Consumer medicine information

Evotaz Tablets

Atazanavir; Cobicistat

BRAND INFORMATION

Brand name

Evotaz

Active ingredient

Atazanavir; Cobicistat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Evotaz Tablets.

What is in this leaflet

Read this leaflet carefully before taking EVOTAZ. This leaflet answers some common questions about EVOTAZ.

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 EVOTAZ 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 EVOTAZ is used for

EVOTAZ contains two active ingredients, atazanavir and cobicistat. Atazanavir belongs to a group of medicines called protease inhibitors. Cobicistat is a type of medicine called a pharmacokinetic enhancer (or "booster"). Cobicistat is included to improve the effect of atazanavir by increasing the level of atazanavir in your body.

EVOTAZ is for adults. EVOTAZ is used in combination with other anti-HIV agents to treat adults 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 the Acquired Immunodeficiency Syndrome or AIDS. AIDS is a serious condition and can lead to death.

How EVOTAZ Works

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

EVOTAZ helps to block HIV protease, an enzyme that is needed for the HIV virus to multiply. EVOTAZ 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.

EVOTAZ 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 EVOTAZ has been prescribed for you.

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

Before you take EVOTAZ

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

When you must not take EVOTAZ

Do not take EVOTAZ if you have an allergy to it or to any other ingredients in the formulation listed at the end of this leaflet.

Do not take EVOTAZ if you have liver disease.

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

  • Other HIV medication including other protease inhibitors (eg. saquinavir, indinavir, elvitegravir, nevirapine, efavirenz, ritonavir)
  • Antimycobacterial medication used to treat conditions such as tuberculosis and leprosy (rifampin, rifabutin, rifapentine)
  • Sildenafil or tadalafil - if you are taking for pulmonary arterial hypertension
  • Cisapride - a medicine used to treat gastric reflux
  • Alfuzosin - a medicine used in bladder disorders
  • Asthma medication containing salmeterol (Seretide, Serevent)
  • Cholesterol reducing medicines (lovastatin, simvastatin, lomitapide)
  • Sleeping tablets containing midazolam or triazolam
  • Medicines to treat psychotic problems containing pimozide or lurasidone
  • Antiarryththmics (eg. dronedarone, quinidine)
  • Calcium channel blockers (eg. bepridil)
  • Medicines to treat migraine or severe headaches which contain ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine)
  • Herbal products which contain St John's wort (Hypericum perforatum)
  • Irinotecan - a medicine used to treat cancer
  • Medicines to treat hepatitis C containing elbasvir/grazoprevir or glecaprevir/pibrentasvir

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 use EVOTAZ after the expiry date printed on the back of the pack. If this medicine is taken after the expiry date has passed, it may not work as well.

Do not take EVOTAZ if the packaging is torn or shows signs of tampering.

Before you start to take EVOTAZ

Tell your doctor if you:

  1. are taking any other HIV medication
  2. have allergies to:
  • any other medicines you have been given or purchased
  • substances such as foods, preservatives or dyes.
Symptoms of an allergic reaction may include:
swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing, or severe and sudden onset of pinkish, itchy swellings on the skin, also called hives;
  1. are pregnant or intend to become pregnant. EVOTAZ is not recommended for use during pregnancy.
  2. are breast feeding or planning to breast-feed. You should not breast-feed if you are HIV positive because of the chance of passing the HIV virus to your baby. Also, it is not known if EVOTAZ can pass into your breast milk and if it can harm your baby. Talk with your doctor about the best way to feed your baby.
  3. currently experience or have experienced any medical conditions especially:
  • kidney problems or are undergoing kidney dialysis treatment
  • 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 or older
    - are of Aboriginal or Torres Strait Islander origin
    - have a history of acute kidney injury
  • 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 EVOTAZ in the blood, increasing the chance of side effects
  • haemophilia, haemophiliac patients may experience increased bleeding when taking EVOTAZ
  • 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 use EVOTAZ.

Taking other medicines

EVOTAZ has the potential to adversely interact with many other drugs.

Be sure to inform your doctor of all medications you are taking including prescribed drugs, over the counter products, natural therapies, vitamin supplements and recreational drugs.

