Consumer medicine information

Tybost Tablets

Cobicistat

BRAND INFORMATION

Brand name

Tybost

Active ingredient

Cobicistat

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

Read all of this leaflet carefully before you start taking this medicine.

This leaflet answers some of the common questions about TYBOST tablets.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist about your medical condition or treatment. If you have further questions, please ask your doctor or your pharmacist.

This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

Medicines are sometimes prescribed for conditions that are not mentioned in this leaflet.

Do not use TYBOST for a condition for which it was not prescribed.

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

What is TYBOST

How TYBOST works

TYBOST contains the active substance cobicistat.

TYBOST is a type of medicine called a pharmacokinetic enhancer (or “booster”), which is used with one of the two following medicines for the treatment of HIV:

  • Reyataz (atazanavir) and
  • Prezista (darunavir).
  • TYBOST helps increase the levels of these HIV medicines in your body.

Use in children

TYBOST is for adults. TYBOST has not been studied in children under the age of 18 or adults aged 65 and over.

Does TYBOST cure HIV or AIDS

TYBOST does not treat HIV infection or AIDS; it helps improve the effect of the HIV medicines:

  • Reyataz (atazanavir) and
  • Prezista (darunavir).

The long-term effects of TYBOST are not known at this time. People taking TYBOST may still get opportunistic infections or other conditions that happen with HIV infection.

Opportunistic infections are infections that develop because the immune system is weak.

Some of these conditions are:

  • pneumonia,
  • herpes virus infections, and
  • Mycobacterium avium complex (MAC) infection.

This medicine is only available from a pharmacist after it has been prescribed by a doctor who specialises in the treatment of HIV infection.

If you wish to continue receiving treatment with TYBOST it is important you remain under the care of a hospital or doctor who specialises in the treatment of HIV infection.

Does TYBOST reduce the risk of passing HIV to others

TYBOST does not lower your chance of passing HIV to other people through sexual contact, sharing needles, or being exposed to your blood.

For your health and the health of others, it is important to always practice safer sex by using a latex or polyurethane condom or other barrier to lower the chance of passing the infection through semen, vaginal secretions, or blood.

Never re-use or share needles.

Before you take TYBOST

When you must not take it

Together with your doctor, you need to decide whether TYBOST is right for you.

Do not take TYBOST if you are allergic to:

  • cobicistat or
  • any of the other ingredients of Tybost

Some of the symptoms of an allergic reaction may include:

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

The ingredients of TYBOST are listed in the product description section of this leaflet.

Do not take TYBOST if you take other HIV medicines such as:

  • Fosamprenavir (e.g.Telzir)
  • Lopinavir (e.g. Kaletra).
  • Saquinavir (e.g.Invirase)
  • STRIBILD
  • GENVOYA
  • Ritonovir (e.g. Norvir)
  • Tipranavir (e.g.Aptivus)

Do not take TYBOST if you take:

  • alfuzosin hydrochloride (e.g. Xatral)
  • carbamazepine (e.g. Tegretol)
  • ergot-containing medicines like dihydroergotamine, ergotamine (e.g. Cafergot, Dihydergot, Migerot)
  • lovastatin (e.g. Mevacor)
  • midazolam (e.g.Hypnovel)
  • phenobarbital
  • phenytoin (e.g.Dilantin )
  • rifabutin (e.g.Mycobutin)
  • sildenafil (e.g. Revatio)
  • simvastatin (e.g. Invast/Zimcol)
  • St John’s Wort or products containing St John’s Wort.
  • tadalafil (e.g.Cialis/Adcirca)
  • triazolam (e.g.Halcion)

Medicines that may affect your kidneys unless you have discussed this with your doctor.

This is not a complete list of medicines that you should tell your doctor about.

Do not take TYBOST after the expiry or “use by” date (EXP) printed on the bottle. If you take it after the expiry date has passed, it may not work as well.

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes. Tell your doctor if you have, or have had, any of the following medical conditions:

  • kidney problems or are undergoing kidney dialysis treatment.
  • liver problems, including hepatitis B or C virus infection.

Tell your doctor if you are taking any other HIV medicines (e.g. atazanavir or darunavir).

Tell your doctor if you are allergic to foods, dyes, preservatives or any other medicines.

Tell your doctor if you are pregnant, or likely to become pregnant during your course of medication. We do not know if TYBOST can harm your unborn child. You and your doctor will need to decide if TYBOST is right for you.

