What is Prezista?

• PREZISTA™ is an oral tablet used for the treatment of HIV (Human Immunodeficiency Virus) infection in adults. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). PREZISTA™ is a type of anti-HIV drug called a protease (PRO-tee-ase) inhibitor.

How does Prezista work?

• PREZISTA™ blocks HIV protease, an enzyme which is needed for HIV to multiply. When used with other anti-HIV medicines, PREZISTA™ may reduce the amount of HIV in your blood (called "viral load") and increase your CD4 (T) cell count. HIV infection destroys CD4 (T) cells, which are important to the immune system. The immune system helps fight infection. Reducing the amount of HIV and increasing the CD4 (T) cell count may improve your immune system and, thus, reduce the risk of death or infections that can happen when your immune system is weak (opportunistic infections).

• PREZISTA™ is always taken with and at the same time as 100 mg of ritonavir (Norvir), in combination with other anti-HIV medicines.

Who should not take Prezista?

• Together with your doctor, you need to decide whether taking PREZISTA™ is right for you.

• Do not take PREZISTA™ if you:

• are allergic to darunavir or any of the other ingredients in PREZISTA™

• are allergic to ritonavir (Norvir ® )

• take any of the following types of medicines because you could experience serious side effects:

Type of Drug	Examples of Generic Names (Brand Names)
Antihistamines (to treat allergy symptoms)	astemizole (Hismanal ® ) terfenadine (Seldane ® )
Ergot Derivatives (to treat migraine and headaches)	dihydroergotamine (D.H.E. 45 ® , Migranal ® ) ergonovine ergotamine (Wigraine ® , Ergostat ® , Cafergot ® , Ergomar ® ) methylergonovine
Gastrointestinal Motility Agent (to treat some digestive conditions)	cisapride (Propulsid ® )
Neuroleptic (to treat psychiatric conditions)	pimozide (Orap ® )
Sedative/hypnotics (to treat trouble with sleeping and/or anxiety)	midazolam (Versed ® ) triazolam (Halcion ® )

How should I take Prezista?

• Take PREZISTA™ tablets every day exactly as prescribed by your doctor. You must take ritonavir (Norvir ® ) at the same time as PREZISTA™. The usual dose is 600 mg (two 300 mg tablets) of PREZISTA™, together with 100 mg (one 100 mg capsule) of ritonavir (Norvir ® ), twice daily every day. It may be easier to remember to take PREZISTA™ and ritonavir (Norvir ® ) if you take them at the same time every day. If you have questions about when to take PREZISTA™ and ritonavir (Norvir ® ), your doctor can help you decide which schedule works for you.

• Take PREZISTA™ and ritonavir (Norvir ® ) with food. The type of food is not important. Swallow the tablets whole with a drink such as water, milk, or any other nutritional drink. Do not chew the tablets.

• Continue taking PREZISTA™ and ritonavir (Norvir ® ) unless your doctor tells you to stop. Take the exact amount of PREZISTA™ and ritonavir (Norvir ® ) that your doctor tells you to take, right from the very start. To help make sure you will benefit from PREZISTA™ and ritonavir (Norvir ® ), you must not skip doses or interrupt therapy. If you don't take PREZISTA™ and ritonavir (Norvir ® ) as prescribed, the beneficial effects of PREZISTA™ and ritonavir (Norvir ® ) may be reduced or even lost.

• If you miss a dose of PREZISTA™ or ritonavir (Norvir ® ) by more than 6 hours, wait and then take the next dose of PREZISTA™ and ritonavir (Norvir ® ) at the regularly scheduled time. If you miss a dose of PREZISTA™ or ritonavir (Norvir ® ) by less than 6 hours, take your missed dose of PREZISTA™ and ritonavir (Norvir ® ) immediately. Then take your next dose of PREZISTA™ and ritonavir (Norvir ® ) at the regularly scheduled time.

• You should always take PREZISTA™ and ritonavir (Norvir ® ) together with food.

