Drug: Aptivus
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 C31H33F3N2O5S 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.
Source: http://www.rxlist.com
The following adverse reactions are described, in greater detail, in other sections:
APTIVUS/ritonavir (500/200 mg BID) + OBRc
(n=749; 757.4 patient-exposure years) Comparator PI/ritonavirb + OBR
(n=737; 503.9 patient-exposure years) Blood and Lymphatic Disorders Anemia 3.3% (3.4) 2.3% (3.4) Neutropenia 2.0% (2.0) 1.0% (1.4) Gastrointestinal Disorders Diarrhea 15.0% (16.5) 13.4% (21.6) Nausea 8.5% (9.0) 6.4% (9.7) Vomiting 5.9% (6.0) 4.1% (6.1) Abdominal pain 4.4% (4.5) 3.4% (5.1) Abdominal pain upper 1.5% (1.5) 2.3% (3.4) General Disorders Pyrexia 7.5% (7.7) 5.4% (8.2) Fatigue 5.7% (5.9) 5.6% (8.4) Investigations Weight decreased 3.1% (3.1) 2.2% (3.2) ALT increased 2.0% (2.0) 0.5% (0.8) GGT increased 2.0% (2.0) 0.4% (0.6) Metabolism and Nutrition Disorders Hypertriglyceridemia 3.9% (4.0) 2.0% (3.0) Hyperlipidemia 2.5% (2.6) 0.8% (1.2) Dehydration 2.1% (2.1) 1.1% (1.6) Musculoskeletal and Connective Tissue Disorders Myalgia 2.3% (2.3) 1.8% (2.6) Nervous System Disorders Headache 5.2% (5.3) 4.2% (6.3) Peripheral neuropathy 1.5% (1.5) 2.0% (3.0) Psychiatric Disorders Insomnia 1.7% (1.7) 3.7% (5.5) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 2.1% (2.1) 1.0% (1.4) Skin and Subcutaneous Tissue Disorders Rash 3.1% (3.1) 3.8% (5.7) aExcludes laboratory abnormalities that were Adverse Events
bComparator 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
cOptimized Background Regimen Less Common Adverse Reactions Other adverse reactions reported in < 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 mgBID) + OBR
(n=738) Comparator PI/ritonavir + OBR*
(n=724) Hematology WBC count decrease Grade 3 < 2.0 x 103/μL 5.4% (5.6) 4.8% (7.7) Grade 4 < 1.0 x 103/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) *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 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. Read the Aptivus (tipranavir) Side Effects Center for a complete guide to possible side effectsLearn More »
- Hepatic Impairment and Toxicity [see WARNINGS AND PRECAUTIONS]
- Intracranial Hemorrhage [see WARNINGS AND PRECAUTIONS]
- Rash [see WARNINGS AND PRECAUTIONS]
APTIVUS/ritonavir (500/200 mg BID) + OBRc
(n=749; 757.4 patient-exposure years) Comparator PI/ritonavirb + OBR
(n=737; 503.9 patient-exposure years) Blood and Lymphatic Disorders Anemia 3.3% (3.4) 2.3% (3.4) Neutropenia 2.0% (2.0) 1.0% (1.4) Gastrointestinal Disorders Diarrhea 15.0% (16.5) 13.4% (21.6) Nausea 8.5% (9.0) 6.4% (9.7) Vomiting 5.9% (6.0) 4.1% (6.1) Abdominal pain 4.4% (4.5) 3.4% (5.1) Abdominal pain upper 1.5% (1.5) 2.3% (3.4) General Disorders Pyrexia 7.5% (7.7) 5.4% (8.2) Fatigue 5.7% (5.9) 5.6% (8.4) Investigations Weight decreased 3.1% (3.1) 2.2% (3.2) ALT increased 2.0% (2.0) 0.5% (0.8) GGT increased 2.0% (2.0) 0.4% (0.6) Metabolism and Nutrition Disorders Hypertriglyceridemia 3.9% (4.0) 2.0% (3.0) Hyperlipidemia 2.5% (2.6) 0.8% (1.2) Dehydration 2.1% (2.1) 1.1% (1.6) Musculoskeletal and Connective Tissue Disorders Myalgia 2.3% (2.3) 1.8% (2.6) Nervous System Disorders Headache 5.2% (5.3) 4.2% (6.3) Peripheral neuropathy 1.5% (1.5) 2.0% (3.0) Psychiatric Disorders Insomnia 1.7% (1.7) 3.7% (5.5) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 2.1% (2.1) 1.0% (1.4) Skin and Subcutaneous Tissue Disorders Rash 3.1% (3.1) 3.8% (5.7) aExcludes laboratory abnormalities that were Adverse Events
bComparator 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
cOptimized Background Regimen Less Common Adverse Reactions Other adverse reactions reported in < 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 mgBID) + OBR
(n=738) Comparator PI/ritonavir + OBR*
(n=724) Hematology WBC count decrease Grade 3 < 2.0 x 103/μL 5.4% (5.6) 4.8% (7.7) Grade 4 < 1.0 x 103/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) *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 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. Read the Aptivus (tipranavir) Side Effects Center for a complete guide to possible side effectsLearn More »
Source: http://www.rxlist.com
APTIVUS must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in plasma levels of tipranavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.
