Consumer medicine information

Symtuza 800/150/200/10 Tablets

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide

BRAND INFORMATION

Brand name

Symtuza

Active ingredient

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Symtuza 800/150/200/10 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 SYMTUZA 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 SYMTUZA against the benefits this medicine is expected to have for you.

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

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

What SYMTUZA is used for

SYMTUZA is a single tablet regiment used to treat adults and adolescents 12 years of age and older who weigh at least 40 kg, who are infected by HIV (Human Immunodeficiency Virus).

SYMTUZA contains four active ingredients which work in combination for the treatment of HIV. These active ingredients are darunavir, cobicistat, emtricitabine and tenofovir alafenamide.

Darunavir, emtricitabine and tenofovir alafenamide are called antiretroviral medicines. Darunavir is medicine known as a protease inhibitor. Emtricitabine is a medicine known as a nucleoside reverse transcriptase inhibitor. Tenofovir alafenamide is a medicine known as a nucleotide reverse transcriptase inhibitor. Each of these three active ingredients work to reduce the amount of HIV in your body.

Cobicistat is a type of medicine called a pharmacokinetic enhancer (or "booster"). Cobicistat helps to increase the levels of darunavir 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.

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

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

Before you take SYMTUZA

When you must not use it:

Do not take SYMTUZA:

  • if you are allergic (hypersensitive) to darunavir, cobicistat, emtricitabine, tenofovir alafenamide or any of the other ingredients of SYMTUZA listed at the end 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 SYMTUZA:

  • 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 SYMTUZA after the expiry date it may not work.

SYMTUZA should not be given to children younger than 12 years of age or weighing less than 40 kg.

Do not combine SYMTUZA with any of the following medicines:

  • alfuzosin (to treat an enlarged prostate)
  • astemizole or terfenadine (to treat allergy symptoms)
  • amiodarone, bepridil, disopyramide, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine (to treat irregular heartbeats)
  • ivabradine or ranolazine (to treat heart disease)
  • apixaban (used to reduce blood clotting)
  • cisapride (to treat some stomach conditions)
  • colchicine (to treat gout) if you have renal/hepatic impairment
  • lovastatin, simvastatin or lomitapide (to lower cholesterol levels)
  • lurasidone or pimozide (to treat psychiatric conditions)
  • midazolam or triazolam (to treat trouble with sleeping and/or anxiety)
  • carbamazepine, phenobarbital, phenytoin (medicines to prevent seizures)
  • 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) which is a herbal supplement used for depression and anxiety
  • naloxegol (to treat constipation caused by taking opioids)
  • dapoxetine (to treat premature ejaculation)

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

Serious problems can happen if you take any of the medicines listed above with SYMTUZA.

In addition, you should also not take SYMTUZA with medicines that contain tenofovir disoproxil fumarate, lamivudine, or adefovir dipivoxil, or any anti-HIV medicines that have to be taken with ritonavir or cobicistat boosters.

This is 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 SYMTUZA (see Taking other medicines).

Before you start to use it:

Take special care with SYMTUZA:

SYMTUZA is not a cure for HIV infection.

SYMTUZA 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 SYMTUZA 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 SYMTUZA.

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

  • Problems with your liver, including hepatitis B and C.
    Your doctor may need to evaluate how severe your liver disease is before deciding if you can take SYMTUZA. If you have hepatitis B, liver problems may become worse after you stop taking SYMTUZA. It is important not to stop taking SYMTUZA without talking to your doctor first.
  • Diabetes.
    SYMTUZA, like some other anti-HIV medicines, might increase sugar levels in the blood.
  • Problems with your kidney.
    Your doctor should do blood and urine test before starting and during treatment with SYMTUZA. Your doctor may tell you to stop taking SYMTUZA if you develop new or worse kidney problems.
  • 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 SYMTUZA 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 SYMTUZA.

Taking other medicines:

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

  • Tell your doctor if you are taking any of the following: alfuzosin, amiodarone, apixaban, astemizole, bepridil, carbamazepine, cisapride, colchicine, dapoxetine, disopyramide, dronedarone, elbasvir/grazoprevir, ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine), flecainide, ivabradine, lidocaine (systemic), lomitapide, lovastatin, lurasidone, mexiletine, midazolam, naloxegol, phenobarbital, phenytoin, pimozide, propafenone, quinidine, ranolazine, rifampin, sildenafil, simvastatin, products that contain St John's wort (Hypericum perforatum), terfenadine or triazolam. You must not take these medicines while taking SYMTUZA.
  • If you take SYMTUZA with some other medicines, the effects of SYMTUZA 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. SYMTUZA might reduce the effectiveness of hormonal contraceptives and/or increase their side effects. Therefore, alternative methods of non-hormonal 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 etexilate, edoxaban, rivaroxaban, warfarin) or to prevent blood clots (ticagrelor, clopidogrel).
    - medicines to lower cholesterol levels (atorvastatin, pitavastatin, pravastatin, rosuvastatin).
    - medicines for your immune system (cyclosporin, everolimus, tacrolimus, sirolimus). Your doctor might want to do some additional tests.
    - medicines to control asthma (budesonide, fluticasone, salmeterol).
    - corticosteroids (prednisone, dexamethasone, betamethasone, mometasone, 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 (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 SYMTUZA.
    - medicines for erectile dysfunction (avanafil, vardenafil, sildenafil, tadalafil)
    - medicines to treat depression and anxiety (amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone)
    - sedatives (buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem)
    - medicines to treat psychiatric conditions (perphenazine, quetiapine, risperidone, thioridazine)
    - medicines to prevent seizures (oxcarbazepine, clonazepam)
    - medicines to treat excessive sleepiness (armodafinil, modafinil)

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

Taking SYMTUZA

Always use SYMTUZA 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 SYMTUZA available so that you don't run out. For example, in case you cannot return home, need to travel or stay in a hospital. This is very important because the amount of virus may start to increase if the medicine is stopped for even a short time.

How much SYMTUZA to take:

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

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

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

Instructions:

  • Take SYMTUZA with food.
  • Swallow the tablets with a drink such as water, milk, or any other nutritional drink.
  • Take SYMTUZA at approximately the same time each day.
  • If you are unable to swallow the whole tablet, tell your doctor. SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be taken with food immediately after splitting. Your doctor will determine whether SYMTUZA or its individual components are right for you.

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 SYMTUZA?

If you forget to take SYMTUZA

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.

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

If you think you or anybody else has taken too much SYMTUZA, 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 SYMTUZA

Things you must do:

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

If you have both HIV infection and hepatitis B, it is very important not to stop taking SYMTUZA without talking to your doctor first. You may require blood tests for several months after stopping SYMTUZA treatment. In some patients with advanced liver disease or cirrhosis, stopping SYMTUZA treatment may lead to worsening of hepatitis, which may be life-threatening.

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

  • Symptoms of infection.
    Tell your doctor immediately if you notice any symptoms of infection. In some patients with advanced HIV 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, enabling the body to fight infections that may have been present with no obvious symptoms.

