Consumer medicine information

Tivicay

Dolutegravir

BRAND INFORMATION

Brand name

Tivicay

Active ingredient

Dolutegravir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tivicay.

What is in this leaflet?

Please read this leaflet carefully before you take TIVICAY. This leaflet answers some common questions about TIVICAY (dolutegravir). It does not contain all of 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 expected benefits of you taking TIVICAY against the risks this medicine could have for you.

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

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

What is TIVICAY used for?

TIVICAY is used to treat HIV (human immunodeficiency virus) infection in adults and in children over 6 years old.

TIVICAY does not cure HIV infection; it reduces the amount of virus in your body and keeps it at a low level. TIVICAY also increases the CD4 cell count in your blood. CD4 cells are a type of white blood cells that are important in helping your body to fight infection.

TIVICAY is used, in combination with other anti-retroviral medicines (combination therapy), to treat HIV infection in adults and children over 6 years old. To control your HIV infection, and to stop your illness from getting worse, you must keep taking all your medicines, unless your doctor tells you to stop taking any.

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

TIVICAY is not addictive.

There is not enough information to recommend the use of this medicine for children under the age of 6 years.

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

Before you take TIVICAY

When you must not take it

You must not take TIVICAY if:

  • you're taking another medicine called dofetilide (to treat heart conditions).

Do not take TIVICAY if you have an allergy to:

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

Some of the symptoms of an allergic reaction may include:

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

If you think any of these apply to you, don't take TIVICAY until you have checked with your doctor.

Tell your doctor if you:

  • have liver problems, including hepatitis B or C.

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

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Some other conditions may develop during HIV treatment.

Symptoms of infection and inflammation
People with advanced HIV infection (AIDS) have weak immune systems and are more likely to develop serious infections (opportunistic infections). When they start treatment, the immune system becomes stronger, so the body starts to fight infections.

Symptoms of infection and inflammation may develop, caused by either:

  • old, hidden infections flaring up again as the body fights them
  • the immune system attacking healthy body tissue (autoimmune disorders)

The symptoms of autoimmune disorders may develop many months after you start taking medicine to treat your HIV infection.

Symptoms may include:

  • muscle weakness and/or muscle pain
  • joint pain or swelling
  • weakness beginning in the hands and feet and moving up towards the trunk of the body
  • palpitations or tremor
  • hyperactivity (excessive restlessness and movement).

If you get any symptoms of infection or if you notice any of the symptoms above:
Tell your doctor immediately. Don't take other medicines for the infection without your doctor's advice.

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

If you are pregnant, or think you could be, or if you are planning to have a baby, don't take TIVICAY without checking with your doctor.

Your doctor will consider the benefit to you and the risk to your baby of taking TIVICAY while you're pregnant.

If you could get pregnant while taking TIVICAY, you need to use a reliable method of contraception to prevent pregnancy. Your doctor can discuss with you the risks and benefits involved.

Where possible, women who are HIV-positive should not breast feed, because HIV infection can be passed on to the baby in breast milk.

It is not known whether the ingredients of TIVICAY can pass into breast milk and harm your baby.

If you have not told your doctor about any of the above, tell him/her before you start taking TIVICAY.

Taking other medicines

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

Don't take TIVICAY with this medicine:

  • dofetilide or pilsicainide, to treat heart conditions

Some medicines and TIVICAY may interfere with each other. These include.

Tell your doctor if you are taking any of the medicines in the following list:

  • metformin, to treat diabetes
  • medicines called antacids, to treat indigestion and heartburn.
  • calcium and iron supplements.
  • etravirine, efavirenz, fosamprenavir/ritonavir, nevirapine or tipranavir/ritonavir, to treat HIV infection
  • rifampicin, to treat tuberculosis (TB) and other bacterial infections
  • phenytoin and phenobarbital, to treat epilepsy
  • carbamazepine, to treat epilepsy and bipolar disorder
  • St. John's wort, (Hypericum perforatum), a herbal remedy to treat depression

These medicines may be affected by TIVICAY or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

How do I take TIVICAY?

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

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

How much to take

Adults

  • The usual dose of TIVICAY is one 50 mg tablet, once a day; or
  • For HIV infection that is resistant to other medicines similar to TIVICAY, the usual dose of TIVICAY is one 50 mg tablet, twice a day.

Your doctor will decide on the correct dose of TIVICAY for you.

Children

Your doctor will decide on the correct dose of TIVICAY for your child, depending on the weight of the child.

How to take it

Swallow the tablets whole with a full glass of water.

Antacid medicines

Antacids, to treat indigestion and heartburn, can stop TIVICAY being absorbed into your body and make it less effective.

Do not take an antacid during the 6 hours before you take TIVICAY, or for at least 2 hours after you take it. Other acid-lowering medicines like ranitidine and omeprazole can be taken at the same time as TIVICAY.

Talk to your doctor for further advice on taking acid-lowering medicines with TIVICAY.

Calcium or iron supplements

Calcium or iron supplements can stop TIVICAY being absorbed into your body and make it less effective.

Do not take a calcium or iron supplement during the 6 hours before you take TIVICAY, or for at least 2 hours after you take it. If you take food with TIVICAY, then you can take calcium and iron supplements at the same time as TIVICAY.

When to take it

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

It does not matter if you take this medicine before or after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

If you miss a dose, take it as soon as you remember. But if it is less than 4 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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

Do not take a double dose to make up for the dose that you missed.

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (In Australia call 131126. In New Zealand call 0800 POISON or 0800 764 766) for advice if you think you or anyone else may have taken too much TIVICAY, even if there are no signs of discomfort or poisoning. If you are not sure what to do, contact your doctor or pharmacist. You may need urgent medical attention.

While you are using TIVICAY

You will need regular blood tests For as long as you're taking TIVICAY, your doctor will arrange regular blood tests to check for side effects.

Stay in regular contact with your doctor TIVICAY helps to control your condition, but it is not a cure for HIV infection. You need to keep taking it every day to stop your illness from getting worse. Because TIVICAY does not cure HIV infection, you may still develop other infections and illnesses linked to HIV infection.

Keep in touch with your doctor, and don't stop taking TIVICAY without your doctor's advice.

Protect other people

HIV infection is spread by sexual contact with someone who has the infection, or by transfer of infected blood (for example, by sharing injection needles). TIVICAY will not stop you passing HIV infection on to other people. To protect other people from becoming infected with HIV:

  • Use a condom when you have oral or penetrative sex.
  • Don't risk blood transfer - for example, don't share needles.

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking TIVICAY.

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

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

Things you must not do

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

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

TIVICAY can make you dizzy and have other side effects that make you less alert.

Don't drive or use machines unless you are sure you're not affected.

Side effects

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

This medicine helps most people with HIV, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

When you're being treated for HIV, it can be hard to tell whether a symptom is a side effect of TIVICAY or other medicines you are taking, or an effect of the HIV disease itself. So it is very important to talk to your doctor about any changes in your health.

Some side effects may only be seen in your blood tests and may not appear immediately after you start taking TIVICAY. If you get any of these effects, and if they are severe, your doctor may advise you to stop taking TIVICAY.

As well as the effects listed below for TIVICAY, other conditions can develop during combination therapy for HIV.

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

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

Allergic reactions

  • See a doctor as soon as possible if you develop a rash.

Allergic reactions are uncommon in people taking TIVICAY. Signs include:

  • skin rash
  • a high temperature (fever)
  • lack of energy (fatigue)
  • swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing
  • muscle or joint aches.

