Usage
- Atazanavir + Ritonavir is prescribed, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and children 6 years and older weighing at least 15 kg.
- Pharmacological classification: Antiretroviral, Protease inhibitor. Ritonavir acts as a pharmacokinetic booster, increasing atazanavir plasma levels.
- Mechanism of action: Atazanavir selectively inhibits the viral protease enzyme, preventing cleavage of viral polyproteins and immature, noninfectious viral particles. Ritonavir inhibits the metabolism of atazanavir, thus boosting its plasma concentrations.
Alternate Names
- Atazanavir sulfate/Ritonavir
- Brand names: Reyataz (atazanavir), Norvir (ritonavir), Evotaz (atazanavir/ritonavir)
How It Works
- Pharmacodynamics: Atazanavir inhibits HIV-1 protease, resulting in the formation of immature, non-infectious virions. Ritonavir, a potent inhibitor of CYP3A4, boosts the levels of Atazanavir by reducing its metabolism.
- Pharmacokinetics: Atazanavir is well absorbed orally, particularly when administered with food. It is primarily metabolized by the liver, specifically by CYP3A4. Ritonavir significantly inhibits CYP3A4-mediated metabolism, significantly increasing atazanavir exposure. Atazanavir is primarily eliminated in the feces, with a smaller portion excreted in the urine. Ritonavir is also metabolized by CYP3A4 and primarily eliminated in the feces.
- Mode of action: Atazanavir binds to the active site of the HIV-1 protease enzyme, preventing it from cleaving viral polyproteins, which are essential for the maturation of new virus particles.
- Elimination pathways: Atazanavir primarily undergoes hepatic metabolism by CYP3A enzymes (mainly CYP3A4) and is excreted in the feces. Ritonavir undergoes extensive hepatic metabolism, also primarily by CYP3A4, with primarily fecal excretion.
Dosage
Standard Dosage
Adults:
- Treatment-naive: Atazanavir 300 mg + Ritonavir 100 mg once daily with food.
- Treatment-experienced: Atazanavir 300 mg + Ritonavir 100 mg once daily with food.
- Unable to tolerate Ritonavir (treatment-naive only): Atazanavir 400 mg once daily with food.
Children (6 years and older, weighing at least 15 kg):
- Body weight 15 kg to less than 35 kg: Atazanavir 200 mg + Ritonavir 100 mg once daily with food.
- Body weight at least 35 kg: Atazanavir 300 mg + Ritonavir 100 mg once daily with food.
- Pediatric patients less than 6 years: Check available formulations with lower Atazanavir and Ritonavir content.
Special Cases:
- Elderly Patients: No specific dose adjustment is required unless there is renal or hepatic impairment.
- Patients with Renal Impairment: No dose adjustment required unless the patient is treatment-experienced and on hemodialysis. Treatment is not recommended in this specific case.
- Patients with Hepatic Dysfunction: Use with caution. In treatment-naive adults, Atazanavir without Ritonavir is recommended at a dose of 400mg for Child-Pugh A and 300mg for Child-Pugh B. Atazanavir with ritonavir is not recommended in patients with hepatic impairment.
- Patients with Comorbid Conditions: Patients with diabetes, hyperlipidemia, and hemophilia should be monitored closely due to potential exacerbation of these conditions.
Clinical Use Cases
- Atazanavir + Ritonavir is indicated for chronic HIV management and not typically used in acute clinical situations like intubation, surgical procedures, mechanical ventilation, ICU care, or emergency situations.
Dosage Adjustments
- Dosage adjustments may be necessary in specific situations, such as:
- Coadministration with acid-reducing agents (H2-receptor antagonists, proton-pump inhibitors): Adjust Atazanavir dose as needed or switch the acid-reducing agent.
- Coadministration with other antiretroviral drugs (e.g., efavirenz, tenofovir): Adjust doses as necessary.
- Hepatic impairment: Modify Atazanavir dosage.
- Pregnancy: No dose adjustment needed, except for the specific cases outlined above.
Side Effects
Common Side Effects
- Nausea, vomiting, diarrhea
- Abdominal pain
- Headache
- Fatigue
- Jaundice (usually mild and reversible)
- Rash
Rare but Serious Side Effects
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Hepatitis (including cases of hepatic failure)
- Pancreatitis
- Heart block or conduction problems (especially with preexisting conditions)
Long-Term Effects
- Hyperbilirubinemia (elevated bilirubin levels)
- Cholelithiasis (gallstones)
- Nephrolithiasis (kidney stones)
- Lipodystrophy (changes in body fat distribution)
- Insulin resistance and hyperglycemia
- Hyperlipidemia (elevated cholesterol and triglycerides)
- Increased bleeding in patients with hemophilia
Adverse Drug Reactions (ADR)
- Severe skin reactions (SJS, TEN)
- Hepatotoxicity
- Pancreatitis
- Cardiac conduction abnormalities
Contraindications
- Hypersensitivity to atazanavir or ritonavir
- Coadministration with drugs highly dependent on CYP3A or UGT1A1 for clearance where elevated levels can lead to serious or life-threatening events.
- Coadministration with strong CYP3A4 inducers (rifampin, St. John’s wort).