HIV therapy may increase your sense of well being. Even when you feel better, do not stop taking SYMTUZA. 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 SYMTUZA. If you are undergoing anaesthesia, tell your anaesthetist that you are taking SYMTUZA.

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

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

Side Effects

Like all medicines, SYMTUZA 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 SYMTUZA.

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

The most common side effects are:

  • headache
  • abdominal pain, diarrhoea
  • rash (see information below)
  • fatigue

SYMTUZA 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 SYMTUZA. 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 SYMTUZA. Skin rash may affect more than 1 in 10 patients receiving SYMTUZA. Although most rashes are mild and disappear after a while when treatment is continued, a rash can occasionally be severe or potentially life-threatening. 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 SYMTUZA must be stopped.

Tell your doctor if you experience the following side effects:

  • upper abdominal pain that radiates into the back which may be due to inflammation of the pancreas
  • increased blood fat levels
  • diabetes
  • symptoms of infection

Like other anti-HIV medicines, SYMTUZA may cause serious side effects, including:

  • raised blood sugar and worsening of diabetes.
  • immune reactivation syndrome. In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started, including SYMTUZA.
  • muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been serious.
  • new or worsening of kidney problems.

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 SYMTUZA, 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

SYMTUZA tablets should be kept out of reach of children, in a location where the temperature stays below 30°C. Store in the original package with the dessicant inside the bottle in order to protect the tablets from moisture. Keep the bottle tightly closed.

What it looks like:

SYMTUZA 800/150/200/10 film-coated tablet: yellow to yellow-brownish capsule-shaped 2.2 x 1.1 cm tablet, debossed with “8121” on one side and “JG” on the opposite side.

Each plastic bottle contains 30 tablets.

Ingredients

Active ingredients:

  • darunavir 800 mg (as darunavir ethanolate)
  • cobicistat 150 mg (on silicon dioxide)
  • emtricitabine 200 mg
  • tenofovir alafenamide 10 mg (as tenofovir alafenamide fumarate)

Other ingredients:

  • croscarmellose sodium
  • magnesium stearate
  • microcrystalline cellulose
  • silicon dioxide
  • OPADRY II complete film coating system 85F120020 YELLOW (ARTG PI No. 114529)

Sponsor

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

Registration numbers

Registration number of SYMTUZA 800/150/200/10 film-coated tablets: AUST R 312623

This leaflet was prepared in 27 March 2023.

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

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Symtuza

Active ingredient

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide

Schedule

S4

 

1 Name of Medicine

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide.

2 Qualitative and Quantitative Composition

Symtuza 800/150/200/10 mg tablets contain 800 mg of darunavir (as 867 mg darunavir ethanolate), 150 mg of cobicistat (as 288.5 mg of cobicistat on silicon dioxide), 200 mg of emtricitabine and 10 mg of tenofovir alafenamide (as 11.2 mg tenofovir alafenamide fumarate).
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Symtuza is supplied as a 2.2 x 1.1 cm, yellow to yellowish brown, capsule-shaped, film-coated tablet, debossed with "8121" on one side and "JG" on the opposite side.

4 Clinical Particulars

4.1 Therapeutic Indications

Symtuza is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and adolescents (aged 12 years and older with body weight at least 40 kg). Genotypic testing should guide the use of Symtuza (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

4.2 Dose and Method of Administration

Dose in adults.

The recommended dose of Symtuza is one tablet taken once daily with food.

Dose in adolescents (12-17 years of age).

In adolescent patients aged 12 years and older weighing at least 40 kg, the recommended dosage is one tablet taken once daily with food. No dose has been established for Symtuza for paediatric patients 3-11 years of age or weighing less than 40 kg (see Section 5.2 Pharmacokinetic Properties, Special populations). Symtuza should not be used in paediatric patients below 3 years of age in view of toxicity observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age (see Section 5.3 Preclinical Safety Data).

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

Limited information is available on the use of Symtuza in patients aged 65 and over (see Section 5.2 Pharmacokinetic Properties, Special populations). Therefore, Symtuza should be used with caution in elderly patients.

Method of administration.

Symtuza should be administered orally once daily with food. The type of food does not affect the exposure to the components of Symtuza (see Section 5.2 Pharmacokinetic Properties, Absorption). Symtuza should be swallowed whole without breaking or crushing to ensure administration of the entire dose. For patients who are unable to swallow the whole tablet, Symtuza may be split into two pieces using a tablet-cutter, and the entire dose should be taken with food immediately after splitting.
If a dose of Symtuza is missed within 12 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of Symtuza with food as soon as possible. If a missed dose is noticed later than 12 hours after the time it is usually taken, it should not be taken and the patient should resume the usual dosing schedule.
After therapy with Symtuza has been initiated, patients should not alter the dosage or discontinue therapy without instruction of their healthcare provider. Separate pharmaceutical forms of the components of Symtuza are available, either alone or in combination products. Therefore, if patients are unable to swallow the Symtuza tablet, require a dose modification of any of the components of Symtuza, or discontinue treatment with Symtuza, alternatively, the pharmaceutical forms of the individual components may be used. Please refer to the respective product information for proper use of these products.

Dosage adjustment.

Hepatic insufficiency.

No dose adjustment of Symtuza is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Symtuza has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and there are only limited data regarding the use of Symtuza components in this population, therefore, specific dosage recommendations cannot be made. Symtuza should be used with caution in patients with severe hepatic impairment (see Section 5.2, Special populations).

Renal insufficiency.

Symtuza should not be initiated in patients who have an estimated glomerular filtration rate according to the Cockcroft-Gault formula for creatinine clearance (eGFRCG) below 30 mL/min (see Section 5.2, Special populations).
Symtuza should be discontinued in patients with eGFRCG that declines below 30 mL/min during treatment.
No dose adjustment of Symtuza is required in patients with an eGFRCG of 30 mL/min or above.

Pregnancy and postpartum.

Treatment with darunavir/cobicistat (two of the components of Symtuza) during pregnancy results in low darunavir exposure (see Section 5.2, Special populations). Therefore, therapy with Symtuza should not be initiated during pregnancy, and women who become pregnant during therapy with Symtuza should be switched to an alternative regimen (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Darunavir/ritonavir in combination with emtricitabine/tenofovir alafenamide may be considered as an alternative.

4.3 Contraindications

Hypersensitivity to darunavir, cobicistat, emtricitabine, tenofovir alafenamide, or to any of the excipients.
Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. Symtuza 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, antiarrhythmic drugs (e.g. amiodarone, bepridil, disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine), apixaban, astemizole, cisapride, colchicine (in patients with renal and/or hepatic impairment), dapoxetine, dronedarone, elbasvir/grazoprevir, ergot alkaloids (e.g. dihydroergotamine, ergotamine, ergonovine and methylergonovine), ivabradine, lomitapide, lovastatin, lurasidone, naloxegol, oral midazolam, pimozide, ranolazine, sildenafil (when used for treatment of pulmonary arterial hypertension), simvastatin, terfenadine and triazolam (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform. Co-administration of Symtuza with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance. Patients taking Symtuza should not use products containing potent CYP3A inducers such as carbamazepine, phenobarbital, phenytoin, rifampin, or St. John's wort.

