Reyataz (Generic Atazanavir) is an anti-retroviral drug that belongs to the protease inhibitors.

• It is used in the treatment of HIV-1 infection with other antiretroviral agents in patients ≥3 months weighing more than 5 kg

• It is not recommended in pediatric patients <3 months due to the risk of kernicterus

Atazanavir Dose in Adults

Reyataz (Atazanavir) dose in the Treatment of HIV-1 infection:

• Antiretroviral-naive patients:

  • dosage is Atazanavir 300 mg orally once daily plus ritonavir 100 mg or
  • cobicistat 150 mg orally once daily or
  • atazanavir 400 mg orally once daily in patients who are unable to tolerate ritonavir.

• Antiretroviral-experienced patients:

  • Atazanavir 300 mg orally once daily plus ritonavir 100 mg or
  • cobicistat 150 mg orally once daily.
  •  Atazanavir is not given without ritonavir in antiretroviral-experienced patients with prior virologic failure.

• Pregnant patients, antiretroviral-naive or experienced:

  • Atazanavir 300 mg orally once daily is given along with ritonavir 100 mg once daily.
  • Some experts increase the dose to atazanavir 400 mg once daily plus ritonavir 100 mg once daily in the second and third trimesters.
  • It should not be used if both tenofovir disoproxil fumarate and an H2 antagonist are used.
  • Postpartum dosage adjustment is not required.
  • Observe patient for side effects, especially within 2 months after delivery.

Dosage adjustments for concomitant therapy:

• Coadministration with efavirenz:

  • Antiretroviral-naive patients:

    • Atazanavir 400 mg + ritonavir 100 mg + efavirenz 600 mg
    • All are given once daily but at different times
    • Atazanavir and ritonavir should be given with food and efavirenz on an empty stomach.

  • Antiretroviral-experienced patients:

    • Synchronous use not recommended due to decreased atazanavir exposure.

• Administration with didanosine buffered or enteric-coated formulations:

  • Give atazanavir 2 hours before or 1 hour after didanosine

• Coadministration with H2 antagonists:

  • Antiretroviral-naive patients:

    • Atazanavir 300 mg + ritonavir 100 mg
    • It is given simultaneously, or at least 10 hours after an H2 antagonist equivalent dose of less than 80 mg famotidine/day

  • Patients unable to tolerate ritonavir:

    • Atazanavir 400 mg once daily
    • It is given at least 2 hours before or at least 10 hours after an H2 antagonist equivalent daily dose of less than 40 mg famotidine

  • Antiretroviral-experienced patients:

    • Atazanavir 300 mg + ritonavir 100 mg
    • It is given simultaneously  or at least 10 hours after an H2 antagonist equivalent dose of ≤40 mg famotidine/day

  • Antiretroviral-experienced pregnant patients in the second or third trimester:

    • Atazanavir 400 mg + ritonavir 100 mg is given simultaneously with, or at least 10 hours after an H antagonist.

• It is not recommended if both tenofovir disoproxil fumarate and an H2 antagonist are used.

• Co-administration with proton pump inhibitors:

  • Antiretroviral-naive patients:

    • Atazanavir 300 mg plus ritonavir 100 mg is given 12 hours after a proton pump inhibitor equivalent dose of ≤20 mg omeprazole/day

  • Antiretroviral-experienced patients:

    • Concurrent use not advised.

• Co-administration with tenofovir disoproxil fumarate:

  • Antiretroviral-naive patients:

    • Atazanavir 300 mg + ritonavir 100 mg can be given with tenofovir disoproxil fumarate 300 mg
    • They all can be given as a single daily dose

  • Antiretroviral-experienced patients:

    • Atazanavir 300 mg + ritonavir 100 mg given with tenofovir disoproxil fumarate 300 mg
    • If H2 antagonist coadministered then  increase atazanavir to 400 mg (plus ritonavir 100 mg) once daily

  • Antiretroviral-experienced pregnant patients in the second or third trimester:

    • Atazanavir 400 mg + ritonavir 100 mg.

• Its use is not recommended if tenofovir disoproxil fumarate and an H2 antagonist are used.

Atazanavir Dose in Childrens

Reyataz (Atazanavir) dose in the treatment of HIV-1 infection:

• It should be used in combination with other antiretroviral agents.

• ritonavir-boosted regimen (preferred regimen): Antiretroviral-naïve and experienced patients:

• Oral powder:

  • Infants ≥3 months, Children, and Adolescents: Oral:

  • 5 - 15 kg:

    • Atazanavir 200 mg along with ritonavir 80 mg once daily.
    • In antiretroviral-naïve patients weighing 5 -10 kg unable to tolerate this dose, can use atazanavir 150 mg + ritonavir 80 mg once daily with close HIV viral load monitoring.