Your doctor may decide to carry out tests on your liver, kidneys or blood, and may tell you to stop taking TIVICAY.

Very common side effects

These may affect more than 1 in 10 people:

  • headache
  • diarrhoea
  • feeling sick (nausea)

Common side effects

These may affect up to 1 in 10 people:

  • rash
  • itching (pruritus)
  • being sick (vomiting)
  • stomach (abdominal) pain or discomfort
  • difficulty in sleeping (insomnia)
  • dizziness
  • abnormal dreams
  • depression (feelings of deep sadness and unworthiness)
  • anxiety
  • lack of energy (fatigue)
  • wind (flatulence)

Uncommon side effects

These may affect up to 1 in 100 people:

  • inflammation of the liver (hepatitis)
  • an inflammatory condition which may develop as the immune system becomes stronger (immune reconstitution syndrome or 'IRIS')
  • allergic reaction (hypersensitivity) (see earlier in this section for more details)
  • suicidal thoughts*
  • suicidal attempt*
  • joint pain
  • muscle pain
  • weight gain

* mainly in patients who have had depression or mental health problems before

Rare side effects

These may affect up to 1 in 1000 people:

  • liver failure (signs may include yellowing of the skin and the whites of the eyes or unusually dark urine

Other side Effects that may show up in blood tests

Other side effects have occurred in some people but their exact frequency is unknown:

  • increase in bilirubin (a substance produced by the liver) in the blood
  • an increase in the level of enzymes produced in the muscles (creatine phosphokinase, creatinine)

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

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

After using TIVICAY

Storage

Keep your tablets in the bottle until it is time to take them.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

10 mg tablets only - Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove the desiccant.

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

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

Disposal

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

Product description

What it looks like

10 mg - White, film-coated, round, biconvex tablets debossed with 'SV 572' on one side and '10' on the other side.

25 mg - Pale yellow, film-coated, round, biconvex tablets debossed with 'SV 572' on one side and '25' on the other side.

50 mg - Yellow, film-coated, round, biconvex tablets debossed with 'SV 572' on one side and '50' on the other side.

TIVICAY is available in bottles of 30 tablets with child-resistant closure.

The 10 mg tablet bottles contain a desiccant to reduce moisture. Once the bottle has been opened, keep the desiccant in the bottle, do not remove it.

Ingredients

TIVICAY contains 10 mg, 25 mg or 50 mg of dolutegravir (as dolutegravir sodium) as the active ingredient.

  • mannitol
  • microcrystalline cellulose
  • povidone
  • sodium starch glycolate Type A
  • sodium stearyl fumarate
  • polyvinyl alcohol
  • titanium dioxide
  • macrogol 3350
  • talc
  • iron oxide yellow (25 mg and 50 mg tablets only)

Supplier

ViiV Healthcare Pty Ltd
Level 4, 436 Johnston St,
Abbotsford, Victoria, 3067
Australia.

Where to go for further information:

Pharmaceutical companies are not in a position to give people an individual diagnosis or medical advice. Your doctor or pharmacist is the best person to give you advice on the treatment of your condition. You may also be able to find general information about your disease and its treatment from patient information groups and product specific organisations.

This leaflet was prepared on 23 October 2019.

Version 9.0

TIVICAY:

10 mg - AUST R 312782

25 mg - AUST R 312781

50mg - AUST R 205212

Trademarks are owned by or licensed to the ViiV Healthcare group of companies.

© 2019 ViiV Healthcare group of companies or its licensor.

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Tivicay

Active ingredient

Dolutegravir

Schedule

S4

 

1 Name of Medicine

Dolutegravir.

6.7 Physicochemical Properties

The chemical (IUPAC) name for dolutegravir sodium is Sodium (4R,12aS)-9- {[(2,4- difluorophenyl) methyl]carbamoyl}- 4-methyl-6,8 -dioxo-3,4,6,8,12,12a -hexahydro-2H- pyrido[1',2':4,5] pyrazino[2,1-b][1,3] oxazin-7-olate.
Molecular formula: C20H18F2N3NaO5.
Molecular weight of 441.36 g/mol.
The partition coefficient (log P) for dolutegravir sodium is 2.2 and the pKa is 8.2.
Dolutegravir sodium is slightly soluble in water.

Chemical structure.


CAS number.

1051375-19-9.

2 Qualitative and Quantitative Composition

Each tablet contains 10 mg, 25 mg or 50 mg of dolutegravir (as dolutegravir sodium).
Dolutegravir sodium is a white to light yellow powder.
Tivicay is supplied as film-coated tablets each containing 10.5 mg, 26.3 mg or 52.6 mg of dolutegravir sodium, equivalent to 10 mg, 25 mg or 50 mg of dolutegravir free acid.
Tivicay tablets also contain mannitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

10 mg.

White, film-coated, round, biconvex tablets debossed with 'SV 572' on one side and '10' on the other side.

25 mg.

Pale yellow, film-coated, round, biconvex tablets debossed with 'SV 572' on one side and '25' on the other side.

50 mg.

Yellow, film-coated, round, biconvex tablets, debossed with 'SV 572' on one side and '50' on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tivicay film-coated tablets contain dolutegravir (as dolutegravir sodium) which is an integrase inhibitor active against Human Immunodeficiency Virus (HIV).
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and preprocessed substrate DNA resulted in IC50 values of 2.7 nanomolar and 12.6 nanomolar. In vitro, dolutegravir dissociates slowly from the active site of the wild type integrase DNA complex (t1/2 71 hours).

Pharmacodynamic effects.

In a randomised, dose ranging trial, HIV-1 infected patients treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dose dependent antiviral activity, with mean declines from baseline to day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.

Antiviral activity in cell culture.

Dolutegravir exhibited antiviral activity against laboratory strains of wild type HIV-1 in peripheral blood mononuclear cells (PBMC) and MT4 cells with mean EC50s of 0.5 nanomolar to 2.1 nanomolar.
In a viral integrase susceptibility assay using the integrase coding region from 13 clinically diverse clade B isolates, dolutegravir demonstrated antiviral potency similar to laboratory strains, with a mean EC50 of 0.52 nanomolar. When tested in PBMC assays against a panel consisting of 24 HIV-1 clinical isolates [group M (clade A, B, C, D, E, F and G) and group O] and 3 HIV-2 clinical isolates, the geometric mean EC50 was 0.20 nanomolar and EC50 values ranged from 0.02 to 2.14 nanomolar for HIV-1, while the geometric mean EC50 was 0.18 nanomolar and EC50 values ranged from 0.09 to 0.61 nanomolar for HIV-2 isolates.

Antiviral activity in combination with other antiviral agents.

The antiviral activity of dolutegravir in vitro was not antagonistic with the integrase inhibitor (INI) raltegravir; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz or nevirapine; the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir or stavudine; the protease inhibitors (PIs) amprenavir or lopinavir; the CCR5 coreceptor antagonist maraviroc; or the fusion inhibitor enfuvirtide. Dolutegravir antiviral activity was not antagonistic when combined with the HBV reverse transcriptase inhibitor adefovir, or inhibited by the antiviral ribavirin.

Resistance in vitro.

Dolutegravir resistant viruses were selected in studies of potential resistance using different wild type strains and clades of HIV-1. Amino acid substitutions that emerged during passaging included E92Q, G193E, G118R, S153F or Y, and R263K, and were associated with decreased susceptibility to dolutegravir of up to 11-fold.
In resistance development studies starting with the single raltegravir resistance mutants Q148H, Q148K or Q148R, additional mutations detected during passage with dolutegravir included E138K/Q148K, E138K/Q148R, Q140S/Q148R and G140S/Q148R, which all exhibited greater than tenfold reductions in sensitivity to dolutegravir.

