Aptivus

Generic Name: Tipranavir
Class: HIV Protease Inhibitors
VA Class: AM800
Chemical Name: 2-Pyridinesulfonamide, –(3 - [[1R] - 1 - [[6R] - 5,6 - dihydro - 4 - hydroxy - 2 - oxo - 6 - [2 - phenylethyl] - 6 - propyl - 2H - pyran - 3 - yl]propyl]phenyl) - 5 - (trifluoromethyl) -
Molecular Formula: C₃₁H₃₃F₃N₂O₅S
CAS Number: 174484-41-4

Introduction

Antiretroviral; HIV protease inhibitor (PI).^{1 4}

Uses for Aptivus

Treatment of HIV Infection

Treatment of HIV-1 infection.¹ Must be used in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir) and other antiretroviral agents.¹

Used in patients who are antiretroviral-experienced and infected with HIV-1 resistant to multiple HIV PIs.¹

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Not recommended in antiretroviral-naive individuals because of inferior virologic efficacy.^{1 200}

Risks versus benefits not established in pediatric patients <2 years of age.¹

Consider the following factors when initiating ritonavir-boosted tipranavir: Use with other active antiretrovirals is associated with greater likelihood of treatment response; genotypic or phenotypic viral resistance testing and/or treatment history should guide therapy; number of baseline primary PI mutations affects virologic response to the drug; caution advised in patients at increased risk of hepatotoxicity or bleeding or in patients receiving certain drugs concomitantly.¹ (See Cautions and see Interactions.)

Aptivus Dosage and Administration

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).^{1 200} Do not use without low-dose ritonavir.^{1 200}

Take tipranavir and low-dose ritonavir at same time.¹

If tipranavir is taken with ritonavir capsules or oral solution, take the drugs with or without meals.¹

If tipranavir is taken with ritonavir tablets, take the drugs with a meal.¹

Capsules

Swallow tipranavir capsules whole; do not chew.¹

Assess children for ability to swallow capsules; consider oral solution in those unable to reliably swallow capsules.¹

Oral Solution

Use oral solution in those who have difficulty swallowing capsules.¹

Oral solution is a clear yellow viscous liquid; supplied with an oral dispensing syringe.¹

Dosage

Pediatric Patients

Treatment of HIV Infection

Oral

Dosage is based on body weight or body surface area.¹ To avoid medication errors, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.¹

Children 2–18 years of age: 14 mg/kg (375 mg/m²) twice daily with ritonavir 6 mg/kg (150 mg/m²) twice daily.¹ If this dosage is not tolerated due to adverse effects, consider reducing dosage to 12 mg/kg (290 mg/m²) twice daily with ritonavir 5 mg/kg (115 mg/m²) twice daily provided the virus is not resistant to multiple HIV PIs.¹

Adults

Treatment of HIV Infection

Oral

500 mg twice daily with low-dose ritonavir (200 mg twice daily).¹

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Do not exceed adult dosage.¹

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in mild hepatic impairment (Child-Pugh class A).¹ Contraindicated in moderate or severe hepatic impairment (Child-Pugh class B or C).¹

Renal Impairment

Renal clearance of tipranavir negligible; decreased total body clearance not expected in renal impairment.¹ Some experts state dosage adjustment not necessary.²⁰⁰

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Aptivus

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C).¹

• Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, certain antiarrhythmics, cisapride, ergot alkaloids, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], oral midazolam, triazolam, lovastatin, simvastatin).¹ (See Specific Drugs under Interactions.)

• Concomitant use with potent CYP3A inducers (e.g., rifampin, St. John’s wort [Hypericum perforatum]) when such use may result in decreased plasma concentrations of tipranavir and possible loss of virologic response.¹

Warnings/Precautions

Sensitivity Reactions

Dermatologic Reactions

Mild to moderate rash, including maculopapular rash and possible photosensitivity reactions reported.¹ Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus also reported.¹ Discontinue if severe rash occurs.¹

Rash reported in healthy, HIV-negative women receiving a single dose of ethinyl estradiol followed by ritonavir-boosted tipranavir.^{1 6} (See Estrogens/Progestins under Interactions.)