• If a dose of PREZISTA™ or ritonavir (Norvir ® ) is skipped, do not double the next dose. Do not take more or less than your prescribed dose of PREZISTA™ or ritonavir (Norvir ® ) at any one time.

What are the possible side effects of Prezista?

• Like all prescription drugs, PREZISTA™ can cause side effects. The following is not a complete list of side effects reported with PREZISTA™ when taken either alone or with other anti-HIV medicines. Do not rely on this leaflet alone for information about side effects. Your doctor can discuss with you a more complete list of side effects.

• Your healthcare professional should do blood tests prior to initiating combination treatment including PREZISTA. Patients with liver diseases such as hepatitis B and hepatitis C may have worsening of their liver disease with PREZISTA™ and may need more frequent monitoring of blood tests. PREZISTA™ has been reported to cause liver problems which may be life-threatening. It was not always clear if PREZISTA™ caused these liver problems because some patients had other illnesses or were taking other medicines.

• Mild to moderate rash has been reported in 7% of subjects receiving PREZISTA™. In some patients, PREZISTA has been reported to cause a severe or life-threatening rash. Contact your healthcare provider if you develop a rash. Your healthcare provider will advise you whether your symptoms can be managed on therapy or whether PREZISTA™ should be stopped.

• As with other protease inhibitors, PREZISTA may cause side effects, including:

• high blood sugar (hyperglycemia) and diabetes. This can happen in patients taking PREZISTA™ or other protease inhibitor medicines. Some patients have diabetes before starting treatment with PREZISTA™ which gets worse. Some patients get diabetes during treatment with PREZISTA™. Some patients will need changes in their diabetes medicine. Some patients may need new diabetes medicine.

• increased bleeding in patients with hemophilia. This may happen in patients taking PREZISTA™ as it has been reported with other protease inhibitor medicines.

• changes in body fat. These changes can happen in patients taking anti-HIV medicines. The changes may include an increased amount of fat in the upper back and neck, breast, and around the back, chest, and stomach area. Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.

• immune reconstitution syndrome. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms.

Important Safety Information

• Do not take PREZISTA™ if you are allergic to PREZISTA™ or any of its ingredients, or ritonavir (Norvir ® ).

• Please refer to the ritonavir (Norvir ® ) Product Information (PI and PPI) for additional information on precautionary measures.

• Taking PREZISTA™ with certain medicines could cause serious and/or life-threatening side effects or may result in loss of its effectiveness. Do not take PREZISTA™ if you are taking the following medicines:

• astemizole (Hismanal ® ), terfenadine (Seldane ® ), dihydroergotamine ( D.H.E.45 ® , Migranal ® ), ergonovine, ergotamine (Wigraine ® , Ergostat ® , Cafergot ® , Ergomar ® ), methylergonovine, cisapride (Propulsid ® ), pimozide (Orap ® ), midazolam (Versed ® ), triazolam (Halcion ® ), rifampin (Rifadin ® , Rifater ® , Rifamate ® ), lopinavir/ritonavir (Kaletra ® ), saquinavir (Invirase ® ), lovastatin ( Mevacor ® ), pravastatin (Pravachol ® ), simvastatin (Zocor ® ), carbamazepine (Tegretol ® , Carbatrol ® ), phenobarbital, phenytoin (Dilantin ® , Phenytek ® ), or products containing St. John's Wort.

• Before taking PREZISTA™, tell your doctor if you are taking sildenafil (Viagra ® ), vardenafil (Levitra ® ), tadalafil (Cialis ® ), atorvastatin (Lipitor ® ), atorvastatin/amlodipine (Caduet ® ), or rosuvastatin (Crestor ® ). This is not a complete list of medicines. Be sure to tell your doctor about all the medicines you are taking or plan to take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

• Tell your doctor if you are taking estrogen-based contraceptives. PREZISTA™ might reduce the effectiveness of estrogen-based contraceptives. You must take additional precautions for birth control such as condom.

