Consumer medicine information

Prezcobix Tablets

Darunavir; Cobicistat

BRAND INFORMATION

Brand name

Prezcobix

Active ingredient

Darunavir; Cobicistat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

Read all of this leaflet carefully before you start taking this medicine This leaflet answers some common questions about PREZCOBIX tablets. 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 being given PREZCOBIX against the benefits this medicine is expected to have for you.

If you have any concerns about being given PREZCOBIX ask your doctor.

Keep this leaflet while you are taking PREZCOBIX. You may need to read it again.

What PREZCOBIX is used for

PREZCOBIX is used to treat adults, who are infected by HIV (Human Immunodeficiency Virus).

PREZCOBIX contains two active ingredients which work in combination for the treatment of HIV. These active ingredients are darunavir and cobicistat.

Darunavir is an antiretroviral medicine. It belongs to a group of medicines called protease inhibitors. Darunavir works by reducing the amount of HIV in your body. Reducing the amount of HIV in your blood improves your immune system, and reduces the risk of developing illnesses as a result of HIV infection.

Cobicistat is a type of medicine called a pharmacokinetic enhancer (or "booster"). Cobicistat helps increase the levels of darunavir, the HIV medicine in your body.

PREZCOBIX can be taken with other anti-HIV medicines. Your doctor will discuss with you which combination of medicines will work best with PREZCOBIX.

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

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

Before you take PREZCOBIX

When you must not use it:

Do not take PREZCOBIX:

  • if you are allergic (hypersensitive) to darunavir, cobicistat or any of the other ingredients of PREZCOBIXlisted in the Ingredient section of this document.
  • Symptoms of an allergic reaction may include rash, itching or hives on the skin, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

Do not take PREZCOBIX:

  • if the packaging is torn or shows signs of tampering.
  • if the expiry date (month and year) printed on the pack has passed. If you take PREZCOBIX after the expiry date it may not work.

PREZCOBIX should not be given to children younger than 18 years of age.

Do not combine PREZCOBIX with any of the following medicines:

  • alfuzosin (to treat an enlarged prostate)
  • astemizole or terfenadine (to treat allergy symptoms)
  • cisapride (to treat some stomach conditions)
  • colchicine (to treat gout) if you have renal/hepatic impairment
  • amiodarone, bepridil, disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine or dronedarone (to treat irregular heartbeats)
  • ivabradine or ranolazine (to treat heart disease)
  • lomitapide, lovastatin or simvastatin (to lower cholesterol levels)
  • midazolam or triazolam (to treat trouble with sleeping and/or anxiety)
  • lurasidone or pimozide (to treat psychiatric conditions)
  • apixaban (used to reduce blood clotting)
  • carbamazepine, phenobarbital, phenytoin (medicines to prevent seizures or to treat trigeminal neuralgia)
  • ergot alkaloids i.e. dihydroergotamine, ergonovine, ergotamine, methylergonovine (to treat migraine and headaches)
  • sildenafil (to treat pulmonary arterial hypertension)
  • rifampin (to treat some infections such as tuberculosis)
  • elbasvir/grazoprevir (to treat hepatitis C)
  • products that contain St John's wort (Hypericum perforatum)
  • naloxegol (to treat opioid induced constipation)
  • dapoxetine (to treat premature ejaculation)

If you are taking any of these, ask your doctor about switching to another medicine.

This not a complete list of medicines. Therefore, tell your doctor about all medicines you take.

There are other medicines that you need to be careful of when taking PREZCOBIX (see Taking other medicines).

Before you start to use it:

Take special care with PREZCOBIX:

PREZCOBIX is not a cure for HIV infection.

PREZCOBIX does not reduce the risk of passing HIV to others through sexual contact or blood. Therefore, you must continue to use appropriate precautions to prevent passing HIV on to others.

People taking PREZCOBIX can still develop infections or other illnesses associated with HIV. You should continue to keep in regular contact with your doctor and to monitor your health while taking PREZCOBIX.

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

  • Kidney problems or are undergoing kidney dialysis treatment.
  • Problems with your liver, including hepatitis B and C.
    Your doctor may need to evaluate your liver before deciding if you can take PREZCOBIX.
  • Diabetes.
    PREZCOBIX, like some other anti-HIV medicines, might increase sugar levels in the blood.
  • Haemophilia.
    Anti-HIV medicines, such as PREZCOBIX, might increase the risk of bleeding in patients with this blood clotting disorder.
  • Are allergic to foods, dyes, preservatives, sulfa medicines (sulphonamides) or any other medicines.

Tell your doctor immediately if you are pregnant or breastfeeding, or intend to become pregnant or breastfeed.

Do not take PREZCOBIX if you are pregnant or breastfeeding. It is recommended that HIV infected women should not breastfeed their infants because of the possibility of your baby becoming infected with HIV through your breast milk and because of the unknown effects of the medicine on your baby. If you are a woman who has or will have a baby, talk with your doctor about the best way to feed your baby.

If you have not told your doctor about any of the above, tell them before you start treatment with PREZCOBIX.

Taking other medicines:

Some medicines may affect the levels of PREZCOBIX or PREZCOBIX may affect the level of other medicines in the body when they are taken at the same time as PREZCOBIX. Your doctor might want to do some additional blood tests.

For this reason, tell your doctor about all medicines you take, including medicines you can buy without a prescription from a pharmacy, supermarket or health food shop.

Know the medicines you take. Keep a list of medicines and show it to your doctor and pharmacist when you get a new medicine. Your doctor and your pharmacist can tell you if you can take these medicines with PREZCOBIX

