Aptivus

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Aptivus uses

• Warning: hepatotoxicity and intracranial hemorrhage
•   indications and usage
•   dosage and administration
•   dosage forms and strengths
•   contraindications
•   warnings and precautions
•   adverse reactions
•   drug interactions
•   use in specific populations
•   overdosage
•   description
•   clinical pharmacology
•   nonclinical toxicology
•   clinical studies
•   how supplied/storageand handling
•   patient counseling information
• Aptivus reviews

WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE

Hepatotoxicity:

Clinicalhepatitis and hepatic decompensation, including some fatalities, havebeen reported. Extra vigilance is warranted in patients with chronichepatitis B or hepatitis C co-infection, as these patients have anincreased risk of hepatotoxicity [ see Warnings and Precautions (5.1) ].

Intracranial Hemorrhage:

Both fatal and non-fatal intracranialhemorrhage have been reported [ see Warnings and Precautions (5.2) ].

WARNING: HEPATOTOXICITY andINTRACRANIAL HEMORRHAGE

See full prescribinginformation for complete boxed warning.

• Clinical hepatitis and hepatic decompensationincluding some fatalities. Extra vigilance is warranted in patientswith chronic hepatitis B or hepatitis C co-infection. (5.1)
• Fatal and non-fatal intracranial hemorrhage (5.2)

Contraindications, Drug Interactions (4.2)

9/2016

1  INDICATIONS AND USAGE

Aptivus, co-administered with ritonavir,is indicated for combination antiretroviral treatment of HIV-1 infectedpatients who are treatment-experienced and infected with HIV-1 strainsresistant to more than one protease inhibitor (PI).

This indication is based on analyses of plasma HIV-1RNA levels in two controlled studies of APTIVUS/ritonavir of 48 weeksduration in treatment-experienced adults and one open-label 48-weekstudy in pediatric patients age 2 to 18 years. The adult studies wereconducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI,PI) treatment-experienced adults with evidence of HIV-1 replicationdespite ongoing antiretroviral therapy.

The following points should be considered when initiatingtherapy with APTIVUS/ritonavir:

• The use of APTIVUS/ritonavir in treatment-naïve patientsis not recommended [ see Warnings and Precautions (5.1) ].
• The use of other active agents with APTIVUS/ritonavir isassociated with a greater likelihood of treatment response [ see Clinical Pharmacology (12.4) and Clinical Studies (14) ].
• Genotypic or phenotypic testing and/or treatment historyshould guide the use of APTIVUS/ritonavir [ see ClinicalPharmacology (12.4) ]. The number of baseline primary protease inhibitor mutations affectsthe virologic response to APTIVUS/ritonavir [ seeClinical Pharmacology (12.4) ].
• Use caution when prescribing APTIVUS/ritonavir to patientswith elevated transaminases, hepatitis B or C co-infection or patientswith mild hepatic impairment [ see Warnings and Precautions (5.1) ].
• Liver function tests should be performed at initiation oftherapy with APTIVUS/ritonavir and monitored frequently throughoutthe duration of treatment [ see Warnings and Precautions (5.1) ].
• The drug-drug interaction potential of APTIVUS/ritonavirwhen co-administered with other drugs must be considered prior toand during APTIVUS/ritonavir use [ see Contraindications (4.2) and Drug Interactions (7) ].
• Use caution when prescribing APTIVUS/ritonavir in patientswho may be at risk for increased bleeding or who are receiving medicationsknown to increase the risk of bleeding [ see Warningsand Precautions (5.4) ].
• The risk-benefit of APTIVUS/ritonavir has not been establishedin pediatric patients <2 years of age.

There are no study results demonstratingthe effect of APTIVUS/ritonavir on clinical progression of HIV-1.

Aptivus, a protease inhibitor, co-administeredwith ritonavir, is indicated for combination antiretroviral treatmentof HIV-1 infected patients who are treatment-experienced and infectedwith HIV-1 strains resistant to more than one protease inhibitor (1)

• Do not use APTIVUS/ritonavir in treatment-naïve patients (1)

2  DOSAGE AND ADMINISTRATION

Aptivus must be co-administered with ritonavir to exertits therapeutic effect. Failure to correctly co-administer APTIVUSwith ritonavir will result in plasma levels of Aptivus that willbe insufficient to achieve the desired antiviral effect and will altersome drug interactions.

• Aptivus co-administered with ritonavir capsules or solutioncan be taken with or without meals
• Aptivus co-administered with ritonavir tablets must onlybe taken with meals

[see Clinical Pharmacology ]

Aptivus may be administered as either capsules or oralsolution to either pediatric or adult patients.

Due to the need for co-administration of Aptivus withritonavir, please refer to the ritonavir prescribing information.

• Adults: 500 mg Aptivus, co-administered with 200 mg ritonavir,twice daily (2.1)
• Pediatric patients (age 2 to 18 years): Dosing is basedon body weight or body surface area not to exceed adult dose (2.2)
• Aptivus taken with ritonavir capsules orsolution 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)

2.1  Adults

The recommended adult dose of Aptivus is500 mg (two 250 mg capsules or 5 mL oral solution) co-administeredwith 200 mg of ritonavir, twice daily.

2.2  Pediatric Patients

Healthcareprofessionals should pay special attention to accurate calculationof the dose of Aptivus, transcription of the medication order, dispensinginformation and dosing instruction to minimize risk for medicationerrors, overdose, and underdose.

Prescribers should calculate the appropriate dose of Aptivus foreach individual child based on body weight (kg) or body surface area(BSA, m²) and should not exceed the recommendedadult dose.

Before prescribingAPTIVUS 250 mg capsules, children should be assessed for the abilityto swallow capsules. If a child is unable to reliably swallow an APTIVUScapsule, the Aptivus oral solution formulation should be prescribed.

The recommended pediatric dose of APTIVUSis 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 mgco-administered with ritonavir 200 mg twice daily. For children whodevelop intolerance or toxicity and cannot continue with Aptivus 14mg/kg with 6 mg/kg ritonavir, physicians may consider decreasing thedose 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 resistantto 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:

aptivus-formula

3  DOSAGE FORMS AND STRENGTHS

Capsules: 250 mg, pink, oblong capsulesimprinted with TPV 250

Oral solution:100 mg/mL, yellow, viscous clear liquid with a buttermint-butter toffeeflavor

• Capsules: 250 mg (3)
• Oral solution: 100 mg/mL (3)

4  CONTRAINDICATIONS

• Patients with moderate or severe hepatic impairment (4.1, 5.1)
• Use with drugs highly dependent on CYP 3A for clearanceor are potent CYP 3A inducers (4.2, 5.3, 7)

4.1  Hepatic Impairment

Aptivus is contraindicated in patients withmoderate or severe (Child-Pugh Class B or C, respectively) hepaticimpairment [ see Warnings and Precautions (5.1) ].

4.2  Drug Interactions

Co-administration of APTIVUS/ritonavir withdrugs that are highly dependent on CYP 3A for clearance or are potentCYP 3A inducers are contraindicated. These recommendationsare based on either drug interaction studies or they are predictedinteractions due to the expected magnitude of interaction and potentialfor serious events or loss of efficacy. For information regardingclinical recommendations [ see Drug Interactions (7.2) ].

Table 1      Drugs that are Contraindicatedwith Aptivus Co-Administered with Ritonavir

DrugClass	Drugs withinClass that are Contraindicated with Aptivus Co-administeredwith Ritonavir	ClinicalComments:
Alpha 1-adrenoreceptor antagonist	Alfuzosin	Potentially increased alfuzosin concentrationscan result in hypotension.
Antiarrhythmics	Amiodarone, bepridil, flecainide,propafenone, quinidine	Potential for serious and/or life-threateningreactions such as cardiac arrhythmias secondary to increases in plasmaconcentrations of antiarrhythmics.
Antimycobacterials	Rifampin	May lead to loss of virologic responseand possible resistance to Aptivus or to the class of protease inhibitorsor other co-administered antiretroviral agents.
Ergot derivatives	Dihydroergotamine, ergonovine,ergotamine, methylergonovine	Potential for acute ergot toxicity characterizedby peripheral vasospasm and ischemia of the extremities and othertissues.
GI motility agent	Cisapride	Potential for cardiac arrhythmias.
Herbal products	St. John's wort (hypericumperforatum)	May lead to loss of virologic responseand possible resistance to Aptivus or to the class of protease inhibitors.
HMG CoA reductase inhibitors	Lovastatin, simvastatin	Potential for myopathy including rhabdomyolysis.
Antipsychotics	Pimozide Lurasidone	Potential for cardiac arrhythmias. Potential for serious and/or life-threatening reactions.
PDE-5 inhibitors	Sildenafil (Revatio) [fortreatment of pulmonary arterial hypertension]	A safe and effective dose has not beenestablished when used with APTIVUS/ritonavir. There is increased potentialfor sildenafil-associated adverse events (which include visual disturbances,hypotension, prolonged erection, and syncope).
Sedatives/hypnotics	Oral midazolam, triazolam	Prolonged or increased sedation or respiratorydepression.

Due to the need for co-administrationof Aptivus with ritonavir, please refer to the ritonavir prescribinginformation for a description of ritonavir contraindications.

5  WARNINGS AND PRECAUTIONS

Please refer to the ritonavir prescribing informationfor additional information on precautionary measures.

• Hepatic Impairment: Discontinue for signs and symptoms ofclinical hepatitis or asymptomatic increases in ALT/AST >10 timesULN or asymptomatic increases in ALT/AST 5-10 times ULN with concomitantincreases in total bilirubin. Monitor liver function tests prior totherapy and frequently thereafter.
• Intracranial Hemorrhage/Platelet Aggregation and Coagulation:Use with caution in patients at risk for increased bleeding or whoare receiving medications that increase the risk of bleeding (5.2, 5.4)
• The concomitant use of APTIVUS/ritonavir and certain otherdrugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatmentfor potential drug interactions. (5.3, 7.2)
• Rash: Discontinue and initiate appropriate treatment ifsevere skin reaction occurs or is suspected. (5.6) Use with caution in patients with a known sulfonamideallergy. (5.7)
• Patients may develop new onset or exacerbations of diabetesmellitus, hyperglycemia (5.8), immunereconstitution syndrome (5.9), redistribution/accumulationof body fat (5.10), and elevatedlipids. (5.11) Monitor cholesteroland triglycerides prior to therapy and periodically thereafter.
• Hemophilia: Spontaneous bleeding may occur, and additionalfactor VIII may be required (5.12)

5.1  Hepatic Impairmentand Toxicity

Clinicalhepatitis and hepatic decompensation, including some fatalities, werereported with Aptivus co-administered with 200 mg of ritonavir. Thesehave generally occurred in patients with advanced HIV-1 disease takingmultiple concomitant medications. A causal relationship to APTIVUS/ritonavircould not be established. Physicians and patients should be vigilantfor 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 symptomsof clinical hepatitis should discontinue APTIVUS/ritonavir treatmentand seek medical evaluation.

Allpatients should be followed closely with clinical and laboratory monitoring,especially those with chronic hepatitis B or C co-infection, as thesepatients have an increased risk of hepatotoxicity. Liver functiontests 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 than10 times the upper limit of normal occur, APTIVUS/ritonavir therapyshould be discontinued. If asymptomatic elevations in AST or ALT between5 – 10 times the upper limit of normal and increases in total bilirubingreater than 2.5 times the upper limit of normal occur, APTIVUS/ritonavirtherapy should be discontinued.

Treatment-experienced patients with chronic hepatitis B or hepatitisC co-infection or elevated transaminases are at approximately 2-foldrisk for developing Grade 3 or 4 transaminase elevations or hepaticdecompensation. In two large, randomized, open-label, controlled clinicaltrials with an active comparator (1182.12 and 1182.48) of treatment-experiencedpatients, Grade 3 and 4 increases in hepatic transaminases were observedin 10.3% (10.9/100 PEY) receiving APTIVUS/ritonavir through week 48.In a study of treatment-naïve patients, 20.3% (21/100 PEY) experiencedGrade 3 or 4 hepatic transaminase elevations while receiving APTIVUS/ritonavir500 mg/200 mg through week 48.

Aptivus is principally metabolized by the liver. Caution shouldbe exercised when administering APTIVUS/ritonavir to patients withmild hepatic impairment (Child-Pugh Class A) because Aptivus concentrationsmay be increased [ see Clinical Pharmacology (12.3) ].

5.2  Intracranial Hemorrhage

Aptivus, co-administered with 200 mg ofritonavir, has been associated with reports of both fatal and non-fatalintracranial hemorrhage. Many of these patients had other medicalconditions or were receiving concomitant medications that may havecaused or contributed to these events. No pattern of abnormal coagulationparameters has been observed in patients in general, or precedingthe development of ICH. Therefore, routine measurement of coagulationparameters is not currently indicated in the management of patientson Aptivus.

5.3  Risk of SeriousAdverse Reactions Due to Drug Interactions

Initiation of APTIVUS/ritonavir, a CYP3Ainhibitor, in patients receiving medications metabolized by CYP3Aor initiation of medications metabolized by CYP3A in patients alreadyreceiving APTIVUS/ritonavir, may increase plasma concentrations ofmedications metabolized by CYP3A. Initiation of medications that inhibitor induce CYP3A may increase or decrease concentrations of APTIVUS/ritonavir,respectively. These interactions may lead to:

• Clinically significant adverse reactions, potentially leadingto severe, life-threatening, or fatal events from greater exposuresof concomitant medications.
• Clinically significant adverse reactions from greater exposuresof APTIVUS/ritonavir.
• Loss of therapeutic effect of APTIVUS/ritonavir and possibledevelopment of resistance.

See Table 4 for steps toprevent or manage these possible and known significant drug interactions,including dosing recommendations . Consider the potential fordrug interactions prior to and during APTIVUS/ritonavir therapy; reviewconcomitant medications during APTIVUS/ritonavir therapy; and monitorfor the adverse reactions associated with the concomitant medications .

