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Brand Name: Aptivus  Audio
Drug Class: Protease Inhibitors

Drug Description
Tipranavir is a non-peptidic protease inhibitor (PI) belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides.[1]

HIV/AIDS-Related Uses
Tipranavir was approved by the FDA on June 22, 2005, for use with ritonavir for combination antiretroviral treatment of HIV infection.[2]

Tipranavir co-administered with ritonavir is indicated for combination treatment of HIV-1 infected patients who are treatment experienced and infected with HIV-1 strains resistant to multiple PIs. Use of other active agents in addition to the tipranavir/ritonavir combination is associated with a greater likelihood of treatment response. Genotypic and phenotypic testing or treatment history should be considered when prescribing tipranavir, as the number of baseline primary PI mutations affects the virologic response to tipranavir.[3]

Because of concerns regarding tipranavir's safety profile, physicians are cautioned to consider its use only in patients for whom other effective regimens are not available.[4]

The use of tipranavir/ritonavir is not recommended in treatment-naïve adults. The risk-benefit of tipranavir/ritonavir has not been established in pediatric patients less than 2 years of age.[5] Pediatric formulations are currently being evaluated in HIV-infected patients ages 2 to 18 years in Phase I, II, and III clinical trials.[6][7]

Dosing Information

Mode of Delivery
Oral.[8]

Dosage Form
Capsules containing tipranavir 250 mg.[9]

Oral Solution containing tipranavir 100mg/mL.[10]

The recommended adult dose of tipranavir is 500 mg (two 250 mg capsules or 5 mL oral soultion) co-administered with ritonavir 200 mg twice daily, taken with or without food.[11]

The recommended pediatric dose of tipranavir is 14mg/kg co-administered with ritonavir 6mg/kg (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) twice daily, not to exceed a maximum dose of tipranavir 500 mg with ritonavir 200 mg twice daily. For pediatric patients who develop intolerance or toxicity, physicians may consider decreasing the dose to tipranavir 12 mg/kg with ritonavir 5mg/kg (or tipranavir 290 mg/m2 co-administered with ritonavir 115 mg/m2) twice daily provided their virus is not resistant to multiple PIs.[12]

Storage
Store capsules in a refrigerator at 2 C to 8 C (36 F to 46 F) prior to opening the bottle. After opening, store at 25 C (77 F); excursions permitted to 15 C to 30 C (59 F to 86 F). Use within 60 days of opening the bottle.[13]

Store oral solution at 25 C (77 F); excursions permitted to 15 C to 30 C (59 F to 86 F). Do not refrigerate or freeze. Use within 60 days of opening the bottle.[14]

Pharmacology
Tipranavir is a non-peptidic PI that inhibits processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. It demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M, non-clade B isolates. When used with other antiretrovirals in vitro, tipranavir was shown to be additive to antagonistic with other PIs and generally additive with non-nucleoside reverse transcriptase inhibitors and nucleoside reverse transcriptase inhibitors. Tipranavir was synergistic with the fusion inhibitor enfuvirtide.[15]

Absorption of tipranavir in humans is limited, although no absolute quantification of absorption is available.[16] To achieve effective plasma concentrations and a twice-daily dosing regimen, tipranavir must be co-administered with 200 mg of ritonavir. In a dose-ranging evaluation in 113 HIV-uninfected male and female volunteers, there was a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir after co-administration with ritonavir twice daily as compared with administration of twice-daily tipranavir alone.[17] Tipranavir is more than 99.9% bound to plasma proteins. It is not known whether tipranavir is distributed into human cerebrospinal fluid or semen.[18]

Tipranavir is in FDA Pregnancy Category C. No adequate or well-controlled studies of tipranavir have been done in pregnant women. In laboratory animal studies, no teratogenicity was detected in pregnant rats and rabbits at exposure levels approximately 1.1-fold and 0.1-fold human exposure. Fetal toxicity was observed in rats at exposure levels approximately 0.8-fold normal human exposure at the recommended dose. Tipranavir should be used during pregnancy only when the potential benefit justifies the potential risk to the fetus. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to antiretroviral agents. Physicians may register patients by calling 1-800-258-4263 or online at http://www.APRegistry.com. Because of both the potential for HIV transmission and possible side effects of tipranavir, mothers should be instructed not to breastfeed if they are receiving tipranavir.[19]