Medicines for HIV:
EVOTAZ may be given with other anti-HIV medicines. Some of these anti-HIV medicines may affect the way EVOTAZ works, and EVOTAZ 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 also tell your doctor if you are taking any of the following medicines:

  • Medicines that may affect your kidneys unless you have discussed this with your doctor
  • Other medicines to treat HIV (eg. ritonavir, didanosine, tenofovir disoproxil fumurate, efavirenz, nevirapine, etravirine, rilpivirine, maraviroc, saquinavir, indinavir, other protease inhibitors)
  • Medicines to treat hepatitis (eg. telaprevir, bocepravir, sofosbuvir/ velpatasvir/ voxilaprevir)
  • Analeptics (eg. modafinil)
  • Medicines used to treat cancer (eg. dasatinib, nilotinib, vinblastine, vincristine)
  • Anticoagulants (eg. warfarin, dabigatran, apixaban, dabigatran, betrixaban, edoxaban)
  • Antineoplastic medication (irinotecan)
  • Beta blockers (eg. metoprolol, carvedilol, timolol)
  • 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 famotidine or others 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 EVOTAZ. Depending on your medical history these medicines may not be suitable for you. Talk to your doctor for further information.
  • Macrolide or ketolide antibiotics (eg. clarithromycin, erythromycin) used to treat various infections
  • Medicines to lower cholesterol (eg. atorvastatin, rosuvastatin, pravastatin, fluvastatin)
  • Antifungal medication (eg. ketoconazole, voriconazole) used to treat fungal infections
  • Anticonvulsant medications (eg. carbamazepine, phenytoin, phenobarbital, clonazepam, ethosuximide) used to treat epilepsy
  • Erectile dysfunction agents used to treat impotence (eg. sildenafil, tadalafil, vardenafil).
  • 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 EVOTAZ 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 EVOTAZ. These medicines should be taken one hour before or two hours after EVOTAZ.
  • Drugs that affect the electrical activity of the heart
  • Oral contraceptives - EVOTAZ 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.
  • Corticosteroids
  • Neuroleptics (eg. perphenazine, risperidone, thioridazine)
  • Pain medications (eg. buprenorphine, naloxone, methadone, fentanyl, tramadol)
  • Gout medications (colchicine)
  • Sedatives (eg. midazolam, triazolam, buspirone, diazepam)
  • Bosentan, a medication used to treat pulmonary arterial hypertension.

This is not a complete list of medicines you should tell your doctor about. It is important that you tell your doctor or pharmacist about the medicines you are taking, even if they are not listed in this leaflet. They will be able to provide you with more information than is contained within this leaflet on the medicines you need to be careful with, or should avoid while taking EVOTAZ.

Your doctor will be able to advise you about the most appropriate medications to treat your condition.

How to take EVOTAZ

EVOTAZ 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.

How much to take

Take EVOTAZ exactly as your doctor tells you to take it. Do not change your dose unless your doctor tells you to. Do not stop taking EVOTAZ without first talking to your doctor.

How to take it

Swallow the tablet whole with a drink such as a glass of water or fruit juice. The dose of EVOTAZ should be taken with food. Taking EVOTAZ with food is important to get the right medicine levels in your body.

When to take EVOTAZ

You may take EVOTAZ tablets at any time. It is recommended, however, that you take your medicine at about the same time each day. Taking EVOTAZ at the same time each day will have the best effect. It will also help you remember when to take the tablets.

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

How long to take it

EVOTAZ helps control your condition but does not cure it. Therefore you must take EVOTAZ every day as directed by your doctor. Continue taking EVOTAZ for as long as your doctor tells you to.

Do not stop taking EVOTAZ 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 it 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 EVOTAZ. If you miss doses the virus may become resistant to your HIV medicines.

If you take too much (overdose)

Immediately call your doctor or the Poisons Information Centre on 131126 in Australia, or go to the Accident and Emergency Centre at your nearest hospital if you or anyone else takes too much EVOTAZ.

Do this even if there are no signs of discomfort or poisoning. This may need urgent medical attention.

While you are using EVOTAZ

Things you must do

  • If you become pregnant while taking EVOTAZ, tell your doctor immediately.
  • If you are about to start taking any new medicines, tell your doctor and pharmacist that you are taking EVOTAZ. EVOTAZ may interfere with the medicine you are taking.
  • If you are about to have any medical tests, tell your doctor that you are taking EVOTAZ. EVOTAZ may interfere with the results of these tests.
  • If you plan to have surgery, tell your doctor or dentist that you are taking EVOTAZ. You may wish to discuss disclosure issues with your doctor about who should know you are taking EVOTAZ.
  • You should have your liver functions and blood tested when your doctor advises on a regular basis to ensure that your body chemistry is functioning normally and that EVOTAZ is working.

Things you must not do

  • Do not give EVOTAZ to anyone else, even if they have the same condition as you.
  • Do not use EVOTAZ to treat any other complaints unless your doctor tells you to.
  • Do not stop taking EVOTAZ without checking with your doctor.
  • Avoid doing things that can spread HIV infection since EVOTAZ does not stop you from passing the HIV infection to others.

Things to be careful of

  • Be careful driving or operating machinery until you know how EVOTAZ affects you. Make sure you know how you react to EVOTAZ before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy.
  • Make sure that you visit your doctor regularly throughout your entire course of treatment with EVOTAZ.

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 EVOTAZ. EVOTAZ 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.