5.4  Effects on Platelet Aggregation and Coagulation

APTIVUS/ritonavir should be used with cautionin patients who may be at risk of increased bleeding from trauma,surgery or other medical conditions, or who are receiving medicationsknown to increase the risk of bleeding such as antiplatelet agentsand anticoagulants, or who are taking supplemental high doses of vitaminE.

In rats, Aptivus treatmentalone induced dose-dependent changes in coagulation parameters, bleedingevents and death. Co-administration with vitamin E significantly increasedthese effects [ see Nonclinical Toxicology ]. However, analysesof stored plasma from adult patients treated with Aptivus capsulesand pediatric patients treated with Aptivus oral solution (which containsa vitamin E derivative) showed no effect of APTIVUS/ritonavir on vitaminK-dependent coagulation factors (Factor II and Factor VII), FactorV, or on prothrombin or activated partial thromboplastin times.

In in vitro experiments, Aptivus was observed to inhibit human plateletaggregation at levels consistent with exposures observed in patientsreceiving APTIVUS/ritonavir.

5.5  Vitamin E Intake

Patients taking Aptivus oral solution shouldbe advised not to take supplemental vitamin E greater than a standardmultivitamin as Aptivus oral solution contains 116 IU/mL of vitaminE which is higher than the Reference Daily Intake (adults 30 IU, pediatricsapproximately 10 IU).

5.6  Rash

Rash, including urticarial rash, maculopapularrash, and possible photosensitivity, has been reported in subjectsreceiving APTIVUS/ritonavir. In some cases rash was accompanied byjoint pain or stiffness, throat tightness, or generalized pruritus. In controlled adult clinical trials, rash was observed in 10% of females and in 8% of males receiving APTIVUS/ritonavirthrough 48 weeks of treatment. The median time to onset of rash was53 days and the median duration of rash was 22 days. The discontinuationrate for rash in clinical trials was 0.5%. In an uncontrolled compassionateuse program (n=3920), cases of rash, some of which were severe, accompaniedby myalgia, fever, erythema, desquamation, and mucosal erosions werereported. In the pediatric clinical trial, the frequency of rash (allgrades, all causality) through 48 weeks of treatment was 21%. Overall,most of the pediatric patients had mild rash and 5 (5%) had moderaterash. Overall 3% of pediatric patients interrupted Aptivus treatmentdue to rash and the discontinuation rate for rash in pediatric patientswas 0.9%. Discontinue and initiate appropriate treatment if severeskin rash develops.

5.7  Sulfa Allergy

Aptivus should be used with caution in patientswith a known sulfonamide allergy. Aptivus contains a sulfonamidemoiety. The potential for cross-sensitivity between drugs in the sulfonamideclass and Aptivus is unknown.

5.8  Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbationof pre-existing diabetes mellitus and hyperglycemia have been reportedduring post-marketing surveillance in HIV-1 infected patients receivingprotease inhibitor therapy. Some patients required either initiationor dose adjustments of insulin or oral hypoglycemic agents for treatmentof these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemiapersisted in some cases. Because these events have been reported voluntarilyduring clinical practice, estimates of frequency cannot be made anda causal relationship between protease inhibitor therapy and theseevents has not been established.

5.9  Immune ReconstitutionSyndrome

Immune reconstitutionsyndrome has been reported in patients treated with combination antiretroviraltherapy, including Aptivus. During the initial phase of combinationantiretroviral treatment, patients whose immune system responds maydevelop an inflammatory response to indolent or residual opportunisticinfections, which may necessitate furtherevaluation and treatment.

Autoimmunedisorders (such as Graves’ disease, polymyositis, and Guillain-Barrésyndrome) have also been reported to occur in the setting of immunereconstitution, however, the time to onset is more variable, and canoccur many months after initiation of treatment.

5.10 Fat Redistribution

Redistribution/accumulation of body fatincluding central obesity, dorsocervical fat enlargement (buffalohump), peripheral wasting, facial wasting, breast enlargement, and"cushingoid appearance" have been observed in patients receiving antiretroviraltherapy. The mechanism and long-term consequences of these eventsare currently unknown. A causal relationship has not been established.

5.11 Elevated Lipids

Treatment with Aptivus co-administered with200 mg of ritonavir has resulted in large increases in the concentrationof total cholesterol and triglycerides [ see AdverseReactions ].Triglyceride and cholesterol testing should be performed prior toinitiating APTIVUS/ritonavir therapy and at periodic intervals duringtherapy. Lipid disorders should be managed as clinically appropriate;taking into account any potential drug-drug interactions [ see Drug Interactions (7.2) ].

5.12 Patients with Hemophilia

There have been reports of increased bleeding,including spontaneous skin hematomas and hemarthrosis in patientswith hemophilia type A and B treated with protease inhibitors. Insome patients additional Factor VIII was given. In more than halfof the reported cases, treatment with protease inhibitors was continuedor reintroduced if treatment had been discontinued. A causal relationshipbetween protease inhibitors and these events has not been established.

5.13 Resistance/CrossResistance

Because thepotential for HIV-1 cross-resistance among protease inhibitors hasnot been fully explored in APTIVUS/ritonavir treated patients, itis unknown what effect therapy with Aptivus will have on the activityof subsequently administered protease inhibitors.

6  ADVERSE REACTIONS

The following adverse reactions are described, in greater detail,in other sections:

• Hepatic Impairment and Toxicity [ see Warningsand Precautions ]
• Intracranial Hemorrhage [ see Warningsand Precautions (5.2) ]
• Rash [ see Warnings and Precautions (5.6) ]

Due to the need for co-administrationof Aptivus with ritonavir, please refer to ritonavir prescribing informationfor ritonavir-associated adverse reactions.

Because clinical trials are conducted under widely varyingconditions, adverse reaction rates observed in the clinical trialsof a drug cannot be directly compared to rates in the clinical trialsof another drug and may not reflect the rates observed in clinicalpractice.

• 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 frequentadverse 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.

6.1  Clinical Trialsin Adults

Aptivus, co-administeredwith ritonavir, has been studied in a total of 6308 HIV-1 positiveadults as combination therapy in clinical studies. Of these, 1299treatment-experienced patients received the dose of 500/200 mg BID.Nine hundred nine (909) adults, including 541 in the 1182.12 and 1182.48controlled clinical trials, have been treated for at least 48 weeks[ see Clinical Studies (14) ].

In 1182.12and 1182.48 in the APTIVUS/ritonavir arm, the most frequent adversereactions were diarrhea, nausea, pyrexia, vomiting, fatigue, headache,and abdominal pain. The 48-Week Kaplan-Meier rates of adverse reactionsleading to discontinuation were 13.3% for APTIVUS/ritonavir-treatedpatients and 10.8% for the comparator arm patients.

Adverse reactions reported in the controlled clinicaltrials 1182.12 and 1182.48, based on treatment-emergent clinical adversereactions of moderate to severe intensity (Grades 2 - 4) in at least2% of treatment-experienced subjects in either treatment group aresummarized in Table 2 below.

	Percentage ofpatients (rate per 100 patient-exposure years)
	APTIVUS/ritonavir (500/200mg BID) + OBRc (n=749;757.4 patient-exposure years)	Comparator PI/ritonavirb + OBR (n=737; 503.9 patient-exposure years)
a Excludeslaboratory abnormalities that were Adverse Events
b Comparator PI/ritonavir:lopinavir/ritonavir 400/100 mg BID, indinavir/ritonavir 800/100 mgBID, saquinavir/ritonavir 1000/100 mg BID, amprenavir/ritonavir 600/100mg BID
c Optimized BackgroundRegimen
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 TissueDisorders
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 MediastinalDisorders
Dyspnea	2.1% (2.1)	1.0% (1.4)
Skin and Subcutaneous Tissue Disorders
Rash	3.1% (3.1)	3.8% (5.7)

Less Common AdverseReactions

Other adverse reactions reportedin <2% of adult patients (n=1474) treated with APTIVUS/ritonavir500/200 mg in Phase 2 and 3 clinical trials are listed below by bodysystem:

Bloodand Lymphatic System Disorders : thrombocytopenia

Gastrointestinal Disorders : abdominal distension, dyspepsia, flatulence, gastroesophagealreflux disease, pancreatitis

General Disorders : influenza-like illness,malaise

HepatobiliaryDisorders : 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, facialwasting, hyperamylasemia, hypercholesterolemia, hyperglycemia, mitochondrialtoxicity

Musculoskeletaland Connective Tissue Disorders : muscle cramp

Nervous System Disorders : dizziness, intracranial hemorrhage, somnolence

Psychiatric Disorders : sleep disorder

Renal and Urinary Disorders : renalinsufficiency

Skin and Subcutaneous System Disorders : exanthem,lipoatrophy, lipodystrophy acquired, lipohypertrophy, pruritus

LaboratoryAbnormalities

Treatment-emergent laboratoryabnormalities reported at 48 weeks in the controlled clinical trials1182.12 and 1182.48 in adults are summarized in Table 3 below.

			Randomized, ControlledClinical Trials 1182.12 and 1182.48
			Percentage ofPatients (rate per 100 patient-exposure years)
		Limit	APTIVUS/ritonavir (500/200mg BID) + OBR (n=738)	Comparator PI/ritonavir +OBR* (n=724)
*Comparator PI/ritonavir: lopinavir/ritonavir 400/100mg BID, indinavir/ritonavir 800/100 mg BID, saquinavir/ritonavir 1000/100mg BID, amprenavir/ritonavir 600/100 mg BID
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)

In controlled clinical trials 1182.12and 1182.48 extending up to 96 weeks, the proportion of patients whodeveloped Grade 2-4 ALT and/or AST elevations increased from 26% atweek 48 to 32.1% at week 96 with APTIVUS/ritonavir. The risk of developingtransaminase elevations is greater during the first year of therapy.

6.2  Clinical Trialsin Pediatric Patients

Aptivus, co-administered with ritonavir, has been studied in a totalof 135 HIV-1 infected pediatric patients age 2 through 18 years ascombination therapy. This study enrolled HIV-1 infected, treatment-experiencedpediatric patients (with the exception of 3 treatment-naïve patients),with baseline HIV-1 RNA of at least 1500 copies/mL. One hundred andten (110) patients were enrolled in a randomized, open-label 48-weekclinical trial (Study 1182.14) and 25 patients were enrolled in otherclinical studies including Expanded Access and Emergency Use Programs.

The adverse reactions profile seen in Study1182.14 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 mostfrequently reported adverse reactions (Grade 2-4, all causes) in pediatricpatients. Rash was reported more frequently in pediatric patientsthan in adults.

The most commonGrade 3-4 laboratory abnormalities were increases in CPK (11%), ALT(6.5%), and amylase (7.5%).

Dueto previous reports of both fatal and non-fatal intracranial hemorrhage(ICH), an analysis of bleeding events was performed. At 48 weeks oftreatment, the frequency of pediatric patients with any bleeding adversereactions was 7.5%. No drug related serious bleeding adverse reactionwas reported. The most frequent bleeding adverse reaction was epistaxis(3.7%). No other bleeding adverse reaction was reported in frequencyof >1%. Additional trial follow-up through 100 weeks showed a cumulative12% frequency of any bleeding adverse reaction.

7  DRUG INTERACTIONS

See also Contraindications, Warnings and Precautions (5.3), and Clinical Pharmacology (12.3) .

Co-administration of Aptivus can alter theconcentrations of other drugs and other drugs may alter the concentrationof Aptivus. The potential for drug-drug interactions must be consideredprior to and during therapy. (4.2, 5.3, 7)

7.1  Potential for APTIVUS/ritonavirto Affect Other Drugs

Aptivus co-administered with ritonavir at the recommended dose isa net inhibitor of CYP 3A and may increase plasma concentrations ofagents that are primarily metabolized by CYP 3A. Thus, co-administrationof APTIVUS/ritonavir with drugs highly dependent on CYP 3A for clearanceand for which elevated plasma concentrations are associated with seriousand/or life-threatening events is contraindicated [ see Contraindications (4.2) ]. Co-administration with other CYP 3A substrates may requirea dose adjustment or additional monitoring [ seeDrug Interactions (7) ].

Clinically significant drug-druginteractions of Aptivus co-administered with ritonavir are summarizedin Table 4 below.

A phenotypiccocktail study was conducted with 16 healthy volunteers to quantifythe influence of 10 days of APTIVUS/ritonavir capsule administrationon the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2C19(omeprazole), 2D6 (dextromethorphan) and the activity of intestinaland hepatic CYP 3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin).This study determined the first-dose and steady-state effects of 500mg of Aptivus co-administered with 200 mg of ritonavir twice dailyin capsule form. Aptivus oral solution co-administered with ritonavircapsules demonstrated similar effects as Aptivus capsules co-administratedwith ritonavir.

There was nonet 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 wasmoderate induction at steady state. There was modest inhibition ofCYP 2C19 at the first dose, but there was marked induction at steadystate. Potent inhibition of CYP 2D6 and both hepatic and intestinalCYP 3A4/5 activities were observed after first dose and steady state.

Intestinal and hepatic P-gp activity wasassessed by administering oral and intravenous digoxin, respectively. The digoxin results indicate P-gp was inhibited after the first doseof APTIVUS/ritonavir followed by induction of P-gp over time. Thus,it is difficult to predict the net effect of Aptivus administeredwith ritonavir on oral bioavailability and plasma concentrations ofdrugs that are dual substrates of CYP 3A and P-gp. The net effectwill vary depending on the relative affinity of the co-administereddrugs for CYP 3A and P-gp, and the extent of intestinal first-passmetabolism/efflux. An in vitro induction study in human hepatocytes showed an increase in UGT1A1by Aptivus similar to that evoked by rifampin. The clinical consequencesof this finding have not been established.

7.2  Potential for OtherDrugs to Affect Aptivus

Aptivus is a CYP 3A substrate and a P-gp substrate. Co-administration of APTIVUS/ritonavir and drugs that induce CYP 3Aand/or P-gp may decrease Aptivus plasma concentrations. Co-administrationof APTIVUS/ritonavir and drugs that inhibit P-gp may increase tipranavirplasma concentrations. Co-administration of APTIVUS/ritonavir withdrugs that inhibit CYP 3A may not further increase Aptivus plasmaconcentrations, because the level of metabolites is low followingsteady-state administration of APTIVUS/ritonavir 500/200 mg twicedaily.