Tell your doctor if you are breastfeeding, or likely to breastfeed during your course of medication. You should not breast-feed if you are HIV-positive because of the chance of passing the HIV virus to your baby.

It is not known if TYBOST can pass into your breast milk and if it can harm 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.

Taking other medicines

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

Some medicines may affect the levels of TYBOST or TYBOST may affect the levels of other medicines in the body when they are taken at the same time as TYBOST.

Your doctor may change your other medicines or change their doses. Other medicines, including herbal products may affect TYBOST.

For this reason, it is very important to let your doctor or pharmacist know what medications, herbal supplements, or vitamins you are taking.

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 TYBOST.

Do not start any new medicines while you are taking TYBOST without first talking with your doctor or pharmacist.

How to take TYBOST

Take the exact amount of TYBOST your doctor has prescribed for you.

Never change the dose on your own.

Do not stop this medicine unless your healthcare provider tells you to stop.

How much to take

The usual dose is one TYBOST tablet orally, once daily.

How to take it

Always take TYBOST with Reyataz® (atazanavir) or Prezista® (darunavir).

Always take TYBOST with food. Taking TYBOST with food is important to get the right drug levels in your body.

If you forget to take TYBOST

Do not miss a dose of TYBOST.

If you forget to take TYBOST, take your missed dose right away then take your next dose as usual with Reyataz (atazanavir) or Prezista (darunavir).

Do not take a double dose to make up for a forgotten dose.

Continue with your regular dosing schedule.

When your TYBOST supply starts to run low, get more from your doctor or pharmacy. This is very important because the virus in your blood may become resistant to the HIV medicine Reyataz (atazanavir) or Prezista (darunavir) if TYBOST is stopped for even a short time and become harder to treat.

Do not change your dose or stop taking TYBOST without first talking to your doctor.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre: 131126 (Australia) and 0800 764 766 (New Zealand) or go to the accident and emergency department at your nearest hospital if you think you or anyone else may have taken too many TYBOST tablets. Do this even if there are no signs of discomfort or poisoning. This may need urgent medical attention.

While you are taking TYBOST

Things you must not do

Do not breast-feed. See “Before you start to take it”

Avoid doing things that can spread HIV infection since TYBOST 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 practice 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.

Things to be careful of

Be careful driving or operating machinery until you know how TYBOST affects you. If you are dizzy, have trouble concentrating, or are drowsy, avoid activities that may be dangerous, such as driving or operating machinery.

Side Effects

Like all medicines, TYBOST can have side effects, although not everybody gets them. Some may be serious and need medical attention.

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

Check with your doctor as soon as possible if you have any problems while taking TYBOST, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

TYBOST and REYATAZ (atazanavir) may cause the following common side effects:

  • presence of jaundice seen in the white part of the eyes and yellowing of the skin and/or eyes.

Additional side effects may include:

  • headache
  • nausea
  • diarrhea

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Talk to your doctor or pharmacist if you don’t understand anything in this list.

Ask your doctor or pharmacist for a more complete list of side effects of TYBOST and all the medicines you will take. This is not a complete list of side effects possible with TYBOST.

After taking TYBOST

Storage

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

Keep TYBOST tablets in a cool, dry place where it stays below 25 °C.

Do not store TYBOST or any other medicine in a bathroom or near a sink.

Do not leave TYBOST in the car or on a window sill. Heat and dampness can destroy some medicines.

Keep your TYBOST tablets in the bottle with the cap tightly closed until you take them. If you take TYBOST tablets out of their pack they may not keep well.

Product description

What the tablets look like

TYBOST is the brand name of your medicine.

TYBOST tablets are round, film-coated and orange in colour.

Each tablet is debossed with “GSI” on one side and plain faced on the other side.

TYBOST tablets are supplied in bottles containing 30 tablets.

Ingredients

Each TYBOST tablet contains 150 mg of the active ingredient cobicistat.

Each TYBOST tablet also contains the following ingredients:

  • cellulose-microcrystalline (E460)
  • silicon dioxide
  • croscarmellose sodium
  • magnesium stearate (E572).

Film-coating:

  • Sunset yellow FCF (FD&C yellow #6)
  • aluminum lake (E110)
  • polyethylene glycol
  • polyvinyl alcohol
  • talc (E553B)
  • titanium dioxide (E171)
  • yellow iron oxide (E172).

