Elizabeta Zisovska, Skopje, Republic of Macedonia The comments are extracted and supported by the Drug register (for registered drugs in Republic of Macedonia) issued by the ministry of health, Republic of Macedonia General comments: 1. For children, the dosage should be adjusted according to the body weight, i.e. mg/kg, because of the different proportion weight/age. ). It is more difficult to prescribe the doses/m 2 (it needs nomogram and calculations ) 2. Recommendation: the dosage should be determined for a single dose, i.e. mg/kg/dose, and to determine the number of doses and the time interval between the doses, depending of the medicament and its elimination (for example: mg/kg/dose, 4 times per day, every 6 hours, or drug-mg/kg/dose, 3 times per day, every 8 hours), because of the limited excretion and possible cumulative effect especially in neonates. Sometimes the number of doses have to be restricted compared to the adult ones. Especially in neonatal age the medicines can be even prescribed every 18 hours (for prematures). 3. Specificity of the pediatric patients: -age groups (neonate fullterm and premature, infant, small children, school children, adolescence). in neonatal period the physiological functions which determine the pharmacokinetics are changing very fast, day to day, because of postnatal maturation of kidneys and liver, and also protein contents of body fluids, and all these facts require to determine four groups of neonates: birthweight <2000 grams and <7 days; BW<2000 g and >7 days, neonates with BW>2000 and < 7 days and BW>2000 g and >7 days. 4. Although the pain is a category that is not investigated deeply in neonates and infants, it is recommended to administer pain relief in painful procedures and in postoperative period Specific Comments to the WHO Model list (Draft) 1. Anaestethics 1.1. general anaesthaesia 1.1.1. halothane is out of use two years ago 1.2. local anaesthetics their use is preferable as infiltrative anaesthesia in painful procedures, for example intraarticular injections, introduction of intraarterial catheters, punction of bone medulla, stiching 1.2.1. Lidocain hidrochlorid, exists Lidocain hydrochlorid for injection amp (40 mg+0,025 mg)/2ml in vial. This mode of labeling the vial maybe is appropriate for easier determination of the prescribed dose of 3 mg/kg, or 7 mg/kg. 1.2.2. for Lidocain adrenalin (epinephrin) also should be recommended to label the vial (solution pro injectionem) in mg (In Macedonia registered as Lidocain 2% adrenalin 40 mg + (0,025 mg/2 ml) and is probably easier to prescribe the dosage in mg. For dental anaelgesia for children it is recommended 20-30 mg of the medicament (1-1,5 ml). 1.3. preoperative medications 1.3.1. to determine the doses for children according to the age or body weight 1.3.2. Diazepam-there are other forms of the medicament: tablets of 2 mg, 5 mg and 10 mg; solution for injection 10 mg/2 ml, and suppositories 5 mg and 10 mg for those who vomit 1
1.3.3. Morphine solution for injection 4 mg/ml and 20 mg/ml. It could be administered also subcutaneous in dose 0,05-0,2 mg/kg/day divided in 3-4 doses. I agree that it should be determined the dosage for neonates for IM and SC administration. Used as an analgesia and sedation is administered in continuous infusion in dose 10 mcg/kg/hour. Consider its use in the management of neonatal abstinence syndrome. The use and dose of morphine in NAS is titrated according to the severity of drug withdrawal in the infant. This is evaluated using the scores derived from the Finnegan Score Chart. Starting regime - 0.5mg/kg/day given 6th hourly, if not effective may be increased to 0.7mg/kg/day 6th hourly. Maximum dose 0.9mg/kg/day 1.3.4. recommended the use of suxamethonium administered to facilitate the endotracheal intubation in infants > 2kg or > 7 days age (guideline only) by producing skeletal muscle relaxation. Vial of 200 mg and 500 mg. Given diluted in dose of 1 mg/kg given as a stat IV dose. 1.3.5. consider the use of Dormicum (midazolam) for sedation mainly, but it can be used for endotracheal intubation for single use in dose 0,1 mg/kg (bolus dose). Comes in vial 5 mg/5 ml. 2. Analgesics 2.1. non-opioids 2.1.1. acetylsalycilic acid. Forms-tablets of 100 mg, 300 mg and 500 mg. Because of the risk of Rey-syndrome, the use in pediatrics is restricted only for children over 12 years, very rare for pain relief in arthralgia, muscle pain and headache. It could be administered also as an antiagregatic medicament. Contraindicated in patients with flu and varicella. 