- Moderate to severe hepatic impairment (when used in combination with ritonavir).
Drug Interactions
- Atazanavir and Ritonavir are primarily metabolized by CYP3A4. Therefore, drugs that induce or inhibit CYP3A4 can affect their plasma concentrations:
- CYP3A4 inducers (rifampin, St. John’s wort): decrease atazanavir and ritonavir levels.
- CYP3A4 inhibitors (ketoconazole, itraconazole): increase atazanavir and ritonavir levels.
- Antacids: Separate administration by at least 2 hours.
- H2-receptor antagonists (e.g., famotidine, ranitidine): Adjust dosing time and/or atazanavir dose.
- Proton pump inhibitors (e.g., omeprazole, lansoprazole): Adjust dosing time and/or atazanavir dose.
- Other antiretrovirals (e.g., efavirenz, tenofovir, didanosine): Adjust doses as needed.
- Drugs that prolong the QT interval (amiodarone, quinidine): Use with caution and monitor.
- Hormonal contraceptives: Atazanavir/Ritonavir may decrease the effectiveness; alternative contraception recommended.
Pregnancy and Breastfeeding
- Atazanavir + Ritonavir can be used during pregnancy but should be used with caution and monitoring, especially regarding jaundice in neonates.
- Monitor bilirubin levels in newborns exposed to Atazanavir + Ritonavir during pregnancy.
- Data on breastfeeding is limited, but Atazanavir is likely present in breast milk. Discuss benefits and risks with the patient.
Drug Profile Summary
- Mechanism of Action: HIV-1 protease inhibitor boosted by ritonavir
- Side Effects: Nausea, vomiting, jaundice, rash, hyperbilirubinemia, hepatic dysfunction, metabolic abnormalities
- Contraindications: Hypersensitivity, coadministration with certain drugs (CYP3A4 inducers, UGT1A1 substrates, strong CYP3A inhibitors)
- Drug Interactions: Numerous drug interactions, particularly through CYP3A4
- Pregnancy & Breastfeeding: Can be used in pregnancy with caution; data on breastfeeding is limited.
- Dosage: 300 mg atazanavir + 100 mg ritonavir once daily with food (adults).
- Monitoring Parameters: Liver function tests, bilirubin, lipids, blood glucose, renal function tests, viral load, CD4 cell count.
Popular Combinations
- Atazanavir + Ritonavir is typically combined with two other antiretroviral agents, such as nucleoside reverse transcriptase inhibitors (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs).
- Examples: Atazanavir/Ritonavir + Tenofovir disoproxil fumarate/Emtricitabine or Atazanavir/Ritonavir + Abacavir/Lamivudine
Precautions
- General Precautions: Monitor liver function, bilirubin levels, lipids, and blood glucose. Screen for and manage any potential drug interactions.
- Specific Populations:
- Pregnant Women: Monitor for jaundice in newborns.
- Breastfeeding Mothers: Discuss risks and benefits.
- Children & Elderly: Follow age-appropriate dosing guidelines and monitor closely.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Atazanavir + Ritonavir?
A: For treatment-naive adults: Atazanavir 300 mg + Ritonavir 100 mg once daily with food. For pediatric patients, please refer to pediatric dosage guidelines above. Dose adjustments may be necessary based on drug interactions, renal impairment, and other factors.
Q2: What are the most common side effects?
A: The most common side effects include nausea, vomiting, diarrhea, abdominal pain, jaundice, rash, and headache.
Q3: What are the serious side effects of Atazanavir + Ritonavir?
A: Serious side effects can include severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatitis, pancreatitis, and cardiac conduction abnormalities.
Q4: Can Atazanavir + Ritonavir be used in pregnancy?
A: Yes, it can be used during pregnancy, but careful monitoring of both the mother and the neonate, especially for hyperbilirubinemia and jaundice is important. Discuss benefits and risks with the patient.
Q5: What are the major drug interactions with Atazanavir + Ritonavir?
A: Atazanavir + Ritonavir interact with numerous drugs, including CYP3A4 inducers and inhibitors, antacids, H2-receptor antagonists, proton pump inhibitors, and other antiretroviral agents. Refer to drug interaction guidelines above for more detailed information.
Q6: What should be monitored in patients receiving Atazanavir + Ritonavir?
A: Patients receiving Atazanavir + Ritonavir should have regular monitoring of liver function tests, bilirubin levels, lipid profile, blood glucose, and renal function tests. HIV viral load and CD4 counts should also be regularly assessed.
Q7: What is the role of Ritonavir in this combination?
A: Ritonavir acts as a pharmacokinetic booster, inhibiting the metabolism of atazanavir and significantly increasing its plasma concentrations. This allows for once-daily dosing of Atazanavir.
Q8: Can Atazanavir be used without Ritonavir?
A: In certain specific cases where the patient is treatment-naive and cannot tolerate ritonavir, Atazanavir can be used as monotherapy at a dose of 400 mg once daily.
Q9: What if a patient misses a dose of Atazanavir + Ritonavir?
A: If a dose is missed within 12 hours of the usual time, it should be taken with food as soon as possible. If it is closer to the time of the next dose, the missed dose should be skipped, and the patient should resume their regular dosing schedule. Double dosing should be avoided.