Sulfonamide Sensitivity

Tipranavir contains a sulfonamide moiety; use with caution in patients with known sulfonamide allergy.¹ Potential for cross-sensitivity between drugs with sulfonamide moieties and tipranavir unknown.¹

Hepatic Effects

Hepatitis and hepatic decompensation (including some fatalities) reported; causal relationship not established.¹ Hepatotoxicity generally has occurred in patients with advanced HIV infection receiving multiple concomitant drugs.¹

Increased concentrations of serum hepatic transaminases (grade 3 and 4) reported.¹

Evaluate hepatic function prior to and frequently during treatment.¹ Patients with coexisting HBV or HCV infection or elevated serum transaminases prior to therapy may be at increased risk for hepatotoxicity, including further transaminase increases or hepatic decompensation.¹

Discontinue if signs or symptoms of hepatitis develop, if asymptomatic increases in serum AST or ALT of >10 times the ULN occur, or if asymptomatic increases in AST or ALT of 5–10 times the ULN and increases in total bilirubin of >2.5 times the ULN develop.¹

Clinicians and patients should be vigilant for appearance of signs or symptoms of hepatitis (e.g., fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, acholic stools, liver tenderness, hepatomegaly).¹ (See Hepatic Impairment under Cautions.)

Intracranial Hemorrhage

Intracranial hemorrhage (including some fatalities) reported.^{1 9} Other medical conditions or concomitant therapy may have caused or contributed to these events.^{1 9}

Ritonavir-boosted tipranavir therapy not associated with abnormal coagulation parameters; abnormal coagulation parameters have not preceded intracranial hemorrhage.^{1 9} Change in coagulation parameters (e.g., increased PT, increased aPTT, decreased vitamin K dependent factors) observed in rats given tipranavir; effects on these parameters increased in rats given concomitant vitamin E in the form of d-alpha-tocopherol polyethylene glycol 1000 succinate; changes in coagulation parameters not observed in other species (i.e., dogs) given tipranavir.¹

Manufacturer states that routine monitoring of coagulation parameters not necessary.¹

Interactions

Tipranavir must be used with low-dose ritonavir (ritonavir-boosted tipranavir).¹ Failure to administer with recommended low-dose ritonavir will result in subtherapeutic tipranavir concentrations and inadequate antiviral response.¹ Consider the usual cautions, precautions, and contraindications associated with ritonavir.¹

Concomitant use with certain drugs is not recommended or requires particular caution (e.g., sildenafil, tadalafil, vardenafil).^{1 200} (See Specific Drugs under Interactions.)

Effects on Platelets and Coagulation

Tipranavir inhibits platelet aggregation in vitro.¹

Caution advised in patients who may be at risk for increased bleeding from trauma, surgery, or other medical conditions; those receiving concomitant drugs known to increase the risk of bleeding (i.e., anticoagulants, antiplatelet agents); and those receiving high-dose vitamin E.¹

Vitamin E

Each mL of tipranavir oral solution contains 116 units of vitamin E.¹ Vitamin E content of usual dosages of this formulation exceeds recommended daily intake.¹

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus or exacerbation of preexisting diabetes mellitus reported with use of HIV PIs; diabetic ketoacidosis has occurred.¹

Initiate or adjust antidiabetic therapy (e.g., insulin, oral hypoglycemic agents) as needed.¹ (See Oral Hypoglycemic Agents under Interactions.)

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii], reactivation of herpes simplex and herpes zoster); this may necessitate further evaluation and treatment.¹

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and general cushingoid appearance.¹

Lipid Effects

Increased concentrations of total serum cholesterol and triglycerides reported.¹

Determine serum cholesterol and triglyceride concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate.¹ (See HMG-CoA Reductase Inhibitors under Interactions.)

Hemophilia A and B

Spontaneous bleeding reported with HIV PIs; causal relationship not established.¹

Use with caution in patients with history of hemophilia A or B.¹ Increased hemostatic therapy (e.g., antihemophilic factor) may be needed.¹

HIV Resistance

Potential for cross-resistance with other HIV PIs not evaluated.¹ Effect of ritonavir-boosted tipranavir therapy on subsequent therapy with other HIV PIs unknown.¹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263 or .^{1 202}

Some experts state safety and pharmacokinetic data insufficient to recommend routine ritonavir-boosted tipranavir in pregnant women.²⁰²

Lactation

Not known whether distributed into milk.^{6 202}

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.¹

Pediatric Use

Safety and efficacy not established in children <2 years of age.¹

Adverse effects reported in children generally similar to those reported in adults; rash reported more frequently in children than in adults.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

Use with caution and monitor because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Hepatic Impairment

Use caution since tipranavir concentrations may be increased.¹

Contraindicated in moderate or severe hepatic impairment (Child-Pugh class B or C).^{1 200}

Risk for further elevations in hepatic enzyme concentrations or severe liver disease in patients with chronic HBV or HCV or increased AST or ALT concentrations prior to therapy.¹ (See Hepatic Effects under Cautions.)

