Consumer medicine information

Atazanavir Mylan

Atazanavir

BRAND INFORMATION

Brand name

Atazanavir Mylan

Active ingredient

Atazanavir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Atazanavir Mylan.

What is in this leaflet

This leaflet answers some common questions about ATAZANAVIR MYLAN. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ATAZANAVIR MYLAN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What ATAZANAVIR MYLAN is used for

ATAZANAVIR MYLAN belongs to a group of medicines called protease inhibitors.

ATAZANAVIR MYLAN is used in combination with other anti-HIV agents to treat adults and children aged between 6 and 18 years of age who are infected with Human Immunodeficiency Virus (HIV).

What is HIV
HIV is a virus that kills important cells in the immune system over time (e.g. CD4 cells). When HIV has killed enough of the immune cells, your body becomes prone to certain types of infections. Some infections are the cause of "AIDS-defining" illnesses. This is when someone is said to have developed Acquired Immunodeficiency Syndrome or AIDS. AIDS is a serious condition and can lead to death.

How ATAZANAVIR MYLAN works

When HIV infects cells in the immune system, it takes over part of the cell's internal workings and uses the contents of the cell to produce new viruses.

ATAZANAVIR MYLAN helps to block HIV protease, an enzyme that is needed for the HIV virus to multiply. ATAZANAVIR MYLAN may lower the amount of HIV in your blood and help your body keep its supply of CD4 and T-cells. Interfering with the production of new viruses helps to reduce the total amount of HIV in the body and slows down the damage to the immune system.

ATAZANAVIR MYLAN is not a cure for HIV infection. Taking it will not necessarily prevent the illnesses that commonly occur in people with HIV infection or AIDS. You can still infect other people with HIV while you are taking this medicine.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

ATAZANAVIR MYLAN is not addictive.

This medicine is available only with a doctor's prescription.

Before you take ATAZANAVIR MYLAN

It is important that you check the information below before you take ATAZANAVIR MYLAN.

When you must not take it

Do not take ATAZANAVIR MYLAN if you have an allergy to:

  • any medicine containing atazanavir
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take ATAZANAVIR MYLAN if you have severe liver disease.

Do not take ATAZANAVIR MYLAN if you are currently taking any of these medicines:

  • rifampicin - a medicine used to treat tuberculosis
  • sildenafil - if you are taking it for pulmonary arterial hypertension
  • irinotecan - a medicine used to treat some cancers
  • cisapride - a medicine used to treat gastric reflux
  • alfuzosin - a medicine used in bladder disorders
  • asthma medications salmeterol (Seretide, Serevent)
  • cholesterol reducing medicines (lovastatin, simvastatin)
  • sleeping tablets containing midazolam or triazolam
  • medicines used to treat psychotic problems containing pimozide or lurasidone
  • medicines to treat migraine or severe headaches which contain ergotamine
  • herbal products which contain St John's wort (Hypericum perforatum)
  • protease inhibitor - indinavir (Crixivan)
  • medicines used to treat hepatitis C containing elbasvir/grazoprevir or glecaprevir/pibrentasvir

If you are taking ATAZANAVIR MYLAN with another medicine for the treatment of HIV called ritonavir, then you should not take certain medicines such as calcium channel blockers including bepridil or a medication known as quinidine. You should also inform your doctor if you are taking fluticasone propionate.

If you are not sure if any of these medicines are in the products you are taking, talk to your doctor or pharmacist.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or intend to become pregnant. Experience is limited with the use of ATAZANAVIR MYLAN in pregnant women. Therefore, it should not be used during pregnancy unless it is clearly needed. If there is an urgent need to consider ATAZANAVIR MYLAN during pregnancy, your doctor will discuss with you the benefits and risks of taking it.

Tell your doctor if you are breast feeding or planning to breast-feed. It is not known whether ATAZANAVIR MYLAN passes into breast milk. Therefore, to avoid possible side effects in the nursing infant, mothers should stop breast- feeding if they are taking ATAZANAVIR MYLAN (breast- feeding can also transfer HIV to babies)

Tell your doctor if you have or have had any of the following medical conditions:

  • liver problems including hepatitis, yellowing of the skin or eyes (jaundice) or prior use of medicines toxic to the liver. Liver problems may cause higher levels of ATAZANAVIR MYLAN in the blood, increasing the chance of side effects
  • have any of the following risk factors for chronic kidney disease:
    - diabetes
    - high blood pressure
    - established heart problems (heart failure or heart attack) or have had a stroke
    - a family history of kidney failure
    - are obese with a body mass index (BMI) 30 or higher
    - are a smoker
    - are 60 years of age or older
    - are of Aboriginal or Torres Strait Islander origin
    - have a history of acute kidney injury
  • haemophilia; haemophiliac patients may experience increased bleeding when taking ATAZANAVIR MYLAN any problems with irregular heart beat
  • diabetes or impaired glucose tolerance

If you have not told your doctor about any of the above, tell them before you start taking ATAZANAVIR MYLAN.

Taking other medicines

ATAZANAVIR MYLAN has the potential to adversely interact with many other drugs.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Medicines for HIV
ATAZANAVIR MYLAN will be given with other anti-HIV medicines; some of these anti-HIV medicines may affect the way ATAZANAVIR MYLAN works, and ATAZANAVIR MYLAN may affect the way some other anti-HIV medicines work.

Your doctor has all the current information on the effects these medicines have on one another and will discuss with you the combination of medicines that you should be taking.

Medicines for other conditions
You should tell your doctor if you are taking any of the following medicines:

  • medicines to treat hepatitis (e.g. telaprevir, bocepravir, sofosbuvir/ velpatasvir/ voxilaprevir)
  • proton-pump inhibitors or histamine-2 receptor antagonists (medicines used to treat stomach ulcers or other stomach disorders). If you plan to take or are currently taking either histamine-2 receptor antagonists (such as cimetidine, famotidine, ranitidine or other medicines in this class) or proton-pump inhibitors (such as omeprazole or others in this class of medicine), then you must speak to your doctor as these may reduce the effectiveness of ATAZANAVIR MYLAN. Depending on your medical history these medicines may not be suitable for you. Talk to your doctor for further information
  • macrolide antibiotics (clarithromycin, roxithromycin, erythromycin or azithromycin) used to treat various infections
  • antifungal medication (voriconazole) used to treat fungal infections
  • anticonvulsant medications (carbamazepine, phenytoin, phenobarbital or lamotrigine) used to treat epilepsy
  • erectile dysfunction agents used to treat impotence - sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra)
  • amiodarone, bepridil, lignocaine, quinidine or tricyclic antidepressants - if you take any of these medicines, your doctor may ask you to have blood tests just to make sure that ATAZANAVIR MYLAN and the other medicine are not affecting the way each medicine works
  • calcium channel blockers (such as diltiazem, felodipine, nifedipine, nicardipine or verapamil) - medicines used to treat high blood pressure
  • antacids and buffered medicines reduce the absorption of ATAZANAVIR MYLAN. These medicines should be taken one hour before or two hours after ATAZANAVIR MYLAN.
  • drugs that affect the electrical activity of the heart
  • oral contraceptives - ATAZANAVIR MYLAN may affect the safety and effectiveness of birth control pills or the patch. Speak to your doctor about the type of contraception that is most suitable for you
  • pain medications (buprenorphine)
  • gout medications (colchicine)
  • bosentan (Tracleer), a medication used to treat pulmonary arterial hypertension

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take ATAZANAVIR MYLAN

ATAZANAVIR MYLAN should be given only when prescribed by your doctor.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How much to take

If you are new to HIV treatment, your doctor may prescribe ATAZANAVIR MYLAN 400 mg (2 x 200 mg capsules) once a day with food

OR

ATAZANAVIR MYLAN 300 mg once daily (either as one 300 mg capsule or two 150 mg capsules) with ritonavir (100 mg daily) taken with food.