Anti-HIV activity against resistant strains.

Reverse transcriptase inhibitor and protease inhibitor resistant strains: dolutegravir demonstrated equivalent potency against 2 non-nucleoside (NN)-RTI resistant, 3 nucleoside (N)-RTI resistant, and 2 PI resistant HIV-1 mutant clones (1 triple and 1 sextuple) compared to the wild type strain.

Cross resistance: integrase inhibitor resistant HIV-1 strains.

Sixty integrase inhibitor resistant mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions) were produced from wild type virus NL-432 using site directed mutagenesis. Dolutegravir showed anti-HIV activity (susceptibility) with FC < 5 against 27 of 28 integrase inhibitor resistant mutant viruses with single substitutions including T66A/I/K, E92Q/V, Y143C/H/R, Q148H/K/R, and N155H. A G118R substitution conferred a 10-fold reduction in dolutegravir susceptibility but has not been observed during dolutegravir clinical studies. The single INSTI resistance substitutions T66K, I151L, and S153Y conferred a > 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a > 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).

Cross resistance: integrase inhibitor resistant HIV-2 strains.

Site directed mutant HIV-2 viruses were constructed based on patients infected with HIV-2 and treated with raltegravir who showed virologic failure. HIV-2 mutants with combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D were associated with fourfold reductions in dolutegravir susceptibility, while susceptibility of viruses with E92Q/N155H and G140S/Q148R substitutions were decreased 8.5 and 17-fold, respectively.

Clinical isolates from raltegravir treatment virologic failure patients.

Thirty clinical isolate samples with genotypic and phenotypic resistance to raltegravir (median FC > 81) were examined for susceptibility to dolutegravir (median FC 1.5). The median FC to dolutegravir for isolates containing changes at G140S + Q148H was 3.75; G140S + Q148R was 13.3; T97A + Y143R was 1.05 and N155H was 1.37.
Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analysed for susceptibility to dolutegravir. Dolutegravir has a less than or equal to 10 FC against 93.9% of the 705 clinical isolates. Dolutegravir has a ≤ 10 FC against 67 (73%) of the 92 clinical isolates with Q148 + ≥ 2 INSTI resistance substitutions and 168 (91%) of the 184 isolates with Q148 + 1 INSTI resistance substitutions.

Resistance in vivo: integrase inhibitor naïve patients.

No INI-resistant mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with dolutegravir 50 mg once daily in treatment naïve studies (SPRING-1, SPRING-2, SINGLE, FLAMINGO and GEMINI studies). In the SAILING study for treatment experienced (and integrase naïve) patients (n = 354 in the dolutegravir arm), treatment emergent integrase substitutions were observed at week 48 in 4 of 17 patients receiving dolutegravir with virologic failure. Of these four, 2 subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, 1 subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and 1 subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Resistance in vivo: integrase inhibitor resistant patients.

The VIKING-3 study examined dolutegravir (plus optimised background therapy) in patients with pre-existing INI resistance. Thirty-six patients (36/183) experienced protocol defined virologic failure through to week 24. Of these, 32 had paired baseline and PDVF resistance data for analysis and 17/32 (53%) had treatment emergent mutations. Treatment emergent mutations or mixtures of mutations observed were L74L/M (n = 1), E92Q (n = 2), T97A (n = 9), E138K/A/T (n = 8), G140S (n = 2), Y143H (n = 1), S147G (n = 1), Q148H/K/R (n = 4), N155H (n = 1) and E157E/Q (n = 1). Fourteen of the 17 patients with virus exhibiting treatment emergent mutations harboured Q148 pathway virus present at baseline or historically. Five further subjects experienced PDVF between weeks 24 and 48, and 2 of these 5 had treatment emergent mutations. Treatment emergent mutations or mixtures of mutations observed were L74I (n = 1), N155H (n = 2).
The VIKING-4 study examined dolutegravir (plus optimised background therapy) in subjects with primary genotypic resistance to INIs at Screening in 30 subjects. Treatment-emergent mutations observed were consistent with those observed in the VIKING-3 study.

Resistance in vivo: virologically supressed patients.

SWORD-1 and SWORD-2 are identical studies that examined stable suppressed subjects receiving 2 NRTIs plus either an INI, an NNRTI, or a PI, that switched to dolutegravir plus rilpivirine (n = 513) or remained on their current antiviral regimen (n = 511). The number of subjects who met the protocol-defined confirmed virologic withdrawal (CVW) criteria was low across the pooled SWORD-1 and SWORD-2 studies. Two subjects from each treatment arm met CVW criteria at any time through Week 48. NNRTI resistance associated substitution K101K/E mixture with no decreased susceptibility to rilpivirine (FC = 1.2) was observed in one subject with identified adherence issues that received dolutegravir plus rilpivirine. No integrase resistance was observed. This subject's viral load was 1,059,771 copies/mL at the suspected virologic withdrawal visit, and on resumption of dolutegravir plus rilpivirine the viral load decreased to 1,018 copies/mL at the confirmatory visit and was < 50 copies/mL at the withdrawal visit. No resistance-associated substitutions were observed for the other three subjects meeting CVW criteria.

Effects on electrocardiogram.

In a randomised, placebo controlled, crossover trial, 42 healthy patients received single dose oral administrations of placebo, dolutegravir 250 mg suspension (exposures approximately 3-fold of the 50 mg once daily dose at steady state), and moxifloxacin (400 mg, active control) in random sequence. Dolutegravir did not prolong the QTc interval for 24 hours postdose. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) was 1.99 msec (1 sided 95% upper CI: 4.53 msec).

Effects on renal function.

The effect of dolutegravir on serum creatinine clearance (CrCl), glomerular filtration rate (GFR) using iohexol as the probe and effective renal plasma flow (ERPF) using para-aminohippurate (PAH) as the probe was evaluated in an open label, randomised, 3 arm, parallel, placebo controlled study in 37 healthy patients, who were administered dolutegravir 50 mg once daily (n = 12), 50 mg twice daily (n = 13) or placebo once daily (n = 12) for 14 days. A modest decrease in CrCl was observed with dolutegravir within the first week of treatment, consistent with that seen in clinical studies. Dolutegravir at both doses had no significant effect on GFR or ERPF. These data support in vitro studies which suggest that the small increases in creatinine observed in clinical studies are due to the nonpathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.

Clinical trials.

Antiretroviral naïve patients.

The efficacy of Tivicay in HIV infected, therapy naïve patients is based on data from two randomised, international, double blind, active controlled trials, 96 week data from SPRING-2 (ING113086) and SINGLE (ING114467). This is supported by 96 week data from an open label and active controlled study FLAMINGO (ING114915) and additional data from the open-label phase of SINGLE to 144 weeks. The efficacy of dolutegravir in combination with lamivudine in adults is supported by 48-week primary endpoint data from two identical 148-week, randomised, multicentre, double-blind, non-inferiority studies GEMINI-1 (204861) and GEMINI-2 (205543).
In SPRING-2, 822 adults were randomised and received at least one dose of either Tivicay 50 mg once daily or raltegravir 400 mg twice daily, both administered with fixed dose dual NRTI therapy (either ABC/3TC or TDF/FTC). At baseline, median patient age was 36 years, 14% were female, 15% non-white, and 12% had hepatitis B and/or C co-infection and 2% were CDC class C; these characteristics were similar between treatment groups.
In the SPRING-2 study through 96 weeks, virologic suppression (HIV-1 RNA < 50 copies/mL) in the dolutegravir group (81%) was non-inferior to the raltegravir group (76%) based on a margin of -10% [difference (95% CI) 4.5% (-1.1%, 10.0%)]. The median change in CD4+ T cell count from baseline were 230 cells/mm3 in the group receiving Tivicay and the raltegravir group at 48 weeks and 276 cells/mm3 in the group receiving dolutegravir compared to 264 cells/mm3 the raltegravir group at 96 weeks.
In SINGLE, 833 patients were randomised and received at least one dose of either Tivicay 50 mg once daily with fixed dose abacavir lamivudine (DTG + ABC/3TC) or fixed dose efavirenz tenofovir emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-white, 7% had hepatitis C co-infection and 4% were CDC class C, these characteristics were similar between treatment groups.
In the SINGLE study at week 48, virologic suppression (HIV-1 RNA < 50 copies/mL) in the Tivicay + ABC/3TC arm was 88%, which was superior to the EFV/TDF/FTC arm (81%), based on the primary analysis (p = 0.003). At week 96, the percentage of participants virologically suppressed (i.e. having < 50 copies/mL using a missing, switch or discontinuation = failure analysis) was 80% for those on the Tivicay + ABC/3TC regimen vs. 72% for those on EFV/TDF/FTC [difference (95% CI) 8.0% (2.3%, 13.8%)]. The higher responses on DTG + ABC/3TC were driven by withdrawals due to AEs and missing data.
The adjusted mean change in CD4+ T cell count from baseline were 267 cells/mm3 in the group receiving Tivicay + ABC/3TC and 208 cells/mm3 for the EFV/TDF/FTC arm in SINGLE at 48 weeks. The adjusted difference and 95% CI was 58.9 (33.4, 84.4), p < 0.001 (repeated measure model adjusting for the baseline stratification factors: baseline HIV-1 RNA and baseline CD4+ T cell count, among other factors). This analysis was prespecified and adjusted for multiplicity. The median time to viral suppression was 28 days in the group receiving Tivicay + ABC/3TC and 84 days in the EFV/TDF/FTC arm in SINGLE at 48 weeks (p < 0.0001). This analysis was prespecified and adjusted for multiplicity.
At 144 weeks in the open-label phase, virologic suppression in the dolutegravir + ABC/3TC arm was 71% and in the EFV/TDF/FTC arm it was 63%, treatment difference was 8.3% (2.0%, 14.6%).
The primary endpoint and other week 48 outcomes (including outcomes by key baseline covariates) for SPRING-2 and SINGLE are shown in Table 5.
In both SPRING-2 and SINGLE studies virologic suppression (HIV-1 RNA < 50 copies/mL), treatment differences were comparable across baseline characteristics (gender, race and age).
Through 96 weeks in SINGLE and SPRING-2, no INI-resistant mutations or treatment emergent resistance in background therapy were isolated on the Tivicay containing arms. In SPRING-2, four patients on the raltegravir arm failed with major NRTI mutations and one patient developed raltegravir resistance; in SINGLE, six patients on the EFV/TDF/FTC arm failed with mutations associated with NNRTI resistance and one developed a major NRTI mutation.
In FLAMINGO (ING114915), an open label and active controlled study, 484 HIV-1 infected antiretroviral naïve adults were randomised and received one dose of either dolutegravir 50 mg once daily or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily, both administered with fixed dose dual NRTI therapy (either ABC/3TC or TDF/FTC). At baseline, median patient age was 34 years, 15% were female, 28% nonwhite, 10% had hepatitis B and/or C coinfection, and 3% were CDC class C; these characteristics were similar between treatment groups.
Virologic suppression (HIV-1 RNA < 50 copies/mL, snapshot algorithm: missing, switch or discontinuation = failure) in the dolutegravir group (90%) was superior to the DRV/r group (83%) at 48 weeks. The adjusted difference in proportion and 95% CI were 7.1% (0.9, 13.2), p = 0.025. At Week 96 virologic suppression in the dolutegravir group was 80% and in the DRV/r group it was 68%, treatment difference was 12.4% (4.7%, 20.2%). No treatment emergent primary INI, PI or NRTI resistance mutations were observed for subjects in the dolutegravir or DRV + RTV treatment groups. Treatment failure due to 'no virologic data' was 10 (4%) in the dolutegravir group and 24 (10%) in the DRV + RTV group.
Sustained virological response was demonstrated in the SPRING-1 study (ING112276), in which 88% of patients receiving Tivicay 50 mg (n = 51) once daily had HIV-1 RNA < 50 copies/mL, compared to 72% of patients in the efavirenz group (n = 50) at 96 weeks. No INI-resistant mutations or treatment emergent resistance in background therapy were isolated with Tivicay 50 mg once daily through 96 weeks.
In GEMINI-1 (204861) and GEMINI-2 (205543), identical 148-week, randomised, double-blind, multicentre, non-inferiority studies, 1433 adult HIV-1 infected antiretroviral naïve subjects were randomised and received a two-drug regimen dolutegravir 50 mg plus lamivudine 300 mg once daily or dolutegravir 50 mg once daily with fixed dose tenofovir/emtricitabine (TDF/FTC). Subjects were enrolled with a screening plasma HIV-1 RNA of 1000 c/mL to ≤ 500,000 c/mL. At baseline, in the pooled analysis of all patients, median patient age was 33 years, 15% were female, 32% non-white, 6% had hepatitis C co-infection and 9% were CDC Stage 3; these characteristics were similar between treatment groups. Virologic suppression (HIV-1 RNA < 50 copies/mL) in the dolutegravir plus lamivudine group (91% [pooled data]) was non-inferior to the dolutegravir plus TDF/FTC group (93% [pooled data]) at 48 weeks. The adjusted difference in proportion and 95% CI were -1.7% (-4.4, 1.1). The results of the pooled analysis were in line with those of the individual studies, for which the primary endpoint (difference in proportion < 50 copies/mL plasma HIV-1 RNA at week 48 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus TDF/FTC) was met. The adjusted difference was -2.6% (95% CI: -6.7; 1.5) for GEMINI-1 and -0.7% (95% CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%. Through 48 weeks in the GEMINI-1 and GEMINI-2 studies, no cases of emergent resistance to the integrase- or NRTI-class were seen in either the dolutegravir plus lamivudine or comparator dolutegravir + TDF/FTC arms. For both pooled treatment groups, the overall lipid profiles were generally improved from baseline, and the proportions of subjects showing favourable improvements in total cholesterol/HDL cholesterol ratio were similar between the 2 treatment groups. See Table 6.

Antiretroviral experienced (and integrase inhibitor naïve) patients.

In the international, multicentre, double blind SAILING study (ING111762), 719 HIV-1 infected, ART experienced adults were randomised and received either Tivicay 50 mg once daily or raltegravir 400 mg twice daily with investigator selected background regimen (BR) consisting of up to 2 agents (including at least one fully active agent). At baseline, median patient age was 43 years, 32% were female, 50% nonwhite, 16% had hepatitis B and/or C coinfection, and 46% were CDC class C. All patients had at least two class ART resistance, and 49% of patients had at least 3 class ART resistance at baseline.
In the SAILING study, virologic suppression (HIV-1 RNA < 50 copies/mL) in the dolutegravir arm (71%) was statistically superior to the raltegravir arm (64%), at week 48 (p = 0.030). Virologic suppression (HIV-1 RNA < 50 copies/mL) treatment differences were comparable across the baseline characteristics of gender, race, and HIV subtype. The mean changes in CD4+ T cell count from baseline based on observed data were 113 cells/mm3 (n = 326) at week 24 and 162 cells/mm3 (n = 294) at week 48 in the group receiving Tivicay and 106 cells/mm3 (n = 326) at week 24 and 153 cells/mm3 (n = 283) at week 48 for the raltegravir group.
At week 48, 21 (6%) DTG subjects and 45 (12%) RAL subjects experienced PDVF. Statistically fewer patients failed therapy with treatment emergent resistance in the IN gene on Tivicay (4/354, 1%) than on raltegravir (17/361, 5%) (p = 0.003).
Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 7.

