Consumer medicine information

Juluca

Dolutegravir; Rilpivirine

BRAND INFORMATION

Brand name

Juluca

Active ingredient

Dolutegravir; Rilpivirine

Schedule

SUMMARY CMI

JULUCA

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 JULUCA?

JULUCA contains the active ingredients dolutegravir and rilpivirine. JULUCA is used to treat human immunodeficiency virus (HIV) infection.

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

2. What should I know before I take JULUCA?

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

Do not use JULUCA if you are taking any of the following medicines: dofetilide, pilsicainide, fampridine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampicin, rifapentine, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, dexamethasone and products containing St John's wort.

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 JULUCA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with JULUCA 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 use JULUCA?

The usual dosage of JULUCA is one tablet once a day with a meal.
If you taken certain other medications this will affect when you can take JULUCA.
Swallow the tablet whole with a glass of water.

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

5. What should I know while taking JULUCA?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking JULUCA. For as long as you are taking JULUCA 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.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how JULUCA affects you. JULUCA may cause dizziness or make you feel less alert than normal.
Looking after your medicine	Store JULUCA in the bottle below 30°C.

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

6. Are there any side effects?

Side effects that have been reported include headache, dizziness, nausea, vomiting, stomach pains or discomfort, diarrhoea, increased wind (flatulence), decreased appetite, weight gain, depression, anxiety, difficulty sleeping or falling asleep (insomnia), abnormal dreams, sleep disorders, fatigue, a lack of energy, feeling drowsy, itching, joint pain and muscle pain.

Serious side effects include allergic reactions, suicidal thoughts and behaviours and liver failure. Urgent medical attention is required.

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

JULUCA

Active ingredient(s): dolutegravir and rilpivirine (as hydrochloride)

Consumer Medicine Information (CMI)

This leaflet provides important information about using JULUCA. 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 JULUCA.

Where to find information in this leaflet:

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

1. Why am I taking JULUCA?

JULUCA contains the active ingredients dolutegravir and rilpivirine.

Dolutegravir belongs to a group of antiretroviral medicines called integrase inhibitors (INIs). Rilpivirine belongs to a group of antiretroviral medicines called non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs).

JULUCA is used to treat human immunodeficiency virus (HIV) infection.

JULUCA does not cure HIV infection however it keeps the amount of virus in your body at a low level. This helps maintain the number of CD4+ cells in your blood. CD4+ cells are a type of white blood cell that are important in helping your body to fight 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 JULUCA 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 JULUCA?

Warnings

Do not take JULUCA if:

you are allergic to dolutegravir, rilpivirine 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 take any of the following medicines:
- dofetilide or pilsicainide, used to treat heart conditions
- fampridine, used to treat multiple sclerosis
- carbamazepine, oxcarbazepine, phenobarbital, phenytoin, medicines known as anticonvulsants used to treat epilepsy and prevent seizures
- rifampicin, rifapentine, medicines used to treat some bacterial infections such as tuberculosis
- omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, proton pump inhibitor medicines used to prevent and treat stomach ulcers, heartburn or acid reflux disease
- dexamethasone, a corticosteroid medicine used in a variety of conditions such as inflammation and allergic reactions
- products containing St John's Wort (hypericum perforatum), a herbal product used to treat depression

Check with your doctor if you:

have any other medical conditions
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

Check with your doctor if you are pregnant or intend to become pregnant.

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

Your doctor can discuss with you the benefits and risks of taking JULUCA whilst pregnant or breastfeeding.

It is important to use a reliable method of contraception to prevent pregnancy.

Taking dolutegravir (one of the components in JULUCA tablets) at the time of becoming pregnant or during the first 12 weeks of pregnancy may increase the risk of a type of birth defect known as neural tube defects such as spina bifida (a malformed spinal cord).

Women who are HIV positive should not breastfeed as HIV infection can be passed onto the baby through the breastmilk. Dolutegravir is known to pass into the breastmilk in small amounts.

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.

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 JULUCA and affect how it works.

metformin, a medicine used to treat diabetes
medicines known as antacids which are used to treat indigestion and heartburn
famotidine, cimetidine, nizatidine, ranitidine (H2-receptor antagonists) used to treat indigestion and heartburn
calcium and iron supplements (non-antacids)
rifabutin, a medicine used to treat some bacterial infections such as tuberculosis
clarithromycin, erythromycin, antibiotics used to treat bacterial infections
methadone, a medicine used for pain
efavirenz, etravirine, nevirapine, non-nucleoside reverse transcriptase inhibitors (NNRTIs) used to treat HIV infection
any other medicines used to treat HIV infection

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

4. How do I take JULUCA?

How much to take

The usual dosage of JULUCA is one tablet taken once a day with a meal.
Follow the instructions provided and use JULUCA until your doctor tells you to stop.

When to take JULUCA

Your doctor or pharmacist will tell you when to take JULUCA each day.
If you take an antacid medicine to treat indigestion or heartburn, you must take JULUCA at least 4 hours before or 6 hours after you take the antacid.

Talk to your doctor or pharmacist for further advice on taking antacid medicines with JULUCA.

If you take H2-receptor antagonists to treat indigestion and heartburn (e.g. famotidine, cimetidine, nizatidine, ranitidine) you should take JULUCA at least 4 hours before or 12 hours after you take the H2-receptor antagonist.
If you take calcium or iron supplements, you must take JULUCA at least 4 hours before or 6 hours after you take a calcium or iron containing supplement. However, provided you take JULUCA with a meal, you can take calcium and iron supplements at the same time as JULUCA.
If you take rifabutin to treat bacterial infections such as tuberculosis, you must also take a 25 mg dose of rilpivirine at the same time as you take JULUCA.

How to take JULUCA

Swallow the tablet whole with a drink of water.
It is important to take JULUCA with a meal. A protein-rich nutritional drink alone does not replace a meal.

If you forget to take JULUCA

JULUCA should be taken regularly at the same time each day.

If it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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

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

If you take too much JULUCA

If you think that you have taken too much JULUCA, 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 JULUCA?

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 JULUCA as intended

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

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.

Stay in regular contact with your doctor

JULUCA 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 JULUCA 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 JULUCA affects you.

JULUCA may cause dizziness or make you feel less alert than normal.

Looking after your medicine

Follow the instructions on the bottle 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 dizziness nausea and vomiting stomach pains or discomfort diarrhoea increased wind (flatulence) decreased appetite, weight gain depression, anxiety difficulty sleeping or difficulty falling asleep (insomnia) abnormal dreams sleep disorders fatigue, lack of energy, feeling drowsy itching joint pain muscle pain	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 suicidal thoughts and behaviours (especially in patients who have had depression or mental health problems before) liver failure, signs include yellowing of the skin and whites of the eyes or unusually dark urine	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.

Some side effects will only show up following a blood test. These include:

inflammation in the liver
increase in the level of liver enzymes
increase in bilirubin levels (a substance produced by the liver)
increase in the level of enzymes produced in the muscles (creatine phosphokinase, creatinine)

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 JULUCA contains

Active ingredient (main ingredients)	dolutegravir rilpivirine (as hydrochloride)
Other ingredients (inactive ingredients)	croscarmellose sodium iron oxide red iron oxide yellow lactose monohydrate macrogol 3350 magnesium stearate mannitol microcrystalline cellulose polysorbate 20 polyvinyl alcohol povidone purified talc silicified microcrystalline cellulose sodium starch glycollate type A sodium stearylfumarate titanium dioxide
Potential allergens	lactose monohydrate mannitol

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

What JULUCA looks like

JULUCA tablets are pink, film coated, oval, biconvex shaped debossed with "SV J3T" on one side.

JULUCA is available in bottles of 30 tablets. The bottle contains a desiccant. Once the bottle is opened, keep the desiccant in the bottle.

AUST R 291356

Who distributes JULUCA

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 on 13 December 2022.

Version 4.0

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Juluca

Active ingredient

Dolutegravir; Rilpivirine

Schedule

1 Name of Medicine

Dolutegravir (as dolutegravir sodium) and rilpivirine (as rilpivirine hydrochloride).

2 Qualitative and Quantitative Composition

Juluca film-coated tablets contain 50 mg of dolutegravir (as dolutegravir sodium) and 25 mg of rilpivirine (as rilpivirine hydrochloride).
Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water. The partition coefficient (log P) for dolutegravir sodium is 2.2 and the pKa is 8.2.
Rilpivirine hydrochloride is a white to off-white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range, its pKa is 5.6 (pyrimidine moiety) and log P between 1-octanol and a phosphate solution (pH 7.0) is 4.86 (at 21°C).
Juluca tablets also contain: mannitol and lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pink, film-coated, oval, biconvex tablets debossed with 'SV J3T' on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Juluca (dolutegravir/rilpivirine) is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of virological failure and no known or suspected resistance to any non-nucleoside reverse transcriptase inhibitor or integrase inhibitor (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Juluca therapy should be initiated by a physician experienced in the management of HIV infection.
If the patient misses a dose of Juluca, the patient should take it with a meal as soon as they remember if it is more than 12 hours until the next dose. If the next dose is due within 12 hours, the patient should skip the missed dose and resume the usual dosing schedule.
Separate preparations of dolutegravir and rilpivirine are available where dose adjustment or discontinuation of one of the individual components is indicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In these cases the physician should refer to the individual product information.

Adults.

The recommended dose of Juluca in adults is one tablet once daily taken orally with a meal.

Adolescents and children.

Juluca is not recommended in paediatric patients below 18 years of age due to insufficient safety and efficacy data.

Elderly.

There are limited data available on the use of Juluca in patients aged 65 years and over. Caution should be exercised in administration of Juluca in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See Section 5.2 Pharmacokinetic Properties, Special patient populations.)

Renal impairment.

No dosage adjustment is required in patients with mild or moderate renal impairment. In patients with severe or end stage renal disease, the combination of Juluca with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. No data are available in subjects receiving dialysis. (See Section 5.2 Pharmacokinetic Properties, Special patient populations.)
Dolutegravir has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when Juluca is co-administered with a drug that has dosing adjustment recommendations guided by estimated creatinine clearance.

Hepatic impairment.

No dosage adjustment of Juluca is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). Juluca has not been studied in patients with severe hepatic impairment (Child-Pugh score C); therefore, Juluca is not recommended in these patients (see Section 5.2 Pharmacokinetic Properties, Special patient populations).

Women of child bearing potential and pregnancy.

The safety and efficacy of Juluca in pregnancy have not yet been established. Lower exposures of dolutegravir and rilpivirine were observed during pregnancy. No recommendations for dose adjustments can be made for Juluca. Therefore, use of Juluca during pregnancy is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Use in pregnancy; Section 4.6 Fertility, Pregnancy and Lactation, Pregnancy; Section 5.2 Pharmacokinetic Properties, Special patient populations).
A benefit-risk assessment should be considered at the time of conception through the first trimester due to the potential risk of neural tube defects (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.3 Contraindications

Juluca is contraindicated in patients with known hypersensitivity to dolutegravir or rilpivirine or to any of the FDC excipients.
Juluca is contraindicated in combination with the following (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions):
products with narrow therapeutic windows, that are substrates of organic cation transporter 2 (OCT2), including but not limited to antiarrhythmic agents dofetilide or pilsicainide, or the potassium channel blocker fampridine;
anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin;
antimycobacterials rifampicin, rifapentine;
proton pump inhibitors (such as omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole);
glucocorticoid systemic dexamethasone (except as a single dose treatment);
St. John's wort (Hypericum perforatum).

4.4 Special Warnings and Precautions for Use

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 Juluca 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 Juluca or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.

Hepatotoxicity.

Hepatic adverse events have been reported in patients receiving a dolutegravir- or rilpivirine containing regimen. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Additionally, in some patients receiving dolutegravir containing regimens, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity including elevated serum liver biochemistries and hepatitis have also been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to acute liver failure has been reported with dolutegravir-containing products, including liver transplant with Triumeq (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

Patients with hepatitis B or C.

No clinical data are available in patients with hepatitis B co-infection. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus. Limited data is available in patients with hepatitis C co-infection. A higher incidence of liver chemistry elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with hepatitis C compared to those who were not co-infected. Monitoring of liver function is recommended in patients with hepatitis B and/or C co-infection.

Immune reactivation syndrome.

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Depressive disorders.

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation) have been reported with rilpivirine or dolutegravir. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to Juluca and to determine whether the risks of continued therapy outweigh the benefits.

Opportunistic infections.

Patients receiving Juluca 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.

Pregnancy.

The safety and efficacy of Juluca in pregnancy have not yet been established. Lower exposures of dolutegravir or rilpivirine were observed when taken once daily, in combination with a background regimen, during pregnancy. In phase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure. No recommendations for dose adjustments can be made for Juluca. Therefore, use of Juluca during pregnancy is not recommended (see Section 4.6 Fertility, Pregnancy and Lactation; Section 5.2 Pharmacokinetic Properties, Special patient populations).

Use in hepatic impairment.

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

Use in renal impairment.

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

Use in the elderly.

Clinical trials of Juluca did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of Juluca in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

There are no clinical study data with dolutegravir plus rilpivirine in the paediatric population.

Effects on laboratory tests.

See Table 1.

In the SWORD studies increases in serum creatinine occurred within the first four weeks of treatment with dolutegravir plus rilpivirine and remained stable through 48 weeks. A mean change from baseline of 8.22 micromol/L (range: -26.5 micromol/L to 51.2 micromol/L) was observed after 48 weeks of treatment. These changes are related to inhibition of active transport, and are not considered to be clinically relevant as 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 rilpivirine. 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.
No clinically relevant differences in lipid profiles were noted throughout the 48 weeks in either treatment group.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Caution should be given to prescribing Juluca with medicinal products that may reduce the exposure of dolutegravir or rilpivirine.
Juluca contains dolutegravir plus rilpivirine and any interactions that have been identified with either component individually may occur with Juluca. There are no significant drug interactions between dolutegravir and rilpivirine.

Effect of Juluca on the pharmacokinetics of other agents.

Effect of dolutegravir on the pharmacokinetics of other agents.

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). In vivo dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2. 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 2). Given the in vivo exposure, dolutegravir has a low potential to affect the transport of MATE2-K substrates in vivo.
In vitro, dolutegravir inhibited the basolateral renal transporters: organic anion transporter (OAT) 1 (IC₅₀= 2.12 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.
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. 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.

Effect of rilpivirine on the pharmacokinetics of other agents.

In vitro, rilpivirine inhibited the MATE2-K transporter (IC₅₀ < 0.05 microM), and may slow the elimination of MATE2-K substrates in vivo.
Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.
Based on different elimination routes for rilpivirine no clinically relevant drug interactions are expected with the following medications: abacavir, emtricitabine, lamivudine, maraviroc, ribavirin, stavudine, and zidovudine.
Interactions with medicinal products are listed in Table 2.

Effect of other agents on the pharmacokinetics of dolutegravir/rilpivirine.

Effect of other agents on the pharmacokinetics of dolutegravir.

Dolutegravir is metabolised 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 may increase dolutegravir plasma concentration (see Table 2).
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.
Dolutegravir should not be co-administered with polyvalent cation-containing antacids. Juluca is recommended to be administered at least 4 hours before or 6 hours after taking antacid products.
Interactions with medicinal products are listed in Table 2.

Effect of other agents on the pharmacokinetics of rilpivirine.

Rilpivirine is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see Section 5.2 Pharmacokinetic Properties). Co-administration of rilpivirine with medicinal products that induce CYP3A may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of rilpivirine. Co-administration of rilpivirine and medicinal products that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.
Co-administration of rilpivirine with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of rilpivirine.
Interactions with medicinal products are listed in Table 2.

QT prolonging drugs.

There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicinal products that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram (see Section 5.1 Pharmacodynamic Properties). Juluca should be used with caution when co-administered with a medicinal product with a known risk of Torsades de Pointes.
Established and theoretical interactions with selected antiretrovirals and non antiretroviral medicinal products are listed in Table 2. The list of drug-drug interactions is not all-inclusive. Recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and/or potential for serious adverse events or loss of efficacy. Juluca 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 and/or rilpivirine on human 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).
In rats, there were no effects on mating or fertility with rilpivirine up to 400 mg/kg/day (dose that showed maternal toxicity) associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily).
(Category B1)
The safety and efficacy of Juluca in pregnancy have not yet been established. Lower exposures of dolutegravir or rilpivirine were observed when taken once daily, in combination with a background regimen, during pregnancy. In phase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure. No recommendations for dose adjustments can be made for Juluca. Therefore, use of Juluca during pregnancy is not recommended (see Section 5.2 Pharmacokinetic Properties, Special patient populations).
Juluca should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. Women of childbearing potential should be informed about the potential risk of neural tube defects with dolutegravir and counselled about the use of effective contraception. It is recommended that pregnancy testing is conducted prior to initiation of Juluca. If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on Juluca, the risks and benefits of continuing Juluca should be discussed with the patient. Factors to consider should include feasibility of switching, tolerability, ability to maintain viral suppression, actual gestational age, risk of transmission to the infant and the available data around the potential risk of neural tube defects and other pregnancy outcomes for dolutegravir and alternative antiretroviral drugs.
No studies on the effect on embryofetal development have been conducted with the dolutegravir/rilpivirine combination.
In a birth outcome surveillance study in Botswana, a numerically higher rate of neural tube defects was identified with exposure to dolutegravir compared to non-dolutegravir-containing antiretroviral regimens at the time of conception, however, the difference was not statistically significant. Seven cases of neural tube defects were reported in 3,591 deliveries (0.19%) to mothers taking dolutegravir-containing regimens at the time of conception, compared with 21 cases in 19,361 deliveries (0.11%) to mothers taking non-dolutegravir-containing regimens from the time of conception (Prevalence Difference 0.09%; 95% CI -0.03, 0.30).
The seven neural tube defect cases reported with dolutegravir included three cases of myelomeningocele, two cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, an increased risk of neural tube defects was not identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with five infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy.
A causal relationship of these events to the use of dolutegravir has not been established. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births. As most neural tube defects occur within the first 4 weeks of foetal development (approximately 6 weeks after the last menstrual period) this potential risk would concern women exposed to dolutegravir at the time of conception and in early pregnancy.
Further study data from other sources including the Antiretroviral Pregnancy Registry, clinical trials, and post-marketing data are currently insufficient to further address the risk of neural tube defects with dolutegravir. There have been spontaneous reports of neural tube defects with use of dolutegravir-containing regimens.
More than 1,000 outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.
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 1000 mg/kg daily from days 6 to 18 of gestation was associated with marked maternal toxicity but did not elicit developmental toxicity or teratogenicity in the offspring (0.56 times the clinical exposure based on AUC).
Placental transfer of rilpivirine or its metabolites from dam to fetus was demonstrated in rats. Studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect on reproductive function with rilpivirine. There was no clinically relevant teratogenicity with rilpivirine in rats and rabbits. The exposures at the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily.
Dolutegravir and rilpivirine use during pregnancy have been evaluated in the Antiretroviral Pregnancy Registry (APR) in over 600 and 610 women, respectively (as of July 2019). Available human data from the APR do not show an increased risk of major birth defects for dolutegravir or rilpivirine compared to the background rate (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Dolutegravir readily crosses the placenta in humans. In HIV-infected pregnant women, 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.
Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 pregnant women during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during pregnancy compared with postpartum (6-12 weeks). Virologic response was preserved throughout the trial period. No mother to child transmission occurred in all 10 infants born to the mothers who completed the trial and for whom the HIV status was available. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected adults.
Health experts recommend that where possible HIV infected women do not breast feed 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 breast feeding 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 postpartum, the median (range) dolutegravir breast milk to maternal plasma ratio was 0.033 (0.021 to 0.050). It is not known if rilpivirine is secreted in human milk. In nonclinical studies, rilpivirine was detected in the plasma of suckling rats following maternal dosing.

4.7 Effects on Ability to Drive and Use Machines

There have been no studies to investigate the effect of Juluca on driving performance or the ability to operate machinery. The clinical status of the patient and the adverse event profile Juluca 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.

Juluca contains dolutegravir plus rilpivirine, therefore the adverse drug reactions (ADRs) associated with these individual components may be expected.
The safety assessment of Juluca in HIV-1-infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine is based on the pooled primary Week 48 analyses of data from 2 identical, international, multicentre, open-label trials, SWORD-1 and SWORD-2 (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. See Table 3.

The majority of adverse events reported during treatment with dolutegravir plus rilpivirine (DTG + RPV) or current antiretroviral regimen (CAR) were Grade 1 (DTG + RPV 48%, CAR 48%) or Grade 2 (DTG + RPV 23%, CAR 20%) in severity. Grade 3 or 4 adverse events were reported in 5% and < 1% of patients receiving DTG + RPV, and 3% and < 1% of patients receiving treatment with CAR.
There were no treatment-emergent adverse drug reactions (ADRs) (Grades 2 to 4) with an incidence of at least 2% in either treatment arm. ADRs (all grades) observed in at least 1% of subjects in either treatment arm of the pooled analysis of the SWORD-1 and SWORD-2 trials are provided in Table 4.

In the pooled analyses, the proportion of subjects who discontinued treatment due to an adverse event was 4% in subjects receiving dolutegravir plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects receiving dolutegravir plus rilpivirine and less than 1% on the current antiretroviral regimen. The incidence of serious adverse events was 5% in subjects receiving dolutegravir plus rilpivirine and 4% in subjects who remained on their current antiretroviral regimen.
Adverse drug reactions (ADRs) identified in an analysis of pooled data from Phase 2b and Phase 3 clinical studies 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 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000) and very rare (< 1/10,000), including isolated reports.
The ADRs observed for dolutegravir plus rilpivirine in analysis of pooled data from Phase 3 clinical trials (SWORD-1 and SWORD-2) were consistent with the ADR profiles and severities for the individual components when administered with other antiretroviral agents. No additional ADRs or increased frequency or severity of ADRs were observed with the combination of dolutegravir plus rilpivirine.

Paediatric population.

There are no clinical study data with dolutegravir plus rilpivirine in the paediatric population.

Co-infection with hepatitis B or C.

A higher incidence of liver chemistry elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with hepatitis C compared to those who were not co-infected. Dolutegravir plus rilpivirine has not been studied in patients with hepatitis B co-infection.

Post-marketing data.

In addition to the adverse reactions included from clinical trial data, below are adverse reactions identified during post-approval use of dolutegravir in combination with other antiretroviral agents. These events have been chosen for inclusion due to a potential causal connection to dolutegravir.

Musculoskeletal and connective disorders.

Uncommon: arthralgia, myalgia.

Investigations.

Common: weight increase.
The following event has been reported in a dolutegravir-containing regimen. The contribution of dolutegravir in this case is unclear.

Hepatobiliary disorders.

Rare: acute hepatic failure.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

Experience with overdose of Juluca, or the individual components, dolutegravir and rilpivirine is limited.

Treatment.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
There is no specific treatment for overdose with Juluca. If overdose occurs, the patient should be treated supportively with appropriate monitoring, vital signs, ECG (QT interval), and observation of the clinical status of the patient, as necessary. As dolutegravir and rilpivirine are highly bound to plasma proteins, it is unlikely they 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_1/2 71 hours).
Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.

Pharmacodynamic effects.

Antiviral activity in cell culture. Dolutegravir exhibited antiviral activity against laboratory strains of wild type HIV-1 in peripheral blood mononuclear cells (PBMCs) and MT4 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.
Rilpivirine exhibited activity against laboratory strains of wild type HIV-1 in an acutely infected T-cell line with a median EC₅₀ value for HIV-1/IIIB of 0.73 nanoM (0.27 nanogram per mL). Although rilpivirine demonstrated limited in vitro activity against HIV-2 with EC₅₀ values ranging from 2,510 to 10,830 nanoM treatment of HIV-2 infection with rilpivirine is not recommended in the absence of clinical data.
Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (clade A, B, C, D, F, G, H) primary isolates with median EC₅₀ values ranging from 0.07 to 1.01 nanoM and group O primary isolates with EC₅₀ values ranging from 2.88 to 8.45 nanoM.
Antiviral activity in combination with other antiviral agents. The antiviral activity of dolutegravir in vitro was not antagonistic with the integrase inhibitor (INI) raltegravir; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz or nevirapine; the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir or stavudine; the protease inhibitors (PIs) amprenavir or lopinavir; the CCR5 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.
Rilpivirine showed no antagonistic antiviral activity in combination with the NRTIs: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine; the PIs: amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir; the NNRTIs: efavirenz, etravirine and nevirapine; the fusion inhibitor enfuvirtide; the entry inhibitor maraviroc, and the INI raltegravir.
The combination of dolutegravir plus rilpivirine evaluated in an in vitro two-drug combination study showed no antagonistic interactions.
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 naive subjects was 1.20 microgram/mL, 19 times higher than the estimated PA-EC₉₀.
Resistance in vitro. Dolutegravir-resistant viruses were selected in studies of potential resistance using different wild type strains and clades of HIV-1. Amino acid substitutions that emerged during passaging included E92Q, G193E, G118R, S153F or Y, and R263K, and were associated with decreased susceptibility to dolutegravir of up to 11-fold.
In resistance development studies starting with the single raltegravir resistance mutants Q148H, Q148K or Q148R, additional mutations detected during passage with dolutegravir included E138K/Q148K, E138K/Q148R, Q140S/Q148R and G140S/Q148R, which all exhibited greater than ten-fold reductions in sensitivity to dolutegravir.
Rilpivirine-resistant strains were selected in cell culture starting from wild type HIV-1 of different origins and clades as well as NNRTI-resistant HIV-1. The most commonly observed amino acid substitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I.
Resistance in vivo. The number of subjects who met the protocol-defined confirmed virologic withdrawal (CVW) criteria was low across the pooled SWORD-1 and SWORD-2 studies. Two subjects from each treatment group met CVW criteria at any time through Week 48. NNRTI resistance associated substitution K101K/E mixture with no decreased susceptibility to rilpivirine (FC=1.2) was observed in one subject with identified adherence issues that received dolutegravir plus rilpivirine. This subject's viral load was 1,059,771 copies/mL at the suspected virologic withdrawal visit, and on resumption of dolutegravir plus rilpivirine the viral load decreased to 1,018 copies/mL at the confirmatory visit and was < 50 copies/mL at the withdrawal visit. No resistance-associated substitutions were observed for the other three subjects meeting CVW criteria.

Treatment-naive HIV-1 infected subjects on dolutegravir.

No integrase-resistant mutations or treatment-emergent resistance to the NRTI backbone therapy were isolated with dolutegravir 50 mg once daily in treatment-naive studies (SPRING-1, SPRING-2, SINGLE and FLAMINGO studies).

Treatment-naive HIV-1 infected subjects on rilpivirine.

In a Week 96 pooled analyses of virologic failures with baseline viral load ≤ 100,000 copies/mL and resistance to rilpivirine (n = 5), subjects had cross-resistance to efavirenz (n = 3), etravirine (n = 4), and nevirapine (n = 1).
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). A G118R substitution conferred a 10-fold reduction in dolutegravir susceptibility but has not been observed during dolutegravir clinical studies. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a 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).

Site-directed NNRTI mutant virus.

In a panel of 67 HIV-1 recombinant laboratory strains with one amino acid substitution at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showed antiviral activity (FC ≤ BCO) against 64 (96%) of these strains. The single amino acid substitutions associated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself, but the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine.
Considering all of the available in vitro and in vivo data, the following amino acid substitutions, when present at baseline, are likely to affect the activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, or M230L.

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.
Rilpivirine retained sensitivity (FC ≤ BCO) against 62% of 4786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.
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).
The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady-state. Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc.
When supratherapeutic doses of 75 mg and 300 mg once daily of rilpivirine were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) ms, respectively. Steady-state administration of rilpivirine 75 mg and 300 mg once daily resulted in a mean C_max approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state C_max observed with the 25 mg once daily dose of rilpivirine.
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 studies. Dolutegravir at both doses had no significant effect on GFR or ERPF. These data support in vitro studies which suggest that the small increases in creatinine observed in clinical studies are due to the nonpathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.
Effects on bone. In a DEXA substudy which evaluated 81 patients, mean bone mineral density (BMD) significantly increased from baseline to week 48 in subjects who switched to dolutegravir plus rilpivirine (46 patients; 1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (35 patients; 0.05% total hip and 0.15% lumbar spine; p = 0.014 and p = 0.039, respectively). The effect on fracture rate was not studied. The long-term clinical significance of these BMD changes is not known.
Adrenal function. In the pooled phase III trials for rilpivirine, at Week 96, the overall mean change from baseline in basal cortisol was -19.1 nanomol/L in the rilpivirine group, and -0.6 nanomol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine group (+18.4 ± 8.36 nanomol/L) than in the efavirenz group (+54.1 ± 7.24 nanomol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range (> 248 nanomol/L for basal and > 500 nanomol/L for stimulated values respectively). Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.

Clinical trials.

The efficacy of Juluca is supported by data from 2 randomised, open-label, controlled trials (SWORD-1 [201636] and SWORD-2 [201637]) in virologically suppressed patients switching from their current antiretroviral regimen (CAR) to dolutegravir plus rilpivirine. SWORD-1 and SWORD-2 are identical 148-week, Phase III, randomised, multicentre, parallel-group, non-inferiority studies. Subjects were enrolled if they had been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening with no history of virological failure and had no known or suspected resistance to either dolutegravir or rilpivirine. A total of 1,024 adult HIV-1 infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INSTI, an NNRTI, or a PI) received treatment in the studies. Subjects were randomised 1:1 to continue their CAR or be switched to a two-drug regimen dolutegravir plus rilpivirine administered once daily. At Week 52, subjects who were originally assigned to continue their CAR and remained virologically suppressed switched to dolutegravir plus rilpivirine and are planned to be followed to Week 148. The primary efficacy endpoint for the SWORD studies was the proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Week 48 (Snapshot algorithm for the ITT-E population).
At baseline, in the pooled analysis, the median age of subjects was 43 years, 22% female, 20% non-White, 11% were CDC Class C (AIDS), and 11% had CD4+ cell count less than 350 cells per mm³; these characteristics were similar between treatment arms. In the pooled analysis, 54%, 26%, and 20% of subjects were receiving an NNRTI, PI, or INI (respectively) as their baseline third treatment agent class prior to randomisation and was similar between treatment arms.
The pooled primary analysis demonstrated that dolutegravir plus rilpivirine is non-inferior to CAR, with 95% of subjects in both arms achieving the primary endpoint of < 50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshot algorithm (Table 6).
The primary endpoint and other outcomes (including outcomes by key baseline covariates) for the pooled SWORD-1 and SWORD-2 studies are shown in Table 6.

Antiretroviral pregnancy registry.

The APR has received reports of over 600 exposures to dolutegravir during pregnancy resulting in live births, as of July 2019. These consist of over 370 exposures during the first trimester, over 230 exposures during the second/third trimester and included 12 and 9 birth defects, respectively. The prevalence (95% CI) of defects among live births exposed to dolutegravir in the first trimester was 3.2% (1.7%, 5.5%) and in the second/third trimester, 3.8% (1.7%, 7.0%).
The APR has received reports of over 610 exposures to rilpivirine during pregnancy resulting in live birth, as of July 2019. These consist of over 420 exposures during the first trimester, over 190 exposures during the second/third trimester and included 6 and 3 birth defects, respectively. The prevalence (95% CI) of defects among live births exposed to rilpivirine in the first trimester was 1.4% (0.5, 3.0%) and in the second/third trimester, 1.6% (0.3, 4.5%).
The available data from the APR do not indicate a significant increase in risk of major birth defects for dolutegravir or rilpivirine compared to the background rates in two population based surveillance systems (Metropolitan Atlanta Congenital Defects Program with defects of 2.72 per 100 live births and the Texas Birth Defects Registry with 4.17 per 100 live births). However, the APR data are currently insufficient to provide evidence regarding the risk of neural tube defects associated with dolutegravir.

Children.

There are no clinical study data with Juluca in the paediatric population.

5.2 Pharmacokinetic Properties

One Juluca tablet is bioequivalent to one dolutegravir 50 mg tablet and one rilpivirine 25 mg tablet administered together with a meal.
Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is between low to moderate. In Phase 1 studies in healthy subjects, between-subject CVb% for AUC and C_max ranged from ~20 to 40% and C_T from 30 to 65% across studies. The between-subject PK variability of dolutegravir was higher in HIV-infected subjects than healthy subjects and CVb% was estimated to be 30-50% for AUC and C_max, and at 55-140% for C_T. Within-subject variability (CVw%) is lower than between-subject variability.
The pharmacokinetic properties of rilpivirine have been evaluated in healthy subjects and in antiretroviral treatment-naive HIV-1 infected patients. Systemic exposure to rilpivirine was generally lower in HIV-1 infected patients than in healthy subjects.

Absorption.

Dolutegravir is rapidly absorbed following oral administration, with median T_max at 2 to 3 hours post dose for tablet formulation. The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of tablet formulations, in general, dolutegravir exhibited nonlinear pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however increase in dolutegravir systemic exposure appears dose proportional from 25 mg to 50 mg.
After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4-5 hours. The absolute bioavailability of dolutegravir or rilpivirine has not been established.

Effect of food.

Juluca should be taken with a meal. When Juluca was taken with a meal, the absorption of both dolutegravir and rilpivirine was increased. Moderate and high fat meals increased the dolutegravir AUC_(0-∞) by approximately 87% and C_max by approximately 75%. Rilpivirine AUC_(0-∞) was increased by 57% and 72% and C_max by 89% and 117%, with moderate and high fat meals respectively, compared to fasted conditions.
Food increases the extent and slows the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC_(0-∞) by 33%, 41%, and 66%, increased C_max by 46%, 52%, and 67%, prolonged T_max to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. These increases are not clinically significant.
The exposure to rilpivirine was approximately 40% lower when taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.

Distribution.

Dolutegravir is highly bound (approximately 99.3%) to human plasma proteins based on in vitro data. The apparent volume of distribution (following oral administration of suspension formulation) is estimated at 12.5 L. Binding of dolutegravir to plasma proteins was independent of concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. Free fraction of dolutegravir in plasma is estimated at approximately 0.2 to 1.1% in healthy subjects, approximately 0.4 to 0.5% in subjects with moderate hepatic impairment, and 0.8 to 1.0% in subjects with severe renal impairment and 0.5% in HIV-1 infected patients.
Dolutegravir is present in cerebrospinal fluid (CSF). In 12 treatment-naive subjects receiving a regimen of dolutegravir plus abacavir/lamivudine for 16 weeks, dolutegravir concentration in CSF averaged 16.2 nanogram/mL at Week 2 and 12.6 nanogram/mL at Week 16, ranging from 3.7 to 23.2 nanogram/mL (comparable to unbound plasma concentration; 16.8 mg/mL at week 2 and 23 nanogram/mL at week 16, ranging from 3.81 to 32.1 nanogram/mL). CSF:plasma concentration ratio of dolutegravir ranged from 0.11 to 2.04%. Dolutegravir concentrations in CSF exceeded the IC₅₀, (0.52 nanoM = 0.2 nanogram/mL) supporting the median reduction from baseline in CSF HIV-1 RNA of 2.2 log after 2 weeks and 3.4 log after 16 weeks of therapy.
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue, and vaginal tissue were 6 to 10% of that in corresponding plasma at steady-state. AUC was 7% in semen and 17% in rectal tissue, of those in corresponding plasma at steady-state.
Rilpivirine is highly bound (approximately 99.7%) to plasma proteins in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g. cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism.

Dolutegravir is primarily metabolised via UGT1A1 with a minor CYP3A component (9.7% of total dose administered in a human mass balance study). Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged drug is low (< 1% of the dose).
In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.

Excretion.

Dolutegravir has a terminal half-life of ~14 hours and an apparent clearance (CL/F) of 0.56 L/hr. Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-one percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).
Rilpivirine has a terminal elimination half-life of approximately 45 hours. After single dose oral administration of ¹⁴C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of total dose) were detected in urine.