Clinically significantdrug-drug interactions of Aptivus co-administered with ritonavir aresummarized in Table 4 below.

Table 4      Established and OtherPotentially Significant Drug Interactions: Alterations in Dose orRegimen May be Recommended Based on Drug Interaction Studies or PredictedInteraction

↑ increase, ↓ decrease, ↔ no change,↕ unable to predict
Concomitant Drug Class: Drug name	Effect onConcentration of Aptivus or Concomitant Drug	Clinical Comment
HIV-1 AntiviralAgents
Fusion Inhibitors:
Enfuvirtide	↑ Aptivus	At steady state, Aptivus trough concentrationswere approximately 45% higher in patients co-administered enfuvirtidein the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended.
Non-NucleosideReverse Transcriptase
Inhibitors:
Etravirine	↓ Etravirine	APTIVUS/ritonavir when coadministered with etravirinemay cause a significant decrease in the plasma concentrations of etravirineand loss of therapeutic effect of etravirine. Etravirine and APTIVUS/ritonavirshould not be coadministered.
Rilpivirine	The use of rilpivirine co-administered with APTIVUS/ritonavirhas not been studied.	Concomitant use of rilpivirine with Aptivus/ritonavir may causean increase in the plasma concentrations of rilpivirine (inhibitionof CYP3A enzymes). Rilpivirine is not expected to affect the plasmaconcentrations of Aptivus/ritonavir.
Nucleoside ReverseTranscriptase
Inhibitors:
Abacavir	↓ Abacavir AUC by approximately 40%	Clinical relevance of reduction in abacavir levelsnot established. Dose adjustment of abacavir cannot be recommendedat this time.
Didanosine (EC)	↓ Didanosine	Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavirdosing by at least 2 hours.
Zidovudine	↓ Zidovudine AUC by approximately 35%. ZDV glucuronideconcentrations were unaltered.	Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease Inhibitors (co-administeredwith 200 mg of ritonavir):
Fosamprenavir Lopinavir Saquinavir	↓ Amprenavir ↓ Lopinavir ↓Saquinavir	Combining a protease inhibitor with APTIVUS/ritonaviris not recommended.
Protease Inhibitors (co-administeredwith 100 mg of ritonavir):
Atazanavir	↓ Atazanavir ↑ Aptivus
Virus Integrase Strand Transfer Inhibitors:
Raltegravir	↓ Raltegravir	APTIVUS/ritonavir reduces plasmaconcentrations of raltegravir. Since comparable efficacy was observedfor this combination in phase 3 studies, dose adjustment is not recommended.
Agents for Opportunistic Infections
Antifungals:
Fluconazole Itraconazole Ketoconazole Voriconazole	↑ Aptivus, ↔ Fluconazole	Fluconazole increases Aptivus concentrations butdose adjustments are not needed. Fluconazole doses >200 mg/day arenot recommended.
	↑ Itraconazole (not studied)
	↑ Ketoconazole (not studied)	Based on theoretical considerations itraconazoleand ketoconazole should be used with caution. High doses (>200 mg/day)are not recommended.
	↕ Voriconazole (not studied)
		Due to multiple enzymes involvedwith voriconazole metabolism, it is difficult to predict the interaction.
Antimycobacterials:
Clarithromycin	↑ Aptivus, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycinmetabolite	No dose adjustment of Aptivus or clarithromycin forpatients with normal renal function is necessary.
		For patients with renal impairment the following dosage adjustmentsshould be considered: For patients with CLCR 30 to 60 mL/minthe dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/minthe dose of clarithromycin should be decreased by 75%.
Rifabutin	Aptivus not changed, ↑ Rifabutin ↑ Desacetyl-rifabutin	Single dose study. Dosage reductions of rifabutin by 75% are recommended(e.g., 150 mg every other day). Increased monitoring for adverse eventsin patients receiving the combination is warranted. Further dosagereduction may be necessary.
Other AgentsCommonly Used
Anticonvulsants:
Carbamazepine Phenobarbital Phenytoin	↓ Aptivus	Caution should be used when prescribing carbamazepine,phenobarbital and/or phenytoin. Aptivus may be less effective dueto decreased Aptivus plasma concentration in patients taking theseagents concomitantly.
Valproic Acid	↓ Valproic Acid	Caution should be used when prescribing valproicacid. Valproic acid may be less effective due to decreased valproicacid plasma concentration in patients taking Aptivus concomitantly.
Antidepressants:
Trazodone	↑ Trazodone	Concomitant use of trazodone and APTIVUS/ritonavir may increaseplasma concentrations of trazodone. Adverse events of nausea, dizziness,hypotension, and syncope have been observed following co-administrationof trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitorsuch as APTIVUS/ritonavir, the combination should be used with cautionand a lower dose of trazodone should be considered.
Desipramine	Combination with APTIVUS/ritonavir not studied ↑ Desipramine	Dosage reduction and concentration monitoring ofdesipramine is recommended.
Selective Serotonin-Reuptake Inhibitors:	Combination with APTIVUS/ritonavir not studied	Antidepressants have a wide therapeutic index, butdoses may need to be adjusted upon initiation of APTIVUS/ritonavirtherapy.
Fluoxetine Paroxetine Sertraline	↑ Fluoxetine ↑ Paroxetine ↑Sertraline
Anti-HCV agents:
Boceprevir	Co-administration of Aptivus and boceprevir has notbeen studied.	With concomitant use, changes in exposure were observed both forboceprevir and certain protease inhibitors used for the treatmentof HIV-1 infection or either medication. Information is not availableregarding Aptivus 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 notbeen studied.	With concomitant use, changes in exposure were observed both fortelaprevir and certain protease inhibitors used for the treatmentof HIV-1 infection or telaprevir. Information is not available regardingtipranavir or telaprevir exposure with concomitant use. It is notrecommended to co-administer telaprevir with APTIVUS/ritonavir.
Anti-gout:
Colchicine	↑ Colchicine	In patients with renal or hepatic impairment, coadministrationof colchicine in patients on APTIVUS/ritonavir is contraindicated. In combination with APTIVUS/ritonavir, the followingdosage adjustments are recommended in patients with normal renal andhepatic function: Treatmentof gout 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. Prophylaxis of gout flares: Co-administrationof colchicine in patients on APTIVUS/ritonavir : 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. Treatment of familial Mediterranean fever(FMF): Co-administration of colchicine in patients on APTIVUS/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twicea day).
Antipsychotics:
Quetiapine	↑ Quetiapine	Initiation of Aptivus with ritonavir in patients takingquetiapine: Consider alternativeantiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6of the current dose and monitor for quetiapine-associated adversereactions. Refer to the quetiapine prescribing information for recommendationson adverse reaction monitoring. Initiation of quetiapine in patients taking Aptivus with ritonavir: Refer to the quetiapine prescribing informationfor 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 significantlyhigher with oral than parenteral administration. Therefore, APTIVUSshould not be given with orally administered midazolam [ see Contraindications (4) ]. If Aptivus is co-administered with parenteral midazolam,close clinical monitoring for respiratory depression and/or prolongedsedation should be exercised and dosage adjustments should be considered.
Buprenorphine/naloxone	↔ Buprenorphine ↓ Aptivus	APTIVUS/ritonavir did not resultin changes in the clinical efficacy of buprenorphine/naloxone. Comparedto historical controls Aptivus Cmin wasdecreased approximately 40% with this combination. Dose adjustmentscannot be recommended.
Calcium ChannelBlockers: Diltiazem Felodipine Nicardipine Nisoldipine Verapamil	Combination with APTIVUS/ritonavirnot studied. Cannot predict effect of TPV/ritonavir on calcium channelblockers that are dual substrates of CYP3A and P-gp due to conflictingeffect of TPV/ritonavir on CYP3A and P-gp. ↕Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but notclear whether it is a P-gp substrate) ↕ Verapamil	Caution is warranted and clinicalmonitoring of patients is recommended.
Disulfiram/Metronidazole	Combination with TPV/ritonavirnot studied	Aptivus capsules contain alcohol that can producedisulfiram-like reactions when co-administered with disulfiram orother drugs which produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists Bosentan	↑ Bosentan	Co-administration of bosentan in patientson APTIVUS/ritonavir: In patientswho have been receiving APTIVUS/ritonavir for at least 10 days, startbosentan at 62.5 mg once daily or every other day based upon individualtolerability. Co-administrationof APTIVUS/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hoursprior to initiation of APTIVUS/ritonavir. Afterat least 10 days following the initiation of APTIVUS/ritonavir, resumebosentan at 62.5 mg once daily or every other day based upon individualtolerability.
HMG-CoA ReductaseInhibitors:
Atorvastatin Rosuvastatin	↑ Atorvastatin ↓ Hydroxy-atorvastatinmetabolites ↑ Rosuvastatin	Avoid co-administration with atorvastatin.
Hypoglycemics:
	Combination with APTIVUS/ritonavir not studied	Careful glucose monitoring is warranted.
Glimepiride Glipizide Glyburide Pioglitazone	↔ Glimepiride (CYP 2C9) ↔ Glipizide (CYP 2C9) ↔ Glyburide (CYP 2C9) ↕ Pioglitazone (CYP 2C8 and CYP3A4)
Repaglinide	↕ Repaglinide (CYP 2C8 and CYP 3A4)
Tolbutamide	↔ Tolbutamide (CYP 2C9) Theeffect of TPV/ritonavir on CYP 2C8 substrate is not known.
Immunosuppressants:
	Combination with APTIVUS/ritonavir not studied. Cannotpredict effect of TPV/ritonavir on immunosuppressants due to conflictingeffect of TPV/ritonavir on CYP 3A and P-gp.	Increased frequency of monitoring of plasma levelsof immunosuppressant drugs is recommended.
Cyclosporine Sirolimus Tacrolimus	↕ Cyclosporine ↕ Sirolimus ↕ Tacrolimus
Inhaled betaagonist: Salmeterol	↑Salmeterol	Concurrent administration of APTIVUS/ritonaviris not recommended. The combination may result in increased risk ofcardiovascular adverse events associated with salmeterol, includingQT prolongation, palpitations, and sinus tachycardia.
Inhaled/Nasal Steroids:
Fluticasone	↑ Fluticasone	Concomitant use of fluticasonepropionate and APTIVUS/ritonavir may increase plasma concentrationsof fluticasone propionate, resulting in significantly reduced serumcortisol concentrations. Co-administration of fluticasone propionateand APTIVUS/ritonavir is not recommended unless the potential benefitto the patient outweighs the risk of systemic corticosteroid sideeffects.
Narcotic Analgesics:
	Combinations with APTIVUS/ritonavir not studied	Dosage increase and long-term use ofmeperidine are not recommended due to increased concentrations ofthe metabolite normeperidine which has both analgesic activity andCNS stimulant activity (e.g., seizures).
Meperidine	↓ Meperidine, ↑ Normeperidine
Methadone	↓ Methadone ↓ S-Methadone,↓ R-Methadone	Dosage of methadone may need to be increased whenco-administered with Aptivus and 200 mg of ritonavir.
Oral Contraceptives/Estrogens:
Ethinyl estradiol	↓ Ethinyl estradiol concentrations by 50%	Alternative methods of nonhormonal contraceptionshould be used when estrogen based oral contraceptives are co-administeredwith Aptivus and 200 mg of ritonavir. Patients using estrogens ashormone replacement therapy should be clinically monitored for signsof estrogen deficiency. Women using estrogens may have an increasedrisk of non-serious rash.
Proton Pump Inhibitors:
Omeprazole	↓ Omeprazole, ↔ Aptivus	Dosage of omeprazole may need to be increased whenco-administered with Aptivus and ritonavir.
PDE-5 Inhibitors:
Sildenafil Tadalafil Vardenafil	Only the combination of tadalafil with APTIVUS/ritonavirhas been studied (at doses used for treatment of erectile dysfunction).	Co-administration with APTIVUS/ritonavir may resultin an increase in PDE-5 inhibitor-associated adverse events, includinghypotension, syncope, visual disturbances, and priapism.
	↑ Sildenafil (not studied) ↑ Tadalafil with first dose APTIVUS/ritonavir ↔ Tadalafilat APTIVUS/ritonavir steady-state ↑ Vardenafil (not studied)	Use of PDE-5 inhibitors for pulmonary arterialhypertension (PAH): Use of sildenafil (Revatio) is contraindicated when usedfor the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4.2)]. The following dose adjustments are recommended for use oftadalafil (Adcirca) with APTIVUS/ritonavir: Co-administration of tadalafil (Adcirca)in patients on APTIVUS/ritonavir: In patients receiving APTIVUS/ritonavir for at leastone week, start Adcirca at 20 mg once daily. Increase to 40 mg oncedaily based upon individual tolerability. Co-administration of APTIVUS/ritonavir in patients on tadalafil(Adcirca): Avoid useof 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 basedupon individual tolerability.
		Use of PDE-5inhibitors for erectile dysfunction: Concomitant use of PDE-5 inhibitors with APTIVUS/ritonavirshould be used with caution and in no case should the starting doseof: 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.
Warfarin	↔ S-Warfarin	Frequent INR (internationalnormalized ratio) monitoring upon initiation of APTIVUS/ritonavirtherapy.

8  USE IN SPECIFIC POPULATIONS

The risk-benefit has not been establishedin pediatric patients <2 years of age

8.1  Pregnancy

Teratogenic Effects, Pregnancy Category C.

Investigation of fertility and early embryonic developmentwith Aptivus disodium was performed in rats, teratogenicity studieswere performed in rats and rabbits, and pre- and post-natal developmentwere explored in rats.

No teratogenicitywas detected in reproductive studies performed in pregnant rats andrabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day Aptivus,respectively, at exposure levels approximately 1.1-fold and 0.1-foldhuman exposure. At 400 mg/kg/day and above in rats, fetal toxicity(decreased sternebrae ossification and body weights) was observed,corresponding to an AUC of 1310 μM·h or approximately 0.8-fold humanexposure at the recommended dose. In rats and rabbits, fetal toxicitywas not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, correspondingaccordingly to C_max/AUC_0-24h levels of 30.4 μM/340 μM·h and 8.4 μM/120 μM·h. These exposure levels(AUC) are approximately 0.2-fold and 0.1-fold the exposure in humansat the recommended dose.

