|
APTIVUS(tipranavir) capsules
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use APTIVUS safely and effectively. See full prescribing information for APTIVUS.
APTIVUS® (tipranavir) capsules
APTIVUS® (tipranavir) oral solution
Initial U.S. Approval: 2005
WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE
See full prescribing information for complete boxed warning.
-
Clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection. (5.1)
-
Fatal and non-fatal intracranial hemorrhage (5.2)
RECENT MAJOR CHANGES
|
Warnings and Precautions |
|
|
Risk of Serious Adverse Reactions Due to Drug Interactions (5.3) |
3/2015 |
INDICATIONS AND USAGE
APTIVUS, a protease inhibitor, 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 (1)
-
Do not use APTIVUS/ritonavir in treatment-naïve patients (1)
DOSAGE AND ADMINISTRATION
-
Adults: 500 mg APTIVUS, co-administered with 200 mg ritonavir, twice daily (2.1)
-
Pediatric patients (age 2 to 18 years): Dosing is based on body weight or body surface area not to exceed adult dose (2.2)
-
APTIVUS taken with ritonavir capsules or solution can be taken with or without meals (2)
-
APTIVUS taken with ritonavir tablets must be taken with meals (2)
-
Store unopened bottles of APTIVUS capsules in the refrigerator (16)
-
Do not freeze or refrigerate APTIVUS oral solution (16)
DOSAGE FORMS AND STRENGTHS
Capsules: 250 mg (3)
Oral solution: 100 mg/mL (3)
CONTRAINDICATIONS
-
Patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment (4.1, 5.1)
-
Use with drugs highly dependent on CYP 3A for clearance or are potent CYP 3A inducers (4.2, 5.3, 7)
WARNINGS AND PRECAUTIONS
-
Hepatic Impairment: Discontinue for signs and symptoms of clinical hepatitis or asymptomatic increases in ALT/AST >10 times ULN or asymptomatic increases in ALT/AST 5-10 times ULN with concomitant increases in total bilirubin. Monitor liver function tests prior to therapy and frequently thereafter. (5.1)
-
Intracranial Hemorrhage/Platelet Aggregation and Coagulation: Use with caution in patients at risk for increased bleeding or who are receiving medications that increase the risk of bleeding (5.2, 5.4)
-
The concomitant use of APTIVUS/ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.3,7.2)
-
Rash: Discontinue and initiate appropriate treatment if severe skin reaction occurs or is suspected. (5.6) Use with caution in patients with a known sulfonamide allergy. (5.7)
-
Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.8), immune reconstitution syndrome (5.9), redistribution/accumulation of body fat (5.10), and elevated lipids. (5.11) Monitor cholesterol and triglycerides prior to therapy and periodically thereafter.
-
Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required (5.12)
ADVERSE REACTIONS
-
In adults the most frequent adverse reactions (incidence >4%) were diarrhea, nausea, pyrexia, vomiting, fatigue, headache, and abdominal pain (6.1)
-
In pediatric patients (age 2 to 18 years) the most frequent adverse reactions were generally similar to those seen in adults. However, rash was more frequent in pediatric patients than in adults. (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Co-administration of APTIVUS can alter the concentrations of other drugs and other drugs may alter the concentration of tipranavir. The potential for drug-drug interactions must be considered prior to and during therapy. (4.2, 5.3, 7)
USE IN SPECIFIC POPULATIONS
The risk-benefit has not been established in pediatric patients <2 years of age (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 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 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 (5.1)].
-
The use of other active agents with APTIVUS/ritonavir is associated with a 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 B or C co-infection or patients with mild hepatic impairment [see Warnings and Precautions (5.1)].
-
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 (5.1)].
-
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 (4.2) and Drug Interactions (7)].
-
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 (5.4)].
-
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 information.
2.1 Adults
The recommended adult dose of APTIVUS is 500 mg (two 250 mg capsules or 5 mL oral solution) co-administered with 200 mg of ritonavir, twice daily.
2.2 Pediatric Patients (age 2 to 18 years)
Healthcare professionals should pay special attention to accurate calculation of the dose of APTIVUS, transcription of the medication order, dispensing information 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 a 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 6 mg/kg ritonavir (or 375 mg/m2 co-administered with ritonavir 150 mg/m2) taken twice daily not to exceed a 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 6 mg/kg ritonavir, physicians may consider decreasing the dose to APTIVUS 12 mg/kg with 5 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 (6.2), Use in Specific Populations (8.4), and Clinical Studies (14.2)].
Body surface area can be calculated as follows:
3 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
4 CONTRAINDICATIONS
4.1 Hepatic Impairment
APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Warnings and Precautions (5.1)].
4.2 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 (7.2)].
Due to the need for co-administration of APTIVUS with ritonavir, please refer to the ritonavir prescribing information for a description of ritonavir contraindications.
5 WARNINGS AND PRECAUTIONS
Please refer to the ritonavir prescribing information for additional information on precautionary measures.
5.1 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 eva luation.
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 (12.3)].
5.2 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.
5.3 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:
-
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.
See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during APTIVUS/ritonavir therapy; review concomitant medications during APTIVUS/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].
5.4 Effects on Platelet Aggregation and Coagulation
APTIVUS/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who are taking supplemental high doses of vitamin E.
In rats, tipranavir treatment alone induced dose-dependent changes in coagulation parameters, bleeding events and death. Co-administration with vitamin E significantly increased these effects [see Nonclinical Toxicology (13.2)]. However, analyses of stored plasma from adult patients treated with APTIVUS capsules and pediatric patients treated with APTIVUS oral solution (which contains a vitamin E derivative) showed no effect of APTIVUS/ritonavir on vitamin K-dependent coagulation factors (Factor II and Factor VII), Factor V, or on prothrombin or activated partial thromboplastin times.
In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir.
5.5 Vitamin E Intake
Patients taking APTIVUS oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin as APTIVUS oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).
5.6 Rash
Rash, including urticarial rash, maculopapular rash, and possible photosensitivity, has been reported in subjects receiving APTIVUS/ritonavir. In some cases rash was accompanied by joint pain or stiffness, throat tightness, or generalized pruritus. In controlled adult clinical trials, rash (all grades, all causality) was observed in 10% of females and in 8% of males receiving APTIVUS/ritonavir through 48 weeks of treatment. The median time to onset of rash was 53 days and the median duration of rash was 22 days. The discontinuation rate for rash in clinical trials was 0.5%. In an uncontrolled compassionate use program (n=3920), cases of rash, some of which were severe, accompanied by myalgia, fever, erythema, desquamation, and mucosal erosions were reported. In the pediatric clinical trial, the frequency of rash (all grades, all causality) through 48 weeks of treatment was 21%. Overall, most of the pediatric patients had mild rash and 5 (5%) had moderate rash. Overall 3% of pediatric patients interrupted APTIVUS treatment due to rash and the discontinuation rate for rash in pediatric patients was 0.9%. Discontinue and initiate appropriate treatment if severe skin rash develops.
5.7 Sulfa Allergy
APTIVUS should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and APTIVUS is unknown.
|
|