  • 15 to <25 kg:

    • Atazanavir 250 mg  plus ritonavir 80 mg once daily
  • ≥25 kg:
    • Atazanavir 300 mg plus ritonavir 100 mg once daily

Oral capsule:

• Children ≥6 years and Adolescents <18 years weighing ≥15 kg: Oral:
  • 15 kg to <35 kg:
    • Atazanavir 200 mg plus ritonavir 100 mg once daily
  • ≥35 kg:
    • Atazanavir 300 mg along with ritonavir 100 mg once daily

• Adolescents ≥18 years:

  • Atazanavir 300 mg orally once daily along with ritonavir 100 mg or cobicistat 150 mg once daily

• Ritonavir unboosted regimen:

  • The ritonavir-boosted atazanavir dosing regimen is favored
  • Guidelines do not recommend unboosted regimens.
  • The oral powder is not used for unboosted regimens.

• Antiretroviral-naïve patients: Oral capsule:

  • Adolescents weighing ≥40 kg who are not able to tolerate ritonavir: Oral:

    • 13 to <18 years:

      • Atazanavir 620 mg/m /dose once daily (without ritonavir);
      • Plasma concentrations should be monitored to ensure adequate concentrations are achieved.

• Adolescents ≥18 years:
  • Atazanavir 400 mg once daily

• Dosing adjustments for concomitant therapy:

  • Coadministration with didanosine buffered or enteric-coated formulations:

    • Infants ≥3 months, Children, and Adolescents:
      • Give atazanavir 2 hours before or 1 hour after didanosine​​​​​​​

• Coadministration with H2 -receptor antagonists:

  • Antiretroviral-naïve patients:

    • Infants ≥3 months, Children, and Adolescents:
      • The daily dose of atazanavir plus ritonavir should be given at the same time or at least 10 hours after, the H - receptor antagonist

  • Patients unable to tolerate ritonavir:

    • Adolescents ≥18 years:
      • Atazanavir 400 mg is given once daily given at least 2 hours before or at least 10 hours after an H antagonist

  • Antiretroviral-experienced patients:

    • Infants ≥3 months, Children, and Adolescents:
      • The daily dose of atazanavir is given along with ritonavir simultaneously with, or at least 10 hours after, the H -receptor antagonist

• Coadministration with proton pump inhibitor:

  • Antiretroviral-naïve patients:

    • Infants ≥3 months, Children, and Adolescents:
      • The daily dose of atazanavir is given along with ritonavir 12 hours after the proton pump inhibitor

  • Antiretroviral-experienced patients:

    • Concurrent use not advised

• Co-administration with efavirenz:

  • Adolescents ≥18 years:

    • Antiretroviral-naive patient:

      • Atazanavir 400 mg is given along with ritonavir 100 mg given + efavirenz 600 mg
      • All are given  once daily but at different times
      • Atazanavir and ritonavir should be given with food and efavirenz on an empty stomach.

    • Antiretroviral-experienced patients:

      • Concurrent use not advised due to decreased atazanavir exposure

• Coadministration with tenofovir disoproxil fumarate:

  • Adolescents ≥18 years:

    • Antiretroviral-naïve patients:

      • Atazanavir 300 mg plus ritonavir 100 mg given with tenofovir 300 mg

    • Antiretroviral-experienced patients:

      • Atazanavir 300 mg plus ritonavir 100 mg given with tenofovir 300 mg

Reyataz (Atazanavir) pregnancy Risk Factor: B

• Atazanavir crosses the human placenta at very low levels.
• Cord blood concentrations were reported to be between 13% and 21% of maternal serum concentrations during delivery.
• There has been no evidence of an increased risk for teratogenic effects.
• Preterm births are more likely to occur when a mother is taking antiretroviral medication.
• There has been an increase in stillbirths, low birth weights, and infants of small gestational age have been observed.
• Because of the potential for adverse neonatal outcomes, maternal ART should never be stopped.
• All infants who have been exposed to antiretroviral medication should be followed up for a long time.
• Children with significant organ system abnormalities (especially the heart or CNS) should be examined for possible mitochondrial dysfunction.
• Protease inhibitors are used to treat hyperglycemia, diabetes mellitus new onset, and diabetic ketoacidosis. It isn't known if this increases with pregnancy.
• Neonatal exposure to atazanavir in utero can lead to hyperbilirubinemia and hypoglycemia.
• Atazanavir, when combined with low-dose ritonavir, is the preferred protease inhibitor for HIV infected pregnant women who are antiretroviral naive (initial treatment), who have received ART therapy previously but need to restart, who have poor tolerance or poor virologic responses to current regimens, and who are not yet pregnant but trying to conceive.
• Atazanavir is not used in treatment-experienced pregnant females using both H - receptor blockers and tenofovir.
• Experts recommend that you take higher doses in the second and third trimesters.
• It is possible to monitor therapeutic drug use.
• To keep HIV-positive pregnant women under the age of 18 from contracting perinatal HIV, it is strongly recommended that they receive ART.
• Monitoring during pregnancy is more frequent than monitoring in nonpregnant women.
• All HIV-positive females should continue ART postpartum. ART can also be modified after birth

