Immunosuppressive therapy for kidney transplant in children and young people

Basiliximab

3.1 Basiliximab (Simulect, Novartis Pharmaceuticals) is a monoclonal antibody that acts as an interleukin‑2 receptor antagonist. It has a marketing authorisation in the UK for the prophylaxis of acute organ rejection in people having a kidney transplant. The indication includes children and young people aged 1 to 17 years. The summary of product characteristics states that basiliximab is to be used concomitantly with ciclosporin for microemulsion- and corticosteroid-based immunosuppression, in patients with panel-reactive antibodies less than 80%, or in a triple maintenance immunosuppressive regimen containing ciclosporin for microemulsion, corticosteroids and either azathioprine or mycophenolate mofetil.

3.2 Basiliximab is administered intravenously. In children and young people weighing less than 35 kg, the recommended total dose is 20 mg given in 2 doses of 10 mg each. In children and young people weighing 35 kg or more, the recommended dose is 40 mg given in 2 doses of 20 mg each.

3.3 Basiliximab is available in 10‑mg and 20‑mg vials at a price of £758.69 and £842.38 respectively (excluding VAT; British national formulary [BNF] online [accessed August 2017]), equating to £1,517 per course of treatment for a patient weighing under 35 kg and £1,685 for a patient weighing 35 kg or more.

Rabbit anti-human thymocyte immunoglobulin

3.4 Rabbit anti-human thymocyte immunoglobulin (r‑ATG; Thymoglobuline, Sanofi) is made by injecting human thymus cells into rabbits. The drug contains immunoglobulins (antibodies) that attach to and destroy some of the cells of the immune system. It has a marketing authorisation in the UK for the prevention of graft rejection in kidney transplant. The summary of product characteristics states that it is usually used with other immunosuppressive drugs, but does not state whether the indication includes children and young people. It also advises that no recommendation about dosage for children and young people can be made, but that available information indicates that they do not need a different dosage to adults.

3.5 r‑ATG is administered intravenously, at a dose of 1 to 1.5 mg/kg/day for 3 to 9 days after a kidney transplant (a cumulative dose of 3 to 13.5 mg/kg).

3.6 r‑ATG is available in 25‑mg vials at a price of £158.77 (excluding VAT; BNF online [accessed August 2017]). The assessment group (AG) estimated that the cost of induction therapy with r‑ATG for a 10‑year‑old boy is £2,101 (assuming vials are shared so that there is no wastage).

Immediate-release tacrolimus

3.8 Brands of immediate-release tacrolimus include Adoport (Sandoz), Capexion (Mylan), Modigraf (Astellas Pharma), Perixis (Accord Healthcare), Prograf (Astellas Pharma), Tacni (Teva) and Vivadex (Dexcel Pharma). All of these formulations have marketing authorisations in the UK for the prophylaxis of transplant rejection in people having a kidney transplant. Adoport, Capexion, Perixis, Prograf, Tacni and Vivadex are administered orally as capsules, twice a day. Prograf can also be administered intravenously. Modigraf consists of granules for oral suspension.

3.9 For all brands of immediate-release tacrolimus, the summary of product characteristics recommends an initial dose for children (age range not specified) of 0.3 mg/kg/day orally or 0.075 to 0.100 mg/kg/day intravenously and states that the dosage is usually reduced in the period after the transplant.

3.10 Modigraf (tacrolimus granules for oral suspension) is available in sachets of 0.2 mg and 1 mg at a price of £7.13 per mg (excluding VAT; BNF online [accessed August 2017]). The company has agreed a nationally available price reduction for Modigraf with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence. Tacrolimus immediate-release capsules are available as 0.5 mg, 0.75 mg, 1 mg, 2 mg and 5 mg capsules (depending on the brand), the price of which varies by brand. The AG calculated that the average cost paid by the NHS for immediate-release tacrolimus capsules is £0.52 per mg (excluding VAT; data from the Electronic Market Information Tool [eMIT], Commercial Medicines Unit). The AG estimated that the weekly cost of maintenance therapy with immediate-release tacrolimus capsules for a 10‑year‑old boy is £34. Adoport is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.

Prolonged-release tacrolimus

3.11 Prolonged-release tacrolimus (Advagraf, Astellas Pharma) is administered orally as a capsule, once a day. It has a marketing authorisation in the UK for the prophylaxis of transplant rejection in adults having a kidney transplant. The summary of product characteristics recommends an initial dose for adults of 0.2 to 0.3 mg/kg/day. The dosage is usually reduced in the period after the transplant. It also states that the safety and efficacy of prolonged-release tacrolimus in children under 18 years have not yet been established and that limited data are available but no recommendation on dosage can be made.

3.12 Prolonged-release tacrolimus (Advagraf) is available as 0.5‑mg, 1‑mg, 3‑mg and 5‑mg capsules at a price of £1.07 to £1.43 per mg (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with prolonged-release tacrolimus for a 10‑year‑old boy is £47 (using the list price and the dosage for adults). Advagraf is available to the NHS with a nationally available price reduction agreed between the company and the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.

3.13 Another brand of prolonged-release tacrolimus, Envarsus (Chiesi) obtained a marketing authorisation for adults after the scope for this appraisal was finalised. The brand name Envarsus was not included in the AG's search for evidence and Chiesi was not asked to submit evidence for the appraisal.

Belatacept

3.14 Belatacept (Nulojix, Bristol-Myers Squibb) is a soluble fusion protein designed to selectively inhibit CD28-mediated co‑stimulation of T‑cells. Belatacept, in combination with corticosteroids and a mycophenolic acid, has a marketing authorisation in the UK for prophylaxis of graft rejection in adults having a kidney transplant. The summary of product characteristics recommends that an interleukin‑2 receptor antagonist is added to this belatacept-based regimen. It also states that the safety and efficacy of belatacept in children and adolescents under 18 years have not yet been established and that no data are available.

3.15 Belatacept is administered intravenously. The recommended dose for adults is 10 mg/kg on the day of the transplant, followed by 10 mg/kg on days 5, 14, 28, 56 and 84 and then 5 mg/kg every 4 weeks from then on.

3.16 Belatacept is available in 250‑mg vials at a price of £354.52 (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with belatacept for a 10‑year‑old boy is £56 (using the dosage for adults and assuming vials are shared so that there is no wastage).

Mycophenolate mofetil

3.17 Mycophenolate mofetil (generic) has a marketing authorisation in the UK, in combination with ciclosporin and corticosteroids, for the prophylaxis of acute transplant rejection in people having a kidney transplant. Mycophenolate mofetil can be administered orally (capsules or an oral suspension) or intravenously. The summary of product characteristics states that the recommended daily dose for children and young people (aged 2 to 18 years) is 1,200 mg/m² up to a maximum of 2 g per day. See the summary of product characteristics for dosage recommendations for patients with a body surface area below 1.5 m².

3.18 The price of mycophenolate mofetil varies by brand. The oral suspension (CellCept) is available in 175‑ml containers of 1 g/5 ml suspension at a price of £3.29 per g (excluding VAT; BNF online [accessed August 2017]). At the time of the initial committee discussion (July 2015), the average cost paid by the NHS for mycophenolate mofetil capsules was £0.38 per g (excluding VAT; data from eMIT, Commercial Medicines Unit). The AG estimated that the weekly cost of maintenance therapy with mycophenolate mofetil capsules for a 10‑year‑old boy is between £1.74 and £3.48.

Mycophenolate sodium

3.19 Mycophenolate sodium (Myfortic, Novartis Pharmaceuticals), in combination with ciclosporin and corticosteroids, has a marketing authorisation in the UK for the prophylaxis of acute transplant rejection in adults having a kidney transplant. The summary of product characteristics states that insufficient data are available to support the efficacy and safety of mycophenolate sodium in children and adolescents. It is administered orally, at a recommended dose for adults of 1.44 g per day.

3.20 Mycophenolate sodium is available in 180 mg and 360 mg tablets at a price of £4.48 per g (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with mycophenolate sodium for a 10‑year‑old boy is £50 (using the dosage for adults).

Sirolimus

3.21 Sirolimus (Rapamune, Pfizer) is an antiproliferative that blocks a protein called mammalian target of rapamycin (mTOR). It has a marketing authorisation in the UK for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. It is recommended to be used initially with ciclosporin and corticosteroids for 2 to 3 months, and may be continued only if ciclosporin can be progressively discontinued. The summary of product characteristics states that the safety and efficacy of sirolimus in children and adolescents under 18 years have not been established.

3.22 Sirolimus is administered orally as a tablet or solution. The recommended dose for adults is 6 mg initially, followed by 2 mg per day for 2 to 3 months, then adjusted to obtain blood trough levels of 4 to 12 nanograms/ml.

3.23 Sirolimus is available as 0.5 mg, 1 mg and 2 mg tablets and a 1 mg/ml oral solution, at a net price of £2.71 to £4.60 per mg (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with sirolimus for a 10‑year‑old boy is £40 (using the dosage for adults).

Everolimus

3.24 Everolimus (Certican, Novartis Pharmaceuticals) is an antiproliferative that blocks mTOR. It has a marketing authorisation for the prophylaxis of organ rejection in adults having a kidney transplant, who are at low to moderate immunological risk. The summary of product characteristics states that everolimus should be used with ciclosporin and corticosteroids. Everolimus is administered orally as a tablet. The recommended initial dose for adults is 1.5 mg/day. The summary of product characteristics states that there is insufficient experience to recommend the use of everolimus in children and adolescents.

3.25 Everolimus is available in 0.25‑mg, 0.5‑mg and 0.75‑mg tablets at a net price of £9.90 per mg (excluding VAT; BNF online [accessed August 2017]). The AG estimated that the weekly cost of maintenance therapy with everolimus for a 10‑year‑old boy is £104 (using the dosage for adults).

3.26 Costs for all of the technologies may vary in different settings because of negotiated procurement discounts.