Your doctor may monitor your kidney function prior to, and during your treatment with EVOTAZ. Your doctor may switch you to an alternative treatment if your kidney function changes.

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

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 EVOTAZ.

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 hospitalization.

Yellowing of the skin or eyes
One of the other side effects that can occur with EVOTAZ 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, short of breath, or weakness in arms and legs
  • allergic reaction - swelling of the face, lips, or throat which makes breathing difficult

These are very serious side effects. If you have them, you may have had a serious reaction to EVOTAZ. You may need urgent medical attention or hospitalisation.

This is not a complete list of side effects, other side effects not listed above may also occur in some patients.

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

Do not be alarmed by this list of possible side effects. You may not experience any of them or only some of them.

After using EVOTAZ

Storage

Store EVOTAZ tablets in a cool dry place where the temperature stays below 25°C.

Keep your tablets in the bottle with the cap tightly closed until it is time to take them. If you take the tablets out of the bottle they may not keep as well.

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

Keep EVOTAZ tablets where children cannot reach them. 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 EVOTAZ tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

EVOTAZ tablets are oval, biconvex, pink film-coated, debossed on one side with "3641" and plain on the other side. Each bottle contains 30 tablets.

Ingredients

Each tablet contains:

Active ingredients:

  • 300 mg atazanavir (as atazanvir sulfate) and 150 mg cobicistat per tablet

Other ingredients:

Microcrystalline cellulose, croscarmellose sodium, sodium starch glycollate, crospovidone, stearic acid, magnesium sterate, hydroxypropylcellolose, and silicon dioixde.

The film-coating is made from hypromellose, titanium dioxide, purified talc, glycerol triacetate, and red iron oxide.

Registration Numbers

EVOTAZ 300 mg atazanavir/150 mg cobicistat - AUST R 229476

Sponsored by

Bristol-Myers Squibb Australia Pty Ltd,
4 Nexus Court, Mulgrave,
Victoria 3170, Australia

This information in no way replaces the advice of your doctor or pharmacist.

Date of Preparation: October 2019

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Evotaz

Active ingredient

Atazanavir; Cobicistat

Schedule

S4

 

1 Name of Medicine

Evotaz (atazanavir/cobicistat).

6.7 Physicochemical Properties

Atazanavir.

The chemical name for atazanavir sulfate is (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 mass: 802.9 (sulfate); 704.9 (free base).
Atazanavir sulfate is a white to pale yellow crystalline powder with a solubility of 4 to 5 mg/mL free base equivalents in water at 24°C. The partition coefficient (log Po/b) for atazanavir sulfate is 3.8 (pH of aqueous medium: 7.0 (sodium phosphate buffer)) and the pKa is 4.7.

Chemical structure.

Atazanavir sulfate has the following structural formula:

CAS number.

CAS Registry No: 229975-97-7.

Cobicistat.

The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)- 1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4- (morpholin-4-yl)butanoyl]amino}- 1,6-diphenylhexan-2-yl]carbamate.
Molecular formula: C40H53N7O5S2. Molecular mass: 776.0. Cobicistat is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20°C. The partition coefficient of cobicistat is 4.3 (n-octanol/phosphate buffer pH 8.5) and the pKa are 1.8, 2.5 and 6.4.

Chemical structure.

It has the following structural formula:

CAS number.

CAS Registry No: 1004316-88-4.

2 Qualitative and Quantitative Composition

Evotaz is a fixed-dose combination tablet for oral administration containing 300 mg atazanavir as atazanavir sulfate and 150 mg cobicistat.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Evotaz tablets are oval, biconvex, pink film-coated, debossed with "3641" on one side and plain on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Evotaz is a fixed dose combination of the HIV-1 antiviral drug atazanavir sulfate boosted by the pharmacokinetic enhancer cobicistat. 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. Cobicistat is a selective, mechanism based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as atazanavir or darunavir, where bioavailability is limited and half-life is shortened due to CYP3A dependent metabolism.

Clinical trials.

