhibitor resistance associated substitutions (1-4 or ≥5) in subjects who received Aptivus (Tipranavir) /ritonavir with or without new enfuvirtide. The following observations were made:
Analyses of pediatric clinical trial 1182.14 also demonstrated that response to therapy was influenced by the number of baseline protease inhibitor mutations present.
Aptivus (Tipranavir) nonclinical Toxicology
Long-term carcinogenicity studies in mice and rats have been conducted with tipranavir. Mice were administered 30, 150 or 300 mg/kg/day tipranavir, 150/40 mg/kg/day tipranavir/ritonavir in combination, or 40 mg/kg/day ritonavir. The incidences of benign hepatocellular adenomas and combined adenomas/carcinomas were increased in females of all groups except the low dose of tipranavir. These tumors were also increased in male mice at the high-dose of tipranavir and the tipranavir/ritonavir combination group. Hepatocellular carcinoma incidence was increased in female mice given the high dose of tipranavir and both sexes receiving tipranavir/ritonavir. The combination of tipranavir and ritonavir caused an exposure-related increase in this same tumor type in both sexes. The clinical relevance of the carcinogenic findings in mice is unknown. Systemic exposures in mice (based on AUC or C) at all dose levels tested were below those in humans receiving the recommended dose level. Rats were administered 30, 100 or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ritonavir in combination, or 10 mg/kg/day ritonavir. No drug-related findings in male rats were observed. At the highest dose of tipranavir, an increased incidence of benign follicular cell adenomas of the thyroid gland was observed in female rats. Based on AUC measurements, exposure to tipranavir at this dose level in rats is approximately equivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans, because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction.
Tipranavir showed no evidence of mutagenicity or clastogenicity in a battery of five and tests including the Ames bacterial reverse mutation assay using and , 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 C of 258 μM in females. Based on C levels in these rats, as well as an exposure (AUC) of 1670 μM•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 Aptivus (Tipranavir) /ritonavir BID.
In preclinical studies in rats, tipranavir treatment induced dose-dependent changes in coagulation parameters (increased prothrombin time, increased activated partial thromboplastin time, and a decrease in some vitamin K dependent factors). In some rats, these changes led to bleeding in multiple organs and death. The co-administration of vitamin E in the form of TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) with tipranavir 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. Clinical evaluation of coagulation effects on HIV-1-infected patients demonstrated no tipranavir plus ritonavir effect and no effect of the vitamin E-containing oral solution on coagulation parameters [].
Aptivus (Tipranavir) clinical Studies
The following clinical data is derived from analyses of 48-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 (Tipranavir) /ritonavir on clinical progression of HIV-1.
These studies evaluated treatment response at 48 weeks in a total of 1483 patients receiving either Aptivus (Tipranavir) 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 new enfuvirtide prior to randomization. Randomization was stratified by choice of comparator protease inhibitor and use of new enfuvirtide.
After Week 8, patients in the control group who met the protocol defined criteria of initial lack of virologic response or confirmed virologic failure had the option of discontinuing treatment and switching to Aptivus (Tipranavir) /ritonavir in a separate roll-over study.
Demographics and baseline characteristics were balanced between the Aptivus (Tipranavir) /ritonavir arm and control arm. In both studies combined, the 1483 patients had a median age of 43 years (range 17-80), and were 86.3% male, 75.6% white, 12.9% black, and 0.9% Asian. The median baseline plasma HIV-1 RNA for both treatment groups was 4.8 (range 2.0 to 6.8) log copies/mL and median baseline CD4+ cell count was 162 (range 1 to 1894) cells/mm. Overall, 38.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL, 58.6% had a baseline CD4+ cell count ≤200 cells/mm, and 57.8% had experienced an AIDS defining Class C event at baseline.
Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 10.1% of patients had previously used enfuvirtide. In baseline patient samples (n=454), 97% of the HIV-1 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 48.7%, amprenavir in 26.4%, saquinavir in 21.8% and indinavir in 3.1% of patients. A total of 85.1% were possibly resistant or resistant to the pre-selected comparator protease inhibitors. Approximately 21% of patients used enfuvirtide during the study of which 16.6% in the Aptivus (Tipranavir) /ritonavir arm and 13.2% in the comparator/ritonavir arm represented first time use of enfuvirtide (new enfuvirtide).
Treatment response and efficacy outcomes of randomized treatment through Week 48 of studies 1182.12 and 1182.48 are shown in Table 12.