Common Adverse Effects

Diarrhea, nausea, pyrexia, fatigue, vomiting, headache, abdominal pain.¹

Interactions for Aptivus

Drug interaction studies were conducted using ritonavir-boosted tipranavir.¹

Tipranavir metabolized principally by CYP3A4.¹

Tipranavir with low-dose ritonavir inhibits CYP3A and 2D6.¹

Tipranavir is a P-glycoprotein substrate and is both a weak inhibitor and potent inducer of P-glycoprotein transport system.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A4 with possible alteration in metabolism of tipranavir, ritonavir, and/or other drug.¹

Inducers or Inhibitors of the P-glycoprotein Transport System

Pharmacokinetic interactions likely with drugs that are P-glycoprotein inhibitors or inducers with possible altered metabolism of tipranavir or the other drug.¹

Specific Drugs

Drug	Interaction	Comments
Abacavir	Decreased abacavir AUC1 In vitro evidence of additive antiretroviral effects 1	Clinical importance unknown1 Appropriate dosages for concomitant use with respect to safety and efficacy not established 1 200
Alfuzosin	Possible increased alfuzosin concentrations and risk of hypotension1	Concomitant use contraindicated1
Antacids	Decreased tipranavir concentrations and AUC1	Administer ritonavir-boosted tipranavir 2 hours before or 1 hour after antacids200
Antiarrhythmic agents (amiodarone, flecainide, propafenone, quinidine)	Possible increased concentrations of antiarrhythmic agents1	Concomitant use contraindicated1
Anticoagulants (warfarin)	Possible altered warfarin concentrations;200 potential for increased risk of bleeding1	Use with caution;1 monitor INR, especially when initiating or discontinuing ritonavir-boosted tipranavir; adjust warfarin dosage as needed1 200
Anticonvulsants (carbamazepine, phenobarbital, phenytoin, valproic acid)	Carbamazepine: Possible increased carbamazepine concentrations; possible decreased tipranavir concentrations1 200 Phenobarbital, phenytoin: Possible decreased tipranavir concentrations1 200 Valproic acid: Possible decreased valproic acid concentrations and decreased anticonvulsant efficacy1	Carbamazepine, phenytoin: Use with caution;1 consider an alternative anticonvulsant; if used concomitantly, monitor anticonvulsant and tipranavir concentrations200 Phenobarbital, valproic acid: Use with caution1
Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)	Fluconazole: Increased tipranavir concentrations and AUC;1 200 no clinically important effect on fluconazole concentrations1 Itraconazole or ketoconazole: Increased antifungal concentrations1 Voriconazole: Altered voriconazole concentration1 200	Fluconazole: Fluconazole dosage adjustment not needed, but fluconazole dosage >200 mg daily not recommended;1 200 if high fluconazole dosage indicated, consider an alternative HIV PI or antiretroviral agent from another class200 Itraconazole or ketoconazole: Use concomitantly with caution; antifungal dosage >200 mg daily not recommended 1 200 Voriconazole: Do not use concomitantly unless potential benefits outweigh risks;200 if used, consider monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly200
Antimycobacterials, rifamycins (rifabutin, rifampin)	Rifabutin: Increased rifabutin concentrations; no change in tipranavir concentrations200 1 Rifampin: Possible decreased tipranavir concentrations; possible decreased antiretroviral activity and increased risk of tipranavir resistance1 200 Rifapentine: Possible decreased tipranavir concentrations200	Rifabutin: Reduce rifabutin dosage to 150 mg every other day or 3 times weekly (further reduction may be needed); increase monitoring for adverse effects;1 200 monitor for antimycobacterial response and consider therapeutic drug monitoring200 Rifampin: Concomitant use contraindicated 1 Rifapentine: Concomitant use not recommended200
Antiplatelet agents	Potential for increased risk of bleeding1
Atazanavir	Ritonavir-boosted tipranavir: Decreased atazanavir concentrations and AUC and increased tipranavir concentrations and AUC1 In vitro evidence of additive to antagonistic antiretroviral effects1	Atazanavir (with or without low-dose ritonavir): Concomitant use not recommended1
Benzodiazepines	Possible increased concentrations of midazolam or triazolam; potential for serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression)1	Concomitant use with oral midazolam or triazolam contraindicated;1 some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation200
Boceprevir	Concomitant use with ritonavir-boosted tipranavir not studied; concomitant use with other ritonavir-boosted PIs (ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) decreases concentrations and AUCs of boceprevir and the HIV PIs17 185 and may reduce efficacy of HCV and HIV treatment17 18 Concomitant use with low-dose ritonavir alone results in decreased boceprevir concentrations and AUC185	Concomitant use with ritonavir-boosted PIs not recommended12 If boceprevir was initiated for treatment of chronic HCV in a patient coinfected with HIV receiving a suppressive antiretroviral regimen containing a ritonavir-boosted PI, inform patient of possible drug interaction and closely monitor for HCV treatment response and potential HCV and HIV virologic rebound12 17 18 200
Bosentan	Possible increased bosentan concentrations1	In patients already receiving ritonavir-boosted tipranavir for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir-boosted tipranavir; after ≥10 days of ritonavir-boosted tipranavir, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1
Buprenorphine, buprenorphine/naloxone	Decreased tipranavir concentrations;1 200 no effect on clinical efficacy of buprenorphine/naloxone1	Dosage adjustments cannot be recommended;1 consider monitoring tipranavir concentrations200