  • Tell your doctor if you are taking any of the following: amiodarone, bepridil, disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine, dronedarone, apixaban, midazolam, triazolam, ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine), astemizole, terfenadine, cisapride, pimozide, lurasidone, alfuzosin, sildenafil, colchicine, lomitapide, lovastatin, simvastatin, ivabradine, ranolazine, rifampicin, elbasvir/grazoprevir, carbamazepine, phenobarbital, phenytoin, products that contain St John's wort (Hypericum perforatum), naloxegol or dapoxetine. You must not take these medicines while taking PREZCOBIX.
  • Tell your doctor if you take other anti-HIV medicines. PREZCOBIX can be combined with some other anti-HIV medicines while other combinations are not recommended.
  • If you take PREZCOBIX with some other medicines, the effects of PREZCOBIX or other medicines might be influenced. The dosage of some medicines may need to be changed. Some combinations are not recommended. Tell your doctor if you take any of the following:
    - oestrogen-based hormonal contraceptives. PREZCOBIX might reduce the effectiveness of hormonal contraceptives. Therefore, additional or alternative (non-hormonal) methods of contraception are recommended. If you take a contraceptive containing drospirenone your potassium levels might become elevated.
    - medicines for heart disease (amlodipine, diltiazem, felodipine, nifedipine, nicardipine, tadalafil, verapamil).
    - medicines to treat certain heart disorders (digoxin, carvedilol, metoprolol, timolol, bosentan)
    - medicines used to reduce clotting of the blood (dabigatran etexcilate, edoxaban, rivaroxaban, warfarin) or to prevent blood clots (ticagrelor, clopidogrel).
    - medicines to lower cholesterol levels (pravastatin, atorvastatin, rosuvastatin, pitavastatin). The risk of muscle tissue disorder might be increased. Atorvastatin, rosuvastatin, or pravastatin, at a reduced starting dose, could be used as an alternative.
    - medicines for your immune system (cyclosporine, tacrolimus, sirolimus, everolimus, rapamycin). Your doctor might want to do some additional tests.
    - medicines to treat asthma (salmeterol).
    - corticosteroids (betamethasone, budesonide, dexamethasone, fluticasone, mometasone, prednisone, triamcinolone).
    - medicines to treat cancer (dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine).
    - medicines to treat pain (fentanyl, oxycodone, tramadol).
    - medicines to treat narcotic dependence (buprenorphine/naloxone, methadone).
    - medicines to treat malaria (artemether/lumefantrine).
    - medicines to treat hepatitis C (telaprevir, boceprevir, glecaprevir/pibrentasvir).
    - medicines to treat urinary disorders (fesoterodine, solifenacin).
    - medicines to treat nausea and vomiting (domperidone).
    - medicines to treat fungal infections (clotrimazole, fluconazole, isavuconazole, itraconazole, ketoconazole, posaconazole, voriconazole).
    - medicines to treat some infections such as tuberculosis (rifabutin, rifapentine).
    - medicines against bacterial infections (clarithromycin, erythromycin and telithromycin).
    - medicines to treat gout (colchicine). If you have renal/hepatic impairment, do not take colchicine with PREZCOBIX.
    - medicines for erectile dysfunction (avanafil, vardenafil, tadalafil, sildenafil).
    - medicines to treat depression and anxiety (paroxetine, sertraline, amitriptyline, desipramine, imipramine, nortriptyline, and trazodone).
    - sedatives (buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem).
    - medicines to treat psychiatric conditions (risperidone, thioridazine, quetiapine, perphenazine).
    - medicines to prevent seizures or to treat trigeminal neuralgia (oxcarbazepine, clonazepam).
    - medicines to treat excessive sleepiness (armodafinil, modafinil).

This is not a complete list of medicines. Tell your doctor about all medicines that you are taking.

Taking PREZCOBIX

Adults

Always use PREZCOBIX exactly as your doctor has told you. You must check with your doctor if you are not sure.

Make sure that you always have enough PREZCOBIX available so that you don't run out. For example, in case you cannot return home, need to travel or stay in a hospital.

How much PREZCOBIX to take:

The usual dose of PREZCOBIX is one tablet orally, once daily with food.

You must take PREZCOBIX every day and always with food. PREZCOBIX cannot work properly without food. You must eat a meal or a snack within 30 minutes prior to taking your PREZCOBIX. The type of food is not important.

Even if you feel better, do not stop taking PREZCOBIX without talking to your doctor.

Instructions:

  • Take PREZCOBIX with food.
  • Swallow the tablets with a drink such as water, milk, or any other nutritional drink.

Take your other HIV medicines used in combination with PREZCOBIX as recommended by your doctor.

Removing the child resistant cap

The plastic bottle comes with a child resistant cap and should be opened as follows:

  • Push the plastic screw cap down while turning it counter clockwise.
  • Remove the unscrewed cap.

What do I do if I forget to take PREZCOBIX?

If you forget to take PREZCOBIX
If you notice within 12 hours, you must take the tablets immediately. Always take with food. If you notice after 12 hours, then skip the intake and take the next doses as usual. Do not take a double dose to make up for a forgotten dose.

Please refer to your doctor for instructions on missed doses of other HIV medicines used in combination with PREZCOBIX.

What do I do if I take too much? (overdose):

If you think you or anybody else has taken too much PREZCOBIX, contact your doctor, pharmacist or the Poisons Information Centre who will advise you what to do.

You can contact the Poisons Information Centre by dialling:

  • Australia: 13 11 26

Or go to the accident and emergency department at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. This may need urgent medical attention.

While you are taking PREZCOBIX

Things you must do:

Do not stop taking PREZCOBIX without talking to your doctor first.

Tell your doctor if you have any medical conditions, especially the following:

  • Symptoms of infection.
    In some patients with advanced HIV infection and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response. This improvement enables the body to fight infections that may have been present prior to taking PREZCOBIX, with no obvious symptoms.

HIV therapy may increase your sense of well being. Even when you feel better, do not stop taking PREZCOBIX. Talk to your doctor first.

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor will want to do some blood, urine and other tests from time to time to check on your progress.

Be sure to follow up your doctor's instructions about other medicines you should take, and other things you should do.

Ask your doctor or pharmacist if you have any questions.

Tell any other doctors and pharmacists who are treating you that you are taking PREZCOBIX. If you are undergoing anaesthesia, tell your anaesthetist that you are taking PREZCOBIX.

If you are about to be started on any new medicines, tell your doctor or pharmacist that you are taking PREZCOBIX.

If you become pregnant while taking PREZCOBIX, tell your doctor immediately. You must not take PREZCOBIX if you are pregnant.

If you have any further questions on the use of this product, ask your doctor.

Things you must not do:

  • Do not breastfeed. See "Before you start to use it".
  • Avoid doing things that can spread HIV infection since PREZCOBIX does not stop you from passing the HIV infection to others:
  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes or razor blades.
  • Do not have any kind of sex without protection. Always practise safer sex by using a latex or polyurethane condom or other barrier to reduce the chance of passing the infection through semen, vaginal secretions, or blood.
  • Do not take PREZCOBIX if the packaging is torn or shows signs of tampering.

Things to be careful of

Driving and using machines

Do not operate machines or drive if you feel dizzy after taking PREZCOBIX.

Side Effects

Like all medicines, PREZCOBIX can have side effects. Some of these effects may be serious.

Tell your doctor or pharmacist if you do not feel well while you are being treated with PREZCOBIX.

When treating HIV infection, it is not always easy to identify what side effects are caused by PREZCOBIX, which are caused by other medicines you are taking, or which are caused by the HIV infection itself.

The most common side effects are:

  • nausea, vomiting
  • headache
  • abdominal pain, diarrhoea
  • passing wind
  • rash (see information below), itching or hives on the skin

PREZCOBIX may change some values of your blood chemistry. These can be seen in the results of blood tests. Your doctor will explain these to you.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests prior to initiating PREZCOBIX. If you have chronic hepatitis B or C infection, your doctor should check your blood tests more often because you have an increased chance of developing liver problems. Talk to your doctor about the signs and symptoms of liver problems. These may include yellowing of your skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on your right side below your ribs.

