Latazanavir
Latazanavir - General Information
Latazanavir (formerly known as BMS-232632) is an antiretroviral drug of the protease inhibitor (PI) class. Like other antiretrovirals, it is used to treat infection of human immunodeficiency virus (HIV). Latazanavir is distinguished from other PIs in that it can be given once-daily (rather than requiring multiple doses per day) and has lesser effects on the patient's lipid profile (the amounts of cholesterol and other fatty substances in the blood). Like other protease inhibitors, it is used only in combination with other HIV medications. The U.S. Food and Drug Administration (FDA) approved atazanavir on June 20, 2003. [Wikipedia]
Pharmacology of Latazanavir
Latazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). It is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Latazanavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.
Latazanavir for patients
A statement to patients and healthcare providers is included on the product's bottle label:
ALERT: Find out about medicines that should NOT be taken with REYATAZ. A Patient Package Insert (PPI) for REYATAZ is available for patient information.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using REYATAZ. Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
Patients should be informed that REYATAZ is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that there are currently no data demonstrating that therapy with REYATAZ can reduce the risk of transmitting HIV to others through sexual contact.
REYATAZ may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St. John's wort.
Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of a PDE5 inhibitor-associated adverse events including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor.
Patients should be informed that atazanavir may p roduce changes in the electrocardiogram (PR prolongation). Patients should consult their physician if they are experiencing symptoms such as dizziness or lightheadedness.
REYATAZ should be taken with food to enhance absorption.
Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time. It is unknown whether long-term use of REYATAZ will result in a lower incidence of lipodystrophy than with other protease inhibitors.
Patient Information Leaflet
REYATAZTM (RAY-ah-taz) (generic name = atazanavir sulfate)
Capsules
ALERT: Find out about medicines that should NOT be taken with REYATAZ. Read the section "What important information should I know about taking REYATAZ with other medicines?"
Read the Patient Information that comes with REYATAZ before you start using it and each time you get a refill. There may be new information. This leaflet provides a summary about REYATAZ and does not include everything there is to know about your medicine. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.
What is REYATAZ?
REYATAZ is a prescription medicine used with other anti-HIV medicines to treat people who are infected with the human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). REYATAZ is a type of anti- HIV medicine called a protease inhibitor. HIV infection destroys CD4+ (T) cells, which are important to the immune system. The immune system helps fight infection. After a large number of T cells are destroyed, AIDS develops. REYATAZ helps to block HIV protease, an enzyme that is needed for the HIV virus to multiply. REYATAZ may lower the amount of HIV in your blood, help your body keep its supply of CD4+ (T) cells, and reduce the risk of death and illness associated with HIV.
Does REYATAZ cure HIV or AIDS?
REYATAZ does not cure HIV infection or AIDS. At present there is no cure for HIV infection. People taking REYATAZ may still get opportunistic infections or other conditions that happen with HIV infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections. It is very important that you see your healthcare provider regularly while taking REYATAZ.
REYATAZ does not lower your chance of passing HIV to other people through sexual contact, sharing needles, or being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by using a latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood. Never use or share dirty needles.
Who should not take REYATAZ?
Do not take REYATAZ if you:
· are taking certain medicines. Serious life-threatening side effects or death may happen. Before you take REYATAZ, tell your healthcare provider about all medicines you are taking or planning to take. These include other prescription and nonprescription medicines, vitamins, and herbal supplements.
· are allergic to REYATAZ or to any of its ingredients. The active ingredient is atazanavir sulfate. See the end of this leaflet for a complete list of ingredients in REYATAZ. Tell your healthcare provider if you think you have had an allergic reaction to any of these ingredients.
What should I tell my healthcare provider before I take REYATAZ?
Tell your healthcare provider:
· If you are pregnant or planning to become pregnant. It is not known if REYATAZ can harm your unborn baby. Pregnant women have experienced serious side effects when taking REYATAZ with other HIV medicines called nucleoside analogues. You and your healthcare provider will need to decide if REYATAZ is right for you. If you use REYATAZ while you are pregnant, talk to your healthcare provider about the Antiretroviral Pregnancy Registry.