2.1.2. ibuprofen-there are several other forms: tabl 200 mg, tabl 400 mg, and also oral solution 100 mg/5 ml (contains 100 ml) and crème 1 g (10%) for local use. The dosage for the children depends on the indication: 20 mg/kg/day divided in 3-4 doses, and for juvenile rheumathoid arthritis in dose of 40 mg/kg/day. For children with less of 30 kg, the maximum daily dose is 500 mg. The crème is suitable for children older than 12 years. 2.1.3. paracetamol: there are several other forms: tablets 500 mg, oral solution 120 mg/5 ml, suppositories of 80 mg, 150 mg, 300 mg and 600 mg (the last two mainly for adults). Dosage: children up to 6 years-10-15 mg/kg/dose for maximum 4 doses; 6-12 years-250-500 mg/doses, 3-4 times per day; infants of 3-6 months-suppositories 2-3 times per day supp 80 mg; infants of 7-12 months-150 mg/dose 3-4 times per day. 2.2. opioid analgesics 3. antiallergics and medicines used in anaphylaxis 3.1. dexamethason registered for children in dose of 0,02-0,1 mg/kg/dose, twice per day. Forms: tablets 0,5 mg and vial solutio per injectionem 4 mg/ml 3.2. epinephrine (adrenalin) hydrochlorid-suitable for neonates as well, for treatment of acute circulatory collapse in continuous infusion and with low dosage: 0.05-0.1mcg/kg/min; High dosage: 0.2-1mcg/kg/min. Adrenalin could be used in bradycardia and hypotension in dose 0,01-0,03 mg/kg/dose and could be repeated every 5 minutes 2-3 times. Also can be administered endotracheally while resuscitating the neonate, and this indication is confirmed and included in the textbooks also 3.3. hydrocortisone-consider its use as adjunct therapy for persistent hypoglycaemia in dose 2-10mg/kg/day / 12th hourly for neonates, infuse over 1 minute as bolus by proximal cannula site injection. Comes in tablets 20 mg; and vials 250 mg/10 ml 2
4. antidotes 5. anticonvulsants 5.1. carbamazepine in tablets only of 200 mg. Used in children, the dosage adjusted according to the age (< one year, 1-5 years and > 5 years of age) 5.2. diazepam-forms: tablets 2 mg, 5 mg, 10 mg; suppositories: 5 mg and 10 mg. Consider its rectal use for children who can not take the medicine orally, and the dose should be determined according to the body weight (0,2-0,3 mg/kg/dose). 5.3. phenobarbital available in forms: tablets of 15 mg and 100 mg and pulvis for solution amp 220 mg/2 ml. There is no oral liquid 5.4. phenytoin-there are only tablets of 100 mg, and is recommended only for children >2 years of age. Difficult for administration because there is no solution for oral use. 5.5. valproic acid-tablets gastroresistant from 150 mg, 300 mg, and 500 mg; oral solution 300 mg/1 ml. For children <15 years suitable dose of 20-30 mg/kg/dose, 2-3 times per day. 6. anti infective medicines 6.1.anthelmintics 6.1.1. intestinal levamisol is not registered mebendazol-tablets of 100 mg and peroral suspension 30 ml (100 mg/5 ml). there are not registered pyrantel, prasinqantel and niclosamid 6.1.2 and 6.1.3 no registered medicines here, and for review-check the doses for children, especially those <2 years 6.2. antibacterials General comments: It is important to note the growing resistance after long use, and the need for change the antibiotics from the same group, because of it. Also, in neonates and infants to consider the possibility of muscle induration if given IM, and to prefer medicines for IV or SC use. Consider cephalosporines of later generations because of the low resistance, and keep them as monotherapy. 6.2.1. beta lactams amoxicillin-available Capsules 250 mg and 500 mg, granules for oral liquid 125 mg/5 ml, and 250 mg/5 ml. I don't see need for another form (suggested 12 mg/1,25 ml) amoxiclav-here exists the pediatric suspension (125 mg +31,5 mg)/5 ml, than (250 mg +62,5 mg)/5ml, both for three times per day, and also (400 mg +57 mg)/5 ml for dose twice per day. Check the last form (400 + 57) for children use, because of the toxic effects of the clavulanic acid in small children <1 years ampicillin-there is registered oral liquid 250 mg/5 ml and capsules 250 and 500 mg penicillins-consider administration based on IU/kg, not one of them in IU and the other in mg/kg. Cloxacillin-vial 1 g; capsule 250 mg; oral 125 mg/5 ml; suspension (very suitable for small children) Phenoxymethylpenicillin-only tablets 1 000 000 IU. The use in children possible only for those >6 years. Need for oral liquid for younger Procain benzylpenicillin-vial 800 000 IU and 3 000 000 IU 3
Ceftriaxon-I agree to be included in core list, as by the guidelines to use it in late onset infections as per antibiogram Imipenem cilastatin-for strict use as per antibiogram if the senzitivity is restricted. Check the use for neonates 6.2.2. other antibacterials Chloramphenicol-restrict use only where antibiogram shows sensitivity, but consider dose of 25 mg/kh BW once daily in neonates in the first 7 days, the same dose for premature infants with <2000 g over 7 days, and 50 mg/kg BW given twice daily for neonates older than 7 days. Topical use is not so restricted. Ciprofloxacin-tablets 250 mg, 500 mg, vial of concentrate 100 mg/10 ml, infusion solution 100 mg/50 ml, 400 mg/200 ml. Restricted use for children, only according to the antibiogram if others show resistance Doxycycline (and other tetracyclines) are not used for children <12 years Spectinomycine-I don t t think it is necessary to be included in the list Trimetoprim isolated maybe has no need to be included Sulfonamides restricted for use in the first 7 days of life (because of albumin binding possibility) 6.2.4: Antituberculotics-unfortunately there are difficulties in availability of pediatric formulations All aminoglycozides are second-line medicines for TB 6.3: Antifungal medicines Nystatin-preferably oral solution especially for neonates, in form of 24 ml of 100 000/ml solution, ointment 20 g 100 000 IU/g. Vaginal tablets??? 6.4 Antiviral medicines 6.4.1: Antiherpes-aciclovir oral restricted use only for children >2 years. In neonates, used for treatment of neonatal herpes simplex infections, varicella zoster infections with CNS and pulmonary involvement, and herpes simplex encephalitis. 6.4.2.3.Protease inhibitors not registered for children, new policy needed 6.5.3.Antimalarial medicines-malaria is eradicated in this region. Only prophylaxis administered for those going in endemic areas 7. Antimigraine medicines: acetylsalicylic acid and propranolol not used for this indications. Only paracetamol indicated 8. antineoplastic drugs-specific protocols in use, and need specific review. 9. palliative care 10. medicines affecting the blood a. iron medicines-salts ferrous sulphate as drops-available b. useful ferrous maltose complex also in oral solution consider the starting period (AAP recommends to start after 40 days in premature neonates), and it will be very useful if the earlier start will be studied (only one study starting ferrous medicine from the 15-th day after the delivery) phytomenadion-reconsider its use in prophylaxis and therapeutic doses in neonates medicines affecting coagulation-reconsider its necessity 11. blood products 4
12. cardiovascular medicines-needs specific review of cardiologists because of specific 13. dermatological medicines a. if povidone iodide included, consider its use after TSH-screening performed 14. diagnostic agents 15. disinfectants-what is their role in pediatric treatment? 16. diuretics a. furosemid-solution 20 mg/2 ml and tablets 40 mg, dose 2 mg/kg/day in 2 doses. Consider its use in congestive cardiac failure, prerenal failure and chronic Neonatal Lung Disease b. spironolacton-registered for children, tablets 25 mg and 100 mg; therapy not longer than 30 days c. hydrochlorothiazide-tablets 25 mg and 50 mg; children 2 mg/kg/day 17. gastrointestinal medicine a. ranitidine: solution vial 50 mg/5 ml; 50 mg/2 ml; tablets: 150 mg, 300 mg consider its use in NICU while hypoxia persists and mechanical ventilation performed (stress ulcusses). Used to maintain the gastric ph >4 when infants are nil by mouth and receiving dexamethasone for the management of Bronchopulmonary Dysplasia (BPD). b. laxatives-senna not recommended in children <12 years 18. hormones 19. immunological medicines and vaccines a. there is an immunization calendar specific for each country. Consider creating list of contraindications (general and specific) for each vaccine, especially after administration of blood and blood products and immunomodulating medicines. 20. muscle relaxants 21. ophtalmological preparations a. acyclovir ointment 3% b. consider use after microbiological analysis (eye swab) 22. antioxidants 23. peritoneal dyalisis-specific compositions 24. antipsychotic medicines-specific disorders, and need specific review. Valproic acid belongs to a group of medications called anticonvulsants. Anticonvulsants are used to control seizure disorders, but in psychiatry Valproic Acid may also be used to stabilize mood, especially in Bipolar Disorders. 25. medicines on respiratory tract 26. solutions correcting body fluids-specific guidelines for corrections, according to the disturbances 27. vitamins and minerals a. calcium gluconate maybe could be included in core list? Consider use during exchange transfusion in neonates 5