SPONSOR

TYBOST tablets are supplied in

Australia by:

Gilead Sciences Pty Ltd
Level 6, 417 St Kilda Road
Melbourne, Victoria 3004

In New Zealand:

Gilead Sciences (NZ)
c/- PricewaterhouseCoopers
Level 8 Pricewaterhousecoopers Tower
188 Quay Street
Auckland 1010

Date of preparation: 2 November 2016

AUST R 200445

TYBOST, STRIBILD and GENVOYA are trademarks of Gilead Sciences, Inc. or one of its related companies. All other trademarks referenced herein are the property of their respective owners.

Published by MIMS August 2017

BRAND INFORMATION

Brand name

Tybost

Active ingredient

Cobicistat

Schedule

S4

 

1 Name of Medicine

Tybost (cobicistat).
Cobicistat is one of the active substances in the single tablet regimens; Stribild, Genvoya.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 150 mg of cobicistat.
Cobicistat is a white to pale yellow solid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Tybost tablet is round, film coated and orange in colour. Each tablet is debossed with 'GSI' on one side and plain faced on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Tybost is indicated as a pharmacokinetic enhancer of appropriate HIV-1 protease inhibitors in adults (see Section 4.2 Dose and Method of Administration).

4.2 Dose and Method of Administration

Dosage (dose and interval).

Tybost must be coadministered with atazanavir or darunavir. The recommended dose of Tybost is one tablet, once daily taken orally with food.
The recommended dose of Tybost and that of the coadministered protease inhibitor, atazanavir or darunavir, are presented in Table 1. As Tybost is used in combination with atazanavir or darunavir, also consult the product information for atazanavir or darunavir.
Tybost is not recommended for use with HIV-1 protease inhibitors other than those presented in Table 1.

Dosage adjustment.

Renal impairment.

No dose adjustment of Tybost is required in patients with renal impairment, including those with severe renal impairment (see Section 5.1 Pharmacodynamic Properties).
Tybost has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when Tybost is coadministered with a drug that has dosing adjustment recommendations guided by estimated creatinine clearance. For example, Tybost should not be initiated as part of a regimen containing emtricitabine, lamivudine, tenofovir disoproxil fumarate or adefovir dipivoxil in patients who have an estimated creatinine clearance below 70 mL/min since dose adjustment of these drugs is required below 50 mL/min and such dose adjustments have not been established in combination with Tybost (see Section 4.4 Special Warnings and Precautions for Use, Effects on serum creatinine; Section 4.8 Adverse Effects (Undesirable Effects)).

Hepatic impairment.

No dose adjustment of Tybost is required in patients with mild or moderate hepatic impairment (see Section 5.1 Pharmacodynamic Properties).

Not recommended during pregnancy.

Tybost coadministered with darunavir is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters (see Section 4.6, Use in pregnancy).
Tybost coadministered with atazanavir is not recommended for use during pregnancy because of substantially lower exposures of cobicistat during the second and third trimesters (see Section 4.6, Use in pregnancy).
Tybost coadministered with darunavir or atazanavir should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with Tybost coadministered with darunavir or atazanavir (see Section 4.6, Use in pregnancy).

4.3 Contraindications

Coadministration is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, and with drugs that are potent inducers of CYP3A due to the potential for loss of virologic response and possible resistance to Tybost. Therefore, coadministration is contraindicated with, but not limited to, the following drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions):
Alpha 1-adrenoreceptor antagonists: alfuzosin.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Antimycobacterials: rifabutin, rifampin, rifapentine.
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine.
Gastrointestinal (GI) motility agents: cisapride.
Herbal products: St. John's wort (Hypericum perforatum).
HMG-CoA reductase inhibitors: lovastatin, simvastatin.
Other lipid-modifying agents: lomitapide.
Neuroleptics: pimozide.
Phosphodiesterase-5 (PDE-5) inhibitors: sildenafil and tadalafil for the treatment of pulmonary arterial hypertension.
Sedative/ hypnotics: orally administered midazolam, triazolam.

4.4 Special Warnings and Precautions for Use

Drug interactions.

Tybost is a potent mechanism based CYP3A inhibitor. Initiating treatment with Tybost in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already receiving Tybost may result in increased plasma concentration of these concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to serious and/or life threatening or fatal events. Coadministration of cobicistat 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 therapeutic effect. The potential for drug-drug interactions must be considered prior to and during therapy with Tybost. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with Tybost.
See Section 4.3 Contraindications for drugs that are contraindicated due to potentially serious and/or life threatening events, significant drug interactions or loss of effectiveness. Also, see Table 2 for a listing of drugs with established and other potentially significant drug-drug interactions.
Tybost is a pharmacokinetic enhancer of atazanavir and darunavir. Prescribers should consult the product information of atazanavir and darunavir for a description of additional contraindicated drugs and significant drug-drug interactions associated with these drugs.