· If you are breast-feeding. You sho uld not breast- feed if you are HIV-positive because of the chance of passing HIV to your baby. Also, it is not known if REYATAZ can pass into your breast milk and if it can harm your baby. If you are a woman who has or will have a baby, talk with your healthcare provider about the best way to feed your baby.
· If you have liver problems or are infected with the hepatitis B or C virus. See "What are the possible side effects of REYATAZ?"
· If you have diabetes. See "What are the possible side effects of REYATAZ?"
· If you have hemophilia. See "What are the possible side effects of REYATAZ?"
· About all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Keep a list of your medicines with you to show your healthcare provider. For more information, see "What important information I should know about taking REYATAZ with other medicines?" and "Who should not take REYATAZ?" Some medicines can cause serious side effects if you also take REYATAZ.
How should I take REYATAZ?
Take REYATAZ once every day exactly as instructed by your healthcare provider. Your healthcare provider will prescribe the amount of REYATAZ that is right for you.
· For adults who have never taken anti-HIV medicines before, the usual dose is 400 mg (two 200-mg capsules) once daily taken with food.
· For adults who have taken anti-HIV medicines in the past, the usual dose is 300 mg (two 150-mg capsules) plus 100 mg of NORVIR (ritonavir) once daily taken with food.
Your dose will depend on your liver function and on the other anti-HIV medicines that you are taking. REYATAZ is always used with other anti-HIV medicines. If you are taking REYATAZ with SUSTIVA (efavirenz) or with VIREAD (tenofovir disoproxil fumarate), you should also be taking NORVI (ritonavir).
· Always take REYATAZ with food (a meal or snack) to help it work better. Swallow the capsules whole. Do not open the capsules. Try to take REYATAZ at the same time each day.
· If you are taking antacids or Videx (didanosine) Chewable/Dispersible Buffered Tablets, take REYATAZ 2 hours before or 1 hour after these medicines.
· Do not change your dose or stop taking REYATAZ without first talking with your healthcare provider. It is important to stay under a healthcare provider's care while taking REYATAZ.
· When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of REYATAZ. The amount of HIV in your blood may increase if the medicine is stopped for even a short time.
· If you miss a dose of REYATAZ, take it as soon as possible and then take your next scheduled dose at its regular time. If, however, it is within 6 hours of your next dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not double the next dose. It is important that you do not miss any doses of REYATAZ or your other anti-HIV medicines.
· If you take more than the prescribed dose of REYATAZ, call your healthcare provider or poison control center right away.
Can children take REYATAZ?
REYATAZ has not been fully studied in children under 16 years of age. REYATAZ should not be used in babies under the age of 3 months.
What are the possible side effects of REYATAZ?
The following list of side effects is not complete. Report any new or continuing symptoms to your healthcare provider. If you have questions about side effects, ask your healthcare provider. Your healthcare provider may be able to help you manage these side effects.
REYATAZ can cause the following side effects:
· rash (redness and itching) sometimes occurs in patients taking REYATAZ, most often in the first few weeks after the medicine is started. Rashes usually go away within 2 weeks with no change in treatment. Tell your healthcare provider if rash occurs.
· yellowing of the skin or eyes. These effects may be due to increases in bilirubin levels in the blood (bilirubin is made by the liver). Call your healthcare provider if your skin or the white part of your eyes turn yellow. Although these effects may not be damaging to your liver, skin, or eyes, it is important to tell your healthcare provider promptly if they occur.
· a change in the way your heart beats (heart rhythm change). Call your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
· diabetes and high blood sugar (hyperglycemia) sometimes happen in patients taking protease inhibitor medicines like REYATAZ. Some patients had diabetes before taking protease inhibitors while others did not. Some patients may need changes in their diabetes medicine.
