IDWeek 2019: ViiV Healthcare to present 20 abstracts from its innovative R&D portfolio with focus on 2-drug and long-acting regimens and mental health impact of HIV

Issued: London, UK

ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer Inc. and Shionogi Limited as shareholders, today announced it will present 20 abstracts from the company’s HIV research and development programs, as well as its community-based research initiatives, at the Infectious Disease Society of America (IDSA) IDWeek 2019, 2-6 October, in Washington, DC. The data highlight ViiV Healthcare’s commitment to not only develop innovative medicines that address the unmet need that still exists in HIV treatment, but also advance understanding of the emotional experiences and overall well-being of those who live with HIV.

Kimberly Smith, M.D., Head of Research & Development at ViiV Healthcare, said: “People living with HIV are increasingly asking for a variety of treatment options to meet their evolving needs, and our data presentations at IDWeek 2019 show how ViiV Healthcare is delivering on this request. We are excited to be sharing data that describe the longer-term efficacy and safety of our 2-drug regimens and additional information relating to patient preferences for our long-acting regimen. We will also be presenting data that underscore the need to place additional attention on the role of mental health and well-being, especially as individuals age while living with HIV.” 

Data supporting 2-drug regimens (2DRs)

ViiV Healthcare is presenting data that describe the longer-term safety and efficacy of 2DRs, as well as patient adherence and preference with respect to these treatment regimens:

• Six years of data (Week 312) from the LATTE study describes the longer-term efficacy and safety of the investigational 2DR of ViiV Healthcare’s cabotegravir and Janssen’s rilpivirine as a maintenance therapy in virologically suppressed patients.^[1] These data underpin ongoing research efforts into this combination as a long-acting injectable regimen for adults living with HIV.
• Pooled data from the ATLAS and FLAIR studies^[2] at Week 48 regarding injection timing of cabotegravir and rilpivirine.

• Patient-reported outcomes from additional studies will be presented on the long-acting regimen of cabotegravir and rilpivirine.^[3,4]
• Results of subgroup efficacy analyses by baseline disease and demographic characteristics (secondary endpoint) from the pooled GEMINI 1 & 2 studies at Week 96 evaluating Dovato (dolutegravir plus lamivudine) in treatment-naïve adults with HIV-1.^[5]
• Week 148 data regarding treatment satisfaction and symptom burden before and after switching to Juluca (dolutegravir plus rilpivirine) from the SWORD 1 & 2 studies.^[6]

Data on the impact of HIV on the community

Recognising that achieving viral suppression is only one aspect of living with HIV, ViiV Healthcare will present data from innovative research initiatives that help to better understand the factors that contribute to quality of life in people living with HIV:

• Findings from the Positive Perspectives survey, an international survey conducted by ViiV Healthcare, which evaluated the perspectives and attitudes of people living with HIV.^[7]
• The RISE study, a cross-sectional survey designed to obtain an up-to-date understanding of the unmet needs in virally suppressed people living with HIV in the US.^[8]

The full list of data that will be presented by ViiV Healthcare at IDWeek 2019 is listed below:

Cabotegravir and rilpivirine

Format	Abstract Title	Author / Presenter	Abstract / Poster Number	Time (ET) / Location
Oral	Patient Adherence to Long-Acting Cabotegravir + Rilpivirine Through 48 Weeks of Maintenance Therapy in the Phase 3 ATLAS and FLAIR Studies	Paula Teichner	884	Thurs 3 Oct, 3:30 – 3:45 PM   Room 144 ABC
Poster	Population Pharmacokinetic (PPK) Modeling and Simulation of Long-Acting (LA) Cabotegravir (CAB) to Inform Strategies following Dosing Interruptions in HIV-1 Infected Subjects	Susan Ford	1532	Fri 4 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Women's Perspectives on and Experiences with Long-acting Injectable Anti-retroviral Therapy in the United States and Spain: the Potential Role of Gender in Patient Preferences	Wendy Davis	2497	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Pharmacokinetics of Cabotegravir (CAB) and Rilpivirine (RPV) Long-Acting (LA) Injectables in HIV-infected Individuals through 48 Weeks in the FLAIR and ATLAS Phase 3 Studies	Parul Patel	2495	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Perceptions of and Preferences for Oral or Long-Acting Injectable Antiretroviral Treatment Regimens in the United States and Canada	Cindy Garris	2499	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C
Oral	Long term efficacy, safety and durability of CAB and RPV as two drug oral maintenance therapy – LATTE Week 312 results	David A Margolis	2840	Sat 5 Oct, 2:15 – 2:30 PM   Room 144

Dovato (dolutegravir/lamivudine)

Format	Abstract Title	Author / Presenter	Abstract / Poster Number	Time (ET) / Location
Oral	Durable Efficacy of Two-Drug Regimen (2DR) of Dolutegravir (DTG) plus Lamivudine (3TC) in Antiretroviral Treatment-Naïve Adults with HIV-1 Infection at 96 Weeks: Subgroup Analyses in the GEMINI Studies	Jean van Wyk	2842	Sat 5 Oct, 2:45 – 3:00 PM   Room 144

Dolutegravir

Format	Abstract Title	Author / Presenter	Abstract / Poster Number	Time (ET) / Location
Poster	Risk of Type 2 Diabetes Mellitus after Antiretroviral Therapy Initiation in Individuals Living with HIV in the United States	Ricky Hsu	341	Thurs 3 Oct, 12:15 – 1:30 PM   Hall B + C
Oral	Changes in BMI Associated with Antiretroviral Regimens in Treatment-Experienced, Virologically Suppressed Individuals Living with HIV	Karam Mounzer	978	Fri 4 Oct, 11:00 – 11:15 AM   Room 206
Poster	Virologic Failure In ART Naïve Patients Initiating on a Dolutegravir or Elvitegravir Based Regimen	Michael Wohlfeiler	2488	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C

Juluca (dolutegravir/rilpivirine)

Format	Abstract Title	Author / Presenter	Abstract / Poster Number	Time (ET) / Location
Poster	SWORD 1&2: Switch from TDF Containing Regimen to DTG+RPV Maintains Bone Mineral Density and Decreases Bone Turnover Markers Over 148 Weeks	Lesley Kahl	319	Thurs 3 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Characteristics and Outcomes Over First 12 Months of a Two-Drug Regimen (Dolutegravir/Rilpivirine) for Treatment of HIV-1 in the United States	Gerald Pierone	2483	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Patient Reported Outcomes After Switching to a 2-Drug Regimen of Dolutegravir + Rilpivirine: Week 148 Results from the Sword-1 and Sword-2 Studies	Alan Oglesby	2484	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Real World Experience with Dolutegravir Plus Rilpivirine Two-Drug Regimen	Douglas Ward	2485	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C

Fostemsavir

Format	Abstract Title	Author / Presenter	Abstract / Poster Number	Time (ET) / Location
Poster	Fostemsavir drug-drug interaction profile, an attachment inhibitor and oral prodrug of temsavir, for heavily treatment experienced HIV-1 infected patients	Katy Moore	2500	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Systematic Literature Review of Multiclass Resistance in Heavily Treatment Experienced Persons with HIV	Julie Priest	2510	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C

Additional abstracts

Format	Title of abstract	Author/ Presenter	Abstract/ Poster Number	Time (ET) / Location
Poster	Experiences and Emotional Challenges of Antiretroviral Treatment (ART) - Findings from the Positive Perspectives Study	Benjamin Young	1329	Fri 4 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Mental Health, Quality of Life, and Accessibility to Care Among Virally-Suppressed People Living with HIV in the United States	Tammeka Evans	1257	Fri Oct 4, 12:15 – 1:30 PM   Hall B + C
Poster	Decreasing Adherence to Antiretroviral Therapy over 4 Years of Follow-up in a Commercially-Insured Population of Patients with HIV	Julie Priest	2512	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C
Poster	Qualitative Thematic Analysis of Social Media Data to Assess Perceptions of Daily Oral and Long-Acting Injectable Antiretroviral Treatment among People Living with HIV	Cindy Garris	2496	Sat 5 Oct, 12:15 – 1:30 PM   Hall B + C

About cabotegravir

Cabotegravir is an investigational integrase inhibitor (INI) and is not approved by regulatory authorities anywhere in the world. Cabotegravir is being developed by ViiV Healthcare for the treatment and prevention of HIV. It is being evaluated as a long-acting formulation for intramuscular injection and also as a once-daily oral tablet for use as a lead-in, to establish the tolerability of cabotegravir prior to long-acting injection.

About rilpivirine long-acting

Rilpivirine long-acting is an investigational, prolonged-release suspension for intramuscular injection being developed by Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, and is not approved by regulatory authorities anywhere in the world.

About Dovato (dolutegravir/lamivudine)

Dovato is approved as a complete regimen for the treatment of HIV-1 infection in adults with no known antiretroviral treatment history and with no known substitutions associated with resistance to either dolutegravir or lamivudine. Dovato is a once-daily, single-tablet, two-drug regimen that combines the integrase strand transfer inhibitor (INSTI) dolutegravir (Tivicay, 50 mg) with the nucleoside analogue reverse transcriptase inhibitor (NRTI) lamivudine (Epivir, 300 mg).

Like a DTG-based three-drug regimen, Dovato uses only two drugs to inhibit the viral cycle at two different sites. INSTIs, like dolutegravir, inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Lamivudine is an NRTI that works by interfering with the conversion of viral RNA into DNA which in turn stops the virus from multiplying. 

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

IMPORTANT SAFETY INFORMATION (ISI)

The following ISI is based on the Highlights section of the Prescribing Information for Dovato.  Please consult the full Prescribing Information for all the labeled safety information for Dovato.

WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV-1): EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV

• All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.

• Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment

DOSAGE AND ADMINISTRATION

• Prior to or when initiating DOVATO, test patients for HBV infection.
• Pregnancy Testing: Perform pregnancy testing before initiation of DOVATO in individuals of childbearing potential.
• One tablet taken orally once daily with or without food.
• The dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with carbamazepine or rifampin. If DOVATO is coadministered with carbamazepine or rifampin, take one tablet of DOVATO once daily, followed by an additional dolutegravir 50-mg tablet, approximately 12 hours from the dose of DOVATO.

CONTRAINDICATIONS

• Prior hypersensitivity reaction to dolutegravir or lamivudine.
• Coadministration with dofetilide.

WARNINGS AND PRECAUTIONS

• Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported with dolutegravir. Discontinue DOVATO immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction.
• Hepatotoxicity has been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with DOVATO. Monitoring for hepatotoxicity is recommended.
• Embryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Avoid use of DOVATO at the time of conception through the first trimester of pregnancy due to the risk of neural tube defects. Advise individuals of childbearing potential to use effective contraception.
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues.
• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy.

ADVERSE REACTIONS

The most common adverse reactions (all grades) observed in ≥2% (in those receiving DOVATO) were headache, diarrhea, nausea, insomnia, and fatigue.

DRUG INTERACTIONS

• DOVATO is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral drugs for the treatment of HIV-1 infection is not recommended.
• Refer to the full prescribing information for important drug interactions with DOVATO.

USE IN SPECIFIC POPULATIONS

• Pregnancy: Avoid use of DOVATO at the time of conception through the first trimester due to the risk of neural tube defects.
• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission.
• Females and males of reproductive potential: Pregnancy testing and contraception are recommended in individuals of childbearing potential.
• Renal Impairment: DOVATO is not recommended in patients with creatinine clearance less than 50 mL/min.
• Hepatic Impairment: DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C).

Please refer to the US Prescribing Information.

About Juluca (dolutegravir/rilpivirine)

Juluca is ViiV Healthcare’s first two-drug regimen (2DR), once-daily, single-pill that combines dolutegravir 50mg (ViiV Healthcare), the most widely prescribed integrase inhibitor (INI) worldwide, with the nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine 25mg (Janssen Sciences Ireland UC). Juluca was granted marketing authorisation by regulatory authorities in the United States in November 2017, the European Union and Canada in May 2018, and Australia in June 2018.^{[9],[10],[11],[12]} ViiV Healthcare has also submitted regulatory marketing applications in other countries worldwide.

Juluca is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen for at least six months with no history of virological failure and no known or suspected resistance to any NNRTI or INI.⁹

Two essential steps in the HIV life cycle include reverse transcription – when the virus turns its RNA (ribonucleic acid) copy into DNA (deoxyribonucleic acid) – and integration – the moment when viral DNA becomes part of the host cell’s DNA. These processes require two enzymes called nucleoside reverse transcriptase and integrase. NNRTIs and INIs interfere with the action of these two enzymes to prevent the virus from replicating. This decrease in replication can lead to less virus being available to cause subsequent infection of uninfected cells.

U.S. IMPORTANT SAFETY INFORMATION: JULUCA (dolutegravir and rilpivirine) tablets

Professional Indication(s) and Important Safety Information

Indication and Usage for JULUCA

JULUCA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for ≥6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of JULUCA.

Important Safety Information

CONTRAINDICATIONS

JULUCA is contraindicated in patients:

• with previous hypersensitivity reaction to dolutegravir or rilpivirine.
• receiving dofetilide, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, systemic dexamethasone (>1 dose), St. John’s wort, and proton pump inhibitors (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole).

WARNINGS AND PRECAUTIONS

Skin and Hypersensitivity Reactions:

• Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in <1% of subjects receiving dolutegravir in Phase 3 clinical trials.
• Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens and have been accompanied by fever and/or organ dysfunctions including elevations in hepatic serum biochemistries.
• Discontinue JULUCA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (such as severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, mucosal involvement, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, and difficulty breathing), as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including laboratory parameters with liver aminotransferases, should be monitored and appropriate therapy initiated.

Hepatotoxicity:

• Hepatic adverse events have been reported, including cases of hepatic toxicity, in patients without pre-existing hepatic disease or other identifiable risk factors.
• 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. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn.
• Monitoring for hepatotoxicity is recommended.

Depressive Disorders:

• Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation) have been reported.
• Promptly evaluate patients with severe depressive symptoms.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:

• The concomitant use of JULUCA and other drugs may result in known or potentially significant drug interactions, see Contraindications and Drug Interactions sections. Rilpivirine doses 3 and 12 times higher than the recommended dose can prolong the QTc interval. Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes. Consider the potential for drug interactions prior to and during therapy with JULUCA and monitor for adverse reactions.

ADVERSE REACTIONS: Most common adverse reactions with JULUCA (incidence ≥2%, all Grades) were diarrhea (2%) and headache (2%).

DRUG INTERACTIONS

• Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
• Drugs that induce or inhibit CYP3A or UGT1A1 may affect the plasma concentrations of the components of JULUCA.
• Drugs that increase gastric pH or containing polyvalent cations may decrease plasma concentrations of the components of JULUCA.
• Consider alternatives to prescribing JULUCA with drugs with a known risk of Torsade de Pointes.
• Consult the full Prescribing Information for JULUCA for more information on potentially significant drug interactions, including clinical comments.

USE IN SPECIFIC POPULATIONS

• Pregnancy:There are insufficient prospective pregnancy data to adequately assess the risk of birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established.
• Lactation:Breastfeeding is not recommended due to the potential for HIV-1 transmission and the potential for adverse reactions in nursing infants.

DOSAGE AND ADMINISTRATION

• Dosage:1 tablet taken orally once daily with a meal for adult patients.
• Recommended Dosage of JULUCA with Rifabutin Coadministration: Take an additional 25-mg tablet of rilpivirine with JULUCA once daily with a meal for the duration of the rifabutin coadministration.

Full US prescribing information is available at:

https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Juluca/pdf/JULUCA-PI-PIL.PDF

For the EU Summary of Product Characteristics, please visit:

https://www.medicines.org.uk/emc/product/9246

About fostemsavir

Fostemsavir is an investigational prodrug of temsavir, an HIV-1 attachment inhibitor class, and is not authorised by regulatory authorities anywhere in the world. Fostemsavir is being developed by ViiV Healthcare for the treatment of HIV-1-infected heavily treatment-experienced patients in combination with other antiretroviral agents.

About ViiV Healthcare

ViiV Healthcare is a global specialist HIV company established in November 2009 by GlaxoSmithKline (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV and for people who are at risk of becoming infected with HIV. Shionogi joined in October 2012. The company’s aim is to take a deeper and broader interest in HIV/AIDS than any company has done before and take a new approach to deliver effective and innovative medicines for HIV treatment and prevention, as well as support communities affected by HIV.

For more information on the company, its management, portfolio, pipeline and commitment, please visit www.viivhealthcare.com.

About GSK

GSK is a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. For further information please visit www.gsk.com/about-us.

References

[1] Margolis DA, Sutton KC, De Vente D, et al. Long term efficacy, safety and durability of CAB and RPV as two drug oral maintenance therapy – LATTE Week 312 results. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[2] Teichner P, Cutrell A, D'Amico R, et al. Patient adherence to long-acting cabotegravir + rilpivirine through 48 weeks of maintenance therapy in the Phase 3 ATLAS and FLAIR studies. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[3] Garris C, Heidenreich S, Arthurs E, et al. Perceptions of and preferences for oral or long-acting injectable antiretroviral treatment regimens in the United States and Canada. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[4] Mantsios A, Murray M, Karver TS, et al. CARLA Women Women’s perspectives on and experiences with long-acting injectable anti-retroviral therapy in the United States and Spain: the potential role of gender in patient preferences. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[5] van Wyk J, Man C, Sievers J, et al. Durable efficacy of two-drug regimen (2dr) of dolutegravir (dtg) plus lamivudine (3tc) in antiretroviral treatment-naïve adults with hiv-1 infection at 96 weeks: subgroup analyses in the GEMINI studies. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[6] Oglesby A, Angelis K, Punekar Y, et al. Juluca SWORD PROs data. Patient reported outcomes after switching to a 2-drug regimen of dolutegravir + rilpivirine:  Week 148 results from the SWORD-1 and SWORD-2 studies. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[7] Young B, Marcotullio S, Punekar Y, et al. Experiences and emotional challenges of antiretroviral treatment (ART) - findings from the positive perspectives study. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[8] Evans TM, Cutts KN, Swinburn P, et al. Mental health, quality of life, and accessibility to care among virally-suppressed people living with HIV in the United States. Planned presentation at the Infectious Disease Society of America (IDSA) IDWeek™ 2019, 2-6 October, Washington, DC.

[9] Juluca EU Summary of Product Characteristics www.ema.europa.eu.

[10] Juluca (dolutegravir and rilpivirine) Prescribing Information. U.S Approval 2017.

[11] Health Canada. Juluca certified product information document. 18 May 2018.

[12] Australian Government. Department of Health Therapeutic Goods Administration. Juluca Product Information - ARTG ID 291356. Available at: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2018-PI-01956-1&d=2018062916114622483  Last accessed September 2019.