Tipranavir

Tipranavir is used for: HIV infection

Oral HIV Infection 500 mg PO q12hr; coadministration with ritonavir 200 mg PO q12hr is required (boosted therapy) Administration with ritonavir essential to achieve correct dosing and adequate blood levels Hepatic Impairment Mild (Child-Pugh class A): Dose adjustment not necessary Moderate-to-severe (Child-Pugh class B or C): Concurrent use contraindicated

HIV Infection Indicated for treatment of HIV-1 infected patients who are treatment-experienced and infected with HIV-1 strains resistant to more than one protease inhibitor; must be used with ritonavir in addition to other antiretrovirals <2 years: Safety and efficacy not established >2 years: 14 mg/kg plus ritonavir 6 mg/kg PO q12hr, OR 375 mg/m² plus ritonavir 150 mg/m² PO q12hr Not to exceed adult dose of 500 mg plus ritonavir 200 mg PO q12hr Administration with ritonavir essential to achieve correct dosing and adequate blood levels

Renal Impairment Dose adjustment not necessary

Should be taken with food.

Hypersensitivity Moderate-severe hepatic impairment (Child-Pugh Class B & C) Drugs that are contraindicated with tipranavir (when coadministered 'boosted' with ritonavir) include alpha1-adrenoreptor agonists (eg, alfuzosin), antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, quinidine), rifampin, voriconazole, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, lovastatin, simvastatin, lurasidone, pimozide, sildenafil (when used for PAH), midazolam, and triazolam

Child-Pugh class A. Chronic hepatitis B or C co-infection. Not to be used in patients with pre-treatment liver enzymes levels >5 times the upper limit of normal. Monitor LFTs before and during treatment; more frequent monitoring is needed in patients with underlying hepatic diseases. Discontinue treatment if liver function worsens; stop permanently in patients with liver enzymes >10 times the upper limit of normal or those who develop signs/symptoms of clinical hepatitis. Patients at increased risk of bleeding or taking antiplatelet drugs or anticoagulants. Monitor cholesterol and triglyceride before and during therapy. Patients with known sulfonamide allergy. Pregnancy, lactation.

Pregnancy Prospective pregnancy data from the APR and an Expanded Access program are not sufficient to adequately assess risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; tipranavir use during pregnancy has been evaluated in a limited number of women as reported by the APR and an Expanded Access program, and available data show no birth defects in 13 first trimester exposures compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP); rate of miscarriage not reported in the APR; methodological limitations of APR include the use of MACDP as the external comparator group; MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation In animal reproduction studies, fetal toxicities were observed with tipranavir at maternally toxic doses with systemic exposures (AUC) less than those in humans at recommended human dose Based on prospective reports to APR and an Expanded Access program for approximately 17 live births following exposure to tipranavir-containing regimens (including 13 live births exposed in the first trimester and 4 live births exposed in the second/third trimester), there were no birth defects reported in live-born infants; tipranavir has been shown to cross placenta Lactation The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breast-feed their infants to avoid risking postnatal transmission of HIV-1 infection; there is no information regarding presence of tipranavir in human milk, effects on breastfed infant, or on milk production; tipranavir is present in rat milk; because of potential for (1) HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV-positive patients), and any possible adverse effects of drug, mothers should not breastfeed if they are receiving drug

May decrease the levels/effects of abacavir, phenytoin, phenobarbitone, delavirdine, didanosine (separate admin by 2 hr), methadone, PPIs and omeprazole, theophylline derivatives, valproic acid, zidovudine. May increase the levels/effects of antifungal agents, benzodiazepines, calcium channel blockers, fluticasone, CYP3A4 substrates (e.g. ciclosporin, mirtazapine, nateglinide, nefazodone, sildenafil, tacrolimus and venlafaxine), digoxin, eplerenone, fentanyl, flecainide, HMG-CoA reductase inhibitors, immunosuppressive agents (e.g. sirolimus, tacrolimus), normeperidine, nefazodone, pimozide, propafenone, TCAs. Serum levels may be reduced by antacids, anticonvulsants, CYP3A4 inducers, nevirapine, rifampin derivatives, tenofovir. Serum levels may be increased by antifungal agents, cimetidine, clarithromycin, enfuvirtide, fusidic acid, protease inhibitors. Increased risk of rash when used with hormonal contraceptives. Potentially Fatal: May increase toxicity (peripheral ischaemia, vasospasm) of ergot derivatives. Concurrent use with midazolam and triazolam is contraindicated due to increased risk of toxicity. May cause malignant arrhythmias when used with cisapride. Increased risk of myopathy/rhabdomyolysis when used with lovastatin and simvastatin. Concurrent use with quinidine, amiodarone or rifampin is contraindicated.

Side effects of Tipranavir : >10% Diarrhea (15%) Rash (3-21%) Hypertriglyceridemia (61%) Increased transaminases (26-32%) 1-10% Abdominal pain (4%) Dyspnea (2%) Epistaxis (4%) Dehydration (2%) Fatigue (6%) Headache (5%) Weight loss (3%) Nausea (5-9%) Pyrexia (6%) Anemia (3%) Vomiting (6%) Myalgia (2%) <1% Dizziness Hepatitis Decreased apetite Flu-like syndrome Hyperbilirubinemia Insomnia Increased lipase

Tipranavir is a non-peptide protease inhibitor that exerts its antiviral activity against HIV-1 by binding to the protease activity site and inhibits the enzymatic activity. In doing so, it prevents cleavage of these polyproteins, resulting in the formation of immature, noninfectious viral particles.