Skin rash has been reported in patients receiving PREZCOBIX. Occasionally a rash can be severe or potentially life threatening. In patients taking PREZCOBIX and raltegravir, rashes (generally mild or moderate) may occur more frequently than in patients taking either drug separately. It is important to consult your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether PREZCOBIX must be stopped.

Tell your doctor if you experience the following side effects:

  • loss of appetite
  • increased blood fat levels
  • diabetes
  • symptoms of infection

Some side effects are typical for anti-HIV medicines in the same family as PREZCOBIX. These are:

  • raised blood sugar and worsening of diabetes.
  • immune reactivation syndrome. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started, including PREZCOBIX. In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur after you start taking medicines for treatment of your HIV infection. Autoimmune disorders may occur many months after the start of treatment.
  • increased bleeding in patients with haemophilia.
  • muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been serious.

If you experience any of these side effects and they worry you, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Tell your doctor if you notice signs or symptoms of infections, such as a fever or rashes. Some people with HIV who have had infections in the past may experience a return of symptoms soon after taking anti-HIV medicines.

If you think you are having an allergic reaction to PREZCOBIX, tell your doctor immediately or go to Accident and Emergency at your nearest hospital.

Symptoms usually include some or all of the following:

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

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

Product Description

Storage

PREZCOBIX tablets should be kept out of reach of children, in a location where the temperature stays below 30°C.

What it looks like:

PREZCOBIX 800/150 mg film-coated tablet: Pink oval-shaped tablet, debossed with "800" on one side and "TG" on the opposite side. Each plastic bottle contains 30 tablets.

Ingredients

Active ingredients:

  • darunavir 800 mg (as darunavir ethanolate)
  • cobicistat 150 mg

Other ingredients:

  • hypromellose
  • silicon dioxide
  • microcrystalline cellulose
  • crospovidone
  • magnesium stearate
  • Opadry II complete film coating system 85F140053 Pink (ARTG PI No. 109886) (Film Coating)

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Rd
Macquarie Park NSW 2113 Australia
Telephone: 1800 226 334

Registration numbers
800/150 mg tablet: AUST R 231198

This leaflet was prepared in 27 March 2023.

® PREZCOBIX is a registered trademark of Janssen-Cilag Pty Ltd.

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Prezcobix

Active ingredient

Darunavir; Cobicistat

Schedule

S4

 

1 Name of Medicine

Darunavir/cobicistat.

2 Qualitative and Quantitative Composition

Prezcobix 800/150 mg tablets contain 800 mg of darunavir (as 867.28 mg darunavir ethanolate) and 150 mg of cobicistat.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Prezcobix 800/150 mg film-coated tablet.

Pink oval-shaped tablet, debossed with "800" on one side and "TG" on the opposite side.

4 Clinical Particulars

4.1 Therapeutic Indications

Prezcobix, a fixed dose combination of darunavir and cobicistat, is indicated in combination with other antiretroviral agents for the treatment of adult patients with human immunodeficiency virus-1 (HIV-1) infection in:
Antiretroviral treatment-naive patients.
Antiretroviral treatment-experienced patients with no darunavir resistance associated mutations and who have plasma HIV-1 RNA < 100,000 copies/mL.
Antiretroviral treatment-experienced but HIV protease inhibitor-naive patients for whom HIV-1 genotype testing is unavailable (see Section 4.2 Dose and Method of Administration).

4.2 Dose and Method of Administration

Dose in adults.

The recommended dose regimen is Prezcobix one tablet taken once daily with food. The type of food does not affect the exposure to Prezcobix.
For antiretroviral treatment-experienced patients* HIV-1 genotype testing is recommended.
*Darunavir resistance associated mutations: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V.
When HIV genotypic testing is not feasible:
Prezista (darunavir) should be used for protease inhibitor-experienced patients. See Prezista Product Information for dosing recommendations;
Prezcobix can be used in protease inhibitor naïve patients.

Dose in paediatric patients (17 years of age and younger).

The safety and efficacy of Prezcobix have not been established in paediatric patients.

Dose in elderly (65 years of age and older).

Limited information is available on the use of Prezcobix in patients 65 and older. Therefore, Prezcobix should be used with caution in this age group (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Prezcobix consists of the HIV protease inhibitor darunavir and the pharmacokinetic enhancer cobicistat. Prezcobix should be swallowed whole without breaking or crushing to ensure administration of the entire dose.
After therapy with Prezcobix has been initiated, patients should not alter the dosage or discontinue therapy without instruction of their physician. If discontinuation of therapy with the components of Prezcobix is indicated, dose modification of darunavir is necessary, or patients are unable to swallow the Prezcobix tablet. Please see respective Product Information for proper use of the products.
Prezcobix must be taken with food. The type of food does not affect the exposure to Prezcobix (see Section 5.2 Pharmacokinetic Properties).
If a dose of Prezcobix is missed by less than 12 hours, the missed dose should be taken as soon as possible. If the dose of Prezcobix was missed by more than 12 hours, the next dose should be taken at the next regularly scheduled time. Doses should be taken with food and should not be doubled.

Dosage adjustment.

Hepatic insufficiency.

There are no pharmacokinetic data obtained with Prezcobix in patients with hepatic impairment. However, there are pharmacokinetic data for the single agents of Prezcobix, darunavir and cobicistat.
Darunavir and cobicistat are metabolised by the liver. Studies with darunavir/ritonavir and with cobicistat single agent suggest no dose adjustment is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
There are no data regarding the use of darunavir and/or cobicistat with severe hepatic impairment, therefore, specific dosage recommendations cannot be made. Prezcobix should be used with caution in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Renal insufficiency.

No dose adjustment is required in patients with renal impairment.
Prezcobix should not be initiated as part of a regimen containing emtricitabine, lamivudine, tenofovir disoproxil fumarate or adefovir 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 Prezcobix (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects; Section 5.2 Pharmacokinetic Properties).

Pregnancy and postpartum.

Treatment with Prezcobix during pregnancy results in low darunavir exposure (see Section 5.2 Pharmacokinetic Properties). Therefore, therapy with Prezcobix should not be initiated during pregnancy, and women who become pregnant during therapy with Prezcobix should be switched to an alternative regimen (see Section 4.4 Special Warnings and Precautions for Use). Darunavir/ritonavir may be considered as an alternative.