Bupropion	Decreased bupropion AUC200	Titrate bupropion dosage based on clinical response200
Calcium-channel blocking agents (e.g., diltiazem, felodipine, nicardipine, nisoldipine, verapamil)	Altered concentrations of calcium-channel blocking agents 1	Use concomitantly with caution; clinical monitoring recommended1
Colchicine	Increased colchicine concentrations1	Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir-boosted tipranavir1 Colchicine for treatment of gout flares: In those receiving ritonavir-boosted tipranavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1 Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted tipranavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1 Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted tipranavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1
Cisapride	Potential for serious and/or life-threatening effects such as cardiac arrhythmias 1	Concomitant use contraindicated1
Clarithromycin	Slightly increased clarithromycin concentrations; decreased hydroxyclarithromycin concentrations; increased tipranavir concentrations1 200	Modification of usual dosage of clarithromycin or tipranavir not necessary in patients with normal renal function; reduce clarithromycin dosage by 50% if Clcr 30–60 mL/minute and reduce by 75% if Clcr <30 mL/minute1 200
Corticosteroids (fluticasone)	Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations with ritonavir-boosted tipranavir resulting in decreased cortisol concentrations1 200 Systemic dexamethasone: Possible decreased tipranavir concentrations200	Fluticasone nasal spray/oral inhalation: Concomitant use with ritonavir-boosted tipranavir not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 200 Systemic dexamethasone: Use concomitantly with caution;200 consider alternative corticosteroid for long-term use200
Darunavir	Data not available regarding concomitant use200 No in vitro evidence of antagonistic antiretroviral effects 204
Delavirdine	In vitro evidence of additive antiretroviral effects 1
Didanosine	Decreased didanosine concentrations and decreased tipranavir concentrations1 In vitro evidence of additive antiretroviral effects 1	For optimal absorption, administer didanosine at least 2 hours before or after tipranavir 1 200
Disulfiram	Potential pharmacokinetic interaction with alcohol contained in tipranavir capsules; possible disulfiram-like reaction1
Efavirenz	Decreased tipranavir concentrations and no change in efavirenz concentrations using tipranavir 500 mg twice daily and ritonavir 100 mg twice daily with efavirenz 600 mg once daily1 In vitro evidence of additive antiretroviral effects 1	Some experts state dosage adjustments not necessary200
Emtricitabine	In vitro evidence of additive antiretroviral effects 1
Enfuvirtide	Increased tipranavir trough concentrations1 In vitro evidence of synergistic antiretroviral effects1	Dosage adjustments not recommended1
Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	Potential for serious or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of extremities)1	Concomitant use contraindicated 1 If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving tipranavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202
Estrogens/Progestins	Hormonal contraceptives: Decreased ethinyl estradiol concentrations with oral contraceptive preparations1 200	Use alternative nonhormonal or additional contraception methods1 200 Hormone replacement: Monitor for signs of estrogen deficiency1 200
Etravirine	Decreased etravirine concentrations and possible decreased antiretroviral efficacy; increased tipranavir concentrations200 214 No in vitro evidence of antagonistic antiretroviral effects214	Do not used concomitantly200 214
Fosamprenavir	Possible decreased amprenavir concentrations1	Concomitant use not recommended;1 200 appropriate dosages for concomitant use with respect to safety and efficacy not established200
HMG-CoA reductase inhibitors (statins)	Atorvastatin, lovastatin, rosuvastatin, simvastatin: Increased concentrations and AUCs of the antilipemic agent and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 186 200	Atorvastatin: Avoid concomitant use1 186 200 Lovastatin: Concomitant use contraindicated1 186 200 Rosuvastatin: Dosage adjustments not necessary200 Simvastatin: Concomitant use contraindicated1 186 200
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Potential for altered immunosuppressive agent concentrations1	Monitor plasma concentrations of immunosuppressive agent if used concomitantly1
Lamivudine	Pharmacokinetic interactions unlikely1 In vitro evidence of additive antiretroviral effects1
Loperamide	Decreased loperamide concentrations; no clinically important change in tipranavir concentrations1
Lopinavir/ritonavir	Decreased lopinavir concentrations and AUC1 200 In vitro evidence of additive to antagonistic or additive to synergistic antiretroviral effects1 207	Concomitant use not recommended;1 200 appropriate dosages for concomitant use with respect to safety and efficacy not established200
Maraviroc	No clinically important effect on maraviroc pharmacokinetics200 224 No in vitro evidence of antagonistic antiretroviral effects 224	Recommended maraviroc dosage is 300 mg twice daily, provided regimen does not include a potent CYP3A inhibitor or inducer14 200 224
Meperidine	Potential for decreased meperidine concentrations, increased normeperidine concentrations 1	Manufacturer of tipranavir does not recommend increasing meperidine dosage or concomitant long-term use because of potential for increased normeperidine concentrations and possible analgesic and CNS-stimulating activity (e.g., seizures) 1