Integrase inhibitor resistant patients.

In the phase IIb, international multicentre, open label, single arm, noncomparative sequential cohort VIKING pilot study (ING112961), two sequential cohorts of patients with multiclass resistance including resistance to HIV integrase inhibitors were enrolled to examine the antiviral activity of Tivicay 50 mg once daily (n = 27) vs. 50 mg twice daily (n = 24) after 10 days of functional monotherapy. Responses were greater with twice daily (1.8 log10 change from baseline in HIV RNA) than with once daily dosing (1.5 log10 change from baseline, adjusted difference 0.3 log10, p = 0.017). Higher response rates with twice daily dosing were maintained with continued Tivicay dosing and optimization of the background regimen through 48 weeks of therapy (33% vs. 71% < 50 copies/mL, intent-to-treat exposed (ITT-E) population TLOVR analysis). A comparable safety profile was observed across doses. Subsequently, VIKING-3 examined the effect of Tivicay 50 mg twice daily over 7 days of functional monotherapy, followed by optimised background therapy and continued Tivicay twice daily treatment.
In the multicentre, open label, single arm, noncomparative VIKING-3 study (ING112574), HIV-1 infected, ART experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Tivicay 50 mg twice daily with the current failing background regimen for 7 days but with optimised background ART from day 8. One hundred and eighty three patients enrolled, 133 with INI resistance at screening and 50 with only historical evidence of resistance (and not at screening). At baseline, median patient age was 48 years, 23% were female, 29% nonwhite, and 20% had hepatitis B and/or C coinfection. Median baseline CD4+ was 140 cells/mm3, median duration of prior ART was 14 years, and 56% were CDC class C. Patients showed multiple class ART resistance at baseline: 79% had ≥ 2 NRTI, 75% ≥ 1 NNRTI, and 71% ≥ 2 PI major mutations; 62% had non-R5 virus. The Virological Outcome (VO) population excluded patients who stopped therapy for non-efficacy reasons, and those with major protocol deviations (incorrect dolutegravir dosing, intake of prohibited co-medication). The VO population is a subset of the ITT-E population.
Mean change from baseline in HIV RNA at day 8 (primary endpoint) was -1.4 log10 (95% CI -1.3 - -1.5 log10, p < 0.001). Response was associated with baseline INI mutation pathway, as shown in Table 8.
After the monotherapy phase, patients had the opportunity to re-optimise their background regimen when possible.
Of the 183 patients who completed 24 weeks on study or discontinued before data cut off, 126 (69% [95% CI: 62%, 76%]) had < 50 copies/mL RNA at week 24 (ITT-E, snapshot algorithm). Patients harbouring virus with Q148 with additional Q148 associated secondary mutations had lower response at week 24 (Table 9). Background overall susceptibility score (OSS) was not associated with week 24 response.
The response rate at week 48 was sustained with 116/183 (63% [95% CI: 56%, 70%]) subjects having HIV-1 RNA < 50 copies/mL (ITT-E, snapshot algorithm). Response was also sustained through week 48 in subjects harbouring virus with Q148 with additional Q148 associated secondary mutations. The proportion of subjects with HIV RNA < 50 copies/mL at week 48 was 88/113 (78%) for no Q148 mutations, 19/31 (61%) for Q148 + 1 and 4/16 (25%) for Q148 + ≥ 2 secondary mutations (VO population, snapshot algorithm).
Virologic suppression (HIV-1 RNA < 50 copies/mL) was comparable across baseline characteristics (gender, race and age). The median change in CD4+ T cell count from baseline for VIKING-3 based on observed data was 61 cells/mm3 at week 24 (n = 163) and 110 cells/mm3 at week 48 (n = 145).
In the multicentre, double blind, placebo controlled VIKING-4 study (ING116529), 30 HIV-1 infected, ART experienced adults with current virological failure on an integrase inhibitor containing regimen and primary genotypic resistance to INIs at screening, were randomised to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for 7 days with all subjects receiving open label dolutegravir plus optimised background regimen from day 8. At baseline, median patient age was 49 years, 20% were female, 58% non-white, and 23% had hepatitis B and/or C co-infection. Median baseline CD4+ was 160 cells/mm3, median duration of prior ART was 13 years, and 63% were CDC Class C. Subjects showed multiple class ART resistance at baseline: 80% had ≥ 2 NRTI, 73% ≥ 1 NNRTI, and 67% ≥ 2 PI major mutations; 83% had non-R5 virus. Sixteen of 30 subjects (53%) harboured Q148 virus at baseline. The primary endpoint treatment comparison at day 8, showed that dolutegravir 50 mg twice daily was superior to placebo, with an adjusted mean treatment difference for the change from baseline in plasma HIV-1 RNA at day 8 of -1.2 log10 copies/mL (95% CI -1.5, -0.8 log10 copies/mL, p < 0.001). At week 48, 12/30 (40%) subjects had HIV-1 RNA < 50 copies/mL (ITT-E, Snapshot algorithm).
In a combined analysis of VIKING-3 and VIKING-4 (n = 186, VO population), the proportion of subjects with HIV RNA < 50 copies/mL at Week 48 was 123/186 (66%). The proportion of subjects with HIV RNA < 50 copies/mL was 96/126 (76%) for No Q148 mutations, 22/41 (54%) for Q148+1 and 5/19 (26%) for Q148+ ≥ 2 secondary mutations.

Virologically suppressed patients.

The efficacy of dolutegravir plus rilpivirine is supported by data from 2 randomised, open-label, controlled trials (SWORD-1 [201636] and SWORD-2 [201637]) in virologically suppressed patients switching from their current antiretroviral regimen (CAR).
SWORD-1 and SWORD-2 are identical 148-week, Phase III, randomised, multicenter, parallel-group, non-inferiority studies. A total of 1,024 adult HIV-1 infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INI, an NNRTI, or a PI) received treatment in the studies. Subjects were randomised 1:1 to continue their CAR or be switched to a two-drug regimen dolutegravir plus rilpivirine administered once daily. At Week 52, subjects who were originally assigned to continue their CAR and remained virologically suppressed switched to dolutegravir plus rilpivirine and are planned to be followed to Week 148. The primary efficacy endpoint for the SWORD studies was the proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Week 48 (Snapshot algorithm for the ITT-E population).
At baseline, in the pooled analysis, the median age of subjects was 43 years, 22% female, 20% non-white, 11% were CDC Class C (AIDS), and 11% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment arms. In the pooled analysis, 54%, 26%, and 20% of subjects were receiving an NNRTI, PI, or INI (respectively) as their baseline third treatment agent class prior to randomisation and was similar between treatment arms.
The pooled primary analysis demonstrated that dolutegravir plus rilpivirine is non-inferior to CAR, with 95% of subjects in both arms achieving the primary endpoint of < 50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshot algorithm (Table 10).
The primary endpoint and other outcomes (including outcomes by key baseline covariates) for the pooled SWORD-1 and SWORD-2 studies are shown in Table 10.