If you have been on previous HIV treatment, the usual dose is ATAZANAVIR MYLAN 300 mg once daily (either as one 300 mg capsule or two 150 mg capsules) with ritonavir (100 mg daily) taken with food.

You doctor will tell you what dose of ATAZANAVIR MYLAN you should take.

If you are between the ages of 6 and 18 years, the dose of ATAZANAVIR MYLAN will be different. Please follow your doctor's instructions.

How to take it

Swallow the capsules whole with a drink such as a glass of water or fruit juice.

The dose of ATAZANAVIR MYLAN should be taken with food.

When to take it

You may take ATAZANAVIR MYLAN capsules at any time. It is recommended, however, that you take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Talk to your doctor or pharmacist to work out when it is best for you to take your doses of ATAZANAVIR MYLAN.

How long to take it

Continue taking your medicine for as long as your doctor tells you. This medicine helps to control your condition but does not cure it.

Do not stop taking this medicine unless your doctor tells you to - even if you feel better.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to take it.

Otherwise take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints and inform your doctor that you have missed a dose.

It is very important not to miss your doses of ATAZANAVIR MYLAN. If you miss doses the virus may become resistant to your HIV medicines.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you or anyone else may have taken too much ATAZANAVIR MYLAN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking ATAZANAVIR MYLAN

Things you must do

If you are about to be started on any new medicine, remind your doctor or pharmacist that you are taking ATAZANAVIR MYLAN.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. You may wish to discuss disclosure issues with your doctor about who should know that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately. Pregnant women have experienced serious side effects when taking this medicine in combination with didanosine (Videx) and stavudine (Zerit).

You should have your liver function and blood tested on a regular basis when your doctor advises you to ensure that your body chemistry is functioning normally and that ATAZANAVIR MYLAN is working.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take ATAZANAVIR MYLAN to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how ATAZANAVIR MYLAN affects you. Some patients taking ATAZANAVIR MYLAN have experienced dizziness. It is not known if this was caused by ATAZANAVIR MYLAN. Make sure you know how you react to ATAZANAVIR MYLAN before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy.

Things that may help your condition

Things that may help your general health are suggested below:

  • exercise
  • healthy eating
  • stress reduction
  • counselling
  • regular visits to your doctor to monitor your health
  • good oral hygiene
  • support groups

Talk with your doctor about all of the above suggestions. You can also access further information about HIV and services for people with HIV by contacting your local AIDS Council, Positive Living Centre or PLWHA organisation.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ATAZANAVIR MYLAN.

This medicine helps most people with HIV infection, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Your doctor may monitor your kidney function prior to, and during, your treatment with ATAZANAVIR MYLAN.

Tell your doctor if you notice any of the following and they worry you:

  • nausea, diarrhoea, dyspepsia (upset stomach), flatulence (wind)
  • headache, fatigue, dizziness, insomnia
  • vomiting
  • loss of strength and energy

These are some of the more common side effects of ATAZANAVIR MYLAN.

Tell your doctor or pharmacist immediately if you notice any of the following:

  • tingling of the hands or feet
  • abdominal pain, abdominal distension or tenderness, vomiting
  • changes to the distribution of fat on your body
  • pain in the joints, muscle pain
  • ulcers in the mouth, oesophagus (pain or burning on swallowing) or stomach (pain or indigestion)
  • rash
  • change in heart rhythm, fainting

These are serious side effects. You may need urgent medical attention or hospitalisation.

Yellowing of the skin or eyes
One of the other side effects that can occur with ATAZANAVIR MYLAN is yellowing of the skin (jaundice) or eyes (scleral icterus). Yellowing of the skin or eyes is caused by an increase in a substance called bilirubin. Bilirubin is formed naturally by the breakdown of red blood cells and is usually excreted by the liver.

Call your doctor if your skin or the whites of your eyes turn yellow. Although it is unlikely that these effects will cause damage to your skin, eyes or liver, it is important that you tell your doctor promptly if they occur.

Gallbladder disorders (which may include gallstones and gallbladder inflammation)
If you develop any signs or symptoms of gallstones (pain in the right or middle upper stomach, fever, nausea or vomiting, or yellowing of skin and whites of eyes), tell your doctor promptly.

Kidney stones
If you develop signs or symptoms of kidney stones (pain in your side, blood in your urine, pain when you urinate) tell your doctor promptly.

If any of the following happen, tell your doctor immediately, or go to the Accident and Emergency Centre at your nearest hospital:

  • liver problems including yellowing of the skin or eyes, also called jaundice; this may occur with vomiting, fever and dark coloured urine
  • lactic acidosis - symptoms include nausea, vomiting, unusual or unexpected stomach discomfort, feeling very weak and tired, shortness of breath, or weakness in the arms and legs
  • allergic reaction - swelling of the face, lips, or throat which makes breathing difficult

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking ATAZANAVIR MYLAN

Storage

Store your capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store ATAZANAVIR MYLAN or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and- a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any that is left over.

Product description

What it looks like

ATAZANAVIR MYLAN 200 mg capsules - have a blue opaque cap and greenish-blue opaque body filled with a white to pale yellow powder. The capsule is axially printed with MYLAN over AR200 in black ink on both the cap and body.

ATAZANAVIR MYLAN 300 mg capsules - have a red opaque cap and greenish-blue opaque body, filled with a white to pale yellow powder. The capsule is axially printed with MYLAN over AR300 in black ink on both the cap and body.

Ingredients

ATAZANAVIR MYLAN capsules contain either 200 mg or 300 mg of atazanavir (as sulfate) as the active ingredient.

They also contain the following inactive ingredients:

  • lactose monohydrate
  • crospovidone
  • magnesium stearate
  • gelatin
  • titanium dioxide
  • iron oxide yellow (E172)
  • iron oxide red (E172)
  • brilliant blue (E133)
  • erythrosine (E127)
  • TekPrint SW-9008 black ink

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

ATAZANAVIR MYLAN is supplied in Australia by:

Alphapharm Pty Limited
(ABN 93 002 359 739)
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
Phone: (02) 9298 3999
www.mylan.com.au

Australian registration numbers:

ATAZANAVIR MYLAN 200 mg: AUST R 255296

ATAZANAVIR MYLAN 300 mg: AUST R 255297

This leaflet was prepared in February 2019.

ATAZANAVIR MYLAN_cmi \Feb19/00

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Atazanavir Mylan

Active ingredient

Atazanavir

Schedule

S4

 

1 Name of Medicine

Atazanavir (as sulfate).

2 Qualitative and Quantitative Composition

Each capsule contains either 150 mg, 200 mg or 300 mg of atazanavir (as sulfate) as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Atazanavir Mylan 150 mg capsule.

A No.1, greenish-blue opaque cap and blue opaque body, hard-shell gelatin capsule filled with white to pale yellow powder. The capsule is axially printed with Mylan over AR150 in black ink on both the cap and body.

Atazanavir Mylan 200 mg capsule.

A No.0, blue opaque cap and greenish-blue opaque body, hard-shell gelatin capsule filled with white to pale yellow powder. The capsule is axially printed with Mylan over AR200 in black ink on both the cap and body.

Atazanavir Mylan 300 mg capsule.

A No.00, red opaque cap and greenish-blue opaque body, hard-shell gelatin capsule filled with white to pale yellow powder. The capsule is axially printed with Mylan over AR300 in black ink on both the cap and body.

4 Clinical Particulars

4.1 Therapeutic Indications

Atazanavir is indicated for the treatment of HIV-1 infection, in combination with other antiretroviral agents.
This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts from controlled studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

General dosing recommendations.