There have been no clinical efficacy studies conducted with Evotaz, however the bioequivalence of Evotaz with coadministered atazanavir and cobicistat was demonstrated.
The safety and efficacy of atazanavir with cobicistat in HIV-1 infected patients were evaluated in a randomized, double blind, active controlled phase III trial (study GS-US-216-0114) in HIV-1 infected patients with baseline estimated creatinine clearance above 70 mL/min who were treatment naïve (n = 692). In study GS-US-216-0114, patients were randomized in a 1:1 ratio to receive either atazanavir 300 mg + cobicistat 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily, each administered with a fixed background regimen (BR) containing tenofovir DF 300 mg and emtricitabine 200 mg administered as single tablet. Randomization was stratified by screening HIV-1 RNA level (≤ 100,000 copies/mL or > 100,000 copies/mL). The mean age of patients was 37 years (range 19-70), 83% were male, 60% were white, 18% were black and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 3.2-6.4). The mean baseline CD4+ cell count was 352 cells/mm3 (range 1-1455) and 17% had CD4+ cell counts ≤ 200 cells/mm3. Forty percent of patients had baseline viral loads > 100,000 copies/mL. Treatment outcomes at 48 weeks are presented in Table 5.
Atazanavir + cobicistat + tenofovir DF/ emtricitabine was noninferior in achieving HIV-1 RNA < 50 copies/mL when compared to atazanavir + ritonavir + tenofovir DF/ emtricitabine. In study GS-US-216-0114, the mean increase from baseline in CD4+ cell count at week 48 was 213 cells/mm3 in patients receiving atazanavir + cobicistat + tenofovir DF/ emtricitabine and 219 cells/mm3 in patients receiving atazanavir + ritonavir + tenofovir DF/ emtricitabine.

5.2 Pharmacokinetic Properties

One Evotaz tablet is bioequivalent to one atazanavir capsule (300 mg) plus one cobicistat tablet (150 mg) following single, oral dose administration with a light meal in healthy subjects (n = 62).
The effect of cobicistat on atazanavir pharmacokinetics was demonstrated in the pharmacokinetic substudy (n = 48) of the phase III study GS-US-216-0114 in which HIV-1 infected patients received atazanavir + cobicistat or atazanavir + ritonavir, both in combination with tenofovir disoproxil fumarate (DF) 300 mg/ emtricitabine 200 mg. The steady-state pharmacokinetic parameters of atazanavir were comparable when boosted with cobicistat versus ritonavir as shown in Table 6 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Absorption.

Atazanavir.

The steady-state atazanavir Cmax, AUCtau, and Ctau (mean ± SD) following multiple doses of atazanavir 300 mg with cobicistat 150 mg once daily in HIV infected subjects (n = 22) with a light meal were 3.9 ± 1.9 microgram/mL, 46.1 ± 26.2 microgram.hr/mL, and 0.80 ± 0.72 microgram/mL, respectively, and median Tmax was approximately 3.5 hours postdose.

Cobicistat.

In a trial where subjects were instructed to take coadministered atazanavir and cobicistat with food, the median cobicistat Tmax was approximately 3.0 hours postdose. Steady-state cobicistat Cmax, AUCtau, and Ctau (mean ± SD), values were 1.5 ± 0.5 microgram/mL, 11.1 ± 4.5 microgram.hr/mL, and 0.05 ± 0.07 microgram/mL, respectively (n = 22).

Food effect.

Administration of a single dose of Evotaz with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 42% increase in atazanavir Cmax, a 28% increase in atazanavir AUC, a 31% increase in cobicistat Cmax, and a 24% increase in cobicistat AUC relative to the fasting state. Administration of a single dose of Evotaz with a high fat meal (1038 kcal, 59 g fat, 37 g protein) resulted in a 14% reduction in atazanavir Cmax with no change in atazanavir AUC or cobicistat exposures (Cmax, AUC) relative to the fasting state. The 24 hour atazanavir concentration following a high fat meal was increased by approximately 23% due to delayed absorption; the median Tmax increased from 2.0 to 3.5 hours. Atazanavir Cmax and AUCs after a high fat meal decreased 36% and 25%, respectively, in comparison to a light meal; however the 24 hour atazanavir concentration was similar when Evotaz was given with a light meal or a high fat meal.

Distribution.

Atazanavir.

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 1000 nanogram/mL).

Cobicistat.

Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2.

Metabolism.

Atazanavir.

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.

Cobicistat.

Cobicistat is metabolized via CYP3A (major) and CYP2D6 (minor) mediated oxidation and does not undergo glucuronidation.

Excretion.

Atazanavir.

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.

Cobicistat.

Following oral administration of 14C-cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and faeces and do not contribute to the CYP3A inhibitory activity of cobicistat. Eighty six percent and 8.2% of the dose were recovered in faeces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of cobicistat is approximately 3.5 hours.

Pharmacokinetics in special populations.

Hepatic impairment.

Evotaz is not recommended in patients with hepatic impairment. The impact of hepatic impairment on the pharmacokinetics of the combination of atazanavir and cobicistat has not been assessed.

Atazanavir.

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 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Cobicistat.

Cobicistat is primarily metabolised and eliminated by the liver. A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment (Child-Pugh class B). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with mild to moderate impairment and healthy subjects. The effect of severe hepatic impairment (Child-Pugh class C) on the pharmacokinetics of cobicistat has not been studied.

Renal impairment.

Atazanavir.

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; estimated creatinine clearance < 30 mL/min using 24 hour urinary creatinine and serum creatinine levels), including those on haemodialysis, at multiple doses of 400 mg 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).

Cobicistat.