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 to prevent transmission should be taken.

Patients with HIV-1 harbouring mutations.

Symtuza should not be used in experienced patients who are:
virologically failing and harbor any mutations associated with resistance to the antiretroviral components of Symtuza;
virologically suppressed and have any known or suspected mutations associated with resistance to the antiretroviral components of Symtuza (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects).

Patients co-infected with HIV and hepatitis B (HBV) or C (HCV) virus.

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
The safety and efficacy of Symtuza in patients co-infected with HIV-1 and HBV and/or HCV have not been established.
Discontinuation of Symtuza therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis (see Section 5.1 Pharmacodynamic Properties, Mechanism of action for emtricitabine and tenofovir alafenamide). Patients co-infected with HIV and HBV who discontinue Symtuza should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-HBV therapy may be warranted. In patients with advanced liver disease or cirrhosis, discontinuation of anti-HBV therapy is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Symtuza should not be administered concomitantly with medicinal products containing tenofovir disoproxil (e.g. fumarate, phosphate, or succinate), lamivudine, or adefovir dipivoxil used for the treatment of HBV infection.

Hepatotoxicity.

In patients receiving darunavir, cases of drug induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) have been reported in 0.5% of patients. Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased risk for liver function abnormalities including severe hepatic adverse events.
Appropriate laboratory testing should be conducted prior to initiating therapy with Symtuza 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 Symtuza 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) should prompt consideration of interruption or discontinuation of Symtuza.

Severe skin reactions.

In patients receiving darunavir, severe skin reactions may occur. These include conditions accompanied with fever and/or elevations of transaminases (reported in 0.4% of patients). Rarely (< 0.1%) Stevens-Johnson Syndrome and very rarely (< 0.01%) toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported. Discontinue Symtuza 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.
Darunavir contains a sulfonamide moiety. Symtuza 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 initiation 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.

Hyperglycaemia/diabetes mellitus.

New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been reported in patients receiving antiretroviral therapy, including HIV PIs. In some of these patients 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 the development of diabetes mellitus or hyperglycaemia.
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)).

Effects on estimated creatinine clearance.

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function (see Section 5.1 Pharmacodynamic Properties, Effects on serum creatinine and the product information for cobicistat). This effect should be considered when Symtuza is co-administered with a drug that has dosing adjustment recommendations guided by estimated creatinine clearance.

Nephrotoxicity.

Post marketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide containing products; while most of these cases were characterised by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events.
Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including non-steroidal anti-inflammatory drugs, are at increased risk of developing renal-related adverse reactions.
Prior to or when initiating Symtuza, and during treatment with Symtuza on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue Symtuza in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
In the phase 3 clinical trials of Symtuza there were no cases of proximal renal tubulopathy, including Fanconi syndrome, reported in the Symtuza group through week 96.

Lactic acidosis/severe hepatomegaly with steatosis.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of Symtuza, and tenofovir disoproxil fumarate, another prodrug of tenofovir. Treatment with Symtuza should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). No cases of lactic acidosis were reported in phase 3 clinical trials.

Interactions with medicinal products.

Symtuza can cause and/or is subject to drug interactions which may be life-threatening or result in lack of efficacy, see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Co-administration of Symtuza 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).

Use in the elderly.

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

Paediatric use.

No dose has been established for Symtuza for paediatric patients 3-11 years of age or weighing less than 40 kg (see Section 5.2 Pharmacokinetic Properties, Special populations). Symtuza should not be used in paediatric patients below 3 years of age in view of toxicity observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age (see Section 5.3 Preclinical Safety Data).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interaction studies have been performed using Symtuza. Interactions that may occur with Symtuza are determined by interactions that have been identified with any of its components.

Darunavir and cobicistat.

Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6, and an inhibitor of P-glycoprotein (P-gp).
Cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the transporters P-gp, BCRP, MATE1, 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 Symtuza with 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). Co-administration of Symtuza 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.
Darunavir and cobicistat are metabolized by CYP3A. Drugs that induce CYP3A activity are expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and possible development of resistance (see Section 4.3 Contraindications). Co-administration of Symtuza and other medicinal products that inhibit CYP3A may increase plasma concentrations of darunavir and cobicistat.
Symtuza should not be administered concomitantly with medicinal products requiring pharmacokinetic enhancing with ritonavir or cobicistat.

Emtricitabine.

Emtricitabine (FTC) is not an inhibitor of human CYP450 enzymes. In vitro and clinical drug interaction studies have shown that the potential for CYP-mediated interactions involving FTC with other medicinal products is low.
FTC is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug interactions due to competition for renal excretion have been observed; however, co-administration of FTC with drugs that are eliminated by active tubular secretion may increase concentrations of FTC and/or the co-administered drug. Drugs that decrease renal function may increase concentrations of FTC.

Tenofovir alafenamide.

Tenofovir alafenamide (TAF) is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro. It is not an inhibitor or inducer of CYP3A in vivo.
TAF is a substrate of the efflux transporter P-gp. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of Symtuza and development of resistance. Co-administration of Symtuza with drugs that inhibit P-gp may increase the absorption and plasma concentration of TAF.
Expected interactions between Symtuza with potential concomitant drugs are listed in Table 1 and are based on studies conducted with the components of Symtuza, as individual agents or in combination, or are predicted interactions. It should be noted that the interaction profile of darunavir depends on whether ritonavir or cobicistat was used as pharmacokinetic enhancer; refer to the product information for darunavir for further information.
Symtuza is a complete antiretroviral treatment regimen. Therefore, information regarding drug interactions with other antiretroviral products is not provided.
The list of examples of drug-drug interactions is not comprehensive and therefore the product information of each drug that is co-administered with Symtuza 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No reproductive toxicity studies have been conducted with darunavir, cobicistat, emtricitabine and tenofovir alafenamide in combination.

Darunavir.

In a study conducted in rats, there were no effects on mating or fertility with DRV treatment up to 1000 mg/kg/day and exposure levels below (AUC 0.6-fold) of that in human at the clinically recommended 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 1.7-fold higher than human exposures at the recommended 150 mg daily dose.

Emtricitabine.

Reproductive studies were conducted in rats, mice, and rabbits. Animal studies did not indicate harmful effects of FTC with respect to fertility, pregnancy, fetal parameters, parturition, or postnatal development. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 40 times higher than human exposures at the recommended 200 mg daily dose.

Tenofovir alafenamide.