4.3 Contraindications

Hypersensitivity to darunavir, cobicistat or to any of the excipients.
Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. Prezcobix should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Examples include alfuzosin, astemizole, apixaban, cisapride, colchicine (in patients with renal and/or hepatic impairment), dapoxetine, dronedarone, elbasvir/grazoprevir, ivabradine, lomitapide, lovastatin, lurasidone, oral midazolam, naloxegol, pimozide, ranolazine, ergot alkaloids (e.g. dihydroergotamine, ergotamine, ergonovine and methylergonovine), sildenafil (when used for treatment of pulmonary arterial hypertension), simvastatin, terfenadine, and triazolam and antiarrhythmic drugs (e.g. amiodarone, bepridil, flecainide, systemic lidocaine, quinidine) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Darunavir and cobicistat are both substances of the cytochrome P450 3A (CYP3A) isoform. Co-administration of Prezcobix with CYP3A inducers may lead to lower exposures of darunavir and cobicistat and potential loss of efficacy of darunavir and possible resistance. Patients taking Prezcobix should not use products containing potent CYP3A inducers such as carbamazepine, phenobarbital, phenytoin, rifampin or St. John's wort (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Patients should be advised that current antiretroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV. Appropriate precautions should continue to be employed.

Severe skin reactions.

During the darunavir clinical development program (N=3063), where darunavir was co-administered with low-dose ritonavir, severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. Stevens-Johnson syndrome has been rarely (< 0.1%) reported; and during post-marketing experience toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis have been reported very rarely (< 0.01%). Discontinue Prezcobix immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Rash (all severity grades, regardless of causality) occurred in 10.3% of patients treated with darunavir/ritonavir (see Section 4.8 Adverse Effects (Undesirable Effects)). Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in patients using darunavir/ritonavir was 0.5%.
Rash occurred more commonly in treatment-experienced subjects receiving regimens containing darunavir/ritonavir + raltegravir compared to subjects receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
In a single-arm trial investigating darunavir 800 mg once daily in combination with cobicistat 150 mg once daily and other antiretrovirals, 15.7% of patients experienced rash, and 2.2% discontinued treatment due to rash. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing.
Darunavir contains a sulfonamide moiety. Prezcobix should be used with caution in patients with a known sulfonamide allergy. In clinical studies with darunavir/ritonavir, the incidence and severity of rash was similar in patients with or without a history of sulfonamide allergy.

Immune reconstitution inflammatory syndrome.

In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Autoimmune disorders such as Graves' disease and autoimmune hepatitis have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Metabolic disorders.

Diabetes mellitus/hyperglycaemia.

New onset diabetes mellitus, hyperglycemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including HIV PIs. In some of these patients the hyperglycemia 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 the development of diabetes mellitus or hyperglycemia.
Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see Section 4.8 Adverse Effects (Undesirable Effects)).

Interactions with medicinal products.

See Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Co-administration of Prezcobix with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Prezcobix should not be used in combination with another antiretroviral that requires pharmacokinetic boosting. Prezcobix should not be used concurrently with products or regimens containing darunavir, ritonavir or cobicistat.

Patients with co-existing conditions.

Haemophiliac patients.

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Patients with hepatic impairment.

There are no pharmacokinetic data obtained with Prezcobix in patients with hepatic impairment. However, there are pharmacokinetic data for the single agents of Prezcobix, darunavir and cobicistat. Prezcobix should be used with caution in patients with severe hepatic impairment.
Data demonstrated that the steady state pharmacokinetic parameters of darunavir co-administered with low-dose ritonavir in subjects with mild and moderate hepatic impairment were comparable with those in healthy subjects. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dose adjustment for Prezcobix is required in patients with mild or moderate hepatic impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Hepatotoxicity.

Drug induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. During the darunavir clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.
Appropriate laboratory testing should be conducted prior to initiating therapy with Prezcobix and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Prezcobix treatment.
Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on Prezcobix should prompt consideration of interruption or discontinuation of treatment.

Patients with renal impairment.

Since the renal clearance of darunavir and cobicistat is limited, a decrease in total body clearance of darunavir and cobicistat is not expected in patients with renal impairment. As darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function (also see Section 5.1 Pharmacodynamic Properties, Effects on serum creatinine and Product Information for cobicistat). An increase in serum creatinine due to cobicistat's inhibitory effect generally does not exceed 0.4 mg per dL from baseline. This effect should be considered when Prezcobix is co-administered with a drug that has dosing adjustment recommendations guided by estimated creatinine clearance.

Use in the elderly.

As limited information is available on the use of Prezcobix in patients aged 65 and over, caution should be exercised in the administration of Prezcobix in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Prezcobix in paediatric patients have not been established.

Effects on laboratory tests.

None known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Prezcobix contains darunavir and cobicistat, and interactions that have been identified either with darunavir (in combination with cobicistat or low-dose ritonavir) or with cobicistat determine the interactions that may occur with Prezcobix.
Darunavir and cobicistat are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to lower plasma concentrations of darunavir and cobicistat, which could potentially lead to loss of efficacy of darunavir and possible development of resistance (see Section 4.3 Contraindications). Co-administration of Prezcobix and other drugs that inhibit CYP3A may increase plasma concentrations of darunavir and cobicistat.
Prezcobix should not be used in combination with another antiretroviral that requires pharmacokinetic boosting. Prezcobix should not be used concurrently with products or regimens containing darunavir, ritonavir or cobicistat.
Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6, and an inhibitor of P-gp. Cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the transporters P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), or multidrug resistance protein 1 (MDR1). Co-administration of Prezcobix and medicinal products primarily metabolized by CYP3A and/or CYP2D6 may result in increased plasma concentrations of such medicinal products, which could increase or prolong their therapeutic effect and can be associated with serious and/or life-threatening adverse events (see Section 4.3 Contraindications). Coadministration of Prezcobix with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect.
The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer, therefore there may be different recommendations for the use of darunavir with concomitant medicines. In Table 1 it is specified when recommendations for Prezcobix differ from those for darunavir boosted with low dose ritonavir. See Product Information for Prezista (darunavir) for further information.
For additional drug-drug interactions with darunavir or cobicistat, consult their respective Product Information when using Prezcobix.
The list of examples of drug-drug interactions is not comprehensive and therefore the Product Information of each drug that is co-administered with Prezcobix should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration.

Other HIV protease inhibitors.

The concomitant administration of darunavir/ritonavir and HIV PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such concomitant administration is not recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There was no effect on mating or fertility with darunavir or cobicistat treatment in rats. No effect on mating or fertility is expected with Prezcobix.

Darunavir.

In a study conducted in rats, there were no effects on mating with darunavir treatment up to 1000 mg/kg/day, but exposure levels were below (AUC -0.5 fold) that in humans at the clinically recommended dose. The number of corporea lutea and hence the number of live young was lower for females at 1000 mg/kg/day darunavir, and correlated with lower maternal bodyweight; the NOEL for effects on fertility was 200 mg/kg/day darunavir (corresponding to an exposure level 0.3-fold that in humans at the recommended clinical dose).

Cobicistat.

Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 4-fold higher than human exposures at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2-fold higher than human exposures at the recommended 150 mg daily dose.
(Category B2)
There are no adequate and well-controlled studies of Prezcobix, darunavir, or cobicistat in pregnant women.
Prezcobix in combination with a background regimen was evaluated in a clinical trial of 7 pregnant women during the second and third trimesters, and postpartum (6-12 weeks). The pharmacokinetic data demonstrate that exposure to darunavir and cobicistat was substantially lower during pregnancy compared with postpartum (see Section 5.2 Pharmacokinetic Properties). Virologic response was sustained throughout the study period in 5 out of 6 women who completed the study; the subject with virologic failure was not compliant with study medication.
Therapy with Prezcobix should not be initiated during pregnancy, and women who become pregnant during therapy with Prezcobix should be switched to an alternative regimen (see Section 4.2 Dose and Method of Administration). Darunavir/ritonavir may be considered as an alternative.
At clinically relevant exposures of darunavir and cobicistat, animal studies do not indicate direct or indirect harmful effects with respect to developmental or reproductive toxicity.
 It is not known whether darunavir, cobicistat or their metabolites are excreted in human milk. Animal studies have demonstrated that darunavir and cobicistat are excreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving Prezcobix.
In a pre and postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient reduction in body weight of the offspring during lactation. This was attributed to drug exposure via the milk. No post-weaning functions were affected with darunavir alone or in combination with ritonavir.
In juvenile rats directly dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age, mortality was observed and, in some of the animals, convulsions. Within this age range exposures in plasma, liver and brain were dose and age dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood brain barrier. No treatment related mortalities were noted in juvenile rats dosed at 1000 mg/kg darunavir (single dose) on day 26 of age or at 500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were comparable to those observed in adult rats. Due to uncertainties regarding the rate of development of the human blood brain barrier and liver enzymes, darunavir/ritonavir should not be used in paediatric patients below 3 years of age.

4.7 Effects on Ability to Drive and Use Machines

No trials on the effects of Prezcobix, darunavir, or cobicistat on the ability to drive or use machines have been performed. However, dizziness has been reported in some patients during treatment with regimens containing darunavir and should be borne in mind when considering a patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

A causal relationship with darunavir/cobicistat cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The overall safety profile of Prezcobix is based on all available clinical data from the Phase 3 single-arm trial (GS-US-216-0130) and on all available clinical trial and post-marketing data on darunavir/ritonavir and cobicistat in combination with other antiretroviral agents, and is consistent with the data presented below.
Adverse Drug Reactions (ADRs) to darunavir/ritonavir or to cobicistat are considered ADRs to Prezcobix unless otherwise specified.

Adverse reactions in trials with darunavir/cobicistat 800/150 mg q.d.

The safety of darunavir in combination with cobicistat has been evaluated in a Phase 3 single-arm trial (GS-US-216-0130), in which 295 treatment-naïve patients and 18 treatment-experienced patients received darunavir 800 mg once daily in combination with cobicistat 150 mg once daily as single agents and other antiretrovirals for at least 48 weeks. The median exposure in 313 patients treated with darunavir/cobicistat was 64.3 weeks.
The majority of the ADRs reported during treatment with darunavir/cobicistat in GS-US-216-0130 were mild in severity. The most frequent (≥ 5%) ADRs to darunavir/cobicistat that were moderate to severe (Grade 2-4) were diarrhea and rash. The most frequent (≥ 1%) ADR that was severe (Grade 3 or 4) was drug hypersensitivity. All other Grade 3 or 4 ADRs were reported in less than 1% of the patients, 3.8% of the patients discontinued treatment due to ADRs.
ADRs of Grades 2-4 severity reported in GS-US-216-0130, considered ADRs to Prezcobix are presented in Table 2.
Laboratory abnormalities, Grade 2-4, reported in GS-US-216-0130 and considered ADRs are shown in Table 3.
In the Phase 3 single-arm trial (GS-US-216-0130), a decrease in the estimated glomerular filtration rate, as estimated by the Cockcroft-Gault formula (eGFRCG), was noted at Week 2, which remained stable through week 48. The mean eGFRCG change from baseline was -9.6 mL/min at Week 2, and -11.5 mL/min at week 24, and -9.6 mL/min at week 48.
In addition to trial GS-US-216-0130, the safety of darunavir in combination with cobicistat has been evaluated in the control arm (darunavir/cobicistat fixed-dose combination + emtricitabine [FTC]/tenofovir disoproxil fumarate [TDF]) of the Phase 3 trial TMC114FD2HTX3001 (AMBER) in treatment-naïve subjects over 48 weeks. The safety results of the AMBER trial were generally similar to the results in trial GS-US-216-0130.

Adverse drug reactions in trials with darunavir/ritonavir 800/100 mg q.d.

Adverse drug reactions Grade 2-4 reported in the ARTEMIS trial (192 weeks) using darunavir/ritonavir 800/100 mg q.d. and considered ADRs to Prezcobix are presented in Table 4.
Laboratory abnormalities, Grade 2-4, in the ARTEMIS trial (192 weeks) using darunavir/ritonavir 800 mg/100 q.d. and considered ADRs to Prezcobix are shown in Table 5.
Additional ADRs of at least moderate intensity, reported in clinical trials with darunavir/ritonavir were gynecomastia and abdominal distension.

Post-marketing data.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported during postmarketing experience. The frequencies are provided according to the following convention: Very common ≥ 1/10, Common ≥ 1/100 and < 1/10, Uncommon ≥ 1/1000 and < 1/100, Rare ≥ 1/10,000 and < 1/1000, Very rare < 1/10,000 including isolated reports.
In Table 6, adverse reactions are presented by frequency category based on spontaneous reporting rates.

Effects of combination antiretroviral therapy.

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (immune reconstitution inflammatory syndrome). Autoimmune disorders such as Graves' disease and autoimmune hepatitis have also been reported in the context of immune reconstitution inflammatory syndrome (see Section 4.4 Special Warnings and Precautions for Use).
There have been reports of increased spontaneous bleeding in haemophilia patients receiving PIs.
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of HIV protease inhibitors, particularly in combination with NRTIs.

Special populations.

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

Limited information is available on the use of Prezcobix in patients co-infected with hepatitis B and/or C virus. In patients co-infected with hepatitis B or C virus receiving darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in patients receiving darunavir/ritonavir who were not co-infected, except for increased hepatic enzymes. The pharmacokinetic exposure with darunavir/ritonavir in co-infected patients was comparable to that in patients without co-infection.

Reporting suspected adverse reactions.

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.

4.9 Overdose

Human experience of acute overdose with Prezcobix is limited. Single doses up to 3200 mg of the oral solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
Limited clinical experience with cobicistat is available at doses higher than the therapeutic dose. 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.

Management of overdosage.

There is no specific antidote for overdose with Prezcobix. Treatment of overdose with Prezcobix consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
Since darunavir and cobicistat are highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substances.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for systemic use, Antivirals for treatment of HIV infection, Combinations - ATC code: J05AR22.

Mechanism of action.

Darunavir.