Atazanavir Mylan capsules must be taken with food.
Atazanavir Mylan capsules should be taken whole. The recommended doses are to be administered using combinations of registered capsule strengths; e.g. a dose of 300 mg may be administered as one 300 mg capsule or two 150 mg capsules.
The recommended oral dosage of atazanavir depends on the treatment history of the patient and the use of other co-administered drugs. When co-administered with H2-receptor antagonists, or proton-pump inhibitors, dose separation may be required (see recommendations below).
When co-administered with didanosine buffered or enteric-coated formulations atazanavir should be given (with food) 2 hours before or 1 hour after didanosine.
Atazanavir without ritonavir is not recommended for treatment-experienced patients with prior virologic failure.
Efficacy and safety of atazanavir with ritonavir in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses might alter the safety profile of atazanavir and therefore is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using this agent.
For further information see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Table 20, Table 21.

Dose recommendations for therapy-naïve adult patients.

Atazanavir 400 mg once daily o Atazanavir 300 mg with ritonavir 100 mg once daily.

Concomitant therapy.

Atazanavir without ritonavir is not recommended when co-administered with the drugs listed below. Atazanavir 300 mg with ritonavir 100 mg should be administered with any of the following.
Tenofovir (disoproxil fumarate).
Efavirenz: co-administration of atazanavir with efavirenz is not recommended. If the combination of atazanavir and efavirenz is judged to be unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir both administered as a single dose with food and efavirenz administered on an empty stomach, preferably at bedtime.
H2-receptor antagonist: the H2-receptor antagonist dose should not exceed a 40 mg dose equivalent of famotidine twice daily. Atazanavir 300 mg and ritonavir 100mg should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
Proton-pump inhibitors: the proton-pump inhibitor dose should not exceed a 20 mg dose equivalent of omeprazole and must be taken approximately 12 hours prior to the atazanavir 300 mg and ritonavir 100 mg dose.

Dose recommendations for therapy-experienced adult patients.

Atazanavir 300 mg with ritonavir 100 mg once daily
Atazanavir without ritonavir is not recommended for treatment experienced patients with prior virologic failure.

Concomitant therapy.

Whenever a H2-receptor antagonist is given to a patient receiving atazanavir with ritonavir, the H2-receptor antagonist dose should not exceed a dose equivalent to famotidine 20 mg twice daily, and the atazanavir and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
Atazanavir 300 mg with ritonavir 100 mg once daily if taken with a H2-receptor antagonist.
Atazanavir 400 mg with ritonavir 100 mg once daily if taken with both tenofovir and a H2-receptor antagonist.
Proton-pump inhibitors should not be used in treatment-experienced patients receiving atazanavir.
Efavirenz: In treatment-experienced patients, atazanavir should not be co-administered with efavirenz.

Paediatric patients (6-18 years of age).

The dosage of atazanavir for treatment naïve and treatment experienced paediatric patients (6 to 18 years of age) is shown in Table 1 and should not exceed the recommended adult dosage.
Atazanavir Mylan capsules must be taken with food.
For treatment-naïve patients at least 13 years of age and at least 40 kg, who are unable to tolerate ritonavir, the recommended dose is atazanavir 400 mg (without ritonavir) once daily with food.

Paediatric patients less than 6 years of age.

There are no dosing recommendations for atazanavir in paediatric patients less than 6 years of age. Atazanavir should not be administered to paediatric patients below 3 months of age due to the risk of kernicterus.

Patients with renal impairment.

For patients with renal impairment, including those with severe renal impairment who are not managed by haemodialysis, no dosage adjustment is required for atazanavir. Treatment-naïve patients with end stage renal disease managed with haemodialysis should receive atazanavir 300 mg with ritonavir 100 mg.
Atazanavir should not be administered to HIV-treatment experienced patients with end stage renal disease managed with haemodialysis (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

Atazanavir should be used with caution in patients with mild to moderate hepatic insufficiency. A dose reduction to 300 mg once daily should be considered for patients with moderate hepatic insufficiency (Child-Pugh Class B). Atazanavir should not be used in patients with severe hepatic insufficiency (Child-Pugh Class C, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). Atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment and should be used with caution in patients with mild hepatic impairment. Atazanavir with ritonavir is not recommended for patients with moderate to severe impairment.

4.3 Contraindications

Hypersensitivity to atazanavir or to any of the excipients (see Section 6.1 List of Excipients).
Patients with severe hepatic insufficiency. Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, for patients with mild to moderate hepatic insufficiency; Section 5.2 Pharmacokinetic Properties).
Atazanavir Mylan is contraindicated in combination with the following.
Rifampicin.
Lurasidone.
Simvastatin or lovastatin.
Medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows. Co-administration may result in competitive inhibition of the metabolism of these medicinal products and create the potential for serious and/or life-threatening adverse events such as cardiac arrhythmia (e.g. cisapride, pimozide), prolonged sedation or respiratory depression (e.g. orally administered midazolam, triazolam), or other events (e.g. ergot derivatives).
Products containing St. John's wort (Hypericum perforatum).
Alfuzosin.
Salmeterol.
Elbasvir/grazoprevir. Co-administration may result in potential increase in the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.
Glecaprevir/pibrentasvir. Co-administration may result in increased ALT elevations due to an increase in glecaprevir and pibrentasvir plasma concentrations.
The PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension. A safe and effective dose in combination with atazanavir has not been established for sildenafil when used for the treatment of pulmonary arterial hypertension. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope). For use of atazanavir with sildenafil (when used for the treatment of erectile dysfunction), please see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

4.4 Special Warnings and Precautions for Use

Hyperbilirubinemia and jaundice.

Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin, and this may be associated with scleral icterus and jaundice in some patients. This isolated hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hyperbilirubinemia was related to atazanavir plasma concentrations and not generally associated with elevation of serum transaminases. Preclinical studies suggest that elevation in bilirubin was not associated with haemolysis and was related to inhibition of UDP-glucuronosyl transferase (UGT) by atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin > 5 times ULN. Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiac effects.

Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been rare reports of second-degree AV block and other conduction abnormalities and no reports of third-degree AV block (see Section 4.9 Overdose). In clinical trials, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n = 920), 5.2% of lopinavir/ritonavir-treated patients (n = 252), 10.4% of nelfinavir-treated patients (n = 48), and in 3.0% of efavirenz-treated patients (n = 329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience, atazanavir should be used with caution in patients with pre-existing conduction system disease (e.g. marked first-degree AV block or second- or third-degree AV block) (see Section 5.2 Pharmacokinetic Properties, Effects on electrocardiogram).
In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A4 substrate, there was a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one half should be considered and electrocardiographic monitoring is recommended. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval. When used in combination with atazanavir, there is no need to adjust the dose of atenolol (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers (other than atenolol), verapamil and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolized by CYP3A4 (e.g. verapamil) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Particular caution should be used when prescribing atazanavir in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances).

Rash.

In controlled clinical trials (n = 1597), rash (all grades, regardless of causality) occurred in 21% of patients treated with atazanavir. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of initiating therapy with atazanavir. In most patients, rash resolves within 2 weeks while continuing atazanavir therapy. The discontinuation rate for rash in clinical trials was 0.4%. Atazanavir should be discontinued if severe rash develops.
Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome have been reported in patients receiving atazanavir. Patients should be advised of the signs and symptoms and monitored closely for skin reactions.

Haemophilia.

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some patients, additional factor VIII was given. In most reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitor therapy and these events has not been established. Haemophiliac patients should be made aware of the possibility of increased bleeding.

Fat redistribution.

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Diabetes mellitus/hyperglycaemia.

New onset diabetes mellitus, hyperglycaemia, and exacerbation of existing diabetes mellitus have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with agents that have been associated with development of diabetes or hyperglycaemia.

Immune reconstitution syndrome.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Lactic acidosis.