In vitro metabolism studies with human liver microsomes indicate that cytochrome P (CYP) 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. The oral clearance of tipranavir decreased after the addition of ritonavir, which may represent diminished first-pass clearance of the drug at the gastrointestinal tract as well as the liver. Tipranavir metabolism in the presence of 200 mg ritonavir is minimal. Administration of 14-C tipranavir to patients receiving tipranavir/ritonavir 500/200 mg dosed to steady-state showed that unchanged tipranavir accounted to 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, all at trace levels.[20] Administration of 14-C tipranavir to patients receiving tipranavir/ritonavir 500/200 mg dosed to steady-state showed that 82.3% of radioactivity was excreted in feces, while only 4.4% of the radioactive dose administered was recovered in urine.[21]

In two Phase III studies, multiple PI-resistant HIV-1 isolates from 59 highly treatment-experienced patients who received tipranavir/ritonavir and experienced virologic rebound developed amino acid substitutions associated with resistance to tipranavir. The most common amino acid substitutions that occurred in greater than 20% of virologic failure isolates were L33V/I/F, V82T, and I84V. Tipranavir resistance was detected at virologic rebound after an average of 38 weeks of tipranavir/ritonavir treatment with a median 14-fold decrease in tipranavir susceptibility. Cross resistance among PIs has been observed. Tipranavir-resistant viruses that emerged in vitro had decreased susceptibility to the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, and ritonavir but remained sensitive to saquinavir.[22]

Genotypic or phenotypic analysis of baseline virus may help determine tipranavir susceptibility before initiating treatment. Regression analyses of baseline or on-treatment HIV-1 genotypes from 860 highly treatment-experienced patients in Phase II and III studies demonstrated that mutations at the following 16 amino acid codons were associated with reduced virologic response at 24 weeks and/or reduced tipranavir susceptibility: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, or I84V. Analyses of virologic outcome by number of primary PI mutations present at baseline showed reduced response rates if five or more PI-associated mutations were present at baseline and participants did not receive enfuvirtide concomitantly with tipranavir with ritonavir.[23]

Adverse Events/Toxicity
Tipranavir, coadministered with ritonavir, has been associated with reports of both fatal and nonfatal intracranial hemorrhage. This combination has also been associated with clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in individuals with chronic hepatitis B or hepatitis C virus co-infection, as these individuals have an increased risk of hepatotoxicity. Symptoms of hepatitis include fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, acholic stools, liver tenderness, or hepatomegaly.[24]

The most frequent adverse effects of tipranavir are diarrhea, nausea, pyrexia, fatigue, headache, abdominal pain, and vomiting. (Because of the requirement for co-administration of ritonavir with tipranavir, refer to ritonavir prescribing information for ritonavir-associated adverse reactions) The 48-Week Kaplan-Meier rates of adverse reactions leading to discontinuation were 13.3% for tipranavir/ritonavir-treated patients and 10.8% for the comparator arm patients.[25]

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving PI therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made, and a causal relationship between PI therapy and these events has not been established.[26]

Mild to moderate rashes, including urticarial rash, maculopapular rash, and possible photosensitivity, have been reported in people receiving tipranavir/ritonavir. In controlled adult clinical trials, rash was observed in 10% of female participants and 8% of male participants receiving tipranavir/ritonavir through 48 weeks of treatment. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving tipranavir/ritonavir. In a pediatric clinical trial, the frequency of rash through 48 weeks of treatment was 21%. Overall, most of the pediatric patients had mild rash and 5% had moderate rash. Overall, 3% of pediatric patients interrupted tipranavir treatment due to rash and the discontinuation rate for rash in pediatric patients was 0.9%. If severe rash develops, treatment should be discontinued.[27]

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been observed in patients with hemophilia type A and B treated with PIs. In some patients, additional Factor VIII was required. In greater than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.[28]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tipranavir. During the initial phase of combination antiretroviral treatment, a patient whose immune system improves may develop an inflammatory response to indolent or residual opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus infections, Pneumocystis jirovecii pneumonia, or tuberculosis. Symptoms of immune reconstitution syndrome necessitate further evaluation and treatment.[29]