There were no effects on fertility, mating performance or early embryonic development when tenofovir alafenamide was administered to male rats at a dose up to 160 mg/kg/day, equivalent to 155 times the human dose based on body surface area comparisons, for 28 days prior to mating and to female rats for 14 days prior to mating through day seven of gestation.
(Category B2)
There are no human data on the use of Symtuza during pregnancy. Darunavir/cobicistat (800/150 mg once daily) 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, Special populations, Pregnancy and postpartum). 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. No pharmacokinetic data are available for emtricitabine and tenofovir alafenamide during pregnancy.
Therapy with Symtuza should not be initiated during pregnancy, and women who become pregnant during therapy with Symtuza should be switched to an alternative regimen (see Section 4.2 Dose and Method of Administration, Dosage adjustment, Pregnancy and postpartum). Darunavir/ritonavir in combination with emtricitabine/tenofovir alafenamide may be considered as an alternative.
At clinically relevant exposures, animal studies with Symtuza components do not indicate developmental or reproductive toxicity (see Section 5.3 Preclinical Safety Data, Toxicology).

Darunavir.

In a study conducted in rats with DRV treatment up to 1000 mg/kg/day and exposure levels below (AUC 0.6-fold) of that in human at the clinically recommended dose, there was no teratogenicity with DRV in rats and rabbits when treated alone, nor in mice when treated in combination with ritonavir. The exposure levels were lower than those with the recommended clinical dose in humans. In addition, rats treated with combination with ritonavir showed no teratogenicity with the increase in exposure levels which are higher than those with the recommended clinical dose in humans.

Cobicistat.

Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-foetal no observed adverse effects levels (NOAELs) in rats and rabbits were respectively 1.7 and 4.1 times higher than the exposure in humans at the recommended daily dose of 150 mg.

Emtricitabine.

No evidence of embryofoetal toxicity or teratogenicity was observed in mice or rabbits at respective emtricitabine exposures (AUC) of 40- and 7.3-fold the clinical exposure. Impaired weight gain observed in pregnant rabbits at doses resulting in emtricitabine exposures (AUC) at least 26 times the clinical exposure was not associated with any adverse foetal effects.

Tenofovir alafenamide.

Embryo‐foetal development studies have been performed in rats and rabbits which revealed no evidence of embryolethality, foetotoxicity or teratogenicity due to tenofovir alafenamide. The embryo-foetal NOAELs in rats and rabbits occurred at TAF exposures (AUC) similar to and 85 times higher than, respectively, the exposure in humans at the recommended daily dose.
 Emtricitabine is excreted in human milk. It is not known whether darunavir, cobicistat, or tenofovir alafenamide are excreted in human milk. Animal studies have demonstrated that darunavir, cobicistat, and tenofovir are excreted in milk.
There is insufficient information on the effects of cobicistat, emtricitabine, and tenofovir in newborns/infants, and children below 3 years of age should not be exposed to darunavir (see Section 5.3 Preclinical Safety Data, Toxicology, Juvenile toxicity). Therefore, Symtuza should not be used during breast-feeding.
In order to avoid transmission of HIV to the infant, HIV infected women should be instructed not to breast-feed.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Symtuza or its components on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of darunavir/cobicistat/emtricitabine/tenofovir alafenamide based on the comprehensive assessment of the available information. A causal relationship with darunavir/cobicistat/emtricitabine/tenofovir alafenamide 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 Symtuza is based on the week 48 data from two randomized, comparative phase 3 trials, TMC114FD2HTX3001 (AMBER) and TMC114 IFD3013 (EMERALD), and on all available clinical trial and post-marketing data of its components. The Week 96 safety profile of Symtuza is consistent with the Week 48 Symtuza safety profile. As Symtuza contains darunavir, cobicistat, emtricitabine, and tenofovir alafenamide, the adverse reactions associated with each of the individual compounds may be expected.

Adverse reactions in treatment-naïve adults.

The safety profile of Symtuza in treatment-naïve HIV-1 infected adults is based on week 48 data from a randomized, double-blind, active-controlled trial TMC114FD2HTX3001 (AMBER) where a total of 362 subjects received Symtuza once daily and 363 subjects received a combination of fixed-dose combination of darunavir and cobicistat and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (F/TDF). Adverse reactions (≥ Grade 2 severity) reported in AMBER are shown in Table 2.
The median exposure in patients treated with Symtuza was 96.1 weeks. The majority of the adverse reactions reported during treatment with Symtuza were mild in severity. The most frequent (≥ 2%) adverse reactions (≥ Grade 2 severity) to Symtuza were diarrhea, rash and headache. No Grade 4 adverse reactions were reported. 2.2% of the patients discontinued treatment due to adverse reactions.
Laboratory abnormalities (≥ Grade 2 severity), reported in AMBER and considered adverse reactions are shown in Table 3.

Adverse reactions in virologically-suppressed adults.

The safety profile of Symtuza in virologically-suppressed HIV-1 infected adults is based on week 48 data from 1141 subjects in a randomized, open-label, active-controlled trial, TMC114IFD3013 (EMERALD), in which 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with emtricitabine and tenofovir disoproxil fumarate switched to Symtuza, and 378 subjects continued their treatment regimen of a boosted protease inhibitor with emtricitabine and tenofovir disoproxil fumarate. Overall, the safety profile of Symtuza in subjects in this study was similar to that in treatment naïve-subjects. The median exposure in patients treated with Symtuza was 96.1 weeks. The most frequent (≥ 2%) adverse reactions (≥ Grade 2 severity) to Symtuza were diarrhea, headache, and abdominal pain. One Grade 4 adverse reaction was reported (diabetes mellitus). The proportion of subjects who discontinued treatment with Symtuza due to adverse reactions, regardless of severity, was 0.5%. Adverse reactions (≥ Grade 2 severity) reported in EMERALD are shown in Table 4.
Laboratory abnormalities (≥ Grade 2 severity), reported in EMERALD and considered adverse reactions are shown in Table 5.
The following additional adverse reactions have been observed in darunavir trials:

Hepatobiliary disorders.

Acute hepatitis.

Immune system disorders.

Immune reconstitution inflammatory syndrome.

Reproductive system and breast disorders.

Gynecomastia.

Skin and subcutaneous tissue disorders.

Stevens-Johnson syndrome.

Post-marketing data.

In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported for Symtuza components during post-marketing experience (Table 6). Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the table, the frequencies are provided according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), and very rare (< 1/10,000, including isolated reports). See Section 4.4 Special Warnings and Precautions for Use.

Description of selected adverse reactions.

Rash.

Rash is a common adverse reaction in patients treated with darunavir. Rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. In the phase 3 trial investigating Symtuza as a single tablet regimen in treatment-naïve patients, 13% of patients receiving Symtuza (N = 362) experienced rash (most of which were grade 1), of which 1.7% of patients discontinued treatment due to rash.

Decrease estimated creatinine clearance.