In pre-and post-development studies in rats, Aptivus showed no adverseeffects at 40 mg/kg/day (~0.2-fold human exposure), but caused growthinhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day(~0.8-fold human exposure). No post-weaning functions were affectedat any dose level.

There areno adequate and well-controlled studies in pregnant women for thetreatment of HIV-1 infection. Aptivus should be used during pregnancyonly if the potential benefit justifies the potential risk to thefetus.

AntiretroviralPregnancy Registry

To monitor maternal-fetaloutcomes of pregnant women exposed to Aptivus, an Antiretroviral PregnancyRegistry has been established. Physicians are encouraged to registerpatients by calling (800) 258-4263.

8.3  Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1infected mothers not breast-feed their infants to avoid risking postnataltransmission of HIV-1. Because of both the potential for HIV-1 transmissionand any possible adverse effects of Aptivus, mothers should be instructednot to breast-feed if they are receiving Aptivus.

8.4  Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologicresponses of Aptivus oral solution and capsules were evaluated inHIV-1 infected pediatric patients age 2 to 18 years [ see Adverse Reactions and ClinicalStudies (14.2) ].

The most frequent adversereactions (grades 2-4) were similar to those described in adults. However, rash was reported more frequently in pediatric patients thanin adults [ see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ].

The risk-benefit has not been established in pediatricpatients <2 years of age.

8.5  Geriatric Use

Clinical studies of APTIVUS/ritonavir did not include sufficientnumbers of subjects aged 65 and over to determine whether they responddifferently than younger subjects. In general, caution should be exercisedin the administration and monitoring of Aptivus in elderly patientsreflecting the greater frequency of decreased hepatic, renal, or cardiacfunction, and of concomitant disease or other drug therapy.

8.6  Hepatic Impairment

Aptivus is principally metabolized bythe liver. Caution should be exercised when administering APTIVUS/ritonavirto patients with mild (Child-Pugh Class A) hepatic impairment becausetipranavir concentrations may be increased [ seeClinical Pharmacology (12.3) ]. APTIVUS/ritonavir is contraindicated in patients withmoderate or severe (Child-Pugh Class B or Child-Pugh Class C) hepaticimpairment [ see Contraindications (4.1) ].

10  OVERDOSAGE

Thereis no known antidote for Aptivus overdose. Treatment of overdose shouldconsist of general supportive measures, including monitoring of vitalsigns and observation of the patient’s clinical status. If indicated,elimination of unabsorbed Aptivus should be achieved by emesisor gastric lavage. Administration of activated charcoal may also beused to aid in removal of unabsorbed drug. Since Aptivus is highlyprotein bound, dialysis is unlikely to provide significant removalof the drug.

11  DESCRIPTION

Aptivus is a protease inhibitor of HIV-1belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides.

The chemical name of Aptivus 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. Aptivus has thefollowing structural formula and is a single stereoisomer with the1R, 6R configuration.

Aptivus is a white to off-whiteto slightly yellow solid. It is freely soluble in dehydrated alcoholand propylene glycol, and insoluble in aqueous buffer at pH 7.5.

Aptivus soft gelatin capsules are for oraladministration. Each capsule contains 250 mg Aptivus. The majorinactive ingredients in the capsule are dehydrated alcohol (7% w/wor 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, mono/diglyceridesof caprylic/capric acid and gelatin.

Aptivus oral solution is available in a strength of100 mg/mL of Aptivus. Aptivus oral solution is a yellow, viscousclear liquid with a buttermint-butter toffee flavor. The major inactiveingredients in the oral solution are polyethylene glycol 400, vitaminE polyethylene glycol succinate (TPGS), purified water, and propyleneglycol. Each milliliter of Aptivus oral solution contains 116 IU ofvitamin E, and when taken at the recommended maximum dose of 500 mg/200mg tipranavir/ritonavir BID results in a daily dose of 1160 IU.

aptivus-structure

12  CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Aptivus is an antiviral drug [ see Clinical Pharmacology ].

12.2 Pharmacodynamics

ECG Evaluation

Theeffect of APTIVUS/ritonavir on the QTcF interval was measured in astudy in which 81 healthy subjects received the following treatmentstwice daily for 2.5 days: APTIVUS/ritonavir (500/200 mg), APTIVUS/ritonavirat a supra-therapeutic dose (750/200 mg), and placebo/ritonavir (-/200mg). After baseline and placebo adjustment, the maximum mean QTcFchange was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mgdose and 8.3 ms (1-sided 95% Upper CI: 10.9 ms) for the supra-therapeutic750/200 mg dose.

Antiviral Activity in vivo

The medianInhibitory Quotient (IQ) determined from 264 treatment-experiencedadult patients was about 80 (inter-quartile range: 31-226), from thecontrolled clinical trials 1182.12 and 1182.48. The IQ is definedas the Aptivus trough concentration divided by the viral EC₅₀ value, corrected for protein binding. There was arelationship between the proportion of patients with a ≥1 log₁₀ reduction of viral load from baseline at week 48 andtheir IQ value. Among the 198 patients receiving APTIVUS/ritonavirwith no new enfuvirtide use (e.g., new enfuvirtide, defined as initiationof enfuvirtide for the first time), the response rate was 23% in thosewith an IQ value <80 and 59% in those with an IQ value ≥80. Amongthe 66 patients receiving APTIVUS/ritonavir with new enfuvirtide,the response rates in patients with an IQ value <80 versus thosewith an IQ value ≥80 were 55% and 71%, respectively. These IQ groupsare derived from a select population and are not meant to representclinical breakpoints.

12.3 Pharmacokinetics

In order to achieve effective Aptivus plasma concentrations anda twice-daily dosing regimen, co-administration of Aptivus with ritonaviris essential [ see Dosage and Administration ]. Ritonavir inhibitshepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pumpand possibly intestinal CYP 3A. In a dose-ranging evaluation in 113HIV-1 negative male and female volunteers, there was a 29-fold increasein the geometric mean morning steady-state trough plasma concentrationsof Aptivus following Aptivus co-administered with low-dose ritonavir(500/200 mg twice daily) compared to Aptivus 500 mg twice daily withoutritonavir. In adults the mean systemic ritonavir concentration when200 mg of ritonavir was given with 500 mg of Aptivus was similar tothe concentrations observed when 100 mg was given with the other proteaseinhibitors.

Figure 1 displaysmean plasma concentrations of Aptivus and ritonavir at steady statefor 30 HIV-1 infected adult patients dosed with 500/200 mg tipranavir/ritonavirfor 14 days.

Figure 1      Mean Steady State Aptivus Plasma Concentrations(95% CI) with Ritonavir Co-administration (tipranavir/ritonavir 500/200mg BID)

Absorptionand Bioavailability

Absorption of Aptivus in humans is limited, althoughno absolute quantification of absorption is available. Tipranaviris a P-gp substrate, a weak P-gp inhibitor, and appears to be a potentP-gp inducer as well. In vivo data suggest that tipranavir/ritonavir, at the dose of 500/200 mg,is a P-gp inhibitor after the first dose and induction of P-gp occursover time. Aptivus trough concentrations at steady-state are about70% lower than those on Day 1, presumably due to intestinal P-gp induction. Steady state is attained in most subjects after 7-10 days of dosing.

Dosing Aptivus 500 mg with 200 mg ritonavircapsules twice daily for greater than 2 weeks and without meal restrictionproduced the pharmacokinetic parameters for male and female HIV-1positive patients presented in Table 5.

Table 5      Pharmacokinetic Parameters^a of tipranavir/ritonavir 500/200 mg for HIV-1 PositivePatients by Gender

Parameter	Females (n=14)	Males (n=106)
a Population pharmacokineticparameters reported as mean ± standard deviation
Cptrough (μM)	41.6 ± 24.3	35.6 ± 16.7
Cmax (μM)	94.8 ± 22.8	77.6 ± 16.6
Tmax (h)	2.9	3.0
AUC0-12h (μM-h)	851 ± 309	710 ± 207
CL (L/h)	1.15	1.27
V (L)	7.7	10.2
t1/2 (h)	5.5	6.0

Effectsof Food on Oral Absorption

For Aptivus capsules or oral solution co-administeredwith ritonavir capsules at steady-state, no clinically significantchanges in Aptivus C_max, Cp12h, and AUCwere observed under fed conditions compared to fasted conditions [ see Dosageand Administration (2) ]. The effect of food on Aptivus exposure when Aptivus capsulesor oral solution is co-administered with ritonavir tablets has not been evaluated [ see Dosage and Administration (2) ]. For information on the effect of food on the bioavailabilityof ritonavir tablets, please refer to the ritonavir tablet prescribinginformation.

Distribution

Tipranaviris extensively bound to plasma proteins (>99.9%). It binds to bothhuman serum albumin and α-1-acid glycoprotein. The mean fraction oftipranavir (dosed without ritonavir) unbound in plasma was similarin clinical samples from healthy volunteers and HIV-1 positive patients. Total plasma Aptivus concentrations for these samples ranged from9 to 82 μM. The unbound fraction of Aptivus appeared to be independentof total drug concentration over this concentration range.

No studies have been conducted to determinethe distribution of Aptivus into human cerebrospinal fluid or semen.

Metabolism

In vitro metabolism studies with human livermicrosomes indicated that CYP 3A4 is the predominant CYP enzyme involvedin Aptivus metabolism.

Theoral clearance of Aptivus decreased after the addition of ritonavir,which may represent diminished first-pass clearance of the drug atthe gastrointestinal tract as well as the liver.

The metabolism of Aptivus in the presence of 200mg ritonavir is minimal. Administration of ¹⁴C-tipranavir to subjects that received APTIVUS/ritonavir 500/200mg dosed to steady-state demonstrated that unchanged Aptivus accountedfor 98.4% or greater of the total plasma radioactivity circulatingat 3, 8, or 12 hours after dosing. Only a few metabolites were foundin plasma, and all were at trace levels. In feces, unchanged Aptivus represented the majorityof fecal radioactivity (79.9% of fecal radioactivity). The most abundantfecal metabolite, at 4.9% of fecal radioactivity (3.2% of dose), wasa hydroxyl metabolite of Aptivus. In urine, unchanged tipranavirwas found in trace amounts (0.5% of urine radioactivity). The mostabundant urinary metabolite, at 11.0% of urine radioactivity (0.5%of dose) was a glucuronide conjugate of Aptivus.

Elimination

Administrationof ¹⁴C-tipranavir to subjects (n=8) thatreceived APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstratedthat most radioactivity (median 82.3%) was excreted in feces, whileonly a median of 4.4% of the radioactive dose administered was recoveredin urine. In addition, most radioactivity (56%) was excreted between24 and 96 hours after dosing. The effective mean elimination half-lifeof tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infectedadult patients (n=120) was approximately 4.8 and 6.0 hours, respectively,at steady state following a dose of 500/200 mg twice daily with alight meal.

SpecialPopulations

Renal Impairment

Aptivus pharmacokinetics have not been studied in patientswith renal dysfunction. However, since the renal clearance of tipranaviris negligible, a decrease in total body clearance is not expectedin patients with renal insufficiency.

Hepatic Impairment

In a study comparing 9 HIV-1 negative patients with mild hepatic impairment to 9 HIV-1 negative controls,the single and multiple dose plasma concentrations of Aptivus andritonavir were increased in patients with hepatic impairment, butwere within the range observed in clinical trials. No dosing adjustmentis required in patients with mild hepatic impairment.

The influence of moderate hepatic impairment (Child-PughClass B) or severe hepatic impairment (Child-Pugh Class C) on themultiple-dose pharmacokinetics of Aptivus administered with ritonavirhas not been evaluated [ see Dosage and Administration (2), Contraindications (4.1), and Warnings and Precautions (5.1) ].

Gender

Evaluationof steady-state plasma Aptivus trough concentrations at 10-14 hafter dosing from the controlled clinical trials 1182.12 and 1182.48demonstrated that females generally had higher Aptivus concentrationsthan males. After 4 weeks of APTIVUS/ritonavir 500/200 mg BID, themedian plasma trough concentration of Aptivus was 43.9 μM for femalesand 31.1 μM for males. The difference in concentrations does not warranta dose adjustment.

Race

Evaluation of steady-stateplasma Aptivus trough concentrations at 10-14 h after dosing fromthe controlled clinical trials 1182.12 and 1182.48 demonstrated thatwhite males generally had more variability in Aptivus concentrationsthan black males, but the median concentration and the range makingup the majority of the data are comparable between the races.

Geriatric Patients

Evaluation of steady-state plasma tipranavirtrough concentrations at 10-14 h after dosing from the controlledclinical trials 1182.12 and 1182.48 demonstrated that there was nochange in median trough Aptivus concentrations as age increasedfor either gender through 65 years of age. There were an insufficientnumber of women greater than age 65 years in the two trials to evaluatethe elderly.

Pediatric Patients

Among pediatricpatients in clinical trial 1182.14, steady-state plasma tipranavirtrough concentrations were obtained 10 to 14 hours following studydrug administration. Pharmacokinetic parameters by age group are presentedin Table 6.

Parameter	2 to <6years (n=12)	6 to <12years (n=8)	12 to 18 years (n=6)
a Population pharmacokineticparameters reported as mean ± standard deviation
Cptrough (μM)	59.6 ± 23.6	66.3 ± 12.5	53.3 ± 32.4
Cmax (μM)	135 ± 44	151 ± 32	138 ± 52
Tmax (h)	2.5	2.6	2.7
AUC0-12h (μM-h)	1190 ± 332	1354 ± 256	1194 ± 517
CL/F (L/h)	0.34	0.45	0.99
V (L)	4.0	4.7	5.3
t1/2 (h)	8.1	7.1	5.2

DrugInteractions

Drug interaction studies were performed with APTIVUScapsules co-administered with ritonavir, and other drugs likely tobe co-administered and some drugs commonly used as probes for pharmacokineticinteractions. The effects of co-administration of Aptivus with 200mg ritonavir on the AUC, C_max, and C_min of Aptivus or the co-administered drug, are summarizedin Tables 7 and 8, respectively. For information regarding clinicalrecommendations see Drug Interactions (7.2) .