Use with antiretrovirals.

Dosing recommendations have only been established for use of Tybost with either atazanavir or darunavir once daily. Tybost should not be used as a pharmacokinetic enhancer to boost any other HIV-1 protease inhibitor, since dosing recommendations for such coadministration have not been established and may result in insufficient plasma level of the protease inhibitor leading to loss of therapeutic effect and development of resistance (see Section 4.2 Dose and Method of Administration).
Tybost coadministered with atazanavir or darunavir should not be used in combination with another antiretroviral that requires boosting (i.e. another protease inhibitor or elvitegravir), since dosing recommendations for such combination have not been established and may result in decreased plasma concentrations of atazanavir, darunavir and/or the other antiretroviral leading to loss of therapeutic effect and development of resistance.
Tybost should not be used in combination with other products containing cobicistat or with products or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

Use in renal impairment.

Tybost has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating Tybost, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance, or when coadministered with drugs with dosing adjustment recommendations guided by estimated creatinine clearance.
Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 35 micromol/L from baseline should be monitored and evaluated for evidence of tubulopathy.

New onset or worsening renal impairment when used with tenofovir disoproxil fumarate.

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

Use in the elderly.

Clinical studies of Tybost did not contain sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Caution should be exercised when prescribing Tybost to the elderly, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

Safety and effectiveness of Tybost in children less than 18 years of age have not been established.

Effects on laboratory tests.

There are no known interactions of Tybost with any laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of cobicistat on the pharmacokinetics of concomitant drugs.

Tybost is a potent mechanism based inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Drugs that are extensively metabolized by CYP3A and have high first-pass metabolism appear to be the most susceptible to large increases in exposure when coadministered with Tybost (see Section 4.3 Contraindications). Coadministration of cobicistat with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s) (see Section 4.4 Special Warnings and Precautions for Use). Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 2.
Tybost is a weak inhibitor of CYP2D6. Tybost is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Tybost is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, UGT1A1, or MDR1.
Cobicistat is an inhibitor of the following transporter: P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Coadministration of Tybost with drugs that are substrates of P-gp, BCRP, OATP1B1 and OATP1B3 may result in increased plasma concentrations of such drugs.

Effect of concomitant drugs on the pharmacokinetics of cobicistat.

Tybost is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of Tybost. Coadministration of Tybost with drugs that induce CYP3A may result in decreased plasma concentration of the booster cobicistat and consequently that of atazanavir or darunavir, which may result in loss of therapeutic effect and possible development of resistance (see Section 4.3 Contraindications). Coadministration of Tybost with drugs that inhibit CYP3A may result in increased plasma concentration of cobicistat.

Established and other potentially significant interactions.

Table 2 provides dosing recommendations as a result of drug interactions with Tybost. These recommendations are based on either drug interactions studies or predicted interactions due to the expected magnitude of interaction and potential for serious and/or life-threatening events or loss of therapeutic effect.
For additional drug-drug interactions with atazanavir or darunavir, consult their respective product information when using Tybost.
The table is not all inclusive (see Section 4.3 Contraindications).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-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) approximately similar to human exposures at the recommended 150 mg daily dose.
(Category B1)
There are no adequate and well controlled clinical studies of Tybost in pregnant women. Animal reproductive studies did not indicate direct or indirect harmful effects of cobicistat with respect to pregnancy, foetal development, parturition, or postnatal development. Animal reproductive studies are not always predictive of human response.
Lower exposures of cobicistat have been reported during pregnancy compared to postpartum. Treatment during pregnancy may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therefore, Tybost is not recommended during pregnancy.
An alternative regimen is recommended for individuals who become pregnant during therapy with Tybost. Viral load should be closely monitored during pregnancy.
Because Tybost must be used in combination with atazanavir or darunavir, also refer to the product information for pregnancy category of atazanavir and darunavir.
In a rat study, foetal development was unaffected by an oral dose of cobicistat resulting in a drug exposure (AUC) that was 1.9-fold higher than in humans receiving the 150 mg daily dose. There was a tendency for reduced foetal weight and increases in skeletal variations with a higher dose that was associated with reduced maternal food consumption and bodyweight gain. Treatment of rabbits with a dose resulting in a drug exposure approximately 3 times that in humans receiving the 150 mg daily dose did not affect foetal development.
 Studies in rats have demonstrated that cobicistat is secreted into milk.
It is not known whether cobicistat is excreted in human milk. Because of the potential for both HIV transmission and for serious adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving Tybost.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Tybost on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

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.