Cobicistat increases serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function as assessed, for instance, by using Cystatin C (Cyst C) as filtration marker.
In the phase 3 trial of Symtuza in treatment-naïve patients, increases in serum creatinine and decreases in eGFRCG occurred at the first on-treatment assessment (week 2) and remained stable through 96 weeks. At week 48, changes from baseline were smaller with darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) than with darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (D+C+F/TDF). The median change in eGFRCG was -5.5 mL/min with D/C/F/TAF and -12 mL/min with D/C+F/TDF (p = < 0.001). Using Cyst C as filtration marker, the median changes in estimated glomerular filtration rate calculated using the CKD-EPI (eGFRCKD-EPI Cyst C) formula were respectively 4.0 mL/min/1.73 m2 and 1.6 mL/min/1.73 m2 (p = 0.001). At Week 96, the median change in eGFRCG was -5.2 mL/min with D/C/F/TAF. Using Cyst C as filtration marker, the median change in estimated glomerular filtration rate calculated using the CKD-EPI (eGFRCKD-EPI Cyst C) formula (N=22) was +4.4 mL/min/1.73 m2 with D/C/F/TAF.

Special populations.

Paediatric patients.

The safety of Symtuza in paediatric patients has not been investigated. However, the safety of Symtuza components was evaluated through the clinical studies TMC114-C230 (N = 12) for darunavir with ritonavir and GS-US-292-0106 (N = 50) for a fixed-dose combination containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide. Data from these studies showed that the overall safety profile in adolescent patients aged 12 to < 18 years and weighing at least 40 kg was similar to that observed in the adult population.

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

Limited information is available on the use of Symtuza components in patients co-infected with hepatitis B and/or C virus. In co-infected patients receiving darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in patients who were not co-infected, except for increased hepatic enzymes. The pharmacokinetic exposure in co-infected patients was comparable to that in patients without co-infection. The safety of emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet was evaluated in approximately 70 HIV/HBV co-infected patients receiving treatment for HIV in an open-label clinical study (GS-US-292-1249). Based on this limited experience, the safety profile of emtricitabine and tenofovir alafenamide in patients with HIV/HBV co-infection appears to be similar to that in patients with HIV-1 monoinfection.

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 Symtuza is limited. If overdose occurs, the patient must be monitored for evidence of toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).
There is no specific antidote for overdose with Symtuza. Treatment of overdose with Symtuza 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 bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Emtricitabine can be removed by hemodialysis, which removes approximately 30% of the dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.
For further information on the management of overdose, contact the Poison Information Centre on 131126 (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.

Symtuza consists of the HIV protease inhibitor darunavir (DRV), the pharmacokinetic enhancer cobicistat (COBI), the nucleoside reverse transcriptase inhibitor emtricitabine (FTC), and the nucleotide reverse transcriptase inhibitor tenofovir alafenamide (TAF).

Darunavir.

DRV 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. DRV tightly binds to the HIV-1 protease with a KD of 4.5 x 10-12 M. DRV shows resilience to the effects of HIV protease inhibitors resistance-associated mutations. DRV 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 DRV, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.

Emtricitabine.

FTC is a nucleoside analogue of 2'-deoxycytidine. FTC is phosphorylated by cellular enzymes to form FTC triphosphate. FTC triphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. FTC has activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus. FTC triphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there was no evidence of toxicity to mitochondria in vitro and in vivo.

Tenofovir alafenamide.

TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). TAF is permeable into cells and due to increased plasma stability and intracellular activation through hydrolysis by cathepsin A, TAF is more efficient than TDF in concentrating tenofovir in peripheral blood mononuclear cells (PBMCs) or HIV target cells including lymphocytes and macrophages. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir has activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus. In vitro studies have shown that both FTC and tenofovir can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses.

Pharmacodynamic effects.

Microbiology. Antiviral activity in vitro.

Darunavir.

DRV exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human PBMCs, and human monocytes/macrophages with median EC50 (50% effective concentration) values ranging from 1.2 to 8.5 nanoM (0.7 to 5.0 nanogram/mL). DRV 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 DRV increases by a median factor of 5.4 in the presence of human serum. DRV showed synergistic antiviral activity when studied in combination with the HIV PIs amprenavir, nelfinavir, or ritonavir, and additive antiviral activity when studied in combination with the PIs atazanavir, indinavir, lopinavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine, the NNRTIs delavirdine, efavirenz, etravirine, rilpivirine, or nevirapine, and the fusion inhibitor enfuvirtide. No antagonism was observed between DRV 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 DRV, FTC, or TAF.

Emtricitabine.

The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and PBMCs. The EC50 values for FTC were in the range of 0.0013 to 0.64 microM. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 microM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 microM). In two-drug combination studies of FTC with NRTIs (abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine), NNRTIs (delavirdine, efavirenz, nevirapine, and rilpivirine), PIs (amprenavir, nelfinavir, ritonavir, and saquinavir), and the integrase strand transfer inhibitor elvitegravir additive to synergistic effects were observed. No antagonism was observed for these combinations.

Tenofovir alafenamide.

The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T lymphocytes. The EC50 values for TAF were in the range of 2.0 to 14.7 nanoM. TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nanoM) and strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nanoM). In a study of TAF with a broad panel of representatives from the major classes of approved anti-HIV agents (NRTIs, NNRTIs, INSTIs, and PIs), additive to synergistic effects were observed. No antagonism was observed for these combinations.
Resistance in vitro.

Darunavir.

In vitro selection of DRV-resistant virus from wild-type HIV-1 was lengthy (> 3 years). The selected viruses were unable to grow in the presence of DRV concentrations above 400 nanoM. Viruses selected in these conditions and showing decreased susceptibility to DRV (range: 23- to 50-fold) harboured 2 to 4 amino acid mutations in the protease gene. The decreased susceptibility to DRV of the emerging viruses in the selection experiment could not be explained by the emergence of these protease mutations. In vitro selection of DRV-resistant HIV-1 (range: 53- to 641-fold change [FC] in EC50 values) from 9 HIV-1 strains harboring 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 DRV 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 DRV. 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.
In vivo, DRV RAMs (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) in HIV-1 protease were derived from clinical trial data of antiretroviral therapy experienced patients, which were all protease inhibitor experienced patients.

Cobicistat.

No in vitro resistance can be demonstrated due to its lack of antiviral activity.

Emtricitabine.

HIV-1 isolates with reduced susceptibility to FTC have been selected in cell culture. Reduced susceptibility to FTC was associated with M184V/I mutations in HIV-1 reverse transcriptase (RT).

Tenofovir alafenamide.

HIV-1 isolates with reduced susceptibility to TAF have been selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R mutation in HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed. HIV-1 isolates with the K65R mutation have low-level reduced susceptibility to abacavir, FTC, tenofovir, and lamivudine. In vitro drug resistance selection studies with TAF have shown no development of high-level resistance after extended culture.
Cross-resistance in vitro.

Darunavir.

Cross-resistance has been observed among HIV PIs. DRV 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 DRV. Cross-resistance between DRV and the N(t)RTIs, the NNRTIs, the fusion inhibitors, CCR5 co-receptors agonists, or the integrase inhibitors is unlikely because the viral targets for those inhibitors are different.

Emtricitabine.

FTC-resistant viruses with the M184V/I mutation were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine. Viruses harboring mutations conferring reduced susceptibility to stavudine and zidovudine - thymidine analogue-associated mutations - (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N mutation or other mutations associated with resistance to NNRTIs was susceptible to FTC.