Table 7      Drug Interactions: PharmacokineticParameters for Aptivus in the Presence of Co-administered Drugs

Co-administered Drug	Co-administered Drug Dose (Schedule)	tipranavir/ritonavir Drug Dose (Schedule)	n	PK	Ratio (90% Confidence Interval) of Aptivus PharmacokineticParameters with/without Co-administered Drug; No Effect = 1.00
					Cmax	AUC	Cmin
*steady state comparison to historicaldata (n) ↑ increase, ↓ decrease, ↔ no change, ↕ unableto 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 (23doses)	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 (23doses)	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 (23doses)	25	↔	1.02 (0.94, 1.10)	1.02 (0.92, 1.13)	1.07 (0.86, 1.34)

Co-administered Drug	Co-administeredDrug Dose (Schedule)	tipranavir/ritonavirDrug Dose (Schedule)	n	PK	Ratio (90% ConfidenceInterval) of Co-administered Drug Pharmacokinetic Parameterswith/without tipranavir/ritonavir; No Effect= 1.00
					Cmax	AUC	Cmin
a HIV-1 positivepatients b Buprenorphine/Naloxonemaintenance patients c HIV-1positive patients (tipranavir/ritonavir 250 mg/200 mg, 750 mg/200mg and 1250 mg/100 mg) and healthy volunteers (tipranavir/ritonavir500 mg/100 mg and 750 mg/200 mg) d Normalized sum of parent drug (rifabutin) and active metabolite(25-O-desacetyl-rifabutin) e Intensive PK analysis f Druglevels obtained at 8-16 hrs post-dose g n = 14 for Cmin h Administered as Valacyclovir ↑ increase, ↓ decrease,↔ no change, ↕ unable to predict
Abacavira	300 mg BID (43 doses)	250/200 mg BID 750/100 mg BID 1250/100 mg BID (42 doses)	28 14 11	↓ ↓ ↓	0.56 (0.48, 0.66) 0.54 (0.47, 0.63) 0.48 (0.42, 0.53)	0.56 (0.49, 0.63) 0.64 (0.55, 0.74) 0.65 (0.55, 0.76)	- - -
Acyclovirh	500 mg (1 dose)	500/200 mg BID (23doses)	26	↔	0.95 (0.88, 1.02)	1.07 (1.04, 1.09)	-
Amprenavir/ritonavira	600/100 mg BID (27doses)	500/200 mg BID (28doses)	16 74	↓ ↓	0.61 (0.51, 0.73)e	0.56 (0.49, 0.64)e -	0.45 (0.38, 0.53)e 0.44 (0.39, 0.49)f
Atazanavir/ritonavir	300/100 mg QD (9doses)	500/100 mg BID (34doses)	13	↓	0.43 (0.38, 0.50)	0.32 (0.29, 0.36)	0.19 (0.15, 0.24)
Atorvastatin	10 mg (1 dose)	500/200 mg BID (17doses)	22	↑	8.61 (7.25, 10.21)	9.36 (8.02, 10.94)	5.19 (4.21, 6.40)
Orthohydroxy-atorvastatin			21, 12, 17	↓	0.02 (0.02, 0.03)	0.11 (0.08, 0.17)	0.07 (0.06, 0.08)
Parahydroxy-atorvastatin			13, 22, 1	↓	1.04 (0.87, 1.25)	0.18 (0.14, 0.24)	0.33 (NA)
Buprenorphine/ Naloxoneb	16/4 mg 24/6 mg (daily)	500/200 mg BID (16doses)
Buprenorphine			10	↔	0.86 (0.68, 1.10)	0.99 (0.80, 1.23)	0.94 (0.74, 1.19)
Carbamazepine	100 mg BID (29 doses)	500/200 mg (1 dose)	7	↔	1.04 (1.00, 1.07)	1.05 (1.02, 1.09)	1.17 (1.11, 1.24)
	(43 doses)	(15 doses)	7	↔	1.10 (0.85, 1.42)	1.08 (0.91, 1.27)	1.07 (0.90, 1.27)
	200 mg BID (29 doses)	500/200 mg (1 dose)	17	↔	1.00 (0.96, 1.04)	1.04 (1.00, 1.08)	1.16 (1.11, 1.22)
	(43 doses)	(15 doses)	17	↑	1.22 (1.11, 1.34)	1.26 (1.15, 1.38)	1.35 (1.22, 1.50)
Clarithromycin	500 mg BID (25doses)	500/200 mg BID (15doses)	21	↑	0.95 (0.83, 1.09)	1.19 (1.04, 1.37)	1.68 (1.42, 1.98)
14-OH-clarithromycin			21	↓	0.03 (0.02, 0.04)	0.03 (0.02, 0.04)	0.05 (0.04, 0.07)
Didanosinec	200 mg BID, ≥60 kg 125 mg BID, <60 kg (43 doses)	250/200 mg BID 750/100mg BID 1250/100 mg BID (42 doses)	10 8 9	↓ ↔ ↔	0.57 (0.42, 0.79) 0.76 (0.49, 1.17) 0.77 (0.47, 1.26)	0.67 (0.51, 0.88) 0.97 (0.64, 1.47) 0.87 (0.47, 1.65)	- - -
	400 mg (1 dose)	500/100 mg BID (27doses)	5	↔	0.80 (0.63, 1.02)	0.90 (0.72, 1.11)	1.17 (0.62, 2.20)
Efavirenzc	600 mg QD (15 doses)	500/100 mg BID 750/200mg BID (15 doses)	24 22	↔ ↔	1.09 (0.99, 1.19) 1.12 (0.98, 1.28)	1.04 (0.97, 1.12) 1.00 (0.93, 1.09)	1.02 (0.92, 1.12) 0.94 (0.84, 1.04)
Ethinyl estradiol	0.035 mg (1 dose)	500/100 mg BID 750/200mg BID (21 doses)	21 13	↓ ↓	0.52 (0.47, 0.57) 0.48 (0.42, 0.57)	0.52 (0.48, 0.56) 0.57 (0.54, 0.60)	- -
Fluconazole	200 mg (Day 1) then 100 mg QD (6 or 12 doses)	500/200 mg BID (2or 14 doses)	19 19	↔ ↔	0.97 (0.94, 1.01) 0.94 (0.91, 0.98)	0.99 (0.97, 1.02) 0.92 (0.88, 0.95)	0.98 (0.94, 1.02) 0.89 (0.85, 0.92)
Lopinavir/ritonavira	400/100 mg BID (27doses)	500/200 mg BID (28doses)	21 69	↓ ↓	0.53 (0.40, 0.69)e -	0.45 (0.32, 0.63)e -	0.30 (0.17, 0.51)e 0.48 (0.40, 0.58)f
Loperamide	16 mg (1 dose)	750/200 mg BID (21doses)	24	↓	0.39 (0.31, 0.48)	0.49 (0.40, 0.61)	-
N-Demethyl-Loperamide			24	↓	0.21 (0.17, 0.25)	0.23 (0.19, 0.27)	-
Lamivudinea	150 mg BID (43doses)	250/200 mg BID 750/100mg BID 1250/100 mg BID (42 doses)	64 46 35	↔ ↔ ↔	0.96 (0.89, 1.03) 0.86 (0.78, 0.94) 0.71 (0.62, 0.81)	0.95 (0.89, 1.02) 0.96 (0.90, 1.03) 0.82 (0.66, 1.00)	- - -
Methadone	5 mg (1 dose)	500/200 mg BID (16 doses)	14	↓	0.45 (0.41, 0.49)	0.47 (0.44, 0.51)	0.50 (0.46, 0.54)
R-methadone					0.54 (0.50, 0.58)	0.52 (0.49, 0.56)	-
S-methadone					0.38 (0.35, 0.43)	0.37 (0.34, 0.41)	-
Nevirapinea	200 mg BID (43doses)	250/200 mg BID 750/100mg BID 1250/100 mg BID (42 doses)	26 22 17	↔ ↔ ↔	0.97 (0.90, 1.04) 0.86 (0.76, 0.97) 0.71 (0.62, 0.82)	0.97 (0.91, 1.04) 0.89 (0.78, 1.01) 0.76 (0.63, 0.91)	0.96 (0.87, 1.05) 0.93 (0.80, 1.08) 0.77 (0.64, 0.92)
Norethindrone	1.0 mg (1 dose)	500/100 mg BID 750/200mg BID (21 doses)	21 13	↔ ↔	1.03 (0.94, 1.13) 1.08 (0.97, 1.20)	1.14 (1.06, 1.22) 1.27 (1.13, 1.43)	- -
Raltegravir	400 mg BID	500/200 mg BID	15	↓	0.82 (0.46, 1.46)	0.76 (0.49, 1.19)	0.45 (0.31, 0.66)g
Rifabutin	150 mg (1 dose)	500/200 mg BID (15 doses)	20	↑	1.70 (1.49, 1.94)	2.90 (2.59, 3.26)	2.14 (1.90, 2.41)
25-O-desacetyl-rifabutin			20	↑	3.20 (2.78, 3.68)	20.71 (17.66, 24.28)	7.83 (6.70, 9.14)
Rifabutin + 25-O- desacetyl-rifabutind			20	↑	1.86 (1.63, 2.12)	4.33 (3.86, 4.86)	2.76 (2.44, 3.12)
Rosuvastatin	10 mg (1 dose)	500/200 mg BID (24doses)	16	↑	2.23 (1.83, 2.72)	1.26 (1.08, 1.46)	1.06 (0.93, 1.20)
Saquinavir/ritonavira	600/100 mg BID (27doses)	500/200 mg BID (28doses)	20 68	↓ ↓	0.30 (0.23, 0.40)e -	0.24 (0.19, 0.32)e -	0.18 (0.13, 0.26)e 0.20 (0.16, 0.25)f
Stavudinea	40 mg BID ≥60 kg 30 mg BID <60 kg (43 doses)	250/200 mg BID 750/100mg BID 1250/100 mg BID (42 doses)	26 22 19	↔ ↔ ↔	0.90 (0.81, 1.02) 0.76 (0.66, 0.89) 0.74 (0.69, 0.80)	1.00 (0.91, 1.11) 0.84 (0.74, 0.96) 0.93 (0.83, 1.05)	- - -
Tadalafil	10 mg (1 dose)	500/200 mg (1 dose)	17	↑	0.78 (0.72, 0.84)	2.33 (2.02, 2.69)	-
	10 mg (1 dose)	500/200 mg BID (17doses)	17	↔	0.70 (0.63, 0.78)	1.01 (0.83, 1.21)	-
Tenofovir	300 mg (1 dose)	500/100 mg BID 750/200mg BID (23 doses)	22 20	↓ ↓	0.77 (0.68, 0.87) 0.62 (0.54, 0.71)	0.98 (0.91, 1.05) 1.02 (0.94, 1.10)	1.07 (0.98, 1.17) 1.14 (1.01, 1.27)
Zidovudinec	300 mg BID 300mg BID 300 mg BID (43 doses)	250/200 mg BID 750/100mg BID 1250/100 mg BID (42 doses)	48 31 23	↓ ↓ ↓	0.54 (0.47, 0.62) 0.51 (0.44, 0.60) 0.49 (0.40, 0.59)	0.58 (0.51, 0.66) 0.64 (0.55, 0.75) 0.69 (0.49, 0.97)	- - -
	300 mg (1 dose)	500/100 mg BID 750/200mg BID (23 doses)	29 25	↓ ↔	0.39 (0.33, 0.45) 0.44 (0.36, 0.54)	0.57 (0.52, 0.63) 0.67 (0.62, 0.73)	0.89 (0.81, 0.99) 1.25 (1.08, 1.44)
Zidovudine glucuronide		500/100 mg BID 750/200mg BID (23 doses)	29 25	↑ ↑	0.82 (0.74, 0.90) 0.82 (0.73, 0.92)	1.02 (0.97, 1.06) 1.09 (1.05, 1.14)	1.52 (1.34, 1.71) 1.94 (1.62, 2.31)

aptivus-figure-1

12.4 Microbiology

Mechanism of Action

Aptivus (TPV) is an HIV-1 protease inhibitorthat inhibits the virus-specific processing of the viral Gag and Gag-Polpolyproteins in HIV-1 infected cells, thus preventing formation ofmature virions.

Antiviral Activity

Aptivus inhibitsthe replication of laboratory strains of HIV-1 and clinical isolatesin acute models of T-cell infection, with 50% effective concentrations(EC₅₀) ranging from 0.03 to 0.07 μM (18-42ng/mL). Aptivus demonstrates antiviral activity in cell cultureagainst a broad panel of HIV-1 group M non-clade B isolates (A, C,D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolateshave reduced susceptibility in cell culture to Aptivus with EC₅₀ values ranging from 0.164 -1 μM and 0.233-0.522 μM,respectively. When used with other antiretroviral agents in cell culture,the combination of Aptivus was additive to antagonistic with otherprotease inhibitors (amprenavir, atazanavir, indinavir, lopinavir,nelfinavir, ritonavir, and saquinavir) and generally additive withthe NNRTIs (delavirdine, efavirenz, and nevirapine) and the NRTIs(abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir,and zidovudine). Aptivus was synergistic with the HIV-1 fusioninhibitor enfuvirtide. There was no antagonism of the cell culturecombinations of Aptivus with either adefovir or ribavirin, usedin the treatment of viral hepatitis.

Resistance

In cell culture:

HIV-1 isolates with a decreased susceptibility to Aptivus havebeen selected in cell culture and obtained from patients treated withAPTIVUS/ritonavir (TPV/ritonavir). After 9 months of culture in TPV-containingmedia, HIV-1 isolates with 87-fold reduced susceptibility to tipranavirwere selected in cell culture; these contained 10 protease substitutionsthat developed in the following order: L33F, I84V, K45I, I13V, V32I,V82L, M36I, A71V, L10F, and I54V/T. Changes in the Gag polyproteinCA/P2 cleavage site were also observed following drug selection. Experimentswith site-directed mutants of HIV-1 showed that the presence of 6substitutions in the protease coding sequence (I13V, V32I, L33F, K45I,V82L, I84V) conferred >10-fold reduced susceptibility to Aptivus.

