SINGLE STUDY DATA UP TO 144 WEEKS

Transcription

1 SINGLE STUDY DATA UP TO 144 WEEKS Efficacy and safety of dolutegravir (DTG) in treatment-naïve subjects UK/DLG/0083/14a(2) Date of preparation: February 2017 Prescribing information is available at the end of this presentation

2 DECLARATION OF INTEREST

3 Heavily Treatment Experienced Continuin g ART INIs BOOSTED Pls ATRIPLA KEY STUDIES SINGLE Treatment-naïve patients TRIUMEQ QD vs Atripla QD (N=833) SUPERIOR EFFICACY vs Atripla at weeks 48 (primary endpoint), 96 and 144 FLAMINGO Treatment-naïve patients DTG + 2 NRTIs QD vs DRV/r + 2 NRTIs QD (N=484) SUPERIOR EFFICACY vs darunavir/r at weeks 48 (primary endpoint) and 96 ARIA Treatment-naïve women TRIUMEQ QD vs ATV/r + TDF/FTC QD (N=495) SUPERIOR EFFICACY vs atazanavir/r at week 48 (primary endpoint) SPRING-2 Treatment-naïve patients DTG + 2 NRTIs QD vs RAL + 2 NRTIs BID (N=822) NON-INFERIOR EFFICACY vs raltegravir at weeks 48 (primary endpoint) and 96 SAILING Treatment-experienced, INI-naïve patients DTG QD + BR* vs RAL BID + BR* (N=719) SUPERIOR EFFICACY vs raltegravir at week 48 (primary endpoint) STRIIVING Treatment-experienced, stable-switch patients TRIUMEQ QD vs continuing ARV regimen (N=551) NON-INFERIOR EFFICACY up to weeks 24 (primary endpoint) and 48 VIKING-3 Heavily treatment experienced patients with RAL and/or EVG resistant HIV-1 DTG 50mg BD + OBR** (N=183)-single-arm study SUSTAINED EFFICACY up to weeks 24 (primary endpoint) and 48 DTG 50mg + ABC 600mg/3TC 300mg were used. Bioequivalence has been demonstrated.13 * BR - background regimen ** OBR - optimised background regimen Clotet B et al. Lancet. 2014;383(9936): Orrell C et al. Presented at 21st International AIDS Conference, 18th-22nd July, 2016; Durban, South Africa. Abstract THAB0205LB. 3. Walmsley S et al. N Engl J Med. 2013;369(19): Walmsley S et al. J Acquir Immune Defic Syndr. 2015;70: Molina J-M et al. Lancet HIV.2015;2(4):e127-e136. January Raffi F et al. Lancet Infect Dis. 2013;13: Raffi F et al. Lancet. 2013; 381: Cahn P et al. Lancet. 2013; 382: Trottier B et al. Presented at 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, 17th-21st September, 2015; San Diego, CA. LB Lake JE et al. Presented at 21st International AIDS Conference, 18th-22nd July, 2016; Durban, South Africa. Abstract THAB Castagna A et al. J Infect Dis. 2014; 210:

4 Adapted from Walmsley S, et al. N Engl J Med 2013; 369: ; Pappa K, et al. Oral presentation at: 54th ICAAC 2014; H-647a SINGLE STUDY DESIGN Treatment-naïve, HIV-1 positive HLA-B*5701 negative HIV-1 RNA 1000 c/ml Creatinine clearance >50 ml/min Stratified by baseline viral load and CD4 cell count DTG 50 mg QD plus ABC/3TC FDC plus EFV/TDF/FTC placebo (n=414) EFV/TDF/FTC QD plus DTG + ABC/3TC FDC placebo (n=419) DTG 50 mg QD plus ABC/3TC open label EFV/TDF/FTC QD open label Week 48 Week 96 Week 144 Primary endpoint: Proportion with HIV-1 RNA <50 c/ml at Week 48, FDA snapshot analysis (-10% non-inferiority margin with pre-specified tests for superiority)