Methadone	Decreased methadone concentrations;1 opiate withdrawal unlikely but may occur200	Methadone dosage adjustment may be necessary;1 monitor for opioid withdrawal and increase methadone dosage as clinically indicated200
Metronidazole	Potential interaction with alcohol present in tipranavir capsules; possible disulfiram-like reaction1
Nelfinavir	In vitro evidence of additive to antagonistic antiretroviral effects1
Nevirapine	No clinically important effect on nevirapine concentrations;1 200 effect on tipranavir concentrations unknown200 In vitro evidence of additive antiretroviral effects 1	Dosage adjustments not necessary200
Omeprazole	Decreased omeprazole concentrations; no change in tipranavir concentrations1	Increased omeprazole dosage may be necessary1
Oral antidiabetic agents (glimepiride, glipizide, glyburide, pioglitazone, repaglinide, tolbutamide)	Potential for altered concentrations of antidiabetic agents1	Careful glucose monitoring warranted 1
Pimozide	Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias)1	Concomitant use contraindicated1
Raltegravir	Decreased raltegravir concentrations and AUC1	Dosage adjustments not needed1 200
Rilpivirine	Possible increased rilpivirine concentrations; not expected to affect tipranavir concentrations226 No in vitro evidence of antagonistic antiretroviral effects 226	Dosage adjustments not necessary200
Ritonavir	Increased tipranavir concentrations and AUC;1 200 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted tipranavir)1
St. John’s wort (Hypericum perforatum)	Potential decreased tipranavir concentration; possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance1	Concomitant use contraindicated1
Salmeterol	Possible increased salmeterol concentrations and increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia1	Concomitant use not recommended1
Saquinavir	Decreased saquinavir concentrations and AUC1 In vitro evidence of additive to antagonistic antiretroviral effects1	Concomitant use not recommended;1 200 appropriate dosages for concomitant use with respect to safety and efficacy not established200
Selective serotonin-reuptake inhibitors (SSRIs)	Fluoxetine, paroxetine, sertraline: Possible increased SSRI concentrations.1	SSRI dosage adjustment may be necessary when ritonavir-boosted tipranavir is initiated1
Sildenafil	Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1	Sildenafil for treatment of pulmonary arterial hypertension (PAH): Concomitant use with ritonavir-boosted tipranavir contraindicated1 Sildenafil for treatment of erectile dysfunction: Do not exceed sildenafil dosage of 25 mg once every 48 hours; closely monitor for sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1
Stavudine	Pharmacokinetic interaction unlikely1 In vitro evidence of additive antiretroviral effects 1
Tadalafil	Possible increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1	Tadalafil for treatment of PAH in patients who have been receiving ritonavir-boosted tipranavir for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, may increase dosage to 40 mg once daily1 Ritonavir-boosted tipranavir in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating ritonavir-boosted tipranavir; after ≥1 week of the antiretroviral agent, may resume tadalafil at dosage of 20 mg once daily and, if tolerated, may increase dosage to 40 mg once daily1 Tadalafil for treatment of erectile dysfunction: Do not exceed tadalafil dosage of 10 mg once every 72 hours; closely monitor for tadalafil-related adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection, syncope)1 Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily200
Telaprevir	Concomitant use with low-dose ritonavir alone results in decreased telaprevir concentrations and AUC184 Concomitant use with ritonavir-boosted tipranavir not studied; concomitant use with other ritonavir-boosted PIs (ritonavir-boosted atazanavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, lopinavir/ritonavir) decreases concentrations and AUC of telaprevir and decreases concentrations of some of the HIV PIs (darunavir, fosamprenavir)184	Concomitant use not recommended pending further accumulation of data200
Tenofovir	Decreased tenofovir concentrations and AUC; possible decreased tipranavir concentrations and AUC1 200 In vitro evidence of additive antiretroviral effects1	Dosage adjustments not necessary200
Trazodone	Possible increased trazodone concentrations and AUC1 200 Increased risk of trazodone-associated adverse effects (e.g., nausea, dizziness, hypotension, syncope)1	Use with caution;1 consider reduced trazodone dosage;1 use lowest possible trazodone dosage and monitor for CNS and cardiovascular adverse effects200
Tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline)	Amitriptyline, desipramine, imipramine, nortriptyline: Possible increased concentrations of the tricyclic antidepressant1 200	Desipramine: Use reduced desipramine dosage and monitor plasma desipramine concentrations1 Amitriptyline, imipramine, nortriptyline: Use lowest possible antidepressant dosage; titrate antidepressant dosage based on clinical assessment and/or antidepressant concentrations200
Valacyclovir	No clinically important effect on tipranavir or acyclovir concentrations or AUC1
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1	Vardenafil for treatment of erectile dysfunction: Do not exceed vardenafil dosage of 2.5 mg once every 72 hours; closely monitor for vardenafil-related adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1
Vitamin E	Potential for increased risk of bleeding with high-dose vitamin E1
Zidovudine	Decreased zidovudine AUC1 200 In vitro evidence of additive antiretroviral effects1	Clinical importance unknown1 200 Appropriate dosage for concomitant use not established 1 200