• Before taking PREZISTA™, tell your doctor if you have any medical conditions, including allergy to sulfa medicines, diabetes, liver problems (including hepatitis B or C) or hemophilia.

• Tell your doctor if you are pregnant or planning to become pregnant, or are breastfeeding.

• The effects of PREZISTA™ on pregnant women or their unborn babies are not known. You and your doctor will need to decide if taking PREZISTA™ is right for you.

• You should not breastfeed if you have HIV or are taking PREZISTA™.

• Liver problems, which may be life-threatening, have been reported with the use of PREZISTA™. It was not always clear if PREZISTA™ caused these liver problems. Patients with liver disease such as hepatitis B and hepatitis C may have worsening of their liver disease with PREZISTA™. Your healthcare professional should perform blood tests prior to and during your treatment with PREZISTA™.

• Skin rashes ranging from mild to severe or life-threatening have been reported in some patients receiving a PREZISTA™-ritonavir regimen. Contact your doctor if you develop a rash.

• High blood sugar, diabetes or worsening of diabetes, and increased bleeding in people with hemophilia have been reported in patients taking protease inhibitor medicines like PREZISTA™.

• Changes in body fat have been seen in some patients taking anti-HIV medicines. The cause and long-term health effects of these conditions are not known at this time.

• As with other protease inhibitors, taking PREZISTA™ may strengthen the body's immune response enabling it to begin to fight infections that have been hidden. Patients may experience signs and symptoms of inflammation that can include swelling, tenderness or redness.

• The most common side effects include diarrhea, nausea, headache, and common cold. If you experience these or other symptoms, talk to your doctor. Do not stop taking PREZISTA™ or any other medications without first talking to your doctor.

Clinical Trials

Evidence of the efficacy of darunavir and ritonavir in antiretroviral treatment-experienced HIV positive adults is shown in analyses of 24- and 48-week data in two randomized, Phase IIb trials, POWER 1 (TMC114-C213) and POWER 2 (TMC114-C202).

Both of these trials consisted of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all patients were randomized to either darunavir and ritonavir or an investigator-selected antiretroviral regimen, then received the recommended dose of darunavir 600 mg and ritonavir 100 mg.

Participants were required to have a baseline HIV RNA (viral load) of greater than 1000 copies/ml, had previous treatment with PIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), and nucleoside reverse transcriptase inhibitors (NRTIs), and have at least one primary PI mutation at screening, and to be currently taking a stable PI-containing regimen at screening for at least 8 weeks prior to study entry.

• 24-week Primary Analysis Findings

Analyses included 318 patients in TMC114-C213 and 319 patients in TMC114-C202. At 24 weeks, the virologic response rate was evaluated in patients receiving darunavir and ritonavir plus an optimized background regimen (OBR) versus a control group receiving an investigator-selected PI-containing regimen plus an OBR.

The primary analysis from POWER 1 and 2 showed that at 24 weeks, patients in the darunavir/r arm were significantly more likely to achieve a virologic response, achieve undetectable viral load (less than 50 copies/mL) and have an increase in CD4+ cell counts from baseline compared to the patients in the control arm. An intent-to-treat analysis demonstrated the following:

69.5 percent vs. 21 percent achieved a virologic response defined as equal to or greater than 1.0 log10 reduction (90 percent reduction) in viral load from baseline;
45 percent vs. 12.1 percent achieved undetectable viral load (less than 50 copies/mL); and
Patients experienced a CD4+ cell mean increase of 92 cells/mm3 vs.17 cells/mm3 from baseline.

