Table 1 The 10 drugs singled out for an authorised “off-label” use in PPC

HYOSCINA BUTYLBROMIDE

Pill in child > 14 years, supp in child > 6 years: spastic– painful events of urinary and genital tract.

1. Iv administration for intestinal obstruction due to peritonitis in pediatric patients with cancer.

2. Iv administration for reduction of secretions and rattle in terminally ill patient.

Iv: Child 1 month-4 years: 300–500 micrograms/Kg 3–4 times a day (max. Per dose 5 mg)

Child 5–11 years: 5–10 mg 3–4 times a day

Child 12–17 years:10–20 mg 3–4 times a day [24]

DEXMEDETOMIDINE

Procedural analgo-sedation outside the operating room (Not Operating Room Anesthesia - NORA) in children with difficult airway management and child with seizure disorders who must undergo diagnostic studies for locating epileptogenic foci

Analgo-sedation of critical infant and child in ICU, mechanically ventilated and poorly responsive to conventional analgo-sedation treatment.

1. Control of stressful symptoms from disease or procedure and fix sleep outside the ICU in patients in palliative care, not responsive to conventional therapies.

2. Intranasal route of administration.

Iv: 1 mcg/kg in a 10-min bolus, increased up to a maximum of 3 mcg/kg, and followed by a 1 mcg/kg/h infusion [25]

In: 1 to 4 mcg/kg, eventually re-administered at 1 mcg/Kg [25]

FENTANYL

Premedication for any type of anesthesia (also local) both in the postoperative period as during surgery.

1. Transdermal, iv use for acute and/or chronic pain management from cancer and not, in children in PPC.

2. Transmucosal use for procedural/acute/breakthrough pain in PPC.

Transdermal: based on oral morphine dose equivalent (given at 24-h totals). Product monograph: oral morphine 45 mg = 12 mcg/h patch oral morphine < 90 mg = 25 mcg/h patch oral morphine 135–189 mg = 50 mcg/h patch oral morphine 225–314 mg = 75 mcg/h patch [26]

Iv: Child > 6 months and < 50 Kg: bolus 0,5–1 mcg/Kg every 1–2 h, dose to be administered over at least 30 s; infusion 0,5–2 mcg/Kg/h

Child > 50 Kg: bolus 25–50 mcg every 1–2 h, dose to be administered over at least 30 s; infusion 25–200 mcg/h [27]

Transmucosal: Child 2–18 years and weiting > 10 Kg: 15–20 mcg/Kg as a single dose, titrated to a maximum dose of 400 mcg [26]

GABAPENTIN

Pill in child > 6 years: adjunctive therapy in the treatment of partial seizures in the presence or absence of secondary generalization.

> 12 years: monotherapy in the treatment of partial seizures in the presence or absence of secondary generalization

Neuropathic or mixed pain in children older than 2 years in palliative care.

By mouth: Child > 2 years:

Day 1: 10 mg/Kg (maximum single dose 300 mg)

Day 2: 10 mg/Kg twice daily

Day 3 onwards: 10 mg/Kg 3 times daily

Increase further if necessary to a maximum of 20 mg/Kg/dose (maximum single dose 600 g)

Child > 12 years:

The maximum daily dose can be increased according to responde, up to e a maximum of 3600 mg/day [26]

KETAMINE

Im, iv and continuous infusion administering

Use for induction and maintenance of general anesthesia from neonatal and premedication in children older than1 month.

1.Use in patients in PPC for managing procedural or mixed/neuropathic pain that does not respond to other therapy, alone or in combination/replacement for opioid analgesics.

2. Intranasal administration

Im: Neonate: 4 mg/Kg, adjusted according to response, a dose of 4 mg/Kg usually produces 15 min of surgical anaesthesia

Child: 4–13 mg/Kg, adjusted according to response, a dose of 4 mg/Kg sufficient for some diagnostic procedures, a dose of 10 mg/Kg usually produces 12–25 min of surgical anaesthesia [24]

Iv for short procedures: Neonate: 1–2 mg/Kg, adjusted according to response, to be given over at least 60 s, a dose of 1–2 mg/Kg produces 5-1o minutes of surgical anaesthesia

Child 1 month-11 years: 1–2 mg/Kg, adjusted according to response, to be given over at least 60 s, a dose of 1–2 mg/Kg produces 5-1o minutes of surgical

Child 12–17 years: 1–4,5 mg/Kg, adjusted according to response, to be given over at least 60 s, a dose of 2 mg/Kg usually produces 5-1o minutes of surgical [24]

Continuous Iv Infusion:

Child 1 month-17 years: starting dose 40 mcg/Kg/h., increase according to response, usual maximum dose is 100 mcg/Kg/h [26]

Intranasal: Child 1 month-17 years: 0,5–10 mg/kg/dose, start with lower dose and increase according to response [28,29,30,31]

KETOROLAC

The safety and efficacy in children has not been established. The use of the drug is therefore contraindicated below 16 years.