Aptivus Pharmacokinetics

Absorption

Bioavailability

Tipranavir is administered concomitantly with low-dose ritonavir (ritonavir-boosted tipranavir).¹ Ritonavir decreases metabolism of tipranavir, resulting in increased tipranavir plasma concentrations.¹

Following >2 weeks of multiple oral doses given without regard to meals, peak plasma tipranavir concentrations attained approximately 3 hours after a dose.¹

Steady state attained in most patients after 7–10 days.¹ Steady-state trough concentrations are 70% lower than day 1, presumably due to intestinal p-glycoprotein induction.¹

Food

Compared with administration in the fasting state, administration of tipranavir (as capsules or oral solution) and ritonavir (as capsules) with a meal (500–682 kcal, 23–25% calories from fat) does not have a clinically important effect on tipranavir peak plasma concentrations or AUC.¹

Effect of food on administration of tipranavir (as capsules or oral solution) with ritonavir (as tablets) not evaluated.¹

Distribution

Extent

Not known whether distributed into CSF or semen.¹

Not known whether distributed into milk.¹

Plasma Protein Binding

>99%.¹

Binds to albumin and α₁-acid-glycoprotein.¹

Elimination

Metabolism

Tipranavir extensively metabolized by CYP3A4.¹ Only minimal metabolism of tipranavir occurs when administered with ritonavir 200 mg.¹