• Analysis of Patients Reaching 48 Weeks of Treatment

Among 110 patients who had reached 48 weeks of treatment in the darunavir/r arm (total n=131) vs. 120 patients who had reached 48 weeks of treatment in the control arm (total n=124), intent-to-treat data showed the following:

61 percent vs. 15 percent had a virologic response defined as equal to or greater than 1.0 log10 reduction (90 percent reduction) in viral load from baseline
46 percent vs. 10 percent reached undetectable viral load (less than 50 copies/mL)
Patients experienced a CD4+ cell mean increase of 102 cells/mm3 vs.19 cells/mm3 from baseline

Among patients reaching 48 weeks, the most commonly reported adverse events among patients in the darunavir/r arm vs. control arm were diarrhea (20 percent vs. 28 percent), nausea (18 percent vs. 13 percent), headache (15 percent vs. 20 percent), nasopharyngitis (14 percent vs. 11 percent) and fatigue (12 percent vs. 17 percent). Discontinuations because of adverse events were seven percent in the darunavir/r arm vs. five percent in the control arm.

* Lazzarin et al. TMC114 provides durable viral load suppression in treatment-experienced patients: POWER 1 and 2 combined week 48 analysis. 16th International AIDS Conference. August 13-18, 2006. Toronto, Canada. Abstract TUAB0104 (oral).


Resistance and Cross Resistance

• In analyses of 3 different Phase IIb studies using darunavir, multiple PI-resistant HIV-1 isolates were collected from highly treatment-experienced patients who received darunavir 600 mg and ritonavir 100 mg twice daily and experienced virologic failure either by rebound or by never being fully suppressed. These patients developed amino acid substitutions that were associated with decreased susceptibility to darunavir.

• Cross resistance to other PIs has been observed. Darunavir has a less than tenfold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir (Agenerase), atazanavir (Reyataz), indinavir (Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Invirase), and/or tipranavir (Aptivus) showing that viruses to these PIs remain susceptible to darunavir.

• Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed a fold change in EC50 values less than 3 for tipranavir, indicative of limited cross resistance between darunavir and tipranavir. Of the viruses isolated from patients experiencing virologic failure taking darunavir 600 mg and ritonavir 100 mg twice daily, greater than 50% were still susceptible to tipranavir, while less than 5% were susceptible to the other PIs.

• Cross resistance between darunavir and NNRTIs, NRTIs, and fusion inhibitors is unlikely because the viral targets are different.

Pregnancy

• Darunavir is in FDA Pregnancy Category B. There are no adequate and well-controlled studies conducted in pregnant women. Reproduction studies conducted with darunavir have shown no embryotoxicity or teratogenicity in mice, rats, and rabbits.

• To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine (or other antiretrovirals), an Antiretroviral Pregnancy Registry has been established. Physicians may register patients at http://www.APRegistry.com or by calling 1-800-258-4263. It is not known whether darunavir is excreted in human milk; it is excreted in the milk of lactating rats. Because of the potential for HIV transmission and for serious adverse effects from darunavir to the breastfed infant, women should be instructed not to breastfeed while taking darunavir.

Drug and Food Interactions

Darunavir must always be taken with ritonavir 100 mg in combination with other antiretroviral drugs.

Coadministration of darunavir and ritonavir with efavirenz (Sustiva) caused a decrease in darunavir AUC by 13% and minimum serum concentrations (Cmin) by 31%, while the AUC and Cmin of efavirenz increased by 21% and 17%, respectively. The clinical significance has not been established; however, this combination of drugs should be used with caution.

Because didanosine (Videx) must be administered on an empty stomach, didanosine should be administered one hour prior to or two hours after darunavir and ritonavir dosing with food.

Coadministration of darunavir and ritonavir with indinavir (Crixivan) resulted in a serum concentration increase in both darunavir and indinavir. The appropriate dose of indinavir in combination with darunavir and ritonavir has not been established.

Coadministration of darunavir with lopinavir/ritonavir (Kaletra) resulted in a 53% decrease in darunavir AUC. Coadministration of darunavir and ritonavir with saquinavir (Invirase) resulted in a 26% decrease in darunavir AUC. Coadministration of these drugs with darunavir is not recommended.

Both darunavir and ritonavir are inhibitors of CYP3A. Coadministration of darunavir and ritonavir with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse effects.