Clinical Studies ofTreatment-Experienced Patients:

Incontrolled clinical trials 1182.12 and 1182.48, multiple proteaseinhibitor-resistant HIV-1 isolates from 59 treatment-experienced adultpatients who received APTIVUS/ritonavir and experienced virologicrebound developed amino acid substitutions that were associated withresistance to Aptivus. The most common amino acid substitutionsthat developed on 500/200 mg APTIVUS/ritonavir in greater than 20%of APTIVUS/ritonavir virologic failure isolates were L33V/I/F, V82T,and I84V. Other substitutions that developed in 10 to 20% of APTIVUS/ritonavirvirologic failure isolates included L10V/I/S, I13V, E35D/G/N, I47V,I54A/M/V, K55R, V82L, and L89V/M. Evolution at protease gag polyproteincleavage sites was also observed. Among 28 pediatric patients in clinicaltrial 1182.14 who experienced virologic failure or non-response, theemergent protease amino acid codon substitutions were similar to thoseobserved in adult virologic failure isolates.

In clinical trials 1182.12 and 1182.48 Aptivus resistancewas detected at virologic rebound after an average of 38 weeks ofAPTIVUS/ritonavir treatment with a median 14-fold decrease in tipranavirsusceptibility. Similarly, reduced Aptivus susceptibility was associatedwith emergent mutations in pediatric patient isolates.

Cross-resistance

Cross-resistance among protease inhibitors hasbeen observed. Aptivus had <4-fold decreased susceptibilityagainst 90% (94/105) of HIV-1 clinical isolates resistant to amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir. Tipranavir-resistant viruses which emerged in cell culture from wild-typeHIV-1 had decreased susceptibility to the protease inhibitors amprenavir,atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remainedsensitive to saquinavir.

Baseline Genotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baselinevirus may aid in determining Aptivus susceptibility before initiationof APTIVUS/ritonavir therapy. Several analyses were conducted to evaluatethe impact of specific substitutions and combination of substitutionson virologic outcome. Both the type and number of baseline proteaseinhibitor substitutions as well as use of additional active agents(e.g., enfuvirtide) affected APTIVUS/ritonavir response rates in controlledclinical trials 1182.12 and 1182.48 through Week 48 of treatment.

Regression analyses of baseline and/oron-treatment HIV-1 genotypes from 860 treatment-experienced patientsin Phase 2 and 3 trials demonstrated that amino acid substitutionsat 16 codons in the HIV-1 protease coding sequence were associatedwith reduced virologic responses and/or reduced Aptivus susceptibility:L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V,Q58E, H69K, T74P, V82L/T, N83D or I84V.

As-treated analyses were also conducted to assess virologicoutcome by the number of primary protease inhibitor substitutionspresent at baseline. Response rates were reduced if five or more proteaseinhibitor-associated substitutions were present at baseline and subjectsdid not receive concomitant new enfuvirtide with APTIVUS/ritonavir. See Table 9.

Table 9      Controlled Clinical Trials 1182.12 and 1182.48: Proportionof Responders (confirmed ≥1 log₁₀ decreaseat Week 48) by Number of Baseline Primary Protease Inhibitor (PI)Resistance Associated Substitutions

Number of Baseline Primary PI Mutationsa	APTIVUS/ritonavir N=578		Comparator PI/ritonavir N=610
	No New Enfuvirtideb	+ New Enfuvirtidec	No New Enfuvirtideb	+ New Enfuvirtidec
a PrimaryPI mutations include any amino acid substitution at positions 30,32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90
b No new enfuvirtideis defined as recycled or continued use of enfuvirtide or no use ofenfuvirtide
c New enfuvirtideis defined as initiation of enfuvirtide for the first time
Overall	38% (180/470)	69% (75/108)	18% (92/524)	26% (22/86)
1 - 2	62% (24/39)	60% (3/5)	33% (14/43)	0% (0/1)
3 - 4	48% (96/202)	71% (27/38)	23% (45/193)	38% (13/34)
5 +	26% (60/229)	69% (45/65)	11% (33/288)	18% (9/51)

The median change from baselinein plasma HIV-1 RNA at weeks 2, 4, 8, 16, 24 and 48 was evaluatedby the number of baseline primary protease inhibitor resistance associatedsubstitutions (1-4 or ≥5) in subjects who received APTIVUS/ritonavirwith or without new enfuvirtide. The following observations were made:

• Approximately 1.5 log₁₀ decreasein HIV-1 RNA at early time points (Week 2) regardless of the numberof baseline primary protease inhibitor resistance associated substitutions(1-4 or 5+).
• Subjects with 5 or more primary protease inhibitor resistanceassociated substitutions in their HIV-1 at baseline who received APTIVUS/ritonavirwithout new enfuvirtide (n=303) began to lose their antiviral responseafter Week 4.
• Early HIV-1 RNA decreases (1.5-2 log₁₀) were sustained through Week 48 in subjects with 5 or more primaryprotease inhibitor resistance associated substitutions at baselinewho received new enfuvirtide with APTIVUS/ritonavir (n=74).

Baseline Phenotypeand Virologic Outcome Analyses

APTIVUS/ritonavirresponse rates were also assessed by baseline Aptivus phenotype. Relationships between baseline phenotypic susceptibility to Aptivus,mutations at protease amino acid codons 33, 82, 84 and 90, tipranavirresistance-associated mutations, and response to APTIVUS/ritonavirtherapy at Week-48 are summarized in Tables 10 and 11. These baselinephenotype groups are not meant to represent clinical susceptibilitybreakpoints for APTIVUS/ritonavir because the data are based on theselect 1182.12 and 1182.48 patient population. The data are providedto give clinicians information on the likelihood of virologic successbased on pre-treatment susceptibility to APTIVUS/ritonavir in proteaseinhibitor-experienced patients.

Table 10      Response by BaselineTipranavir Phenotype at 48 weeks in the Controlled Clinical Trials1182.12 and 1182.48

Baseline Aptivus Phenotype (Fold Change)a	Proportionof Respondersb with No NewEnfuvirtidec Use N=211	Proportionof Respondersb with New Enfuvirtided Use N=68	TipranavirSusceptibility
a Change in Aptivus EC50 value from wild-typereference
b Confirmed ≥1 log10 decrease at Week 48
c No new enfuvirtide is defined as recycled or continued use of enfuvirtideor no use of enfuvirtide
d New enfuvirtide is defined as initiation of enfuvirtide for thefirst time
0-3	48% (73/153)	70% (33/47)	Susceptible
>3-10	21% (10/48)	53% (8/15)	Decreased Susceptibility
>10	10% (1/10)	50% (3/6)	Resistant

Baseline Aptivus Phenotype (Fold Change)a	# of BaselineProtease Mutations at 33, 82, 84, 90	# of BaselineTipranavir Resistance-Associated Mutationsb	TipranavirSusceptibilityc
a Change in Aptivus EC50 value from wild-typereference b Number of aminoacid substitutions in HIV-1 protease among L10V, I13V, K20M/R/V, L33F,E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T,N83D or I84V c defined by week48 response
0-3	0-2	0-4	Susceptible
>3-10	3	5-7	Decreased Susceptibility
>10	4	8+	Resistant

Analyses of pediatric clinical trial1182.14 also demonstrated that response to therapy was influencedby the number of baseline protease inhibitor mutations present.

13  NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in miceand rats have been conducted with Aptivus. Mice were administered30, 150 or 300 mg/kg/day Aptivus, 150/40 mg/kg/day tipranavir/ritonavirin combination, or 40 mg/kg/day ritonavir. The incidences of benignhepatocellular adenomas and combined adenomas/carcinomas were increasedin females of all groups except the low dose of Aptivus. Thesetumors were also increased in male mice at the high-dose of tipranavirand the tipranavir/ritonavir combination group. Hepatocellular carcinomaincidence was increased in female mice given the high dose of tipranavirand both sexes receiving tipranavir/ritonavir. The combination oftipranavir and ritonavir caused an exposure-related increase in thissame tumor type in both sexes. The clinical relevance of the carcinogenicfindings in mice is unknown. Systemic exposures in mice at all dose levels tested werebelow those in humans receiving the recommended dose level. Rats wereadministered 30, 100 or 300 mg/kg/day Aptivus, 100/26.7 mg/kg/daytipranavir/ritonavir in combination, or 10 mg/kg/day ritonavir. Nodrug-related findings in male rats were observed. At the highest doseof Aptivus, an increased incidence of benign follicular cell adenomasof the thyroid gland was observed in female rats. Based on AUC measurements,exposure to Aptivus at this dose level in rats is approximatelyequivalent to exposure in humans at the recommended therapeutic dose. This finding is probably not relevant to humans, because thyroid follicularcell adenomas are considered a rodent-specific effect secondary toenzyme induction.

Tipranavirshowed no evidence of mutagenicity or clastogenicity in a batteryof five in vitro and in vivo tests including the Ames bacterialreverse mutation assay using S. typhimurium and E. coli, unscheduledDNA synthesis in rat hepatocytes, induction of gene mutation in Chinesehamster ovary cells, a chromosome aberration assay in human peripherallymphocytes, and a micronucleus assay in mice.

Aptivus had no effect on fertility or early embryonicdevelopment in rats at dose levels up to 1000 mg/kg/day, equivalentto a C_max of 258 μM in females. Based on C_max levels in these rats, as well as an exposure (AUC)of 1670 μM·h in pregnant rats from another study, this exposure wasapproximately equivalent to the anticipated exposure in humans atthe recommended dose level of 500/200 mg APTIVUS/ritonavir BID.

13.2 Animal Toxicology and/or Pharmacology

In preclinical studies in rats, Aptivus treatmentinduced dose-dependent changes in coagulation parameters (increasedprothrombin time, increased activated partial thromboplastin time,and a decrease in some vitamin K dependent factors). In some rats,these changes led to bleeding in multiple organs and death. The co-administrationof vitamin E in the form of TPGS (d-alpha-tocopherol polyethyleneglycol 1000 succinate) with Aptivus resulted in a significant increasein effects on coagulation parameters, bleeding events, and death.

In preclinical studies of Aptivus indogs, an effect on coagulation parameters was not seen. Co-administrationof Aptivus and vitamin E has not been studied in dogs. Clinicalevaluation of coagulation effects on HIV-1-infected patients demonstratedno Aptivus plus ritonavir effect and no effect of the vitamin E-containingoral solution on coagulation parameters [ see Effectson Platelet Aggregation and Coagulation (5.4) ].

14  CLINICAL STUDIES

14.1 Adult Patients

The following clinical data is derivedfrom analyses of 48-week data from ongoing studies measuring effectson plasma HIV-1 RNA levels and CD4+ cell counts. At present thereare no results from controlled studies evaluating the effect of APTIVUS/ritonaviron clinical progression of HIV-1.

APTIVUS/ritonavir 500/200 mg BID + optimized background regimen vs. ComparatorProtease Inhibitor/ritonavir BID + OBR

The two clinical trials 1182.12and 1182.48 (RESIST 1 and RESIST 2) are ongoing, randomized, controlled,open-label, multicenter studies in HIV-1 positive, triple antiretroviralclass experienced patients. All patients were required to have previouslyreceived at least two protease inhibitor-based antiretroviral regimensand were failing a protease inhibitor-based regimen at the time ofstudy entry with baseline HIV-1 RNA at least 1000 copies/mL and anyCD4+ cell count. At least one primary protease gene mutation fromamong 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M hadto be present at baseline, with not more than two mutations at codons33, 82, 84 or 90.

These studiesevaluated treatment response at 48 weeks in a total of 1483 patientsreceiving either Aptivus co-administered with 200 mg of ritonavirplus OBR versus a control group receiving a ritonavir-boosted proteaseinhibitor (lopinavir, amprenavir, saquinavir or indinavir) plus OBR.Prior to randomization, OBR was individually defined for each patientbased on genotypic resistance testing and patient history. The investigatorhad to declare OBR, comparator protease inhibitor, and use of newenfuvirtide prior to randomization. Randomization was stratified bychoice of comparator protease inhibitor and use of new enfuvirtide.

After Week 8, patients in the control groupwho met the protocol defined criteria of initial lack of virologicresponse or confirmed virologic failure had the option of discontinuingtreatment and switching to APTIVUS/ritonavir in a separate roll-overstudy.

Demographics and baselinecharacteristics were balanced between the APTIVUS/ritonavir arm andcontrol arm. In both studies combined, the 1483 patients had a medianage of 43 years (range 17-80), and were 86.3% male, 75.6% white, 12.9%black, and 0.9% Asian. The median baseline plasma HIV-1 RNA for bothtreatment groups was 4.8 (range 2.0 to 6.8) log₁₀ copies/mL and median baseline CD4+ cell count was 162 (range 1 to1894) cells/mm³. Overall, 38.4% of patientshad a baseline HIV-1 RNA of >100,000 copies/mL, 58.6% had a baselineCD4+ cell count ≤200 cells/mm³, and 57.8%had experienced an AIDS defining Class C event at baseline.

Patients had prior exposure to a medianof 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 10.1% of patients had previouslyused enfuvirtide. In baseline patient samples (n=454), 97% of theHIV-1 isolates were resistant to at least one protease inhibitor,95% of the isolates were resistant to at least one NRTI, and >75%of the isolates were resistant to at least one NNRTI.

The individually pre-selected protease inhibitor basedon genotypic testing and the patient’s medical history was lopinavirin 48.7%, amprenavir in 26.4%, saquinavir in 21.8% and indinavir in3.1% of patients. A total of 85.1% were possibly resistant or resistantto the pre-selected comparator protease inhibitors. Approximately21% of patients used enfuvirtide during the study of which 16.6% inthe APTIVUS/ritonavir arm and 13.2% in the comparator/ritonavir armrepresented first time use of enfuvirtide (new enfuvirtide).