Oral clearance of tipranavir decreased when administered with ritonavir; this may indicate decreased first-pass effect.¹

Elimination Route

Following administration of ritonavir-boosted tipranavir, eliminated principally in feces as unchanged tipranavir.¹ Approximately 82% of tipranavir dose excreted in feces and 4% excreted in urine.¹

Half-life

Effective mean elimination half-life at steady-state is 4.8–6 hours following administration of ritonavir-boosted tipranavir with a light meal.¹

Special Populations

Renal impairment: Pharmacokinetics not studied, but decreased total body clearance not expected since renal clearance of tipranavir is negligible.¹

Mild hepatic impairment (Child-Pugh class A): increased plasma concentrations, but dosage adjustments not needed.¹ Pharmacokinetics in moderate and severe impairment (Child-Pugh class B and C) not evaluated.¹

Higher tipranavir concentrations reported in females compared with males; dosage adjustments not required.¹

Stability

Storage

Oral

Capsules

2–8°C prior to opening bottle;¹ after opening bottle, store at 25°C (may be exposed to 15–30°C) and use within 60 days.¹

Oral Solution

25°C (may be exposed to 15–30°C);¹ do not refrigerate or freeze.¹ After opening bottle, use within 60 days.¹

Actions and Spectrum

• Tipranavir must be administered in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).¹

• Tipranavir is extensively metabolized by CYP3A; ritonavir is a potent inhibitor of CYP3A.¹ Concomitant use of these drugs results in decreased metabolism and increased plasma concentrations of tipranavir.¹

• Antiretroviral activity is due to tipranavir.¹

• Active against HIV-1¹ Also has some activity against HIV type 2 (HIV-2) in vitro.¹³

• Tipranavir inhibits replication of HIV-1 by interfering with HIV proteases.¹

• Tipranavir-resistant HIV-1, including strains with decreased susceptibility to other HIV PIs, has been reported.¹

Advice to Patients

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.¹ Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.¹

• Importance of using tipranavir with low-dose ritonavir; importance of using these 2 drugs in conjunction with other antiretrovirals.¹

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.¹ Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.¹

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.²⁰⁰ Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.^{1 200}

• Importance of reading patient information provided by the manufacturer.¹

• Importance of taking tipranavir at the same time as ritonavir.¹ If tipranavir is taken with ritonavir capsules or oral solution, take the drugs with or without meals.¹ If tipranavir is taken with ritonavir tablets, take the drugs with a meal.¹

• Importance of swallowing tipranavir capsules whole; capsules should not be chewed.¹

• If a dose is missed, take the dose as soon as it is remembered and take next dose at regularly scheduled time.¹ If a dose is skipped, do not take a double dose to make up for the missed dose.¹

• Importance of patient informing their clinician if they are allergic to sulfonamides.¹

• Possibility of fatal or nonfatal intracranial hemorrhage.¹ Importance of informing clinician of unusual or unexplained bleeding.¹

• Advise patients that severe liver disease (including fatalities) reported.¹ Importance of discontinuing ritonavir-boosted tipranavir and seeking medical attention if signs or symptoms of liver disease (fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, hepatomegaly) occur.¹

• Need for periodic clinical and laboratory monitoring, including liver function tests, prior to and during treatment.¹ Importance of extra vigilance in patients with chronic HBV or HCV coinfection because of increased risk of hepatotoxicity.¹

• Possibility of rash.¹ Importance of discontinuing ritonavir-boosted tipranavir and seeking medical attention if rash with or without joint pain or stiffness, throat tightness, generalized itching, muscle aches, fever, redness, blisters, or skin peeling occurs.¹

• Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., vitamin E supplements) and herbal products (e.g., St. John’s wort), and any concomitant illnesses.¹

• Advise patients receiving selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism) and that any symptoms should be promptly reported to their clinician.¹ Ritonavir-boosted tipranavir should not be used concomitantly with sildenafil used for treatment of pulmonary arterial hypertension (PAH).¹

• Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of the potential interaction with hormonal contraceptives.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise HIV-infected women not to breast-feed.¹

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tipranavir

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	250 mg	Aptivus	Boehringer Ingelheim
	Solution	100 mg/mL	Aptivus	Boehringer Ingelheim

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Aptivus 250MG Capsules (BOEHRINGER INGELHEIM): 120/$1,138.02 or 360/$3,366.83