· if you have liver disease including hepatitis B or C, your liver disease may get worse when you take anti-HIV medicines like REYATAZ.
· some patients with hemophilia have increased bleeding problems with protease inhibitors like REYATAZ.
· changes in body fat. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time.
Other common side effects of REYATAZ taken with other anti-HIV V medicines include nausea; headache; stomach pain; vomiting; diarrhea; depression; fever; dizziness; trouble sleeping; numbness, tingling, or burning of hands or feet; and muscle pain.
What important information should I know about taking REYATAZ with other medicines*?
Do not take REYATAZ if you take the following medicines (not all brands may be listed; tell your healthcare provider about all the medicines you take). REYATAZ may cause serious, life-threatening side effects or death when used with these medicines.
· Ergot medicines: dihydroergotamine, ergonovine, ergotamine, and methylergonovine such as Cafergot, Migranal, D.H.E. 45, ergotrate maleate, Methergine Ò, and others (used for migraine headaches).
· Halcion (triazolam, used for insomnia).
· Versed (midazolam, used for sedation).
· Orap (pimozide, used for Tourette's disorder).
· Propulsid (cisapride, used for certain stomach problems).
Do not take the following medicines with REYATAZ because of possible serious side effects:
· Camptosar (irinotecan, used for cancer),
· Crixivan (indinavir, used for HIV infection). Both REYATAZ and Crixivan sometimes cause increased levels of bilirubin in the blood.
· Cholesterol- lowering medicines Mevacor (lovastatin) or Zocor (simvastatin).
Do not take the following medicines with REYATAZ because they may lower the amount of REYATAZ in your blood. This may lead to an increased HIV viral load. Resistance to REYATAZ or cross-resistance to other HIV medicines may develop:
· Rifampin (also known as Rimactane, Rifadin, Rifater, or Rifamate, used for tuberculosis).
· St. John's wort (Hypericum perforatum), an herbal product sold as a dietary supplement, or products containing St. John's wort.
· "Proton-pump inhibitors" used for indigestion, heartburn, or ulcers such as AcipHexÒ (rabeprazole), NexiumÒ (esomeprazole), PrevacidÒ (lansoprazole), PrilosecÒ
(omeprazole), or ProtonixÒ (pantoprazole).
Do not take the following medicine if you are taking REYATAZ and NORVIR® together.
· VFEND® (voriconazole).
The following medicines may require your healthcare provider to monitor your therapy more closely:
· Cialis (tadalafil), Levitra (vardenafil), or ViagraÒ (sildenafil). REYATAZ may increase the chances of serious side effects that can happen with Cialis, Levitra, or Viagra. Do not use Cialis, Levitra, or Viagra while you are taking REYATAZ unless your healthcare provider tells you it is okay.
· LipitorÒ (atorvastatin). There is an increased chance of serious side effects if you take REYATAZ with this cholesterol- lowering medicine.
· Medicines for abnormal heart rhythm: Cordarone (amiodarone), lidocaine, quinidine (also known as Cardioquin, Quinidex, and others).
· VASCOR (bepridil, used for chest pain).
· Coumadin (warfarin).
· Tricyclic antidepressants such as Elavil (amitriptyline), Norpramin (desipramine), Sinequan (doxepin), Surmontil (trimipramine), Tofranil (imipramine), or Vivactil (protriptyline).
· Medicines to prevent organ transplant rejection: Sandimmune or Neoral (cyclosporin), Rapamune (sirolimus), or Prograf (tacrolimus).
The following medicines may require a change in the dose or dose schedule of either REYATAZ or the other medicine:
· Fortovase, Invirase (saquinavir).
· Norvir (ritonavir).
· Sustiva (efavirenz).
· VidexÒ (didanosine) or antacids.
· VireadÒ (tenofovir disoproxil fumarate).
· Mycobutin (rifabutin).
· Calcium channel blockers such as Cardizem or Tiazac (diltiazem), Covera-HS or Isoptin SR (verapamil) and others.
· Biaxin (clarithromycin).
· Medicines for indigestion, heartburn, or ulcers such as Axid (nizatidine), Pepcid AC (famotidine), Tagamet (cimetidine), or Zantac (ranitidine).
Women who use birth control pills or "the patch" should choose a different kind of contraception. REYATAZ may affect the safety and effectiveness of birth control pills or the patch. Talk to your healthcare provider about choosing an effective contraceptive.
Remember:
1. Know all the medicines you take.
2. Tell your healthcare provider about all the medicines you take.
3. Do not start a new medicine without talking to your healthcare provider.
How should I store REYATAZ?
· Store REYATAZ Capsules at room temperature, 59° to 86° F (15° to 30° C). Do not store this medicine in a damp place such as a bathroom medicine cabinet or near the kitchen sink.
· Keep your medicine in a tightly closed container.
· Throw away REYATAZ when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.
General information about REYATAZ
This medicine was prescribed for your particular condition. Do not use REYATAZ for another condition. Do not give REYATAZ to other people, even if they have the same symptoms you have. It may harm them. Keep REYATAZ and all medicines out of the reach of children and pets.
This summary does not include everything there is to know about REYATAZ. Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Remember no written summary can replace careful discussion with your healthcare provider. If you would like more information, talk with your healthcare provider or you can call 1-800-426-7644.
What are the ingredients in REYATAZ?
Active Ingredient: atazanavir sulfate
Inactive Ingredients: Crospovidone, lactose monohydrate (milk sugar), magnesium stearate, gelatin, FD&C Blue #2, and titanium dioxide.
* VIDEX. is a registered trademark of Bristol-Myers Squibb Company. COUMADIN. and SUSTIVA. are registered trademarks of Bristol-Myers Squibb Pharma Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.
Bristol-Myers Squibb Virology
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.
Latazanavir Interactions
Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors) or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects. Atazanavir is metabolized in the liver by the cytochrome P450 enzyme system. Coadministration of REYATAZ and drugs that induce CYP3A, such as rifampin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Coadministration of REYATAZ and drugs that inhibit CYP3A may increase atazanavir plasma concentrations.
The potential for drug interactions with REYATAZ changes when REYATAZ is coadministered with the potent CYP3A inhibitor ritonavir. The magnitude of CYP3A mediated drug interactions (effect on atazanavir or effect on coadministered drug) may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for Norvir (ritonavir) for information on drug interactions with ritonavir.
Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if antacids, buffered medications, H2-receptor antagonists, and proton-pump inhibitors are administrated with atazanavir.
Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when coadministering REYATAZ with medicinal products known to induce PR interval prolongation (eg, atenolol, diltiazem [see Table 11]).
Drugs that are contraindicated or not recommended for coadministration with REYATAZ are included in Table 10. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
| Table 10: Drugs That Should Not Be Administered with REYATAZ | |
| Drug class: Specific Drugs | Clinical Comment |
| Antimycobacterials: rifampin | Decreases plasma concentrations and AUC of most protease inhibitors by about 90%. This may result in loss of therapeutic effect and development of resistance. |
| Antineoplastics: irinotecan | Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities. |
| Benzodiazepines: midazolam, triazolam | CONTRAINDICATED due to potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. |
| Ergot Derivatives: dihydrorergotamine, ergotamine, ergonovine, methylergonovine | CONTRAINDICATED due to potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI Motility Agent: cisapride | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| HMG-CoA Reductase Inhibitors: lovastatin, simvastatin | Potential for serious reactions such as myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Protease Inhibitors: indinavir | Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. Combinations of these drugs have not been studied and coadministration of REYATAZ and indinavir is not recommended. |
