DOVATO 50/300 dolutegravir (as sodium) 50 mg/lamivudine 300 mg tablet bottle

Australia - English - Department of Health (Therapeutic Goods Administration)

Buy It Now

Active ingredient:
dolutegravir sodium,lamivudine
Available from:
ViiV Healthcare Pty Ltd
Authorization status:
Registered
Authorization number:
309378

DOVATO

Dolutegravir/lamivudine combination tablet

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about DOVATO. It does

not contain all the available

information. It does not take the

place of talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking DOVATO

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What DOVATO is used

for

DOVATO is used to treat HIV

(human immunodeficiency virus)

infection in adults and in children

over the age of 12 years.

DOVATO contains two active

ingredients that are used to treat HIV

infection: dolutegravir and

lamivudine. Dolutegravir belongs to

a group of anti-retroviral medicines

called integrase inhibitors (INIs).

Lamivudine belongs to a group of

anti-retroviral medicines called

nucleoside analogue reverse

transcriptase inhibitors (NRTIs).

DOVATO does not cure HIV

infection, it reduces the amount of

virus in your body and keeps it at a

low level. DOVATO also increases

the CD4 cell count in your blood.

CD4+ cells are a type of white blood

cell that are important in helping

your body to fight infection.

Not everyone responds to treatment

with DOVATO in the same way.

Your doctor will monitor the

effectiveness of your treatment.

Ask your doctor if you have any

questions about why this medicine

has been prescribed for you.

DOVATO is not addictive.

DOVATO is not recommended for

children under the age of 12 years as

the dosage cannot be modified.

DOVATO is only available with a

doctor's prescription.

DOVATO is not expected to affect

your ability to drive a car or operate

machinery.

Before you take

DOVATO

When you must not take it

Do not take DOVATO if:

you have ever had an allergic

reaction to any medicine

containing dolutegravir or

lamivudine.

you are allergic to 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're taking another medicine

called dofetilide or pilsicainide

(to treat heart conditions).

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

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:

liver disease, including hepatitis

B or C

kidney disease

Tell your doctor if you are

pregnant, think you could be

pregnant or plan to become

pregnant.

Your doctor will consider the

benefit to you and the risk to your

baby of taking DOVATO while

you're pregnant

If you could get pregnant while

receiving DOVATO, you need to

use a reliable method of

contraception, to prevent

pregnancy.

Taking dolutegravir (one of the

components of DOVATO) at the

time of becoming pregnant, or during

the first twelve weeks of pregnancy,

may increase the risk of a type of

DOVATO

birth defect, called neural tube

defect, such as spina bifida

(malformed spinal cord).

In babies and infants exposed to

NRTIs during pregnancy or labour,

small temporary increases in blood

levels of a substance called lactate

have been observed. Additionally,

there have been very rare reports of

diseases that affect the nervous

system such as a delayed

development and seizures.

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

If formula feeding is not possible,

you should get advice from your

doctor.

A small amount of the ingredients in

DOVATO can also pass into your

breast-milk.

If you have not told your doctor

about any of the above, tell him/

her before you start taking

DOVATO.

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.

Do not take DOVATO with these

medicines:

dofetilide or pilsicainide to treat

heart conditions

These medicines should not be

used with DOVATO:

emtricitabine, to treat HIV

infection

sorbitol-containing medicines

(usually liquids) used regularly

Tell your doctor if you're being

treated with any of these.

Tell your doctor if you are taking:

metformin, to treat diabetes

medicines called antacids, to treat

indigestion and heartburn. Do not

take an antacid during the 6 hours

before you take DOVATO, or for

at least 2 hours after you take it.

Calcium, magnesium and iron

supplements. Do not take a

calcium, magnesium or iron

supplement during the 6 hours

before you take DOVATO, or for

at least 2 hours after you take it.

If you take food with your

medicine you can take a calcium,

magnesium or iron supplement at

the same time as DOVATO.

etravirine, efavirenz, nevirapine

or tipranavir/ritonavir, to treat

HIV infection

rifampicin, to treat tuberculosis

(TB) and other bacterial

infections

co-trimoxazole, an antibiotic used

to treat Pneumocystis jiroveci

pneumonia (often referred to as

PJP or PCP) or toxoplasmosis

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

DOVATO 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 to take DOVATO

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 or bottle,

ask your doctor or pharmacist for

help.

How much to take

The usual dose of DOVATO in

adults and in children over the age of

12 years weighing at least 40 kg is

one tablet (50 mg dolutegravir and

300 mg lamivudine) taken once a

day.

If you weigh less than 40kg, you

cannot take DOVATO, because the

dose of each component of this

medicine cannot be adjusted to your

weight. Your doctor might prescribe

the components separately for you.

How to take it

Swallow the tablets whole with a

full glass of water.

Antacid medicines

Antacids, to treat indigestion and

heartburn, can stop DOVATO being

absorbed into your body and make it

less effective.

Do not take an antacid during the 6

hours before you take DOVATO, 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 DOVATO.

Talk to your doctor or pharmacist for

further advice on taking acid-

lowering (antacid) medicines with

DOVATO.

Calcium or iron supplements

Calcium or iron supplements can

stop DOVATO 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 DOVATO, or for at least 2

hours after you take it. If you take

food with DOVATO, then you can

take calcium and iron supplements at

the same time as DOVATO.

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.

DOVATO

It does not matter if you take this

medicine before or after food.

How long to take it

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 your next dose

is due within 4 hours, skip the dose

you missed and take the next one at

the usual time. Then continue your

treatment as before.

Do not take a double dose to make

up for the dose that you missed.

Just take it as soon as you

remember.

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 the Poisons Information Centre

(telephone 13 11 26) for advice, or

go to Accident and Emergency at

the nearest hospital, if you think

that you or anyone else may have

taken too much DOVATO. Do this

even if there are no signs of

discomfort or poisoning.

You may need urgent medical

attention.

Don't stop DOVATO without

advice

Take DOVATO for as long as your

doctor recommends. Don't stop

unless your doctor advises you to.

If you have hepatitis B infection,

don't stop DOVATO without your

doctor's advice, as your hepatitis may

come back

While you are using

DOVATO

You will need regular blood tests

For as long as you're taking

DOVATO, your doctor will arrange

regular blood tests to check for side

effects.

Stay in regular contact with your

doctor.

DOVATO 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 DOVATO

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 DOVATO 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). DOVATO 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 DOVATO.

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 take DOVATO to treat any

other complaints unless your

doctor tells you to.

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

DOVATO can make you dizzy and

have other side effects that make

you less alert

Be careful driving or operating

machinery until you know how

DOVATO affects you.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are taking

DOVATO.

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

DOVATO 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 DOVATO. If you get any of

these effects, and if they are severe,

your doctor may advise you to stop

taking DOVATO.

DOVATO

As well as the effects listed below

for DOVATO, other conditions can

develop during therapy for HIV.

Allergic reactions.

See a doctor as soon as possible if

you develop a rash.

Allergic reactions are uncommon in

people taking DOVATO. 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 DOVATO.

Lactic acidosis

Lactic acidosis is a rare but serious

side effect

Some people taking DOVATO, or

other medicines like it (NRTIs),

develop a condition called lactic

acidosis, together with an enlarged

liver.

Lactic acidosis is caused by a build-

up of lactic acid in the body. It is

rare; if it happens, it usually develops

after a few months of treatment. It

can be life-threatening, causing

failure of internal organs.

Lactic acidosis is more likely to

develop in people who have liver

disease, especially in women.

Signs of lactic acidosis include:

deep, rapid, difficult breathing

drowsiness

numbness or weakness in the

limbs

feeling sick (nausea), being sick

(vomiting)

stomach pain.

During your treatment, your doctor

will monitor you for signs of lactic

acidosis. If you have any of the

symptoms listed above or any other

symptoms that worry you see your

doctor as soon as possible.

As well as the conditions listed

above, other side effects 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.

Tell your doctor or pharmacist if

you notice any of the following and

they worry you:

Very common side effects

These may affect more than 1 in 10

people:

Headache

Feeling sick (nausea)

Diarrhoea.

Common side effects:

These may affect up to 1 in 10

people:

Suicidal thoughts (mainly in

patients who have had depression

or mental health problems before)

Depression

Being sick (vomiting)

Stomach pains (abdominal pain)

Stomach (abdominal) discomfort

Wind (flatulence)

Lack of energy (fatigue)

Generally feeling unwell

(malaise)

High Temperature (fever)

Dizziness

Feeling drowsy

Abnormal dreams

Difficulty in sleeping (insomnia)

Anxiety

Hair loss (alopecia)

Rash

Itching (pruritus)

Joint pain (arthralgia)

Muscle disorders

Common side effects that may

show up in your blood tests:

an increase in lactic acid in the

blood, which on rare occasions

can lead to lactic acidosis.

Uncommon side effects

These may affect up to 1 in 100

people:

allergic reaction (See 'allergic

reactions' earlier in this section)

inflammation of the liver

(hepatitis)

Suicide attempt (mainly in

patients who have had depression

or mental health problems before)

muscle pain (myalgia)

weight gain.

Uncommon side effects that may

show up in blood tests are:

a low red blood cell count

(anaemia) or low white blood cell

count (neutropenia)

a decrease in the number of cells

involved in blood clotting

(thrombocytopenia)

an increase in the level of liver

enzymes.

Rare side effects

These may affect up to 1 in 1000

people:

lactic acidosis (see 'lactic acidosis

is a rare but serious side effect'

earlier in this section)

liver failure (signs may include

yellowing of the skin and the

whites of the eyes or unusually

dark urine)

inflammation of the pancreas

(pancreatitis)

breakdown of muscle tissue

(rhabdomyolysis).

Rare side effects that may show up

in blood tests are:

increase in an enzyme called

amylase.

Very rare side effects

These may affect up to 1 in 10,000

people:

tingling or numbness of the hands

and feet (paraesthesiae)

DOVATO

numbness, tingling or weakness

of the arms and legs (peripheral

neuropathy).

Very rare side effects that may

show up in blood tests are:

failure of the bone marrow to

produce new red blood cells (pure

red cell aplasia).

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)

an increase in a kidney function

blood test result (creatinine).

Tell your doctor or pharmacist if

you notice anything that is making

you feel unwell.

Tell your doctor or pharmacist if

any of the side effects gets severe

or troublesome, or if you notice

any side effects not listed in this

leaflet.

Conditions you need to look out for

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 while you're taking

DOVATO, tell your doctor

immediately. Don't take other

medicines for the infection without

your doctor's advice.

After using DOVATO

Storage

Store in the original package. Keep

your tablets in a cool dry place

where the temperature stays below

30°C.

Do not store DOVATO tablets 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

DOVATO tablets are oval, biconvex,

white, film-coated tablet, debossed

with "SV 137" on one face.

They are supplied in a white bottle

which contains 30 tablets.

Ingredients

DOVATO tablets contain 50 mg of

dolutegravir (as sodium) and 300 mg

of lamivudine as the active

ingredients.

DOVATO also contains

Mannitol

Magnesium stearate

Microcrystalline cellulose

Povidone

Sodium starch glycollate Type A,

Sodium stearylfumarate

Hypromellose

Macrogol 400

Titanium dioxide

This medicine does not contain

lactose, sucrose, gluten, tartrazine or

any other azo dyes.

Supplier

DOVATO is supplied in Australia

ViiV Healthcare Pty Ltd

Level 4, 436 Johnston Street

Abbotsford, Victoria, 3067

Australia.

DOVATO: AUST R 309378

Trademarks are owned by or licensed

to the ViiV Healthcare group of

companies.

© 2019 ViiV Healthcare group of

companies or its licensor.

DOVATO

This leaflet was prepared on

September 2019

DOVATO

AUSTRALIAN PRODUCT INFORMATION

DOVATO (dolutegravir/lamivudine fixed-dose combination)

film-coated tablets

1

NAME OF THE MEDICINE

Dolutegravir (as dolutegravir sodium) and lamivudine

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

DOVATO film-coated tablets contain 50 mg of dolutegravir (as dolutegravir sodium) and 300

mg of lamivudine. Product information for dolutegravir and lamivudine contain additional

information.

Dolutegravir sodium is a white to light yellow powder.

Lamivudine is a white to off-white crystalline solid.

DOVATO tablets also contain mannitol.

For the full list of excipients, see Section 6.1 LIST OF EXCIPIENTS.

3

PHARMACEUTICAL FORM

Oval, biconvex, white, film-coated tablet, debossed with “SV 137” on one face.

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

DOVATO (a fixed dose combination of dolutegravir and lamivudine) is indicated for the

treatment of Human Immunodeficiency Virus-1 (HIV-1) infection in antiretroviral treatment-

naïve adults and adolescents (from 12 years of age weighing at least 40 kg) who have no

known or suspected resistance to either antiretroviral component (see section 5.1

PHARMACODYNAMIC PROPERTIES, Clinical trials).

4.2

DOSE AND METHOD OF ADMINISTRATION

DOVATO therapy should be initiated by a physician experienced in the management of HIV

infection.

DOVATO can be taken with or without food.

DOVATO is a fixed-dose tablet and should not be prescribed for patients requiring dosage

adjustments, such as those with creatinine clearance less than 50 mL/min.

Separate preparations of dolutegravir or lamivudine should be administered in cases where

discontinuation or dose adjustments are required. In these cases, the physician should refer

to the individual product information for these medicinal products.

Adults and Adolescents

The recommended dose of DOVATO in adults and adolescents weighing at least 40 kg is

one tablet (containing 50 mg of dolutegravir and 300 mg of lamivudine) once daily.

Children

The safety and efficacy of DOVATO in children aged less than 12 years or weighing less

than 40 kg have not been established. No data are available.

Elderly

There are limited data available on the use of dolutegravir and lamivudine 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). When treating elderly patients, consideration needs to be given

to the greater frequency of decreased hepatic and renal function, haematological

abnormalities, and concomitant medicinal products or disease.

Renal impairment

DOVATO has not been evaluated in subjects with renal impairment. Whilst no dosage

adjustment of dolutegravir is necessary in patients with renal impairment, a dose reduction of

lamivudine is required due to decreased clearance. Therefore, DOVATO is not

recommended for use in patients with a creatinine clearance less than 50 mL/min (see

Section 5.2 PHARMACOKINETIC PROPERTIES, Special patient populations).

Hepatic impairment

DOVATO has not been evaluated in subjects with hepatic impairment. No dosage

adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh

score A or B). No data are available for dolutegravir in patients with severe hepatic

impairment (Child-Pugh score C) (see Section 5.2 PHARMACOKINETIC PROPERTIES,

Special patient populations). DOVATO is not recommended for patients with severe hepatic

impairment.

4.3

CONTRAINDICATIONS

DOVATO is contraindicated in patients with known hypersensitivity to dolutegravir or

lamivudine or to any of the excipients (see Section 6.1 LIST OF EXCIPIENTS).

DOVATO is contraindicated in combination with dofetilide or pilsicainide.

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

The special warnings and precautions relevant to dolutegravir and lamivudine are included in

this section. There are no additional precautions and warnings relevant to DOVATO.

Hypersensitivity reactions

Hypersensitivity reactions have been reported with integrase inhibitors, including

dolutegravir, and were characterised by rash, constitutional findings, and sometimes, organ

dysfunction, including liver injury. Discontinue DOVATO 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 DOVATO or other suspect

agents after the onset of hypersensitivity may result in a life-threatening reaction.

Lactic acidosis/severe hepatomegaly with steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been

reported with the use of antiretroviral nucleoside analogues either alone or in combination,

including lamivudine. A majority of these cases have been in women.

Clinical features which may be indicative of the development of lactic acidosis include

generalised weakness, anorexia, and sudden unexplained weight loss, gastrointestinal

symptoms and respiratory symptoms (dyspnoea and tachypnoea).

Caution should be exercised when administering DOVATO particularly to those with known

risk factors for liver disease. Treatment with DOVATO should be suspended in any patient

who develops clinical or laboratory findings suggestive of lactic acidosis with or without

hepatitis (which may include hepatomegaly and steatosis even in the absence of marked

transaminase elevations).

Serum lipids and blood glucose

Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease

control and life style changes may also be contributing factors. Consideration should be

given to the measurement of serum lipids and blood glucose. Lipid disorders should be

managed as clinically appropriate.

In the GEMINI clinical trials (see Section 5.1 PHARMACODYNAMIC PROPERTIES, Clinical

trials), 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 Section

4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)).

Fat loss or fat gain

Fat loss or fat gain has been reported during combination antiretroviral therapy. The long

term consequences of these events are currently unknown. A causal relationship has not

been established.

Immune Reactivation 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 pneumonia. Any inflammatory symptoms

must be evaluated without delay and treatment initiated when necessary. Autoimmune

disorders (such as Graves’ disease, polymyositis and Guillain-Barré 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 dolutegravir therapy.

Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-

infection (see Patients co-infected with Hepatitis B Virus (HBV) later in this section and

Section 4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)).

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

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are

at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of

concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product

information for these medicinal products.

Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy

when starting therapy with DOVATO in hepatitis B co-infected patients. DOVATO includes

lamivudine, which is active against hepatitis B. Dolutegravir lacks such activity. Lamivudine

monotherapy is generally not considered an adequate treatment for hepatitis B, since the

risk for hepatitis B resistance development is high. If DOVATO is used in patients co-infected

with hepatitis B, an additional antiviral is therefore generally needed. Reference should be

made to treatment guidelines.

Data from clinical trials and marketed use of lamivudine, have shown that some patients co-

infected with chronic HBV disease may experience clinical or laboratory evidence of

recurrent hepatitis upon discontinuation of lamivudine, which may have more severe

consequences in patients with decompensated liver disease. If DOVATO is discontinued in

patients co-infected with HBV, periodic monitoring of both liver function tests and markers of

HBV replication is strongly recommended.

Hepatotoxicity

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an

increased frequency of liver function abnormalities during combination antiretroviral therapy.

Cases of hepatic toxicity, including abnormal liver function tests, hepatitis, and acute liver

failure, have also been reported in patients receiving a dolutegravir-containing regimen who

had no pre-existing hepatic disease or other identifiable risk factors. Monitoring for

hepatotoxicity is recommended. If there is evidence of worsening liver disease, interruption

or discontinuation of treatment must be considered.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use,

biphosphonates, alcohol consumption, severe immunosuppression, higher body mass

index), cases of osteonecrosis have been reported in patients with advanced HIV-disease

and/or long-term exposure to ART. Patients should be advised to seek medical advice if they

experience joint aches and pain, joint stiffness or difficulty in movement.

Opportunistic infections

Patients receiving DOVATO 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

While effective viral suppression with antiretroviral therapy has been proven to substantially

reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to

prevent transmission should be taken in accordance with national guidelines.

Use in hepatic impairment

See Section 4.2 DOSE AND METHOD OF ADMINISTRATION and Section 5.2

PHARMACOKINETIC PROPERTIES, Special patient populations.

Use in renal impairment

See Section 4.2 DOSE AND METHOD OF ADMINISTRATION and Section 5.2

PHARMACOKINETIC PROPERTIES, Special patient populations.

Use in the elderly

See Section 4.2 DOSE AND METHOD OF ADMINISTRATION and Section 5.2

PHARMACOKINETIC PROPERTIES, Special patient populations.

Paediatric use

DOVATO is not currently recommended for the treatment of children less than 12 years of

age as the necessary dose adjustment cannot be made. Clinical data is currently not

available for this combination. Physicians should refer to the individual product information

for dolutegravir and lamivudine.

Effects on laboratory tests

Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir

plus lamivudine and remained stable through 48 weeks. A mean change from baseline of

10.3

mol/L (range: -36.3

mol/L to 55.7

mol/L) was observed after 48 weeks of treatment.

These changes are not considered to be clinically relevant since they do not reflect a change

in glomerular filtration rate (see Section 5.1 PHARMACODYNAMICS, Effects on renal

function).

Small increases in total bilirubin (without clinical jaundice) were observed with dolutegravir

plus lamivudine. These changes are not considered clinically relevant as they likely reflect

competition between dolutegravir and unconjugated bilirubin for a common clearance

pathway (UGT1A1) (see Section 5.2 PHARMACOKINETIC PROPERTIES, Metabolism).

Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise

have also been reported with dolutegravir therapy.

4.5

INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTIONS

Caution should be given to co-administering medications (prescription and non-prescription)

that may reduce the exposure of dolutegravir, lamivudine or medications that may have their

exposure changed by DOVATO).

DOVATO should not be administered concurrently with other medicinal products containing

any of the same active components (dolutegravir and/or lamivudine).

Since the recommended dose of dolutegravir is 50 mg twice daily for patients taking

etravirine (without boosted protease inhibitors), efavirenz, nevirapine rifampicin,

tipranavir/ritonavir, carbamazepine, phenytoin, phenobarbital and St. John’s wort, the use of

DOVATO is not recommended for patients taking these medicines.

Dolutegravir should not be co-administered with polyvalent cation-containing antacids.

DOVATO is thus recommended to be administered 2 hours before or 6 hours after these

agents.

DOVATO is recommended to be administered 2 hours before or 6 hours after taking

calcium, magnesium or iron supplements, or alternatively, administered with food.

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be

considered when starting and stopping coadministration of DOVATO with metformin, to

maintain glycaemic control.

As DOVATO contains dolutegravir and lamivudine, any interactions that have been identified

with these agents individually may occur with DOVATO. Due to the different routes of

metabolism and elimination, no clinically significant drug interactions are expected between

dolutegravir and lamivudine.

Effect of DOVATO on the pharmacokinetics of other agents

Effect of dolutegravir on the pharmacokinetics of other agents

Dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of

cytochrome P450 enzymes, uridine diphosphate glucuronosyl transferase (UGT), or the

transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), bile salt export

pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic

cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2 or MRP4.

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC

> 50

M) 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 Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MRP2 or MRP4. In vitro,

dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir did not have

an effect on midazolam, a CYP3A4 probe. 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, rilpivirine, boceprevir, daclatasvir, and oral

contraceptives containing norgestimate and ethinyl estradiol.

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) (IC

= 1.93

multidrug and toxin extrusion transporter (MATE) 1 (IC

= 6.34

M) and MATE2-K (IC

24.8

M). Given the in vivo exposure, dolutegravir has a low potential to affect the transport

of MATE2-K substrates in vivo. In vivo dolutegravir increases plasma concentrations of

drugs in which excretion is dependent upon OCT2 or MATE1 (dofetilide, pilsicainide or

metformin) (see Table 1).

In vitro, dolutegravir inhibited the basolateral renal transporters: organic anion transporter

(OAT) 1 (IC

= 2.12

M) and OAT3 (IC

= 1.97

M). 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.

Effect of lamivudine on the pharmacokinetics of other agents

Lamivudine does not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or

CYP2D6) and demonstrates no or weak inhibition of the drug transporters OATP1B1,

OATP1B3, BCRP and Pgp, OCT3, MATE1 or MATE2-K. Lamivudine is therefore not

expected to affect the plasma concentrations of drugs that are substrates of these enzymes

or transporters.

Although lamivudine is an inhibitor of OCT1 and OCT2 in vitro, it has low potential to affect

the plasma concentrations of substrates of these transporters at the therapeutic dose

(300mg)/exposure.

Effect of other agents on the pharmacokinetics of DOVATO

Effect of other agents on the pharmacokinetics of dolutegravir

Dolutegravir is eliminated mainly through metabolism by UGT1A1 with some contribution

from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, Pgp, and BCRP in vitro;

therefore 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 or transporters may increase

dolutegravir plasma concentration (see Table 1).

In vitro, dolutegravir is not a substrate of human OATP1B1, OATP1B3, or OCT1, therefore

drugs that solely modulate these transporters are not expected to affect dolutegravir plasma

concentration.

Rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort, etravirine (without

boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir each reduced the

plasma concentrations of dolutegravir significantly and require dolutegravir dose adjustment

to 50 mg twice daily. A separate preparation of dolutegravir is available where a dose

adjustment is required due to drug-drug interactions. An additional dose of 50 mg

dolutegravir should be administered, approximately 12 hours after DOVATO. In these cases

the physician should refer to the dolutegravir product information.

Effect of other agents on the pharmacokinetics of lamivudine

The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and

plasma protein binding, and almost complete renal clearance. Lamivudine is not significantly

metabolised by CYP enzymes. Although lamivudine is a substrate of BCRP and Pgp in

vitro, inhibitors of these efflux transporters are unlikely to affect the disposition of lamivudine

due to its high bioavailability. Lamivudine is an in vitro substrate of MATE1, MATE2-K and

OCT2. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase

lamivudine plasma concentrations however; the resulting increase was of such magnitude

that a dose adjustment is not recommended as it is not expected to have clinical

significance. Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic

elimination plays a minor role in the clearance of lamivudine, drug interactions due to

inhibition of OCT1 are unlikely to be of clinical significance.

Selected drug interactions are presented in Tables 1 and 2. Recommendations are based

on either drug interaction studies performed in adults or predicted interactions due to the

expected magnitude of interaction and potential for serious adverse events or loss of

efficacy. DOVATO is not expected to be co-administered with other HIV-1 antiviral agents

and information is provided for reference.

Table 1:

Drug interactions studied with dolutegravir

Concomitant Drug Class:

Drug Name

Effect on Concentration of

Dolutegravir, Lamivudine, or

Concomitant Drug*

Clinical Comment

HIV-1 Antiviral Agents

Non-nucleoside Reverse

Transcriptase Inhibitor:

Etravirine (ETR) without

boosted protease inhibitors

Dolutegravir

Etravirine without boosted protease inhibitors

decreased plasma dolutegravir concentration.

Since the recommended dose of dolutegravir is

50 mg twice daily for patients taking etravirine

without boosted protease inhibitors., DOVATO

is not recommended for patients taking

etravirine without co-administration of

atazanavir/ritonavir, darunavir/ritonavir or

lopinavir/ritonavir.

Protease Inhibitor:

Lopinavir/ritonavir +

Etravirine

(LPV/RTV+ETR)

Dolutegravir

Lopinavir/ritonavir and etravirine did not change

dolutegravir plasma concentration to a clinically

relevant extent. No dose adjustment is

necessary.

Protease Inhibitor:

Darunavir/ritonavir +

Etravirine

(DRV/RTV+ETR)

Dolutegravir

Darunavir/ritonavir and etravirine did not

change dolutegravir plasma concentration to a

clinically relevant extent. No dose adjustment

is necessary.

Non-nucleoside Reverse

Transcriptase Inhibitor:

Efavirenz (EFV)

Dolutegravir

Efavirenz decreased dolutegravir plasma

concentrations. Since the recommended dose

of dolutegravir is 50 mg twice daily when co-

administered with efavirenz, the co-

administration of efavirenz with DOVATO is not

recommended

Non-nucleoside Reverse

Transcriptase Inhibitor:

Nevirapine

Dolutegravir

Co-administration with nevirapine has the

potential to decrease dolutegravir plasma

concentration due to enzyme induction and has

not been studied. Effect of nevirapine on

dolutegravir exposure is likely similar to or less

than that of efavirenz. Since the recommended

dose of dolutegravir is 50 mg twice daily when

co-administered with nevirapine, the co-

administration of nevirapine with DOVATO is

not recommended.

Protease Inhibitor:

Atazanavir (ATV)

Dolutegravir

Atazanavir increased dolutegravir plasma

concentration. No dose adjustment is

necessary.

Concomitant Drug Class:

Drug Name

Effect on Concentration of

Dolutegravir, Lamivudine, or

Concomitant Drug*

Clinical Comment

180%

Protease Inhibitor:

Atazanavir/ritonavir

(ATV+RTV)

Dolutegravir

121%

Atazanavir/ritonavir increased dolutegravir

plasma concentration. No dose adjustment is

necessary.

Protease Inhibitor:

Tipranavir/ritonavir

(TPV+RTV)

Dolutegravir

Tipranavir/ritonavir decreases dolutegravir

concentrations. Since the recommended dose

of dolutegravir is 50 mg twice daily when co-

administered with tipranavir/ritonavir, The co-

administration of tipranavir/ritonavir with

DOVATO is not recommended

Protease Inhibitor:

Fosamprenavir/ritonavir

(FPV+RTV)

Dolutegravir

Fosamprenavir/ritonavir decreases dolutegravir

concentrations, but based on limited data, did

not result in decreased efficacy in Phase III

studies. No dose adjustment is necessary in

INI-naïve patients.

Protease Inhibitor:

Lopinavir/ritonavir

(LPV+RTV)

Lopinavir/ritonavir did not change dolutegravir

plasma concentration to a clinically relevant

extent. No dose adjustment is necessary.

Protease Inhibitor:

Darunavir/ritonavir

(DRV+RTV)

Dolutegravir

Darunavir/ritonavir did not change dolutegravir

plasma concentration to a clinically relevant

extent. No dose adjustment is necessary.

Nucleoside Reverse

Transcriptase Inhibitor:

Tenofovir (TDF)

Dolutegravir

Tenofovir

Tenofovir did not change dolutegravir plasma

concentration to a clinically relevant extent. No

dose adjustment is necessary.

Concomitant Drug Class:

Drug Name

Effect on Concentration of

Dolutegravir, Lamivudine, or

Concomitant Drug*

Clinical Comment

Other Agents

Dofetilide

Pilsicainide

Dofetilide

Pilsicainide

Co-administration of dolutegravir has the

potential to increase dofetilide or pilsicainide

plasma concentration via inhibition of OCT2

transporter; co-administration has not been

studied. Dofetilide or pilsicainide co-

administration with dolutegravir is

contraindicated due to potential life-threatening

toxicity caused by high dofetilide or pilsicainide

concentration.

Carbamazepine

Dolutegravir

Carbamazepine decreased dolutegravir plasma

concentration. Since the recommended dose of

dolutegravir is 50 mg twice daily when co-

administered with carbamazepine, DOVATO is

not recommended for patients taking

carbamazepine.

Phenytoin

Phenobarbital

St. John’s wort (Hypericum

perforatum)

Dolutegravir

Co-administration with these metabolic

inducers has the potential to decrease

dolutegravir plasma concentration due to

enzyme induction and has not been studied.

The effect of these metabolic inducers on

dolutegravir exposure is likely similar to

carbamazepine. Since the recommended dose

of dolutegravir is 50 mg twice daily when co-

administered with these metabolic inducers,

DOVATO is not recommended for patients

taking these metabolic inducers.

Oxcarbazepine

Dolutegravir

This interaction has not been studied. Although

an inducer of CYP3A4, based on data from

other inducers, a clinically significant decrease

in dolutegravir is not expected. No dose

adjustment is necessary.

Omeprazole

Dolutegravir

Omeprazole did not change dolutegravir

plasma concentrations to a clinically relevant

extent. No dose adjustment is necessary.

Antacids containing

polyvalent cations (e.g.,

Mg, Al)

Dolutegravir

Co-administration of antacids containing

polyvalent cations decreased dolutegravir

plasma concentration. DOVATO is

recommended to be administered 2 hours

before or 6 hours after taking antacid products

containing polyvalent cations.

Calcium supplements

Dolutegravir

DOVATO is recommended to be administered

2 hours before or 6 hours after taking products

containing calcium, or alternatively, administer

with food.

Iron supplements

Dolutegravir

DOVATO is recommended to be administered

at least 2 hours before or 6 hours after taking

products containing iron, or alternatively,

administer with food.

Metformin

Metformin

Co-administration of DOVATO may increase

metformin plasma concentrations. A dose

adjustment of metformin should be considered

Public Summary

Summary for ARTG Entry:

309378

DOVATO 50/300 dolutegravir (as sodium) 50 mg/lamivudine 300 mg tablet bottle

ARTG entry for

Medicine Registered

Sponsor

ViiV Healthcare Pty Ltd

Postal Address

PO Box 18095,MELBOURNE CITY MC, VIC, 8001

Australia

ARTG Start Date

12/09/2019

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. DOVATO 50/300 dolutegravir (as sodium) 50 mg/lamivudine 300 mg tablet bottle

Product Type

Single Medicine Product

Effective date

12/09/2019

Permitted Indications

Indication Requirements

No Indication Requirements included on Record

Standard Indications

No Standard Indications included on Record

Specific Indications

DOVATO (a fixed-dose combination of dolutegravir and lamivudine) is indicated for the treatment of Human Immunodeficiency Virus-1 (HIV-1) infection

in antiretroviral treatment-naïve adults and adolescents (from 12 years of age weighing at least 40 kg) who have no known or suspected resistance to

either antiretroviral component.

Warnings

See Product Information and Consumer Medicine Information for this product

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

24 Months

Store below 30

degrees Celsius

Child resistant closure

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

Components

1. DOVATO 50/300 dolutegravir (as sodium) 50 mg/lamivudine 300 mg tablet bottle

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

Oval, biconvex, white, film-coated tablet, debossed with SV 137 on one

face

Active Ingredients

dolutegravir sodium

52.6 mg

lamivudine

300 mg

Public Summary

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Visit www.tga.gov.au for contact information

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

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Public Summary

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