Tipranavir

Trade Names:
Aptivus
- Capsules 250 mg

Pharmacology

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Tipranavir is a nonpeptide protease inhibitor that prevents formation of mature virions by inhibiting virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells.

Pharmacokinetics

Absorption

In combination with ritonavir: T _max is approximately 3 h; C _max is approximately 95 mcM (women) and 78 mcM (men). Administration with high-fat meal increases bioavailability.

Distribution

Greater than 99.9% protein bound (albumin and alpha-1 acid glycoprotein). Vd is 7.7 L (women) and 10.2 L (men).

Metabolism

Metabolized primarily by CYP3A4. Metabolism in presence of ritonavir is minimal.

Elimination

The t _½ is approximately 6 h. Approximately 82% is excreted in feces (mostly as unchanged tipranavir) and 4% in urine.

Special Populations

Since renal Cl is negligible, renal function impairment is not expected to decrease total body Cl.

Tipranavir and ritonavir plasma concentrations are increased in patients with mild hepatic function impairment (Child-Pugh class A).

Women generally have higher tipranavir concentrations.

Based upon steady-state median plasma trough concentration and range of values, the majority of data are comparable between races.

Indications and Usage

In combination with ritonavir 200 mg for the treatment of HIV-1–infected adult patients with evidence of viral replication who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.

Contraindications

Moderate and severe (Child-Pugh class B and C, respectively) hepatic function impairment; use with drugs highly dependent on CYP3A for clearance for which elevated plasma concentrations are associated with serious or life-threatening events (eg, antiarrhythmic agents [amiodarone, bepridil, flecainide, propafenone, quinidine], antihistamines [eg, astemizole, terfenadine], cisapride, ergot derivative [eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine], midazolam, pimozide, triazolam); hypersensitivity to any component of the product.

Dosage and Administration

PO 500 mg (two 250 mg capsules), coadministered with ritonavir 200 mg, twice daily.

General Advice

• Must be coadministered with ritonavir 200 mg to achieve effective plasma levels on twice-daily regimen.
• Administer each dose with food.
• Swallow capsules whole. Do not open, crush, or chew.

Storage/Stability

Store capsules in refrigerator (36° to 46°F) prior to opening bottle. After opening bottle, store capsules at controlled room temperature (59° to 86°F) and use within 60 days.

Drug Interactions

Tipranavir/ritonavir plasma concentrations may be reduced, decreasing the pharmacologic effects.

Coadministration with tipranavir in combination with ritonavir is contraindicated.

Tipranavir plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Plasma concentrations of these agents may be elevated by tipranavir/ritonavir, increasing the pharmacologic and adverse reactions. Dosage adjustment may be needed.

Fluconazole may increase tipranavir concentrations. Doses of fluconazole, itraconazole, or ketoconazole greater than 200 mg/day are not recommended.

Interactions with these agents have not been studied; however, caution is warranted and monitoring is recommended.

Because tipranavir capsules contain alcohol, a disulfiram-like reaction may occur.

Plasma concentrations of these agents may be reduced by tipranavir/ritonavir, decreasing the pharmacologic effects. Monitor women receiving estrogen replacement therapy for estrogen deficiency.

Should not be coadministered with tipranavir in combination with ritonavir.

Interactions with these agents have not been studied; however, methadone and meperidine concentrations may be reduced, decreasing the pharmacologic effect, and the concentrations of the meperidine metabolite, normeperidine, may be elevated, increasing the risk of seizures. Dosage increase and long-term use of meperidine is not recommended.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions were reported in patients receiving tipranavir/ritonavir.

CNS

Fatigue (4%); headache (3%); asthenia, depression (2%); insomnia (1%); decreased appetite, dizziness, intracranial hemorrhage, malaise, peripheral neuropathy, sleep disorder, somnolence (less than 2%).

Dermatologic

Rash (2%); acquired lipodystrophy, exanthema, lipoatrophy, lipohypertrophy, pruritus (less than 2%).

GI

Diarrhea (11%); nausea (7%); abdominal pain, vomiting (3%); abdominal distension, anorexia, dyspepsia, flatulence, gastroesophageal reflux disease, pancreatitis (less than 2%).

Genitourinary

Renal insufficiency (less than 2%).

Hematologic-Lymphatic

Anemia, neutropenia, thrombocytopenia (less than 2%).

Hepatic

Hepatic failure, hepatitis (less than 2%).

Lab Tests

Increased triglycerides (26%); abnormal LFT (18%); hypercholesterolemia (11%); decreased WBC (4%); hyperamylasemia (3%); increased hepatic enzymes, increased lipase (less than 2%).