A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No meaningful differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects, consistent with low renal clearance of cobicistat.

Age, gender, and race.

The pharmacokinetics of atazanavir or cobicistat in elderly (65 years of age and older) have not been fully evaluated. No clinically important differences in atazanavir pharmacokinetics were observed based on age or gender. No clinically relevant differences in cobicistat pharmacokinetics were observed based on race or gender.

Hepatitis B and/or hepatitis C virus coinfection.

Pharmacokinetics of cobicistat have not been fully evaluated in the hepatitis B and/or C coinfection patients.

Antiviral activity in vitro.

Atazanavir exhibits anti-HIV-1 activity (EC50 of 2.6 to 5.3 nanoM) 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.
Cobicistat has no detectable antiviral activity against HIV-1, HBV or HCV and does not antagonize the antiviral effect of HIV inhibitors.

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).

Resistance in vivo.

Clinical studies of treatment naïve patients receiving atazanavir 300 mg with cobicistat 150 mg.

In an analysis of treatment failure subjects who received atazanavir coadministered with cobicistat in study 114 through week 48, evaluable genotypic data from paired baseline and treatment failure isolates were available for 11 of the 12 virologic failures in this group (3%, 11/344). Among the 11 subjects, 2 developed the emtricitabine associated resistance substitution M184V. No subject developed the tenofovir associated resistance substitution K65R or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data was available for all 12 virologic failures (3%, 12/348) and no subject had emergent resistance to any component of the regimen.

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.

Electrocardiogram.

Atazanavir.

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 predose 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 had 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.

Cobicistat.

The electrocardiographic effects of cobicistat were determined in a study of 48 healthy adult patients. Cobicistat did not prolong QTcF interval at doses of 250 mg and 400 mg, providing exposures 2 and 4-fold above the recommended therapeutic dose. A modest increase in PR interval (+ 9.6 msec) occurred around Cmax, 3 to 5 hours after dosing. This finding was not considered to be clinically significant.

5.3 Preclinical Safety Data

Genotoxicity.

Atazanavir.

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.

Cobicistat.

Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays.

Carcinogenicity.

Atazanavir.

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 tumors was observed in female mice at nontumorigenic doses or male mice at any dose. Exposures in male and female mice at nontumorigenic 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 tumor 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.

Cobicistat.

In a long-term carcinogenicity study in mice, no drug related increases in tumour incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.

Fetal risk summary.

Atazanavir.

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 prenatal 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. Transient reductions in offspring bodyweights were observed in a prenatal and postnatal 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.

Cobicistat.

In a rat study, foetal development was unaffected by an oral dose of cobicistat resulting in a drug exposure (AUC) that was 1.9-fold higher than in humans receiving the 150 mg daily dose. There was a tendency for reduced foetal weight and increases in skeletal variations with a higher dose that was associated with reduced maternal food consumption and bodyweight gain. Treatment of rabbits with a dose resulting in a drug exposure approximately 3 times that in humans receiving the 150 mg daily dose did not affect foetal development.

4 Clinical Particulars

4.1 Therapeutic Indications

Evotaz is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults.

4.3 Contraindications

Evotaz is contraindicated in patients with known hypersensitivity to any of its ingredients (see Section 6.1 List of Excipients).
Patients taking Evotaz should not use medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 or are highly dependent on UGT1A1 for clearance 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).
Evotaz should not be used in combination with elbasvir/grazoprevir because of the potential increase in the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.
Evotaz should not be used in combination with glecaprevir/pibrentasvir because of the increased risk of ALT elevations due to an increase in glecaprevir and pibrentasvir plasma concentrations.
Co-administration of Evotaz with the following is contraindicated due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Alpha 1-adrenoreceptor antagonists: alfuzosin.
Antiarrhythmics: dronedarone, quinidine.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Antimycobacterials: rifabutin, rifampicin, rifapentine.
Antipsychotics: lurasidone.
Antineoplastic: irinotecan.
Calcium channel blocker: bepridil.
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine.
GI motility agents: cisapride.
Hepatitis C direct-acting antivirals: elbasvir/grazoprevir.
Herbal products: St. John's wort (Hypericum perforatum).
Lipid-modifying agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin.
Other lipid-modifying agents: lomitapide.
Neuroleptics: pimozide.
Non-nucleoside reverse transcriptase inhibitors: nevirapine, efavirenz.
PDE-5 inhibitors: sildenafil and tadalafil for the treatment of pulmonary arterial hypertension.
Sedative/ hypnotics: orally administered midazolam, triazolam.
Beta-agonist: salmeterol.

4.4 Special Warnings and Precautions for Use

Use with other antiretroviral products.