Darunavir is an inhibitor of the dimerization and of the catalytic activity of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the formation of mature infectious virus particles.
Darunavir tightly binds to the HIV-1 protease with a KD of 4.5 x 10-12 M.
Darunavir shows resilience to the effects of HIV protease inhibitors Resistance-Associated Mutations (RAMs).
Darunavir is not an inhibitor of any of 13 tested human cellular proteases.

Cobicistat.

Cobicistat is a mechanism based inhibitor of the CYP3A subfamily. Inhibition of CYP3A mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as darunavir, where bioavailability is limited and half-life is shortened by CYP3A dependent metabolism.

Pharmacodynamic effects.

Microbiology.

Antiviral activity in vitro.

Darunavir.

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nanoM (0.7 to 5.0 nanogram/mL). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nanoM.
These EC50 values are well below the 50% cellular toxicity concentration range of 87 microM to > 100 microM.
The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum in vitro.
Darunavir showed synergistic antiviral activity when studied in combination with the HIV protease inhibitors amprenavir, nelfinavir, or ritonavir and additive antiviral activity when studied in combination with the protease inhibitors atazanavir, indinavir, lopinavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, efavirenz, etravirine, rilpivirine, or nevirapine, and the fusion inhibitor enfuvirtide. No antagonism was observed between darunavir and any of those antiretrovirals.

Cobicistat.

Cobicistat has no detectable antiviral activity in cell culture against HIV-1 and does not antagonize the antiviral activity of darunavir.
Resistance in vitro.

Darunavir.

In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 400 nanoM. Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene.
The decreased susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained by the emergence of these protease mutations.
In vitro selection of darunavir-resistant HIV-1 (range: 53-641-fold change [FC] in EC50 values) from 9 HIV-1 strains harbouring multiple PI RAMs resulted in the overall emergence of 22 mutations in the protease, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V and I84V were present in more than 50% of the 9 darunavir-resistant isolates.
A minimum of 8 of these darunavir in vitro selected mutations, from which at least 2 were already present in the protease prior to selection, were required in the HIV-1 protease to render a virus resistant (FC > 10) to darunavir.
In 1113 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir and in 886 baseline isolates from treatment-experienced patients only the subgroups with > 10 PI RAMs showed a median FC for darunavir > 10.
Cross-resistance in vitro. Cross-resistance has been observed among HIV protease inhibitors. Darunavir has a < 10-fold decreased susceptibility against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir.
Seven of the 9 darunavir-resistant viruses selected from PI-resistant viruses had phenotypic data for tipranavir. Six of those showed a FC < 3 for tipranavir, indicative of limited cross-resistance between these 2 protease inhibitors.
Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors, the entry inhibitors or the integrase inhibitors, is unlikely because the viral targets for those inhibitors are different.
Selection of viral resistance in vivo. The resistance profile of Prezcobix is driven by darunavir. Cobicistat does not select any HIV resistance mutations, due to its lack of antiviral activity. The resistance profile of Prezcobix is supported by the analysis of 24 week data from trial GS-US-216-0130 in treatment-naïve and treatment-experienced patients and two Phase 3 trials conducted with darunavir/ritonavir in treatment-naïve and treatment-experienced patients, respectively.
Selection of viral resistance during Prezcobix therapy in vivo. In the 24 week analysis of the GS-US-216-0130 trial, no PI or NRTI RAMs developed in the treatment-naïve patients. One treatment-experienced patient developed a DRV RAM. This mutation was not associated with a decreased susceptibility to darunavir. One treatment-experienced patient developed an NRTI RAM, which was not associated with a decreased susceptibility to the NRTIs included in the background regimen.
Selection of viral resistance during darunavir/ritonavir 800/100 mg q.d. therapy in vivo. In the 192 week analysis of the ARTEMIS trial, the proportion of virologic failures was lower in the group of patients receiving darunavir/ritonavir 800/100 mg q.d. than in patients receiving lopinavir/ritonavir 800/200 mg per day (16.0% vs. 20.5%, respectively). In the virologic failures of the darunavir/ritonavir group, 4 patients with developing PI RAMs were identified. In the virologic failures of the lopinavir/rtv group, 9 patients with developing PI RAMs were identified. None of the developing mutations in the darunavir/ritonavir group or in the lopinavir/rtv group were primary (i.e. major) PI mutations. In 4 virologic failures of the darunavir/ritonavir group and 7 virologic failures of the lopinavir/rtv group, a maximum of 2 developing NRTI RAMs were identified. The development of the NRTI RAM at position 184 (n=9) was associated with a decreased susceptibility to FTC included in the background regimen.
In the 48 week analysis of the ODIN trial the proportion of virologic failures was comparable in the darunavir/ritonavir 800/100 mg q.d. group and the darunavir/ritonavir 600/100 mg b.i.d. group (22.1% vs. 18.2%, respectively). In the virologic failures in the darunavir/ritonavir 800/100 mg q.d. group 7 subjects (12%) with developing PI RAMs were identified, compared to 4 subjects (10%) in the darunavir/ritonavir 600/100 mg b.i.d. group. One virologic failure subject in the darunavir/ritonavir 800/100 mg q.d. group developed primary (i.e. major) PI mutations, which included 3 DRV RAMs, resulting in decreased susceptibility to darunavir. All the virologic failures from the darunavir/ritonavir 600/100 mg b.i.d. group retained susceptibility to darunavir. Four (6.7%) and 3 (7.1%) virologic failures developed 1 or 2 NRTI RAMs in the darunavir/ritonavir 800/100 mg q.d. and the darunavir/ritonavir 600/100 mg b.i.d. groups, respectively. In 3 and 2 of these virologic failures in the darunavir/ritonavir 800/100 mg q.d. and the darunavir/ritonavir 600/100 mg b.i.d. groups, respectively, the development of these NRTI RAMs was associated with a decreased susceptibility to a NRTI included in the treatment regimen.
Cross-resistance with other HIV protease inhibitors in vivo. In the virologic failures of the GS-US-216-130 trial no cross-resistance with other PIs was observed.
In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.
Of the viruses isolated from subjects receiving darunavir/ritonavir 800/100 mg q.d. experiencing virologic failure in the ODIN trial, 98% remained susceptible to darunavir after treatment. In the same group of subjects, 96% to 100% that were susceptible at baseline to amprenavir, atazanavir, indinavir, lopinavir, saquinavir or tipranavir remained susceptible to these protease inhibitors after treatment. In the virologic failures receiving darunavir/rtv 600/100 mg b.i.d. no cross-resistance with other PIs was observed.

Effects on electrocardiogram.

Darunavir.

In a four-way crossover trial, 40 healthy subjects were administered supratherapeutic doses of darunavir 1600 mg and ritonavir 100 mg once daily and darunavir 800 mg and ritonavir 100 mg twice daily (approximately 2 times the recommended darunavir dose) for seven days. When evaluating the 2-sided 90% CI on the time-matched mean changes in QTcF versus placebo, the upper bounds of both darunavir co-administered with ritonavir groups never exceeded the 10 msec boundary.