Tenofovir alafenamide.

The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, FTC, and tenofovir, but retain sensitivity to zidovudine. Multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R showed reduced susceptibility to TAF. HIV-1 containing the K103N or Y181C mutations associated with resistance to NNRTIs were susceptible to TAF. HIV-1 containing mutations associated with resistance to PIs were susceptible to TAF.
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 ms 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.

Emtricitabine.

The effect of FTC on the QT interval is not known.

Tenofovir alafenamide.

In a thorough QT/QTc study in 48 healthy subjects, TAF at the therapeutic dose or at a supratherapeutic dose approximately 5 times the recommended therapeutic dose did not affect the QT/QTc interval and did not prolong the PR interval.
Effects on serum creatinine. The effect of cobicistat on serum creatinine was investigated in a phase 1 study in subjects with normal renal function (eGFRCG ≥ 80 mL/min, N = 12) and mild to moderate renal impairment (eGFRCG 50-79 mL/min, N = 18). A statistically significant change from baseline in eGFRCG 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.
An increase in serum creatinine due to cobicistat's inhibitory effect generally does not exceed 0.4 mg per dL from baseline.

Clinical trials.

The antiretroviral effect of Symtuza is due to the combined activity of darunavir, emtricitabine, and tenofovir alafenamide. The efficacy of Symtuza in HIV-1 treatment-naïve subjects and treatment-experienced subjects was evaluated in phase 3 trials.

Efficacy in adult patients.

HIV-1 treatment naïve patients. The efficacy of Symtuza in HIV-1 treatment-naïve subjects was evaluated in the phase 3 trial TMC114FD2HTX3001 (AMBER) in which subjects were randomized in a 1:1 ratio to receive either Symtuza (N = 362) or a combination fixed-dose combination of darunavir and cobicistat and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (F/TDF) (N = 363) once daily until the last subject had reached Week 48. After Week 48 the trial was unblinded, with all subjects entering the open-label, single-group treatment phase with continued D/C/F/TAF use in the D/C/F/TAF group and switch to D/C/F/TAF in the control group. The median age was 34.0 years (range 18-71), 88.3% were male, 83.2% White, 11.1% Black, and 1.5% Asian. The mean baseline plasma HIV-1 RNA and the median baseline CD4+ cell count were 4.48 log10 copies/mL (range 1.3-6.7, 17.9% had a baseline viral load ≥ 100,000 copies/mL) and 453.0 cells/mm3 (range 38 to 1456 cells/mm3), respectively. Virologic outcomes (ITT) reported in AMBER are shown in Table 7.

Changes in measures of bone mineral density.

In the phase 3 study TMC114FD2HTTX3001 in treatment-naïve patients, Symtuza was associated with no relevant changes in bone mineral density (BMD) compared to decreases in the control group (DRV/COBI+F/TDF) as measured by DXA analysis of hip (LS means percent change: 0.17% vs -2.69%, p < 0.001) and lumbar spine (LS means percent change: -0.68% vs -2.38%, p = 0.004) after 48 weeks of treatment. After 96 weeks of treatment with Symtuza, the LS means percent changes (95% CI) from baseline in BMD at the hip and spine region were respectively: -0.26 (-0.96; 0.45) % and -0.93 (-1.82; -0.05) %.
In the phase 3 study TMC114IFD3013 in treatment experienced patients, improvements in BMD were noted at 48 weeks after switching to Symtuza from a TDF-containing regimen compared to maintaining the TDF-containing regimen. After 96 weeks of treatment with Symtuza, further improvements in BMD were noted when compared to baseline.

Changes in measures of renal function.

In studies in treatment-naïve patients, Symtuza was associated with a lower impact on renal safety parameters (as measured after 48 weeks treatment by estimated glomerular filtration rate by Cockcroft-Gault method) compared to control group (DRV/COBI+F/TDF) (see Section 4.4 Special Warnings and Precautions for Use). In the Symtuza group, there was an improvement of proteinuria (as measured by urine protein to creatinine ratio and urine albumin to creatinine ratio) at week 48 vs. baseline as compared to the control group that used a tenofovir disoproxil fumarate (TDF) based regimen. Through 48 weeks of treatment, no subject discontinued Symtuza due to a treatment-emergent renal adverse event.
An improved renal safety profile was maintained through week 48 in subjects who switched to Symtuza compared with those who stayed on a TDF-containing regimen. In the phase 3 clinical trials of Symtuza including treatment-naïve and treatment-experienced subjects, there were no cases of proximal renal tubulopathy, including Fanconi syndrome, reported in the Symtuza group through week 96.
Clinical trial results in HIV-1 virologically-suppressed subjects who switched to Symtuza. Phase 3 trial TMC114IFD3013 (EMERALD) evaluated the efficacy of Symtuza in virologically-suppressed (HIV-1 RNA less than 50 copies/mL) HIV-1 infected subjects. Subjects were virologically suppressed for at least 2 months and no more than once had a viral load elevation above 50 HIV-1 RNA copies/mL during the year prior to enrollment. Patients were allowed in the study if they had previous failure on any non-darunavir ARV regimen. Patients had no history of virologic failure on darunavir-based regimens, and if historical genotypes were available, absence of darunavir RAMs. Subjects were on a stable antiretroviral regimen (for at least 6 months), consisting of a boosted protease inhibitor [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with emtricitabine and TDF. They either switched to Symtuza (N = 763) or continued their treatment regimen (N = 378) (randomized 2:1). Subjects had a median age of 46 years (range 19-78), 82% were male, 75.5% White, 20.9% Black, and 2.3% Asian. The median baseline CD4+ cell count was 628 x 106 cells/mm3 (range 111-1921 x 106 cells/mm3). Virologic outcomes (ITT) reported in EMERALD are shown in Table 8.

Efficacy in paediatric patients.