Do not use Evotaz in combination with products containing the same components (atazanavir or cobicistat), or with fixed dose products that contain cobicistat. Do not use Evotaz in combination with another antiretroviral that requires a pharmacokinetic enhancer (e.g. elvitegravir) because dosing recommendations for such combinations have not been established and may result in decreased plasma concentrations of the antiretroviral agent, leading to loss of therapeutic effect and development of resistance. Do not use Evotaz with other HIV protease inhibitors. Do not use Evotaz in combination with nevirapine or efavirenz. Evotaz should not be used concurrently with product containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat or ritonavir on CYP3A. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Use in renal impairment.

Effect on serum creatinine.

Dosing recommendations are not available for use of Evotaz in combination with other drugs that require dosing adjustment for renal impairment. Consider alternative medications that do not require dosing adjustments. Cobicistat, a component of Evotaz, has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating Evotaz particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance, or when coadministered with drugs with dosing adjustment recommendations guided by estimated creatinine clearance.
Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 35 micromol/L from baseline should be monitored and evaluated for evidence of tubulopathy. Evotaz should not be initiated in patients with creatinine clearance less than 70 mL/min if one or more coadministered agent requires dose adjustment based on creatinine clearance (e.g. emtricitabine, lamivudine, tenofovir DF or adefovir).

New onset or worsening renal impairment when used with tenofovir DF.

Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat is used in an antiretroviral regimen that contains tenofovir disoproxil fumarate (tenofovir DF).
Do not initiate Evotaz as part of a regimen containing tenofovir DF in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with Evotaz. Patients should be switched to an alternative antiretroviral regimen if estimated creatinine clearance decreases to less than 50 mL/min.
Document estimated creatinine clearance, urine glucose and urine protein (ratio) at baseline and perform routine monitoring during treatment when Evotaz is used with tenofovir DF.
Proteinuria, normoglycemic glycosuria and increased fractional excretion of phosphorous may represent the first signs of tubulopathy and precede any decline in renal function.
Measure serum phosphorus in patients with or at risk for renal impairment.
Avoid use of Evotaz with tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent.

Diabetes mellitus/ hyperglycaemia.

Atazanavir.

New onset diabetes mellitus, hyperglycaemia, and exacerbation of existing diabetes mellitus have been reported during postmarketing 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.

Haemophilia.

Atazanavir.

There have been reports of increased bleeding, including spontaneous skin hematomas and haemarthrosis, in patients with haemophilia type A and B 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.

Atazanavir.

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.

Immune reconstitution syndrome.

Atazanavir.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of Evotaz. 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 jiroveci 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.

Cardiac effects.

Atazanavir.

Atazanavir, a component of Evotaz, has the potential to prolong the PR interval of the electrocardiogram in some patients. Evotaz should be used with caution in patients with pre-existing conduction system disease (e.g. marked first degree atrioventricular (A-V) block or second or third degree A-V block). Caution should be used when coadministering Evotaz with medicinal products known to induce PR interval prolongation especially those that are metabolized by CYP3A (e.g. verapamil) or CYP2D6 (e.g. beta-blockers other than atenolol). Caution should be used when prescribing Evotaz 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). See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Hyperbilirubinemia and jaundice.

Atazanavir.

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 elevated bilirubin in patients receiving Evotaz should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in bilirubin > 5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to Evotaz may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients.

Rash.

Atazanavir.

In controlled clinical trials (n = 1597), rash (all grades, regardless of causality) occurred in approximately 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 with atazanavir was 0.4%. Evotaz 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.

Use in hepatic impairment.

Atazanavir and cobicistat are principally metabolized by the liver. Evotaz is not recommended in patients with hepatic impairment (see Section 4.2 Dose and Method of Administration). Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with Evotaz and during treatment.

Chronic kidney disease.

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

Nephrolithiasis and cholelithiasis.

Atazanavir.

Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV infected patients receiving atazanavir, a component of Evotaz (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing experience). Some patients required hospitalization for additional management and some had complications. As 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.

Lactic acidosis.

Atazanavir.

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.

Paediatric use.

Safety and effectiveness of Evotaz in children less than 18 years of age have not been established. Evotaz should not be administered to paediatric patients below the age of 3 months due to the risk of kernicterus.

Use in the elderly.

There are no data available to make a dose recommendation for patients over the age of 65 years.

Effect on laboratory tests.

The most frequently reported laboratory abnormality in patients receiving regimens containing Evotaz 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 in 37% (6% grade 4). Discontinuation of treatment due to elevated bilirubin was < 1%. Other marked clinical laboratory abnormalities (grade 3 or 4) reported in greater than or equal to 2% of patients receiving regimens containing Evotaz and one or more NRTIs included: elevated creatine kinase (CK) (7%), elevated ALT/SGPT (5%), low neutrophils (5%), elevated AST/ SGOT (3%), and elevated lipase.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug interactions.