Cobicistat.

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

Effects on serum creatinine.

The effect of cobicistat on serum creatinine was investigated in a Phase 1 study in subjects with normal renal function (eGFR ≥ 80 mL/min, N=12) and mild to moderate renal impairment (eGFR 50-79 mL/min, N=18). A statistically significant change of estimated glomerular filtration rate calculated by Cockcroft-Gault method (eGFRCG) from baseline was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (9.9 ± 13.1 mL/min) and mild to moderate renal impairment (11.9 ± 7.0 mL/min).
These decreases in eGFRCG were reversible after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of cobicistat among subjects with normal renal function and mild to moderate renal impairment, indicating cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate.

Clinical trials.

The antiretroviral effect of Prezcobix is due to the darunavir component. The activity of cobicistat as a pharmacokinetic enhancer to darunavir has been demonstrated in pharmacokinetic studies. In these pharmacokinetic studies, the exposure of darunavir 800 mg boosted with cobicistat 150 mg was consistent with that observed when boosted with ritonavir 100 mg. Darunavir as a component of Prezcobix is bioequivalent to darunavir 800 mg once daily in combination with cobicistat 150 mg once daily co-administered as single agents (see Section 5.2 Pharmacokinetic Properties).
The evidence of efficacy of Prezcobix once daily is based on the analysis of 24 week data from study GS-US-216-0130 in treatment-naïve and treatment-experienced patients and two Phase 3 trials ARTEMIS and ODIN conducted with darunavir/ritonavir 800/100 mg q.d. in treatment-naïve and treatment-experienced patients, respectively.
Description of clinical study of darunavir/cobicistat 800/150 mg q.d. in adults.

Efficacy of darunavir 800 mg once daily co-administered with 150 mg cobicistat once daily in treatment-naïve and treatment-experienced patients.

GS-US-216-0130 is a single arm, open-label, Phase 3 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of darunavir with cobicistat in 313 HIV-1 infected adult patients (295 treatment-naïve and 18 treatment-experienced). These patients received darunavir 800 mg once daily in combination with cobicistat 150 mg once daily with an investigator selected background regimen consisting of 2 active NRTIs.
HIV-1 infected patients who were eligible for this trial had a screening genotype showing no darunavir RAMs and plasma HIV-1 RNA ≥ 1000 copies/mL. Virologic response was defined as confirmed plasma HIV-1 RNA viral load < 50 copies/mL using the TLOVR analysis.
The 313 patients in total had a median age of 35 years (range 18-72), 89.1% were male, 59.7% white, 34.5% black, 21.7% Hispanic, and 1.3% Asian. The mean baseline plasma HIV-1 RNA and the median baseline CD4+ cell count were 4.8 log10 copies/mL, 370 x 106 cells/L (range 6 - 1473 x 106 cells/L) and 4.8 log10 copies/mL, 107 x 106 cells/L (range 5 - 643 x 106 cells/L) for the treatment-naïve and treatment-experienced patients respectively.
Table 7 shows the efficacy data of the 24 week analyses from the GS-US-216-0130 trial.

Efficacy of darunavir/cobicistat fixed-dose combination 800/150 mg once daily in treatment-naïve patients.

TMC114FD2HTX3001 (AMBER) is a randomized, active-controlled, double blind, Phase 3 trial to evaluate the efficacy and safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide versus darunavir/cobicistat fixed-dose combination + emtricitabine/tenofovir disoproxil fumarate.
HIV-1 infected patients who were eligible for this trial had a plasma HIV-1 RNA ≥ 1,000 copies/mL. Table 8 shows the 48-week efficacy data of the AMBER trial:
The virological response (< 50 copies/mL) at 48 weeks by baseline viral load and baseline CD4+ cell count is presented in Table 9:
Description of clinical studies of darunavir/ritonavir 800/100 mg q.d. in adults.

Efficacy of darunavir/ritonavir 800/100 mg q.d in treatment-naïve adult patients.

The evidence of efficacy of darunavir/ritonavir 800/100 mg q.d. is based on the analyses of 192 week data from the randomized, controlled, open label Phase 3 trial ARTEMIS in antiretroviral treatment-naïve HIV-1 infected patients comparing darunavir/ritonavir 800/100 mg q.d. with lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg q.d. (TDF) and emtricitabine 200 mg q.d. (FTC).
HIV-1 infected patients who were eligible for this trial had plasma HIV-1 RNA > 5000 copies/mL. Randomizations was stratified by screening plasma viral load and screening CD4+ cell count. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load < 50 copies/mL.
Demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the lopinavir/ritonavir arm. The 343 patients on darunavir/ritonavir 800/100 mg q.d. had a median age of 34 years (range 18-70), 70% were male, 40% white, 23% black, 23% Hispanic, and 13% Asian. The mean baseline plasma HIV-1 RNA was 4.86 log10 copies/mL and the median baseline CD4+ cell count was 228 x 106 cells/L (range 4 - 750 x 106 cells/L).
Table 10 shows the efficacy data of the 48 week and 192 week analyses from the ARTEMIS trial:
In the 48 week analysis, the virologic response (HIV-1 RNA < 50 copies/mL) for the darunavir/ritonavir arm was 83.7% and for the lopinavir/rtv arm 78.3%. Statistical comparisons between the treatment arms at Week 48 confirmed non-inferiority of darunavir/ritonavir versus lopinavir/rtv (p-value < 0.001) for both ITT (Intent-To-Treat) and OP (On Protocol) population.
Analyses of data at 192 weeks of treatment in the ARTEMIS trial demonstrated sustained antiretroviral efficacy and immunological benefit of the darunavir/ritonavir arm. In the 192 week analysis, virologic response (HIV-1 RNA < 50 copies/mL) was 68.8% and 57.2% for the darunavir/ritonavir and lopinavir/ritonavir arm, respectively. Non-inferiority in virologic response was demonstrated (p < 0.001) for both ITT and OP population. Furthermore, statistical superiority of the darunavir/ritonavir arm over the lopinavir/ritonavir arm was demonstrated (p=0.002) for both ITT and OP population.
The virological response (< 50 copies/mL) at 192 weeks by baseline viral load and baseline CD4+ cell count is presented in Table 11:

Efficacy of darunavir/ritonavir 800/100 mg q.d. in treatment-experienced adult patients.

