Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Senniappan S, Alexandrescu S, Tatevian N, et al. Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014;370: DOI: /NEJMoa

2 1 Protocol for the Prescribing of Sirolimus for the treatment of Hyperinsulinaemic Hypoglycaemia (HH) in children Introduction: Sirolimus belongs to the class of medications called mtor (mammalian target of rapamycin) inhibitors. The mammalian target of rapamycin complex (mtorc1) is a serine/threonine kinase regulated by phosphoinositide-3-kinase (PI3K) that integrates amino-acid and energy-sensing pathways in beta-cells. Studies have suggested a role for constitutively activated and overexpressed mtorc1 pathway in the pathogenesis of Hyperinsulinaemic Hypoglycaemia (HH). A suggested mechanism of hyperinsulinism as well as β-cell hyperplasia in diffuse HH has been proposed to involve the constitutive activation of the mtor (mammalian target of rapamycin) pathway with associated exocrine-islet transdifferentiation (6). Rapamycin (Sirolimus) inhibits mtorc1. Recent reports have suggested successful use of both Sirolimus and Everolimus in insulinoma patients. Pharmacokinetics: After oral administration, sirolimus is rapidly absorbed, with an average time to peak serum concentrations in adults of 1 hour after initial dosing and 2 hours after repeated dosing. Systemic bioavailability is approximately 14% with the oral solution. Bioavailability with the tablet is 27% higher than that with the oral solution, indicating that the formulations are not bioequivalent. The two products have been found to be clinically equivalent at the 2mg dose. Administration with food produces variable effects. Bioavailability of the oral solution is decreased when administered with a high-fat meal, but when the tablets are taken with a high-fat meal, bioavailability is increased. Sirolimus is a substrate for cytochrome P450 3A4 (CYP3A4) in the intestinal wall and liver and undergoes counter-transport by P-glycoprotein. It is extensively metabolized through O- demethylation and hydroxylation, forming seven major metabolites. The mean elimination half-life for sirolimus in adult renal transplant patients is 62 ± 16 hours. Data from several paediatric small trials have demonstrated a more rapid clearance in younger children. In a study of 21 transplanted children receiving sirolimus and tacrolimus, the mean half-life of sirolimus was 11.8 ± 5.5 hours, significantly shorter than that reported in adults. Indication: Patients with persistent and severe hyperinsulinaemic hypoglycaemia who are unresponsive to maximal doses of diazoxide (20mg/kg/day) and octreotide (35mcg/kg/day). Sirolimus can only be prescribed following Consultant approval. Age group: 1 month 18 years.

3 2 Inclusion criteria: (all patients confirmed with CHI on hypoglycaemia screen) 1. Term babies, age >4 weeks 2. Patients not responding to maximal doses of Diazoxide and Octreotide Exclusion Criteria: 1. Sepsis/unwell/leucopenia/deranged clotting/any form of other infections 2. Known immune deficiency 3. Preterm 4. Liver/Kidney Problems 5. On immunosuppressants 6. Chronic Lung disease Before starting Sirolimus: 1. Child should be normoglycaemic on IV fluids + Glucagon/Octreotide infusions 2. The diazoxide should be stopped if child is not responding 3. Baseline bloods - FBC, U&E, LFT/GGT/AST, TFT, CRP, clotting screen, blood film, TORCH screen. 4. Fasting cholesterol and triglycerides Dose of Sirolimus: 1. Start at 0.5mg/m 2 /day once daily dose (dose to be given 10am-11am) 2. Check Sirolimus trough level 5 days after starting treatment and titrate the dose by 0.25mg/m 2 /day (rounded to the nearest 0.1mg) as guided by the drug level (aim to send the drug level before 11 am). Check levels 5 days after each dosage adjustment until serum levels maintained within the therapeutic range (Aim for target trough level of 5-15 ng/ml) 3. Once drug level achieved and blood glucose concentrations are stable then gradually reduce and stop the IV fluids, IV glucagon and subcutaneous Octreotide (in this order). 4. Monitor FBC/LFT/U&E every hours or more frequently if any concerns until therapeutic drug level achieved. 5. Sirolimus should be administered either always with food or always without food Follow up: Preparation 1. Monitor weight 2. Blood tests - U&E, LFT + AST/GGT, and TFT, FBC, clotting, fasting cholesterol, and triglycerides 3. Sirolimus level (trough) every 4 weekly unless a change in dose, formulation or schedule (repeat at 7 days after any change). 1mg/ml oral solution (in 60ml bottle) Shelf life - 30 days for opened bottle. 24 hours in the dosing syringe (at room temperature, but not to exceed 25 C). After dilution, the preparation should be used immediately.

4 3 NB. Oral solution contains soya oil and therefore patients allergic to soya or peanut should not take the oral solution. Storage Store in a refrigerator at 2 C - 8 C. Store in the original bottle in order to protect from light. If necessary, the patient may store the bottles at room temperatures up to 25 C for a short period of time (24 hours). Hepatic impairment The clearance of Sirolimus may be reduced in patients with impaired hepatic function. In patients with severe hepatic impairment reduce the maintenance dose by approximately one half. It is recommended that sirolimus whole blood trough levels be closely monitored. Renal impairment No dosage adjustment is required Precautions: Grapefruit and grapefruit juice may interact with sirolimus and could lead to potentially dangerous effects. Do not mix this medicine with grapefruit juice. Avoid eating grapefruit or drinking grapefruit juice whilst taking sirolimus. Live vaccines should not be given whilst using sirolimus and not for 4-8 weeks after stopping treatment (discuss with infectious diseases team before giving live vaccine after stopping sirolimus treatment). The vaccine may not work as well during this time, and may not fully protect from disease. Live vaccines include measles, mumps, rubella (MMR), oral polio, typhoid, chickenpox (varicella), BCG (Bacillus Calmette and Guérin), and nasal flu vaccine. Side effects Increased susceptibility to infections, abdominal pain, constipation, nausea, diarrhea, ascites, stomatitis, oedema, tachycardia, hypertension, hypercholesterolemia, hypertriglyceridemia, venous thromboembolism, pleural effusion, pneumonitis, headache, pyrexia, proteinuria, hemolytic uraemic syndrome, anaemia, thrombocytopenia, thrombotic thrombocytopenic purpura, leucopenia, neutropenia, hypokalaemia, hypophosphatemia, hyperglycaemia, lymphocele, arthralgia, osteonecrosis, epistaxis, acne, rash, impaired healing; less commonly pancreatitis, pulmonary embolism, pulmonary haemorrhage, pericardial effusion, nephrotic syndrome, pancytopenia; rarely interstitial lung disease, alveolar proteinosis, hepatic necrosis, lymphoedema, hypersensitivity reactions (including anaphylactic reactions, angiodema, exfoliative dermatitis, hypersensitivity vasculitis); also reported focal segmental glomerulosclerosis, reversible impairment of male fertility Sucrose and lactose Sirolimus tablets contain sucrose and lactose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucraseisomaltase insufficiency, galactose intolerance, the Lapp lactase deficiency should not take this medicine. Interactions: Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver.

5 4 Blood levels should be monitored closely and doses adjusted accordingly when drugs inhibiting or inducing this enzyme system are started or stopped. Aspirin Low Strength (aspirin) Azithromycin Dose Pack (azithromycin) CellCept (mycophenolate mofetil) Coumadin (warfarin) Fish Oil (omega-3 polyunsaturated fatty acids) Humalog (insulin lispro) Keflex (cephalexin) Lipitor (atorvastatin) Lopressor (metoprolol) Metoprolol Succinate ER (metoprolol) NitroQuick (nitroglycerin) ProAir HFA (albuterol) Protonix (pantoprazole) Spiriva (tiotropium) Symbicort (budesonide/formoterol) Toprol-XL (metoprolol) Valcyte (valganciclovir) Vitamin B Complex 100 (multivitamin) Vitamin D2 (ergocalciferol) Zocor (simvastatin) References 1. Alexandrescu S, Tatevian N, Olutoye O, Brown RE 2010 Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mtor pathway with associated exocrine-islet transdifferentiation and therapeutic implications. Int J Clin Exp Pathol 3: Kulke MH, Bergsland EK, Yao JC 2009 Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 360: Bourcier ME, Sherrod A, DiGuardo M, Vinik AI 2009 Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol Metab 94: Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B 2010 Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 28: Fiebrich HB, Siemerink EJ, Brouwers AH, Links TP, Remkes WS, Hospers GA, de Vries EG 2011 Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues. Oncologist 16: Treatment of Childhood Kaposiform Hemangioendothelioma With Sirolimus. Julie Blatt et al. Pediatr Blood Cancer 2010;55: Sirolimus (Rapamune ). Summary of Product Characteristics, UK. Last updated August Accessed Nov 2011