Carbamazepine, phenobarbital, phenytoin, and rifampin are inducers of CYP450 enzymes and should not be used in combination with darunavir and ritonavir. St. John's wort should also not be used concomitantly with darunavir and ritonavir. Coadministration of these drugs may cause significant decreases in darunavir plasma concentrations and a loss of therapeutic effect to darunavir.

Use of some HMG-CoA reductase inhibitors, including lovastatin and simvastatin, may require dose adjustment if taken concurrently with darunavir and ritonavir because of the potential of serious reactions such as myopathy, including rhabdomyolysis. Coadministration of darunavir and ritonavir with other HMG-CoA reductase inhibitors, such as atorvastatin and pravastatin, should be given at the lowest possible dose of the statin with careful patient monitoring.

Caution must be used when antiarrhythmics, including bepridil, lidocaine, quinidine, and amiodarone, are used concurrently with darunavir and ritonavir. Concentrations of antiarrhythmic drugs may increase. Therapeutic concentration monitoring should be used, if available, to guide patient treatment.

Concurrent use of darunavir and ritonavir with warfarin may decrease warfarin plasma concentrations, and patients should be monitored carefully if they are taking such a regimen.

Concomitant use of trazodone and darunavir and ritonavir may increase plasma concentrations of trazodone, leading to nausea, dizziness, hypotension, and syncope. A lower dose of trazodone should be considered in patients who require this combination of drugs.

Concurrent use of darunavir and ritonavir with clarithromycin may require dose adjustment of the clarithromycin dose in patients with impaired renal function.

Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Plasma concentrations of these two drugs may increase in the presence of darunavir and ritonavir. When coadministration is required, the daily dose of azole should not exceed 200 mg. Concurrent use of darunavir and ritonavir with voriconazole has not been studied. However, concomitant use of voriconazole and 100 mg ritonavir twice daily decreased voriconazole AUC by 39%. Therefore, patients receiving darunavir and ritonavir should not receive voriconazole unless the potential benefit outweighs the risk to the patient.

Rifabutin is an inducer and substrate of CYP450 enzymes. Concomitant use of rifabutin with darunavir and ritonavir is expected to increase rifabutin plasma concentrations. It is recommended to administer rifabutin at a dosage of 150 mg rifabutin once every other day when coadministered with darunavir and ritonavir.

Plasma concentrations of calcium channel blockers, including felodipine, nifedipine, and nicardipine, may increase when given concurrently with darunavir and ritonavir. Caution is warranted and clinical monitoring of patients is recommended.

Plasma concentrations of immunosuppressants, including cyclosporine, tacrolimus, and sirolimus, may be increased when coadministered with darunavir and ritonavir. Therapeutic concentration monitoring for the immunosuppressive agent is recommended when these drugs are taken concurrently.

When methadone is coadministered with darunavir and ritonavir, patients should be monitored for abstinence syndrome, as ritonavir is known to induce the metabolism of methadone, leading to a decrease in methadone's concentrations. An increase in methadone dosage may be considered based on the clinical response.

Plasma concentrations of ethinyl estradiol may be decreased when it is used with darunavir and ritonavir due to the induction of its metabolism by ritonavir. Alternative or additional contraceptive measures should be used when estrogen-based contraceptives are coadministered with darunavir and ritonavir.

Concomitant administration of darunavir and ritonavir with PDE-5 inhibitors, including sildenafil, vardenafil, and tadalafil, should be done with caution. PDE-5 inhibitor dosing should not exceed the doses as indicated by the manufacturer.

Darunavir and ritonavir with selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine should be taken concomitantly with caution. The recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline and paroxetine who start treatment with darunavir and ritonavir should be monitored for antidepressant response.

Contraindications

Darunavir must always be taken with ritonavir 100 mg in combination with other antiretroviral drugs.

Both darunavir and ritonavir are both inhibitors of CYP3A. Coadministration of darunavir and ritonavir with drugs primarily metabolized by CYP3A may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse effects (See section on Drug Interactions above)