Metabolic-Nutritional

Dehydration, diabetes mellitus, facial wasting, hyperglycemia, weight decreased (less than 2%).

Musculoskeletal

Muscle cramps, myalgia (less than 2%).

Respiratory

Bronchitis (3%); cough (1%); dyspnea (less than 2%).

Miscellaneous

Pyrexia (5%); hypersensitivity, influenza-like illness, reactivation of herpes simplex and varicella zoster (less than 2%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined. HIV-infected mothers should not breast-feed infants to avoid risking potential transmission of HIV to infant.

Children

Safety and efficacy not established.

Elderly

Exercise caution in the administration and monitoring of tipranavir, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Hepatic Function

Use with caution in patients with mild hepatic function impairment (Child-Pugh class A). Contraindicated in patients with moderate or severe hepatic function impairment (Child-Pugh class B or C).

Special Risk Patients

Use with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other medical conditions, or who are receiving medication known to increase the risk of bleeding (eg, antiplatelet drugs).

Diabetes mellitus/hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes, and hyperglycemia have been reported in patients receiving protease inhibitor therapy.

Fat redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and cushingoid appearance, have been reported.

Hemophilia

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, and increased need for factor VIII have been reported in patients with hemophilia A and B treated with protease inhibitors.

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy.

Lipid elevations

Large increases in total cholesterol and triglycerides have been reported.

Rash

Mild to moderate rashes, including urticarial, maculopapular, possible photosensitivity, and rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus, have been reported.

Sulfa allergy

Tipranavir contains a sulfonamide moiety. Use with caution in patients with known sulfonamide allergy.

Overdosage

Symptoms

None known.

Patient Information

• Advise patient or caregiver to read the patient information leaflet before starting therapy and with each refill.
• Instruct patient that a dose of ritonavir must be taken at the same time as each dose of the tipranavir in order to ensure max benefit. Caution patient that taking tipranavir by itself can result in therapeutic failure.
• Warn patient that tipranavir/ritonavir combination must also be taken in combination with at least 2 other antiviral agents, and not to change the dose or stop taking any of the other antiviral agents unless advised by health care provider.
• Instruct patient to take tipranavir exactly as prescribed and not to change the dose or discontinue therapy unless advised health care provider.
• Advise patient to take tipranavir with food to increase effectiveness. Caution patient to swallow capsules whole and not to crush, chew, or open.
• Advise patient that if a dose is missed, to take the dose as soon as possible and then return to normal schedule. However, if a dose is skipped, caution patient not to double the dose to catch up, but to continue with normal schedule.
• Instruct patient to discontinue therapy and immediately seek medical evaluation if signs or symptoms of clinical hepatitis develop (eg, appetite loss, dark urine, frequent or persistent nausea, general body discomfort or flu-like symptoms, pale stools, persistent fatigue, tenderness or swelling in right side of stomach area below ribs, yellowing of skin or eyes).
• Advise patient that tipranavir may cause changes in body fat distribution (eg, increased amount of fat in upper back and neck, breasts, and around the back, chest, and stomach area; or loss of fat from arms, legs, and face) and that the cause and long-term health effects of these changes are not know at this time. Advise patient to report changes in body fat distribution to health care provider.
• Inform patient that tipranavir does not completely eliminate HIV virus and, therefore, does not reduce risk of transmitting HIV to others. Appropriate precautions (eg, practice safe sex using a latex or polyurethane condom to lower chance of sexual contact with semen, vaginal secretions, or blood; not using or sharing dirty needles) must still be followed.
• Advise patient that tipranavir is not a cure for HIV infection, and illnesses associated with HIV infection, including opportunistic infections, may continue to be acquired. Patient should remain under health care provider's care.
• Instruct patient not to take any prescription or OTC medications, herbal preparations, or dietary supplements, particularly St. John's wort, unless advised by health care provider. Caution patient not to start any new medication or dietary supplement without talking to health care provider first.
• Instruct patients with diabetes to monitor blood glucose more frequently when drug is started and to inform health care provider of significant changes in readings.
• Advise women using estrogen-based hormonal contraceptives to use additional or alternative contraceptive measures during therapy with tipranavir/ritonavir. Also, patients may have a greater chance of developing a rash while using estrogen-based hormonal contraceptives.
• Advise patients to report any unusual or unexplained bleeding to health care provider.
• Caution HIV-infected mother that breast-feeding could cause HIV infection in the baby.

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