ASPEN ATAZANAVIR 150MG CAPSULE

Indications

• HIV infection in combination with other antiretroviral drugs
• HIV infection in patients previously treated with antiretroviral therapy

Dosage

Children: Children 30 kg and above: 1 tablet (300 mg) twice daily. For children aged 2–17 years: 375 mg twice daily for 15–29 kg, 450 mg twice daily for 30–39 kg, 600 mg twice daily for 40 kg and above. Refer to BNF for Children for specific dosing.

Adults: 1 tablet (300 mg) once daily, taken with food.

Mechanism of action

Atazanavir inhibits the HIV protease enzyme, preventing the cleavage of viral polyproteins into functional proteins, thus inhibiting the maturation of infectious viral particles.

Pharmacodynamics

Atazanavir exhibits antiviral activity against HIV, which is primarily dependent on the inhibition of the HIV protease. This leads to a decrease in viral load and an increase in CD4 cell count in HIV-positive patients.

Pharmacokinetics

Atazanavir is metabolized by the liver, primarily via the cytochrome P450 system (CYP3A4). It has oral bioavailability and its elimination half-life is approximately 7 hours. Renal impairment does not significantly affect its clearance, but caution is advised in patients with severe hepatic impairment.

Contra-indications

• Acute porphyrias

Adverse effects

• Hematuria
• Depression
• Disorientation
• Memory loss
• Myopathy
• Eosinophilia
• Nephritis
• Tubulointerstitial nephritis
• Proteinuria
• Syncope
• Torsade de pointes
• Increased urinary frequency
• Severe rash

Interactions

• Atazanavir + combined hormonal contraceptives: Moderate (affects exposure)
• Atazanavir + dolutegravir: Moderate (increases exposure)
• Atazanavir + macrolides: Moderate (increases exposure)
• Atazanavir + clarithromycin: Moderate (increases exposure)
• Atazanavir + bictegravir: Unknown (increases exposure)
• Atazanavir + maraviroc: Unknown (increases exposure)
• Atazanavir + raltegravir: Unknown (increases exposure)
• Atazanavir + high-dose: Unknown (increases exposure)

Precautions

• Caution in mild hepatic impairment; avoid in moderate to severe impairment
• Monitor viral load and atazanavir concentration during pregnancy
• Avoid if estimated glomerular filtration rate is less than 50 mL/minute/1.73 m2

Pregnancy

Theoretical risk of hyperbilirubinaemia in neonate if used at term.

Breast-feeding

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Storage

Store in a cool, dry place. Protect from light.

Formulations

• Atazanavir 150 mg capsule
• Atazanavir 200 mg capsule
• Atazanavir 300 mg capsule

Mechanism of action

Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2. Atazanavir is an azapeptide HIV-1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) protease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% effective concentration (EC(50)) of 2.6 to 5.3 nM and an EC(90) of 9 to 15 nM in cell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that it functions as an HIV Prt inhibitor. Comparative studies showed that BMS-232632 is generally more potent than the five currently approved HIV-1 Prt inhibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exhibits cytotoxicity only at concentrations 6,500- to 23, 000-fold higher than that required for anti-HIV activity. To assess the potential of this inhibitor when used in combination with other antiretrovirals, BMS-232632 was evaluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive to moderately synergistic antiviral effects. Importantly, combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Our results suggest that BMS-232632 may be an effective HIV-1 inhibitor that may be utilized in a variety of different drug combinations.

Pharmacodynamics

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). 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. Atazanavir 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. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals. Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC₅₀ values above the EC₅₀ values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture for 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 mse