5 BASELINE CHARACTERISTICS Characteristic DTG 50 mg +ABC/3TC QD (n=414) EFV/TDF/FTC QD (n=419) Median age, years (range) 36 (18-68) 35 (18-85) Female, n (%) 67 (16) 63 (15) African American/African Heritage, n (%) 98 (24) 99 (24) CDC class C, n (%) 18 (4) 17 (4) Baseline HIV-1 RNA Median (log10 c/ml) >100,000 c/ml, n (%) 134 (32) 131 (31) Median CD4 cell count, cells/mm <200, % to <350, % to <500, % , % Adapted from Walmsley S, et al. N Engl J Med 2013; 369: and supplementary appendix

6 Proportion with HIV-1 RNA <50 copies/ml DTG + ABC/3TC DEMONSTRATED STATISTICALLY SUPERIOR EFFICACY VS EFV/TDF/FTC AT 48, 96 AND 144 WEEKS DTG + ABC/3TC demonstrated rapid suppression of viral load vs EFV/TDF/FTC (28 days vs 84 days, respectively; P<0.0001) Favours EFV/TDF/FTC W48 W96 W144-5% 95% CI for difference 0 DTG 50 mg + ABC/3TC FDC QD (n=414) 88% 81% Favours DTG + ABC/3TC p=0.003 p=0.006 p= % 72% EFV/TDF/FTC QD (n=419) Week -10% non-inferiority margin with pre-specified tests for superiority ATRIPLA (EFV/TDF/FTC) is not licensed in the UK or Ireland for initial use in treatment-naive patients. 2.5% 2.3% 7.4% Adapted from Walmsley S, et al. N Engl J Med 2013; 369: ; Walmsley S, et al. J Acquir Immune Defic Syndr 2015; vol 70, no 5: % 8.3% 12.3% 13.8% 2% 14.6% 15% DTG + ABC/3TC: 71% EFV/TDF/FTC: 63%

7 Percent With HIV-1 RNA <50 c/ml DTG WAS EFFECTIVE VS ATRIPLA REGARDLESS OF BASELINE VIRAL LOAD Week ,000 >100,000 Baseline plasma HIV-1 RNA, c/ml DTG 50 mg + ABC/3TC FDC QD (n=414) EFV/TDF/FTC QD (n=419) 32% of treatmentnaïve patients had a baseline viral load >100,000 copies/ml P=0.831; test for homogeneity; P value confirms that there is no evidence of heterogeneity in treatment difference across the baseline stratification factors Adapted from: Abstract H-556b Walmsley S, et al. N Engl J Med 2013; 369: and supplementary appendix; Walmsley S, et al. J Acquir Immune Defic Syndr 2015; vol 70, no 5:

8 Adjusted mean change from baseline CD4+ cell count (cells/mm 3 ) DTG HAD STATISTICALLY SUPERIOR CD4 + T-CELL INCREASES VS ATRIPLA UP TO 144 WEEKS DTG + ABC/3TC 267 cells/mm 3 EFV/TDF/FTC 208 cells/mm 3 Week 48 difference in response (95% CI): 59% [33%, 84%]; P<0.001 DTG 50 mg + ABC/3TC FDC QD (n=414) EFV/TDF/FTC QD (n=419) Week DTG + ABC/3TC 325 cells/mm 3 EFV/TDF/FTC 281 cells/mm 3 Week 96 difference in response (95% CI): 44% [14%, 74%]; P=0.004 DTG + ABC/3TC 379 cells/mm 3 EFV/TDF/FTC 332 cells/mm 3 Week 144 difference in response (95% CI): 47% [16%, 78%]; P=0.003 Adapted from: Walmsley S, et al. 52nd ICAAC Sept Abstract H-556b; Walmsley S, et al. N Engl J Med 2013;369: ; Walmsley S, et al. Poster presented at: 21st CROI 2014;Poster 543; Pappa K, et al. Oral presentation at: 54th ICAAC 2014;H-647a

9 Proportion (%) of patients with AE leading to discontinuation FEWER DISCONTINUATIONS DUE TO ADVERSE EVENTS UP TO 144 WEEKS WITH DTG VS ATRIPLA Discontinuations due to AEs were 4% for DTG + ABC/3TC vs 14% for EFV/TDF/FTC at Week DTG 50 mg + ABC/3TC FDC QD (n=414) EFV/TDF/FTC QD (n=419) Week 48 Week 96 Week 144 Adapted from Walmsley S, et al. N Engl J Med 2013; 369: ; Walmsley S, et al. Poster presented at: 21st CROI Poster 543; Pappa K, et al. Oral presentation at: 54th ICAAC 2014 ; H-647a

10 Proportion (%) of patients with AE leading to withdrawal DTG WAS GENERALLY BETTER TOLERATED VS ATRIPLA UP TO 144 WEEKS WITH FEWER DISCONTINUATIONS The incidence of psychiatric or nervous system disorders leading to withdrawal up to 144 weeks was <1% each for DTG + ABC/3TC and 6%, 4% respectively for EFV/TDF/FTC 20 Common AEs leading to withdrawal by system organ class ( 2% in either arm) DTG 50 mg + ABC/3TC FDC QD (n=414) EFV/TDF/FTC QD (n=419) <1 <1 <1 Psychiatric disorders Nervous system disorders Skin and subcutaneous tissue disorders General disorders and administration site conditions 2 Gastrointestinal disorders Adapted from Pappa K, et al. Oral presentation at: 54th ICAAC 2014 ; H-647a

11 Mean change from baseline (SD) in serum creatinine, µmol/l CHANGE FROM BASELINE TO 144 WEEKS IN RENAL PARAMETERS No. of patients DTG 50 mg + ABC/3TC QD EFV/TDF/FTC QD BL Week DTG + ABC/3TC QD EFV/TDF/FTC QD Parameter Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 Urine albumin/creatinine ratio Mean change (SD) 10.2 (9.02) 12.5 (9.98) 12.2 (10.51) -0.7 (8.34) 1.3 (8.70) 1.6 (9.52) Baseline µmol/l: DTG: 75.0 versus EFV/TDF/FTC: 74.6 DTG 50 mg + ABC/3TC QD EFV/TDF/FTC QD Conversion rate: 1 µmol/l = 0.011mg/dL Adapted from Pappa K, et al. ICAAC Abstract H-647a

12 DTG HAS DEMONSTRATED A HIGH BARRIER TO RESISTANCE TO DATE No INI or NRTI resistance seen with DTG up to 144 weeks DTG 50 mg + ABC/3TC FDC QD (n=414) EFV/TDF/FTC QD (n=419) Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 INI-resistant major substitution 0 0 * 0 * N/A N/A N/A NRTI major mutations ** 1 1 NNRTI major mutations N/A N/A N/A *E157Q/P polymorphism detected in 1 patient with no significant change in INI phenotypic susceptibility ** Treatment emergent NRTI mutations detected: K65K/R Treatment-emergent NNRTI mutations detected: K101E (n=1), K103K/N (n=1), G190G/A (n=1) and K103N+G190G/A (n=1) Treatment emergent NRTI mutations detected: K65R Treatment-emergent NNRTI mutations detected: K101E (n=1); K103N (n=1); K103K/N (n=2), G190A (n=1) and K103N+G190G/A (n=1) Treatment-emergent NNRTI mutations detected: K101E (n=1); K103N (n=2); K103K/N (n=2), G190A (n=2) Pappa K, et al. Oral presentation at: 54th ICAAC 2014;H-647a; Walmsley S, et al. N Engl J Med 2013;369: and supplementary appendix; Walmsley S, et al. Poster presented at: 21st CROI Poster 543

13 DTG IN TREATMENT-NAIVE PATIENTS SINGLE STUDY 144 WEEK DATA: SUMMARY DTG + ABC/3TC had statistically superior efficacy vs EFV/TDF/FTC 88% vs 81% were undetectable at 48 weeks (P=0.003) 80% vs 72% remained subsequently undetectable at 96 weeks (P=0.006) 71% vs 63%remained subsequently undetectable at 144 weeks (P=0.010) DTG + ABC/3TC is effective regardless of baseline viral load 83% of treatment-naive patients with HIV-1 RNA > 100,000 copies/ml remained undetectable at 48 weeks DTG + ABC/3TC was still as effective as EFV/TDF/FTC in patients with high baseline viral loads at 96 weeks 69% of treatment-naive patients with HIV-1 RNA > 100,000 copied/ml remained undetectable at 144 weeks DTG + ABC/3TC was generally better tolerated vs EFV/TDF/FTC with fewer discontinuations 2% vs 10% discontinuation due to AEs at 48 weeks 3% vs 11% discontinued due to AEs at 96 weeks 4% vs 14% discontinuation due to AEs at 144 weeks No INI or NRTU resistance up to 144 weeks with DTG + ABC/3TC TIVICAY Summary of Product Characteristics, January 2017; Walmsley S, et al. N Engl J Med 2013; 369: ; Walmsley S, et al. Poster presented at: 21st CROI Poster 543; Pappa K, et al. Oral presentation at: 54th ICAAC 2014; H-647a

14 TIVICAY (DOLUTEGRAVIR) LICENSED INDICATION TIVICAY is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age Population Patients without documented or clinically suspected resistance to the integrase class Patients without documented or clinically suspected resistance to the integrase class, when co-administered with some medicines e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin Patients with resistance to the integrase class (documented or clinically suspected) In the presence of documented resistance including Q secondary mutations from G140A/C/S, E138A/K/T, L741, an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance Adolescents aged 12 and above and weighing at least 40 kg and without documented or suspected resistance to the integrase class Recommended dose 50 mg once daily 50 mg twice daily 50 mg twice daily 100mg twice daily 50 mg once daily TIVICAY Summary of Product Characteristics, January 2017

15 TIVICAY FOR USE SPECIAL WARNINGS AND PRECAUTIONS Integrase class resistance with Q secondary mutations from G140A/C/S, E138A/K/T & L74I Hypersensitivity reactions Immune Reactivation Syndrome Opportunistic infections Drug interactions Osteonecrosis Please consult the Summary of Product Characteristics for full prescribing information TIVICAY Summary of Product Characteristics, January 2017

16 SUPPLEMENTARY SAFETY INFORMATION

17 DTG HAD A LOWER IMPACT ON LIVER CHEMISTRY THAN ATRIPLA AT WEEK 48 Parameter/Criteria, (%) at Week 48 1 DTG 50 mg + ABC/3TC FDC QD (n=414) EFV/TDF/FTC QD (n=419) Subjects meeting 1 FDA stopping criteria 10 ( 2) 39 ( 9) ALT 20xULN 0 0 ALT 5xULN 1 (<1) 2 (<1) ALT 3xULN 5 ( 1) 15 ( 4) Total bilirubin >1.5xULN 3 (<1) 2 (<1) Alkaline phosphatase >1.5xULN 1 (<1) 19 ( 5) ALT and/or AST >3xULN and total bilirubin >1.5xULN ALT, alanine amino transferase; AST, aspartate amino transferase; ULN, upper limit of normal 0 0 Walmsley S, et al. 52nd ICAAC Sept Oral H-556b

18 Proportion (%) of patients with Grade 2 or higher ALT elevations DTG HAD A LOWER IMPACT ON LIVER CHEMISTRY THAN ATRIPLA AT WEEK 144 Grade 2 or higher ALT elevations were observed more commonly in the EFV/TDF/FTC arm than in the DTG + ABC/3TC arm at Week DTG 50 mg + ABC/3TC FDC QD (n=414) EFV/TDF/FTC QD (n=419) Adapted from Walmsley S, et al. Poster presented at: 21st CROI Poster 543; Walmsley S, et al. JAIDS 2015, Vol 70, No. 5,

19 ABBREVIATIONS 3TC, lamivudine ABC, abacavir AE, adverse event ALT, alanine amino transferase AST, aspartate amino transferase BID, twice daily c/ml, copies/ml CDC, Centers for Disease Control CI, confidence interval Cr, creatinine DRV, darunavir DRV/r, darunavir/ritonavir DTG, dolutegravir EFV, efavirenz FDA, Food and Drug Administration FDC, fixed dose combination FTC, emtricitabine HIV, human immunodeficiency virus HSR, hypersensitivity reaction INI, integrase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NNRTI, non-nucleoside reverse transcriptase inhibitor PK, pharmacokinetic QD, once daily RAL, raltegravir RNA, ribonucleic acid TDF, tenofovir disoproxil fumarate ULN, upper limit of normal

20 PRESCRIBING INFORMATION TIVICAY (DOLUTEGRAVIR 50MG TABLETS) (SEE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING) Indication: HIV in >12 years and >40kg as part of combination therapy. Dosing: 50mg once daily with or without food if no proven/ suspected integrase resistance. 50mg twice daily with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John s Wort or rifampicin. Adults with proven/ suspected integrase resistance: 50mg twice daily preferably with food. Elderly: Limited data in 65+ yrs. Caution in severe hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately if suspected. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Pregnancy/ lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, dizziness, rash, pruritus, fatigue, elevations of ALT, AST and CPK, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt. Basic NHS costs: 30 tablets EU/1/13/892/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM S1A Tivicay is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: January Zinc code: UK/DLG/0055/13(9) Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: , medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on

21 PRESCRIBING INFORMATION TRIUMEQ (DOLUTEGRAVIR 50MG/ABACAVIR 600MG/LAMIVUDINE 300MG TABLETS) (SEE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING) Indication: HIV in over 12 years and > 40kg. Screen for HLA-B*5701 prior to use. Do not use if HLA-B*5701 positive. Dose: one tablet once daily with or without food. Elderly: Limited data in 65+ yrs. Creatinine clearance <50ml/min or moderate/severe hepatic impairment: Not recommended. Monitor closely in mild hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Both abacavir and dolutegravir are associated with risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Triumeq without delay if HSR suspected. Never reintroduce any dolutegravir- or abacavir-containing product after suspected HSR. Risks of immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C co-infection. Inconclusive data on relationship between abacavir and MI; minimise all modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Not recommended if dolutegravir required b.d. (with etravirine [without boosted PI], efavirenz, nevirapine, rifampicin, boosted tipranavir, carbamazepine, oxcarbazepine, phenytoin, phenobarbital and St John s Wort). Use with cladribine not recommended. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Caution with metformin: monitor renal function and consider metformin dose adjustment. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for details. Headache, insomnia, sleep/dream disorders, GI disturbance, fatigue, hypersensitivity, anorexia, depression, dizziness, somnolence, lethargy, malaise, cough, nasal symptoms, rash, pruritus, alopecia, arthralgia, myalgia, asthenia, fever, elevations of ALT, AST and CPK, blood dyscrasias, suicidal ideation or suicide attempt, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Basic NHS costs: 30 tablets: EU/1/14/940/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM S1A Triumeq is a registered trademark of the ViiV Healthcare Group of Companies. Date of approval: January 2017 Zinc code: UK/TRIM/0037/14(7) Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: , medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on

22 PRESCRIBING INFORMATION KIVEXA (ABACAVIR 600MG/LAMIVUDINE 300MG TABLETS) (SEE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING) Indications: HIV in adults, adolescents and children weighing at least 25 kg as part of combination therapy. Screen for HLA- B*5701 prior to use. Dose: one tablet daily with or without food. Elderly: No pharmacokinetic data in 65+ yrs. Renal impairment: Creatinine clearance <50ml/min: not recommended. Hepatic impairment: not recommended in moderate or severe hepatic impairment. Monitor closely in mild hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Warnings/precautions: Risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Kivexa without delay if HSR suspected. Never reintroduce any abacavir-containing product after suspected HSR. Risks of virological failure, immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C co-infection. Inconclusive data on relationship between abacavir and MI; minimise modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Use with cladribine, emtricitabine or high doses of co-trimoxazole not recommended. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Hypersensitivity, GI disturbance, headache, anorexia, insomnia, rash, fever, lethargy, fatigue, malaise, arthralgia, muscle disorders, nasal symptoms, cough, alopecia, blood dyscrasias, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis. Basic NHS costs: 30 tablets: EU/1/04/298/002. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM Kivexa is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: October 2016 Zinc code: UK/ABC3TC/0008/13(9) Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: , medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on S1A