Through 48 weeks of treatment, the proportion of patients in the Aptivus (Tipranavir) /ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA
Among all randomized and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm in patients receiving Aptivus (Tipranavir) /ritonavir (N=740) versus +4 cells/mm in the comparator PI/ritonavir (N=727) arm.
Patients in the Aptivus (Tipranavir) /ritonavir arm achieved a significantly better virologic outcome when Aptivus (Tipranavir) /ritonavir was combined with enfuvirtide. Among patients with new enfuvirtide use, the proportion of patients in the Aptivus (Tipranavir) /ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA
The pharmacokinetic profile, safety and activity of Aptivus (Tipranavir) /ritonavir was evaluated in a randomized, open-label, multicenter study. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naïve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. The age ranged from 2 through 18 years and patients were stratified by age (2 to
Demographics and baseline characteristics were balanced between the Aptivus (Tipranavir) /ritonavir dose groups. The 110 randomized pediatric patients had a median age of 11.7 years (range 2 to 18), and were 57.2% male, 68.1% white, 30% black, and 1.8% Asian. The median baseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log copies/mL and median baseline CD4+ cell count was 379 (range 2 to 2578) cells/mm. Overall, 37.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL; 28.7% had a baseline CD4+ cell count ≤200 cells/mm, and 48% had experienced a prior AIDS defining Class C event at baseline. Patients had prior exposure to a median of 4 NRTIs, 1 NNRTI, and 2 PIs.
Eighty three (75%) completed the 48 week period while 25% discontinued prematurely. Of the patients who discontinued prematurely, 9 (8%) discontinued due to virologic failure, and 9 (8%) discontinued due to adverse reactions.
At 48 weeks, 40% of patients had viral load
The dose selection for all age groups was based on the following:
The guidance for possible dose reduction for patients who develop intolerance or toxicity and cannot continue with Aptivus (Tipranavir) /ritonavir 14 mg/kg/6 mg/kg (or 375 mg/m/150 mg/m) is based on the following:
Dose reduction is not appropriate for patients whose virus is resistant to more than one protease inhibitor.
When body surface area (BSA) dosing is converted to mg/kg dosing, the Aptivus (Tipranavir) /ritonavir 375 mg/m/150 mg/m twice daily regimen is similar to 14 mg/kg/6 mg/kg and Aptivus (Tipranavir) /ritonavir 290 mg/m/115 mg/m twice daily regimen is similar to 12 mg/kg/5 mg/kg twice daily [].
Aptivus (Tipranavir) how Supplied/storage And Handling
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 (Tipranavir) oral solution is a clear yellow viscous buttermint-butter toffee flavored liquid containing 100 mg tipranavir in each mL. The solution is supplied in a unit-of-use amber glass bottle providing 95 mL of solution with a child resistant closure. A 5 mL plastic oral dispensing syringe is also provided. (NDC 0597-0002-01).
Aptivus (Tipranavir) patient Counseling Information
Array
Patients should be informed that Aptivus (Tipranavir) 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 (Tipranavir) /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 developing hepatotoxicity.
Liver function tests should be performed prior to initiating therapy with Aptivus (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-fold) for developing further liver enzyme elevations or severe liver disease. Caution should be exercised when administering Aptivus (Tipranavir) /ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients. Aptivus (Tipranavir) should not be given to patients with moderate to severe hepatic impairment.
Patients should be informed that Aptivus (Tipranavir) must be co-administered with ritonavir to ensure its therapeutic effect. Failure to correctly co-administer Aptivus (Tipranavir) 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 (Tipranavir) . Patients should be advised to take Aptivus (Tipranavir) and other concomitant antiretroviral therapy every day as prescribed. Aptivus (Tipranavir) , 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 healthcare professional. If a dose of Aptivus (Tipranavir) 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 (Tipranavir) is not a cure for HIV-1 infection and that they may continue to develop opportunistic infections and other complications associated with HIV-1 disease. The long-term effects of Aptivus (Tipranavir) are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with Aptivus (Tipranavir) can reduce the risk of transmitting HIV-1 to others through sexual contact.
Patient information is supplied as a tear-off following the full prescribing information.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
Aptivus (Tipranavir) ® is a registered trademark used under license from Boehringer Ingelheim International GmbH
Copyright 2011 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED
OT2000ND132011 10003515/10
Aptivus (Tipranavir)
Aptivus (Tipranavir)
Aptivus (Tipranavir)