Children.

In a phase I/II 48 week multicentre, open label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of Tivicay was evaluated in combination regimens in HIV-1 infected infants, children and adolescents.
At 48 weeks, 14 of 23 (61%) children and adolescents (12 to less than 18 years of age) treated with Tivicay once daily (35 mg n = 4, 50 mg n = 19) plus OBR achieved viral load less than 50 copies/mL.
At 24 weeks, 14 of 23 (61%) children (6 to less than 12 years of age) treated with dolutegravir (70 mg, as 35 mg twice daily, n = 1; 50 mg once daily, n = 5; 35 mg once daily, n = 6; 25 mg once daily, n = 8; and 20 mg once daily, n = 3) plus OBR, achieved viral load less than 50 copies/mL. See Table 11.
There are no data available on the use of dolutegravir plus lamivudine as a two-drug regimen in paediatric patients.
There are no clinical study data with dolutegravir plus rilpivirine in the paediatric population.

5.2 Pharmacokinetic Properties

Dolutegravir pharmacokinetics is similar between healthy and HIV infected patients. The PK variability of dolutegravir is between low to moderate. In phase I studies in healthy patients, between patient CVb% for AUC and Cmax ranged from ~20 to 40% and CT from 30 to 65% across studies. The between patient PK variability of DTG was higher in HIV infected patients than healthy patients and CVb% was estimated to be 30-50% for AUC and Cmax, and at 55-140% for Cτ. Within patient variability (CVw%) is lower than between patient variability.

Absorption.

Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours postdose for tablet formulation. The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of tablet formulations, in general, dolutegravir exhibited nonlinear pharmacokinetics with less than dose proportional increases in plasma exposure from 2 to 100 mg; however increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg.
Dolutegravir may be administered with or without food. Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC(0-∞) by 34%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. These increases are not clinically significant.
The absolute bioavailability of dolutegravir has not been established.

Distribution.

Dolutegravir is highly bound (approximately 99.3%) to human plasma proteins based on in vitro data. The apparent volume of distribution (following oral administration of suspension formulation, Vd/F) is estimated at 12.5 L. Binding of dolutegravir to plasma proteins was independent of concentration. Total blood and plasma drug related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. Free fraction of dolutegravir in plasma is estimated at approximately 0.2 to 1.1% in healthy patients, approximately 0.4 to 0.5% in patients with moderate hepatic impairment, and 0.8 to 1.0% in patients with severe renal impairment and 0.5% in HIV-1 infected patients.
Dolutegravir is present in cerebrospinal fluid (CSF). In 12 treatment naïve subjects receiving a regimen of dolutegravir plus abacavir/ lamivudine (3TC) for 16 weeks, dolutegravir concentrations observed in CSF at both week 2 and week 16 exceed the in vitro IC50 against wild type viruses (0.2 nanogram/mL) for all participants.
CSF: plasma concentration ratio of DTG ranged from 0.11 to 2.04%. Dolutegravir concentrations in CSF exceeded the IC50, supporting the median reduction from baseline in CSF HIV-1 RNA of 2.2 log after 2 weeks and 3.4 log after 16 weeks of therapy (see Section 5.1 Pharmacodynamic Properties).
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue, and vaginal tissue were 6 to 10% of that in corresponding plasma at steady state. AUC was 7% in semen and 17% in rectal tissue, of those in corresponding plasma at steady state.

Metabolism.

Dolutegravir is primarily metabolised via UGT1A1 with a minor CYP3A component (9.7% of total dose administered in a human mass balance study). Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged drug is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-one percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).

Excretion.

Dolutegravir has a terminal half-life of ~14 hours and an apparent clearance (CL/F) of 0.56 L/hr.

Special patient populations.

Children.

The pharmacokinetics of dolutegravir was evaluated in 10 children and adolescents 12 to 18 years of age and showed that a dolutegravir dose of 50 mg once daily resulted in dolutegravir exposure in paediatric patients comparable to that observed in adults who received dolutegravir 50 mg once daily (Table 12).
The pharmacokinetics was evaluated in 11 children 6 to 12 years of age and showed that 25 mg once daily in patients weighing at least 20 kg and 35 mg once daily in patients weighing at least 30 kg resulted in dolutegravir exposure comparable to adults. The recommended dose is 50 mg once daily in patients weighing at least 40 kg (Table 12).
Trough concentrations were below 0.5 microgram/mL (the EC95, based on data from Day 10 monotherapy proof of concept study) in nearly 25% simulated subjects in the 15 - < 20 kg and 20 - < 30 kg weight band. In addition, population PK modelling and simulation analyses showed dosing of dolutegravir tablets on a weight-based basis (20 mg, 25 mg, 35 mg, 50 mg) in children of at least 6 years of age weighing at least 15 kg provides comparable exposure to that observed in adults (50 mg), with the lowest weight band of 15 to < 20 kg corresponding to 20 mg daily.

Elderly.

Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure.
Pharmacokinetic data for dolutegravir in patients of > 65 years old are limited.

Renal impairment.

Renal clearance of unchanged drug is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in patients with severe renal impairment (CrCl < 30 mL/min). No clinically important pharmacokinetic differences between patients with severe renal impairment (CrCl < 30 mL/min) and matching healthy patients were observed. No dosage adjustment is necessary for patients with renal impairment. Caution is warranted for INI experienced patients (with certain INI associated resistance substitutions or clinically suspected INI resistance) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to dolutegravir or other co-administered antiretroviral agents. Dolutegravir has not been studied in patients on dialysis, though differences in exposure are not expected.

Hepatic impairment.

Dolutegravir is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with moderate hepatic impairment (Child-Pugh category B) to 8 matched healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the two groups. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.

Polymorphisms in drug metabolising enzymes.

There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomic samples collected in clinical studies in healthy patients, patients with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with patients with genotypes associated with normal metabolism via UGT1A1 (n = 41). Polymorphisms in CYP3A4, CYP3A5, and NR1I2 were not associated with differences in the pharmacokinetics of dolutegravir.

Gender.

The dolutegravir exposure in healthy patients appear to be slightly higher (~20%) in women than men based on data obtained in a healthy patient study (males n = 17, females n = 24). Population PK analyses using pooled pharmacokinetic data from phase IIb and phase III adult trials revealed no clinically relevant effect of gender on the exposure of dolutegravir.

Race.

Population PK analyses using pooled pharmacokinetic data from phase IIb and phase III adult trials revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese patients appear similar to observed parameters in Western (US) patients.

Co-infection with hepatitis B or C.

Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited data on patients with hepatitis B co-infection.

5.3 Preclinical Safety Data

Genotoxicity.

Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.

Carcinogenicity.

In long-term oral carcinogenicity studies conducted with dolutegravir no drug related increases in tumour incidence were found in mice at doses up to 500 mg/kg/day (14 times the human systemic exposure based on AUC at the maximum recommended dose of 50 mg BID) or in rats at doses up to 50 mg/kg/day (12 times the human systemic exposure based on AUC at the maximum recommended dose).

4 Clinical Particulars

4.1 Therapeutic Indications

Tivicay is indicated for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in adults and children over 6 years of age (see Section 4.4 Special Warnings and Precautions for Use, Dual regimens).

4.3 Contraindications

Tivicay is contraindicated in combination with dofetilide.
Tivicay is contraindicated in patients with known hypersensitivity to Tivicay or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Hypersensitivity reactions have been reported with integrase inhibitors, including Tivicay, and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including liver injury. Discontinue Tivicay and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with Tivicay or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.

Immune reconstitution syndrome.