The evidence of comparable efficacy of darunavir/ritonavir 800/100 mg q.d. and darunavir/ritonavir 600/100 mg b.i.d. in treatment-experienced patients with no darunavir RAMs is based on the 48 week analysis of the Phase 3 trial ODIN.
ODIN is a randomized, open-label trial comparing darunavir/ritonavir 800/100 mg q.d. to darunavir/ritonavir 600/100 mg b.i.d. in treatment-experienced HIV-1 infected patients with screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a viral load of > 1000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of ≥ 2 NRTIs selected by the investigator.
Demographics and baseline characteristics were balanced between the darunavir/ritonavir q.d. arm and the darunavir/ritonavir b.i.d. arm. The 590 patients in total had a median age of 40 years (range 18-77), 64% were male, 36% white, 26% black, 18% Hispanic, and 15% Asian. The mean baseline plasma HIV-1 RNA was 4.16 log10 copies/mL and the median baseline CD4+ cell count was 228 x 106 cells/L (range 24 - 1306 x 106 cells/L).
Table 12 shows the efficacy data of the 48 week analysis from the ODIN trial:
In the 48 week analysis, the virologic response defined as a confirmed plasma HIV-1 RNA viral load < 50 copies/mL, was 72.1% for the darunavir/ritonavir q.d. arm and 70.9% for the darunavir/ritonavir b.i.d. arm. Statistical comparisons between the treatment arms at Week 48 confirmed non-inferiority of darunavir/ritonavir q.d. versus darunavir/rtv b.i.d. for both the ITT and OP population (p-value < 0.001).

5.2 Pharmacokinetic Properties

Darunavir steady state exposure was shown to be comparable between Prezcobix and darunavir/ritonavir 800/100 mg q.d. in a bioavailability study in fed conditions in healthy subjects.
Bioequivalence between Prezcobix and darunavir/cobicistat 800/150 mg co-administered as single agents was established under fed and fasted conditions in healthy subjects (TMC114IFD1001).

Absorption.

The absolute oral bioavailability of darunavir alone is approximately 37%.
Darunavir was rapidly absorbed following oral administration of Prezcobix in healthy volunteers. The maximum plasma concentration of darunavir in the presence of cobicistat is generally achieved within 3 to 4.5 hours. Following oral administration of Prezcobix in healthy volunteers, maximum plasma concentrations of cobicistat were observed 2 to 5 hours post-dose for cobicistat.
When administered with food, the relative exposure of darunavir is 1.7-fold higher as compared to intake without food. Therefore, Prezcobix should be taken with food. The type of food does not affect exposure to Prezcobix.

Distribution.

Darunavir.

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha-1-acid glycoprotein.

Cobicistat.

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

Metabolism.

Darunavir.

In vitro experiments with human liver microsomes indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by the hepatic CYP system and almost exclusively by isozyme CYP3A. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir/ritonavir dose was due to the parent drug. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild type HIV.

Cobicistat.

Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.

Excretion.

Darunavir.

After a 400/100 mg 14C-darunavir/ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 L/h and 5.9 L/h, respectively.
The terminal elimination half-life of darunavir was approximately 11 hours when combined with cobicistat.

Cobicistat.

Following oral administration of 14C-cobicistat, 86% and 8.2% of the dose were recovered in faeces and urine, respectively. The median terminal elimination half-life of cobicistat following administration of cobicistat is approximately 3-4 hours.

Special populations.

Paediatrics. The pharmacokinetics of Prezcobix in paediatric patients have not been investigated.
Elderly.

Darunavir.

Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not different in the age range (18 to 75 years) evaluated in HIV infected patients (see Section 4.4 Special Warnings and Precautions for Use).

Cobicistat.

Pharmacokinetics of cobicistat have not been fully evaluated in the elderly (65 years of age and older).
Renal impairment. Prezcobix has not been investigated in patients with renal impairment.

Darunavir.

Results from a mass balance study with 14C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 mL/min, n=20) (see Section 4.4 Special Warnings and Precautions for Use).

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.
Hepatic impairment. Prezcobix has not been investigated in patients with hepatic impairment.

Darunavir.

Darunavir is primarily metabolised and eliminated by the liver. In a multiple-dose study with darunavir co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the steady-state pharmacokinetic parameters of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Cobicistat.

Cobicistat is primarily metabolized 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 moderate impairment and healthy subjects. No dosage adjustment of cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.
Hepatitis B and/or hepatitis C virus co-infection. There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of Prezcobix.
In HIV-infected subjects taking darunavir co-administered with ritonavir, the 48 week analysis of the data from clinical studies in HIV-1 infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.
Pregnancy and postpartum. The exposure to total darunavir boosted with cobicistat after intake of Prezcobix as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6-12 weeks postpartum (see Table 13). The decrease in unbound (i.e. active) darunavir pharmacokinetic parameters (Cmax and AUC24h) during pregnancy compared to postpartum was less pronounced than for total darunavir.
In women receiving Prezcobix during the 2nd trimester of pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared with postpartum; during the 3rd trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with postpartum.

5.3 Preclinical Safety Data

Genotoxicity.

Darunavir.

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.

Cobicistat.

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

Carcinogenicity.

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).

Toxicology.

Darunavir.

Animal toxicology studies have been conducted with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In chronic toxicology studies in rats and dogs, there were only limited effects of treatment with darunavir. In the rat the key target organs identified were the haematopoietic system, the blood coagulation system, liver and thyroid, observed at 100 mg/kg/day and above and at exposures below clinical levels. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated PTT. The observed liver and thyroid changes were considered to reflect an adaptive response to enzyme induction in the rat rather than an adverse effect. In combination toxicity studies with ritonavir, no additional target organs of toxicity were reported in rats. In the dog, no major toxicity findings or key target organs were identified at doses up to 120 mg/kg/day and exposures equivalent to clinical exposure at the recommended dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hypromellose, silicon dioxide, microcrystalline cellulose, crospovidone, magnesium stearate; Opadry II complete film coating system 85F140053 Pink (ARTG PI No. 109886) as the tablet film coating.

6.2 Incompatibilities

Not applicable.

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 30°C. Keep out of the sight and reach of children. Store in the original packaging to protect from moisture.

6.5 Nature and Contents of Container

Prezcobix 800/150 mg film-coated tablets are provided in high density polyethylene (HDPE) plastic bottles containing 30 tablets, fitted with polypropylene (PP) child resistant closures.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Darunavir.

The chemical name for darunavir is [(1S,2R)-3-[[(4-aminophenyl) sulfonyl](2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl ester.
Darunavir has the following structural formula:
It has an empirical formula of C27H37N3O7S and a molecular weight of 547.66.
Darunavir is isolated as darunavir ethanolate, a pseudo-polymorphic form of darunavir. Darunavir ethanolate is a white to off-white powder that is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol, and freely soluble in acetone and dichloromethane.

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.
Cobicistat has the following structural formula:
It has an empirical formula of C40H53N7O5S2 and a molecular weight of 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 (log p) for cobicistat is 4.3 and the pKa is 6.4.

CAS number.

Darunavir.

206361-99-1.

Cobicistat.

1004316-88-4.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine.

Summary Table of Changes