Tipranavir

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[edit] STRUCTURE

Tipranavir.jpg

[edit] MECHANISM OF ACTION

Tipranavir, is a protease inhibitor. It blocks an enzyme required for the proteolytic cleavage of the viral polyprotein precursors to the individual proteins found in infectious HIV. The cleavage of these viral polyproteins is essential for the maturation of infectious virus.
Tipranavir binds to the active site of HIV protease and prevents cleavage of the polyproteins, resulting in the formation of immature non-infectious viral particles.

Tipranavir, taken in combination with other antiviral medicines, reduces the amount of HIV in the blood and keeps it at a low level.
Tipranavir does not cure HIV infection or AIDS, but it may delay the damage to the immune system and the development of infections and diseases associated with AIDS.

Tipranavir is used with Ritonavir, another protease inhibitor that is used as a ‘booster’. Ritonavir inhibits CYP3A4, that normally metabolizes protease inhibitors, therfore, it slows down the rate at which Tipranavir is broken down, increasing its levels in the blood.

[edit] INDICATIONS

Tipranavir is indicated in combination with ritonavir and other antiretroviral agents, to treat patients who are treatment-experienced, aged 2 years and over who are infected with human immunodeficiency virus type 1 (HIV-1), a virus that causes acquired immune deficiency syndrome (AIDS).

Tipranavir should only be used in patients who have no other treatment options. It is used in patients who have already been treated with other antiviral medicines for HIV infection, and in whom HIV-1 strains are resistant to more than one protease inhibitor.

Tipranavir/Ritonavir should not be used in treatment-naïve patients.

[edit] DOSAGE

  • Adults: 500 mg Tipranavir, co-administered with 200 mg ritonavir, twice daily
  • Pediatric patients (age 2 to 18 years): Dosing is based on body weight or body surface area not to exceed adult dose. The recommended dose is 14 mg/kg with 6 mg/kg ritonavir taken twice daily not to exceed a maximum dose of 500 mg co-administered with ritonavir 200 mg twice daily.

[edit] DOSAGE FORMS AND STRENGTHS

  • Capsules: 250 mg
  • Oral solution: 100 mg/mL

[edit] CONTRAINDICATIONS

  • Patients with moderate or severe (Child-Pugh Class B or C) hepatic impairment
  • Use with drugs highly dependent on CYP3A4 for clearance or are potent CYP3A4 inducers. Drugs that are Contraindicated with Tipranavir Co-Administered with Ritonavir are:
Drug Class
Drugs Within Class That Are Contraindicated With Tipranavir/Ritonavir
Clinical Comment
Alpha 1-adrenoreceptorantagonist Alfuzosin
Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics
Amiodarone, bepridil, flecainide, propafenone, quinidine
Potential for serious and/or life-threatening cardiac arrhythmia.
Antimycobacterial Agents
Rifampicin
Plasma concentrations of Tipranivir can be reduced by concomitant use of rifampicin. This may lead to loss of therapeutic effect and possible development of resistance to Tipranavir or other coadministered antiretroviral agents.
Ergot Derivatives
Dihydroergotamine, Ergotamine, Methylergonovine, ergonovine Potential for serious and/or life threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent
Cisapride
Potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Herbal products
St. John's wort (Hypericum perforatum)
Plasma concentrations of Tipranavir can be reduced by concomitant use of the herbal preparation St. John’s wort. This may lead to loss of therapeutic effect and possible development of resistance to Tipranavir or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors
Lovastatin, Simvastatin
Potential for serious reactions such as myopathy including rhabdomyolysis.
Neuroleptics
Pimozide
Potential for serious and/or life threatening reactions such as cardiac arrhythmias
PDE5 Inhibitors
Sildenafil (Revatio®) [for treatment of pulmonary arterial hypertension]
A safe and effective dose has not been established when used with Tipranavir. There is increased potential for sildenafilassociated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Sedative/Hypnotics
Triazolam, oral Midazolam
Potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression

[edit] WARNINGS AND PRECAUTIONS

  • Hepatic Impairment: Discontinue for signs and symptoms of clinical hepatitis or asymptomatic increases in ALT/AST >10 times ULN or asymptomatic increases in ALT/AST 5-10 times ULN with concomitant increases in total bilirubin. Monitor liver function tests prior to therapy and frequently thereafter.
  • Intracranial Hemorrhage/Platelet Aggregation and Coagulation: Use with caution in patients at risk for increased bleeding or who are receiving medications that increase the risk of bleeding
  • Drug Interactions: Consider drug-drug interaction potential to reduce risk of serious or life-threatening adverse reactions
  • Rash: Discontinue and initiate appropriate treatment if severe skin reaction occurs or is suspected. Use with caution in patients with a known sulfonamide allergy.
  • Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia, immune reconstitution syndrome, redistribution/accumulation of body fat, and elevated lipids. Monitor cholesterol and triglycerides prior to therapy and periodically thereafter.
  • Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required

[edit] INTERACTIONS

  • Co-administration of Tipranavir can alter the concentrations of other drugs and other drugs may alter the concentration of tipranavir. The potential for drug-drug interactions must be considered prior to and during therapy

[edit] PREGNANCY AND LACTATION

  • Pregnancy Category C (US). Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Tipranavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of both the potential for HIV-1 transmission and any possible adverse effects of Tipranavir , mothers should be instructed not to breast-feed if they are receiving Tipranavir.

[edit] SIDE EFFECTS

  • In adults the most frequent adverse reactions (incidence >4%) were diarrhea, nausea, pyrexia (fever) , vomiting, fatigue, headache, and abdominal pain
  • In pediatric patients (age 2 to 18 years) the most frequent adverse reactions were generally similar to those seen in adults. However, rash was more frequent in pediatric patients than in adults

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