Experience from clinical trials.

The safety of Tybost is based on a 144 week, phase 3, randomized, active controlled clinical trial (study GS-US-216-0114), in which 692 treatment naïve patients received Tybost boosted atazanavir (N = 344) or ritonavir boosted atazanavir (N = 348) administered with Truvada. Adverse reactions for Tybost boosted atazanavir were consistent with the safety profile of ritonavir boosted atazanavir.
The most frequently reported adverse reactions were associated with elevated bilirubin levels and are listed below by system organ class. Table 3 lists the frequency of adverse reactions (grade 2-4) occurring in at least 3% of patients receiving Tybost boosted atazanavir + Truvada in study GS-US-216-0114.

Laboratory abnormalities.

The frequency of treatment emergent laboratory abnormalities (grade 3-4) occurring in at least 3% of patients receiving Tybost boosted atazanavir + Truvada in study GS-US-216-0114 are presented in Table 4.
Tybost was shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. An increase in serum creatinine due to Tybost's inhibitory effect generally does not exceed 35 micromol/L from baseline. In study GS-US-216-114, decreases in estimated creatinine clearance occurred early in treatment with Tybost, but stabilized thereafter. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by the Cockcroft-Gault method (eGFRCG) after 48 weeks of treatment was -13.4 ± 15.2 mL/min in the Tybost boosted atazanavir + Truvada group and -8.7 ± 14.5 mL/min in the ritonavir boosted atazanavir + Truvada group. The mean (± SD) change in eGFRCG after 144 weeks of treatment was -15.1 ± 16.5 mL/min in the Tybost boosted atazanavir + Truvada group and -8.0 ± 16.8 mL/min in the ritonavir boosted atazanavir + Truvada group (see Section 5.1 Pharmacodynamic Properties).

4.9 Overdose

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Tybost consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) and 0800 764 766 (New Zealand).
Limited clinical experience is available at doses higher than the therapeutic dose of cobicistat. In two studies, single dose of cobicistat 400 mg was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. Since cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group.

All other therapeutic products, ATC code: V03AX03.

Mechanism of action.

Cobicistat is a selective, mechanism based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as atazanavir or darunavir, where bioavailability is limited and half-life is shortened due to CYP3A dependent metabolism.

Antiviral activity.

Cobicistat has no detectable antiviral activity against HIV-1, HBV or HCV and does not antagonize the antiviral effect of HIV protease inhibitors.

Effects on pharmacokinetic enhancement.

The effect of cobicistat on atazanavir pharmacokinetics was demonstrated in the pharmacokinetic substudy (N = 48) of the phase III study GS-US-216-0114 in which HIV-1 infected patients received atazanavir + cobicistat or atazanavir + ritonavir, both in combination with Truvada (tenofovir DF 300 mg/emtricitabine 200 mg). The steady-state pharmacokinetic parameters of atazanavir were comparable when boosted with cobicistat versus ritonavir as shown in Table 5 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The pharmacokinetic enhancing effect of cobicistat on darunavir was evaluated in a phase I clinical trial (study GS-US-216-0115) in 31 healthy patients that were administered darunavir 800 mg in combination with cobicistat 150 mg or ritonavir 100 mg, all once daily, for 10 days. The steady-state pharmacokinetic parameters of darunavir were comparable when boosted with cobicistat versus ritonavir as shown in Table 6. These results were similar to those reported in previous clinical studies of darunavir 800 mg with ritonavir 100 mg once daily (refer to Prezista product information).

Effects on electrocardiogram.

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

Effects on serum creatinine.

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

Clinical trials.

The activity of cobicistat as a pharmacokinetic enhancer to atazanavir or darunavir was demonstrated in pharmacokinetic studies. In these pharmacokinetic studies, the exposure of atazanavir or darunavir boosted with cobicistat 150 mg were consistent with those observed with ritonavir 100 mg (see Section 5.1 Pharmacodynamic Properties, Effects on pharmacokinetic enhancement). For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, please refer to darunavir product information.
The safety and efficacy of Tybost with atazanavir in HIV-1 infected patients were evaluated in a phase 3 randomized, double blind, active controlled study (GS-US-216-0114) in HIV-1 infected patients with baseline estimated creatinine clearance above 70 mL/min who were treatment naïve (N = 692). In study GS-US-216-0114, patients were randomized in a 1:1 ratio to receive either atazanavir 300 mg + cobicistat 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily, each administered with a fixed background regimen containing tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg administered as single tablet Truvada. Randomization was stratified by screening HIV-1 RNA level (≤ 100,000 copies/mL or > 100,000 copies/mL).
The mean age of patients was 37 years (range 19-70), 83% were male, 60% were white, 18% were black and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 3.2-6.4). The mean baseline CD4+ cell count was 352 cells/mm3 (range 1-1455) and 17% had CD4+ cell counts ≤ 200 cells/mm3. Forty percent of patients had baseline viral loads > 100,000 copies/mL.
Treatment outcomes at 48 weeks and 144 weeks are presented in Table 7.
Atazanavir + cobicistat + Truvada (FTC/TDF) was noninferior in achieving HIV-1 RNA < 50 copies/mL when compared with atazanavir + ritonavir + Truvada.
Changes in CD4+ cell counts through 48 and 144 weeks in study GS-US-216-0114 are presented in Table 8.

Drug resistance.

In an analysis of treatment failure patients in study GS-US-216-0114 through week 144, evaluable genotypic data from paired baseline and treatment failure isolates were available for all 21 virologic failures in the Tybost group. Among the 21 patients, 3 developed the emtricitabine (FTC) associated resistance substitution M184V. No subject developed the tenofovir (TDF) associated resistance substitutions K65R or K70E or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures. Among the 19 patients, 1 developed the emtricitabine associated resistance substitution M184V with no tenofovir or primary protease inhibitor associated resistance substitutions.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of Tybost with food in HIV-1 infected patients, peak plasma concentrations were observed 4 hours postdose for cobicistat. The steady-state mean Cmax, AUCtau, and Ctrough (mean ± SD) following multiple doses of Tybost in HIV-1 infected patients (N = 68) were 1.2 ± 0.3 microgram/mL, 10.9 ± 3.8 microgram.h/mL, and 0.07 ± 0.07 microgram/mL, respectively.

Distribution.

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

Metabolism.

Cobicistat is metabolized via CYP3A (major) and CYP2D6 (minor) mediated oxidation and does not undergo glucuronidation. Following oral administration of [14C] cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and faeces and do not contribute to the CYP3A inhibitory activity of cobicistat. Eighty six percent and 8.2% of the dose were recovered in faeces and urine, respectively. The median terminal plasma half-life of cobicistat following administration of Tybost is approximately 3.5 hours.

Effect of food.

A food effect study was not conducted for Tybost. In clinical studies, Tybost was coadministered with atazanavir or darunavir under fed conditions, in accordance with the prescribing information for these agents. It is recommended that Tybost be administered with food.

Age, gender and ethnicity.

No clinically relevant pharmacokinetic differences due to gender or ethnicity have been identified for cobicistat (see Section 4.4 Special Warnings and Precautions for Use).
The pharmacokinetics of cobicistat in paediatric patients have not been established. Pharmacokinetics of cobicistat have not been fully evaluated in the elderly (65 years of age and older).
No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.

Patients with impaired renal function.

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

Patients with hepatic impairment.

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

Hepatitis B and/or hepatitis C virus coinfection.

The pharmacokinetics of cobicistat have not been fully evaluated in patients coinfected with HIV-1 and hepatitis B and/or C.

Assessment of drug interactions.

In drug interaction studies conducted with cobicistat, there was no clinically significant interaction observed between cobicistat and the following drugs: famotidine, R/S-methadone, buprenorphine/naloxone, omeprazole, or telaprevir.
The effects of coadministered drugs on the exposure of cobicistat are shown in Table 9. The effects of cobicistat on the exposure of coadministered drugs are shown in Table 10.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Tybost tablets each contain the following ingredients as excipients:

Tablet core.

Cellulose-microcrystalline (E460), silicon dioxide, croscarmellose sodium, magnesium stearate (E572).

Film coating.

Sunset yellow FCF (FD and C yellow #6), aluminum lake (E110) polyethylene glycol, polyvinyl alcohol, talc (E553B), titanium dioxide (E171), yellow iron oxide (E172).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Tybost is supplied in high density polyethylene (HDPE) bottles containing 30 tablets and a silica gel desiccant, polyester coil and is closed with a child resistant closure.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

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. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:

CAS number.

CAS registry number: 1004316-88-4.
Cobicistat has 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.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes