disclose to [2:<2% of adult patients (n=1474) treated with Aptivus/ritonavir 500/200 mg in Phase 2 and 3 clinical trials are listed below by body system: Blood and Lymphatic System Disorders : thrombocytopenia Gastrointestinal Disorders : abdominal distension, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis General Disorders : influenza-like illness, malaise Hepatobiliary Disorders : hepatitis, hepatic failure, hyperbilirubinemia, cytolytic hepatitis, toxic hepatitis, hepatic steatosis Immune System Disorders : hypersensitivity Investigations : hepatic enzymes increased, liver function test abnormal, lipase increased Metabolism and Nutrition Disorders : anorexia, decreased appetite, diabetes mellitus, facial wasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrial toxicity Musculoskeletal and Connective Tissue Disorders : muscle cramp Nervous System Disorders : dizziness, intracranial hemorrhage, somnolence Psychiatric Disorders : sleep disorder Renal and Urinary Disorders : renal insufficiency Skin and Subcutaneous System Disorders : exanthem, lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus Laboratory Abnormalities Treatment-emergent laboratory abnormalities reported at 48 weeks in the controlled clinical trials 1182.12 and 1182.48 in adults are summarized in Table 3 below. Table 3 Treatment-Emergent Laboratory Abnormalities Reported in 2% of Adult Patients (48-week Analyses) Randomized, Controlled Clinical Trials 1182.12 and 1182.48 Percentage of Patients (rate per 100 patient-exposure years) Limit Aptivus/ritonavir (500/200 mg BID) + OBR (n=738) Comparator PI/ritonavir + OBR* (n=724) *Comparator PI/ritonavir: lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100 mg BID Hematology WBC count decrease Grade 3> <2.0 x 10 3 /μL 5.4% (5.6) 4.8% (7.7) Grade 4> <1.0 x 10 3 /μL 0.3% (0.3) 1.1% (1.7) Chemistry Amylase Grade 3> 2.5 x ULN 5.7% (5.9) 6.4% (10.4) Grade 4 >5 x ULN 0.3% (0.3) 0.7% (1.1) ALT Grade 2 >2.5-5 x ULN 14.9% (16.5) 7.5% (12.4) Grade 3 >5-10 x ULN 5.6% (5.7) 1.7% (2.6) Grade 4 >10 x ULN 4.1% (4.1) 0.4% (0.7) AST Grade 2 >2.5-5 x ULN 9.9% (10.5) 8.0% (13.3) Grade 3 >5-10 x ULN 4.5% (4.6) 1.4% (2.2) Grade 4 >10 x ULN 1.6% (1.6) 0.4% (0.6) ALT and/or AST Grade 2-4 >2.5 x ULN 26.0% (31.5) 13.7% (23.8) Cholesterol Grade 2 >300 400 mg/dL 15.6% (17.7) 6.4% (10.5) Grade 3 >400 500 mg/dL 3.3% (3.3) 0.3% (0.4) Grade 4 >500 mg/dL 0.9% (1.0) 0.1% (0.2) Triglycerides Grade 2 400 750 mg/dL 35.9% (49.9) 26.8% (51.0) Grade 3 >750 1200 mg/dL 16.9% (19.4) 8.7% (14.6) Grade 4 >1200 mg/dL 8.0% (8.4) 4.3% (7.0) In controlled clinical trials 1182.12 and 1182.48 extending up to 96 weeks, the proportion of patients who developed Grade 2-4 ALT and/or AST elevations increased from 26% at week 48 to 32.1% at week 96 with Aptivus/ritonavir. The risk of developing transaminase elevations is greater during the first year of therapy. Clinical Trials in Pediatric Patients Aptivus, co-administered with ritonavir, has been studied in a total of 135 HIV-1 infected pediatric patients age 2 through 18 years as combination therapy. 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. One hundred and ten (110) patients were enrolled in a randomized, open-label 48-week clinical trial (Study 1182.14) and 25 patients were enrolled in other clinical studies including Expanded Access and Emergency Use Programs. The adverse reactions profile seen in Study 1182.14 was similar to adults. Pyrexia (6.4%), vomiting (5.5%), cough (5.5%), rash (5.5%), nausea (4.5%), and diarrhea (3.6%) were the most frequently reported adverse reactions (Grade 2-4, all causes) in pediatric patients. Rash was reported more frequently in pediatric patients than in adults. The most common Grade 3-4 laboratory abnormalities were increases in CPK (11%), ALT (6.5%), and amylase (7.5%). Due to previous reports of both fatal and non-fatal intracranial hemorrhage (ICH), an analysis of bleeding events was performed. At 48 weeks of treatment, the frequency of pediatric patients with any bleeding adverse reactions was 7.5%. No drug related serious bleeding adverse reaction was reported. The most frequent bleeding adverse reaction was epistaxis (3.7%). No other bleeding adverse reaction was reported in frequency of >1%. Additional trial follow-up through 100 weeks showed a cumulative 12% frequency of any bleeding adverse reaction. 7 DRUG INTERACTIONS See also Contraindications (4.2) , Warnings and Precautions (5.3) , and Clinical Pharmacology (12.3) . Potential for Aptivus/ritonavir to Affect Other Drugs Aptivus 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/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 [ see Contraindications (4.2) ]. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring [ see Drug Interactions (7) ]. Clinically significant drug-drug interactions of Aptivus 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/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 co-administered with 200 mg of ritonavir twice daily in capsule form. Aptivus oral solution co-administered with ritonavir capsules demonstrated similar effects as Aptivus 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/ritonavir followed by induction of P-gp over time. Thus, 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. An in vitro 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. Potential for Other Drugs to Affect Tipranavir Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of Aptivus/ritonavir and drugs that induce CYP 3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of Aptivus/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations. Co-administration of Aptivus/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/ritonavir 500/200 mg twice daily. Clinically significant drug-drug interactions of Aptivus co-administered with ritonavir are summarized in Table 4 below. Table 4 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction increase, decrease, no change, unable to predict Concomitant Drug Class: Drug name Effect on Concentration of Tipranavir or Concomitant Drug Clinical Comment HIV-1 Antiviral Agents Fusion Inhibitors: Enfuvirtide Tipranavir At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended. Non-Nucleoside Reverse Transcriptase Inhibitors: Etravirine Etravirine Aptivus/ritonavir when coadministered with etravirine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine. Etravirine and Aptivus/ritonavir should not be coadministered. Rilpivirine The use of rilpivirine co-administered with Aptivus/ritonavir has not been studied. Concomitant use of rilpivirine with Aptivus/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of Aptivus/ritonavir. Nucleoside Reverse Transcriptase Inhibitors: Abacavir Abacavir AUC by approximately 40% Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time. Didanosine (EC) Didanosine Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from Aptivus/ritonavir dosing by at least 2 hours. Zidovudine Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered. Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time. Protease Inhibitors (co-administered with 200 mg of ritonavir): Fosamprenavir Lopinavir Saquinavir Amprenavir Lopinavir Saquinavir Combining a protease inhibitor with Aptivus/ritonavir is not recommended. Protease Inhibitors (co-administered with 100 mg of ritonavir): Atazanavir Atazanavir Tipranavir Virus Integrase Strand Transfer Inhibitors: Raltegravir Raltegravir Aptivus/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended. Agents for Opportunistic Infections Antifungals: Fluconazole Itraconazole Ketoconazole Voriconazole Tipranavir, Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended. Itraconazole (not studied) Ketoconazole (not studied) Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended. Voriconazole (not studied) Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction. Antimycobacterials: Clarithromycin Tipranavir, Clarithromycin, 14-hydroxy-clarithromycin metabolite No dose adjustment of Aptivus 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 CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL CR <30 mL/min the dose of clarithromycin should be decreased by 75%. Rifabutin Tipranavir not changed, Rifabutin Desacetyl-rifabutin 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. Further dosage reduction may be necessary. Other Agents Commonly Used Anticonvulsants: Carbamazepine Phenobarbital Phenytoin Tipranavir Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. Aptivus may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly. Valproic Acid Valproic Acid Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking Aptivus concomitantly. Antidepressants: Trazodone Trazodone Concomitant use of trazodone and Aptivus/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as Aptivus/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. Desipramine Combination with Aptivus/ritonavir not studied Desipramine Dosage reduction and concentration monitoring of desipramine is recommended. Selective Serotonin-Reuptake Inhibitors: Combination with Aptivus/ritonavir not studied Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of Aptivus/ritonavir therapy. Fluoxetine Paroxetine Sertraline Fluoxetine Paroxetine Sertraline Anti-HCV agents: Boceprevir Co-administration of Aptivus and boceprevir has not been studied. With concomitant use, changes in exposure were observed both for boceprevir and certain protease inhibitors used for the treatment of HIV-1 infection or either medication. Information is not available regarding tipranavir or boceprevir exposure with concomitant use. It is not recommended to co-administer boceprevir with Aptivus/ritonavir. Telaprevir Co-administration of Aptivus and telaprevir has not been studied. With concomitant use, changes in exposure were observed both for telaprevir and certain protease inhibitors used for the treatment of HIV-1 infection or telaprevir. Information is not available regarding tipranavir or telaprevir exposure with concomitant use. It is not recommended to co-administer telaprevir with Aptivus/ritonavir. Anti-gout: Colchicine Colchicine In patients with renal or hepatic impairment, coadministration of colchicine in patients on Aptivus/ritonavir is contraindicated. In combination with Aptivus/ritonavir, the following dosage adjustments are recommended in patients with normal renal and hepatic function: Treatment of gout flares: Co-administration of colchicine in patients on Aptivus/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: Co-administration of colchicine in patients on Aptivus/ritonavir : If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Co-administration of colchicine in patients on Aptivus/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antipsychotics: Quetiapine Quetiapine Initiation of Aptivus with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking Aptivus with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: Parenterally administered midazolam Midazolam Midazolam is extensively metabolized by CYP 3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, Aptivus should not be given with orally administered midazolam [ see Contraindications (4) ]. If Aptivus is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustments should be considered. Buprenorphine/naloxone Buprenorphine Tipranavir Aptivus/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir C min was decreased approximately 40% with this combination. Dose adjustments cannot be recommended. Calcium Channel Blockers: Diltiazem Felodipine Nicardipine Nisoldipine Verapamil Combination with Aptivus/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP3A and P-gp due to conflicting effect of TPV/ritonavir on CYP3A and P-gp. Diltiazem Felodipine (CYP3A substrate but not P-gp substrate) Nicardipine Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) Verapamil Caution is warranted and clinical monitoring of patients is recommended. Disulfiram/Metronidazole Combination with TPV/ritonavir not studied Aptivus capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole). Endothelin receptor antagonists Bosentan Bosentan Co-administration of bosentan in patients on Aptivus/ritonavir: In patients who have been receiving Aptivus/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of Aptivus/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of Aptivus/ritonavir. After at least 10 days following the initiation of Aptivus/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. HMG-CoA Reductase Inhibitors: Atorvastatin Rosuvastatin Atorvastatin Hydroxy-atorvastatin metabolites Rosuvastatin Avoid co-administration with atorvastatin. Hypoglycemics: Combination with Aptivus/ritonavir not studied Careful glucose monitoring is warranted. Glimepiride Glipizide Glyburide Pioglitazone Glimepiride (CYP 2C9) Glipizide (CYP 2C9) Glyburide (CYP 2C9) Pioglitazone (CYP 2C8 and CYP 3A4) Repaglinide Repaglinide (CYP 2C8 and CYP 3A4) Tolbutamide Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8 substrate is not known. Immunosuppressants: Combination with Aptivus/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended. Cyclosporine Sirolimus Tacrolimus Cyclosporine Sirolimus Tacrolimus Inhaled beta agonist: Salmeterol Salmeterol Concurrent administration of Aptivus/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/Nasal Steroids: Fluticasone 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. Narcotic Analgesics: Combinations with Aptivus/ritonavir not studied 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). Meperidine Meperidine, Normeperidine Methadone Methadone S-Methadone, R-Methadone Dosage of methadone may need to be increased when co-administered with Aptivus and 200 mg of ritonavir. Oral Contraceptives/Estrogens: Ethinyl estradiol Ethinyl estradiol concentrations by 50% Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with Aptivus and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash. Proton Pump Inhibitors: Omeprazole Omeprazole, Tipranavir Dosage of omeprazole may need to be increased when co-administered with Aptivus and ritonavir. PDE-5 Inhibitors: Sildenafil Tadalafil Vardenafil Only the combination of tadalafil with Aptivus/ritonavir has been studied (at doses used for treatment of erectile dysfunction). Co-administration with Aptivus/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Sildenafil (not studied) Tadalafil with first dose Aptivus/ritonavir Tadalafil at Aptivus/ritonavir steady-state Vardenafil (not studied) Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [ see Contraindications ( 4.2 ) ]. The following dose adjustments are recommended for use of tadalafil (Adcirca) with Aptivus/ritonavir: Co-administration of tadalafil (Adcirca) in patients on Aptivus/ritonavir: In patients receiving Aptivus/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of Aptivus/ritonavir in patients on tadalafil (Adcirca): Avoid use of tadalafil (Adcirca) during the initiation of Aptivus/ritonavir. Stop Adcirca at least 24 hours prior to starting Aptivus/ritonavir. After at least one week following the initiation of Aptivus/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Concomitant use of PDE-5 inhibitors with Aptivus/ritonavir should be used with caution and in no case should the starting dose of: sildenafil exceed 25 mg within 48 hours tadalafil exceed 10 mg every 72 hours vardenafil exceed 2.5 mg every 72 hours Use with increased monitoring for adverse events. Warfarin S-Warfarin Frequent INR (international normalized ratio) monitoring upon initiation of Aptivus/ritonavir therapy. 