Reyataz (Atazanavir) use during breastfeeding:

• Atazanavir can be found in breast milk and is 13% higher than in maternal plasma.
• The risk of HIV transmission after birth does not disappear with infant or maternal antiretroviral treatment.
• To reduce the risk of HIV transmission, pregnant women with HIV should stop breastfeeding.

Atazanavir Dose in Renal Disease:

• Mild to severe impairment:

  • No dosage adjustment required.

• ESRD receiving IHD:

  • In patients with ESRD managed with hemodialysis, atazanavir is not mainly removed during hemodialysis.

• Antiretroviral-naive patients:

  • Atazanavir 300 mg plus ritonavir 100 mg once daily

• Antiretroviral-experienced patients:

  • Not used.

Atazanavir Dose in Liver Disease:

• Atazanavir: Antiretroviral-naive patients:

  • Mild impairment (Child-Pugh class A):

    • Atazanavir 400 mg once daily

  • Moderate impairment (Child-Pugh class B):

    • Atazanavir 300 mg once daily

  • Severe impairment (Child-Pugh class C):

    • Use is not recommended.

• Atazanavir/ritonavir:

  • Mild to severe impairment: Use is not recommended (has not been studied).

Common Side Effects of Reyataz (Atazanavir) Include:

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Increased Serum Cholesterol
  • Increased Amylase

• Gastrointestinal:

  • Nausea

• Hepatic:

  • Increased Serum Bilirubin
  • Jaundice

• Neuromuscular & Skeletal:

  • Increased Creatine Phosphokinase

• Respiratory:

  • Cough

• Miscellaneous:

  • Fever

Less common side effects of Reyataz (Atazanavir) Include:

• Cardiovascular:

  • Peripheral Edema
  • First Degree Atrioventricular Block
  • Second Degree Atrioventricular Block

• Central Nervous System:

  • Headache
  • Peripheral Neuropathy
  • Insomnia
  • Depression
  • Dizziness

• Endocrine & Metabolic:

  • Increased Serum Triglycerides
  • Hyperglycemia
  • Hypoglycemia

• Gastrointestinal:

  • Vomiting
  • Diarrhea
  • Increased Serum Lipase
  • Abdominal Pain

• Hematologic & Oncologic:

  • Decreased Neutrophils
  • Decreased Hemoglobin
  • Decreased Platelet Count

• Hepatic:

  • Increased Serum ALT
  • Increased Serum AST

• Neuromuscular & Skeletal:

  • Myalgia
  • Limb Pain

• Respiratory:

  • Nasal Congestion
  • Oropharyngeal Pain
  • Rhinorrhea
  • Wheezing

Contraindication to Reyataz (Atazanavir) Include:

• Hypersensitivity to atazanavir (or any other component of the medicine) can result in Stevens-Johnson Syndrome, erythema multife, and skin eruptions.
• Therapy along with with alfuzosin, cisapride, elbasvir/grazoprevir, glecaprevir/ pibrentasvir, ergot derivatives, indinavir, irinotecan, lovastatin, lurasidone (when atazanavir is coadministered with ritonavir), midazolam (oral), nevirapine, pimozide, rifampin, sildenafil (when used for pulmonary artery hypertension [eg, Revatio]), simvastatin, St. John's wort, or triazolam

Warnings and precautions

• Elevated Bilirubin

  • Asymptomatic increases in unconjugated bilirubin can occur frequently during therapy. They are easily reversed once treatment is stopped.
  • If bilirubin elevations are associated with jaundice, scleral inflammation or jaundice, consider alternative treatment.
  • If transaminase elevations occur, consider other causes.

• Fat redistribution

  • It can lead to redistribution and accumulation of fat (eg central obesity, buffalo-hump, peripheral waste, breast enlargement or cushingoid appearance).

• Hypersensitivity reactions

  • A number of hypersensitivity events are also caused by protease inhibitors.
  • If severe rash occurs or moderate symptoms are present, it is a good idea to discontinue treatment.

• Immune reconstitution syndrome:

  • Some patients may develop immune reconstitution syndrome, which can cause an inflammatory response to an infection.
  • This could occur during initial HIV treatment, or activation of autoimmune disorders later on in therapy.

• Nephrolithiasis/cholelithiasis:

  • Postmarketing surveillance can reveal gallstones and renal problems.
  • If symptoms persist, you may consider a temporary or permanent suspension of therapy.

• Conductivity abnormalities

  • It can extend the PR interval
  • Patients with conduction abnormalities or medications that prolong AV conduction should have their ECG monitored.

• Diabetes:

  • There are also changes in glucose tolerance, hyperglycemia and exacerbation or new-onset diabetes mellitus.

• Hemophilia A and B:

  • Patients with hemophilia A and B should not use it.

• Hepatic impairment

  • Hepatitis can also be caused by protease inhibitors.
  • Patients with severe hepatic impairment should not use this product.
  • When hepatic impairment exists, it is not recommended that patients take it with ritonavir.

• Renal impairment

  • Postmarketing surveillance has shown cases of chronic kidney disease.
  • Patients at risk of renal impairment or who have preexisting renal disease should consider alternative therapies.
  • Before starting treatment, it is important to have renal laboratory testing done (serum creatinine and estimated CrCl)
  • It is not recommended for use in treatment-experienced patients with ESRD on hemodialysis.
  • Patients with progressive kidney disease should stop receiving therapy.

Atazanavir: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitor:

• Viral load
• CD4
• serum glucose level
• LFT (before initiation and as indicated in patients with existing liver disease),
• bilirubin (as clinically indicated);
• drug levels (with certain concomitant medications),
• ECG monitoring in patients with preexisting prolonged PR interval or with concurrent AV nodal blocking drugs;
• serum creatinine level,
• estimated CrCL,
• urinalysis along with microscopic examination (before initiation and as clinically indicated).

How to take Atazanavir (Reyataz)?

• Administer with food. Give atazanavir 2 hours prior or 1 hour after didanosine buffered formulations, capsules, other buffered medications, or antacids.
• Administer atazanavir (with ritonavir) at the same time, or at least 10 hours after, H -receptor antagonists
• Administer atazanavir (without ritonavir) at least 2 hours prior or at least 10 hours after H -receptor antagonist.
• Administer atazanavir (with ritonavir) 12 hours after giving proton pump inhibitor.

Additional formulation specific information:

• Oral capsules: Swallow capsules whole, should not be opened

Oral powder: Mixing with food:

• While using a spoon, mix the recommended number of oral powder packets with a minimum of one tablespoon of food in a small container.
• Then feed the mixture to the patient.
• Mix an additional one tablespoon of food to the container, and give the patient the residual mixture.

Mix the medicine with a beverage such as milk or water in a small drinking cup:

• While using a spoon, mix the advised number of oral powder packets with a minimum of 30 mL of the beverage in a  cup.
• Give the patient to drink the mixture.
• Add 15 mL more of beverage to the cup
• Then mix, and have the patient drink the remaining mixture.
• If water is used, food should be eaten at the same time.

Mixed the drug with food or beverage and give the entire dose within 60 minutes of preparation (may leave the mixture at room temperature during this 60 minute period). Ensure that the patient eats or drinks all the food or beverage which contains the powder. Additional food can be given after consumption of the entire mixture. Give ritonavir after oral powder administration.

Mechanism of action of Atazanavir (Reyataz):

• Atazanavir binds with the protease activity and inhibits cleavage viral GagPol polyprotein precursors into functional proteins necessary for HIV infection.
• This results in the formation of non-infectious, immature viral particles.

Absorption:

• Rapid; increased with food

Distribution:

• CSF: Plasma concentration ratio (range): 0.0021 - 0.0226

Protein binding:

• 86%; it binds to both alpha -acid glycoprotein and albumin (similar affinity)

Metabolism:

• Mainly Hepatic by cytochrome P450 isoenzyme CYP3A;
• also undergoes biliary elimination;
• It undergoes major biotransformation pathways like mono-oxygenation and deoxygenation;
• Minor pathway metabolism of the parent drug or metabolites include glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation; 2 minor inactive metabolites have been seen

Half-life elimination:

• Unboosted therapy: 7 - 8 hours;
• Boosted therapy (with ritonavir): 9 - 18 hours;
• 12 hours in patients with hepatic impairment

Time to peak, plasma:

• 2 to 3 hours

Excretion:

• Via Feces (79%, 20% of total dose as unchanged drug)
• Via urine (13%, 7% of total dose as unchanged drug)

International Brands of Atazanavir:

• Atavir-A
• MYLAN-Atazanavir
• Reyataz
• TEVA-Atazanavir
• Atazor
• Reyataz

Atazanavir Brands in Pakistan:

 No brands available in Pakistan