Drug interaction trials were not conducted for Evotaz (atazanavir and cobicistat). The recommendations provided are based either on drug interaction studies of unboosted atazanavir, atazanavir boosted with ritonavir, cobicistat, or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect of Evotaz.

Atazanavir.

Atazanavir is metabolized in the liver by the cytochrome P450 enzyme system, and is an inhibitor of CYP3A4. Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A4. Atazanavir is a weak to moderate inhibitor of CYP2C8. Atazanavir is an inhibitor of CYP3A4 and UGT1A1. Coadministration 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. Atazanavir is metabolized in the liver by the cytochrome P450 enzyme system. Coadministration of atazanavir and drugs that induce CYP3A4, such as rifampicin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Coadministration of atazanavir and drugs that inhibit CYP3A4 may increase atazanavir plasma concentrations.

Cobicistat.

Cobicistat is a potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolised by CYP3A. Drugs that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in exposure when coadministered with cobicistat. Thus, coadministration of cobicistat with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events is contraindicated. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring. Cobicistat is a weak inhibitor of CYP2D6. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, UGT1A1, or MDR1.

Evotaz.

Co-administration of Evotaz and drugs primarily metabolized by CYP3A4 (e.g. calcium channel blockers, some HMG-CoA reductase inhibitors, immunosuppressants, and phosphodiesterase (PDE5) inhibitors), UGT1A1, and/or CYP2D6, or drugs that are substrates of P-gp, BCP, OATP1B1, and/or OATP1B3 (e.g. grazoprevir) may result in increased plasma concentrations of the other drug that could increase or prolong both the therapeutic and adverse effects of the other drug.
Co-administration of Evotaz and drugs that induce CYP3A4 (e.g. rifampicin) may decrease atazanavir and cobicistat plasma concentrations and reduce the therapeutic effect of Evotaz.
Co-administration of Evotaz and drugs that inhibit CYP3A4 (e.g. ketoconazole) may increase atazanavir and cobicistat plasma concentrations.
Caution should be used with coadministration of Evotaz and drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g. paclitaxel, repaglinide).
For drugs that are contraindicated with Evotaz, see Section 4.3 Contraindications. Established and potentially significant drug interactions are included in Table 1. These recommendations are based on either drug interaction studies with the components of Evotaz, or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of therapeutic effect of Evotaz.
Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and fluvastatin, dapsone, trimethoprim/ sulfamethoxazole and azithromycin. There were no clinically significant drug interactions observed when atazanavir, a component of Evotaz, was coadministered with fluconazole, paracetamol or atenolol. Atazanavir does not interact with substrates of CYP2D6 (e.g. nortriptyline, desipramine, metoprolol).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Atazanavir.

Atazanavir produced no effects on mating, fertility, or early embryonic development in rats at doses that provided exposures up to two times the exposure in humans given atazanavir at 400 mg once daily. Altered oestrus cycles were observed in female rats treated with oral doses resulting in similar estimated systemic drug exposures (AUC).

Cobicistat.

Cobicistat did not affect mating, fertility, or early embryonic development in rats at exposures approximately three times the exposure in humans given 150 mg once daily. Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) approximately similar to human exposures at the recommended 150 mg daily dose.
(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.
Cases of lactic acidosis, sometimes fatal, and symptomatic hyperlactatemia have been reported in patients (including pregnant women) receiving atazanavir in combination with nucleoside analogues, which are known to be associated with increased risk of lactic acidosis. Female gender and obesity are also known risk factors for lactic acidosis. The contribution of atazanavir to the risk of development of lactic acidosis has not been established.
Evotaz is not recommended during pregnancy nor should it be initiated in pregnant patients (see Section 4.2 Dose and Method of Administration, Pregnancy); an alternative regimen is recommended. Pharmacokinetic data from studies conducted in pregnant women receiving cobicistat showed substantially lower exposures during the second and third trimesters, compared to postpartum, and consequently of the co-administered antiretroviral agent, including atazanavir. Consult the full prescribing information for cobicistat. Pharmacokinetic data from the evaluation of Evotaz in a limited number of pregnant women showed a similar trend in lower exposures of the antiretroviral component, atazanavir.
Hyperbilirubinemia occurred frequently during treatment with atazanavir. It is not known whether Evotaz administered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and young infants. If Evotaz is used during pregnancy additional monitoring should be considered during the prepartum period.
Atazanavir has been detected in human milk. It is not known whether cobicistat is secreted in human milk. No data are available regarding atazanavir or cobicistat effects on milk production. Studies in rats have demonstrated that atazanavir and/or its metabolites and cobicistat are excreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Evotaz.

4.8 Adverse Effects (Undesirable Effects)

Experience from clinical trials.