Cases of lactic acidosis, sometimes fatal, and symptomatic hyperlactatemia have been reported in patients receiving atazanavir in combination with nucleoside analogues, which are known to be associated with increased risk of lactic acidosis. In studies where didanosine and stavudine were administered with atazanavir to patients without prior antiretroviral therapy, lactic acidosis/symptomatic hyperlactatemia was observed in 2.2% of subjects. Female gender and obesity are known risk factors for lactic acidosis. The contribution of atazanavir to the risk of development of lactic acidosis has not been established.

Rare lactose/galactose metabolic conditions.

Patients with rare hereditary problems of galactose intolerance, glucose/galactose malabsorption or the Lapp lactase deficiency should not take atazanavir.

Chronic kidney disease.

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during post-marketing surveillance. Atazanavir should be used with caution, particular in those patients with other risk factors for chronic kidney disease.

Nephrolithiasis and cholelithiasis.

Cases of nephrolithiasis and/or cholelithiasis have been reported during post-marketing surveillance in HIV-infected patients receiving atazanavir therapy. Some patients required hospitalisation for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered.

Use in hepatic impairment.

Atazanavir should be used with caution in patients with mild to moderate hepatic insufficiency. Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications, for patients with severe hepatic insufficiency; Section 5.2 Pharmacokinetic Properties). Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation.

Use in the elderly.

No data available.

Paediatric use.

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of atazanavir is based on data from the open-label, multicentre clinical trial PACTG 1020A conducted in paediatric patients from 3 months to 21 years of age. In this study, 182 paediatric and adolescent patients (83 antiretroviral-naive and 99 antiretroviral-experienced) received once daily atazanavir, with or without ritonavir, in combination with two NRTIs. Atazanavir is recommended for paediatric and adolescent patients from 6 years to 18 years of age (see Section 4.2 Dose and Method of Administration). There are no dosing recommendations for atazanavir in paediatric patients less than 6 years of age. Atazanavir should not be administered to infants below the age of 3 months due to the risk of kernicterus.
Due to potential for inter-patient variability in atazanavir exposures, close monitoring of clinical status for efficacy (HIV RNA viral load and CD4 counts) and signs and symptoms of toxicity is recommended. In clinical trial PACTG 1020A, 50% of patients receiving the recommended capsule dosage regimen required an increase in atazanavir dose to maintain exposure within the target range based on therapeutic drug monitoring. Therefore, consideration should also be given to using therapeutic drug monitoring when it is available and well-validated.
Asymptomatic PR interval prolongation was more frequent in paediatric patients than in adults. Asymptomatic first-degree (23%) and second-degree (1%) AV block was observed in paediatric patients. Caution should be used with medicinal products known to induce PR prolongations. In paediatric patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), atazanavir should be used with caution and only if the benefits exceed the risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g. bradycardia).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Atazanavir is an inhibitor of CYP3A4 and UGT1A1. Co-administration of atazanavir and drugs primarily metabolized by CYP3A4 (e.g. calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and phosphodiesterase inhibitors) or UGT1A1 (e.g. irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects (see Tables 2 and 3). Atazanavir is metabolized in the liver by the cytochrome P450 enzyme system. Co-administration of atazanavir and drugs that induce CYP3A4, such as rifampicin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Co-administration of atazanavir and drugs that inhibit CYP3A4 may increase atazanavir plasma concentrations.
The magnitude of CYP3A4-mediated drug interactions (effect on atazanavir or effect on co-administered drug) may change when atazanavir is co-administered with ritonavir, a potent CYP3A4 inhibitor. The prescribing information for ritonavir should be consulted for information on drug interactions with ritonavir.
Atazanavir solubility decreases as pH increases. The recommended oral dosage of atazanavir depends on the treatment history of the patient and the use of co-administered drugs. Reduced plasma concentrations of atazanavir may occur if antacids, proton-pump inhibitors, buffered medications, and H2-receptor antagonists, are administrated with atazanavir. Please see Table 3 and see Section 4.2 Dose and Method of Administration for recommendations for use of atazanavir with gastric acid lowering medications.
Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when co-administering atazanavir with medicinal products known to induce PR interval prolongation (e.g. atenolol, diltiazem).
Drugs that are contraindicated or not recommended for co-administration with atazanavir are included in Table 2. 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.
In a clinical study of co-administration to healthy subjects of ritonavir 100 mg twice daily and intranasal fluticasone propionate 50 micrograms four times daily for 7 days, the fluticasone propionate plasma levels increased significantly whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI: 82%, 89%). The effect of high fluticasone systemic exposure on ritonavir plasma levels is not yet known.
Systemic corticosteroid effects have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Concomitant use of atazanavir/ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 (e.g. budesonide) is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effect (e.g. Cushing's syndrome and adrenal suppression). Use of corticosteroid that is not metabolised by CYP3A4, (e.g. beclomethasone), could be considered.
In the case of withdrawal of fluticasone propionate co-administered with ritonavir, progressive dose reduction may have to be performed over a longer period.
Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or itraconazole. There were no clinically significant drug interactions observed when atazanavir was co-administered with fluconazole or paracetamol. Atazanavir does not interact with substrates of CYP2D6 (e.g. nortriptyline, desipramine, metoprolol).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Atazanavir produced no effects on mating, fertility or early embryonic development in rats at doses that provided exposures equivalent to (males) and at least two times (females) exposure in humans given 400 mg once daily. Altered oestrus cycles were observed in female rats treated with oral doses resulting in similar estimated systemic drug exposures (AUC).
(Category B2)
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to atazanavir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1800-067-567.

Fetal-risk summary.

No teratogenic effects were observed in rabbits exposed to a comparable human dose of 400 mg daily. No teratogenic effects were observed in rats exposed to the human equivalent of 800 mg daily. In the pre- and postnatal development assessment of rats, transient weight loss or suppression of weight gain occurred in the offspring at maternally toxic doses. Offspring were unaffected at a lower dose which produced maternal exposure equivalent to that observed in humans given 400 mg twice daily.

Clinical considerations.

Atazanavir should be given during pregnancy only after special consideration of the potential benefits and risks (see Section 4.4 Special Warnings and Precautions for Use).
Atazanavir 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially when the activity of atazanavir or the whole regimen may be compromised due to drug resistance. Since there are limited data available and due to inter-patient variability during pregnancy, Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure.
The risk of further decrease in atazanavir exposure is expected when atazanavir is given with medicinal products known to reduce its exposure (e.g. tenofovir or H2-receptor antagonists). If tenofovir or an H2-receptor antagonist is needed, for treatment-experienced pregnant women during the second or third trimester, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend an atazanavir dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced women. No dose adjustment is required for postpartum patients. Patients, however, should be closely monitored for adverse events because atazanavir exposures could be higher during the first two months after delivery.
In clinical trials, fatal cases of lactic acidosis have occurred in pregnant women receiving atazanavir in combination with nucleoside analogues, which are known to be associated with increased risk of lactic acidosis.
Hyperbilirubinaemia (predominantly unconjugated) occurs frequently during treatment with atazanavir. It is not known whether atazanavir administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates. In the prepartum period, additional monitoring and alternative therapy to atazanavir should be considered.

Human data.

Clinical trials: in clinical trial AI424-182, atazanavir/ritonavir (300 mg/100 mg or 400 mg/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved a HIV RNA < 50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir/ritonavir 300 mg/100 mg and 13 of 21 (62%) women on atazanavir/ritonavir 400 mg/100 mg experienced Grades 3 to 4 hyperbilirubinemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.
Forty infants had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. Three of 20 infants (15%) born to women treated with atazanavir/ritonavir 300 mg/100 mg and four of 20 infants (20%) born to women treated with atazanavir/ritonavir 400 mg/100 mg experienced Grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.

Post-marketing data.