| Proton-Pump Inhibitors | Concomitant use of REYATAZ and proton-pump inhibitors is not recommended. Coadministration of REYATAZ with proton-pump inhibitors is expected to substantially decrease REYATAZ plasma concentrations and reduce its therapeutic effect. |
| Herbal Products: St. John's wort (Hypericum perforatum) | Patients taking REYATAZ should not use products containing St. John's wort (Hypericum perforatum) because coadministration may be expected to reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance |
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Table 11: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) |
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Concomitant Drug Class: |
Effect on Concentration of Atazanavir or Concomitant Drug |
Clinical Comment |
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HIV Antiviral Agents |
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Nucleoside Reverse Transcriptase Inhibitors (NRTIs): |
↓ atazanavir |
Coadminist ration of REYATAZ with didanosine buffered tablets did not alter exposure to didanosine; however, exposure to atazanavir was markedly decreased (presumably due to the increase in gastric pH caused by buffers in the didanosine tablets). In addition, it is recommended that didanosine be administered on an empty stomach; therefore, REYATAZ should be given (with food) 2 h before or 1 h after didanosine buffered formulations. Because didanosine EC capsules are to be given on an empty stomach and REYATAZ is to be given with food, they should be administered at different times. |
|
Nucleotide Reverse |
↓ atazanavir |
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. |
|
Non-nucleoside Reverse |
↓ atazanavir |
In treatment-naive patients who receive efavirenz and REYATAZ, the recommended dose is REYATAZ 300 mg with ritonavir 100 mg and efavirenz 600 mg (all once daily), as this combination results in atazanavir exposure that approximates the mean exposure to atazanavir produced by 400 mg of REYATAZ alone. Dosing recommendations for efavirenz and REYATAZ in treatment-experienced patients have not been established. |
|
Non-nucleoside Reverse |
↓ atazanavir |
REYATAZ/ritonavir: The effects of coadministration have not been studied. Nevirapine, an inducer of CYP3A, is expected to decrease atazanavir exposure. In the absence of data, coadministration is not recommended. |
|
Protease Inhibitors: |
↑ saquinavir |
Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy. |
|
Protease Inhibitors: |
↑ atazanavir |
If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for Norvir® (ritonavir) for information on drug interactions with ritonavir. |
|
Protease Inhibitors: |
↑ other protease inhibitor |
REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended. |
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Other Agents |
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Antacids and buffered medications |
↓ atazanavir |
Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 h before or 1 h after these medications. |
|
Antiarrhythmics: |
↑ amiodarone, bepridil, lidocaine (systemic), quinidine |
Coadministration with REYATAZ has the potential to produce serious and/or lifethreatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. |
|
Anticoagulants: |
↑ warfarin |
Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored. |
|
Antidepressants: |
↑ tricyclic |
Coadministration with REYATAZ has the potential to produce serious and/or life- threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. |
|
Antifungals: ketoconazole itraconazole |
REYATAZ/ ritonavir: |
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir. |
|
Antifungals: voriconazole |
Effect is unknown |
Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. However, administration of voriconazole with ritonavir 400 mg every 12 hours decreased voriconazole steady-state AUC by an average of 82%. The effect of lower ritonavir doses on voriconazole is not known at this time. Until data are available, voriconazole should not be administered to patients receiving REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available. |
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Antimycobacterials: |
↑ rifabutin |
A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. |
|
Calcium channel |
↑ diltiazem and |
Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied. |
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eg, felodipine, nifedipine, nicardipine, and verapamil |
↑ calcium channel blocker |
Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. |
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HMG-CoA reductase inhibitors: atorvastatin |
↑ atorvastatin |