Pill and drop: used to treat short term (max 5 days) of moderate postoperative pain.

Iv/im: indicated in the short term treatment (maximum two days) for moderate-severe postoperative pain.

By mouth/im use for treatment of acute pain starting from 16 years of life, iv from 6 months.

By mouth and sublingual use for chidlren 4–15 years old, for a maximum period of 5 days, in patients receiving PPC without vascular access, for management of moderate/severe acute episodic nociceptive pain, which integrate other analgesia if not effective, in the course of pathology eligible to PPC or in terminall illness.

Iv: Child 6 months-15 years: initially 0,5–1 mg/Kg (max. Per dose 15 mg), than 500 mcg/Kg every 6 h (max. Per dose 15 mg) as required for maximum duration of treatment 2 days; maximum 60 mg per day [24]

Im e Iv: Child 16–17 years (body-weight up to 50 Kg): initially 10 mg, than 10–30 mg every 4–6 h as required for maximum duration of treatment 2 days, maximum 60 mg per day

Child 16–17 years (body-weight 50 Kg and above): initially 10 mg, than 10–30 mg every 4–6 h as required for maximum duration of treatment 2 days, maximum 90 mg per day [24]

By mouth/sublingual: Child 4–15 years: 0,5 mg/Kg/ dose, maximum 3 doses/day for maximum duration of treatment 5 days [32]

LIDOCAINE

Peripheral and regional anesthesia, surgical stomatology.

1.Nebulized use for the treatment of cough refractory to other therapies, if pulmonary metastases

2. Intravenous use to treat neuropathic pain in patients in PPC not responsive to conventional therapies.

Nebulized: 5 ml of 0,2% solution every 8 h [33]

Iv: 10–15 mcg/Kg/min [34]

MIDAZOLAM

Iv: conscious sedation before and during diagnostic or therapeutic procedures with or without local anaesthesia; Anesthesia: Premedication before induction of anesthesia; Sedation in ICU.

Children 3 months-18 years: treatment of acute prolonged seizures

Children > 1 month: treatment of status epilepticus or following crises

1. Intranasal use due to less invasiveness and high speed of administration in the absence of venous access, even in urgent cases in patients aged over 1 month in PPC.

2. Intravenous use to manage non-painful distress symptoms during end of life.

Intranasal: 0,2–0,5 mg/Kg/dose [35, 36]

Iv: Child 1 month-17 years: 0,05–0,3 mg/Kg/h [26]

ONDANSETRON

Pill, syrup, vial in children ≥6 months to control chemotherapy-induced nausea and vomiting (CINV).

Vial in children ≥1 month for prevention and treatment of post-operative nausea and vomiting (PONV).

Control of nausea and vomiting during opioid therapy in patients aged > 6 months in palliative care

Iv: Child 1–12 years: 5 mg/m2 (maximum single dose 8 mg) every 8–12 h

Child 12–17 years: 8 mg every 8–12 h [26]

By mouth

Child 6 months-17 years (BSA up to 0.6 m2): 2 mg every 12 h for up to 5 days (dose can be started 12 h after iv administration); maximum 32 mg per day.

Child 6 months-17 years (BSA 0.6–1.2 m2): 4 mg every 12 h for up to 5 days (dose can be started 12 h after iv administration); maximum 32 mg per day.

Child 6 months-17 years (BSA 1.3 m2 and above): 8 mg every 12 h for up to 5 days (dose can be started 12 h after iv administration); maximum 32 mg per day [24]

SCOPOLAMINE

Not marketed in Italy

Treatment of hypersalivation in patients in palliative care and end of life by transdermal route.

Neonate: quarter of a patch every 72 h

Child 1 month to 3 years: quarter of a patch every 72 h

Child 3–10 years: half a patch every 72 h

Child 11–17 years: one patch every 72 h [26]