Clinical Information
Gen. Code and Des.
64398 tipranavir/vitamin E TPGS ORAL SOLUTION 100 MG/ML
GCN and Des.
14234 tipranavir/vitamin E TPGS ORAL SOLUTION 100 MG/ML
Strength
100MG
Dose Form
SOLUTION, ORAL
Product Category
RX Pharmaceuticals
Fine Line Class
850085008510 All Rx Products
DEA Class
NC
OMP Family
AHFS Class
8180808 HIV PROTEASE INHIBITOR ANTIRETROVIRALS
Active Ingredients
10844 tipranavir 174484414
9945 tocophersolan (vitamin E TPGS) 30999065
APTIVUS- tipranavir capsule, liquid filled
APTIVUS- tipranavir solution
Boehringer Ingelheim Pharmaceuticals, Inc.
WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE
Hepatotoxicity:
Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Extra vigilance is warranted in patients with chronic hepatitis or hepatitis co-infection, as these patients have an increased risk of hepatotoxicity
INDICATIONS AND USAGE
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 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-na?ve patients is not recommended [see Warnings and Precautions ].
The use of other active agents with APTIVUS/ritonavir is associated with greater likelihood of treatment response [see Clinical Pharmacology (12.4) and Clinical Studies (14)].
Genotypic or phenotypic testing and/or treatment history should guide the use of APTIVUS/ritonavir [see Clinical Pharmacology (12.4)]. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir [see Clinical Pharmacology (12.4)].
Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis or 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.
There are no study results demonstrating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.
2??DOSAGE AND ADMINISTRATION
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 (12.3) ]
APTIVUS may be administered as either capsules or oral solution to either pediatric or adult patients.
Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing info..
2.1??Adults
The recommended adult dose of APTIVUS is 500 mg (two 250 mg capsules or mL oral solution) co-administered with 200 mg of ritonavir, twice daily.
2.2??Pediatric Patients (age to 18 years)
Healthcare professionals should pay special attention to accurate calculation of the dose of APTIVUS, transcription of the medication order, dispensing info. and dosing instruction to minimize risk for medication errors, overdose, and underdose.
Prescribers should calculate the appropriate dose of APTIVUS for each individual child based on body weight (kg) or body surface area (BSA, m2) and should not exceed the recommended adult dose.
Before prescribing APTIVUS 250 mg capsules, children should be assessed for the ability to swallow capsules. If child is unable to reliably swallow an APTIVUS capsule, the APTIVUS oral solution formulation should be prescribed.
The recommended pediatric dose of APTIVUS is 14 mg/kg with mg/kg ritonavir (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) taken twice daily not to exceed maximum dose of APTIVUS 500 mg co-administered with ritonavir 200 mg twice daily. For children who develop intolerance or toxicity and cannot continue with APTIVUS 14 mg/kg with mg/kg ritonavir, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with mg/kg ritonavir (or APTIVUS 290 mg/m2 co-administered with 115 mg/m2 ritonavir) taken twice daily provided their virus is not resistant to multiple protease inhibitors [see Adverse Reactions , Use in Specific Populations
DOSAGE FORMS AND STRENGTHS
Capsules: 250 mg, pink, oblong capsules imprinted with TPV 250
Oral solution: 100 mg/mL, yellow, viscous clear liquid with buttermint-butter toffee flavor
4??CONTRAINDICATIONS
?Hepatic Impairment
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 info. regarding clinical recommendations [see Drug Interactions ].
Drug Class
Drugs within Class that areContraindicated with APTIVUSCo-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 co-administered 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 info. for description of ritonavir contraindications.
Pregnancy
Teratogenic Effects, Pregnancy Category C.
DESCRIPTION
APTIVUS is 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 molecular formula of C31 H33 F3 N2 O5 and molecular weight of 602.7. Tipranavir has the following structural formula and is single stereoisomer with the 1R, 6R configuration
Drug Interactions
Drug interaction studies were performed with APTIVUS capsules co-administered with ritonavir, and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of APTIVUS with 200 mg ritonavir on the AUC, Cmax and Cmin of tipranavir or the co-administered drug, are summarized in Tables and 8, respectively. For info. regarding clinical recommendations see Drug Interactions .