The efficacy of Symtuza in paediatric patients has not been investigated. However, the use of Symtuza in adolescent patients from the age of 12 years to < 18 years, and weighing at least 40 kg is supported by two clinical studies in HIV-1 infected paediatric patients: TMC114-C230 and GS-US-292-0106. (For more details, refer to the product information of darunavir and the fixed-dose combinations of emtricitabine/tenofovir alafenamide and elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.)
The open-label, phase 2 trial TMC114-C230 was conducted for evaluating the pharmacokinetics, safety, tolerability, and efficacy of darunavir with low dose ritonavir in 12 treatment-naïve HIV-1 infected paediatric patients aged 12 to less than 18 years and weighing at least 40 kg. These patients received darunavir/ritonavir 800/100 mg once daily in combination with other antiretroviral agents. Virologic response was defined as HIV-1 RNA < 50 copies/mL at week 48. Patients had a median age of 14.4 years (range: 12.6-17.3), and 66.7% were female, 58.3% were White, and 41.7% were Black. At baseline, median plasma HIV-1 RNA was 4.92 log10 copies/mL (range: 3.56-5.52), median CD4+ cell count was 282 x 106 cells/L (range: 204-515 x 106 cells/L), and median CD4+ % was 18.3% (range: 12.1-40.8%). Overall, 41.7% had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL. Table 9 shows the virologic outcomes of study TMC114-C230 at week 48. No emergent resistance to darunavir was detected through week 48.
In the open-label study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine and tenofovir alafenamide were evaluated in 50 HIV-1 infected, treatment-naïve adolescents receiving emtricitabine and tenofovir alafenamide (10 mg) together with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients had a median age of 15 years (range: 12-17), and 56% were female, 12% were Asian, and 88% were Black. At baseline, median plasma HIV-1 RNA was 4.7 log10 copies/mL (range: 3.25-6.50), median CD4+ cell count was 456 cells/mm3 (range: 95-1110), and median CD4+ % was 23% (range: 7-45%). Overall, 22% had baseline plasma HIV-1 RNA > 100,000 copies/mL. At 48 weeks, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL (FDA Snapshot), similar to response rates in studies of treatment-naïve HIV-1 infected adults. The mean increase from baseline in CD4+ cell count at week 48 was 224 cells/mm3. No emergent resistance to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide was detected through week 48.

In vivo selection of viral resistance during Symtuza therapy, treatment naïve or virologically suppressed patients.

Over 96 weeks of treatment in the phase 3 studies TMC114FD2HTX3001 (AMBER) in treatment naïve patients and TMC114IFD3013 (EMERALD) in virologically suppressed treatment experienced patients, resistance testing was performed on samples from patients experiencing protocol‑defined virologic failure (PDVF) and who had HIV-1 RNA ≥ 400 copies/mL at failure or at later time points. Emerging resistance in the Symtuza groups is shown in Table 10. No DRV, primary PI, or TDF/TAF resistance-associated mutations were observed.

In vivo cross-resistance in HIV-1 infected, treatment naïve or virologically suppressed patients.

The emtricitabine-resistant virus with the M184M/IV substitution was cross-resistant to lamivudine, but retained sensitivity to abacavir, stavudine, tenofovir, and zidovudine.
For more details on the clinical resistance profile of darunavir, boosted with ritonavir or cobicistat, and emtricitabine/tenofovir alafenamide please refer to the respective product information.

5.2 Pharmacokinetic Properties

The bioavailability of all components of Symtuza was comparable to that when DRV 800 mg, COBI 150 mg, and FTC/TAF 200/10 mg were co-administered as separate formulations; bioequivalence was established following single-dose administration under fed conditions in healthy subjects (N = 96). The bioavailability of the components of Symtuza was not affected when administered orally as a split tablet compared to administration as a tablet swallowed whole.

Absorption.

The absolute bioavailability of a single 600 mg dose of DRV alone was approximately 37% and increased to approximately 82% in the presence of ritonavir. The absolute bioavailability of the FTC 200 mg capsule was 93%.
All components were rapidly absorbed following oral administration of Symtuza in healthy subjects. Maximum plasma concentrations of DRV, COBI, FTC, and TAF were achieved at 4.00, 4.00, 2.00, and 1.50 hours after dosing, respectively.
The exposure (AUC) of DRV and COBI administered as Symtuza was 34% and 29% lower, respectively, in fasted condition compared to fed condition. For FTC and TAF, exposure was comparable in fed and fasted conditions. Therefore, Symtuza should be taken with food. The type of food does not affect exposure to Symtuza.

Distribution.

Darunavir.

DRV is approximately 95% bound to plasma proteins and 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.

Emtricitabine.

In vitro binding of FTC to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 microgram/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.

Tenofovir alafenamide.

In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01 to 25 microgram/mL. Ex-vivo binding of TAF to human plasma proteins in samples collected during clinical studies was approximately 80%. Distribution studies in dogs showed 5.7- to 15-fold higher 14C-radioactivity in lymphoid tissues (iliac, axillary, inguinal and mesenteric lymph nodes, and spleen) 24 hours following administration of an equivalent dose of 14C-TAF relative to 14C-TDF.

Metabolism.

Darunavir.

In vitro experiments with human liver microsomes indicate that DRV primarily undergoes oxidative metabolism. DRV 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 DRV/rtv dose was due to the parent drug. At least 3 oxidative metabolites of DRV have been identified in humans; all showed activity that was at least 10-fold less than the activity of DRV against wild-type HIV.

Cobicistat.

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

Emtricitabine.

Following administration of 14C-FTC, complete recovery of the FTC dose was achieved in urine (~86%) and faeces (~14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of FTC includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~4% of dose). No other metabolites were identifiable.

Tenofovir alafenamide.

Metabolism is a major elimination pathway for TAF in humans, accounting for > 80% of an oral dose. In vitro studies have shown that TAF is metabolized to tenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target cells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In human clinical studies, a 10 mg oral dose of TAF resulted in tenofovir diphosphate concentrations > 4-fold higher in PBMCs and > 90% lower concentrations of tenofovir in plasma as compared to a 300 mg oral dose of TDF. In vitro, TAF is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. TAF is minimally metabolized by CYP3A4. Upon co-administration with the moderate CYP3A inducer probe efavirenz, TAF exposure was not significantly affected.

Excretion.

Darunavir.

After a 400/100 mg 14C-DRV/rtv dose, approximately 79.5% and 13.9% of the administered dose could be retrieved in faeces and urine, respectively. Unchanged DRV accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine, respectively. The intravenous clearance of DRV 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 DRV is approximately 6 hours following administration of Symtuza.

Cobicistat.

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

Emtricitabine.

FTC is primarily excreted by the kidney, by both glomerular filtration and active tubular secretion. Following administration of Symtuza, the elimination half-life of FTC is approximately 17 hours.

Tenofovir alafenamide.

TAF is mainly eliminated following metabolism to tenofovir. The terminal elimination half-life of TAF is approximately 0.3 hours following administration of Symtuza. Tenofovir is eliminated from the body by the kidneys by both glomerular filtration and active tubular secretion. Tenofovir has a median plasma elimination half-life of approximately 32 hours. Renal excretion of intact TAF is a minor pathway with less than 1% of the dose eliminated in urine. The pharmacologically active metabolite, tenofovir diphosphate, has an elimination half-life of approximately 150-180 hours within PBMCs.

Special populations.

Paediatrics (17 years of age and younger). Symtuza has not been investigated in paediatric patients. However, available pharmacokinetic data for the different components of Symtuza indicate that doses of 800 mg darunavir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide result in similar exposures in adolescents aged 12 years and older, weighing at least 40 kg, and adults.

Darunavir.

A dosage of 800 mg once daily in paediatric patients weighing ≥ 40 kg resulted in darunavir exposure that was comparable to that achieved in adults receiving the same dose.

Cobicistat.

Exposures of cobicistat 150 mg achieved in paediatric patients aged 12 to < 18 years were similar to exposures achieved in treatment-naïve adults.

Emtricitabine and tenofovir alafenamide.

Exposures of FTC 200 mg and TAF 10 mg achieved in paediatric patients aged 12 to < 18 years were similar to exposures achieved in treatment-naïve adults.
Elderly (65 years of age and older). Population pharmacokinetic analysis in HIV infected patients showed that DRV pharmacokinetics are not different in the age range evaluated (18 to 75 years).
No clinically relevant pharmacokinetic differences due to age have been identified for cobicistat, emtricitabine, or tenofovir alafenamide.
Renal impairment. The pharmacokinetics of Symtuza have not been investigated in patients with renal impairment. However, there are data for the components of Symtuza.

Darunavir.

Results from a mass balance study with 14C-DRV/rtv showed that approximately 7.7% of the administered dose of DRV is excreted in the urine as unchanged drug. Although DRV has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of DRV were not significantly affected in HIV infected patients with moderate renal impairment (eGFRCG between 30-60 mL/min, N = 20).

Cobicistat.

A study of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with severe renal impairment (eGFRCG < 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.

Emtricitabine.

Mean systemic FTC exposure was higher in patients with severe renal impairment (eGFRCG < 30 mL/min) than in subjects with normal renal function.

Tenofovir alafenamide.

No clinically relevant differences in TAF or tenofovir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment (eGFRCG < 30 mL/min) in studies of TAF. There are no pharmacokinetic data on TAF in patients with eGFRCG < 15 mL/min.
Hepatic impairment. The pharmacokinetics of Symtuza have not been investigated in patients with hepatic impairment. However, there are data for the components of Symtuza.

Darunavir.

DRV is primarily metabolized and eliminated by the liver. In a multiple-dose study with DRV/rtv (600/100 mg) twice daily, it was demonstrated that the steady-state pharmacokinetic parameters of DRV 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 DRV has not been studied.

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.

Emtricitabine.

The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Tenofovir alafenamide.

Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild, moderate, or severe hepatic impairment; no TAF dose adjustment is required in patients with hepatic impairment.
Hepatitis B and/or hepatitis C virus co-infection. There were insufficient data in clinical trials on the pharmacokinetics of its components to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of Symtuza.

Darunavir.

In HIV infected subjects taking DRV/rtv, the 48 week analysis of the data from phase 3 clinical studies indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of DRV.

Cobicistat.

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 cobicistat.

Emtricitabine and tenofovir alafenamide.

Pharmacokinetics of FTC and TAF have not been fully evaluated in patients co-infected with hepatitis B and/or C virus.
Pregnancy and postpartum. The exposure to total darunavir boosted with cobicistat after intake of darunavir/cobicistat 800/150 mg q.d. as a fixed-dose combination tablet was substantially lower during the second and third trimesters of pregnancy compared with 6-12 weeks postpartum (see Table 11). 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 darunavir/cobicistat 800/150 mg q.d. 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.
No pharmacokinetic data are available for emtricitabine and tenofovir alafenamide during pregnancy.

5.3 Preclinical Safety Data

Genotoxicity.

Darunavir.

DRV 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.

Emtricitabine.

Emtricitabine was not mutagenic in bacteria or mouse lymphoma cell assays in vitro nor clastogenic in the mouse micronucleus test in vivo.

Tenofovir alafenamide.

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

Carcinogenicity.

Darunavir.

DRV 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 DRV 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 DRV 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 DRV were between 0.5- and 0.6-fold (mice) and was 0.9-fold (rats), relative to those observed in humans at the recommended therapeutic dose.

Cobicistat.

In a long-term study in mice with doses of up to 50 mg/kg/day in males and 100 mg/kg/day in females (9-21 times the human exposure (AUC) at 150 mg daily), cobicistat treatment did not result in any increased tumour incidences. In a corresponding study in rats, with doses of up to 50 mg/kg/day in males and 30 mg/kg/day in females (2.6 and 2.3 times the human exposure with 150 mg daily), treatment resulted in increased incidence of thyroid follicular cell tumours. Hepatocyte hypertrophy was also observed, and this oncogenic response is most likely related to alterations in thyroid hormones and to be specific to species.

Emtricitabine.

In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (26 times the human systemic exposure at the recommended dose of emtricitabine in Symtuza) or in rats at doses up to 600 mg per kg per day (31 times the human systemic exposure at the recommended dose). Therefore, emtricitabine had demonstrated low carcinogenic potential in mice and rats.

Tenofovir alafenamide.

Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the 300 mg therapeutic dose of tenofovir disoproxil fumarate for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures ~10 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 4 times that observed in humans at the therapeutic dose.

Toxicology.

Darunavir.

Animal toxicology studies have been conducted with DRV 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 DRV. In the rat, the key target organs identified were the hematopoietic 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.

Cobicistat.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QT prolongation, and may slightly prolong the PR interval and decrease left ventricular function at mean concentrations at least 10-fold higher than the human exposure at the recommended 150 mg daily dose.

Emtricitabine.

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.

Tenofovir alafenamide.

Non-clinical studies in rats and dogs revealed bone and kidney as the primary target organs of toxicity. Bone toxicity was observed as reduced bone mineral density.
Juvenile toxicity. In a pre- and postnatal development assessment in rats, DRV with and without ritonavir caused a transient reduction in body weight gain of the offspring during lactation. This was attributed to drug exposure via the milk. No post weaning functions were affected with DRV alone or in combination with ritonavir. In juvenile rats directly dosed with DRV (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 higher than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of DRV and the immaturity of the blood brain barrier. No treatment related mortalities were noted in juvenile rats dosed at 1000 mg/kg DRV (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, DRV should not be used in paediatric patients below 3 years of age.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Croscarmellose sodium, magnesium stearate, microcrystalline cellulose, silicon dioxide*.
*Cobicistat is absorbed on a silicon dioxide carrier.

Film-coat.

Opadry II complete film coating system 85F120020 Yellow (ARTG PI No. 114529).

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

Symtuza tablets are supplied in a white, high density polyethylene (HDPE) bottle and a polypropylene child-resistant closure. Each bottle contains 30 tablets and a desiccant.

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. The partition coefficient (log p) for darunavir is 2.47 and the dissociation constant, pKa, is 2.02.

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.

Emtricitabine.

The chemical name of FTC is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine. FTC is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
Emtricitabine has the following structural formula:
It has an empirical formula of C8H10FN3O3S and a molecular weight of 247.2.
FTC is a white to off-white crystalline powder with a solubility of approximately 112 mg per mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.

Tenofovir alafenamide fumarate.

The chemical name of TAF is L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1- methylethoxy] methyl] phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).
TAF has the following structural formula:
It has an empirical formula of C21H29O5N6P.½(C4H4O4) and a molecular weight of 534.50.
TAF is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20°C.

CAS number.

Darunavir: 206361-99-1.
Cobicistat: 1004316-88-4.
Emtricitabine: 143491-57-0.
Tenofovir alafenamide: 379270-37-8 and tenofovir alafenamide fumarate: 1392275-56-7.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine.

Summary Table of Changes