The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including REYATAZ, are used in combination with atorvastatin. Caution should be exercised. |
|
H2-Receptor antagonists |
↓ atazanavir |
Reduced plasma concentrations of atazanavir are expected if H2-receptor antagonists are administered with REYATAZ. This may result in loss of therapeutic effect and development of resistance. To lessen the effect of H2-receptor antagonists on atazanavir exposure, it is recommended that an H2-receptor antagonist and REYATAZ be administered as far apart as possible, preferably 12 hours apart. |
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Immunosuppressants: cyclosporin, sirolimus, tacrolimus |
↑immunosuppressants |
Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ. |
|
Macrolide antibiotics: clarithromycin |
↑ clarithromycin |
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied. |
|
Hormonal contraceptives: |
↑ ethinyl estradiol |
Coadministration of REYATAZ/ritonavir with hormonal contraceptives has not been studied. However, higher doses of ritonavir, without REYATAZ, decrease contraceptive steroid concentrations. Because contraceptive steroid concentrations may be altered when REYATAZ or REYATAZ/ritonavir is coadministered with oral contraceptives or with the contraceptive patch, alternate methods of nonhormonal contraception are recommended. |
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PDE5 inhibitors: Sildenafil Tadalafil Vardenafil |
↑ sildenafil |
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. |
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Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. |
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Use tadalafil with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. |
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Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events. |
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a For magnitude of interactions see CLINICAL PHARMACOLOGY: Tables 4 and 5. |
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Based on known metabolic profiles, clinically significant drug interactions are e not expected between REYATAZ and fluvastatin, pravastatin, dapsone, trimethoprim/sulfa methoxazole, azithromycin, erythromycin, or fluconazole. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).
Latazanavir Contraindications
REYATAZ is contraindicated in patients with known hypersensitivity to any of its ingredients, including atazanavir.
Coadministration of REYATAZ is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 1.
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Table 1: Drugs That Are Contraindicated with REYATAZ Due to Potential CYP450-Mediated Interactions |
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Drug class |
Drugs within class that are contraindicated with REYATAZ |
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Benzodiazepines |
midazolam, triazolam |
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Ergot Derivatives |
dihydroergotamine, ergotamine, ergonovine, methylergonovine |
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GI Motility Agent |
cisapride |
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Neuroleptic |
pimozide |
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Additional information about Latazanavir
Latazanavir Indication: For use, in combination with other antiretroviral agents, in the treatment of HIV-1 infection.
Mechanism Of Action: Latazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
Drug Interactions: Aluminium This gastric pH modifier decreases the levels/effects of atazanavir
Amiodarone Increased risk of cardiotoxicity and arrhythmias
Amitriptyline Increases the effect and toxicity of tricyclics
Amoxapine Increases the effect and toxicity of tricyclics
Anisindione The protease inhibitor increases the anticoagulant effect
Atorvastatin Increases the effect and toxicity of the statin
Bepridil Increases the effect and toxicity of bepridil
Bismuth Subsalicylate This gastric pH modifier decreases the levels/effects of atazanavir
Calcium This gastric pH modifier decreases the levels/effects of atazanavir
Cimetidine This gastric pH modifier decreases the levels/effects of atazanavir
Cisapride Increased risk of cardiotoxicity and arrhythmias
Clarithromycin Increases levels of clarithromycin
Clomipramine Increases the effect and toxicity of tricyclics
Cyclosporine Increases the effect and toxicity of immunosuppressant
Desipramine Increases the effect and toxicity of tricyclics
Dicumarol The protease inhibitor increases the anticoagulant effect
