Willem Scholten PharmD MPA - World Health Organization · Willem Scholten PharmD MPA Consultant – Medicines and Controlled Substances 6 for both oral and parenteral administration

Willem Scholten PharmD MPA Consultant – Medicines and Controlled Substances

Wielsekade 64 3411 AD Lopik, the Netherlands T +31 348 769 029 M +31 6 4847 3368 E [email protected] Skype wimscholten

VAT Identification Number: NL067732380B01 Chamber of Commerce (KvK): 5956832

Your ref: -

Our ref: 2014-10

World Health Organization Dr N. Magrini, Secretary, Expert Committee on Selection and Use of Essential Medicines av. Appia 20 CH-1211 Genève-27 [email protected]

RE: Application to the 20th Expert Committee on Selection and Use of Essential Medicines

to modify the wording of the listing of certain opioid analgesics

Lopik, 20 October 2014,

Dear Dr Magrini,

The 19th Expert Committee on Selection and Use of Essential Medicines decided to add a number of

morphine preparations, including higher dosages and dosage forms for children, to the Model List of

Essential Medicines and the Model List for Essential Medicines for Children. As alternatives, both lists

mention hydromorphone and oxycodone. With these changes, the lists reflect modern approaches to

pain management in adults and in children.

It was me, as the then Team Leader, Access to Controlled Medicine, World Health Organization, who

applied for these additions, with the support of Members of the Guidelines Development Group for

the WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical


2

Illnesses. The application involved the addition of hydromorphone and oxycodone “as an example of

a class” and explicitly requested that the Essential Medicines List (and the one for Children) mention

that “Two or more alternatives to morphine should be available”. This should be expressed in the

lists for example as a footnote to the square box.

In agreement with the WHO paediatric pain guidelines, the applied wording to refer to

hydromorphone and oxycodone was not limiting.

However, the wording of the 19th Model List and the 4th Model List for Children limit the

alternatives to these two opioids by saying “alternatives limited to hydromorphone and oxycodone”,

but there is not any scientific reason for such limitation to these two opioids only, and also there is

no reason to prefer these two alternatives over several other alternative opioids. The chosen

wording is prohibitive for having an optimal number of alternatives available for difficult cases and

therefore it is very unfortunate.

For this reason, I request again that hydromorphone and oxycodone are added and referred

to in a non-limiting manner, i.e. “as an example of a class” and that a footnote be added that

“two or more alternatives to morphine should be available.”

This request is supported by Dr Allen Finley, Chair of the Guidelines Development Group for the WHO

guidelines on the pharmacological treatment of persisting pain in children with medical illnesses, Dr

John Collins, Member of the same Guidelines Development Group and Prof Dr.med. Lukas Radbruch,

President, International Association for Hospice and Palliative Care (IAHPC) and Chair, Palliative

Medicine, University Hospital Bonn and Director, Palliative Care Centre, Malteser Hospital Seliger

Gerhard Bonn / Rhein-Sieg.

Sincerely,

[SIGNED]

Willem Scholten

Annexes: applications, 21 September 2012


3

Annex 1: application on oxycodone of 21 September 2012, to the 19th Expert Committee on the Selection and Use of Essential Medicines

Application to add oxycodone to the

Essential Medicines List for Children

Summary statement of the proposal for inclusion Pain in children is a public health concern of major significance in most parts of the

world. Although the means and knowledge to relieve pain exists, children’s pain is often not

recognized, is ignored, or even denied. It is important that adequate access to appropriate

opioid medicines be available for the treatment of moderate to severe persisting pain in

children worldwide.

To align the Essential Medicine List for Children (EMLc) with the recently published

WHO guidelines on the pharmacological treatment of persisting pain in children with medical

illnesses [WHO pediatric pain guidelines, 2012: p.78– further referred to as “Guidelines”], it

is necessary to add more opioid preparations to the EMLc. The Guidelines state that if pain

severity associated with a medical illness is assessed as moderate or severe, the administration

of a strong opioid is necessary. In that case morphine is the medicine of choice, although

other strong opioids should be considered and made available to ensure an alternative to

morphine in case of intolerable side-effects. It is advised that two or more strong opioids

should be available for this purpose, and oxycodone is one such strong opioid. Thus, it is

requested that oxycodone be added to the EMLc as an example of the opioid class.

Accordingly, it is necessary to add the oxycodone monograph in the Model Formulary in

accordance to the aforementioned Guidelines.

With this application, we request:

1. Addition of oxycodone preparations as an example of the opioid class to the EMLc.1

2. Addition of a monograph on oxycodone in the WHO Formulary for children

This application is part of a series of three applications:

- Application to add certain morphine formulations to the Essential Medicines List for

Children;

- Application to add oxycodone to the Essential Medicines List for Children; and

- Application to add hydromorphone to the Essential Medicines List for Children.

1 Two or more alternatives to morphine should be available and this should be expressed in the EMLc,

for example as a footnote to the square box.


4

Name of the focal point in WHO submitting or supporting the application Dr. Willem Scholten, Team Leader, Access to Controlled Medicines, Medicines

Access and Rational Use, Department of Essential Medicines and Pharmaceutical Policies,

World Health Organization, Geneva, Switzerland. Email address:

[email protected]. (until 31 October 2012) [email protected] (from 1 November 2012)

Name of the organizations consulted and/or supporting the application Members of the Guidelines Development Group for the WHO guidelines on the

pharmacological treatment of persisting pain in children with medical illnesses reviewed the

draft proposal and support it: Dr Allen Finley, Chair of the GDG and Dr John Collins,

Member.

International Nonproprietary Name of the medicine Oxycodone INN [INN Cumulative List, 2004]

Formulations proposed for inclusion, including a proposal for a monograph in the WHO Model Formulary for children

Preparations to be added to the EMLc

In order to provide adequate pain treatment for persisting pain in children, it is

required that the following formulations of oxycodone be added to the Essential Medicine

List for Children, under section 2.2 Opioid Analgesics:

a. Tablet: 5 mg, 10 mg, 15 mg, 20 mg, 30 mg (as hydrochloride)

b. Tablet (slow-release): 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80

mg,160 mg (as hydrochloride)

c. Capsule: 5 mg, 10 mg, 20 mg (as hydrochloride)

d. Oral liquid: 1 mg/ml, 10 mg/ml, 20 mg/ml (as hydrochloride)

These preparations should be equally added to the palliative care section of the EMLc.

Rationale for these strengths and dosage forms

Introduction

The WHO Guidelines on the Pharmacological Treatment of Persisting Pain in

Children with Medical Illnesses identify four key concepts for the correct use of analgesic

medicines and three of these concepts affect the need and selection for oxycodone

preparations [Guidelines, 2012: pages 38–40]:

• dosing at regular intervals (“by the clock”)

• using the appropriate route of administration (“by the mouth”)

• tailoring treatment to the individual child (“by the individual”).

The WHO Guidelines on the Pharmacological Treatment of Persisting Pain in

Children strongly recommend switching opioids (and/or route of administration) in children


5

in the presence of inadequate analgesic effect with intolerable side-effects. [Guidelines, 2012:

Guidelines 10, p. 44] and alternative opioids and/or dosage forms as an alternative to oral

morphine should be available to practitioners, in addition to morphine, if possible.

[Guidelines, 2012: Guidelines 11, p. 44; both slow-release and immediate-release

preparations should be available [Guidelines, 2012: Guideline 8, p. 43; Guideline 9, p. 43 ];

and oral administration of opioids is the recommended route of administration. [Guidelines,

2012: Guideline 13, p. 45]. Therefore, the availability of a full range of preparations is

essential.

Need for a range of strengths of immediate release tablets or capsules

To obtain a dose that provides adequate relief of pain with an acceptable degree of side-

effects the doses of oxycodone or other strong opioids need to be gradually increased until

effective. Unlike paracetamol and NSAIDs, there is no upper dosage limit for opioid

analgesics because there is no "ceiling" analgesic effect. The appropriate dose is the dose that

produces pain relief for the individual child. The goal of titration to pain relief is to select a

dose that prevents the child from experiencing pain between two doses using the lowest

effective dose. This is best achieved by frequent assessment of the child’s pain relief

response and adjusting the analgesic doses as necessary.

The opioid dose that effectively relieves pain varies widely between children, and in the

same child at different times, and should, therefore, be based on the child's pain severity

assessment. Large opioid doses given at frequent intervals may be necessary to control pain in

some children; these doses may be regarded as appropriate, provided that the side-effects are

minimal or can be managed with other medicines. Therefore, a range of strengths of

oxycodone, as an example of an alternative to morphine, should be added to the EMLc.

[WHO guidelines, p.47]

Need for slow release formulations

Access to multiple strengths of slow-release oxycodone is essential for the treatment of

moderate to severe persisting pain in children as slow-release morphine allow for longer dose

intervals, and this improves the patient’s compliance by reducing dose frequency.

Need for liquid formulations

The oral administration is the preferred route of administration. Older children may be

able to swallow regular or slow-release oxycodone tablets/capsules, but young children and

infants may only be able to use liquid formulations of oxycodone.

Relation to the application for hydromorphone

For patients who do not react well to morphine, the guidelines require that two or more

alternatives to morphine are available. While morphine has a very wide range of preparations


6

for both oral and parenteral administration and for immediate-release and slow-release, this is

not the case for all other strong opioids. Therefore, oxycodon and hydromorphone were

selected as together they have a wider range of administration forms readily available:

injections, tablets, slow-release tablets, capsules and oral liquid are all covered by this

selection.

Why other strong opioids from the guidelines are not selected to serve as the example of a the

class of strong opioids alternative to morphine

Fentanyl: fentanyl may be expensive in some countries and lozenges may be suitable

for breakthrough pain, but less suitable for titrating. Therefore, the range of dosage forms as a

whole may be less suitable than for oxycodone and hydromorphone.

Methadone: the long half-life of methadone makes it more difficult to dose.

International availability - sources, manufacturers and trade names Oxycodone hydrochloride as a starting material is out of patent. Oxycodon tablets, slow-

release tablets, capsules, injections, oral solution and concentrate for oral solution are

available for purchase in a number of countries.

Trade names

Endone, Eubine, Proladone, Oxycontin, OxyIR, Roxicodone, Supeidol and several other

brand names [Martindale, 1999];

Dihydrone, Ducodal, Eucodal, Oksikon, Atoxicodan, Bionin, Bionone, Boncodal,

Codenon, Cofacodal, Dihydrone, Dinarcon, Dolodorin, Dolodorm, Dorsanvite, Ducodal,

Endone, Equimorfin, Eubin, Eudol, Eukdin, Eukodal, Eumorfol, Eumodal, Eutagen,

Hydrocodal, Laokon, Ludonal, Medocodal, Mictoben, Narcobasin, Narcodal, Narcofedrin,

Narcosin, Nargevet, Ocitonargol, Opton, Oxanest, Oxicodal, Oxycon, Pancodine, Pavinal,

Penumbrol, Percodal, Proladona, Pronarcin, Roxicodone, Sanasmol, Scofedal,

Scofol,Scopedron, Tebodal, Tecodin, Valbin and varieties and several other brand names

[Multilingual dictionary of narcotic drugs, 1993];

Dinarkon, Diphydrone, Endocet, Endodan, ETH-Oxydose ,Endone, Endone, Eukodal,

OxyContin, Oxycocet , OxyFast , Oxygesic, OxyNEO, OxyNorm, OxyNormoro, Pancodine,

Percodan, Percodan-Demi, Percocet, Percolone, Primlev, Roxicet, Roxicodone, Roxilox,

Roxiprin, Supeudol, Targin, Thekodin, Tylox [Wikipedia, accessed 18 September 2012].

Preparations and manufacturers in some countries

(Dosage forms and strengths as included in this application only)

Germany2

Tablets 5 mg Oxycodonhydrochlorid G.L. 5 mg Filmtabletten, Tablet, G.L.-Pharma GmbH

2 Bfarm Database: http://www.bfarm.de/DE/Arzneimittel/3_nachDerZulassung/zugel_AM/zugel_AM-node.html


7

Oxygesic Dispersa 5mg Soluble tablet, Mundipharma GmbH

Tablets 10mg

Oxycodonhydrochlorid G.L. 10 mg Filmtabletten, Tablet, G.L.-Pharma GmbH

Oxygesic Dispersa 10mg, Soluble tabletMundipharma GmbH

Tablets 20mg

Oxygesic Dispersa 20mg, Soluble tabletMundipharma GmbH

Capsules 5mg

Oxygesic akut 5 mg, Capsule, Mundipharma GmbH

OxyNorm 5 mg, Capsule, Mundipharma GmbH

Capsules 10mg

Oxygesic akut 10 mg, Capsule , Mundipharma GmbH

OxyNorm 10 mg, Capsule, Mundipharma GmbH

Capsules 20mg

Oxygesic akut 20 mg, Capsule, Mundipharma GmbH OxyNorm 20 mg, Capsule, Mundipharma GmbH

Slow-release tablets 5mg

Oxycodon HCl Lannacher 5 mg Retardtabletten Slow release tablet, Lannacher Heilmittel Ges.m....

Oxycodon-HCI AbZ 5 mg Retardtabletten, Slow release tablet, AbZ-Pharma GmbH

Oxycodon-HCL Accord 5 mg Retardtabletten, Slow release tablet, Accord Healthcare Limited Oxycodon-HCL HEXAL 5 mg Retardtabletten, Slow release tablet, Hexal Aktiengesellschaft

Oxycodon-HCL Sandoz 5 mg Retardtabletten, Slow release tablet, Sandoz Pharmaceuticals GmbH

Oxycodon-HCl STADA 5 mg Retardtabletten, Slow release tablet, Stadapharm GmbH Oxycodon-HCl Winthrop 5 mg Retardtabletten, Slow release tablet, Winthrop Arzneimittel

GmbH

Oxycodon-HCl-CT 5 mg Retardtabletten, Slow release tablet, CT Arzneimittel GmbH - Gesc...

Oxycodon-HCl-ratiopharm 5 mg Retardtabletten, Slow release tablet, ratiopharm GmbH Oxycodonhydrochlorid - 1 A Pharma 5 mg Retardtabletten, Slow release tablet, 1 A Pharma GmbH

Oxycodonhydrochlorid Acino 5 mg Retardtabletten, Slow release tablet, ACINO AG

Oxycodonhydrochlorid G.L. 5 mg Retardtabletten, Slow release tablet, G.L.-Pharma GmbH Oxydolex 5 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....

Oxygesic 5 mg Slow release tablet, Mundipharma GmbH

Oxypro 5 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....

Oxycodon-HCl Aristo 5 mg Retardtabletten, Slow release tablet, Aristo Pharma GmbH Oxycodon-HCl AWD 5 mg Retardtabletten, Slow release tablet, AWD.pharma GmbH & Co. KG

Oxycodon-HCl Develco 5 mg Retardtabletten, Slow release tablet, Develco Pharma GmbH

Oxycodon-HCl dura 5 mg Retardtabletten, Slow release tablet, Mylan dura GmbH


Kancodal HEXAL 10 mg Retardtabletten, Slow release tablet, Hexal Aktiengesellschaft Oxycodon HCl Lannacher 10 mg Retardtabletten , Slow release tablet, Lannacher Heilmittel Ges.m....

Oxycodon-HCl AbZ 10 mg Retardtabletten, Slow release tablet, AbZ-Pharma GmbH

Oxycodon-HCL Accord 10 mg Retardtabletten, Slow release tablet, Accord Healthcare Limited

Oxycodon-HCl AL 10 mg Retardtabletten, Slow release tablet, ALIUD PHARMA GmbH Oxycodon-HCl Aristo 10 mg Retardtabletten, Slow release tablet, Aristo Pharma GmbH


8

Oxycodon-HCl AWD 10 mg Retardtabletten, Slow release tablet , AWD.pharma GmbH & Co.

KG

Oxycodon-HCl beta 10 mg Retardtabletten, Slow release tablet, betapharm Arzneimittel GmbH Oxycodon-HCl Develco 10 mg Retardtabletten, Slow release tablet, Develco Pharma GmbH


Oxycodon-HCl Hexal 10 mg Retardtabletten, Slow release tablet, Hexal Aktiengesellschaft

Oxycodon-HCL Sandoz 10 mg, Slow release tablet, Sandoz Pharmaceuticals GmbH Oxycodon-HCL Sandoz 10 mg Retardtabletten, Slow release tablet, Sandoz Pharmaceuticals GmbH

Oxycodon-HCl STADA 10 mg Retardtabletten, Slow release tablet, Stadapharm GmbH

Oxycodon-HCl Winthrop 10 mg Retardtabletten, Slow release tablet, Winthrop Arzneimittel GmbH Oxycodon-HCl-CT 10 mg Retardtabletten, Slow release tablet. CT Arzneimittel GmbH - Gesc...

Oxycodon-HCl-ratiopharm 10 mg Retardtabletten, Slow release tablet, ratiopharm GmbH

Oxycodonhydrochlorid - 1 A Pharma 10 mg Retardtabletten, Slow release tablet, 1 A Pharma GmbH Oxycodonhydrochlorid Acino 10 mg Retardtabletten, Slow release tablet, ACINO AG

Oxycodonhydrochlorid G.L. 10 mg Retardtabletten, Slow release tablet, G.L.-Pharma GmbH

Oxydolex 10 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....

OXYGESIC 10 mg, Slow release tablet, Mundipharma GmbH Oxygesic 10 mg Retardtabletten, Slow release tablet, PB Pharma GmbH

Oxypro 10 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....


Oxygesic 15 mg Retardtabletten, Slow release tablet, Mundipharma GmbH


Kancodal HEXAL 20 mg Retardtabletten, Slow release tablet, Hexal Aktiengesellschaft

Oxycodon HCl Lannacher 20 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....

Oxycodon-HCl AbZ 20 mg Retardtabletten, Slow release tablet, AbZ-Pharma GmbH Oxycodon-HCL Accord 20 mg Retardtabletten, Slow release tablet, Accord Healthcare Limited

Oxycodon-HCl AL 20 mg Retardtabletten, Slow release tablet, ALIUD PHARMA GmbH

Oxycodon-HCl Aristo 20 mg Retardtabletten, Slow release tablet , Aristo Pharma GmbH Oxycodon-HCl AWD 20 mg Retardtabletten, Slow release tablet , AWD.pharma GmbH & Co.

KG

Oxycodon-HCl beta 20 mg Retardtabletten, Slow release tablet, betapharm Arzneimittel GmbH

Oxycodon-HCl Develco 20 mg Retardtabletten, Slow release tablet, Develco Pharma GmbH Oxycodon-HCl dura 20 mg Retardtabletten, Slow release tablet, Mylan dura GmbH

Oxycodon-HCl HEXAL 20 mg Retardtabletten, Slow release tablet, Hexal Aktiengesellschaft

Oxycodon-HCL Sandoz 20 mg Retardtabletten, Slow release tablet, Sandoz Pharmaceuticals GmbH Oxycodon-HCl STADA 20 mg Retardtabletten, Slow release tablet, Stadapharm GmbH

Oxycodon-HCl Winthrop 20 mg Retardtabletten , Slow release tablet, Winthrop Arzneimittel GmbH

Oxycodon-HCl-CT 20 mg Retardtabletten, Slow release tablet, CT Arzneimittel GmbH - Gesc... Oxycodon-HCl-ratiopharm 20 mg Retardtabletten, Slow release tablet, ratiopharm GmbH

Oxycodonhydrochlorid - 1 A Pharma 20 mg Retardtabletten, Slow release tablet, 1 A Pharma GmbH

Oxycodonhydrochlorid Acino 20 mg Retardtabletten, Slow release tablet , ACINO AG

Oxycodonhydrochlorid G.L. 20 mg Retardtabletten, Slow release tablet, G.L.-Pharma GmbH Oxydolex 20 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....

OXYGESIC 20 mg, Slow release tablet Mundipharma GmbH

Oxygesic 20 mg Retardtabletten, Slow release tablet, PB Pharma GmbH Oxypro 20 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....


Oxycodon-HCl beta 30 mg Retardtabletten, Slow release tablet, betapharm Arzneimittel GmbH Oxygesic 30 mg Retardtabletten, Slow release tablet, Mundipharma GmbH


9

Slow-release tablets 40mg Oxycodon HCl Lannacher 40 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....


Oxycodon-HCL Accord 40 mg Retardtabletten, Slow release tablet, Accord Healthcare Limited

Oxycodon-HCl AL 40 mg Retardtabletten, Slow release tablet, ALIUD PHARMA GmbH Oxycodon-HCl Aristo 40 mg Retardtabletten, Slow release tablet , Aristo Pharma GmbH

Oxycodon-HCl AWD 40 mg Retardtabletten, Slow release tablet , AWD.pharma GmbH & Co.

KG Oxycodon-HCl beta 40 mg Retardtabletten, Slow release tablet, betapharm Arzneimittel GmbH



Oxycodon-HCl HEXAL 40 mg Retardtabletten, Slow release tablet, Hexal Aktiengesellschaft Oxycodon-HCL Sandoz 40 mg Retardtabletten, Slow release tablet, Sandoz Pharmaceuticals GmbH

Oxycodon-HCl STADA 40 mg Retardtabletten, Slow release tablet, Stadapharm GmbH

Oxycodon-HCl Winthrop 40 mg Retardtabletten, Slow release tablet, Winthrop Arzneimittel GmbH Oxycodon-HCl-CT 40 mg Retardtabletten, Slow release tablet, CT Arzneimittel GmbH - Gesc...

Oxycodon-HCl-ratiopharm 40 mg Retardtabletten, Slow release tablet, ratiopharm GmbH

Oxycodonhydrochlorid Acino 40 mg Retardtabletten, Slow release tablet , ACINO AG Oxycodonhydrochlorid G.L. 40 mg Retardtabletten, Slow release tablet, G.L.-Pharma GmbH

Oxydolex 40 mg Retardtabletten , Slow release tablet, Lannacher Heilmittel Ges.m....

OXYGESIC 40 mg, Slow release tablet, Mundipharma GmbH

Oxygesic 40 mg Retardtabletten, Slow release tablet, PB Pharma GmbH Oxypro 40 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....

Slow-release tablets 60mg Oxycodon-HCl beta 60 mg Retardtabletten, Slow release tablet, betapharm Arzneimittel GmbH



Oxycodon HCl Lannacher 80 mg Retardtabletten,Slow release tablet, Lannacher Heilmittel Ges.m....


Oxycodon-HCL Accord 80 mg Retardtabletten, Slow release tablet, Accord Healthcare Limited Oxycodon-HCl AL 80 mg Retardtabletten, Slow release tablet, ALIUD PHARMA GmbH

Oxycodon-HCl Aristo 80 mg Retardtabletten, Slow release tablet, Aristo Pharma GmbH

Oxycodon-HCl AWD 80 mg Retardtabletten, Slow release tablet , AWD.pharma GmbH & Co. KG

Oxycodon-HCl beta 80 mg Retardtabletten, Slow release tablet, betapharm Arzneimittel GmbH


Oxycodon-HCl dura 80 mg Retardtabletten, Slow release tablet, Mylan dura GmbH Oxycodon-HCl HEXAL 80 mg Retardtabletten, Slow release tablet, Hexal Aktiengesellschaft

Oxycodon-HCL Sandoz 80 mg Retardtabletten, Slow release tablet, Sandoz Pharmaceuticals GmbH

Oxycodon-HCl STADA 80 mg Retardtabletten, Slow release tablet, Stadapharm GmbH Oxycodon-HCl Winthrop 80 mg Retardtabletten, Slow release tablet, Winthrop Arzneimittel GmbH

Oxycodon-HCl-CT 80 mg Retardtabletten, Slow release tablet, CT Arzneimittel GmbH - Gesc...

Oxycodon-HCl-ratiopharm 80 mg Retardtabletten, Slow release tablet, ratiopharm GmbH Oxycodonhydrochlorid Acino 80 mg Retardtabletten, Slow release tablet, ACINO AG

Oxycodonhydrochlorid G.L. 80 mg Retardtabletten, Slow release tablet, G.L.-Pharma GmbH

Oxydolex 80 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....

Oxygesic 80 mg, Slow release tablet, Mundipharma GmbH Oxypro 80 mg Retardtabletten, Slow release tablet, Lannacher Heilmittel Ges.m....


10





The Netherlands3


OxyContin 5 mg, Slow-release tablets, Mundipharma OxyContin 5 mg, Slow-release tablets, Fisher Pharma/Mundipharma (parallel import)

Oxycodon-HCl Accord 5 mg, Slow-release tablets, Accord Healthcare Ltd.

Oxycodon HCl Apotex 5 mg, Slow-release tablets, Apotex Europe

Oxycodon HCl Lannacher 5 mg, Slow-release tablets, Lannacher Austria Oxycodon HCl Mundipharma 5 mg Slow-release tablets, Mundipharma

Oxycodon HCl Sandoz 5 mg, Slow-release tablets, Sandoz

Oxycodon HCl 5 mg Teva, Slow-release tablets, Teva


OxyContin 10 mg Slow-release tablets, Mundipharma

OxyContin 10 mg, Slow-release tablets, Fisher Pharma/Mundipharma (parallel import) Oxycodon-HCl Accord 10 mg, Slow-release tablets, Accord Healthcare Ltd.


Oxycodon HCl Lannacher 10 mg, Slow-release tablets, Lannacher Austria Oxycodon HCl Mundipharma 10 mg, Slow-release tablets, Mundipharma

Oxycodon HCl Sandoz retard 10 mg, Slow-release tablets, Sandoz



OxyContin 15 mg, Slow-release tablets, Mundipharma

Oxycodon HCl Mundipharma 15 mg, Slow-release tablets, Mundipharma


OxyContin 20 mg, Slow-release tablets, Mundipharma OxyContin 20 mg, Slow-release tablets, Fisher Pharma/Mundipharma (parallel import)

Oxycodon-HCl Accord 20 mg, Slow-release tablets, Accord Healthcare Ltd.

Oxycodon HCl Apotex 20 mg, Slow-release tablets, Apotex Europe Oxycodon HCl Lannacher 20 mg, Slow-release tablets, Lannacher Austria


Oxycodon HCl Sandoz retard 20 mg, Slow-release tablets, Sandoz

Oxycodon HCl 20 mg Teva, Slow-release tablets, Teva Pharmaceuticals


OxyContin 30 mg, Slow-release tablets, Mundipharma Oxycodon HCl Mundipharma 30 mg, Slow-release tablets, Mundipharma


OxyContin 40 mg Slow-release tablets, Mundipharma OxyContin 40 mg, Slow-release tablets, Fisher Pharma/Mundipharma (parallel import)

Oxycodon-HCl Accord 40 mg Slow-release tablets, Accord Healthcare Ltd.


3 Dutch Medicines Evaluation Board database. www.cbg-meb.nl

http://www.cbg-meb.nl/


11

Oxycodon HCl Lannacher 40 mg, Slow-release tablets, Lannacher Austria

Oxycodon HCl Mundipharma 40 mg Slow-release tablets, Mundipharma Oxycodon HCl Sandoz 40 mg, Slow-release tablets, Sandoz


Slow-release tablets 60mg OxyContin 60 mg, Slow-release tablets, Mundipharma




OxyContin 80 mg, Slow-release tablets, Fisher Pharma/Mundipharma (parallel import)

Oxycodon-HCl Accord 80 mg, Slow-release tablets, Accord Healthcare Ltd. Oxycodon HCl Apotex 80 mg, Slow-release tablets, Apotex Europe

Oxycodon HCl Lannacher 80 mg, Slow-release tablets, Lannacher Austria

Oxycodon HCl Mundipharma 80 mg, Slow-release tablets, Mundipharma Oxycodon HCl Sandoz 80 mg, Slow-release tablets, Sandoz





Capsules 5mg

OxyNorm capsules 5 mg, capsules, Mundipharma

OxyNorm 5 mg capsules, capsules, Fisher Pharma/Mundipharma (parallel import)

Capsules 10mg

OxyNorm capsules 10 mg, capsules, Mundipharma OxyNorm capsules 10 mg, capsules, Fisher Pharma/Mundipharma (parallel import)

Capsules 20 mg

OxyNorm capsules 20 mg, capsules, Mundipharma OxyNorm capsules 20 mg, capsules, Fisher Pharma/Mundipharma (parallel import)

Tablets 5mg OxyNorm Instant 5 mg, Dispersable tablets, Mundipharma

OxyNorm Instant 5 mg, Dispersable tablets, Fisher Pharma/Mundipharma (parallel import)

Oxycodon HCl G.L. 5mg, Tablets, GL Pharma GmbH

Tablets 10 mg

OxyNorm Instant 10 mg, Dispersable tablets, Mundipharma

OxyNorm Instant 10 mg, Dispersable tablets, Fisher Pharma/Mundipharma (parallel import) Oxycodon HCl G.L. 10mg Tablets, GL Pharma GmbH

Tablets 20 mg OxyNorm Instant 20 mg, Dispersable tablets, Mundipharma

Oral liquid 1mg/ml OxyNorm drank 5 mg/ 5 ml, Oral liquid, Mundipharma


12

Oral liquid 10mg/ml

OxyNorm drank 10 mg/ml, Oral liquid, Mundipharma

Switzerland4

Oxycontin Slow release Tabl 5 mg, Mundipharma Medical Company



Oxycontin Slow release Tabl 40 mg, Mundipharma Medical Company Oxycontin Slow release Tabl 80 mg, Mundipharma Medical Company

Oxynorm Oral liquid 10 mg/ml, Mundipharma Medical Company

Oxynorm Capsules 5 mg, Mundipharma Medical Company



USA5

Tablets 5mg

Oxecta 5mg Tablet, King Pharmaceuticals R And D Roxicodone 5mg Tablet, Xanodyne Pharms

Oxycodone Hydrochloride 5mg Tablet, Alvogen Inc

Oxycodone Hydrochloride 5mg Tablet, Avanthi Inc

Oxycodone Hydrochloride 5mg Tablet, Coastal Pharms Oxycodone Hydrochloride 5mg Tablet, Corepharma

Oxycodone Hydrochloride 5mg Tablet, Mallinckrodt Inc

Oxycodone Hydrochloride 5mg Tablet, Nesher Pharms Oxycodone Hydrochloride 5mg Tablet, Rhodes Pharms

Oxycodone Hydrochloride 5mg Tablet, Sun Pharm Inds Inc

Oxycodone Hydrochloride 5mg Tablet, Vintage Pharms

Tablets 10mg

Oxycodone Hydrochloride 10mg, Tablet, Avanthi Inc

Oxycodone Hydrochloride 10mg Tablet, Nesher Pharms Oxycodone Hydrochloride 10mg Tablet, Rhodes Pharms

Tablets 15mg Roxicodone 15mg Tablet, Xanodyne Pharms

Oxycodone Hydrochloride 15mg Tablet, Actavis Totowa

Oxycodone Hydrochloride 15mg Tablet, Alvogen Inc

Oxycodone Hydrochloride 15mg Tablet, Avanthi Inc Oxycodone Hydrochloride 15mg Tablet, Coastal Pharms

Oxycodone Hydrochloride 15mg Tablet, Corepharma

Oxycodone Hydrochloride 15mg Tablet, Mallinckrodt Inc Oxycodone Hydrochloride 15mg Tablet, Nesher Pharms

Oxycodone Hydrochloride 15mg Tablet, Rhodes Pharms

Oxycodone Hydrochloride 15mg Tablet, Sun Pharm Inds Inc Oxycodone Hydrochloride 15mg Tablet, Vintage Pharms

4 Official Swiss Price List at http://bag.e-mediat.net/SL2007.Web.External/Default.aspx?webgrab=ignore 5 FDA Database: http://www.fda.gov/NewsEvents/ProductsApprovals/default.htm

http://bag.e-mediat.net/SL2007.Web.External/Default.aspx?webgrab=ignore


13

Tablets 20mg

Oxycodone Hydrochloride 20mg Tablet, Avanthi Inc Oxycodone Hydrochloride 20mg Tablet, Nesher Pharms


Tablets 30mg Roxicodone 30mg Tablet, Xanodyne Pharms

Oxycodone Hydrochloride 30mg Tablet, Actavis Totowa

Oxycodone Hydrochloride 30mg Tablet, Alvogen Inc Oxycodone Hydrochloride 30mg Tablet, Avanthi Inc

Oxycodone Hydrochloride 30mg Tablet, Coastal Pharms

Oxycodone Hydrochloride 30mg Tablet, Corepharma

Oxycodone Hydrochloride 30mg Tablet, Mallinckrodt Inc Oxycodone Hydrochloride 30mg Tablet, Nesher Pharms


Oxycodone Hydrochloride 30mg Tablet, Sun Pharm Inds Inc Oxycodone Hydrochloride 30mg Tablet, Vintage Pharms

Slow-release tablets 10mg Oxycontin 10mg Extended Release Tablet, Purdue

Roxicodone 10mg Extended Release Tablet, Roxane



Oxycontin 20mg Extended Release Tablet, Purdue



Roxicodone 30mg Extended Release Tablet, Roxane






Capsules 5mg Oxycodone Hydrochloride 5mg, Capsule, Coastal Pharms

Oxycodone Hydrochloride 5mg, Capsule, Lehigh Valley

Oral liquid 1mg/ml

Oxycodone Hydrochloride 1mg/ml, Oral Solution, Vistapharm

Oral liquid 20mg/ml Oxycodone Hydrochloride 20mg/ml, Oral Solution, Lehigh Valley

Oxycodone Hydrochloride 20mg/ml Oral Solution, Vistapharm


14

Whether listing is requested as an individual medicine or as an example of a

therapeutic group Listing is requested as an example of a therapeutic group. According to the

Guidelines, “alternative opioids” (i.e. two or more alternatives) to morphine should be

available and this should be expressed in the EMLc, for example as a footnote to the square

box. [Guidelines, 2012: p. 44] The footnote could read “Examples for alternative opioids for

morphine. Two or more alternatives should be available in addition to morphine.”

Information supporting the public health relevance From a public-health perspective, currently many patients are without access to

essential medicines for pain. WHO policies recommend, and international drug conventions

require that countries make medicines controlled under these conventions readily available to

those in need. Opioid analgesics like morphine, hydrocodone and oxycodone are among these

controlled medicines.

The World Health Organization has a policy to promote the availability of strong

opioids in countries whose policies or legislation unduly does not allow access or availability

to strong opioids [Ensuring Balance, p.5]. Inclusion in the EMLc is essential for enhancing

this policy.

It has been well documented that in most countries of the world, patients do not have

adequate access to opioid analgesics. The various barriers are described in the World

Medicines Report [Milani B and Scholten W, 2011] and in the WHO policy guidelines

Ensuring Balance in National Policies on Controlled Substances, Accessibility and

Availability of Controlled Medicines. [Ensuring balance, 2011: p.5] Legal and policy barriers

are important reasons why these medicines are not available in many countries. Seya et al.

estimate that in 2006 only 464 million people had adequate access to opioid analgesics, and

4.7 billion people had virtually no access [Seya et al, 2011].

The World Health Assembly in its resolution 58.22 “On Cancer prevention and

control” (2005), called on WHO to address access to opioid analgesics [Resolution WHA

58.22, 2005]. Other international bodies such as the International Narcotics Control Board

(e.g. in a special report on the availability of internationally controlled drugs) [Report of the

INCB, 2011] and the UN Commission on Narcotic Drugs, have called for greater access for

patients to these medicines.

In addition, the International Association for the Study of Pain adopted the

Declaration of Montreal, the Union for International Cancer Control published the World

Cancer Declaration and a consortium of 60 international and national organizations initiated

by Pallium India launched the Morphine Manifesto. [Declaration of Montreal, 2011; World

Cancer Declaration, 2006; a Morphine Manifesto, 2012] All these declarations call for

adequate access to pain medicines and treatment of pain worldwide.


15

Treatment details The treatment recommended by the World Health Organization is published in the

WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with

Medical Illnesses. These guidelines address the pharmacological management of persisting

pain in children with medical illnesses. As such, they replace the previous guidelines, Cancer

pain relief and palliative care in children, which exclusively covered cancer pain. [Guidelines,

2012: p. 10]. Treatment details in this application are based on the Guidelines on the

Pharmacological Treatment of Persisting Pain in Children.

For the treatment of pain, no special diagnostics are needed, nor any technical

monitoring facilities. Although in certain stages of treatment monitoring of the patient is

necessary, this refers to clinical monitoring which could include phone calls or home visits to

check on progress, dose tracking, or pulse oximetry and respiratory monitoring in hospital,

depending on circumstances. In (very) rare circumstances it might include urine drug testing.

The treatment of pain requires to be preceded by and go together with a regular

assessment of the pain with simple pain scales, such as the FPS-R scales. Methods are

described in Chapter 2, Evaluation of persisting pain in the paediatric population, of the

guidelines. [Guidelines, 2012: p. 26-35]

Treatment recommendations

Dosage:

Starting dose for opioid-naive patients:

Oral (immediate-release formulation):

infant 1–12 months – 50–125 mcg/kg every 4 hours;

child 1–12 years – 125–200 mcg/kg every 4 hours, max 5 mg.

Oral (slow-release formulation):

child over 8 years – 5 mg every 12 hours.

Continuation: after a starting dose according to the dosages above, the dosage should be

adjusted to the level that is effective (with no maximum), but the maximum dosage

increase is 50% per 24 hours in outpatient settings. Experienced prescribers can

increase up to 100% with careful monitoring of the patient.

Dose for breakthrough pain

Oral (using immediate-release preparation):

infant or child: Additional oxycodone may be administered as frequently as

required with a maximum of 5–10% of the regular daily baseline oxycodone dose.

If repeated breakthrough doses are required, adjust the regular baseline

oxycodone dose guided by the amount of oxycodone required for breakthrough

pain with a maximum increase of 50% per 24 hours.


16

The WHO guidelines on the pharmacological treatment of persisting pain in children

are evidenced based guidelines, produced using the methods prescribed actually for WHO

treatment guidelines. Oxycodone is considered an example of a strong opioid, as an alternative to

morphine, for moderate to severe persisting pain in children. Two or more alternatives to morphine

should be available and this should be expressed in the EMLc, for example as a footnote to the square

box.

According to the WHO guidelines on the pharmacological treatment of persisting pain

in children with medical illnesses, the immediate release oxycodone is initially dosed at 50–

125 mcg/kg every 4 hours for infants aged 1–12 months, and 125–200 mcg/kg every 4 hours

(max 5 mg) for children aged 1 – 12 years. The oral slow-release formulation is dosed 5 mg

every 12 hours for children over 8 years of age. After the appropriate starting dose, the

dosage should be adjusted on an individual basis to the level that it is effective (with no

maximum dose, unless further increase is not possible because of untreatable side-effects).

The maximum dosage increase is 50% per 24 hours in outpatient settings. Experienced

prescribers can increase up to 100% while monitoring the patient carefully. Common adverse

effects of oxycodone include nausea, vomiting, constipation, lightheadedness, drowsiness,

dizziness, sedation, sweating, dysphoria, euphoria, dry mouth, anorexia, spasm of urinary and

biliary tract, pruritus, rash, sweating, palpitation, bradycardia, postural hypotension, and

miosis. Uncommon adverse effects include respiratory depression (dose-related), tachycardia,

and palpitations. Rare adverse effects include syndrome of inappropriate anti-diuretic

hormone secretion (SIADH) and anaphylaxis. However, if titrated correctly, most side effects

can be avoided.

Opioid weaning can be done safely without posing significant health risk to the

patient. From the medical standpoint, weaning opioids should be done slowly by tapering the

opioid dose. For short-term therapy (7–14 days), the original dose can be decreased by 10–

20% of the original dose every 8 hours, increasing gradually the time interval. In the case of a

long-term therapy protocol, the dose should be reduced not more than 10-20% per week.

These pharmacological approaches should be accompanied by measurement of withdrawal

symptoms using a scoring system [WHO guidelines, 2012: p.47].

The Guidelines Development Group on the WHO guidelines on the pharmacological

treatment of persisting pain in children considered the lack of instruction on how to titrate and

how to wean patients on opioids a hazard. Therefore this information is considered essential

for the Formulary monograph. There is a need for comparative trials of opioids in terms of

effectiveness, side-effects and feasibility of use in children with persisting pain due to medical

illnesses.

It should be mentioned that the initial dosage is lower than often recommended

elsewhere [British National Formulary for Children, 2011: p. 256; Scholten W, 2012]. The

experts considered dosages recommended elsewhere as not deprived of risk. Also the lack of

instruction on how to titrate and how to wean patients on opioids is considered a hazard.


17

Therefore this information is considered essential for the Formulary monograph. There is a

need for comparative trials of opioids in terms of effectiveness, side-effects and feasibility of

use in children with persisting pain due to medical illnesses.

Summary of comparative effectiveness in a variety of clinical settings The guidelines provide the evidence for its recommendations in a number of GRADE

tables [WHO guidelines, 2012: p.104 ] and the further justification for each recommendation

is provided in an annex [WHO guidelines, 2012: p.82]. The guidelines also concluded that

more research is needed in order to answer specific questions. The guidelines are based on the

best knowledge currently available. See Annex 1 and 2 of the application for detailed

information regarding the recommendations in the guidelines. Annex 1 contains GRADE

tables regarding oxycodone and Annex 2 contains background information for the

recommendations. (Please also refer to the GRADE Tables in the parallel applications on

morphine and hydrocodone preparations.)

For clinical data please refer to Annexes 1 and 2.

Summary of comparative evidence on safety 1. Estimate of total patient exposure to date Oxycodon has been used as an analgesic since 1939. Since, it has been used in

innumerous patients and it has been shown to be a safe medicine if used correctly. In 2006 the

world used 42.6 tonnes oxycodone, corresponding to 568 million DDDs. [Seya et al.,

unpublished data] The annual consumption by country can be roughly derived from the status

of estimates as published by the International Narcotics Control Board at

http://www.incb.org/incb/narcotic_drugs_estimates.html.

2. Description of adverse effects/reactions Adverse effects:

common – nausea, vomiting, constipation, dry mouth, sedation, biliary spasm,

respiratory depression, muscle rigidity, apnoea, myoclonic movements, asthenia,

dizziness, confusion, dysphoria, euphoria, lightheadedness, pruritus, rash,

somnolence, sweating;

uncommon – hypotension, hypertension, bradycardia, tachycardia, palpitation,

oedema, postural hypotension, miosis, visual disturbances, abdominal cramps,

anorexia, paraesthesia, malaise, agitation, tremor, muscle weakness,

hallucinations, vertigo, mood changes, dependence, drowsiness, anxiety, sleep

disturbances, headache, taste disturbance, agitation, urinary retention,

laryngospasm, bronchospasm;

rare – circulatory depression, cardiac arrest, respiratory arrest, shock, paralytic

ileus, seizures.

Interactions with other medicines:

central nervous system depressants – additive or potentiating effects with

hydromorphone;

http://www.incb.org/incb/narcotic_drugs_estimates.html


18

ethanol* – additive or potentiating effects with hydromorphone, potential fatal

interaction (dose dumping) if used with extended-release hydromorphone

preparations;

monoamine oxidase inhibitors* – severe and unpredictable potentiation of

opioids;

naloxone* – precipitates opioid withdrawal symptoms;

naltrexone* – precipitates opioid withdrawal symptoms;

opioid antagonists/partial agonists* – may precipitate opioid withdrawal

symptoms.

* Indicates severe.

3. Identification of variation in safety due to health systems and patient factors Inter-individual differences exist. Like for other opioid analgesics, the dosage level for

oxycodone needs to be established on an individual base [WHO guidelines, 2012: p. 37],

guided by the outcome of regular pain assessment. Provided that oxycodone is prescribed

when indicated, and titrated and weaned according to the guidelines, it has shown to be a safe

medicine.

Development of dependence on medical treatment is not well documented and it is

assumed that the risk is very limited [Noble, 2008; Minozzi, submitted] and this risk is not a

reason not to treat when indicated.[Minozzi, submitted] On theoretical grounds, it is likely

that pain patients are less susceptible to opioid dependence than other people. [Niikura, 2010]

There are well-described problems with over-prescribing and diversion in a limited

number of countries, although these studies are related to prescription to adults and not to

children. Non-medical use carries substantial risks, including overdose and mortality. It

should be noted that the extensively reported increase in consumption in the United States has

been accompanied by a notable increase in overdose deaths involving prescription opioids

[CDC,2011; CDC, 2012]. While there are insufficient data available to quantify the amounts

diverted to non-medical use from various parts of the drug distribution system, it appears

there is significant theft, fraud and other unlawful conduct [Inciardi JA et al. 2006a; Inciardi

JA et al., 2006b]. A national population-based survey in the United States found that over

70% of those who have reported using opioids non-medically admitted that they obtained the

drug for free from friends or family members or through theft or purchase [SAMSHA, 2011].

Large quantities of prescription opioids have been sold by illegitimate pain clinics and

overdose has occurred predominantly in persons obtaining opioids from non-medical sources

[CDC, 2011]. In a study of unintentional overdose fatalities in West Virginia, 63.1% of the

decedents had used pharmaceuticals with no documented prescriptions, and 55.6% of the

decedents were never prescribed opioid analgesics. In addition, 79.3% of the decedents has

used multiple substances, both illicit and prescription drugs (“polydrug use”), which might

have contributed to their death, and 21.4 % of the decedents had controlled medicines

prescribed by multiple physicians (“doctor shopping”) [Hall AJ et al., 2008]. This study did

not determine, however, whether decedents from the latter group were ‘real’ pain pat ients, or

people seeking drugs for illicit purposes. Another American study, describing 9940 cases of


19

overdose deaths, found 51 cases to whom dosages of 100 mg/day or higher of morphine

equivalents were prescribed during the first three months of a prescription episode, showing

an increased risk for this group [Dunn KM et al., 2010].

In conclusion, although there is no doubt that some, albeit unknown, level of opioid

agonist prescribing and dispensing to pain patients contributes to morbidity and mortality in

the USA, many if not most of these tragedies appear to involve opioids that have been

diverted or obtained through unlawful activities, including those of non-patients.

4. Summary of comparative safety against comparators Opioids are the only class of medicines effective for moderate and severe pain, and

therefore, there are no comparators outside the class. Within the class of opioid analgesics,

there are no outspoken differences in safety with the exception of methadone, because of its

kinetics.

Summary of available data on comparative cost and cost-effectiveness

within the pharmacological class or therapeutic group 1. Range of costs of the proposed medicine The cost of slow release tablets 20 mg tablets in Switzerland ranges from Sfr 2.19 - 2.56

per tablet (USD 2.36 – 2.74 ); for all SR tablet strengths the range is Sfr 2.84 – 8.51 (USD

3.25 – 9.11) per 30 mg oxycodon. The cost of immediate release capsules 5mg ranges from

Sfr 0,80 - 1,14 per capsule (USD 0.85 – 1.22); for all strengths of the capsules the cost ranges

from Sfr 2.53 – 6.86 (USD 2.71 – 7.35) per 30 mg oxycodon. 30ml oral solution 1mg/ml costs

in Switzerland Sfr 44,30 (USD 47.45), which is Sfr 4.43 (USD 4.74) per 30 mg oxycodone.6

The cost of the preparations mentioned in this application, as far as available in the

Netherlands, are as follows:

Preparation/strength

lower

limit

(€)

upper

limit

(€ )

lower

limit

($)

upper

limit

($ )

Tablet 5 mg 0.35 0.35 0.45 0.45

Tablet 10 mg 0.59 0.59 0.76 0.76

SR Tablet 5 mg 0.33 0.39 0.43 0.50

SR Tablet 10 mg 0.44 0.44 0.57 0.57

SR Tablet 15 mg 1.03 1.03 1.33 1.33

SR Tablet 20 mg 0.84 0.84 1.09 1.09

SR Tablet 30 mg 1.63 1.63 2.11 2.11

SR Tablet 40 mg 1.65 1.94 2.13 2.51

SR Tablet 60 mg 3.45 3.45 4.46 4.46

6 The price level for Switzerland as per 1 September 2012; for the Netherlands as per September 2012; exchange rates as per 13 September 2012. Sources: Official Swiss Price List at http://bag.e-mediat.net/SL2007.Web.External/Default.aspx?webgrab=ignore ; College voor Zorgverzekeringen, www.medicijnkosten.nl.



http://www.medicijnkosten.nl/


20

Preparation/strength

lower

limit

(€)

upper

limit

(€ )

lower

limit

($)

upper

limit

($ )

SR Tablet 80 mg 3.12 3.66 4.04 4.73

Caps 5 mg 0.41 0.41 0.53 0.53

Caps 10 mg 0.68 0.68 0.88 0.88

Caps 20 mg 1.37 1.37 1.77 1.77

Oral liquid 1 mg 0.68 0.68 0.88 0.88

2. Comparative cost-effectiveness presented as range of cost per routine There is no standard dosage for oxycodone for adult patients and therefore it is even more

difficult to define a standard dosage for a child. Foley et al. found that the average terminal

cancer patient needs 75 mg morphine a day during the last three months of his or her life.

[Foley, 2006] This corresponds with a dosage of approximately 30 mg oxycodone per day

orally for the treatment of a ten year old child with comparable pain.

The cost of one day of treatment (30 mg) for this child are presented above for the various

preparations available in Switzerland and the Netherlands. For all dosage forms and strengths,

the price range for 30 mg of oxycodone is Sfr 0.80 – 8.51 (US$ 0.85 – 9.11) for Switzerland.

In the Netherlands, the cost of one day of treatment (30 mg) for this child ranges for all

strengths of immediate release tablets from € 1.77 to € 2.10 (US$ 2.29 - 2.72) per 30 mg, for

all strengths of slow-release tablets from € 1.17 to € 2.34 (US$ 1.51 - 3.03) per 30 mg, for all

strengths of capsules from € 2.04 to € 8.22 (US$ 2.64 - 10.63) per 30 mg and for the oral

liquid it is € 20.40 (US $ 26.39) per 30 mg. The overall range is from € 1.17 to € 20.40 (US$

1.51 – 26.39).

As the Swiss price level for medicines is known to be high, the Swiss prices should be

regarded as the upper end of the price range. Among European countries, the Netherlands has

relatively low medicines prices.

Summary of regulatory status of the medicine in several countries Oxycodone was introduced as an analgesic in Germany in 1939. Currently, it is on the

market in Germany, the Netherlands, Switzerland, the United States of America and many

other countries.

Oxycodone is subject to international control under the Single Convention on Narcotic

Drugs, 1961. For enabling good access in all countries, the World Health Organization

published the policy guidelines Ensuring Balance in National Policies on Controlled

Substances, guidance for availability and accessibility of controlled medicines in 2011

[Ensuring Balance, p.4].


21

Availability of pharmacopoeial standards (British Pharmacopoeia,

International Pharmacopoeia, United States Pharmacopoeia) The International Pharmacopoeia, the British Pharmacopoeia and the Unites States

Pharmacopoeia all contain monographs for oxycodone hydrochloride. [The International

Pharmacopoeia, 2011, CD-version; British Pharmacopoeia, 2012, p. 10916; United States

Pharmacopoeia, online version accessed 14 September 2012].

In addition, the United States Pharmacopoeia has monographs on Oxycodone

Hydrochloride oral solution, Oxycodone Hydrochloride Tablets and Oxycodone

Hydrochloride Extended Tablets. [United States Pharmacopoeia, online version accessed 14

September 2012].

Proposed new text for the WHO Model Formulary The publication of the WHO Guidelines on the pharmacological treatment of persisting pain

in children entails also a pharmaceutical profile on oxycodone, following the monograph format of the

WHO Formulary for children. The profile contains updated dosage schedules and instruction for

titrating the patient to adequate pain management and for weaning opioids. A proposed text is

provided below. 7

Oxycodone

ATC Code: N02AA05

Tablet: 5 mg, 10 mg, 15 mg, 20 mg, 30 mg (as hydrochloride).

Tablet (slow release): 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 160 mg (as

hydrochloride).

Capsule: 5 mg, 10 mg, 20 mg (as hydrochloride).

Oral liquid: 1 mg/ml, 10 mg/ml, 20 mg/ml (as hydrochloride).

Indications: moderate to severe persisting pain.

Contraindications: hypersensitivity to opioid agonists or to any component of the

formulation; acute respiratory depression; acute asthma; paralytic ileus; concomitant

use of, or use within 14 days after ending monoamine oxidase inhibitors; raised

intracranial pressure and/or head injury, if ventilation not controlled; coma; use within

24 hours before or after surgery.

Precautions: impaired respiratory function; avoid rapid injection which may precipitate

chest wall rigidity and difficulty with ventilation; bradycardia; asthma; hypotension;

shock; obstructive or inflammatory bowel disorders; biliary tract disease; convulsive

disorders; hypothyroidism; adrenocortical insufficiency; avoid abrupt withdrawal after

7 Proposed monograph identical to the monograph in the WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children (page 78 - 80), except that the terminology “slow-release” is used here.


22

prolonged treatment; diabetes mellitus; impaired consciousness; acute pancreatitis;

myasthenia gravis; hepatic impairment; renal impairment; toxic psychosis.

Skilled tasks: warn the patient or caregiver about the risk of undertaking tasks

requiring attention or coordination, for example, riding a bike.

Dosage:


Oral (immediate-release formulation):

infant 1–12 months – 50–125 mcg/kg every 4 hours;

child 1–12 years – 125–200 mcg/kg every 4 hours, max 5 mg. Oral (slow-release formulation):

child over 8 years – 5 mg every 12 hours.

Continuation: after a starting dose according to the dosages above, the dosage should be

adjusted to the level that is effective (with no maximum), but the maximum dosage

increase is 50% per 24 hours in outpatient settings. Experienced prescribers can

increase up to 100% with careful monitoring of the patient.

Dose for breakthrough pain

Oral (using immediate-release preparation):

infant or child: Additional oxycodone may be administered as frequently as

required with a maximum of 5–10% of the regular daily baseline oxycodone

dose. If repeated breakthrough doses are required, adjust the regular baseline

oxycodone dose guided by the amount of oxycodone required for breakthrough

pain with a maximum increase of 50% per 24 hours.

Dosage discontinuation: for short-term therapy (7–14 days), the original dose can be

decreased by 10–20% of the original dose every 8 hours increasing gradually the time

interval. In the case of a long-term therapy protocol, the dose should be reduced not

more than 10–20% per week (79,80).

Renal impairment: mild (GRF 20–50 ml/min or approximate serum creatinine 150–300

micromol/l) to severe (GFR <10ml/min or serum creatinine > 700 micromol/l) – dose

reduction may be required; start with lowest dose and titrate according to response.

Hepatic impairment: moderate and severe; reduce dose by 50% or avoid use.

Adverse effects:

common – nausea, vomiting, constipation, diarrhoea, dry mouth, sedation, biliary

spasm, abdominal pain, anorexia, dyspepsia, pruritus, somnolence, dizziness;


23

less common – muscle rigidity, hypotension, respiratory depression,

bronchospasm, dyspnoea, impaired cough reflex, asthenia, anxiety, chills, muscle

fasciculation, postural hypotension, hallucinations, vertigo, euphoria, dysphoria,

dizziness, confusion;

uncommon – bradycardia, tachycardia, palpitation, oedema, mood changes,

dependence, drowsiness, sleep disturbances, headache, miosis, visual

disturbances, sweating, flushing, rash, urticaria, restlessness, difficulty with

micturition, urinary retention, ureteric spasm, gastritis, flatulence, dysphagia,

taste disturbance, belching, hiccups, vasodilation, supraventricular tachycardia,

syncope, amnesia, hypoasthesia, pyrexia, amenorrhoea, hypotonia, paraesthesia,

disorientation, malaise, agitation, speech disorder, tremor, dry skin;

rare – raised intracranial pressure, circulatory depression, cardiac arrest,

respiratory arrest, shock, paralytic ileus, seizures.



oxycodone;


opioids;




symptoms.

* Indicates severe.

Notes:

Oxycodone is subject to international control under the Single Convention on Narcotic

Drugs, 1961.

Slow-release oxycodone preparations must not be crushed or chewed; the child must

be able to swallow the whole tablet.

Administer with food to reduce gastrointestinal upset.

Oxycodone is partially metabolized to an active metabolite, oxymorphone, via

CYP2D6 pathway; slow or ultra-fast metabolizers may experience reduced or

enhanced analgesia and dose-related side-effects.

High strength slow-release tablets should only be used in patients who are opioid

tolerant. Administration of these strengths to non-opioid tolerant patients may cause

fatal respiratory depression.

Naloxone is used as an antidote in case of opioid overdose.

Equianalgesic doses:

When converting from oral morphine to oral oxycodone, use an initial dose conversion ratio

of 1.5:1 (e.g. replace 15 mg morphine with 10 mg oxycodone). Then titrate to optimize the

analgesia.

References:

Ashley C, Currie A, eds. The renal drug handbook, 3rd ed. Oxford, Radcliffe Publishing,

2009.


24

Drugdex in Micromedex Healthcare Series [Internet]. New York, NY, Thomson Reuters,

1974–2010 (http://micromedex.hcn.net.au/mdx-full/, accessed 18 August 2011).

Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook, 16th ed. Hudson, OH,

Lexicomp, 2009.

MIMS Online. Sydney, UBM Medica, 2009

(http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2010).

Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ

Group RBS Publishing, 2009.

Twycross R, Wilcock A, eds. Palliative care formulary, 3rd ed. Nottingham,

palliativedrugs.com, 2007.

[End of proposed revised text for the WHO Model Formulary]

Acknowledgements We acknowledge Mrs Margarette Kading for the initial drafting of this application and Dr

Catherine Parmiter-Dreiza for converting it into a first draft following the WHO EML application

format as published in May 2012.

http://micromedex.hcn.net.au/mdx-full/


25

Annex 1: Pertinent GRADE Tables Pertinent parts from the WHO guidelines on the pharmacological treatment of persisting pain

in children with medical illnesses, pages 114 and 115.


26


27

Annex 2: Background to the clinical recommendations Source: Pertinent parts from the WHO guidelines on the pharmacological treatment of persisting pain

in children with medical illnesses, pages 87-92.

A2.2.3 Strong opioids essential in pain treatment

Clinical question

In children with persisting pain due to medical illnesses, what are the benefits as compared to the risks

(hastening death, developing dependence, respiratory depression, influencing the child's development)

of taking regular or intermittent morphine for pain control as compared with a similar group of

patients with persisting pain not taking any opioid analgesics?

Recommendation

4. The use of strong opioid analgesics is recommended for the relief of moderate to severe

persisting pain in children with medical illnesses.

Strong recommendation, low quality of evidence

Domains and considerations

Quality of evidence

Although, no systematic reviews or randomized control trials were retrieved to guide determination of

the balance between the benefits and disadvantages of the use of strong opioids in children, the panel

considered indirect evidence from adult chronic non-cancer pain (71).

The panel noted the following statement, which supported the inclusion of morphine in the 2010

EMLc: “Morphine is the strong opioid of choice in moderate to severe pain in children and this is

confirmed by a number of consensus guidelines. There is extensive clinical experience of its use in

children and its use should be promoted to ensure adequate analgesia as necessary” (72).

Uncertainty: none.

Risks/benefits

Benefits

The efficacy of strong opioids in the relief of pain is well accepted. The panel noted, however, that

studies comparing opioids are possible in this age group provided that acceptable and appropriate trial

methodology is used.

Risks

Risks associated with severe side-effects and mortality arising from medication errors were considered

manageable, although more data on long-term use in children are necessary.

Uncertainty: none


28

Values and acceptability

In favour

The panel valued access to effective treatment of pain in children.

Against

None

Uncertainty: none.

Cost

Although access to strong opioids is variable, price is not generally a significant barrier for a number

of strong opioids.

Uncertainty: none.

Feasibility

Access to strong opioids for medical use remains a challenge worldwide. However, the rational use of

opioid analgesics in countries with limited financial and human resources is feasible and

recommended.

Uncertainty: none.

Policy agenda

Countries should review, and if necessary, revise their policies and regulations to ensure availability

and accessibility of opioid analgesics for the relief of moderate to severe pain in children as provided

for in the preamble of the Single Convention on Narcotic Drugs, 1961.

A2.2.4 Choice of strong opioids

Clinical question

In children with persisting pain due to medical illnesses, what is the evidence to support the use of

morphine as a gold standard for strong opioids as compared to the use of other strong opioids (in

particular fentanyl, hydromorphone, oxycodone and methadone) in order to achieve rapid, effective

and safe pain control?


29

Recommendations

5. Morphine is recommended as the first-line strong opioid for the treatment of persisting

moderate to severe pain in children with medical illnesses.

6. There is insufficient evidence to recommend any alternative opioid in preference to

morphine as the opioid of first choice.

7. Selection of alternative opioid analgesics to morphine should be guided by considerations

of safety, availability, cost and suitability, including patient-related factors.

Strong recommendations, low quality of evidence


Quality of evidence

The panel noted that morphine has been available for a considerable amount of time and that high

quality of evidence is unlikely to be available. The second recommendation was based on comparisons

between different opioids and routes of administration in acute pain and post-operative pain in

children. (Annex 4. Evidence retrieval and appraisal, GRADE tables 2–4, 6, 7). The assessed level of

quality of evidence was downgraded because of the differences in conditions treated and duration of

treatment.

Uncertainty: yes.

Risks/benefits

Benefits

Morphine is well established as first-line strong opioid.

Risks

Risks are well described and considered to be manageable.

Uncertainty: no, for the use of morphine as a first-line opioid analgesic; yes, in relation to the

comparative safety and efficacy of different opioids.


In favour

The panel valued access to effective treatment.

Against

None


30

Uncertainty: none.

Cost

Morphine is relatively inexpensive, although prolonged-release oral solid forms are more costly.

Uncertainty: none.

Feasibility

A wide range of morphine formulations have been already included in the 2010 EMLc:

granules, slow-release (to mix with water) – 20 mg, 30 mg, 60 mg, 100 mg, 200 mg

injection – 10 mg (morphine hydrochloride or morphine sulfate) in 1 ml ampoule

oral liquid – 10 mg (morphine hydrochloride or morphine sulfate)/5 ml

tablet – 10 mg (morphine sulfate)

tablet (prolonged release) – 10 mg, 30 mg, 60 mg, 100 mg, 200 mg (morphine sulfate).

Uncertainty: none.

Research agenda

Comparative trials of strong opioids, including fentanyl, hydromorphone, oxycodone and methadone,

in the treatment of persisting moderate to severe pain in children of all ages with medical illnesses are

needed. They should investigate effectiveness, side-effects and feasibility of use in this population.

Child appropriate oral solid dosage forms are needed.

A2.2.5 Prolonged-release versus immediate-release morphine

Clinical question

In children with persisting pain due to medical illnesses, should prolonged-release morphine be used

in preference to immediate-release morphine to achieve and maintain effective and safe pain control?

Recommendations

8. It is strongly recommended that immediate-release oral morphine formulations be available

for the treatment of persistent pain in children with medical illnesses.


31

9. It is also recommended that child-appropriate prolonged-release oral dosage forms be

available, if affordable.



Quality of evidence

There is insufficient evidence to support the use of prolonged-release over immediate-release

morphine as a sole agent. The only available evidence is in adults (Annex 4. Evidence retrieval and

appraisal, GRADE Table 10). The Cochrane review found that, in spite of the relevance of this

comparison, only 15 studies of 460 participants compared prolonged-release morphine preparations

with immediate-release morphine (115). None of the trials were large, having a median size of 27

participants (age range: 16–73). The results of these trials show that immediate-release and slow-

release morphine formulations are equivalent for pain relief. Approximately 6% of participants

(adults) in the studies who received morphine (any type) experienced intolerable adverse effects.

Uncertainty: yes, in relation to children since no studies are available in this age group.

Risks/benefits

Benefits

Immediate-release oral morphine needs to be administered more frequently, but it is always necessary

in the management of episodic or breakthrough pain.

Risks

Adherence to long-term treatment with immediate-release oral morphine may be problematic.

Uncertainty: none.


In favour

The panel valued access to immediate-release oral morphine and noted that commercially marketed

prolonged-release oral morphine formulations are sometimes the only products available for

procurement.

Against


32

None

Uncertainty: none.

Cost

Immediate-release oral morphine is relatively inexpensive but may not be commercially available in

all countries. Morphine powder for extemporaneous preparation may be available, but requires access

to pharmacists and suitable diluents, and its compounding may be subject to legal restrictions. The

stability of such preparations needs to be investigated.

Uncertainty: none.

Feasibility

No problem of feasibility, rather affordability for prolonged-release morphine formulation.

Uncertainty: none.

Research agenda

Research into appropriate formulations for the extemporaneous preparation of oral liquid morphine is

needed. Dissemination of available evidence on the preparation of stable extemporaneous formulations

is encouraged.

A2.2.6 Opioid rotation and opioid switching

Clinical question

In children with persisting pain due to medical illnesses, what is the evidence to support opioid

rotation policies to prevent dose escalation and side-effects?

Recommendations

10. Switching opioids and/or route of administration in children is strongly recommended in

the presence of inadequate analgesic effect with intolerable side-effects.

11. Alternative opioids and/or dosage forms as an alternative to oral morphine should be

available to practitioners, in addition to morphine, if possible.

12. Routine rotation of opioids is not recommended.



Quality of evidence


33

No systematic reviews or randomized control trials were found in children. A Cochrane Review

exclusively looked for and found no RCTs on opioid switching or rotation in adults and children.

Identified case reports, uncontrolled and retrospective studies were examined in order to determine the

current level of evidence (116). The review concluded that although for patients suffering chronic

cancer pain opioid switching may be the only option for enhancing pain relief and minimizing opioid

toxicity, there is a current lack of an evidence base for this therapeutic strategy. A systematic review

published in 2006 (117), identified one retrospective study of opioid switching in 22 children with

cancer pain. This review described a positive response to switching in patients intolerant to a particular

opioid, but noted that RCTs are lacking and that the observations were based on uncontrolled data.

Uncertainty: yes, in relation to the potential utility of rotation policies; no, in relation to switching of

opioid and/or route of administration in the presence of inadequate effect or intolerable side-effects.

Risks/benefits

Benefits

The panel placed a high value on effective use of adequate doses of the chosen opioid.

Risks

Risks are well described and considered to be manageable. Access to age-appropriate dose conversion

table for different opioids is necessary for safe switching.

Uncertainty: none.


In favour

The panel placed high value on treating rather than not treating pain and providing an alternative when

response is inadequate and side-effects are intolerable.

Against

None

Uncertainty: none.

Cost

Alternative opioids to morphine might be more expensive. However, there are regional variations in

costs and some alternatives to morphine may even be cheaper.

Uncertainty: none.


34

Feasibility

Access to an age-appropriate dose conversion table for different opioids is necessary for safe

switching.

Uncertainty: yes.

Policy and research agenda

The panel requests an update of the 2004 Cochrane review on opioid switching, including data from

children, if available. Opioid rotation policies lend themselves to investigation by prospective trials.

Such research is encouraged. Research on dose conversion in different age groups is necessary.


35

References

A morphine manifesto. J Pain Palliat Care Pharmacother. 2012 Jun;26(2):144-5.

British National Formulary for Children. British Medical Association and Royal

Pharmaceutical Society. 2011.

British Pharmacopoeia. British Pharmacopoeia Secretariat of the Medicines and Healthcare

products Regulatory Agency. 2012.

CDC (2011) Vital Signs: Overdoses of Prescription Opioid Pain Relievers --- United States,

1999—2008. Morbidity and Mortality Weekly. 60(43);1487-1492, Available at:

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6043a4.htm?s_cid=mm6043a4_w

Accessed Jul 2, 2012

CDC (2012) CDC Grand Rounds: Prescription Drug Overdoses — a U.S. Epidemic

61(01);10-13. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm

accessed July 2, 2012

Declaration of Montréal, Declaration that Access to Pain Management Is a Fundamental

Human Right, Montreal, 2011. Accessible at: http://www.iasp-

pain.org/Content/NavigationMenu/Advocacy/DeclarationofMontr233al/default.htm

(Accessed at 13 September 2012).

Kate M. Dunn, PhD; Kathleen W. Saunders, JD; Carolyn M. Rutter, et al. Opioid

Prescriptions for Chronic Pain and Overdose A Cohort Study Ann Intern Med. 2010;152:85-

92.

Ensuring Balance in National Policies on Controlled Substances, guidance for availability and

accessibility of controlled medicines. World Health Organization. Geneva 2011. ISBN 978 92

4 156417 5. Accessible at:

http://whqlibdoc.who.int/publications/2011/9789241564175_eng.pdf

Foley KM, Wagner JL, Joranson DE, Gelband H. Pain control for people with cancer and

AIDS. In: Disease Control Priorities in Developing Countries. 2nd ed. 981- 994. New York:

Oxford University Press; Disease Control Priorities in Developing Countries, KM Foley, JL

Wagner, DE Joranson, Eds, 2006;981–994. Available at:

http://files.dcp2.org/pdf/DCP/DCP52.pdf . (Accessed May 2007).

Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical

overdose fatalities. JAMA 2008;300:2613–20.

Inciardi JA et al. Mechanisms of prescription drug diversion among drug-involved club and

street based populations. Pain Med 2007;8(2):171-183. doi:10.1111/j.1526-

4637.2006.00255.x

http://www.ncbi.nlm.nih.gov/pubmed?term=morphine%20manifesto

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm

http://www.iasp-pain.org/Content/NavigationMenu/Advocacy/DeclarationofMontr233al/default.htm



http://files.dcp2.org/pdf/DCP/DCP52.pdf


36

Inciardi JA et al. Diversion of prescription drugs by health workers in Cincinnati Ohio, in

Subst Use Misuse 2006;41(2):255-264. doi: 10.1080/10826080500391829

International Nonproprietary Names (INN) for Pharmaceutical Substances, Lists 1-90 of

Proposed INN and Lists 1-51 of Recommended INN Cumulative List No.11, World Health

Organization, Geneva, 2004.

Martindale, The Complete Drug Reference, 32nd Ed., the Pharmaceutical Press, London,

1999.

Milani B, Scholten W, Access to Controlled Medicines. In: The World Medicines Situation

2011, 3rd Edition, World Health Organization, Geneva 2011 (Chapter released April 2011).

Accessible at:

http://www.who.int/entity/medicines/areas/policy/world_medicines_situation/WMS_ch19_w

Access.pdf

Minozzi S, Amato L, Vecchi S, Davoli M. Systematic review on dependence following

treatment with opioid analgesics for pain relief. Submitted for publication.

Multilingual dictionary of narcotic drugs, United Nations, New York, 1993. ISBN 92-1-

048056-2.

Niikura K et al. Neuropathic and chronic pain stimuli downregulate central micro -opioid and

dopaminergic transmission. Trends in Pharmacol Sciences, 2010, 31:299-305.

Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic non-

cancer pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom

Manage. 2008;35(2):214-228.

Report of the International Narcotics Control Board on the Availability of Internationally

Controlled Drugs: Ensuring Adequate Access for Medical and Scientific Purposes. New

York, 2011, E/INCB/2010/1/Supp.1, ISBN: 978-92-1-148260-7

http://www.incb.org/pdf/annual-report/2010/en/supp/AR10_Supp_E.pdf

Resolution WHA58.22. Cancer prevention and control. In: Fifty-eighth World Health

Assembly, Geneva, 25 May 2005. A copy of the resolution can be found in:

http://www.who.int/entity/medicines/areas/quality_safety/Framework_ACMP_withcover.pdf

Scholten W. Pediatric morphine dosages. WHO Pharmaceuticals Newsletter. 4; 2012: 26-28.

http://www.who.int/entity/medicines/publications/PharmNewsletter4_12/en/index.html

Seya MJ, Gelders SFAM, Achara UA, Milani B, Scholten WK. A First Comparison between

the Consumption of and the Need for Opioid Analgesics at Country, Regional and Global

Level. J Pain and Palliative Care Pharmacotherapy, 2011; 25: 6-18. Accessible at:

http://informahealthcare.com/doi/pdf/10.3109/15360288.2010.536307

http://www.who.int/entity/medicines/areas/policy/world_medicines_situation/WMS_ch19_wAccess.pdf







37

Substance Abuse and Mental Health Services Administration (SAMSHA), Results from the

2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH

Series H-41, HHS Publication No. (SMA) 11-4658. Rockville, MD: Substance Abuse and

Mental Health Services Administration, 2011. Accessible at :

http://oas.samhsa.gov/NSDUH/2k10NSDUH/2k10Results.pdf

The International Pharmacopoeia, Fourth Edition. World Health Organization. 2011. US

Pharmacopeia, www.usnpf.com


illnesses. World Health Organization. 2012.

http://whqlibdoc.who.int/publications/2012/9789241548120_Guidelines.pdf

World Cancer Declaration. Clin J Oncol Nurs. 2006 Dec;10(6):721-2.


http://www.usnpf.com/


38

Annex 2: application on hydromorphone of 21 September 2012, to the

19th Expert Committee on the Selection and Use of Essential Medicines

Application to add hydromorphone to the

Essential Medicines List for Children

Summary statement of the proposal for inclusion Pain in children is a public health concern of major significance in most parts of the world.

Although the means and knowledge to relieve pain exists, children’s pain is often not recognized, is

ignored, or even denied. It is important that adequate access to appropriate opioid medicines be

available for the treatment of moderate to severe persisting pain in children worldwide.

To align the Essential Medicine List for Children (EMLc) with the recently published WHO

guidelines on the pharmacological treatment of persisting pain in children with medical illnesses

[WHO pediatric pain guidelines, 2012: p.78– further referred to as “Guidelines”], it is necessary to add

more opioids to the EMLc. The Guidelines state that if pain severity associated with a medical illness

is assessed as moderate or severe, the administration of a strong opioid is necessary. In that case

morphine is the medicine of choice, although other strong opioids should be considered and made

available to ensure an alternative to morphine in case of intolerable side-effects. It is advised that two

or more strong opioids should be available for this purpose, and hydromorphone is one such strong

opioid. Thus, it is requested that hydromorphone be added to the EMLc as an example of the opioid

class. Accordingly, it is necessary to add the hydromorphone monograph in the Model Formulary in

accordance to the aforementioned Guidelines.

With this application, we request:

1. Addition of hydromorphone as an example of the opioid class to the EMLc8

2. Addition of a monograph on hydromorphone in the WHO Formulary for children

This application is part of a series of three applications:

- Application to add certain morphine formulations to the Essential Medicines List for Children;

8 Two or more alternatives to morphine should be available and this should be expressed in the EMLc, for

example as a footnote to the square box.


39

- Application to add oxycodone to the Essential Medicines List for Children; and

- Application to add hydromorphone to the Essential Medicines List for Children.

Name of the focal point in WHO submitting or supporting the application

Dr. Willem Scholten, Team Leader, Access to Controlled Medicines, Medicines Access and

Rational Use, Department of Essential Medicines and Pharmaceutical Policies, World Health

Organization, Geneva, Switzerland. Email address:

[email protected]. (until 31 October 2012)

[email protected] (from 1 November 2012)

Name of the organizations consulted and/or supporting the application

Members of the Guidelines Development Group for the WHO guidelines on the

pharmacological treatment of persisting pain in children with medical illnesses reviewed the draft

proposal and support it: Dr Allen Finley, Chair of the GDG and Dr John Collins, Member.

International Nonproprietary Name of the medicine Hydromorphone INN [INN Cumulative List, 2004]

Formulations proposed for inclusion, including a proposal for a monograph in the WHO Model Formulary for children

Preparations to be added to the EMLc

In order to provide adequate pain treatment for persisting pain in children, it is required that

the following formulations of hydromorphone be added to the Essential Medicine List for Children,

under section 2.2 Opioid Analgesics:

a. Injection (as hydrochloride):

1 mg in 1 ml ampoule,



10 mg in 1 ml ampoule

b. Tablet: 2 mg, 4 mg, 8 mg (as hydrochloride).

c. Oral liquid: 1 mg (as hydrochloride)/ml.


40

These preparations should be equally added to the palliative care section of the EMLc.

Rationale for these strengths and dosage forms

Introduction

The WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with

Medical Illnesses identify four key concepts for the correct use of analgesic medicines and three of

these concepts affect the need and selection for hydromorphone preparations [Guidelines, 2012: pages

38–40]:

• dosing at regular intervals (“by the clock”)

• using the appropriate route of administration (“by the mouth”)

• tailoring treatment to the individual child (“by the individual”).

In relation to this, the WHO Guidelines on the Pharmacological Treatment of Persisting Pain

in Children strongly recommend switching opioids (and/or route of administration) in children in

thepresence of inadequate analgesic effect with intolerable side-effects. [Guidelines, 2012: Guidelines

10, p. 44] and alternative opioids and/or dosage forms as an alternative to oral morphine should be

available to practitioners, in addition to morphine, if possible. [Guidelines, 2012: Guidelines 11, p. 44;

both slow-release and immediate-release preparations should be available [Guidelines, 2012:

Guideline 8, p. 43; Guideline 9, p. 43 ]; and oral administration of opioids is the recommended route

of administration. [Guidelines, 2012: Guideline 13, p. 45]. Therefore, the availability of a full range of

preparations is essential.

Need for a range of strengths of injections

The subcutaneous route (via continuous infusion or intermittent bolus through an indwelling

catheter) is widely used and could be a valuable alternative to oral dosages. It is essential that

hydromorphone, injection formulation, be available for the adequate treatment of persisting pain in

children. Hydromorphone, is more widely available for parenteral administration than oxycodone.

In addition to the more common or traditional ways of administering, patient-controlled

analgesia (PCA) is a possible approach to intravenous or subcutaneous administration. It allows

children from approximately the age of seven to self-administer "rescue" doses of analgesics for

breakthrough pain. A pre-set dose is delivered into an infusion line by a computer-driven pump. For

safety, there is a limited lock-out period after each dose so that additional doses cannot be delivered

before a specified time has elapsed. Patient-controlled analgesia may be used alone or with concurrent

continuous infusions. It should be noted that PCA techniques might require access to expensive

equipment.

Need for a range of strengths of immediate release tablets


41

To obtain a dose that provides adequate relief of pain with an acceptable degree of side-

effects the doses of hydrocodone or other strong opioids need to be gradually increased until

effective. Unlike paracetamol and NSAIDs, there is no upper dosage limit for opioid

analgesics because there is no "ceiling" analgesic effect. The appropriate dose is the dose that

produces pain relief for the individual child. The goal of titration to pain relief is to select a

dose that prevents the child from experiencing pain between two doses using the lowest

effective dose. This is best achieved by frequent assessment of the child’s pain relief

response and adjusting the analgesic doses as necessary.

The opioid dose that effectively relieves pain varies widely between children, and in the

same child at different times, and should, therefore, be based on the child's pain severity

assessment. Large opioid doses given at frequent intervals may be necessary to control pain in

some children; these doses may be regarded as appropriate, provided that the side-effects are

minimal or can be managed with other medicines. Therefore, a range of strengths of

hydromorphone, as an example of an alternative to morphine, should be added to the EMLc.

[WHO guidelines, p.47]

Need for liquid formulation

The oral administration is the preferred route of administration. Older children may be able to

swallow regular or slow-release oxycodone tablets/capsules, but young children and infants may only

be able to use liquid formulations of hydromorphone.

Relation to the application for oxycodone

For patients who do not react well to morphine, the guidelines require that two or more

alternatives to morphine are available. While morphine has a very wide range of preparations

for both oral and parenteral administration and for immediate-release and slow-release, this is

not the case for all other strong opioids. Therefore, oxycodon and hydromorphone were

selected as together they have a wider range of administration forms readily available:

injections, tablets, slow-release tablets, capsules and oral liquid are all covered by this

selection.

Why other strong opioids from the guidelines are not selected to serve as the example of a the

class of strong opioids alternative to morphine

Fentanyl: fentanyl may be expensive in some countries and lozenges may be suitable

for breakthrough pain, but less suitable for titrating. Therefore, the range of dosage forms as a

whole may be less suitable than for oxycodone and hydromorphone.

Methadone: the long half-life of methadone makes it more difficult to dose.


42

International availability - sources, manufacturers and trade names Hydromorphone hydrochloride as a starting material is out of patent. Hydromorphone tablets,

injections and oral solution are available for purchase in a number of countries.

Trade names

Dilaudid, Palladone, Hydrostat IR and several other brand names [Martindale 32nd Ed.,

1999];

Algiacton, Assilaudid, Biomorfil, Cofalaudid Cormorphina, Dihydromorfon, Dilauden,

Dilocol, Dimorfona, Dimorphid, Dimorphisid, Escolaudol, Hymorphan, Imorphan Laudacon,

Laudadin, Laudakon, Lucodan, Morficon, Norlaudon, Novelaudon, Percoral, Procorman, Scolaudol,

Semcox and varieties and several other brand names [Multilingual dictionary of narcotic drugs, 1993];

Dilaudid, Dimorphone, Hydal, Hydromorfan, Hymorphan, Hydrostat, Laudicon, Opidol,

Palladone, Sophidone LP [Wikipedia, accessed 13 September 2012].

Preparations and manufacturers in some countries

(Dosage forms and strengths as included in this application only)

Germany9

Dilaudid injection 2 mg, Mundipharma GmbH

Palladon® injekt 2 mg, Mundipharma GmbH

Palladon® injekt 10 mg, Mundipharma GmbH

The Netherlands10

Palladon injection 2 mg/ml, 1 ml, solution for injection or infusion, Mundipharma Pharmaceuticals

B.V.

Palladon injection 10 mg/ml, 1 ml, solution for injection or infusion, Mundipharma Pharmaceuticals

B.V.

Switzerland11

Hydromorphoni HCl Steurli, Oral Solution 1mg/ml, 50 ml, Streuli Pharma AG Pharmazeutika

9 Bfarm Database: http://www.bfarm.de/DE/Arzneimittel/3_nachDerZulassung/zugel_AM/zugel_AM-node.html 10 Dutch Medicines Evaluation Board database. www.cbg-meb.nl 11 Official Swiss Price List at http://bag.e-mediat.net/SL2007.Web.External/Default.aspx?webgrab=ignore

http://www.cbg-meb.nl/



43

USA12

Dilaudid Injection, 1 ml ampoules (1mg/ml), Purdue Pharma

Hydromorphone Hydrochloride Injection 1mg/ml, Hospira

Dilaudid Injection, 1 ml ampoules (2mg/ml), Purdue Pharma


Dilaudid Injection, 1 ml ampoules (4mg/ml) Purdue Pharma,


Dilaudid Injection, 1 ml ampoule (10mg/ml), Purdue Pharma


Hydromorphone Hydrochloride Injection 10mg/ml, Barr

Hydromorphone Hydrochloride Injection 10mg/ml, Akorn

Dilaudid tablets, 2mg, Purdue Pharma

Hydromorphone Hydrochloride Tablets USP, 2 mg, Mallinckrodt Inc.

Hydromorphone Hydrochloride Tablets USP, 2 mg, Lannet


Hydromorphone Hydrochloride Tablets USP, 4 mg, Mallinckrodt Inc.




Hydromorphone Hydrochloride Tablets USP, 8 mg, Elite Labs

Hydromorphone Hydrochloride Tablets USP, 8 mg, Tagi Pharma

Dilaudid Oral Solution, 5mg/5ml, Purdue Pharma,

Hydromorphone Hydrochloride Oral Solution, 5mg/5ml, Roxane

It should be noted from this listing that also in industrialized countries the availability of

appropriate paediatric formulations for immediate release is often deficient.

12 FDA Database: http://www.fda.gov/NewsEvents/ProductsApprovals/default.htm


44

Whether listing is requested as an individual medicine or as an

example of a therapeutic group

Listing is requested as an example of a therapeutic group. According to the Guidelines,

“alternative opioids” (i.e. two or more alternatives) to morphine should be available and this should be

expressed in the EMLc, for example as a footnote to the square box. [Guidelines, 2012: p. 44] The

footnote could read “Examples for alternative opioids for morphine. Two or more alternatives should

be available in addition to morphine.”

Information supporting the public health relevance

From a public-health perspective, currently many patients are without access to essential

medicines for pain. WHO policies recommend, and international drug conventions require, that

countries make medicines controlled under these conventions readily available to those in need.

Opioid analgesics like morphine, hydrocodone and oxycodone are among these controlled medicines.

The World Health Organization has a policy to promote the availability of strong opioids in

countries whose policies or legislation unduly does not allow access or availability to strong opioids

[Ensuring balance, p.5]. Inclusion in the EMLc is essential for enhancing this policy.

It has been well documented that in most countries of the world, patients do not have adequate

access to opioid analgesics. The various barriers are described in the World Medicines Report [Milani

B and Scholten W, 2011] and in the WHO policy guidelines Ensuring Balance in National Policies

on Controlled Substances, Accessibility and Availability of Controlled Medicines. [Ensuring balance,

2011: p.5] Legal and policy barriers are important reasons why these medicines are not available in

many countries. Seya et al. estimate that in 2006 only 464 million people had adequate access to

opioid analgesics, and 4.7 billion people had virtually no access [Seya et al, 2011].

The World Health Assembly in its resolution 58.22 “On Cancer prevention and control”

(2005), called on WHO to address access to opioid analgesics [Resolution WHA 58.22, 2005]. Other

international bodies such as the International Narcotics Control Board (e.g. in a special report on the

availability of internationally controlled drugs) [Report of the INCB, 2011] and the UN Commission

on Narcotic Drugs, have called for greater access for patients to these medicines.

In addition, the International Association for the Study of Pain adopted the Declaration of

Montreal, the Union for International Cancer Control published the World Cancer Declaration and a


45

consortium of 60 international and national organizations initiated by Pallium India launched the

Morphine Manifesto. [Declaration of Montreal, 2011; World Cancer Declaration, 2006; a Morphine

Manifesto, 2012] All these declarations call for adequate access to pain medicines and treatment of

pain worldwide.

Treatment

The treatment recommended by the World Health Organization is published in the WHO

Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses.

These guidelines address the pharmacological management of persisting pain in children with medical

illnesses. As such, they replace the previous guidelines, Cancer pain relief and palliative care in

children, which exclusively covered cancer pain. [Guidelines, 2012: p. 10]. Treatment details in this

application are based on the Guidelines on the Pharmacological Treatment of Persisting Pain in

Children.

For the treatment of pain, no special diagnostics are needed, nor any technical monitoring

facilities. Although in certain stages of treatment monitoring of the patient is necessary, this refers to

clinical monitoring which could include phone calls or home visits to check on progress, dose

tracking, or pulse oximetry and respiratory monitoring in hospital, depending on circumstances. In

(very) rare circumstances it might include urine drug testing.

The treatment of pain requires to be preceded by and go together with a regular assessment of

the pain with simple pain scales, such as the FPS-R scales. Methods are described in Chapter 2,

Evaluation of persisting pain in the paediatric population, of the guidelines. [Guidelines, 2012: p. 26-

35]

Treatment recommendations

Dosage:


Oral (using immediate-release formulations):

child – initially 30 – 80 mcg/kg per dose (maximum 2 mg per dose) every 3–4

hours.

Subcutaneous or intravenous:

child – initially 15 mcg/kg per dose slowly over at least 2–3 minutes every 3–6

hours.

Continuation: after a starting dose according to the dosages above, the dosage

should be adjusted to the level that is effective (with no maximum), but the

maximum dosage increase is 50% per 24 hours in outpatient settings. Experienced

prescribers can increase up to 100% with close monitoring of the patient.


46

The WHO guidelines on the pharmacological treatment of persisting pain in children are

evidenced based guidelines, produced using the methods prescribed actually for WHO treatment

guidelines. Hydromorphone is considered an example of a strong opioid, as an alternative to

morphine, for moderate to severe persisting pain in children. Two or more alternatives to morphine

should be available and this should be expressed in the EMLc, for example as a footnote to the square

box.

The guidelines provide the evidence for its recommendations in a number of GRADE tables

[WHO guidelines, 2012: p.104 ] and the further justification for each recommendation is provided in

an annex [WHO guidelines, 2012: p.82]. The guidelines also concluded that more research is needed

in order to answer specific questions. The guidelines are based on the best knowledge currently

available. See Annex 1 and 2 of the application for detailed information regarding the

recommendations in the guidelines. Annex 1 contains GRADE tables regarding morphine and Annex

2 contains background information for the recommendations. (Please also refer to the GRADE Tables

in the parallel applications on morphine and oxycodone preparations.)

According to the WHO guidelines on the pharmacological treatment of persisting pain in

children with medical illnesses, the oral formulation of hydromorphone is initially dosed at 30-80

mcg/kg every 3-4 hours for children. The subcutaneous or intravenous formulation of hydromorphone

is initially dosed at 15 mcg/kg over at least 2-3 minutes every 3-6 hours in children. After the

appropriate starting dose, the dosage should be adjusted on an individual basis to the level that it is

effective (with no maximum dose, unless further increase is not possible because of untreatable side-

effects). The maximum dosage increase is 50% per 24 hours in outpatient settings. Experienced

prescribers can increase up to 100% while monitoring the patient carefully. Common adverse effects

of hydromorphone include nausea, vomiting, constipation, dry mouth, sedation, biliary spasm,

respiratory depression, muscle rigidity, apnoea, myoclonic movements, asthenia, dizziness, confusion,

dysphoria, euphoria, lightheadedness, pruritus, rash, somnolence, and sweating. Uncommon adverse

effects include hypotension, hypertension, bradycardia, tachycardia, palpitation, oedema, postural

hypotension, miosis, visual disturbances, abdominal cramps, anorexia, paraesthesia, malaise, agitation,

tremor, muscle weakness, hallucinations, vertigo, mood changes, dependence, drowsiness, anxiety,

sleep disturbances, headache, taste disturbance, agitation, urinary retention, laryngospasm, and

bronchospasm. Rare adverse effects include circulatory depression, cardiac arrest, respiratory arrest,

shock, paralytic ileus, and seizures. However, if titrated correctly, most side effects can be avoided.

Opioid weaning can be done safely without posing significant health risk to the patient. From

the medical standpoint, weaning opioids should be done slowly by tapering the opioid dose. For short-

term therapy (7–14 days), the original dose can be decreased by 10–20% of the original dose every 8

hours, increasing gradually the time interval. In the case of a long-term therapy protocol, the dose

should be reduced not more than 10-20% per week. These pharmacological approaches should be


47

accompanied by measurement of withdrawal symptoms using a scoring system [WHO guidelines,

p.47].

The Guidelines Development Group on the WHO guidelines on the pharmacological

treatment of persisting pain in children considered the lack of instruction on how to titrate and how to

wean patients on opioids is considered a hazard. [Scholten W, 2012 ] Therefore this information is

considered essential for the Formulary monograph. There is a need for comparative trials of opioids in

terms of effectiveness, side-effects and feasibility of use in children with persisting pain due to

medical illnesses. Hydromorphone is considered an example of a strong opioid choice, as an

alternative to morphine, for moderate to severe persisting pain in children. Two or more alternatives

to morphine should be available and this should be expressed in the EMLc, for example as a footnote

to the square box.

The experts considered dosages recommended elsewhere as not deprived of risk. Also the

lack of instruction on how to titrate and how to wean patients on opioids is considered a hazard.

Therefore this information is considered essential for the Formulary monograph. There is a need for

comparative trials of opioids in terms of effectiveness, side-effects and feasibility of use in children

with persisting pain due to medical illnesses.

Summary of comparative effectiveness in a variety of clinical settings

The guidelines provide the evidence for its recommendations in a number of GRADE tables

[WHO guidelines, 2012: p.104 ] and the further justification for each recommendation is provided in

an annex [WHO guidelines, 2012: p.82]. The guidelines also concluded that more research is needed

in order to answer specific questions. The guidelines are based on the best knowledge currently

available. See Annex 1 and 2 of the application for detailed information regarding the

recommendations in the guidelines. Annex 1 contains GRADE tables regarding morphine and Annex

2 contains background information for the recommendations. (Please also refer to the GRADE Tables

in the parallel applications on morphine and oxycodone preparations.)

For clinical data please refer to Annexes 1 and 2.

Summary of comparative evidence on safety

5. Estimate of total patient exposure to date Hydromorphone has been used as an analgesic since 1926. Since, it has been used in innumerous

patients and it has been shown to be a safe medicine if used correctly. In 2006 the world used 10.2

tonnes hydrocodone or 510 million DDDs. [Seya et al., unpublished data] The annual consumption by


48

country can be roughly derived from the status of estimates as published by the International Narcotics

Control Board at http://www.incb.org/incb/narcotic_drugs_estimates.html.

6. Description of adverse effects/reactions Adverse effects:












ileus, seizures.



hydromorphone;



preparations;


opioids;




symptoms.

* Indicates severe.

7. Identification of variation in safety due to health systems and patient factors Inter-individual differences exist. Like for other opioid analgesics, the dosage level for

hydrocodone needs to be established on an individual base [WHO guidelines, 2012: p. 37], guided by

the outcome of regular pain assessment. Provided that hydrocodone is prescribed when indicated, and

titrated and weaned according to the guidelines, it has shown to be a safe medicine.

Development of dependence on medical treatment is not well documented and it is assumed that

the risk is very limited [Noble, 2008; Minozzi, submitted] and this risk is not a reason not to treat

when indicated.[Minozzi, submitted] On theoretical grounds, it is likely that pain patients are less

susceptible to opioid dependence than other people. [Niikura, 2010]

There are well-described problems with over-prescribing and diversion in a limited number of

countries, although these studies are related to prescription to adults and not to children. Non-medical

http://www.incb.org/incb/narcotic_drugs_estimates.html


49

use carries substantial risks, including overdose and mortality. It should be noted that the extensively

reported increase in consumption in the United States has been accompanied by a notable increase in

overdose deaths involving prescription opioids [CDC,2011; CDC, 2012]. While there are insufficient

data available to quantify the amounts diverted to non-medical use from various parts of the drug

distribution system, it appears there is significant theft, fraud and other unlawful conduct [Inciardi JA

et al. 2006a; Inciardi JA et al., 2006

b]. A national population-based survey in the United States found

that over 70% of those who have reported using opioids non-medically admitted that they obtained the

drug for free from friends or family members or through theft or purchase [SAMSHA, 2011]. Large

quantities of prescription opioids have been sold by illegitimate pain clinics and overdose has occurred

predominantly in persons obtaining opioids from non-medical sources [CDC, 2011]. In a study of

unintentional overdose fatalities in West Virginia, 63.1% of the decedents had used pharmaceuticals

with no documented prescriptions, and 55.6% of the decedents were never prescribed opioid

analgesics. In addition, 79.3% of the decedents has used multiple substances, both illicit and

prescription drugs (“polydrug use”), which might have contributed to their death, and 21.4 % of the

decedents had controlled medicines prescribed by multiple physicians (“doctor shopping”) [Hall AJ et

al., 2008]. This study did not determine, however, whether decedents from the latter group were ‘real’

pain patients, or people seeking drugs for illicit purposes. Another American study, describing 9940

cases of overdose deaths, found 51 cases to whom dosages of 100 mg/day or higher of morphine

equivalents were prescribed during the first three months of a prescription episode, showing an

increased risk for this group [Dunn KM et al., 2010].

In conclusion, although there is no doubt that some, albeit unknown, level of opioid agonist

prescribing and dispensing to pain patients contributes to morbidity and mortality in the USA, many if

not most of these tragedies appear to involve opioids that have been diverted or obtained through

unlawful activities, including those of non-patients.

8. Summary of comparative safety against comparators Opioids are the only class of medicines effective for moderate and severe pain, and therefore,

there are no comparators outside the class. Within the class of opioid analgesics, there are no

outspoken differences in safety with the exception of methadone, because of its kinetics.

Summary of available data on comparative cost and cost-effectiveness

within the pharmacological class or therapeutic group

3. Range of costs of the proposed medicine The cost of 1 ampoule of 2mg/ml, 1 ml is € 1.93 (US$ 2.49); that of an ampoule 10mg/ml, 1ml is

€ 9.67 (US$ 12.51) in the Netherlands. The cost of 50ml oral solution 1mg/ml is in Switzerland Sfr

34,50 (USD 36.95).13

13 The price level for Switzerland as per 1 September 2012; for the Netherlands as per September 2012; exchange rates as per 13 September 2012. Sources: Official Swiss Price List at http://bag.e-



50

4. Comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality adjusted life year gained)

There is no standard dosage for hydromorphone for adult patients and therefore it is even more

difficult to define a standard dosage for a child. The wide variability of prices around the world further

confuses the picture. Foley et al. found that the average terminal cancer patient needs 75 mg morphine

a day during the last three months of his or her life. [Foley, 2006] This corresponds with a dosage of

approximately 5 mg hydromorphone per day orally (or 2.5 mg per day parenterally) for the treatment

of a ten year old child with comparable pain.

If treated with oral solution at the price in Switzerland, one day of treatment costs US$ 3.96; if

treated parenterally, at the Dutch price level, the daily cost ranges from US$ 2.99-3.15.

As the Swiss price level for medicines is known to be high, the Swiss prices should be regarded as

the upper end of the price range. Among European countries, the Netherlands has relatively low

medicines prices.

Summary of regulatory status of the medicine in several countries Hydrocodone was first marketed in Germany in 1926. Currently, it is on the market in Germany,

the Netherlands, the United States of America and many other countries, but often in limited ranges of

dosage forms and strengths.

Hydrocodone is subject to international control under the Single Convention on Narcotic Drugs,

1961. For enabling good access in all countries, the World Health Organization published the policy

guidelines Ensuring Balance in National Policies on Controlled Substances, guidance for availability

and accessibility of controlled medicines in 2011 [Ensuring Balance, p.4].

Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia)

The International Pharmacopoeia, the British Pharmacopoeia and the Unites States

Pharmacopoeia all contain monographs for hydromorphone hydrochloride. [The International

Pharmacopoeia, 2011, CD-version; British Pharmacopoeia, 2012, p. 10916; United States


mediat.net/SL2007.Web.External/Default.aspx?webgrab=ignore ; College voor Zorgverzekeringen, www.medicijnkosten.nl.


http://www.medicijnkosten.nl/


51

In addition, the United States Pharmacopoeia has monographs onHydromorphone

Hydrochloride oral solution and Hydromorphone Hydrochloride Tablets. [United States


Proposed new text for the WHO Model Formulary The publication of the WHO Guidelines on the pharmacological treatment of persisting pain

in children entails also a pharmaceutical profile on hydromorphone, following the monograph format

of the WHO Formulary for children. The profile contains updated dosage schedules and instruction for

titrating the patient to adequate pain management and for weaning opioids. A proposed text is

provided below.14

Hydromorphone

ATC Code: N02AA03

Injection: 1 mg in 1 ml ampoule, 2 mg in 1 ml ampoule, 4 mg in 1 ml ampoule, 10 mg in 1

ml ampoule (as hydrochloride).

Tablet: 2 mg, 4 mg, 8 mg (as hydrochloride). Oral liquid: 1 mg (as hydrochloride)/ml.

Indications: moderate to severe persisting pain.

Contraindications: hypersensitivity to opioid agonists or to any component of the formulation;

acute respiratory depression; acute asthma; paralytic ileus; concomitant use of, or use within 14

days after ending monoamine oxidase inhibitors; raised intracranial pressure and/or head

injury, if ventilation not controlled; coma; use within 24 hours before or after surgery.

Precautions: impaired respiratory function; avoid rapid injection which may precipitate chest

wall rigidity and difficulty with ventilation; bradycardia; asthma; hypotension; shock;

obstructive or inflammatory bowel disorders; biliary tract disease; convulsive disorders;

hypothyroidism; adrenocortical insufficiency; avoid abrupt withdrawal after prolonged

treatment; diabetes mellitus; impaired consciousness; acute pancreatitis; myasthenia gravis;

hepatic impairment; renal impairment; toxic psychosis.

Skilled tasks: warn the patient or caregiver about the risk of undertaking tasks

requiring attention or coordination, for example, riding a bike.

Dosage:


Oral (using immediate-release formulations):

14 Proposed monograph identical to the monograph in the WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children (page 66 - 68),


52

child – initially 30 – 80 mcg/kg per dose (maximum 2 mg per dose) every 3–4

hours.

Subcutaneous or intravenous:

child – initially 15 mcg/kg per dose slowly over at least 2–3 minutes every 3–6

hours.

Continuation: after a starting dose according to the dosages above, the dosage

should be adjusted to the level that is effective (with no maximum), but the

maximum dosage increase is 50% per 24 hours in outpatient settings. Experienced

prescribers can increase up to 100% with close monitoring of the patient.

Dosage discontinuation: after short-term therapy (7–14 days), the original dose can be

decreased by 10–20% of the original dose every 8 hours, increasing gradually the time

interval. After long-term therapy, the dose should be reduced not more than 10–20%

per week (79,80).

Renal impairment: moderate (GFR 10–20ml/min or serum creatinine 300–700 micromol/l)

and severe (GFR <10ml/min or serum creatinine >700 micromol/l) – reduce dose, start with

lowest dose and titrate according to response.

Hepatic impairment: use with caution and reduce initial dose in all degrees of

impairment.

Adverse effects:












ileus, seizures.



hydromorphone;



preparations;


opioids;



53



symptoms.

* Indicates severe.

Notes:

Hydromorphone is subject to international control under the Single Convention on

Narcotic Drugs, 1961.

Hydromorphone is a potent opioid and significant differences exist between oral and

intravenous dosing. Use extreme caution when converting from one route to another.

Give with food or milk to decrease gastrointestinal upset.

Extended-release preparations are available; however, these are not indicated for use

in the paediatric setting.

Naloxone is used as an antidote in case of opioid overdose.

Equianalgesic doses:

Hydromorphone - morphine vice versa

According to manufacturers, oral hydromorphone is 7.5 times more potent than

morphine; however, when switching from morphine to hydromorphone, some suggest

the ratio is 5:1 (i.e. the dose of hydromorphone should be 1/5 of the morphine dose), and

when switching from hydromorphone to morphine a ratio of 1:4 should be used (i.e. the

morphine dose should be 4 times the hydromorphone dose).

Parenteral hydromorphone to oral hydromorphone

If switching from parenteral to oral hydromorphone, oral doses are less than one-half as

effective as parenteral doses (may only be 1/5 as effective). Doses may need to be titrated

up to 5 times the IV dose.

References: Ashley C, Currie A, eds. The renal drug handbook, 3rd ed. Oxford, Radcliffe Publishing, 2009.

Drugdex in Micromedex Healthcare Series [online database]. New York, NY, Thomson Reuters,

1974–2010 (http://micromedex.hcn.net.au/mdx-full/, accessed 6 August 2011).

Hodding JH, Kraus DM, Taketomo CK. Pediatric dosage handbook, 16th ed. Hudson, OH, Lexicomp,

2009.

MIMS [online database]. Sydney, UBM Medica, 2009

(http://www.mimsonline.com.au/Search/Search.aspx, accessed 10 February 2011).

Paediatric Formulary Committee. British national formulary for children 2009. London, BMJ Group

RBS Publishing, 2009.

World Health Organization, WHO guidelines on the pharmacological treatment of persisting pain in

children with medical illnesses. World Health Organization, Geneva, 2012. ISBN 978 92 4 154812

0. Accessible at: http://whqlibdoc.who.int/publications/2012/9789241548120_Guidelines.pdf

http://micromedex.hcn.net.au/mdx-full/


54

[End of proposed revised text for the WHO Model Formulary]

Acknowledgements We acknowledge Mrs Margarette Kading for the initial drafting of this application and Dr

Catherine Parmiter-Dreiza for converting it into a first draft following the WHO EML application

format as published in May 2012.


55

Annex 1: Pertinent GRADE Tables

Pertinent parts from the WHO guidelines on the pharmacological treatment of persisting pain in

children with medical illnesses, pages 107 and 110.


56


57

Annex 2: Background to the clinical recommendations Source: Pertinent parts from the WHO guidelines on the pharmacological treatment of persisting pain

in children with medical illnesses, pages 87-92.

A2.2.3 Strong opioids essential in pain treatment

Clinical question

In children with persisting pain due to medical illnesses, what are the benefits as compared to the risks

(hastening death, developing dependence, respiratory depression, influencing the child's development)

of taking regular or intermittent morphine for pain control as compared with a similar group of

patients with persisting pain not taking any opioid analgesics?

Recommendation

4. The use of strong opioid analgesics is recommended for the relief of moderate to severe

persisting pain in children with medical illnesses.

Strong recommendation, low quality of evidence


Quality of evidence

Although, no systematic reviews or randomized control trials were retrieved to guide determination of

the balance between the benefits and disadvantages of the use of strong opioids in children, the panel

considered indirect evidence from adult chronic non-cancer pain (71).

The panel noted the following statement, which supported the inclusion of morphine in the 2010

EMLc: “Morphine is the strong opioid of choice in moderate to severe pain in children and this is

confirmed by a number of consensus guidelines. There is extensive clinical experience of its use in

children and its use should be promoted to ensure adequate analgesia as necessary” (72).

Uncertainty: none.

Risks/benefits

Benefits

The efficacy of strong opioids in the relief of pain is well accepted. The panel noted, however, that

studies comparing opioids are possible in this age group provided that acceptable and appropriate trial

methodology is used.


58

Risks

Risks associated with severe side-effects and mortality arising from medication errors were considered

manageable, although more data on long-term use in children are necessary.

Uncertainty: none


In favour

The panel valued access to effective treatment of pain in children.

Against

None

Uncertainty: none.

Cost

Although access to strong opioids is variable, price is not generally a significant barrier for a number

of strong opioids.

Uncertainty: none.

Feasibility

Access to strong opioids for medical use remains a challenge worldwide. However, the rational use of

opioid analgesics in countries with limited financial and human resources is feasible and

recommended.

Uncertainty: none.

Policy agenda

Countries should review, and if necessary, revise their policies and regulations to ensure availability

and accessibility of opioid analgesics for the relief of moderate to severe pain in children as provided

for in the preamble of the Single Convention on Narcotic Drugs, 1961.


59

A2.2.4 Choice of strong opioids

Clinical question

In children with persisting pain due to medical illnesses, what is the evidence to support the use of

morphine as a gold standard for strong opioids as compared to the use of other strong opioids (in

particular fentanyl, hydromophone, oxycodone and methadone) in order to achieve rapid, effective and

safe pain control?

Recommendations

5. Morphine is recommended as the first-line strong opioid for the treatment of persisting

moderate to severe pain in children with medical illnesses.

6. There is insufficient evidence to recommend any alternative opioid in preference to

morphine as the opioid of first choice.

7. Selection of alternative opioid analgesics to morphine should be guided by considerations

of safety, availability, cost and suitability, including patient-related factors.



Quality of evidence

The panel noted that morphine has been available for a considerable amount of time and that high

quality of evidence is unlikely to be available. The second recommendation was based on comparisons

between different opioids and routes of administration in acute pain and post-operative pain in

children. (Annex 4. Evidence retrieval and appraisal, GRADE tables 2–4, 6, 7). The assessed level of

quality of evidence was downgraded because of the differences in conditions treated and duration of

treatment.

Uncertainty: yes.

Risks/benefits

Benefits

Morphine is well established as first-line strong opioid.

Risks


60

Risks are well described and considered to be manageable.

Uncertainty: no, for the use of morphine as a first-line opioid analgesic; yes, in relation to the

comparative safety and efficacy of different opioids.


In favour

The panel valued access to effective treatment.

Against

None

Uncertainty: none.

Cost

Morphine is relatively inexpensive, although prolonged-release oral solid forms are more costly.

Uncertainty: none.

Feasibility

A wide range of morphine formulations have been already included in the 2010 EMLc:

granules, modified release (to mix with water) – 20 mg, 30 mg, 60 mg, 100 mg, 200 mg

injection – 10 mg (morphine hydrochloride or morphine sulfate) in 1 ml ampoule

oral liquid – 10 mg (morphine hydrochloride or morphine sulfate)/5 ml

tablet – 10 mg (morphine sulfate)

tablet (prolonged release) – 10 mg, 30 mg, 60 mg, 100 mg, 200 mg (morphine sulfate).

Uncertainty: none.

Research agenda

Comparative trials of strong opioids, including fentanyl, hydromorphone, and methadone, in the

treatment of persisting moderate to severe pain in children of all ages with medical illnesses are

needed. They should investigate effectiveness, side-effects and feasibility of use in this population.


61

Child appropriate oral solid dosage forms are needed.

A2.2.5 Prolonged-release versus immediate-release morphine

Clinical question

In children with persisting pain due to medical illnesses, should prolonged-release morphine be used

in preference to immediate-release morphine to achieve and maintain effective and safe pain control?

Recommendations

8. It is strongly recommended that immediate-release oral morphine formulations be available

for the treatment of persistent pain in children with medical illnesses.

9. It is also recommended that child-appropriate prolonged-release oral dosage forms be

available, if affordable.



Quality of evidence

There is insufficient evidence to support the use of prolonged-release over immediate-release

morphine as a sole agent. The only available evidence is in adults (Annex 4. Evidence retrieval and

appraisal, GRADE Table 10). The Cochrane review found that, in spite of the relevance of this

comparison, only 15 studies of 460 participants compared prolonged-release morphine preparations

with immediate-release morphine (115). None of the trials were large, having a median size of 27

participants (age range: 16–73). The results of these trials show that immediate-release and modified-

release morphine formulations are equivalent for pain relief. Approximately 6% of participants

(adults) in the studies who received morphine (any type) experienced intolerable adverse effects.

Uncertainty: yes, in relation to children since no studies are available in this age group.

Risks/benefits

Benefits

Immediate-release oral morphine needs to be administered more frequently, but it is always necessary

in the management of episodic or breakthrough pain.

Risks


62

Adherence to long-term treatment with immediate-release oral morphine may be problematic.

Uncertainty: none.


In favour

The panel valued access to immediate-release oral morphine and noted that commercially marketed

prolonged-release oral morphine formulations are sometimes the only products available for

procurement.

Against

None

Uncertainty: none.

Cost

Immediate-release oral morphine is relatively inexpensive but may not be commercially available in

all countries. Morphine powder for extemporaneous preparation may be available, but requires access

to pharmacists and suitable diluents, and its compounding may be subject to legal restrictions. The

stability of such preparations needs to be investigated.

Uncertainty: none.

Feasibility

No problem of feasibility, rather affordability for prolonged-release morphine formulation.

Uncertainty: none.

Research agenda

Research into appropriate formulations for the extemporaneous preparation of oral liquid morphine is

needed. Dissemination of available evidence on the preparation of stable extemporaneous formulations

is encouraged.

A2.2.6 Opioid rotation and opioid switching


63

Clinical question

In children with persisting pain due to medical illnesses, what is the evidence to support opioid

rotation policies to prevent dose escalation and side-effects?

Recommendations

10. Switching opioids and/or route of administration in children is strongly recommended in

the presence of inadequate analgesic effect with intolerable side-effects.

11. Alternative opioids and/or dosage forms as an alternative to oral morphine should be

available to practitioners, in addition to morphine, if possible.

12. Routine rotation of opioids is not recommended.



Quality of evidence

No systematic reviews or randomized control trials were found in children. A Cochrane Review

exclusively looked for and found no RCTs on opioid switching or rotation in adults and children.

Identified case reports, uncontrolled and retrospective studies were examined in order to determine the

current level of evidence (116). The review concluded that although for patients suffering chronic

cancer pain opioid switching may be the only option for enhancing pain relief and minimizing opioid

toxicity, there is a current lack of an evidence base for this therapeutic strategy. A systematic review

published in 2006 (117), identified one retrospective study of opioid switching in 22 children with

cancer pain. This review described a positive response to switching in patients intolerant to a particular

opioid, but noted that RCTs are lacking and that the observations were based on uncontrolled data.

Uncertainty: yes, in relation to the potential utility of rotation policies; no, in relation to switching of

opioid and/or route of administration in the presence of inadequate effect or intolerable side-effects.

Risks/benefits

Benefits

The panel placed a high value on effective use of adequate doses of the chosen opioid.

Risks

Risks are well described and considered to be manageable. Access to age-appropriate dose conversion

table for different opioids is necessary for safe switching.


64

Uncertainty: none.


In favour

The panel placed high value on treating rather than not treating pain and providing an alternative when

response is inadequate and side-effects are intolerable.

Against

None

Uncertainty: none.

Cost

Alternative opioids to morphine might be more expensive. However, there are regional variations in

costs and some alternatives to morphine may even be cheaper.

Uncertainty: none.

Feasibility

Access to an age-appropriate dose conversion table for different opioids is necessary for safe

switching.

Uncertainty: yes.

Policy and research agenda

The panel requests an update of the 2004 Cochrane review on opioid switching, including data from

children, if available. Opioid rotation policies lend themselves to investigation by prospective trials.

Such research is encouraged. Research on dose conversion in different age groups is necessary.


65

References

A morphine manifesto. J Pain Palliat Care Pharmacother. 2012 Jun;26(2):144-5.

British National Formulary for Children. British Medical Association and Royal Pharmaceutical

Society. 2011.

British Pharmacopoeia. British Pharmacopoeia Secretariat of the Medicines and Healthcare products

Regulatory Agency. 2012.

CDC (2011) Vital Signs: Overdoses of Prescription Opioid Pain Relievers --- United States,

1999—2008. Morbidity and Mortality Weekly. 60(43);1487-1492, Available at:

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6043a4.htm?s_cid=mm6043a4_w

Accessed Jul 2, 2012

CDC (2012) CDC Grand Rounds: Prescription Drug Overdoses — a U.S. Epidemic

61(01);10-13. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm

accessed July 2, 2012

Declaration of Montréal, Declaration that Access to Pain Management Is a Fundamental Human

Right, Montreal, 2011. Accessible at: http://www.iasp-

pain.org/Content/NavigationMenu/Advocacy/DeclarationofMontr233al/default.htm (Accessed at 13

September 2012).

Kate M. Dunn, PhD; Kathleen W. Saunders, JD; Carolyn M. Rutter, et al. Opioid

Prescriptions for Chronic Pain and Overdose A Cohort Study Ann Intern Med. 2010;152:85-

92.

Ensuring Balance in National Policies on Controlled Substances, guidance for availability and

accessibility of controlled medicines. World Health Organization. Geneva 2011. ISBN 978 92 4

156417 5. Accessible at: http://whqlibdoc.who.int/publications/2011/9789241564175_eng.pdf

Foley KM, Wagner JL, Joranson DE, Gelband H. Pain control for people with cancer and

AIDS. In: Disease Control Priorities in Developing Countries. 2nd ed. 981- 994. New York:

Oxford University Press; Disease Control Priorities in Developing Countries, KM Foley, JL

Wagner, DE Joranson, Eds, 2006;981–994. Available at:

http://files.dcp2.org/pdf/DCP/DCP52.pdf . (Accessed May 2007).

http://www.ncbi.nlm.nih.gov/pubmed?term=morphine%20manifesto

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm




http://files.dcp2.org/pdf/DCP/DCP52.pdf


66

Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical

overdose fatalities. JAMA 2008;300:2613–20.

Inciardi JA et al. Mechanisms of prescription drug diversion among drug-involved club and

street based populations. Pain Med 2007;8(2):171-183. doi:10.1111/j.1526-

4637.2006.00255.x

Inciardi JA et al. Diversion of prescription drugs by health workers in Cincinnati Ohio, in

Subst Use Misuse 2006;41(2):255-264. doi: 10.1080/10826080500391829

International Nonproprietary Names (INN) for Pharmaceutical Substances, Lists 1-90 of Proposed

INN and Lists 1-51 of Recommended INN Cumulative List No.11, World Health Organization,

Geneva, 2004.

Martindale, The Complete Drug Reference, 32nd Ed., the Pharmaceutical Press, London, 1999.

Milani B, Scholten W, Access to Controlled Medicines. In: The World Medicines Situation 2011, 3rd

Edition, World Health Organization, Geneva 2011 (Chapter released April 2011). Accessible at:

http://www.who.int/entity/medicines/areas/policy/world_medicines_situation/WMS_ch19_wAccess.p

df

Minozzi S, Amato L, Vecchi S, Davoli M. Systematic review on dependence following treatment with

opioid analgesics for pain relief. Submitted for publication.

Multilingual dictionary of narcotic drugs, United Nations, New York, 1993. ISBN 92-1-048056-2.

Niikura K et al. Neuropathic and chronic pain stimuli downregulate central micro -opioid and

dopaminergic transmission. Trends in Pharmacol Sciences, 2010, 31:299-305.

Noble M, Tregear SJ, Treadwell JR, Schoelles K. Long-term opioid therapy for chronic non-cancer

pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manage.

2008;35(2):214-228.

Report of the International Narcotics Control Board on the Availability of Internationally Controlled

Drugs: Ensuring Adequate Access for Medical and Scientific Purposes. New York, 2011,




67

E/INCB/2010/1/Supp.1, ISBN: 978-92-1-148260-7 http://www.incb.org/pdf/annual-

report/2010/en/supp/AR10_Supp_E.pdf

Resolution WHA58.22. Cancer prevention and control. In: Fifty-eighth World Health Assembly,

Geneva, 25 May 2005. A copy of the resolution can be found in:


Scholten W. Pediatric morphine dosages. WHO Pharmaceuticals Newsletter. 4; 2012: 26-28.


Seya MJ, Gelders SFAM, Achara UA, Milani B, Scholten WK. A First Comparison between the

Consumption of and the Need for Opioid Analgesics at Country, Regional and Global Level. J Pain

and Palliative Care Pharmacotherapy, 2011; 25: 6-18. Accessible at:


Substance Abuse and Mental Health Services Administration (SAMSHA), Results from the

2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH

Series H-41, HHS Publication No. (SMA) 11-4658. Rockville, MD: Substance Abuse and

Mental Health Services Administration, 2011. Accessible at :


The International Pharmacopoeia, Fourth Edition. World Health Organization. 2011.

US Pharmacopeia, www.usnpf.com


illnesses. World Health Organization. 2012.

http://whqlibdoc.who.int/publications/2012/9789241548120_Guidelines.pdf

World Cancer Declaration. Clin J Oncol Nurs. 2006 Dec;10(6):721-2.







http://www.usnpf.com/

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Willem Scholten PharmD MPA - World Health Organization · Willem Scholten PharmD MPA Consultant – Medicines and Controlled Substances 6 for both oral and parenteral administration