In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) 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 and sometimes can be an atypical presentation.
Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of Tivicay therapy. Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B coinfected patients (see Section 4.8 Adverse Effects (Undesirable Effects)).

Opportunistic infections.

Patients receiving Tivicay or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Transmission of infection.

Patients should be advised that current antiretroviral therapy, including Tivicay, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

Dual regimens.

Rilpivirine and dolutegravir.

The dual regimen of rilpivirine and dolutegravir is only suitable for the treatment of HIV-1 infection in those patients who are virologically suppressed (HIV-1 RNA < 50 copies/mL) where there is no known or suspected resistance to either ART component.

Lamivudine and dolutegravir.

The dual regimen of lamivudine and dolutegravir is only suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to either ART component.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special patient populations.

Use in renal impairment.

See Section 4.2 Dose and Method and Administration; Section 5.2 Pharmacokinetic Properties, Special patient populations.

Use in the elderly.

There are limited data available on the use of Tivicay in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Paediatric use.

The safety and efficacy of Tivicay has not yet been established in children (< 6 years or weighing less than 15 kg).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Table 4.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Caution should be given to co-administering medications (prescription and nonprescription) that may change the exposure of Tivicay or medications that may have their exposure changed by Tivicay (see Section 4.3 Contraindications).
The recommended adult dose of Tivicay is 50 mg twice daily when co-administered with etravirine (without boosted protease inhibitors), efavirenz, nevirapine, tipranavir/ ritonavir, rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort. In paediatric patients, the weight-based once daily dose should be administered twice daily.
Tivicay should not be co-administered with polyvalent cation-containing antacids. Tivicay is recommended to be administered two hours before or six hours after these agents.
Tivicay is recommended to be administered 2 hours before or 6 hours after taking calcium, magnesium or iron supplements, or alternatively, administered with food.
Tivicay increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping co-administration of dolutegravir with metformin, to maintain glycaemic control.

Effect of Tivicay on the pharmacokinetics of other agents.

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) (IC50 = 1.93 micromolar), multidrug and toxin extrusion transporter (MATE)1 (IC50 = 6.34 micromolar) and MATE2-K (IC50 = 24.8 micromolar). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2. In vivo dolutegravir may increase plasma concentrations of drugs in which excretion is dependent upon OCT2 or MATE1 (dofetilide and metformin) (see Table 2). Given dolutegravir's in vivo exposure, it has a low potential to affect the transport of MATE2-K substrates in vivo.
In vitro, dolutegravir inhibited the basolateral renal transporters: organic anion transporter (OAT)1 (IC50 = 2.12 micromolar) and OAT3 (IC50 = 1.97 micromolar). However, dolutegravir had no notable effect on the in vivo pharmacokinetics of the OAT substrates tenofovir and para-aminohippurate, and therefore has low propensity to cause drug interactions via inhibition of OAT transporters.
In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50 > 50 micromolar) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.
In drug interaction studies, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir, ritonavir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, boceprevir, daclatasvir and oral contraceptives containing norgestimate and ethinyl estradiol.

Effect of other agents on the pharmacokinetics of Tivicay.

Dolutegravir is metabolised by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.
In vitro, dolutegravir is not a substrate of human organic anion transporting polypeptide (OATP)1B1, OATP1B3, or OCT1, therefore drugs that solely modulate these transporters are not expected to affect dolutegravir plasma concentration.
Selected drug interactions are presented in Table 2. Recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of Tivicay on human male or female fertility. Tivicay did not affect male or female mating or fertility in rats at doses up to 1000 mg/kg/day associated with an exposure level 24 times the clinical exposure based on AUC at the maximum recommended dose of 50 mg BID.
(Category B1)
Tivicay should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. Women of childbearing potential should undergo pregnancy testing before initiation of Tivicay and Tivicay should be avoided in the first trimester. Women of childbearing potential who are taking Tivicay should use effective contraception throughout treatment.
There are no adequate and well-controlled studies of Tivicay in pregnant women. The effect of Tivicay on human pregnancy is unknown.
As of May 2018, in an ongoing birth outcome surveillance study in Botswana, there have been 4 cases of neural tube defects reported out of 426 births (0.94%) to mothers who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.12% (14/11,300) in the non-dolutegravir arm and 0.09% (61/66,057) in the HIV-uninfected arm. Four cases reported with dolutegravir included one case each of encephalocele, anencephaly, myelomeningocele, and iniencephaly. No infant born to a woman who started dolutegravir during pregnancy had a neural tube defect (n = 2,812). A causal relationship of these events to the use of dolutegravir has not been established.
Data analysed to date from other sources including the APR, clinical trials, and post-marketing data are insufficient to address the risk of neural tube defects with dolutegravir. Due to the limited understanding of the types of neural tube defects reported with dolutegravir use and because the date of conception may not be determined with precision, avoid use of Tivicay at the time of conception and in the first trimester of pregnancy.
In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta and no evidence of teratogenicity, reproductive function, relevant embryonic or fetal toxicity, including neural tube defects, was identified.
Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (27 times the 50 mg human clinical exposure based on AUC at the maximum recommended dose of 50 mg BID).
Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of gestation was associated with marked maternal toxicity, but did not elicit developmental toxicity or teratogenicity in the offspring (0.4 times the clinical exposure based on AUC).
It is expected that dolutegravir will be secreted into human milk based on studies in lactating rats and their offspring, although this has not been confirmed in humans. The extent of excretion of dolutegravir in human breast milk is unknown.
Breastfeeding is not advised because of the potential for HIV transmission from mother to child, and the potential risk of adverse events due to antiretroviral drug excretion in breast milk.
In settings where formula feeding is unsafe or unavailable, the World Health Organisation has provided guidelines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

Antiretroviral naïve patients.

The safety assessment of Tivicay in HIV-1 infected treatment-naïve patients is based on the analyses of 96-week data from 2, international, multicentre, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and 48-week data from the international, multicentre, open-label FLAMINGO (ING114915) trial.
In SPRING-2, 822 patients were randomised and received at least 1 dose of either Tivicay 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate/ lamivudine or emtricitabine/ tenofovir). Through 96 weeks the rates of discontinuation due to adverse events were 1% in patients receiving Tivicay 50 mg once daily + either abacavir sulfate/ lamivudine (ABC/3TC) or tenofovir/ emtricitabine (TDF/FTC) and 2% in patients receiving raltegravir 400 mg twice daily + either abacavir sulfate/ lamivudine or emtricitabine/ tenofovir.
In SINGLE, 833 patients were randomised and received at least 1 dose of either Tivicay 50 mg with fixed dose abacavir sulfate/ lamivudine once daily or fixed dose efavirenz/ tenofovir/ emtricitabine (EFV/TDF/FTC) once daily. Through 96 weeks the rates of discontinuation due to adverse events were 3% in patients receiving Tivicay 50 mg once daily + abacavir sulfate/ lamivudine and 12% in patients receiving efavirenz/ emtricitabine/ tenofovir once daily.
Treatment emergent adverse reactions (adverse events assessed as causally related by the investigator) of moderate to severe intensity with a ≥ 2% frequency in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 3. Side by side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
Laboratory abnormalities with a worsening grade from baseline in ≥ 2% (for grades 3 to 4 combined) of patients are presented in Table 4. Side by side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
In a multicentre, open label trial (FLAMINGO), 243 subjects received Tivicay 50 mg once daily versus 242 subjects who received darunavir 800 mg/ ritonavir 100 mg once daily, both in combination with investigator selected NRTI background regimen (either ABC/3TC or TDF/FTC). There were 484 subjects included in the efficacy and safety analyses. Through 48 weeks, the rates of adverse events leading to discontinuation were 2% in subjects receiving Tivicay and 4% in subjects receiving darunavir/ ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.
Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE.
In identical 148-week, randomised, double-blind, multicentre, non-inferiority studies (GEMINI-1 and GEMINI-2), 1433 subjects where treated with a two-drug regimen of dolutegravir 50 mg plus lamivudine 300 mg once daily (n = 716) verses fixed dose tenofovir/emtricitabine (TDF/FTC) (n = 717) (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Through 48 weeks, the rates of adverse events leading to discontinuation in the pooled analysis were 2% of subjects in both treatment arms. The ADRs observed for the combination of dolutegravir and lamivudine in these studies were generally consistent with the ADR profiles and severities for the individual components when administered with other antiretroviral agents.