Redistribution of body fat, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy.[30]

Treatment with tipranavir/ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed prior to initiation of tipranavir and ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate.[31]

Tipranavir should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety.[32]

The adverse reactions profile seen in pediatric Study 1182.14 was similar to adults. Pyrexia, vomiting, cough, rash, nausea, and diarrhea were the most frequently reported adverse reactions. Rash was reported more frequently in pediatric patients than in adults. 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.[33]

Drug And Food Interactions
Tipranavir coadministered with ritonavir may be taken with or without food. Antacids reduce the absorption of tipranavir, requiring timing adjustments of antacid use. When tipranavir co-administered with ritonavir was given with 20 mL of aluminum and magnesium-based liquid antacid, tipranavir concentration under the concentration-time curve (AUC), peak plasma concentrations (Cmax), and serum concentration were reduced. Consideration should be given to separating tipranavir/ritonavir dosing from antacid administration to prevent reduced absorption of tipranavir.[34]

Tipranavir co-administered with ritonavir at the recommended dosage is a net inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by this enzyme. Co-administration of tipranavir/ritonavir with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious or life-threatening events is contraindicated.[35]

Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, tipranavir should not be given with orally administered midazolam. If tipranavir/ritonavir is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised, and dosage adjustment should be considered.[36]

Dose adjustments for abacavir, enteric-coated didanosine, or zidovudine may be necessary if these antiretrovirals are administered with tipranavir/ritonavir. Concurrent use of abacavir and tipranavir/ritonavir causes abacavir's AUC to decrease by about 40%. Clinical relevance of this reduction in abacavir AUC is not established, and dose adjustment of abacavir cannot be recommended at this time. Concurrent use of didanosine and tipranavir/ritonavir causes serum concentrations of didanosine to decrease. Clinical relevance of this reduction in didanosine AUC is not established. For optimal absorption, didanosine should be separated from tipranavir/ritonavir dosing by at least 2 hours. Concurrent use of zidovudine and tipranavir/ritonavir causes zidovudine's AUC to decrease by about 35%. Clinical relevance of this reduction in AUC is not established, and dose adjustment of zidovudine cannot be recommended at this time.[37]

A decrease in serum concentrations of amprenavir, lopinavir, or saquinavir is observed when any of these drugs are administered with tipranavir/ritonavir; combining any of these other PIs with tipranavir/ritonavir is not recommended. No formal drug interaction data are currently available for the concomitant use of tipranavir/ritonavir with PIs other than amprenavir, lopinavir, or saquinavir.[38]

Fluconazole increases tipranavir concentrations when fluconazole is administered concurrently with tipranavir/ritonavir, but dose adjustments are not needed. High doses of azoles (e.g., fluconazole, itraconazole, ketoconazole, voriconazole) above 200 mg/day are not recommended for patients taking tipranavir/ritonavir. Because of the multiple enzymes involved in voriconazole metabolism, it is difficult to predict the drug-drug interactions between voriconazole and tipranavir/ritonavir.[39]

No dose adjustment of clarithromycin is necessary when clarithromycin is administered concurrently with tipranavir/ritonavir in patients with normal renal function. However, for patients with renal impairment, dosage adjustments should be made. For patients with a creatinine clearance (CLCR) of 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%; for patients with CLCR of less than 30 mL/min, the dose of clarithromycin should be reduced by 75%. In a single-dose study of rifabutin with tipranavir/ritonavir, rifabutin and desacetyl-rifabutin serum concentration levels increased. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving these drugs concurrently is warranted; further dosage reduction may be necessary.[40]

Concomitant use of trazodone and tipranavir/ritonavir may increase plasma concentrations of trazodone, leading to nausea, dizziness, hypotension, and syncope. A lower dose of trazodone should be considered in patients who require this combination of drugs. Dosage reduction and concentration monitoring of desipramine is recommended.[41]

Tipranavir/ritonavir with selective serotonin reuptake inhibitors (SSRIs) fluoxetine, paroxetine, or sertraline should be taken concomitantly with caution. Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of tipranavir/ritonavir therapy.[42]