Treatment response and efficacy outcomesof randomized treatment through Week 48 of studies 1182.12 and 1182.48are shown in Table 12.

Table 12      Outcomes of Randomized Treatment Through Week48 (Pooled Studies 1182.12 and 1182.48)

Outcome		APTIVUS/ritonavir(500/200 mg BID) + OBR (N=746)		ComparatorProtease Inhibitor*/ritonavir + OBR (N=737)
*Comparatorprotease inhibitors were lopinavir, amprenavir, saquinavir or indinavirand 85.1% of patients were possibly resistant or resistant to thechosen protease inhibitors. aPatients achieved and maintained a confirmed ≥1 log10 HIV-1 RNA drop from baseline through Week 48 without prior evidenceof treatment failure. bPatientsdid not achieve a 0.5 log10 HIV-1 RNA dropfrom baseline and did not have viral load <100,000 copies/mL byWeek 8. cDeath only countedif it was the reason for treatment failure. dIncludes patients who were lost to-follow-up, withdrawnconsent, non-adherent, protocol violations, added/changed backgroundantiretroviral drugs for reasons other than tolerability or toxicity,or discontinued while suppressed.
Virologic Respondersa (confirmed at least 1 log10 HIV-1 RNA below baseline)		33.8%		14.9%
Virologic failures		55.1%		77.3%
	Initial lack of virologic response by Week 8b Rebound Never suppressed		33.0% 18.9% 3.2%		57.9% 16.4% 3.0%
Deathc or discontinued due to adverse events		5.9%		1.9%
	Death Discontinueddue to adverse events		0.5% 5.4%		0.3% 1.6%
Discontinued dueto other reasonsd		5.2%		5.8%

Through 48 weeks of treatment, theproportion of patients in the APTIVUS/ritonavir arm compared to thecomparator PI/ritonavir arm with HIV-1 RNA <400 copies/mL was 30.3%and 13.6% respectively, and with HIV-1 RNA <50 copies/mL was 22.7%and 10.2% respectively. Among all randomized and treated patients,the median change from baseline in HIV-1 RNA at the last measurementup to Week 48 was -0.64 log₁₀ copies/mL inpatients receiving APTIVUS/ritonavir versus -0.22 log₁₀ copies/mL in the comparator PI/ritonavir arm.

Among all randomized and treated patients, the medianchange from baseline in CD4+ cell count at the last measurement upto Week 48 was +23 cells/mm³ in patientsreceiving APTIVUS/ritonavir (N=740) versus +4 cells/mm³ in the comparator PI/ritonavir (N=727) arm.

Patients in the APTIVUS/ritonavir arm achieveda significantly better virologic outcome when APTIVUS/ritonavir wascombined with enfuvirtide. Among patients with new enfuvirtide use,the proportion of patients in the APTIVUS/ritonavir arm compared tothe comparator PI/ritonavir arm with HIV-1 RNA <400 copies/mL was52.4% and 19.6% respectively, and with HIV-1 RNA <50 copies/mLwas 37.3% and 14.4% respectively [ see Clinical Pharmacology (12.2, 12.4) ]. The median change from baseline in CD4+ cellcount at the last measurement up to Week 48 was +89 cells/mm³ in patients receiving APTIVUS/ritonavir in combinationwith newly introduced enfuvirtide (N=124) and +18 cells/mm³ in the comparator PI/ritonavir (N=96) arm.

14.2 Pediatric Patients

The pharmacokinetic profile, safety andactivity of APTIVUS/ritonavir was evaluated in a randomized, open-label,multicenter study. This study enrolled HIV-1 infected, treatment-experiencedpediatric patients (with the exception of 3 treatment-naïve patients),with baseline HIV-1 RNA of at least 1500 copies/mL. The age rangedfrom 2 through 18 years and patients were stratified by age (2 to<6 years, 6 to <12 years and 12 to 18 years). One hundred andten (110) patients were randomized to receive one of two APTIVUS/ritonavirdose regimens: 375 mg/m²/150 mg/m² dose (N=55) or 290 mg/m²/115 mg/m² dose (N=55), plus backgroundtherapy of at least two non-protease inhibitor antiretroviral drugs,optimized using baseline genotypic resistance testing. All patientsinitially received Aptivus oral solution. Pediatric patients who were12 years or older and received the maximum dose of 500/200 mg BIDcould subsequently change to Aptivus capsules at day 28 [ see Adverse Reactions (6.2), Usein Specific Populations (8.4), ClinicalPharmacology (12.3), and Microbiology (12.4) ].

Demographics and baseline characteristicswere balanced between the APTIVUS/ritonavir dose groups. The 110 randomizedpediatric patients had a median age of 11.7 years (range 2 to 18),and were 57.2% male, 68.1% white, 30% black, and 1.8% Asian. The medianbaseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log₁₀ copies/mL and median baseline CD4+ cell count was379 (range 2 to 2578) cells/mm³. Overall,37.4% of patients had a baseline HIV-1 RNA of >100,000 copies/mL;28.7% had a baseline CD4+ cell count ≤200 cells/mm³, and 48% had experienced a prior AIDS defining Class C event atbaseline. Patients had prior exposure to a median of 4 NRTIs, 1 NNRTI,and 2 PIs.

Eighty three (75%)completed the 48 week period while 25% discontinued prematurely. Ofthe patients who discontinued prematurely, 9 (8%) discontinued dueto virologic failure, and 9 (8%) discontinued due to adverse reactions.

At 48 weeks, 40% of patients had viralload <400 copies/mL. The proportion of patients with viral load<400 copies/mL tended to be greater (70%) in the youngest groupof patients, who had less baseline viral resistance, compared to theolder groups (37% and 31%). The HIV-1 RNA results are presented inTable 13.

Table13      Proportion of Patients with HIV-1 RNA <400 copies/mL (<50copies/mL) by age and dose*

APTIVUS/ritonavirDose Regimen	2 to <6 years (N=20)	6 to <12 years (N=38)	12 to18 years (N=52)
* The number of baseline Aptivus resistance-associatedsubstitutions were fewer in the 2 to <6 year old patients thanthe 6 to 18 year old patients enrolled in study 1182.14
375 mg/m2/150 mg/m2	n=10 70% (42%)	n=19 50% (39%)	n=26 33% (30%)
290 mg/m2/115 mg/m2	n=10 70% (54%)	n=19 37% (32%)	n=26 31% (23%)

The dose selection for all age groupswas based on the following:

• A greater proportion of patients receiving APTIVUS/ritonavir375 mg/m²/150 mg/m² compared to 290 mg/m²/115 mg/m² achieved HIV-1 RNA <400 and <50 copies/mL.
• A greater proportion of patients 6 to 18 years of age withmultiple baseline protease inhibitor resistance-associated substitutionsreceiving APTIVUS/ritonavir 375 mg/m²/150mg/m² achieved HIV-1 RNA <400 copies/mLat 48 weeks compared to patients receiving APTIVUS/ritonavir 290 mg/m²/115 mg/m².
• No clinically significant increase in adverse event ratesobserved with 375 mg/m²/150 mg/m² compared to 290 mg/m²/115mg/m².
• Overall, 6 (5%) patients ages 6 to 18 had AIDS definingillness during the treatment period and all received the 290 mg/m²/115 mg/m² dose.

The guidance for possible dose reductionfor patients who develop intolerance or toxicity and cannot continuewith APTIVUS/ritonavir 14 mg/kg/6 mg/kg (or 375 mg/m²/150 mg/m²) is based on the following:

• The 290 mg/m²/115 mg/m² twice daily regimen provided Aptivus plasma concentrationssimilar to those obtained in adults receiving 500/200 mg twice daily. The 375 mg/m²/150 mg/m² twice daily regimen provided Aptivus plasma concentrations 37%higher than those obtained in adults receiving 500/200 mg twice daily.
• The observed response rates for APTIVUS/ritonavir dose of290 mg/m²/115 mg/m² as shown in Table 13.

Dose reduction is not appropriatefor patients whose virus is resistant to more than one protease inhibitor.

When body surface area (BSA) dosing isconverted to mg/kg dosing, the APTIVUS/ritonavir 375 mg/m²/150 mg/m² twice dailyregimen is similar to 14 mg/kg/6 mg/kg and APTIVUS/ritonavir 290 mg/m²/115 mg/m² twice dailyregimen is similar to 12 mg/kg/5 mg/kg twice daily [ see Dosage and Administration (2.2) ].

16  HOW SUPPLIED/STORAGEAND HANDLING

APTIVUScapsules 250 mg are pink, oblong soft gelatin capsules imprinted inblack with "TPV 250". They are packaged in HDPE unit-of-use bottleswith a child resistant closure and 120 capsules. (NDC 0597-0003-02)

Aptivus oral solution is a clear yellowviscous buttermint-butter toffee flavored liquid containing 100 mgtipranavir in each mL. The solution is supplied in a unit-of-use amberglass 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 refrigerator2°-8°C (36°-46°F) prior to opening the bottle. Afteropening the bottle, the capsules may be stored at25°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 mustbe used within 60 days after first opening the bottle.

Store in a safe place out of the reachof children.

17  PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patientlabeling (Patient Information).

• Hepatic Impairment and Toxicity
  

  Inform patients that Aptivus co-administered with 200mg of ritonavir, has been associated with severe liver disease, includingsome deaths. Patients with signs or symptoms of clinical hepatitisshould 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 orC co-infection, as these patients have an increased risk of developinghepatotoxicity.
  

  Liver function tests should be performed prior to initiatingtherapy with Aptivus and 200 mg of ritonavir, and frequently throughoutthe duration of treatment. Patients with chronic hepatitis B or Cco-infection or elevations in liver enzymes prior to treatment areat increased risk (approximately 2-fold) for developing further liverenzyme elevations or severe liver disease. Caution should be exercisedwhen administering APTIVUS/ritonavir to patients with liver enzymeabnormalities or history of chronic liver disease. Increased liverfunction testing is warranted in these patients. Aptivus should notbe given to patients with moderate to severe hepatic impairment.
  

• Intracranial Hemorrhage
  

  Inform patients that Aptivus co-administered with 200mg of ritonavir has been associated with reports of both fatal andnon-fatal intracranial hemorrhage. Patients should report any unusualor unexplained bleeding to their physician.
  

• Drug Interactions
  

  Aptivus may interact with some drugs; therefore, advisepatients to report to their healthcare provider the use of any otherprescription or non-prescription medications or herbal products, particularlySt. John’s wort.
  

• Use of Vitamin E
  

  Advise patients taking Aptivus oral solution not totake supplemental vitamin E greater than a standard multivitamin asAPTIVUS oral solution contains 116 IU/mL of vitamin E and when takenat the recommended maximum dose of 500 mg/200 mg tipranavir/ritonavirBID, results in a daily dose of 1160 IU. This intake is higher thanthe Reference Daily Intake (adults 30 IU, pediatrics approximately10 IU).
  

• Rash
  

  Rash,including flat or raised rashes or sensitivity to the sun, have beenreported in approximately 10% of subjects receiving Aptivus. Somepatients who developed rash also had one or more of the followingsymptoms: joint pain or stiffness, throat tightness, generalized itching,muscle aches, fever, redness, blisters, or peeling of the skin. Womentaking birth control pills may get a skin rash. Tell patients to discontinueuse of Aptivus and call their physician right away if any of thesesymptoms develop.
  

• Sulfa Allergy
  

  Tell patients to report any history of sulfonamideallergy to the physician.
  

• Contraceptives
  

  Women receiving estrogen-based hormonal contraceptivesshould be instructed that additional or alternative contraceptivemeasures should be used during therapy with APTIVUS/ritonavir. Theremay be an increased risk of rash when Aptivus is given with hormonalcontraceptives.
  

• Fat Redistribution
  

  Inform patients that redistribution or accumulationof body fat may occur in patients receiving antiretroviral therapyand that the cause and long-term health effects of these conditionsare not known at this time.
  

• Administration
  

  Inform patients that Aptivus must be co-administeredwith ritonavir to ensure its therapeutic effect. Failure to correctlyco-administer Aptivus with ritonavir will result in reduced plasmalevels of Aptivus that may be insufficient to achieve the desiredantiviral effect.
  

  • Aptivus co-administered with ritonavir capsules or solutioncan be taken with or without meals
  • Aptivus co-administered with ritonavir tablets must onlybe taken with meals
  Tell patients that sustained decreasesin plasma HIV-1 RNA have been associated with a reduced risk of progressionto AIDS and death. Patients should remain under the care of a physicianwhile using Aptivus. Advise patients to take Aptivus and other concomitantantiretroviral therapy every day as prescribed. Aptivus, co-administeredwith ritonavir, must be given in combination with other antiretroviraldrugs. Patients should not alter the dose or discontinue therapy withoutconsulting with their healthcare professional. If a dose of APTIVUSis missed, patients should take the dose as soon as possible and thenreturn to their normal schedule. However, if a dose is skipped thepatient should not double the next dose.
  

  Aptivus is not a cure for HIV-1 infection and patientsmay continue to experience illnesses associated with HIV-1 infection,including opportunistic infections. Patients should remain under thecare of a physician when using Aptivus.
  

  Patients should be advised to avoid doing things thatcan spread HIV-1 infection to others.
  

  • Do not share needles or other injectionequipment.
  • Do not share personal items that can haveblood 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 polyurethanecondom to lower the chance of sexual contact with semen, vaginal secretions,or blood.
  • Do not breastfeed. Itis not known if Aptivus can be passed to your baby in your breastmilk and whether it could harm your baby. Also, mothers with HIV-1should not breastfeed because HIV-1 can be passed to the baby in thebreast milk.

FDA-Approved PatientLabeling

Patientinformation is supplied as a tear-off following the full prescribinginformation.

Distributed by:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield,CT 06877 USA

Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY.

APTIVUS® is a registeredtrademark used under license from Boehringer Ingelheim InternationalGmbH

Copyright © 2016 BoehringerIngelheim International GmbH

ALL RIGHTS RESERVED

OT2000SI212016

10003515/15

PatientInformation

APTIVUS®

(tipranavir) capsules 250 mg

APTIVUS®

(tipranavir) oral solution 100 mg/mL

Read the Patient Information that comeswith Aptivus before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the placeof talking with your healthcare professional about your medical conditionor treatment. You should stay under a healthcare professional’s carewhile taking Aptivus.