Antiretroviral experienced (and integrase inhibitor naïve) patients.

In an international, multicentre, double-blind trial SAILING (ING111762), 719 HIV-1 infected, antiretroviral treatment-experienced adults were randomised and received either Tivicay 50 mg once daily or raltegravir 400 mg twice daily with investigator selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of discontinuation due to adverse events were 2% (7/357) in patients receiving Tivicay 50 mg once daily + background regimen and 4% (13/362) in patients receiving raltegravir 400 mg twice daily + background regimen.
The only treatment emergent adverse reaction (adverse event assessed as causally related by the investigators) of moderate to severe intensity with a ≥ 2% frequency in either treatment group was diarrhea, 2% (6/357) in patients receiving Tivicay 50 mg once daily + background regimen and 1% (5/362) in patients receiving raltegravir 400 mg twice daily + background regimen.
Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment naïve (SPRING-2 and SINGLE) trials.

Integrase inhibitor resistant patients.

In a multicentre, open-label, single-arm trial VIKING-3 (ING112574), 183 HIV-1 infected, antiretroviral treatment experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Tivicay 50 mg twice daily with the current failing background regimen for 7 days and with optimised background therapy from day 8. The rate of discontinuation due to adverse events was 4% of patients at week 48.
Treatment emergent ADRs in VIKING-3 were generally similar compared with observations with the 50 mg once daily dose in adult phase III trials.
The most common treatment emergent laboratory abnormalities (> 5% for grades 2 to 4 combined) observed in VIKING-3 at week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4/183) of subjects had a grade 3 to 4, treatment emergent hematology laboratory abnormality, with neutropenia (2% [3/183]) being the most frequently reported.

Changes in clinical laboratory values.

Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. In treatment naïve patients a mean change from baseline of 9.96 micromol/L (range: 53 micromol/L to 54.8 micromol/L) was observed after 48 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment experienced patients. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate (GFR) (see Section 5.1 Pharmacodynamic Properties, Effects on renal function).
Small increases in total bilirubin (without clinical jaundice) were observed on dolutegravir and raltegravir (but not efavirenz) arms in the clinical trials. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway, uridine diphosphate glucuronosyltransferase (UGT1A1).
Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.

Less common adverse reactions observed in treatment naïve and treatment experienced trials.

The following adverse reactions occurred in < 2% of treatment naïve or treatment experienced patients in any one trial receiving Tivicay in a combination regimen. These events have been included because of their seriousness and assessment of potential causal relationship.

Gastrointestinal disorders.

Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting.

General disorders.

Fatigue.

Hepatobiliary disorders.

Hepatitis.

Psychiatric disorders.

Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.

Immune system disorders.

Hypersensitivity, immune reconstitution syndrome.

Skin and subcutaneous tissue disorders.

Pruritus.

Paediatric population.

Based on limited available data in children and adolescents (6 to less than 18 years of age), there were no additional types of adverse reactions beyond those observed in the adult population.

Co-infection with hepatitis B or C.

In phase III studies, patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some patients with hepatitis B and/or C co-infection at the start of Tivicay therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see Section 4.4 Special Warnings and Precautions for Use).

Post-marketing data.

Musculoskeletal and connective tissue disorders.

Uncommon: arthralgia, myalgia.

Psychiatric disorders.

Common: anxiety.

Investigations.

Uncommon: weight increased.

Hepatobiliary disorders.

Rare: acute hepatic failure*.
*Acute hepatic failure has been reported in a dolutegravir-containing regimen. The contribution of dolutegravir in these cases is unclear.

Reporting suspected adverse effects.

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

4.2 Dose and Method of Administration

Tivicay therapy should be initiated by a physician experienced in the management of HIV infection.
Tivicay can be taken with or without food.

Adults.

Patients infected with HIV-1 without resistance to the integrase class.

The recommended dose of Tivicay is 50 mg once daily.

Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected).

The recommended dose of Tivicay is 50 mg twice daily. The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The following should be considered prior to initiating treatment with Tivicay 50 mg twice daily:
reduced virologic response was observed in subjects treated with Tivicay 50 mg twice daily with an INI resistance Q148H/K/R mutation plus 2 or more additional INI-resistance mutations including, but not limited to G140A/C/S, E138A/K/T, or L74I (see Section 5 Pharmacological Properties).

Adolescents.

In patients who have not previously been treated with an integrase inhibitor, (12 to less than 18 years of age and weighing greater than or equal to 40 kg) the recommended dose of Tivicay is 50 mg once daily.
There are insufficient data to recommend a dose for Tivicay in integrase inhibitor resistant adolescents under 18 years of age.

Children.

In patients infected with HIV-1 without resistance to the integrase class, the recommended dose of dolutegravir in children (6 to less than 12 years of age and weighing at least 15 kg) is determined according to the weight of the child. Dose recommendations according to weight are presented in Table 1.
There are insufficient safety and efficacy data available to recommend a dose for Tivicay in children below age 6 or weighing less than 15 kg.
There is insufficient data to recommend a dose for dolutegravir in integrase inhibitor resistant children.

Populations.

Elderly.

There are limited data available on the use of Tivicay in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Renal impairment.

No dosage adjustment is required in patients with mild, moderate or severe (creatinine clearance (CrCl) < 30 mL/min, not on dialysis) renal impairment. No data are available in patients receiving dialysis, although differences in pharmacokinetics are not expected in this population (see Section 5.2 Pharmacokinetic Properties, Special patient populations).
Tivicay 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 Tivicay is coadministered with a drug that has dosing adjustment recommendations guided by estimated creatinine clearance.

Hepatic impairment.

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade A or B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C) (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Women of child bearing potential and pregnancy.

There are no adequate and well-controlled studies of Tivicay in pregnant women (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Tivicay on driving performance or the ability to operate machinery.
The clinical status of the patient and the adverse event profile of Tivicay should be borne in mind when considering the patient's ability to drive or operate machinery.

4.9 Overdose

Symptoms and signs.

There is currently limited experience with overdosage in Tivicay.
Limited experience of single higher doses (up to 250 mg in healthy patients) revealed no specific symptoms or signs, apart from those listed as adverse reactions.

Treatment.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
There is no specific treatment for an overdose of Tivicay. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As Tivicay is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tivicay tablets also contain: mannitol, microcrystalline cellulose, povidone, sodium starch glycolate Type A, sodium stearylfumarate, polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, and iron oxide yellow (25 mg and 50 mg tablets only).

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 30°C.

10 mg tablets only.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove desiccant.

6.5 Nature and Contents of Container

Tivicay tablets are supplied in HDPE (high density polyethylene) bottles containing 30 tablets. The 10 mg tablet bottles contain 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.

Summary Table of Changes