Co-administered Drug
Co-administered Drug Dose (Schedule)
tipranavir/ritonavir Drug Dose (Schedule)
n
PK
Ratio (90% Confidence Interval) of Tipranavir Pharmacokinetic Parameters with/withoutCo-administered Drug; No Effect 1.00
Cmax
AUC
Cmin
*steady state comparison to historical data (n)? increase, decrease, no change, unable to predict
Antacids (Maalox?)
20 mL (1 dose)
500/200 mg (1 dose)
23
?
0.75 (0.63, 0.88)
0.73 (0.64, 0.84)
-
Atazanavir/ritonavir
300/100 mg QD(9 doses)
500/100 mg BID(34 doses)
13
?
1.08 (0.98, 1.20)
1.20 (1.09, 1.32)
1.75 (1.39, 2.20)
Atorvastatin
10 mg(1 dose)
500/200 mg BID(14 doses)
22
?
0.96 (0.86, 1.07)
1.08 (1.00, 1.15)
1.04 (0.89, 1.22)
Clarithromycin
500 mg BID(25 doses)
500/200 mg BID*
24 (68)
?
1.40 (1.24, 1.47)
1.66 (1.43, 1.73)
2.00 (1.58, 2.47)
Didanosine
400 mg(1 dose)
500/100 mg BID(27 doses)
5
?
1.32 (1.09, 1.60)
1.08 (0.82, 1.42)
0.66 (0.31, 1.43)
Efavirenz
600 mg QD(8 doses)
500/100 mg BID*
21 (89)
?
0.79 (0.69, 0.89)
0.69 (0.57, 0.83)
0.58 (0.36, 0.86)
750/200 mg BID*
25 (100)
?
0.97 (0.85, 1.09)
1.01 (0.85, 1.18)
0.97 (0.69, 1.28)
Ethinyl estradiol /Norethindrone
0.035/1.0 mg(1 dose)
500/100 mg BID(21 doses)
21
?
1.10 (0.98, 1.24)
0.98 (0.88, 1.11)
0.73 (0.59, 0.90)
750/200 mg BID(21 doses)
13
?
1.01 (0.96, 1.06)
0.98 (0.90, 1.07)
0.91 (0.69, 1.20)
Fluconazole
100 mg QD(12 doses)
500/200 mg BID*
20 (68)
?
1.32 (1.18, 1.47)
1.50 (1.29, 1.73)
1.69 (1.33, 2.09)
Loperamide
16 mg(1 dose)
750/200 mg BID(21 doses)
24
?
1.03 (0.92, 1.17)
0.98 (0.86, 1.12)
0.74 (0.62, 0.88)
Rifabutin
150 mg(1 dose)
500/200 mg BID(15 doses)
21
?
0.99 (0.93, 1.07)
1.00 (0.96, 1.04)
1.16 (1.07, 1.27)
Rosuvastatin
10 mg(1 dose)
500/200 mg BID(24 doses)
16
?
1.08 (1.00, 1.17)
1.06 (0.97, 1.15)
0.99 (0.88, 1.11)
Tadalafil
10 mg(1 dose)
500/200 mg BID(17 doses)
17
?
0.90 (0.80, 1.01)
0.85 (0.74, 0.97)
0.81 (0.70, 0.94)
Tenofovir
300 mg(1 dose)
500/100 mg BID
22
?
0.83 (0.74, 0.94)
0.82 (0.75, 0.91)
0.79 (0.70, 0.90)
750/200 mg BID(23 doses)
20
?
0.89 (0.84, 0.96)
0.91 (0.85, 0.97)
0.88 (0.78, 1.00)
Valacyclovir
500 mg(1 dose)
500/200 mg BID(23 doses)
26
?
1.02 (0.95, 1.10)
1.01 (0.96, 1.06)
0.98 (0.93, 1.04)
Zidovudine
300 mg(1 dose)
500/100 mg BID
29
?
0.87 (0.80, 0.94)
0.82 (0.76, 0.89)
0.77 (0.68, 0.87)
750/200 mg BID(23 doses)