Plasma concentrations of calcium channel blockers (e.g., diltiazem, felodipine, nifedipine, nicardipine, nisoldipine, verapamil) may increase when given concurrently with tipranavir/ritonavir. Caution is warranted and clinical monitoring of patients is recommended.[43]

Tipranavir capsules contain alcohol that can produce disulfiram-like reactions when coadministered with disulfiram or other drugs which produce this reaction (e.g., metronidazole). This combination should be prescribed with caution.[44]

The HMG-CoA reductase inhibitors atorvastatin and rosuvastatin should be administered with careful monitoring if being given concurrently with tipranavir/ritonavir. Physicians should consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin.[45]

Careful glucose monitoring is warranted when tipranavir/ritonavir is administered concurrently with hypoglycemics (e.g., glimepiride, glipizide, glyburide, pioglitazone, repaglinide, tolbutamide).[46]

More frequent concentration monitoring of immunosuppressants (e.g., cyclosporine, sirolimus, tacrolimus) is warranted until blood levels of the immunosuppressant have been stablilized, if these drugs are given concurrently with tipranavir/ritonavir.[47]

Concomitant use of fluticasone propionate and tipranavir with ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-adminstration of these drugs is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.[48]

Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine, which has both analgesic and CNS stimulant activity (e.g., seizures). Dosage of methadone may need to be increased when it is co-administered with tipranavir/ritonavir. Methadone serum concentrations have decreased in the presence of tipranavir/ritonavir.[49]

Alternative methods of nonhormonal contraception should be considered for women taking estrogen-based oral contraceptives concurrently with tipranavir/ritonavir, as ethinyl estradiol concentrations decrease by 50% when these contraceptives are taken with tipranavir and ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash.[50]

Concomitant administration of tipranavir/ritonavir with PDE-5 inhibitors, including sildenafil, vardenafil, and tadalafil, should be done with caution. PDE-5 inhibitor dosing should not exceed the doses as indicated by the manufacturer.[51]

The drug-drug interactions between warfarin and tipranavir/ritonavir cannot be predicted because of the conflicting effect of tipranavir and ritonavir on CYP2C9. Frequent monitoring upon initiation of tipranavir/ritonavir therapy is recommended.[52]

The dosage of omeprazole may need to be increased when co-administered with tipranavir/ritonavir.[53]

Patients taking tipranavir oral solution should be advised not to take supplemental vitamin E at levels greater than that of a standard multivitamin as tipranavir oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake.[54]

Contraindications
Tipranavir is contraindicated in individuals with known hypersensitivity to any of the ingredients in this product. It is also contraindicated in individuals with moderate to severe (Child-Pugh Class B and C, respectively) hepatic insufficiency.[55]

Co-administration of tipranavir/ritonavir with drugs that are highly dependent on CYP3A for clearance or are potent CYP3A inducers are contraindicated. These drugs include amiodarone, bepridil, flecainide, propafenone, quinidine, astemizole, terfenadine, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonamine, cisapride, St. John's wort, lovastatin, simvastatin, pimozide, triazolam, and oral midazolam.[56]

Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Tipranavir.

Chemistry

CAS Name
2-Pyridinesulfonamide, N-(3-((1R)-1-((6R)-, 6-dihydro-4-hydroxy-2-oxo- 6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl) propyl)phenyl)-5-(trifluoromethyl)-[57]

CAS Number
174484-41-4[58]

Molecular Formula
C31-H33-F3-N2-O5-S[59]

Elemental Composition
C 61.78%, H 5.52%, F 9.46%, N 4.65%, O 13.27%, S 5.32%[60]

Molecular Weight
602.7[61]

Physical Description
Tipranavir 250 mg capsules are pink, oblong soft gelatin capsules imprinted in black with "TPV 250."[62]

Tipranavir oral solution is a clear yellow viscous buttermint-butter toffee flavored liquid.[63]

Solubility
Freely soluble in dehydrated alcohol and propylene glycol; insoluble in aqueous buffer at pH 7.5.[64]

Other Names
TPV[65]

Further Reading
Aptivus Capsules Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site.

FDA Antiviral Drugs Advisory Committee: Tipranavir Slide Set; May 19, 2005.