The safety of Evotaz has been established in a phase III randomized, active controlled clinical trial (GS-US-216-0114), in which 692 treatment naïve patients received atazanavir boosted with cobicistat (n = 344) or atazanavir boosted with ritonavir (n = 348) administered with tenofovir DF/ emtricitabine for at least 48 weeks. Adverse reactions for atazanavir boosted with cobicistat were consistent with the safety profile of atazanavir boosted with ritonavir. The most frequently reported adverse reactions were associated with elevated bilirubin levels. Table 2 lists the frequency of adverse reactions (grade 2-4) occurring in at least 3% of patients receiving atazanavir boosted with cobicistat + tenofovir DF/ emtricitabine in study GS-US-216-0114.

Laboratory abnormalities.

The frequency of treatment emergent laboratory abnormalities (grade 3-4) occurring in at least 3% of patients receiving atazanavir boosted with cobicistat + tenofovir DF/ emtricitabine in study GS-US-216-0114 are presented in Table 3.
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. An increase in serum creatinine due to cobicistat's inhibitory effect generally does not exceed 35 micromol/L from baseline. In study GS-US-216-114, decreases in estimated creatinine clearance occurred early in treatment with cobicistat, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 48 weeks of treatment was -13.4 ± 15.2 mL/min in the atazanavir boosted with cobicistat + tenofovir DF/ emtricitabine group and -8.7 ± 14.5 mL/min in the atazanavir boosted with ritonavir + tenofovir DF/ emtricitabine group.

Serum lipids.

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4.

Postmarketing experience.

The following events have been identified during postapproval use of atazanavir. As 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 A-V block, third degree A-V 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.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The recommended adult dosage of Evotaz is one tablet once daily taken orally with food. Administer Evotaz in conjunction with other antiretroviral agents. When coadministered with H2-receptor antagonists or proton pump inhibitors, dose separation may be required (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Evotaz tablets should be taken whole and not broken, cut, or crushed.
If a dose of Evotaz is missed by 12 hours or less, the missed dose of Evotaz should be taken right away. The next dose of Evotaz should be taken at the usual time. If a dose of Evotaz is missed by more than 12 hours, the patient should wait and take the next dose at the usual time. If a dose of Evotaz is missed, the patient should not double the next dose.

Renal impairment.

Evotaz should not be administered to HIV treatment experienced patients with severe renal disease managed with haemodialysis. Cobicistat, a component of Evotaz, has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual glomerular function. Consider this effect when Evotaz is coadministered with a drug that has dosing adjustment recommendations guided by estimated creatinine clearance (see Section 4.4 Special Warnings and Precautions for Use).

Laboratory testing prior to initiation of Evotaz.

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when Evotaz is coadministered with a drug that has dosing adjustment recommendations guided by estimated creatinine clearance. For example, Evotaz should not be initiated as part of a regimen containing emtricitabine, lamivudine, tenofovir disoproxil fumarate or adefovir dipivoxil in patients who have an estimated creatinine clearance below 70 mL/min since dose adjustment of these drugs is required below 50 mL/min and such dose adjustments have not been established in combination with Evotaz (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Evotaz is not recommended in patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Pregnancy.

Evotaz is not recommended during pregnancy nor should it be initiated in pregnant patients; an alternative regimen is recommended. This is due to substantially lower exposures of cobicistat and consequently, lower exposures of co-administered antiretroviral agents, including atazanavir, during the second and third trimesters, compared to postpartum (see Section 4.6 Fertility, Pregnancy and Lactation).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

If overdose occurs with Evotaz, the patient must be monitored for evidence of toxicity. Treatment should consist of general supportive measures including monitoring of vital signs and ECG as well as observation of the patient's clinical status. There is no specific antidote for overdose with Evotaz. Since atazanavir and cobicistat are extensively metabolized by the liver, highly bound to plasma proteins, it is unlikely that Evotaz can be significantly removed by haemodialysis or peritoneal dialysis.

Atazanavir.

Human experience of acute overdose with atazanavir is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self administered overdose of 29.2 g of atazanavir in a HIV infected patient (73 times the 400 mg recommended 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 indirect (unconjugated) hyperbilirubinemia (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)).

Cobicistat.

Limited clinical experience is available at doses higher than the therapeutic dose of cobicistat. In two studies, a single dose of cobicistat 400 mg was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known.
For information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core: microcrystalline cellulose, croscarmellose sodium, sodium starch glycollate, crospovidone, stearic acid, magnesium stearate, hydroxypropylcellulose, and silicon dioxide.
Film coating: hypromellose, titanium dioxide, purified talc, glycerol triacetate, and iron oxide red.

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

Evotaz should be stored below 25°C.

6.5 Nature and Contents of Container

Evotaz is supplied in a high density polyethylene (HDPE) bottle.
Each bottle contains 30 tablets, a silica gel desiccant and is closed with a child-resistant closure.

6.6 Special Precautions for Disposal

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

Summary Table of Changes