As of December 2009, there were 315 identified cases with prospective first trimester exposure to atazanavir and known outcome in the post-marketing database. There was no association between atazanavir and specific birth defects observed in the post-marketing data.

Antiretroviral pregnancy registry data.

As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). There was no association between atazanavir and specific birth defects observed in the APR.
 Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production.
Studies in rats revealed that atazanavir and/or its metabolites are excreted in the milk. Transient reductions in offspring body weights were observed in a pre- and post-natal development study in rats, at a dose that resulted in a systemic drug exposure (AUC) that was approximately 2-fold higher than that expected in humans given the recommended dose.
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving atazanavir.

4.7 Effects on Ability to Drive and Use Machines

Patients should be informed that dizziness has been reported during treatment regimens containing atazanavir.

4.8 Adverse Effects (Undesirable Effects)

Treatment-emergent adverse events in adult treatment-naive patients.

Selected clinical adverse events of moderate or severe intensity reported in treatment-naïve patients receiving combination therapy including atazanavir 300 mg with ritonavir 100 mg or atazanavir 400 mg (without ritonavir) are presented in Tables 4 and 5 respectively. For other information regarding observed or potentially serious adverse events, see Section 4.4 Special Warnings and Precautions for Use.

Treatment-emergent adverse events in treatment-experienced patients.

In Phase III clinical trials, atazanavir has been studied in 144 treatment-experienced patients in combination with two NRTIs (Study 043) and in 229 treatment-experienced patients in combination with either ritonavir, tenofovir, and one NRTI or saquinavir, tenofovir, and one NRTI (Study 045).

Treatment-emergent adverse events in all atazanavir-treated patients.

Atazanavir has been evaluated for safety and tolerability in combination therapy with other antiretroviral medicinal products in controlled clinical trials. There were 1151 patients with 52 weeks median duration of treatment who received atazanavir 400 mg once daily. There were 655 patients with 96 weeks median duration of treatment who received atazanavir 300 mg with ritonavir 100 mg. Adverse events were consistent between patients who received atazanavir 400 mg once daily and patients who received atazanavir 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with atazanavir plus ritonavir.
Among patients who received atazanavir 400 mg once daily or atazanavir 300 mg with ritonavir 100 mg once daily, the only adverse events of any severity reported very commonly with at least a possible relationship to regimens containing atazanavir and one or more NRTIs were nausea (20%), diarrhoea (10%) and jaundice (13%). Among patients receiving atazanavir 300 mg with ritonavir 100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported with a few days to a few months after the initiation of treatment (see Section 4.4 Special Warnings and Precautions for Use).
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy, and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia (see Section 4.4 Special Warnings and Precautions for Use).

Adult patients.

The following adverse events of moderate intensity or greater with at least a possible relationship to regimens containing atazanavir and one or more NRTIs have also been reported. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), or very rare (< 1/10,000).

Immune system disorder.

Uncommon: hypersensitivity.

Metabolism and nutrition disorders.

Uncommon: anorexia, appetite increased, weight decreased, weight gain.

Psychiatric disorders.

Uncommon: anxiety, insomnia, depression, disorientation, sleep disorder, abnormal dream.

Nervous system disorders.

Common: headache;
uncommon: peripheral neuropathy, amnesia, dizziness, somnolence, dysgeusia.

Eye disorders.

Common: scleral icterus.

Cardiac disorders and vascular disorders.

Uncommon: syncope, hypertension;
rare: oedema, palpitation.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnea.

Gastrointestinal disorders.

Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting;
uncommon: dry mouth, flatulence, gastritis, pancreatitis, abdominal distension, stomatitis aphthous.

Hepatobiliary disorders.

Common: jaundice;
uncommon: hepatitis;
rare: hepatosplenomegaly.

Skin and subcutaneous tissue disorders.

Common: rash;
uncommon: alopecia, pruritus, urticaria;
rare: vasodilatation, vesiculobullous rash, eczema.

Musculoskeletal and connective tissue disorders.

Uncommon: arthralgia, muscle atrophy, myalgia;
rare: myopathy.

Renal and urinary disorders.

Uncommon: hematuria, nephrolithiasis, frequency of micturition, proteinuria;
rare: kidney pain.

Reproductive system and breast disorders.

Uncommon: gynecomastia.

General disorders and administration site conditions.

Common: asthenia, lipodystrophy syndrome, fatigue;
uncommon: chest pain, fever, malaise, gait disturbances.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

Paediatric and adolescent patients.

Assessment of the pharmacokinetics, safety, tolerability and efficacy of atazanavir is based on data from the open-label, multicentre clinical trial PACTG 1020A conducted in paediatric patients from 3 months to 21 years of age. The safety profile of atazanavir in paediatric patients (6 to < 18 years of age) is presented below.
The most common Grade 2-4 adverse events ≥ 5%, (regardless of causality) reported in paediatric patients were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhoea (9%), headache (8%), peripheral oedema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%) and rhinorrhoea (6%). Asymptomatic grade 2-4 atrioventricular block was reported in < 2% of patients.
The most common Grade 3-4 laboratory abnormalities occurring in paediatric patients were elevation of total bilirubin (≥ 54.72 micromol/L, 58%), neutropenia (9%) and hypoglycaemia (4%). All other Grade 3-4 laboratory abnormalities occurred with a frequency of less than 3%.

Post-marketing experience.

The following events have been identified during post-approval use of atazanavir. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, or causal connection to atazanavir, or a combination of these factors.

Cardiac disorders and vascular disorders.

Second degree AV block, third-degree AV block, QTc prolongation, Torsades de pointes.

Metabolism and nutrition disorders.

Hyperglycemia, diabetes mellitus.

Renal and urinary disorders.

Nephrolithiasis, interstitial nephritis, chronic kidney disease.

Hepatobiliary disorders.

Cholelithiasis, cholecystitis, cholestasis.

Skin and subcutaneous tissue disorders.

Angioedema.

Laboratory abnormalities.

The percentages of adult treatment-naive patients treated with combination therapy including atazanavir 300 mg with ritonavir 100 mg and atazanavir 400 mg (without ritonavir) with Grade 3-4 laboratory abnormalities are presented in Table 6 and 7, respectively.
The percentages of adult treatment-experienced patients treated with combination therapy including atazanavir with Grade 3-4 laboratory abnormalities are presented in Table 8.
The most frequently reported laboratory abnormality in patients receiving regimens containing atazanavir and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted 37%, (6% Grade 4). Among experienced patients treated with atazanavir 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3-4 total bilirubin elevations. Among naïve patients treated with atazanavir 300 mg once daily with 100 mg ritonavir once daily for a median duration of 96 weeks, 48% had Grade 3-4 total bilirubin elevations.
Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing atazanavir and or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%).
Two percent of patients treated with atazanavir experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

Patients co-infected with hepatitis B and/or hepatitis C virus.

Liver function tests should be monitored in patients with a history of hepatitis B or C.
Among 1151 patients receiving atazanavir 400 mg daily, 177 patients were co-infected with chronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg daily with ritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co-infected patients were more likely to have baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin elevations were observed between these patients and those without viral hepatitis. The frequency of treatment emergent hepatitis or transaminase evaluations in co-infected patients was comparable between atazanavir and comparator regimens).
In studies 008 and 034, 74 patients treated with 400 mg of atazanavir once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. AST levels > 5 times the upper limit of normal (ULN) developed in 9% of the Atazanavir -treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. ALT levels > 5 times ULN developed in 15% of the atazanavir -treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients.
In study AI424-138, 60 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir-emtricitabine were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times ULN developed in 10% (6/60) of the atazanavir/ritonavir-treated patients, and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels > 5 times ULN developed in 10% (6/60) of the atazanavir/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.

Effects on lipids.