- APTIVUS co-administered with ritonavir capsules or solution can be taken with or without meals
- APTIVUS co-administered with ritonavir tablets must only be taken with meals [see CLINICAL PHARMACOLOGY]
Source: http://www.rxlist.com
See also CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY. 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]. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring. 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 Pglycoprotein (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 coadministered 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 steadystate 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
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
↑ Itraconazole (not studied)
↑ Ketoconazole (not studied)
↕ Voriconazole (not studied) Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses > 200 mg/day are not recommended.
Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses ( > 200 mg/day) are not recommended.
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:
↑ 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 coadministration 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 eout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir:
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]. 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 Cmin 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 Pgp 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: Glimepiride
Glipizide
Glyburide
Pioglitazone
Repaglinide
Tolbutamide Combination with APTIVUS/ritonavir not studied ↔ Glimepiride (CYP 2C9)
↔ Glipizide (CYP 2C9)
↔ Glyburide (CYP 2C9)
↕ Pioglitazone (CYP 2C8 and CYP 3A4)
↕ Repaglinide (CYP 2C8 and CYP 3A4)
↔ Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8
substrate is not known. Careful glucose monitoring is warranted. Immunosuppressants: Cyclosporine
Sirolimus
Tacrolimus 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. ↕ Cyclosporine
↕ Sirolimus
↕ Tacrolimus Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended. 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. Coadministration 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: Meperidine Combinations with APTIVUS/ritonavir not
studied
↓ Meperidine, ↑ Normeperidine 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). 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).
↑ Sildenafil (not studied)
↑ Tadalafil with first dose
APTIVUS/ritonavir
↔ Tadalafil at APTIVUS/ritonavir steadystate
↑ Vardenafil (not studied) Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
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:
This monograph has been modified to include the generic and brand name in many instances.
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
↑ Itraconazole (not studied)
↑ Ketoconazole (not studied)
↕ Voriconazole (not studied) Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses > 200 mg/day are not recommended.
Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses ( > 200 mg/day) are not recommended.
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 CLcr 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
- For patients with CLcr < 30 mL/min the dose of clarithromycin should be decreased by 75%.
↑ 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 coadministration 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 eout 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.
- 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.
- Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
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]. 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 Cmin 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 Pgp 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: Glimepiride
Glipizide
Glyburide
Pioglitazone
Repaglinide
Tolbutamide Combination with APTIVUS/ritonavir not studied ↔ Glimepiride (CYP 2C9)
↔ Glipizide (CYP 2C9)
↔ Glyburide (CYP 2C9)
↕ Pioglitazone (CYP 2C8 and CYP 3A4)
↕ Repaglinide (CYP 2C8 and CYP 3A4)
↔ Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8
substrate is not known. Careful glucose monitoring is warranted. Immunosuppressants: Cyclosporine
Sirolimus
Tacrolimus 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. ↕ Cyclosporine
↕ Sirolimus
↕ Tacrolimus Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended. 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. Coadministration 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: Meperidine Combinations with APTIVUS/ritonavir not
studied
↓ Meperidine, ↑ Normeperidine 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). 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).
↑ Sildenafil (not studied)
↑ Tadalafil with first dose
APTIVUS/ritonavir
↔ Tadalafil at APTIVUS/ritonavir steadystate
↑ Vardenafil (not studied) Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
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].
- The following dose adjustments are recommended for use of tadalafil (Adcirca) with 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.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
APTIVUS, 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/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/ritonavir:
- The use of APTIVUS/ritonavir in treatment-naïve patients is not recommended [see WARNINGS AND PRECAUTIONS].
- The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response [see CLINICAL PHARMACOLOGY and Clinical Studies].
- Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir [see CLINICAL PHARMACOLOGY]. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir [see CLINICAL PHARMACOLOGY].
- Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or patients with mild hepatic impairment [see WARNINGS AND PRECAUTIONS].
- Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment [see WARNINGS AND PRECAUTIONS].
- The drug-drug interaction potential of APTIVUS/ritonavir when co-administered with other drugs must be considered prior to and during APTIVUS/ritonavir use [see CONTRAINDICATIONS and DRUG INTERACTIONS].
- Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk for increased bleeding or who are receiving medications known to increase the risk of bleeding [see WARNINGS AND PRECAUTIONS].
- The risk-benefit of APTIVUS/ritonavir has not been established in pediatric patients < 2 years of age.
Source: http://www.rxlist.com
Hepatic Impairment APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see WARNINGS AND PRECAUTIONS]. Drug Interactions Co-administration of APTIVUS/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 [see DRUG INTERACTIONS]. Table 1 : Drugs that are Contraindicated with APTIVUS Co-Administered with Ritonavir
Drug Class Drugs within Class that are Contraindicated with APTIVUS Co-administered with Ritonavir Clinical Comments: Alpha 1-adrenoreceptor antagonist Alfuzosin Potentially increased alfuzosin concentrations can result in hypotension. Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine Potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics. Antimycobacterials Rifampin May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors or other coadministered antiretroviral agents. Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agent Cisapride Potential for cardiac arrhythmias. Herbal products St. John’s wort (hypericum perforatum) May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors. HMG CoA reductase inhibitors Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis. Antipsychotics Pimozide Potential for cardiac arrhythmias. PDE-5 inhibitors Sildenafil (Revatio) [for treatment of pulmonary arterial hypertension] A safe and effective dose has not been established when used with APTIVUS/ritonavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). Sedatives/hypnotics Oral midazolam, triazolam Prolonged or increased sedation or respiratory depression. Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information for a description of ritonavir contraindications. Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.
Drug Class Drugs within Class that are Contraindicated with APTIVUS Co-administered with Ritonavir Clinical Comments: Alpha 1-adrenoreceptor antagonist Alfuzosin Potentially increased alfuzosin concentrations can result in hypotension. Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine Potential for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics. Antimycobacterials Rifampin May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors or other coadministered antiretroviral agents. Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agent Cisapride Potential for cardiac arrhythmias. Herbal products St. John’s wort (hypericum perforatum) May lead to loss of virologic response and possible resistance to APTIVUS or to the class of protease inhibitors. HMG CoA reductase inhibitors Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis. Antipsychotics Pimozide Potential for cardiac arrhythmias. PDE-5 inhibitors Sildenafil (Revatio) [for treatment of pulmonary arterial hypertension] A safe and effective dose has not been established when used with APTIVUS/ritonavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). Sedatives/hypnotics Oral midazolam, triazolam Prolonged or increased sedation or respiratory depression. Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information for a description of ritonavir contraindications. Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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.
Source: http://www.rxlist.com
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 Storage And Handling APTIVUS 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 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-ofuse 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). Storage APTIVUS capsules should be stored in a refrigerator 2°-8°C (36°-46°F) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) and must be used within 60 days after first opening the bottle. APTIVUS oral solution should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Do not refrigerate or freeze. The solution must be used within 60 days after first opening the bottle. Store in a safe place out of the reach of children. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA. Revised: March 2015 Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
Please refer to the ritonavir prescribing information for additional information on precautionary measures. Hepatic Impairment And Toxicity Clinical hepatitis and hepatic decompensation, including some fatalities, were reported with APTIVUS 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/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/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/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/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/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/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/ritonavir 500 mg/200 mg through week 48. Tipranavir is principally metabolized by the liver. Caution should be exercised when administering APTIVUS/ritonavir to patients with mild hepatic impairment (Child-Pugh Class A) because tipranavir concentrations may be increased [see CLINICAL PHARMACOLOGY]. Intracranial Hemorrhage APTIVUS, co-administered with 200 mg of ritonavir, has been associated with reports of both fatal and non-fatal intracranial hemorrhage (ICH). Many of these patients had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal coagulation parameters has been observed in patients in general, or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on APTIVUS. Risk Of Serious Adverse Reactions Due To Drug Interactions Initiation of APTIVUS/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving APTIVUS/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of APTIVUS/ritonavir, respectively. These interactions may lead to:
This monograph has been modified to include the generic and brand name in many instances.
- Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
- Clinically significant adverse reactions from greater exposures of APTIVUS/ritonavir.
- Loss of therapeutic effect of APTIVUS/ritonavir and possible development of resistance.
- Hepatic Impairment and Toxicity
Inform patients that APTIVUS 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/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 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/ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients. APTIVUS should not be given to patients with moderate to severe hepatic impairment. - Intracranial Hemorrhage
Inform patients that APTIVUS co-administered with 200 mg of ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage. Patients should report any unusual or unexplained bleeding to their physician. - Drug Interactions
APTIVUS may interact with some drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medications or herbal products, particularly St. John's wort. - Use of Vitamin E
Advise patients taking APTIVUS oral solution not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL 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. This intake is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU). - Rash
Rash, including flat or raised rashes or sensitivity to the sun, have been reported in approximately 10% of subjects receiving APTIVUS. Some patients who developed rash also had one or more of the following symptoms: joint pain or stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or peeling of the skin. Women taking birth control pills may get a skin rash. Tell patients to discontinue use of APTIVUS and call their physician right away if any of these symptoms develop. - Sulfa Allergy
Tell patients to report any history of sulfonamide allergy to the physician. - Contraceptives
Women receiving estrogen-based hormonal contraceptives should be instructed that additional or alternative contraceptive measures should be used during therapy with APTIVUS/ritonavir. There may be an increased risk of rash when APTIVUS is given with hormonal contraceptives. - Fat Redistribution
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time. - Administration
Inform patients that APTIVUS must be co-administered with ritonavir to ensure its therapeutic effect. Failure to correctly co-administer APTIVUS with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect.- APTIVUS co-administered with ritonavir capsules or solution can be taken with or without meals
- APTIVUS co-administered with ritonavir tablets must only be taken with meals
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. It is not known if APTIVUS can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
This monograph has been modified to include the generic and brand name in many instances.
Source: http://www.rxlist.com
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