8 USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects, Pregnancy Category C. 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 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 max /AUC 0-24h 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of both the potential for HIV-1 transmission and any possible adverse effects of Aptivus, mothers should be instructed not to breast-feed if they are receiving Aptivus. Pediatric Use The safety, pharmacokinetic profile, and virologic and immunologic responses of Aptivus oral solution and capsules were evaluated in HIV-1 infected pediatric patients age 2 to 18 years [ see Adverse Reactions (6.2) and Clinical Studies (14.2) ]. 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 [ see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ]. The risk-benefit has not been established in pediatric patients> <2 years of age. Geriatric Use Clinical studies of Aptivus/ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than 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. Hepatic Impairment Tipranavir is principally metabolized by the liver. Caution should be exercised when administering Aptivus/ritonavir to patients with mild (Child-Pugh Class A) hepatic impairment because tipranavir concentrations may be increased [ see Clinical Pharmacology (12.3) ]. Aptivus/ritonavir is contraindicated in patients with moderate or severe (Child-Pugh Class B or Child-Pugh Class C) hepatic impairment [ see Contraindications (4.1) ]. 10 OVERDOSAGE There is no known antidote for Aptivus 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. 11 DESCRIPTION Aptivus 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 C 31 H 33 F 3 N 2 O 5 S 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 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 oral solution is available in a strength of 100 mg/mL of tipranavir. Aptivus 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 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. 12 CLINICAL PHARMACOLOGY Mechanism of Action Tipranavir is an antiviral drug [ see Clinical Pharmacology (12.4) ]. Pharmacodynamics ECG Evaluation The effect of Aptivus/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: Aptivus/ritonavir (500/200 mg), Aptivus/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: 10.9 ms) for the supra-therapeutic 750/200 mg dose. Antiviral Activity in vivo The median Inhibitory Quotient (IQ) determined from 264 treatment-experienced adult patients was about 80 (inter-quartile range: 31-226), from the controlled clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral EC 50 value, corrected for protein binding. There was a relationship between the proportion of patients with a 1 log 10 reduction of viral load from baseline at week 48 and their IQ value. Among the 198 patients receiving Aptivus/ritonavir with no new enfuvirtide use (e.g., new enfuvirtide, defined as initiation of enfuvirtide for the first time), the response rate was 23% in those with an IQ value> <80 and 59% in those with an IQ value 80. Among the 66 patients receiving Aptivus/ritonavir with new enfuvirtide, the response rates in patients with an IQ value> <80 versus those with an IQ value 80 were 55% and 71%, respectively. These IQ groups are derived from a select population and are not meant to represent clinical breakpoints. Pharmacokinetics In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of Aptivus with ritonavir is essential [ see Dosage and Administration (2) ]. 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 co-administered with low-dose ritonavir (500/200 mg twice daily) compared to Aptivus 500 mg twice daily without ritonavir. In adults the mean systemic ritonavir concentration when 200 mg of ritonavir was given with 500 mg of Aptivus was similar to the concentrations observed when 100 mg was given with the other protease inhibitors. Figure 1 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. Figure 1 Mean Steady State Tipranavir Plasma Concentrations (95% CI) with Ritonavir Co-administration (tipranavir/ritonavir 500/200 mg BID) 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 tipranavir/ritonavir, at the dose of 500/200 mg, is a P-gp inhibitor after the first dose and induction of P-gp occurs over time. 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 Aptivus 500 mg with 200 mg ritonavir capsules twice daily for greater than 2 weeks and without meal restriction produced the pharmacokinetic parameters for male and female HIV-1 positive patients presented in Table 5. Table 5 Pharmacokinetic Parameters a of tipranavir/ritonavir 500/200 mg for HIV-1 Positive Patients by Gender Parameter Females (n=14) Males (n=106) a Population pharmacokinetic parameters reported as mean standard deviation Cp trough (μM) 41.6 24.3 35.6 16.7 C max (μM) 94.8 22.8 77.6 16.6 T max (h) 2.9 3.0 AUC 0-12h (μM h) 851 309 710 207 CL (L/h) 1.15 1.27 V (L) 7.7 10.2 t 1/2 (h) 5.5 6.0 Effects of Food on Oral A pulling down
dependancy Aptivus trendy
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