Unlike other protease inhibitors, atazanavir was not associated with clinically important changes from baseline in LDL cholesterol, triglycerides, or total cholesterol mean plasma concentrations. In studies 007, 008, 034, 043, 045, and 138 there were no clinically important changes from baseline in total serum cholesterol, fasting LDL cholesterol, or fasting triglyceride concentrations. Atazanavir had significantly lower mean percent change from baseline in treatment-naive and protease inhibitor-experienced patients (see Tables 9 and 10).

Lipid changes in treatment-naïve patients receiving combination therapy including atazanavir without ritonavir.

See Table 9.

Lipid changes in treatment-naïve patients receiving combination therapy including atazanavir 300 mg with ritonavir 100 mg once daily.

See Table 10.

Lipid changes in treatment-experienced patients.

The data available on the lipid profile (mean change from baseline) from study 045 are described in the following table (Table 11).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Human experience of acute overdose with atazanavir is limited. Single doses up to 1,200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of atazanavir in an HIV-infected patient (73 times a 400 mg dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At high doses that lead to high drug exposures, jaundice [predominantly due to unconjugated (indirect) hyperbilirubinaemia without associated liver function test changes] or cardiac conduction abnormalities, including PR and/or QT interval prolongations, may be observed (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Treatment of overdose with atazanavir should consist of general supportive measures, including monitoring of vital signs and electrocardiogram and observations of the patient's clinical status. There is no specific antidote for overdose with atazanavir. Since atazanavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Atazanavir is an azapeptide HIV-1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral gag-pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

Antiviral activity in vitro.

Atazanavir exhibits anti-HIV-1 activity (EC50 of 2.6 to 5.3 nanomolar) against a variety of HIV isolates in the absence of human serum. Atazanavir administered 400 mg once daily results in a mean (SD) Cmin of 250 (175) nanogram/mL. The estimated protein-adjusted (in 40% human serum) Cmin is approximately 17 to 98-fold higher than a representative EC50. Combinations of atazanavir with stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive antiviral effects. Combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation.

Resistance in vitro.

HIV-1 isolates with reduced susceptibility to atazanavir (93- to 183-fold resistant) from three different viral strains were selected in vitro. The mutations in these HIV-1 viruses that appeared to contribute to atazanavir resistance included N88S, I50L, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. The I50L substitution, with or without an A71V substitution, conferred atazanavir resistance in recombinant viral clones in a variety of genetic backgrounds. Recombinant viruses containing the I50L mutation were growth impaired and showed increased susceptibility to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir).

Cross-resistance.

Atazanavir susceptibility was evaluated in vitro using a diverse panel of 551 clinical isolates from patients without prior atazanavir exposure. The isolates exhibited resistance to at least one approved protease inhibitor, with resistance defined as ≥ 2.5-fold change in EC50 relative to a reference strain. Greater than 80% of the isolates resistant to 1 or 2 protease inhibitors (with the majority resistant to nelfinavir) retained susceptibility to atazanavir despite the presence of key mutations (e.g. D30N) associated with protease inhibitor resistance. Of 104 isolates displaying nelfinavir-specific resistance, 84 retained susceptibility to atazanavir. There was a clear trend toward decreased atazanavir susceptibility as isolates exhibited resistance to multiple protease inhibitors. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of protease inhibitor-experienced subjects showed that isolates cross-resistant to multiple protease inhibitors were also highly cross-resistant (61%-95%) to atazanavir. Greater than 90% of the isolates containing mutations I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, A71V/T, M46I, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N mutation in addition to other changes were resistant to atazanavir. Atazanavir-resistant isolates were highly cross-resistant (51%-100%) to other protease inhibitors (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 confer cross-resistance.

Resistance in vivo.

Atazanavir-resistant isolates have been obtained from patients experiencing virologic failure on atazanavir therapy.

Clinical studies of treatment-naïve patients receiving atazanavir 400 mg without ritonavir.

There were 23 atazanavir-resistant isolates from studies of treatment-naive patients that showed decreases in susceptibility levels from baseline, and all had evidence of emergence of an I50L substitution on atazanavir therapy (after an average of 50 weeks of therapy) often in combination with an A71V mutation. Phenotypic analysis of the isolates containing the signature mutation I50L showed atazanavir-specific resistance, which coincided with increased susceptibility to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir).

Clinical studies of treatment-naïve patients receiving atazanavir 300 mg with ritonavir 100 mg.

48 weeks of treatment.

The Phase III Study AI424138 included 440 patients randomized to atazanavir/ritonavir and 443 patients randomized to lopinavir/ritonavir. Genotypic analysis was undertaken on patients with virologic failure defined as viral rebound ≥ 400 copies/mL or failure to achieve viral suppression < 400 copies/mL over 48 weeks of treatment or discontinuation due to insufficient viral load response before 48 weeks. Patients with any major protease inhibitor substitutions at amino acid positions 50, 84 and 88 were determined to have resistance to atazanavir/ritonavir. Patients with any major protease inhibitor substitutions at amino acid positions 32, 48 and 82 were determined to have resistance to lopinavir/ritonavir.
For those patients with virologic failure in the first 48 weeks of the study, baseline genotypic analysis was successful for 25 of 27 atazanavir/ritonavir treated patients and 22 of 26 lopinavir/ritonavir treated patients. Paired baseline and on-study genotypic analysis was successful for 17 of 27 atazanavir/ritonavir treated patients and 15 of 26 lopinavir/ritonavir patients. All patients in both arms of the study had baseline PI substitutions. Major PI substitutions were observed at baseline in two patients; both had phenotypic resistance to both atazanavir/ritonavir and lopinavir/ritonavir and both were randomised to the atazanavir/ritonavir arm of the trial.
While on treatment, one patient with major baseline PI substitutions (I54V, V82A, L90M) developed the atazanavir associated major PI substitution 150L. Another atazanavir/ritonavir treated patient with four baseline atazanavir-associated minor PI substitutions (M36I, I62V, A71A/T and I93L) developed phenotypic resistance to atazanavir along with additional atazanavir-associated minor substitutions (L10L/F, A71I, G73S). This patient also developed resistance to 3TC/FTC, didanosine nelfinavir, indinavir, ritonavir, saquinavir and fosamprenavir while remaining sensitive to all other NRTIs, LPV/RTV, tipranavir and darunavir. The isolate remained phenotypically sensitive to TDF despite the presence of K65K/R, K70K/E and M184V.

96 weeks of treatment.

In Phase III study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure ≥ 400 copies/mL or discontinued before achieving suppression on ATV/RTV (n = 39; 9%) and LPV/RTV (n = 39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decreases in ATV susceptibility emerge on therapy with the development of PI substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. Five of the treatment failure isolates in the ATV/RTV arm developed emtricitabine resistance with the emergence of either the MI84I (1 patient) or the M184V (4 patients) substitution on therapy. In the LPV/RTV arm, one virologic failure isolate had a 69-fold decrease in LPV susceptibility emerge on therapy with the development of PI substitutions L10V and V11I in addition to baseline PI substitutions V32I, I54I/V, V82A, L90M, L10I, A71I, G73S and L89V. Six of the failure isolates in the LPV/RTV arm developed emtricitabine resistance with the emergence of the M184V substitution.

Clinical studies of treatment-experienced patients.