Dihydroergotamine Increases the effect and toxicity of ergot derivative
Dihydroquinidine barbiturate Increased risk of cardiotoxicity and arrhythmias
Dihydroxyaluminium This gastric pH modifier decreases the levels/effects of atazanavir
Diltiazem Increases the effect and toxicity of diltiazem
Doxepin Increases the effect and toxicity of tricyclics
Efavirenz Efavirenz decreases the levels/effects of atazanavir
Ergotamine Increases the effect and toxicity of ergot derivative
Erlotinib This CYP3A4 inhibitor increases levels/toxicity of erlotinib
Esomeprazole This gastric pH modifier decreases the levels/effects of atazanavir
Famotidine This gastric pH modifier decreases the levels/effects of atazanavir
Imipramine Increases the effect and toxicity of tricyclics
Indinavir Increased risk of hyperbilirubinemia with this association
Irinotecan Increases levels/effect of irinotecan
Lansoprazole This gastric pH modifier decreases the levels/effects of atazanavir
Lidocaine Increased risk of cardiotoxicity and arrhythmias
Lovastatin Increased risk of myopathy/rhabdomyolysis
Magnesium oxide This gastric pH modifier decreases the levels/effects of atazanavir
Magnesium This gastric pH modifier decreases the levels/effects of atazanavir
Magnesium Sulfate This gastric pH modifier decreases the levels/effects of atazanavir
Methylergonovine Increases the effect and toxicity of ergot derivative
Midazolam Increases the effect and toxicity of benzodiazepine
Nevirapine Nevirapine decreases levels/effect of atazanavir
Acenocoumarol The protease inhibitor increase the anticoagulant effect
Nizatidine This gastric pH modifier decreases the levels/effects of atazanavir
Nortriptyline Increases the effect and toxicity of tricyclics
Omeprazole This gastric pH modifier decreases the levels/effects of atazanavir
Pantoprazole This gastric pH modifier decreases the levels/effects of atazanavir
Pimozide The protease inhibitor increases the effect and toxicity of pimozide
Protriptyline Increases the effect and toxicity of tricyclics
Quinidine Increased risk of cardiotoxicity and arrhythmias
Quinidine barbiturate Increased risk of cardiotoxicity and arrhythmias
Rabeprazole This gastric pH modifier decreases the levels/effects of atazanavir
Ranitidine This gastric pH modifier decreases the levels/effects of atazanavir
Ranolazine Increased levels of ranolazine- risk of toxicity
Rifabutin Increases levels/toxicity of rifabutin
Rifampin Rifampin reduces levels and efficacy of atazanavir
Ritonavir Association with dose adjustment
Sildenafil Increases the effect and toxicity of sildenafil
Simvastatin Increased risk of myopathy/rhabdomyolysis
Sirolimus Increases the effect and toxicity of immunosuppressant
St. John's Wort St. John's Wort decreases the levels/effects of atazanavir
Sunitinib Possible increase in sunitinib levels
Tacrolimus Increases the effect and toxicity of immunosuppressant
Triazolam Increases the effect and toxicity of benzodiazepine
Trimipramine Increases the effect and toxicity of tricyclics
Warfarin The protease inhibitor increases the anticoagulant effect
Sodium bicarbonate This gastric pH modifier decreases the levels/effect of atazanavir
Tenofovir Tenofovir decreases the levels/effects of atazanavir
Food Interactions: Food increases product absorption.
Administration with food reduces pharmacokinetic variability.
Generic Name: Atazanavir
Synonyms: ATV; ATZ; BMS-232632; Atazanavir sulfate
Drug Category: Anti-HIV Agents; Protease Inhibitors
Drug Type: Small Molecule; Approved
Other Brand Names containing Atazanavir: Latazanavir; Reyataz; Zrivada;
Absorption: Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Oral bioavailability is 60-68%.
Toxicity (Overdose): Not Available
Protein Binding: 86% bound to human serum proteins (alpha-1-acid glycoprotein and albumin). Protein binding is independent of concentration.
Biotransformation: Atazanavir is extensively metabolized in humans, primarily by the liver. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.
Half Life: Elimination half-life in adults (healthy and HIV infected) is approximately 7 hours (following a 400 mg daily dose with a light meal). Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose).
Dosage Forms of Latazanavir: Capsule Oral
Chemical IUPAC Name: methyl N-[(2S)-1-[[(2S,3S)-3-hydroxy-4-[[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-[(4-pyridin-2-ylphenyl)methyl]amino]-1-phenylbutan-2-yl]amino]-3,3-dimethyl-1-oxobutan-2-yl]carbamate
Chemical Formula: C38H52N6O7
Atazanavir on Wikipedia: https://en.wikipedia.org/wiki/Atazanavir
Organisms Affected: Human Immunodeficiency Virus