What is the most important information I should know about Aptivus?

Patientstaking Aptivus, together with 200 mg NORVIR^® (ritonavir), may develop severe liver disease that can cause death. If you develop any of the following symptoms of liver problems, youshould stop taking Aptivus and NORVIR^® (ritonavir)and call your healthcare professional right away: tiredness, generalill feeling or "flu-like" symptoms, loss of appetite, nausea (feelingsick to your stomach), yellowing of your skin or whites of your eyes,dark (tea-colored) urine, pale stools (bowel movements), or pain,ache, or sensitivity on your right side below your ribs. If you havechronic hepatitis B or C infection, your healthcare professional shouldcheck your blood tests more often because you have an increased chanceof developing liver problems.

Patients taking Aptivus together with200 mg NORVIR^® (ritonavir) may developbleeding in the brain that can cause death.

You should report any unusualor unexplained bleeding to your healthcare professional if you aretaking Aptivus together with NORVIR^® (ritonavir).

Whatis Aptivus?

Aptivus is a medicine called a "protease inhibitor" that is usedto treat adults with Human Immunodeficiency Virus (HIV). Aptivus blocksHIV protease, an enzyme which is needed for HIV to make more virus. When used with other anti-HIV medicines, Aptivus may reduce the amountof HIV in your blood and increase the number of CD4+ cells. Reducingthe amount of HIV in the blood may keep your immune system healthy,so it can help fight infections.

Aptivus is always taken with NORVIR^® (ritonavir)and at the same time as NORVIR. When you take Aptivus with NORVIR,you must always use at least 2 other anti-HIV medicines.

Does Aptivus cure HIV orAIDS?

APTIVUSdoes not cure HIV infection or AIDS and you may continue to experienceillnesses associated with HIV-1 infection, including opportunisticinfections. You should remain under the care of a doctor when usingAPTIVUS.

Avoid doing things thatcan spread HIV-1 infection.

• Do not share needles or other injectionequipment.
• Do not share personal items that can haveblood 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 polyurethanecondom to lower the chance of sexual contact with semen, vaginal secretions,or blood.

Who should not takeAPTIVUS?

Do not take Aptivus if you:

• are allergic to Aptivus or any of the other ingredientsin Aptivus. See the end of this leaflet for a list of major ingredients.
• are allergic to NORVIR® (ritonavir)
• have moderate to severe liver problems
• take any of the following types of medicines because you could have serious side effects:
  • Migraine headache medicines called "ergot alkaloids". Ifyou take migraine headache medicines, ask your healthcare professionalor pharmacist if any of them are "ergot alkaloids".
  • Halcion^® (triazolam)
  • Orap^® (pimozide)
  • Propulsid^® (cisapride)
  • Versed^® (midazolam) taken orally
  • Pacenone^® (amiodarone)
  • Vascor^® (bepridil)
  • Tambocor^® (flecainide)
  • Rythmol^® (propafenone)
  • Quinaglute dura^® (quinidine)
  • Zocor^® (simvastatin)
  • Mevacor^® (lovastatin)
  • Uroxatral^® (alfuzosin)
  • Revatio^® (sildenafil) for treatmentof pulmonary arterial hypertenstion
  • Lipitor^® (atorvastatin)
  • Latuda^® (lurasidone)
  
  

• take St. John’s wort or Rifampin. It may result in reducedvirologic activity and possible resistance to Aptivus or to theclass of protease inhibitors.

What should I tellmy healthcare professional before I take Aptivus?

Tell your healthcareprofessional about all of your medical conditions, including if you:

• have hemophilia or another medical conditionthat increases your chance of bleeding, or are taking medicines whichincrease your chance of bleeding. These patientsmay have an increased chance of bleeding.
• have liver problems orare infected with hepatitis B or hepatitis C. These patients may haveworsening of their liver disease.
• are allergic to sulfa medicines.
• have diabetes. APTIVUSmay worsen diabetes or high blood sugar levels.
• are pregnant or planning to become pregnant. It is not known if Aptivus can harm your unborn baby. Youand your healthcare professional will need to decide if Aptivus isright for you. If you take Aptivus while you are pregnant, talk toyour healthcare professional about how you can be in the AntiretroviralPregnancy Registry.
• are breast-feeding. Do not breastfeed. It is not known if Aptivus can be passed to your baby inyour breast milk and whether it could harm your baby. Also, motherswith HIV-1 should not breastfeed because HIV-1 can be passed to thebaby in the breast milk.
• are using estrogens for birth control orhormone replacement. Women who use estrogens forbirth control or hormone replacement have an increased chance of developinga skin rash while taking Aptivus. If a rash occurs, it is usuallymild to moderate, but you should talk to your healthcare professionalas you may need to temporarily stop taking either Aptivus or the othermedicine that contains estrogen or female hormones.

Tell your healthcareprofessional about all the medicines you take includingprescription and nonprescription medicines, vitamins and herbal supplements. Aptivus and many other medicines can interact. Sometimesserious side effects will happen if Aptivus is taken with certainother medicines .

• Some medicines cannot be taken at all with Aptivus.
• Some medicines will require a change in dosage if takenwith Aptivus.
• Some medicines will require close monitoring if taken withAPTIVUS.

Do not take Flonase® (fluticasone),Viagra® (sildenafil), Cialis® (tadalafil), Levitra® (vardenafil) orSeroquel® (quetiapine) with APTIVUS/ritonavir without first speakingwith your healthcare professional.

Women taking birth control pills need to use another birth controlmethod. Aptivus makes birth control pills work less well.

If you are taking Aptivus oral solution,which contains vitamin E, you should not take additional vitamin Eother than that contained in a standard multivitamin.

Know all the medicines you take andkeep a list of them with you. Show this list toall your healthcare professionals and pharmacists anytime you geta new medicine you take. They will tell you if you can take theseother medicines with Aptivus. Do not start any newmedicines while you are taking Aptivus without first talking withyour healthcare professional or pharmacist. Youcan ask your healthcare professional or pharmacist for a list of medicinesthat can interact with Aptivus.

How should I take Aptivus?

• Take Aptivus exactly as your healthcare professional hasprescribed. You should check with your healthcare professional orpharmacist if you are not sure. You must take APTIVUSat the same time as NORVIR^® (ritonavir). The adult dose is 500 mg (two 250 mg capsules) of Aptivus,together with 200 mg (two 100 mg capsules/tablets or 2.5 mL of solution)of NORVIR, twice per day. Aptivus with NORVIR must be used togetherwith other anti-HIV medicines.
  • Aptivus taken with ritonavir capsules orsolution can be taken with or without meals
  • Aptivus taken with ritonavir tablets must only be taken with meals
• Children 2 years of age or older can also take Aptivus withritonavir. The child’s healthcare professional will decide the rightdose based on the child’s weight or size. The dose should not exceedthe recommended adult dose.
• Aptivus should not be used in children under 2 years ofage.

Aptivus comes in capsule and oralsolution forms. You should swallow Aptivus capsuleswhole. Do not chew the capsules

• Do not change your dose or stop taking Aptivus without talkingwith your healthcare professional.
• If you take too much Aptivus, call your healthcare professionalor poison control center right away.
• If you forget to take Aptivus, take the next dose of Aptivus,together with NORVIR^® (ritonavir), as soonas possible. Do not take a double dose to make up for a missed dose.
• It is very important to take all your anti-HIV medicinesas prescribed and at the right times of day. This can help your medicineswork better. It also lowers the chance that your medicines will stopworking to fight HIV (drug resistance).
• When your Aptivus supply starts to run low, get more fromyour healthcare professional or pharmacy. This is very important becausethe amount of virus in your blood may increase if the medicine isstopped for even a short period of time. The HIV virus may developresistance to Aptivus and become harder to treat. You should NEVERstop taking Aptivus or your other HIV medicines without talking withyour healthcare professional.

What are the possibleside effects of Aptivus?

Aptivus may cause serious side effects,including:

• liver problems, including liver failureand death. Your healthcare professional should doblood tests to monitor your liver function during treatment with Aptivus. Patients with liver diseases such as hepatitis B and hepatitis C mayhave worsening of their liver disease with Aptivus and should havemore frequent monitoring of blood tests.
• bleeding in the brain. This has occurred in patients treated with Aptivus in clinical trialsand can lead to permanent disability or death. Many of the patientsexperiencing bleeding in the brain had other medical conditions orwere receiving other medications that may have caused or added tobleeding in the brain. Patients with hemophilia or another medicalcondition that increases the chance of bleeding, or patients takingmedicines that may cause bleeding may have an increased chance ofbleeding in the brain.
• rash. Rash, includingflat or raised rashes or sensitivity to the sun, have been reportedin approximately 10% of subjects receiving Aptivus. Some patientswho developed rash also had one or more of the following symptoms:joint pain or stiffness, throat tightness, generalized itching, muscleaches, fever, redness, blisters, or peeling of the skin. Women takingbirth control pills may get a skin rash. If you develop any of thesesymptoms, stop using Aptivus and call your healthcare professionalright away.
• increased bleeding in patients with hemophilia. This can happen in patients taking Aptivus or other proteaseinhibitor medicines.
• diabetes and high blood sugar (hyperglycemia). This can happen in patients taking Aptivus or other proteaseinhibitor medicines. Some patients have diabetes before starting treatmentwith Aptivus which gets worse. Some patients get diabetes during treatmentwith Aptivus. Some patients will need changes in their diabetes medicine. Some patients will need new diabetes medicine.
• increased blood fat (lipid) levels. Your healthcare professional should do blood tests to monitoryour blood fat (triglycerides and cholesterol) during treatment withAPTIVUS. Some patients taking Aptivus have large increases in triglyceridesand cholesterol. The long-term chance of having a heart attack orstroke due to increases in blood fats caused by Aptivus is not knownat this time.
• changes in body fat. Thesechanges have happened in patients taking Aptivus and other anti-HIVmedicines. The changes may include an increased amount of fat in theupper back and neck (“buffalo hump”), breast, and around the back,chest, and stomach area. Loss of fat from the legs, arms, and facemay also happen. The cause and long-term health effects of these conditionsare not known.

The most common side effects of APTIVUSinclude diarrhea, nausea, fever, vomiting, tiredness, headache, andstomach pain. Rash was seen more frequently in children.

It may be hard to tell the difference betweenside effects caused by Aptivus, by the other medicines you are alsotaking, or by the complications of HIV infection. For this reasonit is very important that you tell your healthcare professional aboutany changes in your health. You should report any new or continuingsymptoms to your healthcare professional right away. Your healthcareprofessional may be able to help you manage these side effects.

The list of side effects is not complete. Ask your healthcare professionalor pharmacist for more information.

How should I store Aptivus?

• Store Aptivus capsules in a refrigerator at approximately 36°F to 46°F (2°C to 8°C). Once the bottleis opened, the contents must be used within 60 days. Patients maytake the bottle with them for use away from home so long as the bottleremains at a temperature of approximately 59°F to86°F (15°C to 30°C). You can write the date of openingthe bottle on the label. Do not use after the expiration date writtenon the bottle.
• Store Aptivus oral solution at approximately 59°F to 86°F (15°C to 30°C). Do not refrigerate or freeze. The solution must be used within 60 days after first openingof the bottle.
• Keep Aptivus and all medicines out of thereach of children.

General advice aboutAPTIVUS

Medicinesare sometimes prescribed for purposes other than those listed in aPatient Information leaflet. Do not use Aptivus for a condition forwhich it was not prescribed. Do not give Aptivus to other people,even if they have the same condition you have. It may harm them.

This leaflet summarizes the most importantinformation about Aptivus. If you would like more information, talkwith your healthcare professional. You can ask your pharmacist orhealthcare professional for information about Aptivus that is writtenfor health professionals.

For current prescribing information, scan the code below or for additionalinformation, you may also call Boehringer Ingelheim Pharmaceuticals,Inc. at 1-800-542-6257, or 1-800-459-9906 TTY.

What are the ingredients in Aptivus?

Capsules:

ActiveIngredient: Aptivus

Major Inactive Ingredients: dehydrated alcohol, polyoxyl 35 castor oil, propylene glycol,mono/diglycerides of caprylic/capric acid and gelatin.

Oral Solution:

ActiveIngredient: Aptivus

Major Inactive Ingredients: polyethylene glycol 400, vitamin E polyethylene glycol succinate,purified water, and propylene glycol.

Scan Here Distributed by:

Boehringer Ingelheim Pharmaceuticals, Inc.

Ridgefield,CT 06877 USA

Aptivus^® is a registered trademark used under license fromBoehringer Ingelheim International GmbH

Copyright © 2016 Boehringer Ingelheim InternationalGmbH

ALL RIGHTS RESERVED

OT2000SI212016

10003515/15

Revised: September 2016

Aptivus Oral Solution 100 mg/mL Label

NDC 0597–0002–01

Aptivus Capsules 250 mg Label

NDC: 0597–0003–02

Aptivus OralSolution 100 mg/ML Carton

NDC: 0597–0002–01

Aptivus Carton

Aptivus pharmaceutical active ingredients containing related brand and generic drugs:

• Tipranavir

Aptivus available forms, composition, doses:

• APTIVUS 250MG CAPSULE
• Capsules; Oral; Tipranavir 250 mg
• Solution; Oral; 100 mg / ml

Aptivus destination | category:

• Human:
• HIV protease inhibitors

Aptivus Anatomical Therapeutic Chemical codes:

• J05AE09 - Tipranavir

Aptivus pharmaceutical companies:

• Boehringer Ingelheim

References

1. Dailymed."APTIVUS (TIPRANAVIR) CAPSULE, LIQUID FILLED APTIVUS (TIPRANAVIR) SOLUTION [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."TIPRANAVIR: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "Tipranavir". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Aptivus?

Depending on the reaction of the Aptivus after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Aptivus not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Aptivus addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Aptivus, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Aptivus consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology