2. CRIXIVAN ( Indinavir ) Mr.Somjed Sahasitiwat ( Clinical group ) Mr.Somjed Sahasitiwat ( Clinical group )

3. What is CRIXIVAN  CRIXIVAN ™ is the trade name of Indinavir sulfate, member of PI. It’s a white to off-white, hygroscopic, crystalline powder, MW. is 711.88 Is an oral capsule used for treatment of HIV. Present in 200 mg., 333 mg. and 400 mg.

4. Microbiology HIV protease is an enzyme required for proteolytic cleavage. Indinavir binds to the protease active site and inhibits activity of enzyme Prevents cleavage of viral polyproteins. Formation of immature non- infectious viral particles

5. Pharmacology Rapidly absorbed in the fasted state, Tmax = 0.8 + 0.3 hr. Meal with high calories,fat and protein reduction in AUC and Cmax. Light meal is little or no change in AUC,Cmax or trough concentration

6. Pharmacology Approximately 60% bound to plasma proteins. Excrete in feces 83 + 1% and urine 19 + 3% Less than 20% excreted unchanged in urine Half-life = 1.8 + 0.4 hours Major metabolisms in P-450 (3A4)

7. Pharmacology Mild to moderate hepatic insufficiency. Decreased metabolism of Indinavir. 60% higher mean AUC T1/2 increased to 2.8 + 0.5 hours

8. Pharmacology Renal insufficiency : pharmacokinetics have not been studied Gender : comparable in men and women Race : comparable in Caucasians and Blacks

9. CRIXIVAN should not take with : seldane ™ (terfenadine), hismanal ™ (astemizole) versed™ (midazolam), halcion™ (triazolam) propulsid ™ (cisapride) ergot medications (Wigrane ™ and Cafegot ™ ) Rifampin ( rifadin ™,rifamate ™, rifater ™ or rimactane ™ ) potent inducer of P-450 ( 3a4 )

10. Drugs you can take with CRIXIVAN RETROVIR ™ ( zidovudine, AZT ), EPIVIR ™ ( lamivudine.3TC ), ZERIT ™ ( stavudine.D4t ) isoniazid ( INH ) BACTRIM ™ ( trimetroprim/sulfamethoxazole ) DIFLUCAN ™ ( fluconazole )

11. Drugs you can take with CRIXIVAN BIAXIN ™ ( clarithromycin ) ORTHO-NOVUM 1/35 ( oral contraceptive ) TAGAMET ™ ( cimetidine ) Methadone

12. Drugs Requiring Dose Modification Delaverdine Efavirenz Itraconazole, Ketoconazole Rifabutin

13. Indication and usage In combination with antiretroviral agents is indicated for treatment of HIV infection

14. Dosage and administration Recommended dosage is 800 mg. Orally every 8 hr Administered without food Take with water 1 hr.before or 2 hrs. after meal May be take with light meal For adequate hydration drink at least 1.5 L./ 24 hr.

15. Dose in drugs combination Delavirdine dose reduction of CRIXIVAN to 600 mg. Every 8 hr Didanosine should be take CRIXIVAN at least one 1 hr. apart on empty stomach

16. Dose in drugs combination Efavirenz increase of CRIXIVAN to 1000 mg every 8 hr. Itraconazole and Ketoconazole reduction of CRIXIVAN to 600 mg every 8 hr.

17. Dose in drugs combination Rifabutin reduction of rifabutin to half the standard dose increase of CRIXIVAN to 1000 mg every 8 hr.

18. Specials condition Hepatic Insufficiency mild to moderate hepatic insufficiency due to cirrhosis dosage reduced to 600 mg every 8 hr.

19. Specials condition Nephrolithiasis in addition to adequate hydration who experience nephrolithiasis may include temporary interruption or discontinuation of therapy

20. WARNING Nephrolithiasis has occurred. Adequate hydration is recommended. Hemolytic anemia appropriate measures for the treatment and discontinuation of CRIXIVAN

21. WARNING Hepatitis majority of these patients had confounding medication conditions and/or receiving concomitant therapy.

22. WARNING Hypoglycemia in some cases, diabetic ketoacidosis has occurred. Drug interaction risk of myopathy may increase when use with HMG-CoA reductase inhibitors.

23. Pregnancy CRIXIVAN is the pregnancy category C hyperbillirubinemia has occurred Should be used if potential benefit justifies the potential risk to the fetus.

24. Nursing Mothers Study in lactating rats CRIXIVAN excreted in milk. Not known whether CRIXIVAN is excreted in human milk. Should be discontinue nursing if receiving CRIXIVAN

25. Information for patients CRIXIVAN is not a cure for HIV infection. Patients may to develop opportunistic infections. Not shown reduce the risk of transmission of HIV to other through sexual contact or blood contamination.

26. Information for patients If a dose is missed, should take the next dose at regularly time. Should not double dose. For optimal absorption, should take without food

27. Storage Store in a tightly-closed container at room temp., 15-30  C Protect from moisture. Should be stored in original container. The desiccant should remain in the bottle

28. Special Thanks. Professor John Essigmann, MIT Professor Ram Sasisekharan, MIT Dr. Ganesh Vengataraman, MIT Dr. Maria Kartalou, MIT Dr. Suvit Loprasert, CRI