Paediatric antiretroviral therapy.

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Bonnie Jacobs
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1 Paediatric antiretroviral therapy. Guidelines exist for the choice of first line agents, but do not cover second line agents, other than recommending regimes of adequate potency. We would follow PENTA guidelines, when initiating therapy and then further treatment options would be directed by side effect profile and resistance findings. All the doses in the attached formulary match the PENTA guidelines, and these formulations should be available to the paediatric population at LTH. This has been updated to represent the changes recommended in PENTA 2015.

2 Paediatric HIV formulary NRTI Dosage Formulation Important Side Effects Abacavir (ABC) Liquid: > 3 months: 8mg/kg bd or 16mg/kg od (max. 600mg daily) > 12 years: 300mg bd or 600mg od Tablets: 14-21kg: 300mg od or 150mg bd 21-30kg: 450mg od or 150mg om + 300mg on >30kg/Adult: 600mg od or 300mg bd Tablet: 300mg (yellow, scored) Liquid: 20mg/ml (240ml sugar-free, banana and strawberry flavour, 2 month expiry) Hypersensitivity reaction: fever, rash, nausea, vomiting, dyspnoea, cough, diarrhoea, lethargy GI disturbances Lactic acidosis Advice 1. How to recognise signs of hypersensitivity 2. Importance of regular dosing 3. Can be given with or without 4. Can be crushed and mixed with a small amount of water or Other Total daily dose may be given in 2 divided doses Hypersensitivity reactions may occur within first 6/52 Do HLA-B*5701 test before starting Contraindicated in severe hepatic Didanosine (ddl) Liquid: 3 months - 8 months 100mg/m 2 bd 8 months - 18 years: mg/m 2 od, usual dose 200mg /m 2 od; maximum 400mg od Child dosing using capsules > 6 years and 20-25kg: 200mg od 25-60kg: 250mg od Adult (<60kg): 250mg od (200mg od if coprescribed with tenofovir) (>60kg): 400mg od (250mg od if coprescribed with tenofovir) Tablets (with calcium and magnesium antacids): 25mg Capsules EC: 125mg, 200mg, 250mg, 400mg Powder for oral solution: 10mg/ml (refrigerate, stable for 30days) Peripheral neuropathy, pancreatitis, nausea, diarrhoea Lipodystrophy, lactic acidosis and pancreatitis enhanced in combination with stavudine Antacid tablets: 1. Each dose should be taken as at least 2 tablets (child <1year, 1 tablet) to ensure sufficient antacid 2. Chew thoroughly, crush or disperse in water/clear apple juice 3. Take 2 hours after lopinavir+ritonavir or atazanavir+ritonavir EC capsules: 1. Swallow capsules whole either 2 hours before or 2 hours after 2. Caps can be opened and sprinkled on e.g. yogurt results in decreased exposure. Oral solution: Reconstitute with water and Mylanta Extra strength or Maalox Plus antacid suspensions Discontinue treatment if pancreatitis symptoms develop Not recommended with TDF Should be given on an empty stomach (2hours after and 1 hour before or milk) Reduce dose in renal

3 Emtricitabine (FTC) Child dosing liquid >4 months: 6mg/kg od (max. 240mg od) (FDA approval from 0 months of age) >33kg: 240mg od Child dosing capsules >33kg: 200mg od Capsule: 200mg (white/blue) Liquid: 10mg/ml (170ml, orange, candyflavoured) Contains propylene glycol and kept in the fridge. Headache, diarrhoea, nausea, rash Skin pigmentations on palms and soles, abnormal dreams Exacerbation of hepatitis B on discontinuation 1. Can be administered with or without 240mg oral solution 200mg capsule Dose reduce in renal Do not give with 3TC Lamivudine (3TC) Child dosing liquid Neonate (<30days): 2mg/kg bd 1-3months: 4mg/kg bd 3months - 12years: 4mg/kg bd or 8mg/kg od (max. 300mg/day) Child dosing tablet 14-21kg: 75mg bd or 150mg od 21-30kg: 75mg om + 150mg on or 225mg od >30kg: 150mg bd or 300mg od Tablet: 100mg (butterscotch colour), 150mg (scored, white, Epivir) 300mg (grey, Epivir) Liquid: 50mg/5ml (240ml, banana and strawberry flavour, Epivir, 30 day expiry) Nausea, diarrhoea, headache, fatigue Exacerbation of hepatitis B on discontinuation 1. Can be given with or without 2. Can be crushed and mixed with a small amount of water or Reduce dose in renal Adult >12 years: 150mg bd or 300mg od Tenofovir (TDF) Child dosing granules (1 scoop (scp) = 40mg) 2-8 years: 8mg/kg od 10-12kg 2scp OD 12-14kg 2.5scp OD 14-17kg 3scp OD 17-19kg 3.5scp OD 19-22kg 4scp OD 22-24kg 4.5scp OD 24-27kg 5scp OD 27-29kg 5.5scp OD Granules TDF 40mg/1g scoop (33mg/g TD) Tablets TDF 150/200/250mg (white) TDF 300mg (blue) Headache, nausea, vomiting Renal tubular dysfunction, bone demineralisation Exacerbation of hepatitis on discontinuation 1. Take with or after 2. Tablet can be dispersed in half a glass of water, orange juice or grape juice (bitter taste) Dose reduce in renal Measure baseline renal function, then 4 weekly for 1 year, then 3 monthly Not recommended with ddl

4 29-32kg 6 scp OD 32-34kg 6.5scp OD 34-35kg 7scp OD >35kg 7.5scp OD Child dosing tablets >2 years 17-22kg 150mg OD 22-28kg 200mg OD 28-35kg 250mg OD >35kg 300mg OD Adults 300mg OD (<18yrs: Doses based on tenofovir disoproxil fumarate 300mg 245mg tenofovir disoproxil (as fumerate))

5 Zidovudine (AZT) Stavudine (d4t) NOT USED AS STANDARD Child dosing liquid: >4kg (birth) to <9kg: 12mg/kg bd (max. 300mg bd) >9kg to 30kg: 9mg/kg bd (max. 300mg bd) >30kg: 300mg bd Child dosing capsules 8-13kg: 100mg bd 14-21kg: 100mg om + 200mg on 22-30kg: 200mg bd >30kg 300mg BD Neonate (<13 days): 0.5mg/kg bd <30kg: 1mg/kg bd 30-60kg: 30mg bd >60kg: 40mg bd Capsules: 100mg (white/blue band), Liquid: 50mg/5ml (200ml, sugar-free, strawberry flavoured, 30 day expiry) IV infusion also available Capsules: 20mg (brown), 30mg (light orange/dark orange), 40mg (dark orange) Liquid: 1mg/ml (200ml, powder for reconstitution, cherry flavoured) Granulocytopenia and/or anaemia Nausea, headache, myopathy, hepatitis, nail pigmentation, neuropathy Peripheral neuropathy, pancreatitis, hepatitis, GI disturbances, headache, rash Lipodystrophy, lactic acidosis and pancreatitis enhanced in combination with didanosine 1. Can be given with or without 2. Capsules can be opened and dissolved in water 1. At least one hour before Monitor full blood count after 4/52 treatment, then every 3 months Don t give with stavudine Reduce dose in severe renal Reduce dose in hepatic Switch to alternative antiretroviral if peripheral neuropathy develops Don t give with Zidovudine Reduce dose in renal

6 NNRTI Dosage Formulation Important Side Effects Efavirenz (EFV) Child (3-5years liquid only): 13-15kg: 360mg on 15-20kg: 390mg on 20-25kg: 450mg on kg: 510mg on Child dosing capsules for > 5 year (liquid in brackets): 13-15kg: 200mg on (liq: 270mg on) 15-20kg: 250mg on (liq: 300mg on) 20-25kg: 300mg on (liq: 360mg on) kg: 350mg on (liq: 450mg on) kg: 400mg on (liq: 510mg on) Adult tablets >40kg: 600mg on (liq: 720mg on) Capsules: 50mg (yellow/white), 100mg (white), 200mg (yellow) Tablets: 600mg (yellow) Liquid: 30mg/ml (180ml, sugar-free, strawberry and mint flavoured) Liquid is not bioequivalent to tabs or caps. No PK data on liquid for child < 13kg - use capsules as sprinkles) Rash, mood changes, vivid dreams, hyperchloresterolemia, abdominal pain Advice 1. Tablets can be cut 2. Capsules can be opened and added to liquids or a small amount (1-2 teaspoons) of (has a peppery taste) 3. Give tablets/capsules an hour before or on an empty stomach 4. Preferably give dose at bedtime to reduce CNS side effects 5. High fat meal can increase the EFV exposure. Other No dose adjustment necessary in renal Contraindicated in severe hepatic

7 Etravirine (ETR) Child: >6 years 16-20kg 100mg BD 20-25kg 125mg BD 25-30kg 150mg BD >30kg 200mg BD Adult: 200mg BD Tablets: 25mg, 100mg, 200mg ( all white) Rash (more common in females, usually resolves within 2 weeks), hypersensitivity reactions (most commonly during week 3-6 of treatment) Diarrhoea, flatulence, abdominal pain, headache, pruritis 1. How to recognise signs of hypersensitivity reactions 2. Take with or after 3. Can disperse tablets in water just prior to administration AUC decreased by 50% if taken on an empty stomach Not recommended in severe hepatic Nevirapine (NVP) PRESCRIBE GENERICALLY Child (from birth)immediate release formulations: 4mg/kg OD for 14 days (max 200mg/day), then (<8 years) 7mg/kg BD or (> 8 years) 4mg/kg BD (max 400mg/day) if no rash or LFT abnormalities. Child (> 3 years) extended release formulations: 13kg - 22kg 200mg OD 23kg - 35kg 300mg OD >35kg 400mg OD Immediate release tablets: 200mg (white, scored), Modified release tablets 50mg, 100mg and 400mg (all yellow) Liquid: 50mg/5ml (240ml, six months expiry) Rash, hepatitis, Steven- Johnson syndrome - usually within the first 12 weeks Nausea, headache 1. How to recognise signs of hypersensitivity reactions or hepatitis symptoms 2. Can be administered with or without 3. The MR tablets must be swallowed whole Baseline LFTs, then every 2 weeks for 2 months, then after a month, then regularly No dose adjustment necessary in renal All patients must be initiated on 14 days immediate release Adult: 200mg od 14 days, then increase to 200mg bd or 400mg M/R od if no rash or LFT abnormalities

8 Rilpivirine (RPV) Child: Not recommended Adults ( >18 years) 25mg OD Tablets: 25mg (White) Should be taken with. Exposure is 40% lower on an empty stomach. Caution in severe renal Not recommended in severe hepatic

9 Atazanavir (ATV) Darunavir (DRV) PI Dosage Formulation Important Side Effects Child(6-18years): 15-20kg: 150mg od (+RTV 100mg od) 20-40kg: 200mg od (+RTV 100mg od) >40kg: 300mg od (+RTV 100mg od) Adult: 300mg od (+RTV 100mg od) Child dosing liquid (> 3 years) 10-11kg 200mg BD + RTV 32mg BD 11-12kg 220mg BD + RTV 32mg BD 12-13kg 240mg BD + RTV 40mg BD 13-14kg 260mg BD + RTV 40mg BD 14-15kg 280mg BD + RTV 48mg BD 15-30kg 380mg BD + RTV 50mg BD 30-40kg: 460mg BD + RTV 60mg BD >40kg 600mg BD + RTV 100mg BD Capsules: 150mg (dark blue/light blue), 200mg (dark blue), 300mg (red/blue) Tablets: 75mg (white), 150mg (white), 400mg (light orange), 600mg (orange), 800mg (red) Liquid: 100mg/ml (white suspension) Nausea, headaches, rash, jaundice, elevated total bilirubin Mouth ulcers, dry mouth, hypertension, syncope Haematemesis, chest pain, myocardial infarction Rash, nausea, diarrhoea, headache Contains sulphonamide moiety - check allergies Especially co-trimoxazole Advice 1. Give with or after 2. Avoid indigestion remedies 3. Do not open capsules Other Contraindicated with PPIs Contraindicated in moderate or severe hepatic 1. Give with or after Contraindicated in severe hepatic Child dosing tablets (>3 years) 15-30kg: 375mg BD + RTV 50mg BD 30-40kg: 450mg BD + RTV 60mg BD >40kg: 600mg BD + RTV 100mg BD

10 Adult (ART experienced) 600mg BD + RTV 100mg BD OR 800mg OD + RTV100mg OD

11 Fosamprenavir (FPV) Liquid (>6 years): 25-32kg: 18mg/kg bd (+ RTV 3mg/kg bd) 33-38kg: 18mg/kg bd (+ RTV 100mg bd) >39kg: 700mg bd (+ RTV 100mg bd) Tablets >39kg:700mg bd or 1400mg od (+ RTV 100mg bd) Tablets: 700mg (pink) Liquid: 50mg/ml (grapebubblegum and peppermint flavoured) Rash Perioral paraesthesia, nausea, diarrhoea 1. Give liquid with or after 2. Take tablets with or without Rash may occur within two weeks. Discontinue if severe or associated with systemic/allergic symptoms or mucosal involvement. If mild/moderate usually resolves within 2 weeks Complex interactions Reduce dose in hepatic Lopinavir (+ritonavir) (LPV/r) (Kaletra) Child dosing liquid (without EFV/NVP) 14 days - 6 months 300/75mg/m 2 BD 6 months - 18 years 230/57.5mg/m 2 BD (max 400/100mg BD) (with EFV/NVP) 6 months - 18 years 300/75mg/m 2 BD Tablets: 200mg LPV/ 50mg RTV (yellow), paed tablet: 100mg LPV/25mg RTV (pale yellow) Liquid: 400mg LPV/100mg RTV / 5ml (yellow, store in the fridge) Diarrhoea, headache, nausea, vomiting, electrolyte disturbances Cautious use in hepatic insufficiency 1. Liquid tastes bitter 2. Give liquid with or after 3. Tablets can be given with or without 4. Do not crush tablets Contraindicated in severe hepatic Child dosing tablet (without EFV/NVP) 15-25kg 200/50mg BD 25-35kg 300/75mg BD >35kg 400/100mg BD (with EFV/NVP) 15-20kg 200/50mg BD 20-30kg 300/75mg BD 30-45kg 400/100mg BD >45kg 500/125mg BD Adult 400/100mg BD

12 Ritonavir (RTV) For boosting other PIs. See specific Tablets: 100mg (white) Liquid: 80mg/ml (sugarfree) Contains 42% alcohol and 266mg/ml propylene glycol which can be toxic esp in premature neonates Perioral paraesthesia, nausea, diarrhoea, flushing, rash 1. Give with or after 2. Oral solution can be mixed with chocolate milk to mask bitter taste 3. Do not mix oral solution with water, ensure measuring cup is dry before using If on RTV + ddl, separate administration by at least two hours Increasing reports of Cushing s symptoms in patients on RTV and steroids (mainly fluticasone/triamcinolone) (including intranasal/topical/intraarti cular)

13 Fusion and Entry Inhibitors Maraviroc (MVC) Enfuviritide (T-20) Dosage Formulation Important Side Effects Child: Seek specialist advice Adult (> 40kg): 150mg bd (with CYP3A4 inhibitor) 600mg bd (with potent CYP3A4 inducer) 300mg bd (with NVP) Child (6-16 years): 2mg/kg bd (max. 90mg bd) Adult: 90mg bd Tablets: 150mg, 300mg (blue, film-coated) Subcutaneous injection: 108mg powder for reconstitution (90mg/ml when reconstituted with 1.1ml water for injection) Nausea, vomiting, abdominal pain, constipation, headache, dizziness, pruritus Local injection site reactions Nausea, vomiting, abdominal pain, constipation, diarrhoea Advice 1. Can be given with or without Other Reduce dose in renal Only to be given for CCR5 topic virus When reconstituting, allow to stand for up to 45 minutes to dissolve, do not shake or invert the vial

14 Integrase Inhibitors Dolutegravir (DTG) Dosage Formulation Important Side Effects 15-20kg 20mg OD 20-30kg 25mg OD 30-40kg 35mg OD Tablets 10mg, 25mg 50mg (yellow) Advice Should be taken with to enhance exposure Other Elvitegravir (ELV) Raltegravir (RAL) Child >12 years and >40kg (without integrase resistance) 50mg OD (with integrase resistance) 50mg BD (with potent CYP3A inducers, EFV, FOS/r, rifampicin) 50mg BD >18 years (with ATV) 85mg OD + RTV 100mg OD (with LPV) 85mg OD + RTV 100mg BD (with DRV, FOS) 150mg BD + RTV 100mg BD Child dosing chewable tablet 11-14kg: 75mg BD 14-20mg 100mg BD 20-28kg 150mg BD 28-40kg 200mg BD >40kg 300mg BD Child dosing film coated tablet >6 years and >25kg 400mg BD Tablets 85mg (green), 150mg (green) Tablets: 400mg (pink) Chewable tablet: 25mg (pale yellow) and 100mg (pale orange) Suspension and chewable tablets are not bioequivalent to film coated tablets Nausea, dizziness, insomnia, rash, pancreatitis, elevated ALT, AST, Gamma GT Tablets must not be cut Should be taken with 1. Swallow whole, do not chew (except chewable tablets) 2. Can be given with or without 3. Avoid indigestion remedies 4. Chewable tablets contain phenylalanine CYP450 interactions unlikely Adult (>16 years): 400mg BD

16 Combination Preparations Atripla Combivir (AZT + 3TC) Dosage Formulation Important Side Effects Child: Individual TDF + FTC + EFV doses- max. dose for adults Adult (>12 years and > 40kg): 1 od Child 14-21kg: ½ tablet bd Child 21-30kg: ½ tablet om & 1 tablet on Adult (>30kg): 1 bd Efavirenz 600mg/emtricitabine 200mg/tenofovir 245mg tablets (pink) Zidovudine 300mg/lamivudine 150mg tablets Advice Give on an empty stomach (2 hours after ), preferably before bed time Can be administered with or without. Other Tablets should not be cut Tablets can be cut Can be crushed and added to a small amount of semi-solid or liquid Descovy Eviplera (FTC + RPV + TDF) Child >12 years (>35kg) Dose of Descovy Descovy 200/10 mg once daily Descovy 200/25 mg once daily Child: Not recommended >18 years: 1 tab OD Third agent in HIV treatment regimen Atazanavir with ritonavir or cobicistat Darunavir with ritonavir or cobicistat 1 Lopinavir with ritonavir Dolutegravir, efavirenz, maraviroc, nevirapine, rilpivirine, raltegravir Each tablet contains 200 mg of emtricitabine and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. Emtricitabine 200mg/Rilpivirine 25mg/Tenofovir 300mg Can be administered with or without. Should be taken with Avoid when VL > 100,000 copies/ml Tablets should not be cut Tablets should not be cut Evotaz Child: Not recommended Unlicensed, but D&T agreed: >40kg/14 years and post pubescent 1 tab OD >18 years: 1 tab OD Each tablet contains atazanavir sulphate corresponding to 300 mg atazanavir and 150 mg of cobicistat. Should be taken with

17 Genvoya Child >12 years (>35kg) 1 tab OD Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. Kivexa (ABC + 3TC) PRESCRIBE GENERICALLY Child (<40kg): Individual ABC + 3TC doses BD - max. dose for adults Child & Adult (>40kg): 1 od Abacavir 600mg/lamivudine 300mg tablets (orange) Should be taken with Can be administered with or without Tablets can be cut Odefesy Child >12 years (>35kg) 1 tab OD Each tablet contains 200 mg of emtricitabine, rilpivirine hydrochloride equivalent to 25 mg of rilpivirine and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide. Rezolsta Stribild (ELV + COB + FTC+ TDF) Triumeq (DTG + ABC + 3TC) Trizivir (ABC + 3TC + AZT) Child: Not recommended Unlicensed, but D&T agreed: >40kg/14 years and post pubescent 1 tab OD >18 years: 1 tab OD Child: Not recommended >18 years: 1 tab OD Child (<40kg): Individual ABC + 3TC doses BD - max. dose for adults Child & Adult (>40kg): 1 od Child: Individual ABC + 3TC + AZT doses- max. dose for adults Adult (>18 years): 1 bd Each tablet contains 800 mg of darunavir (as ethanolate) and 150 mg of cobicistat elvitegravir 150mg + cobicistat 150mg + tenofovir 300mg + emtricitabine 200mg Lamivudine 50mg + Abacavir 300mg + Dolutegravir 600mg Abacavir 300mg/lamivudine 150mg/zidovudine Should be taken with Should be taken with Should be taken with Can be administered with or without Can be administered with or Tablets should not be cut

18 300mg tablets (blue-green) without Truvada (TDF + FTC) Child: Individual TDF + FTC doses- max. dose for adults >12years and >35kg: 1 od Tenofovir 245mg/emtricitabine 200mg tablets (blue) Should be taken with Tablets can be cut Can be crushed and added to liquid PCP Prophylaxis Co-trimoxazole <6 months: 120mg OD 6months-5 years: 240mg OD 6-14 years: 480mg OD >14 years: 960mg OD OR Child: 450mg/m 2 BD, three times per week. Dosage Formulation Important Side Effects Written by Jennifer Brown Specialist Clinical Pharmacist (Paediatric Medicine) Checked by Sian Collins, Advanced Clinical Pharmacist (Paediatric Medicine) November 2013 Liquid 240mg/5ml (white/yelloworange suspension) Tablets 480mg + 960mg Updated by Sian Shenton, Advanced Clinical Pharmacist (Paediatric Medicine) April 2017 Diarrhoea; headache; hyperkalaemia; nausea; rash Advice Can be administered with or without Other Discontinue immediately if blood disorders or rash (including Stevens- Johnson syndrome, toxic epidermal necrolysis, photosensitivity) develop. References: Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life BNF for children

Antiretroviral Dosing in Renal Impairment

Antiretroviral Dosing in Renal Impairment Protease Inhibitors (PIs) Atazanavir Reyataz hard capsules 300 mg once daily taken with ritonavir 100 mg once daily No dosage adjustment is needed for atazanavir in renal impairment Atazanavir use in haemodialysis