In contrast, 30% (18 of 60) of atazanavir-resistant isolates from studies of treatment-experienced patients treated with atazanavir (n = 13) or atazanavir plus ritonavir (n = 5) showed evidence of an I50L substitution. The remaining 70% (n = 42) of isolates with emerging resistance on atazanavir therapy and all 40 resistant isolates from patients on atazanavir plus saquinavir showed no evidence of the emergence of the I50L substitution. Instead, these isolates displayed decreased susceptibility to multiple protease inhibitors and contained mutations associated with resistance to multiple protease inhibitors. These mutations included I84V, L90M, A71V/T, N88S/D, and M46I, which conferred atazanavir resistance and reduced the clinical response to atazanavir.
Generally, if multiple protease inhibitor mutations were present in the HIV-1 of the patient at baseline, atazanavir resistance developed through mutations associated with resistance to other protease inhibitors instead of the I50L mutation. These mutations conferred high cross-resistance to other protease inhibitors with > 90% of the isolates resistant to nelfinavir, indinavir, ritonavir, and saquinavir, 83% resistant to lopinavir, and 65% resistant to amprenavir.
In highly treatment-experienced patients receiving atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir and an NRTI), the presence at baseline of fewer than four of the protease inhibitor resistance-associated substitutions 10, 20, 24, 33, 36, 46, 48, 54, 63, 71, 73, 82, 84, or 90 was associated with a greater treatment response at Week 48 (70% with HIV RNA < 400 copies/mL) than the presence of four or more such substitutions (28% with HIV RNA < 400 copies/mL). Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir therapy.

Clinical trials.

Adult patients without prior antiretroviral therapy.

Study AI424138 is a 96-week open-label, randomised, multicentre study of 883 HIV-1 infected treatment-naive patients comparing efficacy and safety of atazanavir/ritonavir (ATV/RTV) 300/100 mg once daily with lopinavir/ritonavir (LPV/RTV) 400/100 mg twice daily each in combination with fixed dose tenofovir/emtricitabine 300/200 once daily. The primary objective of the study was to compare the proportion of patients with HIV RNA < 50 copies/mL at week 48 between ATV/RTV and LPV/RTV. Patient demographic and baseline characteristics were well matched between treatment arms. Overall, patients had a mean age of 36 years (range 19-72), 48% were Caucasian, 18% Black, 9% Asian, 24% Hispanic/ mixed race and 69% were male. The overall median baseline plasma CD4+ cell count was 205 cells/mm3 (range 2 to 810 cells/mm3) and the overall mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 48 and Week 96 are presented in Table 12.
The proportion of responders among patients with high viral loads (i.e. baseline HIV RNA ≥ 100,000 copies/mL) was comparable for the atazanavir/ritonavir (74% at both 48 weeks and 96 weeks) and lopinavir/ritonavir arms (72% at 48 weeks and 66% at 96 weeks). The median increase from baseline in CD4+ cell count was 191 (48 weeks) and 261 (96 weeks) cells/mm3 for the atazanavir/ritonavir arm and 200 (48 weeks) and 273 (96 weeks) cells/mm3 for the lopinavir/ritonavir arm.

Study 034: atazanavir once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine + zidovudine twice daily.

Study AI424-034 was a randomised double-blind, multicentre trial comparing atazanavir (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of zidovudine (300 mg) and lamivudine (150 mg) given twice daily, in 810 antiretroviral treatment-naïve patients. Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies /mL (range 2.2 to 5.9 log10 copies/mL). Treatment response and outcomes through week 48 are presented in Table 13.
The mean increase from baseline in CD4+ cell count was 176 cells/mm for the atazanavir arm and 160 cells/mm3 for the efavirenz arm. See Figure 1.
Study 008 was a 48-week study of two doses of atazanavir 400 mg once daily (n = 181) or 600 mg once daily (n = 195) compared to nelfinavir 1,250 mg BID (n = 91) in combination with stavudine (40 mg) and lamivudine (150 mg) twice daily. At baseline, mean HIV RNA levels were 4.74 log10 copies/mL and 4.73 log10 copies/mL for the atazanavir 400 mg and nelfinavir groups, respectively. The mean CD4 counts at baseline were 294 cells/mm3 and 283 cells/mm3 for the atazanavir 400 mg and nelfinavir groups, respectively. Results from this study are shown in Figure 2 and Table 14.

Adult patients with prior antiretroviral therapy.

Study 045 was a randomised, multicentre trial comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to atazanavir (400 mg once daily) with saquinavir soft gelatine capsules (1,200 mg once daily), and to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily, soft gelatine capsules), each in combination with tenofovir and one NRTI, in 347 (of 358 randomised) patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 280 weeks for NRTIs, and 85 weeks for NNRTIs. The mean baseline CD4 cell count was 336 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.9 log10 copies/mL).
The primary endpoint for this study is the time-averaged difference in change from baseline in HIV RNA through 24 and 48 weeks.
Through the 48 weeks of treatment, the decreases from baseline in HIV RNA levels (primary endpoint) were 1.93 log10 copies/mL for atazanavir + ritonavir and 1.87 log10 copies/mL for lopinavir + ritonavir. The primary endpoint was time-averaged difference in HIV RNA levels, atazanavir + ritonavir minus lopinavir + ritonavir (97.5% Confidence Intervals). Atazanavir + ritonavir was considered to be non-inferior if the upper 97.5% CI for the TAD was less than 0.5 log10 copies/mL.
At 48 weeks, non-inferiority was demonstrated. The time averaged difference in HIV RNA was 0.13 (-0.12; 0.39). The mean decrease from baseline HIV RNA levels for atazanavir + ritonavir was 1.93 log10 copies/mL. For lopinavir + ritonavir the decrease was 1.87 log10 copies/mL.
At 96 weeks the time-averaged difference in HIV RNA levels was 0.14 (-0.13; 0.41). The mean decrease from baseline HIV RNA levels for atazanavir + ritonavir was 2.29 log10 copies/mL, and for lopinavir + ritonavir the mean decrease was 2.08 log10 copies/mL. Durability of efficacy was demonstrated. Further outcomes of treatment are shown in Table 15.
Response to treatment assessed as HIV RNA change from baseline was analysed by baseline genotypic mutation at 48 weeks. Patients who had four or more of the following mutations 10, 20, 24, 32, 33, 36, 46, 68, 50, 54, 63, 71, 73, 82, 84, 90 were considered. The results significantly favoured the lopinavir + ritonavir arm.
Atazanavir plus saquinavir was shown to be inferior to lopinavir plus ritonavir.

Adult patients co-infected with hepatitis B and/or hepatitis C.

Analyses have been performed that compare outcomes in study 008 for those patients without baseline evidence of either chronic HBV or HCV infection with those with chronic HBV and/or HCV. Virologic suppression was comparable for the atazanavir 400 mg once daily patients, regardless of chronic hepatitis status. The Week 48 mean change from baseline in HIV RNA for 19 chronic hepatitis positive patients was -2.46 log10 copies/mL, comparable to -2.51 log10 copies/mL for 132 hepatitis negative patients. In study AI424-138, 42 of 61 patients (69%) co-infected with HBV and/or HCV, achieved confirmed HIV RNA < 50 copies/mL at week 48. Among hepatitis negative patients, 300 of 378 (79%) achieved confirmed HIV RNA < 50 copies/mL at week 48.

Children - PACTG 1020A.

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of atazanavir is based on data from the open-label, multicentre clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age. In this study, 105 patients (43 antiretroviral-naïve and 62 antiretroviral-experienced) received once daily atazanavir, with or without ritonavir, in combination with two NRTIs. Using an ITT analysis, the overall proportions of antiretroviral-naïve and -experienced patients with HIV RNA < 400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naïve and -experienced patients with HIV RNA < 50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naïve patients and 220 cells/mm3 in antiretroviral-experienced patients.

5.2 Pharmacokinetic Properties

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected adult and paediatric patients.

Healthy adult volunteers and HIV-infected patients.

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily (see Table 16).

Absorption.

The Tmax of atazanavir is approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200-800 mg once daily. Steady-state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.

Food effect.

Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400 mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) (i.e. toast with jam, low fat margarine, orange juice and skim milk) resulted in a 70% increase in AUC and a 57% increase in Cmax compared to the fasting state. Administration of a single 400 mg dose of atazanavir (as two 200 mg capsules) with a meal high in calories, fat, and protein (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% and no change in Cmax compared to administration in the fasting state. Administration of atazanavir with either a light meal or a high fat meal decreased the coefficient of variation of AUC and Cmax approximately one-half compared to the fasting state.
Co-administration of a single 300 mg dose of atazanavir and a 100 mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Co-administration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.

Distribution.

Atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 nanogram/mL. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 nanogram/mL).

Metabolism.

Studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites which are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two metabolites of atazanavir, possessing no anti-HIV activity, have been detected in the systemic circulation.

Elimination.

Following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Approximately 26% of the radioactivity in the faeces was due to parent drug, corresponding to 20% of the dose, and 44% of the radioactivity in the urine was due to parent drug, corresponding to 7% of the dose. The mean elimination half-life of atazanavir in healthy volunteers and HIV-infected patients adult patients was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Pharmacokinetics in special populations.

Impaired renal function.

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n = 20), including those on haemodialysis, at multiple doses of 400mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing haemodialysis (n = 10), than in age, weight, and gender matched subjects with normal renal function. Atazanavir was not appreciably cleared during haemodialysis. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following haemodialysis (n = 10), the geometric means for Cmax were 25% and 37% lower, AUC were 28% and 42% lower, and Cmin were 43% and 54% lower, respectively, compared to subjects with normal renal function. The mechanism of this decrease is unknown (see Section 4.2 Dose and Method of Administration).

Impaired hepatic function.

Atazanavir is metabolised and eliminated primarily by the liver. Atazanavir has been studied in adult patients with moderate to severe hepatic impairment after a single 400 mg dose. The mean AUC (0-∞) was 42% greater in patients with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired patients was 12.1 hours compared to 6.4 hours in healthy volunteers (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Age/gender.

A study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female adult subjects (29 young, 30 elderly). There were no clinically significant differences in AUC or Cmax based on age or gender in this study.

Paediatric patient pharmacokinetics.

Children and adolescents (6-18 years of age).

The pharmacokinetic data from paediatric patients receiving atazanavir capsules with ritonavir based on body surface area are presented in Table 17.
Table 18 presents the pharmacokinetics for atazanavir at steady state in paediatric patients predicted by a pharmacokinetic model, summarised by weight ranges that correspond to the recommended doses (see Section 4.2 Dose and Method of Administration, Recommended paediatric dosing).
Atazanavir exposures were predicted based on observed data in 167 paediatric patients and 60 adult patients treated with atazanavir with or without ritonavir. See Section 4.4 Special Warnings and Precautions for Use regarding inter-patient variability in atazanavir exposure parameters.

Children less than 6 years of age.

There are no dosing recommendations for atazanavir in paediatric patients less than 8 years of age as there is insufficient data to recommend a dose. Atazanavir should not be administered to paediatric patients below 3 months of age due to the risk of kernicterus.

Pregnancy.

The pharmacokinetic data from HIV-infected pregnant women receiving atazanavir capsules with ritonavir are presented in Table 19.

Drug interactions.

Atazanavir is metabolized in the liver by CYP3A. Atazanavir inhibits CYP3A4 and UGT1A1 at clinically relevant concentrations with Ki of 2.35 micromolar (CYP3A4 isoform) and 1.9 micromolar, respectively. Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min-1 and Ki value of 0.84 to 1.0 micromolar. Atazanavir is also a direct inhibitor for UGT1A1 (Ki = 1.9 micromolar) and CYP2C8 (Ki = 2.1 micromolar). Atazanavir should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A, or UGT1A1 (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2 or CYP2E1.
Atazanavir is a weak inhibitor of CYP2C8. Caution should be used when atazanavir without ritonavir is co-administered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g. paclitaxel, repaglinide). When atazanavir with ritonavir is co-administered with substrates of CYP2C8, clinically significant interactions are not expected.
Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.
Drugs that induce CYP3A activity may increase the clearance of atazanavir, resulting in lowered plasma concentrations. Co-administration of atazanavir and other drugs that inhibit CYP3A may increase atazanavir plasma concentrations.
Drug interaction studies were performed with atazanavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of atazanavir on the AUC, Cmax, and Cmin are summarized in Tables 20 and 21. For information regarding clinical recommendations, see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Effects on electrocardiogram.

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir in a clinical pharmacology study (study 076), in which oral doses of 400 mg and 800 mg were compared with placebo in 72 healthy subjects. The mean (± SD) maximum change in PR interval from the pre-dose value was 24 (± 15) msec following oral dosing with 400 mg of atazanavir (n = 65) and 60 (± 25) msec following oral dosing with 800 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 (see Section 4.4 Special Warnings and Precautions for Use). In the placebo-controlled study 076, there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia's correction). For HIV-infected patients in study 045 treated with atazanavir + ritonavir, atazanavir + saquinavir, or lopinavir + ritonavir, each with tenofovir and an NRTI (see Section 5.1 Pharmacodynamic Properties, Clinical trials), no female patients had a QTc interval > 470 msec and two male patients has a QTc interval of 450-500 msec. No patients receiving atazanavir + ritonavir, 2 (2%) patients receiving atazanavir + saquinavir, and 1 (< 1%) patient receiving lopinavir + ritonavir had an on-study change in QTc > 60 msec. No atazanavir-treated healthy subject or HIV-infected patient had a QTc interval > 500 msec.

5.3 Preclinical Safety Data

Genotoxicity.

Atazanavir was negative in reverse-mutation assays in bacteria and in in vivo micronucleus and ex vivo DNA repair tests in rats. In an in vitro primary human lymphocyte cytogenetic assay, atazanavir increased the frequency of chromosome aberrations at cytotoxic concentrations in the absence and presence of metabolic activation. However, atazanavir did not induce chromosome aberrations in the absence and presence of metabolic activation at concentrations that were approximately 3 and 22 times the Cmax, respectively, and 12 and 98 times the average steady-state concentration, respectively, in humans given the recommended dose. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

Carcinogenicity.

Carcinogenicity studies with atazanavir were conducted in mice and rats. Mice were administered doses of 20, 40, and 80 mg/kg/day in males and 40, 120, and 360 mg/kg/day in females. In female mice, there was an increase in the incidences of benign hepatocellular adenomas at the highest dose. The exposure in female mice at the high dose is approximately seven times exposure in humans given atazanavir 400 mg once daily. No increase in the incidence of tumours was observed in female mice at non-tumorigenic doses or male mice at any dose. Exposures in male and female mice at non-tumorigenic doses are approximately four times human exposure at 400 mg/day. In rats administered doses of 100, 350, and 1200 mg/kg/day, there was no increased incidence of any tumour type. Exposures in rats at the highest dose are approximately two (males) and six (females) times the exposure in humans given atazanavir 400 mg daily. The increased incidence of benign hepatic adenomas in high-dose female mice was likely the result of increased hepatocellular proliferation secondary to cytotoxic liver changes (single-cell necrosis) and is considered unlikely to have clinical relevance at human therapeutic exposures.

6 Pharmaceutical Particulars

6.1 List of Excipients

Atazanavir Mylan contains the following inactive ingredients: lactose monohydrate, crospovidone, and magnesium stearate.
The capsule shells contain gelatin and titanium dioxide and are coloured with iron oxide yellow (E172), iron oxide red (E172), brilliant blue FCF (E133) and erythrosine (E127).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Container type: bottle.
Pack sizes: 60.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Atazanavir sulfate is an off-white to pale yellow crystalline powder.
Chemical name: (3S,8S,9S,12S)-3,12-Bis (1,1-dimethylethyl)-8-hydroxy-4,11- dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]- 2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1).
Molecular formula: C38H52N6O7.H2SO4.
Molecular weight: 802.9 (sulfate); 704.9 (free base).

Chemical structure.


CAS number.

229975-97-7.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes