Consumer medicine information

Dovato

Dolutegravir; Lamivudine

BRAND INFORMATION

Brand name

Dovato 50/300

Active ingredient

Dolutegravir; Lamivudine

Schedule

SUMMARY CMI

DOVATO

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking DOVATO?

DOVATO contains the active ingredients dolutegravir and lamivudine. DOVATO is used to treat HIV infection.

For more information, see Section 1. Why am I taking DOVATO? in the full CMI.

2. What should I know before I take DOVATO?

Do not use if you have ever had an allergic reaction to dolutegravir, lamivudine or any of the ingredients listed at the end of the CMI.

Do not take DOVATO if you are taking dofetilide or pilsicainide (used to treat heart conditions) or fampridine (for multiple sclerosis).

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take DOVATO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DOVATO and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take DOVATO?

The usual dosage of DOVATO is one tablet once a day
Swallow the tablet whole with a glass of water

More instructions can be found in Section 4. How do I take DOVATO? in the full CMI.

5. What should I know while taking DOVATO?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking DOVATO. For as long as you are taking DOVATO, your doctor will arrange for you to have regular blood tests to check for side effects.
Things you should not do	Do not stop using this medicine suddenly or change the dose without talking to your doctor. Do not take this medicine to treat any other complaints. Do not give this medicine to children under the age of 12.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how DOVATO affects you. DOVATO may cause dizziness and tiredness in some people.
Looking after your medicine	Store DOVATO below 30°C in the pack. Keep this medicine in the pack until it is time to take it.

For more information, see Section 5. What should I know while taking DOVATO? in the full CMI.

6. Are there any side effects?

Side effects that have been reported include headache, feeling sick (nausea) and vomiting, abdominal pain or discomfort, diarrhoea, increased wind (flatulence), fatigue, tiredness, lack of energy, a general feeling of being unwell, fever, dizziness, loss of hair, rash and itching, joint pain, muscle pain, weight gain, abnormal dreams, difficulty sleeping, depression, anxiety, having suicidal thoughts (mainly in patients who have had depression or mental health problems previously).

Allergic reaction has also been reported. Signs include swelling of the lips, tongue, wheezing or difficulty breathing, rash, hives on the skin. If this occurs seek medical attention immediately.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

DOVATO

Active ingredient(s): dolutegravir and lamivudine

Consumer Medicine Information (CMI)

This leaflet provides important information about using DOVATO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using DOVATO.

Where to find information in this leaflet:

1. Why am I taking DOVATO?
2. What should I know before I take DOVATO?
3. What if I am taking other medicines?
4. How do I take DOVATO?
5. What should I know while taking DOVATO?
6. Are there any side effects?
7. Product details

1. Why am I taking DOVATO?

DOVATO contains the active ingredients dolutegravir and lamivudine.

DOVATO belongs to a group of medicines known as antiretrovirals.

DOVATO is used to treat HIV infection in adults and children over the age of 12.

DOVATO does not cure AIDS or HIV infection however it slows down production of HIV in the body. In this way it stops ongoing damage to the body's immune system which fights infection.

You can still pass on HIV when taking this medicine through sexual activity or through passing on blood or bodily secretions which carry the HIV virus, although the risk is lowered by taking antiretroviral therapy.

You should use proper precautions to prevent this from occurring. Discuss with your doctor the precautions needed to avoid infecting other people.

While taking DOVATO and/or any other therapy for HIV, you may continue to develop other infections and other complications of HIV infection. You should keep in regular contact with your doctor.

2. What should I know before I take DOVATO?

Warnings

Do not use DOVATO if:

you are allergic to dolutegravir, lamivudine, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

you are taking dofetilide or pilsicainide (medicines used to treat heart conditions)
you are taking fampridine (a medicine used to treat multiple sclerosis)

Check with your doctor if you:

have any other medical conditions
have or have had any liver disease, including hepatitis B or C
have or have had kidney disease

If you have a long-standing viral infection of your liver (hepatitis B) it may flare up. This can cause serious illness particularly if your liver is already not working very well. If you have both HIV and hepatitis B, when you stop taking DOVATO your doctor is likely to arrange tests from time to time to check how well your liver is working and to measure virus levels.

take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Talk to your doctor if you are pregnant or intend to become pregnant.

In babies and infants exposed to nucleoside analogue reverse transcriptase inhibitors (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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Where possible, women who are HIV-positive should not breast-feed as HIV infection can be passed from the mother to the child in the breast milk. Dolutegravir is known to pass into the breastmilk in small amounts. Talk to your doctor if you are unable to formula feed.

Your doctor can discuss with you the benefits and risks of taking DOVATO whilst pregnant or breast-feeding.

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 and so the body starts to fight infections.

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

old, hidden infections flaring up at 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 medications to treat your HIV infection.

Symptoms may include:

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

If you get symptoms of infection or if you notice any of the symptoms above, tell your doctor immediately. Do not take other medicines for the infection without your doctor's advice.

Children and adolescents

DOVATO is not recommended for use in children under 12 years of age. DOVATO is a fixed dose combination tablet and as such it cannot be adjusted according to the size and weight of the patient.

3. What if I am taking other medicines?

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

Some medicines may interfere with DOVATO and affect how it works.

Do not take DOVATO with these medicines:

dofetilide or pilsicainide which are used to treat heart conditions
fampridine which is used to treat multiple sclerosis

These medicines should not be taken with DOVATO:

emtricitabine - a medicine used to treat HIV infection
sorbitol-containing medicines (usually come in liquid form) when used regularly

Tell your doctor or pharmacist if you are taking any of the medicines below:

metformin, used 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, medicines used to treat HIV infection
rifampicin, a medicine used 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, medicines that treat epilepsy
carbamazepine, a medicine used to treat epilepsy and bipolar disorder
St. John's wort (Hypericum perforatum), a herbal remedy to treat depression

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DOVATO.

4. How do I take DOVATO?

How much to take

The usual dosage of DOVATO in adults and children over the age of 12 and weighing at least 40 kg is one tablet once a day
Follow the instructions provided and use DOVATO until your doctor tells you to stop.

When to take DOVATO

Your doctor or pharmacist will tell you when to take DOVATO each day.

How to take DOVATO

Swallow the tablet whole with a glass of water
Do not halve the tablet
You can take DOVATO with or without food
If you are taking an antacid medicine it can stop DOVATO from 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.
If you are taking calcium or iron supplements they can also stop DOVATO from being absorbed into your body and make it less effective. Do not take your 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 DOVATO with food then you can also take your calcium or iron supplement at the same time as you take DOVATO.

If you forget to take DOVATO

DOVATO should be used regularly at the same time each day.

If your next dose is due within the next 4 hours, skip the dose you missed and take the next dose at the usual time. 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 you missed.

If you take too much DOVATO

If you think that you have taken too much DOVATO, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking DOVATO?

Things you should do

Ensure you have blood tests when you are meant to. It is important that your doctor monitors your health.

Tell your doctor straight away if you:

become pregnant or intend to become pregnant
have not taken DOVATO as intended

Remind any doctor, dentist or pharmacist you visit that you are taking DOVATO.

Things you should not do

Do not stop using this medicine suddenly or change the dose.
Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Do not use this medicine to treat any other complaints unless your doctor tells you to.
Do not give this medicine to children under the age of 12.

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 everyday to stop your illness from getting worse. Because DOVATO does not cure HIV infections, you may still develop other infections and illnesses linked to HIV.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DOVATO affects you.

DOVATO may cause dizziness and tiredness in some people.

Looking after your medicine

Follow the instructions on the pack on how to take care of your medicine properly.

Store it in a cool dry place (below 30°C) away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Within the first few weeks of treatment with anti-HIV medicines, some people, particularly those that have been HIV positive for some time, may develop inflammatory reactions (e.g. pain, redness, swelling, high temperature) which may resemble an infection and may be severe. It is thought that these reactions are caused by a recovery in the body's ability to fight infections, previously suppressed by HIV.

If you become concerned about any new symptoms, or any changes in your health after starting HIV treatment, discuss with your doctor immediately.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

headache
feeling sick (nausea), vomiting
abdominal pain or discomfort
diarrhoea
increased wind (flatulence)
fatigue, tiredness, lack of energy
a general feeling of being unwell (malaise)
fever
dizziness
loss of hair (alopecia)
rash
itching (pruritus)
joint pain (arthralgia), muscle disorders, muscle pain (myalgia)
weight gain
abnormal dreams
difficulty sleeping (insomnia)
depression, anxiety
having suicidal thoughts (mainly in patients who have had depression or mental health problems previously)

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

swelling of the lips, tongue, wheezing or difficulty breathing, rash, hives on the skin. These are all signs of an allergic reaction.
lactic acidosis

If you are taking medication for HIV and become unwell with fast breathing, drowsiness or numbness or weakness in the limbs, stop taking DOVATO and talk to your doctor immediately. The fast breathing is due to high acid levels in the blood. Your liver may not be working properly and gets big and fatty and can be life threatening. This illness occurs more often in women than men.

hepatitis (inflammation of the liver)
increase in liver enzymes

These will be picked up on a blood test.
Signs of liver failure including yellowing of the skin and whites of the eyes, unusually dark urine.

reduced red blood cell count (anaemia)
reduced white blood cell count (neutropenia)
reduced platelet count (thrombocytopenia)

Your doctor will ask you to have blood tests to monitor your levels of blood cells.

signs of an inflamed pancreas (pancreatitis) such as severe stomach pain or cramps, nausea, vomiting
breakdown of muscle tissue (rhabdomyolysis)
tingling or numbness of the hands and feet (paraesthesiae)
tingling or numbness of the arms and legs (peripheral neuropathy)

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Additional side effects which will only be picked up on a blood test include

increase in the enzyme amylase
failure of the bone marrow to produce new red blood cells (pure red cell aplasia)
increase in bilirubin (a substance produced by the liver)
increase in the level of enzymes produced in the muscles (creatinine phosphokinase)
increase in creatinine (a marker of kidney function)

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What DOVATO contains

Active ingredient (main ingredient)	dolutegravir lamivudine
Other ingredients (inactive ingredients)	hypromellose macrogol 400 magnesium stearate mannitol microcrystalline cellulose povidone sodium starch glycollate type A sodium stearylfumarate titanium dioxide
Potential allergens	mannitol

Do not take this medicine if you are allergic to any of these ingredients.

What DOVATO looks like

DOVATO tablets are oval, biconvex, white, film-coated tablets, debossed with "SV 137" on one side.

DOVATO is supplied in bottles of 30 tablets (AUST R 309378).

Who distributes DOVATO

ViiV Healthcare Pty Ltd
Level 4, 436 Johnson Street
Abbotsford VIC 3067
Australia

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

This leaflet was prepared in January 2025.

Version 5.0

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Dovato 50/300

Active ingredient

Dolutegravir; Lamivudine

Schedule

1 Name of 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 adults and adolescents (from 12 years of age weighing at least 40 kg):
in antiretroviral treatment-naïve patients with no antiretroviral treatment history who have no known or suspected resistance to either antiretroviral component; or
to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to the integrase inhibitor class or lamivudine (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.
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.

Risks and benefits of using Dovato in patients with renal impairment should be assessed by a physician experienced in the management of HIV infection and discussed with the patient.
Lamivudine exposure is significantly increased in patients with a creatinine clearance < 50 mL/min. Whilst no dosage adjustment of dolutegravir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Special patient populations, Renal impairment). Therefore, Dovato is not recommended for use in patients with a creatinine clearance less than 30 mL/min. If lamivudine dose adjustment is indicated, Dovato should be discontinued and the individual components should be used to construct the treatment regimen.

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.

Women of child bearing potential and pregnancy.

There is limited information on the use of Dovato in pregnancy. Dovato should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

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 must not be administered concurrently with medicinal products with narrow therapeutic windows, that are substrates of organic cation transporter 2 (OCT2), including but not limited to dofetilide, pilsicainide or fampridine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 jirovecii 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 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) or hepatitis C virus (HCV)) later in this section.

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; Section 5.2 Pharmacokinetic Properties, Special patient populations.

Use in renal impairment.

Administration in subjects with moderate renal impairment.

Patients with a creatinine clearance between 30 and 49 mL/min receiving Dovato may experience a 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥ 50 mL/min. There are no safety data from randomized, controlled trials comparing Dovato to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in < 1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.
Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Dovato should be monitored for lamivudine-related adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with Dovato. Dovato should be discontinued and the individual components should be used to construct the treatment regimen. (See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special patient populations).

Use in the elderly.

See Section 4.2 Dose and Method of Administration; 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 micromol/L (range: -36.3 micromol/L to 55.7 micromol/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 Pharmacodynamic Properties, 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 (IC₅₀ > 50 microM) 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) (IC₅₀ = 1.93 microM), multidrug and toxin extrusion transporter (MATE) 1 (IC₅₀ = 6.34 microM) and MATE2-K (IC₅₀ = 24.8 microM). 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 (for example dofetilide, pilsicainide, fampridine or metformin) (see Table 1).
In vitro, dolutegravir inhibited the basolateral renal transporters: organic anion transporter (OAT) 1 (IC₅₀ = 2.12 microM) and OAT3 (IC₅₀ = 1.97 microM). 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 (300 mg)/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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of dolutegravir or lamivudine on human male or female fertility. No studies on the effect on fertility have been conducted with Dovato. Individually, animal studies indicate no effects of dolutegravir or lamivudine on male or female fertility. Dolutegravir did not affect male or female fertility in rats at doses up to 1,000 mg/kg/day, associated with an exposure level 33 times the clinical exposure based on AUC at the maximum recommended dose of 50 mg once daily (QD). Similarly, lamivudine did not affect male or female fertility in rats at doses up to 2,000 mg/kg twice daily, associated with exposure levels of up to 94 times based on AUC and up to 41 times based on C_max, the clinical exposure at 300 mg QD.
(Category B3)
There is limited data on the use of Dovato in pregnancy. Dovato should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus.
No studies on the effect on embryofetal development have been conducted with the dolutegravir/lamivudine combination.

Summary.

Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini which together include over 14,000 individuals evaluated during pregnancy show similar prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV-negative individuals.
There are insufficient human data on the use of Dovato during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the Antiretroviral Pregnancy Registry (APR) with the individual components of Dovato do not indicate an increased risk of birth defects. The background risk for major birth defects for the indicated population is unknown.
In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognised pregnancies is 2% to 4% and 15% to 20%, respectively.

Data on dolutegravir.

The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. A subsequent analysis was conducted based on a larger cohort from the birth outcome surveillance study in Botswana and included over 9,460 individuals exposed to dolutegravir at conception, 23,664 individuals exposed to non-dolutegravir-containing regimens, and 170,723 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11% (95% CI: 0.05-0.19%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.11%, 95% CI: 0.07-0.16%), or to HIV-negative individuals (0.06%, 95% CI: 0.05-0.08%).
The Eswatini birth outcome surveillance study includes 9,743 individuals exposed to dolutegravir at conception, 1,838 individuals exposed to non-dolutegravir-containing regimens, and 32,259 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08% (95% CI: 0.04-0.16%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%, 95% CI: 0.06-0.56%) or to HIV-negative individuals (0.08%, 95% CI: 0.06-0.12%). The observed prevalence of neural tube defects in infants delivered to individuals taking non-dolutegravir-containing regimens had a wide confidence interval due to low sample size.
Limitations of these birth outcome surveillance studies include insufficient data to determine if baseline characteristics were balanced between the study groups or to assess other factors such as the use of folic acid during the preconception or first trimester periods.
In animal reproductive toxicity studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified.
Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (38 times the human clinical exposure based on AUC at the maximum recommended dose of 50 mg QD).
Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 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 (0.56 times the clinical exposure based on AUC).
Dolutegravir readily crosses the placenta in humans. In pregnant women with HIV, the median (range) foetal umbilical cord concentrations of dolutegravir were 1.28 (1.21 to 1.28) fold greater compared with maternal peripheral plasma concentrations. There is insufficient information on the effects of dolutegravir on neonates.
There are insufficient human data on the use of Dovato during pregnancy to definitively assess a drug-associated risk for birth defects. However, available human data from the APR with the individual components of Dovato do not indicate an increased risk of birth defects. The exposure periods below refer to the trimester of earliest exposure. Only exposures with follow-up data are included.
The APR has received prospective reports of 1,506 exposures to dolutegravir-containing regimens during pregnancy resulting in live births, as of July 2023. These consist of 957 exposures during the first trimester, 549 exposures during the second/third trimester and included 32 and 29 birth defects, respectively. The prevalence (95% CI) of defects among live births exposed to dolutegravir-containing regimens in the first trimester was 3.3% (2.3%, 4.7%) and in the second/third trimester 5.3% (3.6%, 7.5%).
In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. The background risk for major birth defects for the treatment-indicated population is unknown.

Data on lamivudine.

Lamivudine was associated with findings in animal reproductive toxicity studies. Lamivudine was not teratogenic in animal studies, but there were indications of an increase in early embryonic deaths in rabbits at exposure levels comparable to those achieved in man (based on C_max and AUC). However, there was no evidence of embryonic loss in rats at exposure levels of approximately 21 times the clinical exposure (based on C_max).
In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery.
The APR has received prospective reports of 13,185 exposures to lamivudine-containing regimens during pregnancy resulting in live births, as of July 2023. These consist of 5,643 exposures during the first trimester, 7,542 exposures during the second/third trimester and included 173 and 219 birth defects, respectively. The prevalence (95% CI) of defects among live births exposed to lamivudine-containing regimens in the first trimester was 3.1% (2.6%, 3.6%) and in the second/third trimester, 2.9% (2.5%, 3.3%).
In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. The background risk for major birth defects for the treatment-indicated population is unknown.
Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropoenia), metabolic disorders (hyperlactatemia, hyperlipasaemia). These reactions are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Health experts recommend that where possible HIV infected women do not breastfeed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breastfeeding during antiretroviral therapy.
Dolutegravir is excreted in human milk in small amounts. In an open-label randomised study in which HIV-infected treatment naïve pregnant women were administered a dolutegravir based regimen until two weeks post-partum, the median (range) dolutegravir breast milk to maternal plasma ratio was 0.033 (0.021 to 0.050). A study in lactating rats showed that the concentration of lamivudine in milk, was more than four times higher than that in maternal plasma.
In a study following repeat oral dose of either 150 mg lamivudine twice daily (given in combination with 300 mg zidovudine twice daily) or 300 mg lamivudine twice daily, lamivudine was excreted in human breast milk (0.5 to 8.2 microgram/mL) at similar concentrations to those found in serum. In other studies, following repeat oral dose of 150 mg lamivudine twice daily (given either in combination with 300 mg zidovudine or as Combivir or Trizivir) the breast milk: maternal plasma ratio ranged between 0.6 and 3.3. Lamivudine median infant serum concentrations ranged between 18 and 28 nanogram/mL and were not detectable in one of the studies (assay sensitivity 7 nanogram/mL). Intracellular lamivudine triphosphate (active metabolite of lamivudine) levels in breastfed infants were not measured therefore the clinical relevance of the serum concentrations of the parent compound measured is unknown.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Dovato on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated given the pharmacology of these medicinal products. The clinical status of the patient and the adverse event profile of Dovato should be borne in mind when considering the patient's ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

Dovato contains dolutegravir plus lamivudine, therefore the adverse drug reactions (ADRs) associated with these individual components may be expected.
Clinical safety data with Dovato are limited. The safety assessment of Dovato in HIV-1-infected treatment-naïve adult subjects with viral load ≤ 500,000 HIV-1 RNA copies/mL, is based on the pooled week 96 analyses of data from 2 identical, multicentre, double-blind, controlled trials, GEMINI-1 and GEMINI-2. A total of 716 HIV-1 infected adults with no antiretroviral treatment history received at least one dose of dolutegravir 50 mg plus lamivudine 300 mg with a mean duration of exposure of 99 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The safety of Dovato in virologically suppressed adults was based on week 48 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive Dovato once daily or continue with TBR for up to 200 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
An adverse event (AE) is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product. A causal relationship does not necessarily exist between an AE and the medicinal product, but is at least suspected. An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and unintended and for which a causal relationship is at least a reasonable possibility and cannot be ruled out.

Adverse events.

The most common adverse events reported in ≥ 5% of subjects in the group that received Dovato in the GEMINI studies were: nasopharyngitis, diarrhoea, headache, upper respiratory tract infection, syphilis, pharyngitis, back pain, influenza, bronchitis, insomnia and vitamin D deficiency. A summary of adverse events greater than or equal to 3% is provided in Table 3.

The rates of adverse events leading to discontinuation in the pooled analysis were 3% of subjects in both treatment arms. The most common adverse events leading to discontinuation were psychiatric disorders: 1% of subjects in both treatment arms. The incidence of serious adverse events was 9% in both treatment arms.

Adverse drug reactions.

The ADRs observed for the combination of dolutegravir and lamivudine in an analysis of pooled data from phase 3 clinical trials (GEMINI-1 and GEMINI-2) were generally consistent with the ADR profiles and severities for the individual components when administered with other antiretroviral agents.
Treatment emergent ADRs (all grades) observed in at least 2% of subjects in either treatment arm of the week 96 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 4.

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. A single treatment emergent ADR [Nervous system disorders: somnolence; frequency common] was observed with the combination which was not listed in the product information for dolutegravir or lamivudine.
The ADRs observed in the phase 3 clinical trial (TANGO) conducted in antiretroviral therapy experienced, virologically suppressed adult subjects who received Dovato, were generally consistent with the ADR profiles and severities for the individual components when administered with other antiretroviral agents. Insomnia and weight increases, observed in the Dovato arm, were the only treatment emergent ADRs observed in at least 2% of subjects in either treatment arm of the TANGO trial.
ADRs identified in an analysis of pooled data from phase 2b and phase 3 clinical trials of the individual components are listed in Table 5 by MedDRA system organ class and by frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000) and very rare (< 1/10,000), including isolated reports.
In addition to the adverse reactions included from clinical trial data, adverse reactions identified during post-marketing use of dolutegravir and/or lamivudine with other antiretroviral agents have also been listed in Table 5. These events have been chosen for inclusion due to a potential causal connection to dolutegravir and/or lamivudine.

Laboratory abnormalities.

Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity in ≥ 2% of subjects are presented in Table 6. The mean change from baseline observed for selected lipid values is presented in Table 7.

Paediatric population.

There are no clinical study data with Dovato in the paediatric population.
Based on limited available data with the dolutegravir single entity used in combination with other antiretroviral agents to treat adolescents (12 to less than 18 years of age), there were no additional types of adverse reactions beyond those observed in the adult population.
Lamivudine has been investigated separately, and as a part of a dual nucleoside backbone, in combination antiretroviral therapy to treat ART-naïve and ART-experienced HIV-infected paediatric patients (data available on the use of lamivudine in children less than three months are limited). No additional types of undesirable effects have been observed beyond those characterised for the adult population.

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.

4.9 Overdose

Symptoms and signs.

There is currently limited experience with over-dosage in dolutegravir. Limited experience of single higher doses (up to 250 mg in healthy subjects) revealed no specific symptoms or signs, apart from those listed as adverse reactions.
No specific symptoms or signs have been identified following acute overdose with lamivudine, 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.
If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. As dolutegravir 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).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 pre-processed substrate DNA resulted in IC₅₀ values of 2.7 nanoM and 12.6 nanoM. In vitro, dolutegravir dissociates slowly from the active site of the wild type integrase-DNA complex (t_½ 71 hours).
Lamivudine is a NRTI, and is a potent, selective inhibitor of HIV-1 and HIV-2. Lamivudine is metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which is the active moiety with an extended intracellular half-life supporting once daily dosing (see Section 5.2 Pharmacokinetic Properties, Excretion). Lamivudine-TP is a substrate for and competitive inhibitor of HIV reverse transcriptase (RT). However, its main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine-TP shows significantly less affinity for host cell DNA polymerases.

Pharmacodynamic effects.

In a randomized, dose-ranging trial, HIV 1-infected subjects 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 (PBMCs) and MT-4 cells with mean EC₅₀s of 0.5 nanoM to 2.1 nanoM.
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 nanoM. 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 nanoM and EC₅₀ values ranged from 0.02 to 2.14 nanoM for HIV-1, while the geometric mean EC₅₀ was 0.18 nanoM and EC₅₀ values ranged from 0.09 to 0.61 nanoM for HIV-2 isolates.
The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC₅₀ values were in the range of 0.003 to 0.17 microM. The EC₅₀ values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 microM, and against HIV-2 isolates from 0.002 to 0.120 microM in PBMCs.
Antiviral activity in combination with other antiviral agents. In vitro data with dolutegravir combined with lamivudine are not available.
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 co-receptor 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.
No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).
Effect of human serum and serum proteins. The protein adjusted EC₉₀ (PA-IC₉₀) in PBMCs for dolutegravir was estimated to be 64 nanogram/mL. Dolutegravir trough concentration for a single 50 mg dose in integrase inhibitor naïve subjects was 1.20 microgram/mL, 19 times higher than the estimated PA-EC₉₀.
Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).
Resistance in vitro and in vivo (dolutegravir). 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 1.3- to 10-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 ten-fold reductions in sensitivity to dolutegravir.

Treatment-naïve HIV-1 infected subjects receiving dolutegravir.

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.
Resistance in vitro and in vivo (lamivudine). HIV-1 resistance to lamivudine involves the development of a M184I or M184V amino acid change close to the active site of the viral RT. This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. Studies in vitro indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.
Resistance in vivo (dolutegravir plus lamivudine). None of the eleven subjects in the dolutegravir plus lamivudine group or the seven subjects in the dolutegravir plus tenofovir disoproxil/emtricitabine group that met the protocol-defined confirmed virologic withdrawal (CVW) criteria across the pooled GEMINI-1 and GEMINI-2 studies through week 144 had emergent INSTI or NRTI resistance substitutions. No subjects in the dolutegravir plus lamivudine group, and one subject in the tenofovir alafenamide based regimen group met the protocol-defined CVW criteria in the TANGO study through week 144, and there were no emergent INSTI or NRTI resistance substitutions.
Cross-resistance.

Site-directed INSTI mutant virus.

Dolutegravir activity was determined against a panel of 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 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 greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).

Recombinant clinical isolates.

Dolutegravir activity was measured for 705 raltegravir resistant recombinant isolates from clinical practice; 93.9% (662/705) of the isolates had a dolutegravir FC ≤ 10. Dolutegravir had 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.

Cross-resistance conferred by the M184V reverse transcriptase.

Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors. Viruses containing lamivudine resistance-associated mutations (including M184V/I, and K65R/E/N) may exhibit cross-resistance in vitro and in vivo. The M184V mutation can confer resistance to abacavir, didanosine and emtricitabine; the K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, stavudine, and tenofovir.
Resistance patterns may change, and the most up-to-date information in conjunction with resistance testing should be used to inform the choice of therapy.
Effects on electrocardiogram. In a randomised, placebo-controlled, cross-over trial, 42 healthy subjects 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 post dose. 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).
Similar studies were not conducted with lamivudine.
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 subjects, 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 trials. 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 trials 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 subjects.

The efficacy of Dovato is supported by data from two identical 148-week, phase III, randomised, double-blind, multicentre, parallel-group, non-inferiority controlled trials (GEMINI-1 [204861] and GEMINI-2 [205543]). A total of 1,433, HIV-1 infected antiretroviral treatment-naïve adult subjects, defined as having had ≤ 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection, received treatment in the trials. Subjects with pre-existing viral resistance (based on the presence of any major resistance-associated mutation), severe hepatic or renal impairment, HBV positive status or those requiring hepatitis C virus (HCV) therapy were excluded from the trials. HIV-2 infected subjects were not evaluated.
Subjects were enrolled with a screening plasma HIV-1 RNA of 1,000 c/mL to ≤ 500,000 c/mL. Subjects were randomised to a two-drug regimen of dolutegravir 50 mg plus lamivudine 300 mg administered once daily or dolutegravir 50 mg plus tenofovir/emtricitabine 300/200 mg FDC administered once daily. The primary efficacy endpoint for each GEMINI trial 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 33 years (18 - 72 years), 15% were female, 69% were white, 9% were CDC stage 3 (AIDS), 20% had HIV-1 RNA > 100,000 copies/mL, and 8% had CD4⁺ cell count less than 200 cells per mm³; these characteristics were similar between studies and treatment arms.
In the primary week 48 analysis, dolutegravir plus lamivudine was non-inferior to dolutegravir plus tenofovir/emtricitabine FDC in GEMINI-1 and GEMINI-2 studies. This was supported by the pooled analysis, see Table 8.
At 96 weeks in the GEMINI-1 and GEMINI-2 studies, the dolutegravir plus lamivudine group (86% with plasma HIV-1 RNA < 50 copies/mL [pooled data]) remained non-inferior to the dolutegravir plus tenofovir/emtricitabine FDC group (90% with plasma HIV-1 RNA < 50 copies/mL [pooled data]). The adjusted difference in proportions and 95% CI was -3.4% (6.7, 0.0) (see Table 8). The results of the pooled analysis were in line with those of the individual studies, for which the secondary endpoint (difference in proportion of subjects with < 50 copies/mL plasma HIV-1 RNA at week 96 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir/emtricitabine FDC) was met. The adjusted differences of -4.9 (95% CI: -9.8; 0.0) for GEMINI-1 and -1.8 (95% CI: -6.4; 2.7) for GEMINI-2 were within the prespecified non-inferiority margin of -10%.

Virologic outcomes by baseline CD4⁺ (cells/mm³) in GEMINI-1 and GEMINI-2 at week 96 are shown in Table 9. In both trials, lower response rates (HIV-1 RNA < 50 copies/mL) were observed in subjects with baseline CD4⁺ ≤ 200 cells/mm³. These findings were seen irrespective of baseline plasma HIV-1 RNA.

The adjusted mean change from baseline in CD4⁺ cell count based on the pooled analysis at week 96 was 269 cells/mm³ for the group receiving dolutegravir plus lamivudine and 259 cells/mm³ for the group receiving dolutegravir plus tenofovir/emtricitabine FDC.
At 144 weeks in the GEMINI-1 and GEMINI-2 studies, the dolutegravir plus lamivudine group (82% with plasma HIV-1 RNA < 50 copies/mL [pooled data]) remained non-inferior to dolutegravir plus tenofovir/emtricitabine FDC group (84% with plasma HIV-1 RNA < 50 copies/mL [pooled data]). The results of the pooled analysis were in line with those of the individual studies, for which the secondary endpoint (difference in proportion < 50 copies/mL plasma HIV-1 RNA at week 144 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir/emtricitabine FDC) was met. The adjusted difference in proportions and 95% CI for the pooled data was -1.8% (-5.8, 2.1). The adjusted differences of -3.6 (95% CI: -9.4, 2.1) for GEMINI-1 and 0.0 (95% CI: -5.3, 5.3) for GEMINI-2 were within the prespecified non-inferiority margin of -10%.
The mean increase in CD4+ T-cell counts was 302 cells/mm³ in the DTG+3TC arm and 300 cells/mm³ in the DTG+FTC/TDF arm, at week 144.

Virologically suppressed subjects.

The efficacy of Dovato in HIV-infected, antiretroviral therapy experienced, virologically suppressed subjects is supported by data from a 200-week, phase III, randomised, open-label, multicentre, parallel-group, non-inferiority controlled trial (TANGO [204862]). A total of 741 adult HIV-1 infected subjects who were on a stable suppressive TBR received treatment in the studies. Subjects were randomised in a 1:1 ratio to receive Dovato once daily or continue with TBR for up to 200 weeks. Randomisation was stratified by baseline third agent class (protease inhibitor [PI], integrase inhibitor [INSTI], or nonnucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA ≥ 50 c/mL (virologic nonresponse) as per the FDA Snapshot category at week 48 (Snapshot algorithm adjusting for randomization stratification factor: baseline third agent class [INSTI, PI, NNRTI]).
At baseline the median age of subjects was 39 years, 8% were female and 21% non-white, 5% were CDC class C (AIDS) and 98% subjects had baseline CD4⁺ cell count ≥ 200 cells/mm³; these characteristics were similar between treatment arms. Subjects had been on ART for a median of 2.8 years and 2.9 years prior to day 1 for the Dovato and TBR arms, respectively. Most subjects were on INSTI-based TBR, 78% and 80% in the Dovato and TBR arms, respectively.
In the primary 48 week analysis, Dovato was non-inferior to TBR, with < 1% of subjects in both arms experiencing virologic failure (HIV-1 RNA ≥ 50 c/mL) based on the Snapshot algorithm (see Table 10).

In TANGO, treatment outcomes between treatment arms were similar across the stratification factor, baseline third agent class (INSTI/NNRTI/PI), and across subgroups by age, sex, race, baseline CD4 cell count, CDC HIV disease stage and countries. The median change from baseline in CD4⁺ count at week 48 was 22.5 cells per mm³ in subjects who switched to Dovato and 11.0 cells per mm³ in subjects who stayed on TBR.
At 96 weeks in the TANGO study, the proportion of subjects with HIV-1 RNA ≥ 50 c/mL (Snapshot) was 0.3% and 1.1% in the Dovato FDC and TBR groups, respectively. Based on a non-inferiority margin of 4%, Dovato FDC remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.0%, 0.4%) was less than 4% for the ITT E population.
The median change from baseline in CD4⁺ T-cell counts at week 96 was 61 cells/mm³ in the Dovato FDC arm and 45 cells/mm³ in the TBR arm.
At 144 weeks, the proportion of subjects with HIV-1 RNA ≥ 50 c/mL (Snapshot) was 0.3% and 1.3% in the Dovato FDC and TBR groups, respectively. Based on a non inferiority margin of 4%, Dovato FDC remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.4%, 0.2%) was less than 4% for the ITT E population.
The median change from baseline in CD4⁺ T-cell counts at week 144 was 36 cells/mm³ in the DTG+3TC FDC arm and 35 cells/mm³ in the TBR arm.