PMID/16370934 Best B, Haubrich R. Tipranavir: a protease inhibitor for multi-drug resistant HIV-1. Expert Opin Investig Drugs. 2006 Jan;15(1):59-70.

PMID/16432264 Boffito M, Maitland D, Pozniak A. Practical perspectives on the use of tipranavir in combination with other medications: lessons learned from pharmacokinetic studies. J Clin Pharmacol. 2006 Feb;46(2):130-9.

PMID/16788094 Dong BJ, Cocohoba JM. Tipranavir: A Protease Inhibitor for HIV Salvage Therapy (CE) (July/August). Ann Pharmacother. 2006 Jun 20; [Epub ahead of print]

PMID/17263650 Gathe JC Jr, Pierone G, Piliero P, Arasteh K, Rubio R, Lalonde RG, Cooper D, Lazzarin A, Kohlbrenner VM, Dohnanyi C, Sabo J, Mayers D. Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients. AIDS Res Hum Retroviruses. 2007 Feb;23(2):216-23.

PMID/17479503 Hoffman CJ, Gallant JE. When and how to use tipranavir and darunavir. AIDS Read. 2007 Apr;17(4):194-8, 201.

PMID/16802849 King JR, Acosta EP. Tipranavir: a novel nonpeptidic protease inhibitor of HIV. Clin Pharmacokinet. 2006;45(7):665-82.

PMID/18158073 Luna B, Townsend MU. Tipranavir: the first nonpeptidic protease inhibitor for the treatment of protease resistance. Clin Ther. 2007 Nov;29(11):2309-18.

PMID/18158073 Orman JS, Perry CM. Tipranavir: A Review of its Use in the Management of HIV Infection. Drugs. 2008;68(10):1435-63. PMID: 18578560

PMID/17712762 Temesgen Z, Feinberg J. Tipranavir: a new option for the treatment of drug-resistant HIV infection. Clin Infect Dis. 2007 Sep 15;45(6):761-9.

Manufacturer Information
Tipranavir
  Boehringer Ingelheim Pharmaceuticals Inc
  900 Ridgebury Rd / PO Box 368
  Ridgefield,  CT  06877-0368
  (800) 542-6257
    

Aptivus
  Boehringer Ingelheim Pharmaceuticals Inc
  900 Ridgebury Rd / PO Box 368
  Ridgefield,  CT  06877-0368
  (800) 542-6257
    

References
[1] FDA - Aptivus Prescribing Information, June, 2008, p. 12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[2] FDA - Antiretroviral Drugs Used In the Treatment of HIV Infection. Available at: http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118915.htm. Accessed 04/28/09.
[3] FDA - Aptivus Prescribing Information, June, 2008, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[4] FDA - Antiviral Drugs Advisory Committee, May 19, 2005; Tipranavir Slide Set. Available at: http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4139-Web-Slide-Index.htm. Accessed 04/28/09.
[5] FDA - Aptivus Prescribing Information, June, 2008, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[6] ClinicalTrials.gov - Pharmacokinetics and Safety Study of Tipranavir in Combination With Low Dose Ritonavir in HIV-Infected Children. Available at: http://www.clinicaltrials.gov/ct/show/NCT00076999. Accessed 04/28/09.
[7] ClinicalTrials.gov - Emergency Use Program for HTE HIV+ Patients Who Need Tipranavir Treatment. Available at: http://www.clinicaltrials.gov/ct/show/NCT00062660. Accessed 04/28/09.
[8] FDA - Aptivus Prescribing Information, June, 2008, p. 4. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[9] FDA - Aptivus Prescribing Information, June, 2008, p. 4. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[10] FDA - Aptivus Prescribing Information, June, 2008, p. 4. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[11] FDA - Aptivus Prescribing Information, June, 2008, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[12] FDA - What's New at FDA in HIV/AIDS Update - New pediatric dosing for Aptivus, patients 2-18 years, new oral solution, and info on coadministration with midazolam [press release], June 23, 2008. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm121683.htm. Accessed: 04/28/09.
[13] FDA - Aptivus Prescribing Information, June, 2008, p. 24. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[14] FDA - Aptivus Prescribing Information, June, 2008, p. 24. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[15] FDA - Aptivus Prescribing Information, June, 2008, pp. 19-0. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[16] FDA - Aptivus Prescribing Information, June, 2008, p. 13. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[17] FDA - Aptivus Prescribing Information, June, 2008, p. 13. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[18] FDA - Aptivus Prescribing Information, June, 2008, p. 14. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[19] FDA - Aptivus Prescribing Information, June, 2008, pp. 11-2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[20] FDA - Aptivus Prescribing Information, June, 2008, p. 14. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[21] FDA - Aptivus Prescribing Information, June, 2008, p. 14. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[22] FDA - Aptivus Prescribing Information, June, 2008, p. 20. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[23] FDA - Aptivus Prescribing Information, June, 2008, p. 20. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[24] FDA - Aptivus Prescribing Information, June, 2008, p. 24. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[25] FDA - Aptivus Prescribing Information, June, 2008, p. 6. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[26] FDA - Aptivus Prescribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[27] FDA - Aptivus Prescribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[28] FDA - Aptivus Presscribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[29] FDA - Aptivus Prescribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[30] FDA - Aptivus Prescribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[31] FDA - Aptivus Prescribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[32] FDA - Aptivus Prescribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[33] FDA - Aptivus Prescribing Information, June, 2008, p. 5. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[34] FDA - Aptivus Prescribing Information, June, 2008, pp. 14,17. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[35] FDA - Aptivus Prescribing Information, June, 2008, pp. 4,8. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[36] FDA - HIV/AIDS Update - New pediatric dosing for Aptivus, patients 2-18 years, new oral solution, and info on coadministration with midazolam [press release], June 23, 2008. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm121683.htm. Accessed: 04/28/09.
[37] FDA - Aptivus Prescribing Information, June, 2008, p. 8. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[38] FDA - Aptivus Prescribing Information, June, 2008, p. 9. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[39] FDA - Aptivus Prescribing Information, June, 2008, p. 9. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[40] FDA - Aptivus Prescribing Information, June, 2008, p. 9. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[41] FDA - Aptivus Prescribing Information, June, 2008, pp. 9-10. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[42] FDA - Aptivus Prescribing Information, June, 2008, p. 10. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[43] FDA - Aptivus Prescribing Information, June, 2008, p. 10. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[44] FDA - Aptivus Prescribing Information, June, 2008, p. 10. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[45] FDA - Aptivus Prescribing Information, June, 2008, p. 10. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[46] FDA - Aptivus Prescribing Information, June, 2008, p. 10. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[47] FDA - Aptivus Prescribing Information, June, 2008, pp. 10-1. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[48] FDA - Aptivus Prescribing Information, June, 2008, p. 11. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[49] FDA - Aptivus Prescribing Information, June, 2008, p. 11. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 07/02/08.
[50] FDA - Aptivus Prescribing Information, June, 2008, p. 11. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[51] FDA - Aptivus Prescribing Information, June, 2008, p. 11. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[52] FDA - Aptivus Prescribing Information, June, 2008, pp. 10-1. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[53] FDA - Aptivus Prescribing Information, June, 2008, p. 11. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[54] FDA - HIV/AIDS Update - New pediatric dosing for Aptivus, patients 2-18 years, new oral solution, and info on co-administration with midazolam [press release], June 23, 2008. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm121683.htm. Accessed: 04/28/09.
[55] FDA - Aptivus Prescribing Information, June, 2008, p. 4. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[56] FDA - Aptivus Prescribing Information, June, 2008, p. 4. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[57] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 04/28/09.
[58] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 04/28/09.
[59] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 04/28/09.
[60] Calculation. -
[61] FDA - Aptivus Capsules Prescribing Information, June, 2008, p. 12. Available at: http://www.fda.gov/cder/foi/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[62] FDA - Aptivus Prescribing Information, June, 2008, p. 24. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[63] FDA - Aptivus Capsules Prescribing Information, June, 2008, p. 24. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[64] FDA - Aptivus Capsules Prescribing Information, June, 2008, p. 12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021814s005,022292lbl.pdf. Accessed 04/28/09.
[65] Drugs - 2005;65(12):1669-77
Updated May 21, 2009