George Rimmer

0 OCT 2019

Boehringer Ingelheim Limited - Ellesfield Avenue, Bracknell, Berkshire RG12 8YS.

Ms. P Schofield

Senior Coroner for West Sussex Coroner’s Service
County Record Office

Orchard Street

Chichester

West Sussex

PO19 1DD

Dear Ms. Schofield,
Re: Inquest into the death of George Benjamin RIMMER

Thank you for your letter of 16" August 2019 (received 21‘' August 2019) in
relation to the above inquest. We are very sorry to hear about the death of
this gentleman and thank you for the opportunity to review the provision of
Oramorph® Oral Solution 10 mg/5 ml (Oramorph®) to ensure optimal
information is provided to patients.

Boehringer Ingelheim Limited (BIL) takes the safety of our medicines
extremely seriously and ensures compliance with all regulations with respect
to the monitoring of safety, packaging, labelling and provision of information
to healthcare professionals (via the Summary of Product Characteristics
[SmPC] and patients (via the Patient Information Leaflet [PIL]).

Changes have recently been made to the Oramorph® SmPC (ef) and PlL asa
result of the European Medicine Agency (EMA) review of the Periodic Benefit
Risk Evaluation Report (PBRER) for Oramorph® submitted by BIL in 2018. It
should be noted that the EMA reviewed the PBRER’s for all medicines
containing the active ingredient morphine at this time, with many of their
recommendations intended to provide consistency in warnings associated
with the active ingredient (morphine) across all these medicines. BIL
complied with all EMA recommendations and submitted them to the United
Kingdom (UK) Regulatory Agency, the Medicines and Healthcare products
Regulatory Agency (MHRA), who granted approval for the updated text on
19"" December 2018. The PIL version for this update was dated November
2018. There has been a subsequent update to the November 2018 PIL

“~~

Boehringer
Ingelheim

Boehringer Ingelheim Limited

8 October 2019

Telephone +44 (0) 1344 742534
EM)
a

Ellesfield Avenue

Bracknell, Berkshire RG12 8YS
Telephone +44 (0) 1344 424600
Telefax +44 (0) 1344 741444
www.boehringer-ingelheim.co.uk

Directors:

Mr U Bose

(Managing)

Mr B Moynihan

(Finance & Administration)

Registered Office
Ellesfield Avenue
Bracknell, Berkshire RG12 8YS

Registered in England and Wales
No. 711858

Page 2

reflecting an administrative change only in preparation for BREXIT. The
current PIL date is therefore March 2019 “*"2),

In addition, following a request by the MHRA to the manufacturers of opioid
containing medicines in a letter dated 7"* May 2019, the outer carton
labelling “**>) and bottle label “** have been updated to contain the
following boxed statement:

Can cause addiction
Contains opioid

These changes were approved by MHRA for Oramorph?® Oral Solution on 18"
June 2019 and are the only recent non-administrative change to the carton
and bottle labelling.

In responding to your letter of 16" August 2019, we have, as requested,
addressed the 7 “matters of concern”, describing already completed or
proposed actions with associated timeline or explained why we have taken
no action.

We have referred to the current versions of the PIL (March 2019), outer
carton (May 2019) and bottle labelling (May 2019) and also the versions
supplied with the Oramorph® product that we believe would have been
dispensed to Mr Rimmer. The PIL provided to Mr Rimmer inside the
Oramorph® pack we assume to be the June 2015 PIL ef5) version. For your
convenience, we have also included with this letter the June 2015 PIL,
marked with annotations of the changes made in the update to the
November 2018 PIL version "€f® which is identical in wording to the current
(March 2019) PIL except for the name of the Marketing Authorisation Holder.
These changes in the PIL from June 2015 can be summarised as follows:

Changes from June 2015 to November 2018 PIL:

e Addition of a warning to check the suitability of taking Oramorph® if
previously addicted to drugs or alcohol.

e Addition of ‘increased sensitivity to pain’ as a side effect and in
general a re-ordering of the side effects section.

e Addition of wording on the risk of pneumonia from an overdose and
symptoms this may cause.

e Revised wording in the warnings and precautions regarding low
cortisol, changes in sex hormone levels, dependency and withdrawal
symptoms.

Page 3

e Revised wording of the risk of taking Oramorph® with other sedative
medicines.

e Revised wording in the risk of newborn withdrawal if taking
Oramorph® in pregnancy.

e Revised wording warning of withdrawal and associated symptoms.

e Updated adverse event reporting details.

Changes from November 2018 to March 2019 PIL:
e Change in Marketing Authorisation Holder in light of preparations for
BREXIT.

You will see in our responses to the 7 “matters of concern” that whilst we do
consider the PIL, outer carton and bottle labelling versions both now and as
supplied with the Oramorph® Mr Rimmer received, provide sufficient
information to address your concerns, we have proposed one additional
change to each of these documents. These changes are outlined below and
also summarised on page 9.

1. Mr Rimmer was known to swig out of the bottle rather than take a
measured dose as most patients do.

We view this matter of concern as more pertinent to Mr Rimmer’s prescribing
clinician and other healthcare professionals.

As per Good Medical Practice (2013) "'” and Good practice in prescribing
and managing medicines and devices (2013) **® it is the responsibility of
the prescribing clinician to ensure that he/she provides an explanation to the
patient of how and when to take the medicine and how to adjust the dose if
necessary. It is also the expectation that the prescribing clinician describes
the likely benefits, risks and burdens, including serious and common side
effects of any treatment provided. Our view is that guidance provided in
Good Medical Practice and Good practice in prescribing and managing
medicines and devices is particularly relevant when also considering matters
of concern 2, 3 and 4 as listed in your report.

The PIL is provided to supplement the instructions given by the prescribing
clinician. The Oramorph® PIL (both current and the presumed June 2015
version that Mr Rimmer received) provides clear instruction to the patient
that the dose of Oramorph® should be measured using a 5ml spoon (see also
the response to matters of concerns numbers 2 and 6).

Page 4

Conclusion 1

We took no specific action in response to this particular matter of concern.
However please see our response to matter of concern 6, which is closely
related.

2. Mr Rimmer self medicated as required.

As mentioned in point 1 above, in relation to Good Medical Practice, we view
this as a matter of concern more pertinent to Mr Rimmer’s prescribing
clinician and other healthcare professionals involved in his care rather than
BIL.

We have carefully reviewed the current and June 2015 version of the PIL and
consider both versions provide clear instruction on the intended dosing
(amount and frequency) in the section entitled ‘HOW MUCH TO TAKE?’ by the
reminding the patient:

e totake this “..exactly as the doctor has told you”

e the maximum dose is 5 to 10mls (one to two teaspoons)

e tocheck with their doctor or pharmacist if they are not sure.

3, HOW TO TAKE ORAMORPH ORAL SOLUTION

Always take this medicine exactly as your doctor has told you
You should check with your doctor or pharmacist if you are not sure

Taking this medicine

+ Take this medicine by mouth only

+ Use a 5 ml plastic spoon to measure your dose
* They are available from your pharmacist

How much to take
Your doctor will decide the amount of medicine to give you
Adults

« The most that should be taken is 5 to 10 ml (one to two teaspoons)
every four hours

This section also included a statement not to take more than is prescribed
and to discuss with a doctor if the prescribed dose is no longer effective.

Your body may get used to the medicine (tolerance)

+ Do not take more than your doctor has prescribed

+ If you have been taking your medicine for some time you may find
that it does not seem to be working as well as it did If this happens,
talk to your doctor

Page 5

Conclusion 2)

Given the clear instructions in the current PIL (unchanged from the June
2015 version) to take the recommended dose and to seek advice if the
prescribed dose is no longer effective, we took no specific action in response
to this matter of concern.

3. Mr Rimmer’s GP did not recall advising him of the possible
consequences of exceeding the prescribed dose.

We view this point to be directed to Mr Rimmer’s prescribing clinician and
other healthcare professionals involved in his care rather than BIL.
However, as discussed in relation to matters of concern 4 and 5, we do have
clear warnings in the PIL of the consequences (symptoms, signs and risks) if
more than the prescribed dose is taken.

Conclusion 3)
We took no specific action in response to this matter of concern.

4. There was no evidence to show that anyone had counselled Mr
Rimmer with regards to the use of this drug.

Whilst similarly we view this matter of concern as relevant to Mr Rimmer’s
prescribing clinician and other healthcare professionals involved in his care,
we would like to point out that both the current (and also June 2015) PIL
contain clear wording regarding:
e advice to seek medical help in case the patient took “more
ORAMORPH than you should”
e specific guidance / warning as to symptoms and signs they may
notice
e the risk of taking too much including in severe cases,
unconsciousness and death.

Page 6

If you take more ORAMORPH than you should

If you take more of this medicine than you should, talk to a doctor or
go to a hospital straight away Take the medicine pack with you This
js so the doctor knows what you have taken

If you take more than you should, the following effects may happen.
+ The black circle in the centre of your eyes (pupil) gets smaller

+ You breathe more slowly

* You have low blood pressure

People who have taken an overdose may also get pneumonia
from inhaling vomit or foreign matter, symptoms of this may
include breathlessness, cough and fever

In more severe cases, very high doses could cause your blood circulation
and breathing to slow down and cause unconsciousness for a long time,
or even death In children a high dose may cause fits (convulsions)

Please note: In the extract of the wording of the current PIL (March
2019) shown in the screenshot above, the identical wording was used
in the June 2015 PIL, save that the third paragraph “People
who.....cough and fever” was added in this later version.

Conclusion 4

We feel the wording of the PIL (both current and June 2015 version) is
sufficient to warn the patient of the need to take only the dose the doctor
has prescribed, to seek medical help if too much is taken and the warning
signs/symptoms and associated risks of taking too much and therefore we
took no further action to this matter of concern.

5. The leaflet that comes with the bottle does not provide a sufficient
warning of the dangers of taking an excess dose.

We would like to refer to our answer to matter of concern 4). The section of
the PIL entitled ‘If you take more ORAMORPH than you should’, provides
warnings and a clear instruction on what to do in the event of taking more
than the doctor prescribed. This section also provides explicit information
about the dangers of taking an excess dose including the risk of death.

Conclusion 5

Having reviewed the current and June 2015 version wording in light of your
letter, we feel the PIL sufficiently warns of the dangers of taking an excess
dose. Therefore, we took no further action in response to this matter of
concern.

Page 7

6. There is no mention of the dangers of drinking from the bottle and
not measuring the dose.

The ‘HOW TO TAKE ORAMORPH ORAL SOLUTION’ section of the PIL gives
clear instructions on how to administer Oramorph®, by mouth, using a 5m!
spoon (available from a pharmacist) with the maximum dose being one to

two teaspoons every four hours.

We also understand it to be good dispensing practice that a pharmacist
ensures any solution has a measuring spoon (or alternative device) provided.

3. HOW TO TAKE ORAMORPH ORAL SOLUTION

Always take this medicine exactly as your doctor has told you
You should check with your doctor or pharmacist if you are not sure

Taking this medicine

* Take this medicine by mouth only

+ Use a 5 ml plastic spoon to measure your dose
* They are available from your pharmacist

How much to take
Your doctor will decide the amount of medicine to give you

Adults
+ The most that should be taken is 5 to 10 ml (one to two teaspoons)
every four hours

Whilst there is no explicit warning in the PIL not to drink directly from the
bottle, the wording of the ‘HOW TO TAKE ORAMORPH ORAL SOLUTION’ is
also consistent with other oral morphine solutions (eF9, 10)» vailable in the
UK. These also provide specific instructions about measuring the correct
dose but, like Oramorph®, they do not have an explicit warning not to drink
directly from the bottle.

The Oramorph® PIL, the SmPC, bottle and carton labelling, has been
approved by the relevant regulatory authority in the UK, the MHRA, and in
our view, meets their requirements as to the information that must be
provided to patients.

However, we will propose to the MHRA that we include within the ‘HOW TO
TAKE ORAMORPH ORAL SOLUTION’ section the following statement (or
words to that effect to be agreed with the MHRA):

‘Do not drink directly from the bottle as this may result in you taking the
incorrect dose (too little or too much). Drinking from the bottle can result in an
overdose with potential for harmful effects including, but not limited to,
pneumonia, low blood pressure, unconsciousness and even death.’

Page 8

Conclusion 6

We believe the PIL wording is clear and of note, is consistent with other
providers of oral morphine solution "*f%!. However, we will request to the
MHRA that we add to the PIL an explicit warning statement not to drink
directly from the bottle, additionally with text highlighting the risks of doing
so, so mirroring the points made in the text explaining the consequences of
taking too much, as referred to in matter of concern 4.

7. There is no warning on the bottle to act as a reminder of the dangers
of taking an excess dose or of the cumulative effect of taking more
than the prescribed amount.

Please be aware the space to include additional information on the bottle
label is limited and guidance to the patient is covered in detail in the PIL (see
response to matter of concern 4 confirming that the warning symptoms
/signs and risks of an excess dose, including death, are clearly stated).

The bottle and outer carton labelling both currently has the following
statement “To be taken as directed by the prescriber’.

We consider this statement to clearly instruct the patient to follow the advice
of the clinician and is in line with statutory requirements for medicines
supplied on prescription.

As mentioned in our response to matter of concern 6, the SmPC, PIL and
outer carton and bottle labelling for Oramorph® have been reviewed and
approved by the MHRA, meeting required standards.

However, we propose to strengthen and emphasise the wording on both the
bottle label and carton label:
e From ‘To be taken as directed by the prescriber’
e To ‘Must only be taken as directed by the prescriber’,
emboldening the font in this revision, to ensure prominence of the
wording to the patient.

Conclusion 7

We believe the current bottle and carton labelling wording is sufficiently
clear. However, we will request to the MHRA that we amend the wording and
embolden for emphasis the statement regarding “..taken as directed by the
prescriber”.

Page 9

Summary of BIL proposed actions:

We have proposed three new actions, as summarised below:

1. Change to PIL

We propose to add the following wording (or words to that effect) to the
‘HOW TO TAKE ORAMORPH ORAL SOLUTION’ section:

‘Do not drink directly from the bottle as this may result in you taking the
incorrect dose (too little or too much). Drinking from the bottle can result in an
overdose with potential for harmful effects including, but not limited to,
pneumonia, low blood pressure, unconsciousness and even death,’

2. Change to the bottle label

We propose to amend the bottle label (in case the patient misplaces the
outer carton and/or PIL):

e From: ‘To be taken as directed by the prescriber’
e To: ‘Must only be taken as directed by the prescriber’

We further propose the amended text will be emboldened for emphasis.

3. Change to outer carton labelling

Similar to above, we propose to amend the statement on the outer carton:

e From: ‘To be taken as directed by the prescriber’
e To: ‘Must only be taken as directed by the prescriber’
(text will be emboldened for emphasis).

Please be advised that any proposed additions and amendments to the PIL,
bottle and outer carton labelling will need to be reviewed and approved by
both the MHRA (UK) and the Healthcare and Products Regulatory Agency
(HPRA) in Ireland, since we maintain a joint pack for both countries.

Page 10

We will, as part of the submission of these proposed changes to the
regulatory authorities in both the UK and Ireland, provide the MHRA and
HPRA with your letter (redacted for the patient’s name) so they are aware of
the background for our proposed changes. We undertake to submit these
changes to the MHRA and HPRA no later than the end of December 2019,

We trust that we have adequately addressed the maters of concern that you
have raised, but should there be anything further you require, please do not
hesitate to let me know.

Yours sincerely,

Uday Bose
Country Managing Director

References

Please note that references 1-6 are provided in hard copy with this letter, All other
teferences can be found at the website address provided.

1. Summary of Product Characteristics (SmPC)
Oramorph Oral Solution 10 mg/5 ml (Oramorph®)
- current version, revision of text March 2019
https:// .medicines.org.uk/eme/product/902/sm

2. Patient Information Leaflet (PIL)
Oramorph Oral Solution 10 mg/5 ml (Oramorph®)
— current version, updated March 2019
https://www.medicines.org.uk/emc/product/902/pil

3. Artwork for the outer carton (300ml! bottle as example)
Oramorph Oral Solution 10 mg/5 ml (Oramorph®)
— current version, updated May2019

Page 11

10.

Artwork for the bottle label (300ml bottle as example)
Oramorph Oral Solution 10 mg/5 ml (Oramorph®)
- current version, updated May 2019

Patient Information Leaflet (PIL)
Oramorph Oral Solution 10 mg/5 ml (Oramorph®)
- version June 2015

Annotated version of the June 2015 PIL with the changes which were
included in the November 2018 update.

“Good Medical Practice”, General Medical Council, published 25
March 2013
https:// .gmc-uk.org/ethical-guidance/ethical-guidance-for-

doctors/good-medical-practice

“Good practice in prescribing and managing medicines and devices”,
General Medical Council, updated March 2013
https://www.gmc-uk.org/-

/media/documents/Prescribing guidance.pdf 59055247.pdf

Patient Information Leaflet (PIL)
Morphine Sulfate 10mg/5ml Oral Solution, Wockhardt UK Ltd
https://www.medicines.org.uk/emc/product/2629/pil

Patient Information Leaflet (PIL)
Morphine Sulfate 10mg/5ml Oral Solution, Martindale Pharma
https://www.medicines.org.uk/emc/product/3427/pil

Oramorph Oral Solution - Summary of Product Characteristics (SmPC) - print friendly - (emc)

Oramorph Oral Solution

Summary of Product Characteristics Updated 08-Apr-2019 | Boehringer Ingelheim Limited

1. Name of the medicinal product
Oramorph Oral Solution 10 mg/5 ml

2. Qualitative and quantitative composition
Each 5 ml of Oramorph Oral Solution contains 10 mg of Morphine Sulfate

Excipient(s) with known effect Each 5 ml also contains 1500 mg sucrose, 0 525 ml Ethanol (96%), 9 mg methyl
parahydroxybenzoate (E218) and 1 mg propyl parahydroxybenzoate (E216)

For full list of exciptents, see Section 6 1

3. Pharmaceutical form
Oral solution

A clear, colourless oral solution
4. Clinical particulars
4.1 Therapeutic indications

For the relief of severe pain in adults, adolescents (aged 13-18 years) and children (aged 1-12 years)

4.2 Posology and method of administration

Posology

Adults Recommended dose 10-20 mg (5-10 ml) every 4 hours
Maximum daily dose 120 mg per day

Paediatne population

Children 13-18 years Recommended dose 5-20 mg (2 5 - 10 ml) every 4 hours
Maximum daily dose 120 mg per day

Children 6-12 years Recommended dose 5-10 mg (2 5-5 ml) every 4 hours
Maximum daily dose 60 mg per day

Children 1-5 years Recommended dose 5 mg (2 5 mi) every 4 hours
Maximum daily dose 30 mg per day

Children under 1 year Not recommended

Dosage can be increased under medical supervision according to the severity of the pain and the patient's previous
history of analgesic requirements
Special populations

Reductions in dosage may be appropriate tn the elderly and in patients with chronic hepatic disease (for acute hepatic
disease see section 4 3), renal impairment, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy,
shock or where sedation is undesirable

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration ts suddenly discontinued Therefore the dose
should be gradually reduced prior to discontinuation

M yf In

For oral use

When patients are transferred from other morphine preparations to Oramorph Oral preparations dosage titration may be
appropriate

Morphine sulfate ts readily absorbed from the gastro-intestinal tract following oral administration However, when oral

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Oramorph preparations are used in place of parenteral morphine, a 50 % to 100 % increase in dosage ts usually
required in order to achieve the same level of analgesia

4.3 Contraindications

Oramorph is contraindicated in

* patients known to be hypersensitive to morphine sulfate or to any other component of the product
* respiratory depression

+ obstructive airways disease

* paralytic tleus (see section 4 4)

* acute hepatic disease

= acute alcoholism

+ head injuries (see section 4 4)

* coma (see section 4 4)

* increased intracranial pressure (see section 4 4)
* convulsive disorders

* patients with known morphine sensitivity

* concurrent administration with monoamine oxidase inhibitors or within two weeks of discontinuation of their use (see
section 4 5)

* patients with phaeochromocytoma Morphine and some other opioids can induce the release of endogenous histamine
and thereby stimulate catecholamine release

* acute asthma exacerbations (see section 4 4 for information relating to use in controlled asthma)
4.4 Special warnings and precautions for use

Care should be exercised if morphine sulfate ts given
«in the first 24 hours post-operatively,
*in hypothyroidism (see section 4 2),

* and where there ts reduced respiratory function, such as kyphoscoliosis, emphysema, cor pulmonale and severe
obesity

Asthma

It has been suggested that opioids can be used with caution in controlled asthma However, opioids are contraindicated
in acute asthma exacerbations (see section 4 3)

nd increa: I |_pre e

Oramorph ts contraindicated in patients with increased intracranial pressure, head injuries and coma (see section 4 3)
The capacity of morphine to elevate cerebrospinal fluid pressure may be greatly increased in the presence of already
elevated intracranial pressure produced by trauma Also, morphine may produce confusion, miosis, vomiting and other
adverse reactions which may obscure the clinical course of patients with head injury

Abdominal conditions

Morphine sulfate must not be given if paralytic ileus ts likely to occur (see section 4 3), or if the patient has bowel or
obstructive biliary disease Should paralytic ileus be suspected or occur during use, Oramorph should be discontinued
immediately

Caution should be exercised where there is an obstructive bowel disorder, biliary colic, operations on the biliary tract,
acute pancreatitis or prostatic hyperplasia

If constipation occurs this may be treated with the appropriate laxatives
Care should be exercised in patients with inflammatory bowel disease

Morphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and complications
following abdominal surgery

Hypotensive effect

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The administration of morphine may result in severe hypotension in individuals whose ability to maintain homeostatic
blood pressure has already been compromised by depleted blood volume or the concurrent administration of drugs such
as phenothiazine or certain anaesthetics (see section 4 5)

d ind w awal In fe}
Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or

tolerance The risk increases with the time the drug Is used, and with higher doses Symptoms can be minimised with
adjustments of dose or dosage form, and gradual withdrawal of morphine For individual symptoms, see section 4 8

Abuse

Morphine sulfate ts an opioid agonist and controlled drug Such drugs are sought by drug abusers and people with
addiction disorders Morphine sulfate can be abused in a manner similar to other opioid agonists, legal or illicit This
should be considered when prescribing or dispensing morphine tn situations where the physician or pharmacist Is
concerned about an increased risk of misuse, abuse or diversion Morphine should be used with particular care in
patients with a history of alcohol and drug abuse

Morphine sulfate may be abused by inhaling or injecting the product These practices pose a significant risk to the
abuser that could result in overdose and death

Hypersensitivity

Hypersensitivity and anaphylactic reactions have both occurred with the use of Oramorph Care should be taken to elicit
any history of allergic reactions to opiates Oramorph is contraindicated in patients known to be hypersensitive to
morphine sulfate (see section 4 3)

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement
therapy Symptoms of adrenal insufficiency may include e g nausea, vomiting, loss of appetite, fatigue, weakness,
dizziness, or low blood pressure

Decreased sex hormones and increased prolactin

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin
Symptoms include decreased libido, impotence or amenorrhoea

Hyperalgesia
Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses A
morphine dose reduction or change In opioid may be required

Risk in special populations

Morphine is metabolised by the liver and should be used with caution in patients with hepatic disease as oral
bioavailability may be increased It is wise to reduce dosage in chronic hepatic and renal disease, severe
hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy or shock (see section 4 2)

The active metabolite Morphine-6-glucuronide may accumulate in patients with renal failure, leading to CNS and
respiratory depression

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD)

Due to a possible association between ACS and morphine use in SCD patients treated with morphine during a vaso-
occlusive crisis, close monitoring for ACS symptoms is warranted

fro nes n of sedative medici nz e rr ru

Concomitant use of Oramorph Oral Solution and sedative medicines such as benzodiazepines or related drugs may
result in sedation, respiratory depression, coma and death

Because of these risks, co-prescription of Oramorph Oral Solution and sedative medicines should be reserved for
patients for whom alternative treatment options are not possible

Oramorph Oral Solution particularly when prescribed concomitantly with sedative medicines, should be used at the
lowest effective dose for the shortest period of time

Patients should be momtored closely for signs and symptoms of respiratory depresston and sedation !n this respect, it is
strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4 5)

Use with nfampicin

Plasma concentrations of morphine may be reduced by rifampicin The analgesic effect of morphine should be monitored
and doses of morphine adjusted during and after treatment with rifampicin

Excipient related warnings

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Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase
insufficiency should not take this medicine

Oramorph Oral Solution contains the excipients methy! parahydroxybenzoate (E218) and propyl parahydroxybenzoate
(E216) which may cause allergic reactions (possibly delayed)

Oramorph Oral Solution contains 10 vol % ethanol (alcohol) Each dose contains up to 0 81 g of alcohol which is
equivalent to 20 ml beer or 8 3 mi wine Harmful for those suffering from alcoholism To be taken into account in
pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy

4.5 interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression
with hyper- or hypotensive crisis, therefore their concomitant use with Oramorph ts contraindicated (see section 4 3)

Gabapentin

Interactions have been reported in those taking morphine and gabapentin Reported interactions suggest an increase In
opioid adverse events when co-prescribed, the mechanism of which ts not known Caution should be taken where these
medicines are co-prescribed

In a study involving healthy volunteers (N=12), when a 60 mg controlled-release morphine capsule was administered 2
hours prior to a 600 mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin
administered without morphine Therefore, patients should be carefully observed for signs of CNS depression, such as
somnolence, and the dose of gabapentin or morphine should be reduced appropriately

Ritonavir

Although there are no pharmacckinetic data available for concomitant use of ritonavir with morphine, ritonavir may
Increase the activity of glucuronyl transferases Consequently, co-administration of ritonavir and morphine may result in
decreased serum concentrations of morphine with possible loss of analgesic effectiveness

Rifampicin

Rifampicin can reduce the plasma concentration of morphine and decrease Its analgesic effect, the mechanism of which
is not known

Cimetidine
Cimetidine inhibits the metabolism of morphine
S ve medicin: Z ik

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of
sedation, respiratory depression, coma and death because of additive CNS depressant effect The dose and duratton of
concomitant use should be limited (see section 4 4)

fe) NS de.

\t should be noted that morphine potentiates the effects of CNS depressants such as tranquillisers, anaesthetics (see
section 4 4), hypnotics, sedatives, antipsychotics, tricyclic antidepressants and alcohol

Esmolol
Morphine may increase plasma concentrations of esmolol
Di ert e le

Optotd analgesics including morphine may antagonise the actions of domperidone and metoclopramide on gastro-
intestinal activity

Mexiletine
The absorption of mexiletine may be delayed by concurrent use of morphine
Phenothiazine antiemetics

Phenothiazine antiemetics may be given with morphine However, hypotensive effects have to be considered (see
section 4 4)

4.6 Fertility, pregnancy and lactation
Pregnancy

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Although morphine sulfate has been in general use for many years, there is inadequate evidence of safety in human
pregnancy

Morphine is known to cross the placenta Therefore, Oramorph should not be used in pregnancy, especially the first
trimester unless the expected benefit is thought to outweigh any possible risk to the foetus

Newborns whose mothers recetved opioid analgesics during pregnancy should be monitored for signs of neonatal
withdrawal (abstinence) syndrome Treatment may include an opioid and supportive care

The risk of gastric stasis and inhalation pneumonia Is increased tn the mother during labour Since morphine rapidly
crosses the placental barrier it should not be used during the second stage of labour or in premature delivery because of
the risk of secondary respiratory depression in the newborn infant

The quantity of ethanol contained in Oramorph Oral Solution should be considered in pregnant women (See section 4 4)
Breast-feeding

Although morphine sulfate has been in general use for many years, there Is inadequate evidence of safety during
lactation

Morphine is not recommended for nursing mothers Morphine Is excreted in breast milk, and may thus cause respiratory
depression in the newborn infant

Fertility

Long term use of opioid analgesics can cause hypogonadism and adrenal insufficiency in both men and women This 1s
thought to be dose related and can lead to amenorrhoea, reduced libido, infertility and erectile dysfunction

Animal studies have shown that morphine may reduce fertility (see 5 3 preclinical safety data)
4.7 Effects on ability to drive and use machines

Morphine sulfate ts likely to impair ability to drive and to use machinery This effect is even more enhanced, when used
in combination with alcohol or CNS depressants Patients should be warned not to drive or operate dangerous
machinery after taking Oramorph

This medicine can impair cognitive function and can affect a patient's ability to drive safely This class of medicine ts in
the list of drugs included in regulations under 5a of the Road Traffic Act 1988 When prescribing this medicine, patients
should be told

* The medicine ts likely to affect your ability to drive

* Do not drive until you know how the medicine affects you

* Its an offence to drive while under the influence of this medicine

+ However, you would not be committing an offence (called ‘statutory defence’) if
o The medicine has been prescribed to treat a medical or dental problem and

o You have taken It according to the instructions given by the prescriber and in the information provided with the
medicine and

o It was not affecting your ability to drive safely
4.8 Undesirable effects

Data from clinical trials are not available Therefore all frequencies of the undesirable effects are unknown

In normal doses, the commonest side effects of morphine sulfate are nausea, vomiting, constipation, drowsiness and
confusion If constipation occurs, this may be treated with appropriate laxatives The effects of morphine have led to its
abuse and misuse Dependence and addiction may develop with regular, inappropriate use

A full list of currently known adverse reactions 1s presented below

SOC Category Side effect

immune system disorders Hypersensitivity
Anaphylactic reaction (see section 4 4)
Anaphylactoid reactions

Psychratne disorders Confusional state
Restlessness

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Altered mood
Hallucination

Dependence (see section 4 4)

Nervous system disorders Somnolence

Headache
Increased intracranial pressure {see section 4 4)
Allodynia

Hyperalgesia (see section 4 4)

Eye Disorders Miosis

Ear and labynnth disorders Vertigo

Respiratory, thoracic and mediastinal Respiratory depression (see section 4 4 and section 4 6)
disorders

Cardiac disorders Bradycardia
Tachycardia

Palpitations

Vascular disorders Hypotension
Flushing

Gastrointestinal disorders Nausea
Vomiting

Constipation (see section 4 4)

Dry mouth

General disorders and administration site Hypothermia

conditions Drug tolerance (see section 4 4)

Drug withdrawal (abstinence) syndrome (see section 4 4 and section

46)
Hepatobiliary Disorders Biliary colic
Skin and subcutaneous tissue disorders Urticaria
Pruritus
Hyperhidrosis
Musculoskeletal and connective tissue Muscle rigidity
disorders
Renal and unnary disorders Dysuria

Ureteral spasm
Oliguria

Reproductive system and breast disorders Decreased libido

Erectile dysfunction

Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or
tolerance An abstinence syndrome may be precipitated when oproid administration 1s suddenly discontinued or opioid
antagonists administered, or can Sometimes be experienced between doses For management, see 4 4

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Physiological withdrawal symptoms include Body aches, tremors, restless legs syndrome, diarrhoea, abdominal colic,
nausea, flu-like symptoms, tachycardia and mydriasis Psychological symptoms include dysphoric mood, anxiety and
irritabihty In drug dependence, “drug craving” is often involved

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important It allows continued
monitoring of the benefit / risk balance of the medicinal product Healthcare professionals are asked to report any
suspected adverse reactions via

Yellow Card Scheme
Website’ www mhra gov uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose
Symptoms

Signs of morphine toxicity and overdosage are likely to consist of pin-point pupils, respiratory depression and
hypotension Circulatory failure, pneumonia aspiration and deepening coma may occur in more severe cases
Convulsions may occur in infants and children Death may occur from respiratory failure

Treatment

Adults Administer 0 4-2 mg of naloxone intravenously Repeat at 2-3 minute intervals as necessary to a maximum of 10
mg, or by 2 mg in 500 ml of normal saline or 5 % dextrose (4 micrograms/ml) Children 5-10 micrograms per kilogram
body weight intravenously If this does not result in the desired degree of clinical improvement, a subsequent dose of
100 mcg/kg body weight may be administered

Care should always be taken to ensure that the airway Is maintained Assist respiration if necessary Maintain fluid and
electrolyte levels Oxygen, 1v fluids, vasopressors and other supportive measures should be employed as Indicated
Peak plasma concentrations of morphine are expected to occur within 15 minutes of oral ingestion Therefore gastric
lavage and activated charcoal are unlikely to be beneficial

Caution the duration of the effect of naloxone (2-3 hours) may be shorter than the duration of the effect of the morphine
overdose It 1s recommended that a patient who has regained consciousness after naloxone treatment should be
observed for at least 6 hours after the last dose of naloxone

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group Natural opium alkaloids ATC code NO2AA01

Morphine binds to specific receptors which are located at various levels of the central nervous system and also in
various peripheral organs The pain sensation and the affective reaction to pain is relieved by interaction with the
receptors in the central nervous system

5.2 Pharmacokinetic properties

Absorption

Morphine 1s modestly absorbed from the gastrointestinal tract following oral administration Following oral administration
of radiolabelled morphine to humans, peak plasma levels were reached after approximately 15 minutes Morphine
undergoes significant first pass metabolism in the liver resulting in a systemic bioavailability of approximately 25%

Distribution
Approximately one third of morphine in the plasma ts protein bound after a therapeutic dose
Biotransformation

Metabolism of morphine principally involves conjugation to morphine 3- and 6- glucuronides Small amounts are also
metabolised by N-demethylation and N-dealkylation Morphine-6-glucuronide has pharmacological effects
indistinguishable from those of morphine The haif-life of morphine is approximately 2 hours The t1/2 of morphine-6-
glucuronide is somewhat longer

Elimination

A small amount of a dose of morphine is excreted through the bowel into the faeces The remainder Is excreted in the
urine, mainly in the form of conjugates Approximately 90 % of a single dose of morphine ts excreted in the first 24 hours
Enterohepatic circulation of morphine and Its metabolites can occur, and may result in small quantities of morphine to be
present in the urine or faeces for several days after the last dose

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5.3 Preclinical safety data
In male rats, reduced fertility and chromosomal damage in gametes have been reported

6. Pharmaceutical particulars
6.1 List of excipients

Ethanol (96%), corn syrup, sucrose, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216) and
purified water

6.2 Incompatibilities
None stated
6.3 Shelf life

3 years
Discard Oramorph Oral Solution 3 months after first opening

6.4 Special precautions for storage
Do not store above 25°C Store in the original container to protect from light
6.5 Nature and contents of container

Amber glass bottles with a tamper—evident, child resistant polypropylene closure with expanded PE liner are available in
packs of 100 mi, 250 ml, 300 mi or 500 ml

Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling

None stated

7. Marketing authorisation holder
Boehringer Ingelheim International GmbH

Binger Strasse 173
55216 Ingelheim am Rhein
Germany

8. Marketing authorisation number(s)
PL 14598/0114

9. Date of first authorisation/renewal of the authorisation
Date of first authorisation 8!" March 1988

Date of last renewal 30!" June 2005

10. Date of revision of the text
March 2019

Company Contact Details

Boehringer Ingelheim Limited

Address www

Ellesfield Avenue, Bracknell, Berkshire, RG12 8YS http /Awww boehringer-ingelheim co uk
Telephone Fax

+44 (0)1344 424 600, - +44 (0)1344 741 298, »-

Medical Information Direct Line Medical Information e-mail

+44 (0)1344 742579," medinfo@bra boehringer-ingelheim com

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aq Package Leaflet: Information for the User.

ep 2.

Oramorphe Oral Solution
10 mg/5 ml

(morphine sulfate)

Read all of this leaflet carefully before you start taking this medicine.

+ Keep this leaflet You may need to read It again

+ If you have any further questions, ask your doctor or pharmacist

+ This medicine has been prescribed for you Do not pass it on to
others It may harm them, even if their symptoms are the same as
yours

+ If any of the side effects gets troublesome or serious, or if you
notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist

In this leaflet:

1 What ORAMORPH Oral Solution 1s and what tt 1s used for
2 Before you take ORAMORPH Oral Solution

3 How to take ORAMORPH Oral Solution

4 Possible side effects

5 How to store ORAMORPH Oral Solution

6 Further information

1. WHAT ORAMORPH ORAL SOLUTION IS AND WHAT IT IS USED FOR

The name of your medicine 1s ORAMORPH Oral Solution 10 mg/5 ml

(called ORAMORPH in this leaflet)

+ It contains a medicine called morphine sulfate This belongs toa
group of medicines called ‘opioid analgesics’

+ Itis used to relieve severe pain

2, BEFORE YOU TAKE ORAMORPH ORAL SOLUTION

Do not take ORAMORPH if:

+ You are allergic (hypersensitive) to morphine sulfate or any of the
other ingredients of ORAMORPH (listed 1n Section 6 below)

+ You have problems with your lungs or breathing such as
‘hypoventilation’ or ‘Chronic Obstructive Pulmonary Disease’ (COPD)

+ You are having an asthma attack

+ You have sudden or recent liver problems

+ You have recently had a head injury

+ You have something called ‘phaeochromocytoma’ This 1s a rare
tumour which 1s not malignant

+ You have fits (convulsions) or increased pressure inside your skull

+ The person taking the medicine 1s in a deep and prolonged
unconscious state (coma)

+ You are addicted to alcohol or have recently consumed large
amounts of alcohol

+ You are taking or have in the last two weeks taken medication to
treat depression such as monoamine-oxidase inhibitors (MAOIs)

+ You have paralytic ileus (loss of intestinal movement)

Do not take this medicine if any of the above apply to you If you are
not sure, talk to your doctor or pharmacist

Take special care with ORAMORPH

Check with your doctor or pharmacist before taking your medicine if

+ You are pregnant, trying to become pregnant or if you are
breast-feeding

+ You have had an operation within the last 24 hours

+ You have a particular lung problem that causes shortness of breath
called emphysema or you have heart failure

+ You have shock (circulatory failure)

+ You have asthma

+ You have gall bladder problems

» You have long term (chronic) liver or kidney problems

+ You are a man who has prostate problems

+ You have an under-active thyroid gland or swelling of your slan
(myxoedema)

+ Your spine 1s unusually curved (kyphoscoliosis)

« You have bowel problems

+ You have an under-active adrenal gland (adrenocortical
insufficiency)

+ You are very overweight

+ You have once been dependent on drugs or alcohol

If you are not sure if any of the above apply to you, talk to your doctor
or pharmacist before taking ORAMORPH

Warnings and precautions

Talk to your doctor, nurse or pharmacist If you expenence any of the

following symptoms while you are taking ORAMORPH

+ Increased sensitivity to pain despite the fact that you are taking
increasing doses (hyperalgesia) Your doctor will decide whether you
will need a change in dose or a change in strong analgesic (“painkiller”)

+ Weakness, fatigue, lack of appetite, nausea, vomiting or low blood
pressure This may be a symptom of your adrenal glands producing
too httle of a hormone called cortisol, and you may need to take a
hormone supplement

+ Loss of libido (sex drive), difficulty getting an erection, menstrual
periods stopping This may be because of your body producing less
sex hormones

Boehringer
Ingelheim

nN
lh

+ You feel that you are becoming dependent on ORAMORPH while
you are using It You may have started to think alot about when you
can take the next dose, even if you do not need it for the pain This
1s particularly important to look out for 1f you have once been
dependent on drugs or alcohol

+ Withdrawal symptoms The most commen withdrawal symptoms
are mentioned in section 3 If this occurs, your doctor may change
the type of medicine or the times between doses

Other medicines and ORAMORPH

Please tell your doctor or pharmacist if you are taking or have recently
taken any other medicines This includes medicines that you buy
without a prescription and herbal medicines This 1s because
ORAMORPH can affect the way some other medicines work Also
some other medicines can affect the way ORAMORPH works

43773 7/GB/1T

In particular tell your doctor or pharmacist if you are talang any of the
following medicines
+ Medicines to help you sleep, make you feel less anxious or calm you
down such as tranqullisers, hypnotics, sedatives, antipsychotics or
tricyche antidepressants
- Taking ORAMORPH together with sedative medicines such as
benzodiazepines or related medicines increases the risk of
drowsiness, difficulties in breathing (respiratory depression),
coma and may be life-threatening Because of this, taking
ORAMORPH together with these types of medicines should only
be considered when other treatment options are not possible
However if your doctor does prescribe ORAMORPH together with
sedative medicines the dose and duration of taking the
treatments together should be hmited by your doctor
- Please tell your doctor about all sedative medicines you are
talang, and follow your doctor’s dose recommendation closely It
could be helpful to inform friends or relatives to be aware of the
signs and symptoms stated above Contact your doctor if you
experience these symptoms
+ Anaesthetics - used during operations
+ Dompendone, metoclopramide or phenothiazine - medicines for
feeling sick (nausea) and being sick (vomiting)
+ Mexiletine and esmolol - for controtling heart rhythm
+ Ritonavir - for HIV infections
+ Cimetidine - for stomach ulcers, indigestion or heartburn
+ Monoamine oxidase Inhibitors (MAOIs) - for depression
+ Rifampicin - used to treat tuberculosis and other infections
+ Gabapentin - for epilepsy and long lasting pain caused by damage
to the nerves

Taking ORAMORPH with food and drink
You should avotd alcohol whilst taking this medicine

Pregnancy and breast-feeding

Talk to your doctor before taking this medicine If you are pregnant,
trying to become pregnant or if you are breast-feeding If you take
this medicine during pregnancy or while breast-feeding, It may slow
down the baby’s breathing If you take this medicine for a long time
whilst pregnant, 1t may mean that the baby will be born showing
signs of withdrawal, which should be treated by a doctor

Operations and anaesthetics

Tell your doctor or pharmacist if you are due to have an operation or
an anaesthetic or if you have had an operation or an anaesthetic
within the last 24 hours

Driving and using machines
You may feel drowsy while taking this medicine If this happens,
do not drive or use any tools or machines

Additional information for patients in the UK
+ Do not drive while taking this medicine until you know how it
affects you
+ It 1s an offence to drive if this medicine affects your ability to drive
+ However, you would not be committing an offence if
- The medicine has been prescribed to treat a medical or dental
problem and
- You have taken it according to the instructions given by the
prescriber or in the information provided with the medicine and
- It was not affecting your ability to drive safely

Talk to your doctor or pharmacist if you are not sure whether it 1s safe
for you to drive while taking this medicine

Important information about some of the ingredients of
ORAMORPH
This medicine contains

+ Ethanol (Alcohol) This product contains 10 volume % ethanol
(alcohol) Each dose contains up to 0 81 g of alcohol which is
equivalent to 20 ml beer or 8 3 mf wine This medicine 1s harmful if
you are addicted to alcohol The amount of alcohol should also be
considered if you are pregnant or breast-feeding, have long term
(chronic) liver problems or epilepsy, or you are a child

+ Sucrose This product contains 30 g of sucrose in the 100 mi bottle,
90 g of sucrose in the 300 ml bottle, and 150 g of sucrose in the
500 ml bottle When taken according to the dosage recommendations
each dose supplies up to 3 g of sucrose You should not take this
product if you have a bowel condition that makes you intolerant to
some sugars such as fructose, glucose, galactose or sucrose

+ Methyl parahydroxybenzoate (E218) and propyl
parahydroxybenzoate (E216) - These may cause allergic reactions in
some people that could occur some time after taking this medicine
The signs may include swelling of the mouth and face, sudden
breathing difficulties and your blood pressure being lower than normal

3 HOWTO TAKE ORAMORPH ORAL SOLUTION

Always take this medicine exactly as your doctor has tofd you
You should check with your doctor or pharmacist If you are not sure

Taking this medicine

+ Take this medicine by mouth only

+ Use a 5 ml plastic spoon to measure your dose
+ They are available from your pharmacist

How much to take
Your doctor will decide the amount of medicine to give you

Adults
+ The most that shouid be taken 1s 5 to 10 ml (one to two teaspoons)
every four hours
Paedratnc population

Children 13 to 18 years
+ The most that should be taken 1s 2 5 to 10 ml (half to two
teaspoons) every four hours

Children 6 to 12 years
+ The most that should be taken Is 2 5 to 5 ml (half to one
teaspoon) every four hours

Children 1 to 5 years
+ The most that should be taken ts 2 5 ml (half a teaspoon) every
four hours

Children under 1 year
+ Do not give this medicine to children under 1 year

Being given more or less of this medicine

+ For some people, 1t may be necessary for the doctor to give a higher
dose

+ For other people (for example the elderly, people with kidney or
liver problems, an underactive adrenal or thyroid gland or prostate
problems, and people that should not be sedated) the doctor may
decide to use a lower dose

Your body may get used to the medicine (tolerance)

+ Do not take more than your doctor has prescribed

+ If you have been taking your medicine for some time you may find
that 1t does not seem to be working as well as it did If this happens,
talk to your doctor

If you take more ORAMORPH than you should

Tf you take more of this medicine than you should, talk to a doctor or
go toa hospital straight away Take the medicine pack with you This
1s so the doctor knows what you have taken

If you take more than you should, the following effects may happen
+ The black circle in the centre of your eyes (pupil) gets smaller

+ You breathe more slowly

«You have low blood pressure

People who have taken an overdose may also get pneumonia
from inhaling vomit or foreign matter, symptoms of this may
include breathlessness, cough and fever

In more severe cases, very high doses could cause your blood circulation
and breathing to slow down and cause unconsciousness for a long time,
or even death In children a high dose may cause fits (convulstons)

If you forget to take ORAMORPH

+ If you forget a dose, take it as soon as you remember it and take
your next dose at the usual time

+ If itis nearly time for the next dose, slap the missed dose This 1s
because the time between doses should be at least 4 hours

+ Do not take a double dose to make up for a forgotten dose

If you stop taking ORAMORPH

Do not stop treatment with this medicine unless it has been agreed
with your doctor Also, it 1s important you do not stop taking your
medicine suddenly This 1s because your body may have got used to
it If you want to stop treatment with ORAMORPH, ask your doctor
how to slowly decrease the dose so you avoid withdrawal symptoms
Withdrawal symptoms may include body aches, tremors, diarrhoea,
stomach pain, feeling sick, flu-hke symptoms, fast heartbeat and
large pupils Psychological symptoms include an intense feeling of
dissatisfaction, anxiety and irntabihty

4 POSSIBLE SIDE EFFECTS

Like all medicines, ORAMORPH can cause side effects, although not
everybody gets them The following side effects may happen with this
medicine, their frequency 1s not known

Allergic reactions
If you have a severe allergic reaction, stop taking this medicine and
see a doctor straight away Signs may include swelling of the mouth

and face, difficulty breathing, dizziness and skin reactions such as
rash and itching

Tell your doctor straight away 1f you notice the following side effects.

You may need urgent medical treatment:

+ Having a headache This could be a sign of increased pressure inside
your skull

+ Feeling dizzy or unsteady when you stand up This could be a sign of
a temporary fall in blood pressure (orthostatic hypotension)

+ Shallow breathing, with a slow heartbeat (bradycardia) and cold
clammy skin

+ Feeling restless, irritable or having changes in your mood

+ Stomach pain caused by spasm (cramps) of the tubes that carry
urine to the bladder or bile to the intestines

+ Difficulty breathing (not linked to an allergic reaction)

+ Dry mouth or sweating

+ Seeing or hearing things that are not there (hallucinations) or
feeling confused

+ Increased sensitivity to pain

+ Dependence on ORAMORPH or withdrawal symptoms (for symptoms
see Section 3 If you stop talang ORAMORPH) This can happen with
any morphine product

Other side effects

+ Feeling sick (nausea) or being sick (vomiting)

+ Constipation, which can be treated with appropriate laxatives

+ Difficulty in passing water (urine)

+ Feeling drowsy

+ Flushing of your face

+ Your heart rate getting faster (tachycardia) or slower (bradycardia) or
fast and uneven (palpitations)

+ Lower body temperature (hypothermia)

+ Lowered sex drive or erection problems

+ Muscles feeling tense

+ The black circle in the centre of your eyes (pupil) getting smaller (rmosis)

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse
This includes any possible side effects not listed in this leaflet You
can also report side effects directly (see details below) By reporting
side effects you can help provide more information on the safety of
this medicine

United Kingdom

Yellow Card Scheme

Website www mhra gov uk/yellowcard or search for MHRA Yellow
Card in the Google Play or Apple App Store

Treland

HPRA Pharmacovigilance
Earlsfort Terrace

IRL - Dublin 2

Tel +353 16764971

Fax +353 1 6762517
Website www hpra te
e-mail medsafety@hpra 1e

5, HOW TO STORE ORAMORPH ORAL SOLUTION
Keep out of the reach and sight of children

Do not use this medicine after the expiry date which 1s stated on the
bottle label and the outer carton The expiry date refers to the last day
of the month

Do not store ORAMORPH above 25°C Store in the onginal container
in order to protect from hight

Please return any remaining medicine to your pharmacist 3 months
after first opening

Medicines should not be disposed of via wastewater or household
waste Ask your pharmacist how to dispose of medicines no longer
required These measures will help to protect the environment

6 FURTHER INFORMATION

What ORAMORPH contains

+ Each 5 ml contains 10 mg of morphine sulfate as the active
ingredient

+ The other ingredients are alcohol (ethanol), corn syrup, sucrose,
methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate
(E216) and punfied water

What ORAMORPH [ooks like and content of the pack

ORAMORPH 1s a solution and 1s available 1n bottles of 100, 250,

300 and 500 m! The bottles come in cartons

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer
The Marketing Authorisation for ORAMORPH 1s held by

Boehringer Ingelheim International GmbH,
Binger Strasse 173, 55216 Ingelheim am Rhein, Germany

and the solution 1s manufactured by

Istituto de Angeh Srl at
Localita Prulli S1 Sotto n 103/C, 50066 Reggello (FI), Italy

This leaflet was revised in March 2019

© Boehringer Ingelheim Limited 2019
437737/GB/17

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For oral administration only

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medicine until you know how It makes
you feel. See the leaflet inside for
“further information.

| Avold alcoholic drink.
| Keep out of the sight and reach
of children.

Oramorphe
Oral Solution
10 mg/5 ml

morphine sulfate | Discard 3 months after opening,

| Date opened | 1

DO NOT ACCEPT IF SEAL ON THE BOTTLE
| ISBROKEN.

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| | information.
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1 0 mg/5 ml Keep out of the sight and reach of children.

morphine sulfate DO NOT ACCEPT IF SEAL ON THE BOTTLE IS BROKEN,

To be taken as directed by the prescriber. Do not store above 25°C, Store in the

This bottle contains a total of tainer in order t
600 mg of morphine sulfate. eae nln be i sepa ig

This product also contains sucrose, 10 vol% ethanol, methyl parahydroxybenzoate

Each 5 ml contains (E218) and propyl parahydroxybenzoate (E216).
Morphine Sulfate 10 mg See enclosed leaflet for further information.
Can cause addiction eseleh aid rfearlery are
Contail ioid International GmbH,
omare.ope Ingelheim am Rhein, Germany.

300 ml Discard 3 months after opening. py 44598/0114

Date opened / / PA775/14/1
430256/GB/8

File information Mandatory in

Issue date of TD: 08/01/2019
PPM SKU: 7003877
Issuedate of artwork: 29/05/2019

Print colors: PAN BLACK PAN 298 PAN 151

Mat, No, Pack. Site: 430256/GB/8
Min, font size: 8 pl -
V4.0 01/0CT/2012 (please do not change or remove il)

Legend case version:
Perigord No: 504832 P1

Techinical information
a = Batch No, —— b = Expiry date

tc = Manvfacturing date

d= Price/Sample/Cinic

Technical colors

BrDiecu-Legendcase Free area BiLacquer-tree
Bi-Braille | | Bi-Function-vamnish BI-Spot-varnish

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Technical information
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Package Leaflet: Information for the User.

Oramorphe Oral Solution
10 mg/5 ml

(morphine sulfate)

Read all of this leaflet carefully before you start taking this medicine,

+ Keep this leaflet. You may need to read it again.

+ Ifyou have any further questions, ask your doctor or pharmacist.

+ This medicine has been prescribed for you, Do not pass It onto
others. Itmay harm them, even If thelr symptoms are the same as
yours,

+ If any of the side effects gets troublesome or serious, or if you
notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist.

In this leaflet:

1, What ORAMORPH Oral Solution is and what it is used for
2. Before you take ORAMORPH Oral Solution

3, How to take ORAMORPH Oral Solution

4. Possible side effects

5, How to store ORAMORPH Oral Solution:

6, Further information

1, WHAT ORAMORPH ORAL SOLUTION IS AND WHAT IT IS USED FOR

‘The name of your medicine }s ORAMORPH Oral Solution 10 mg/5 mi

(called ORAMORPH in this leaflet),

« Itcontains a medicine called morphine sulfate. This belongs to a
group of medicines called ‘opioid analgesics’

+ Tis used to relleve severe pain

2, BEFORE YOU TAKE ORAMORPH ORAL SOLUTION

Do not take ORAMORPH If:

+ You are allergic (hypersensitive) to morphine sulfate or any of the
‘other Ingredients of ORAMORPH (listed in Section 6 below)

+ You have problems with your lungs or breathing such as
‘hypoventilation’ or ‘Chronic Obstructive Pulmonary Disease’ (COPD)

+ You ate having an asthma attack

+ You have sudden or recent liver problems.

+ You have recently had a head injury

+ You have something called ‘phaeochromocytoma’. This Isa rare
tumour which fs not malignant

+ You have fits (convulsions) or increased pressure Inside your skull

+ The person taking the medicine Is in a deep and prolonged
unconsclous state (coma)

« You are addicted to alcohol or have recently consumed large
amounts of alcohol

+ You are taking or have in the last two weeks taken medication to
treat depression such as monoamine-oxidase inhibitors (MAOIs)

+ You have paralytic ileus (loss of intestinal movement)

Do not take this medicine If any of the above apply to you, If you
are not sure, talk to your doctor or pharmacist.

Take special care with ORAMORPH

Check with your doctor or pharmacist before taking your medicine if;

+ You are pregnant, trying to become pregnant or if you are
breast-feeding

+ You have had an operation within the last 24 hours

+ You have a particular lung problem that causes shortness of breath
called emphysema or you have heart failure

+ You have shock (circulatory failure)

+ You have asthma

+ You have gall bladder problems

+ You have long term (chronic) liver or kidney problems

+ You are a man Who has prostate problems

+ You have an under-aetive thyroid gland or swelling of your skin
(mytoedema)

+ Your spine s unusually curved (kyphascollosts)

+ You have bowel problems

+ You have an under-active adrenal gland (adrenocortical
insufficlency)

+ You are very overweight

Ifyou are not sure if any of the above apply to you, talk to your
doctor or pharmacist before taking ORAMORPH.

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Taking other medicines

Please tell your doctor or pharmacist if you are (aking or have recently
taken any other medicines. This includes medicines that you buy
without a prescription and herbal medicines. This s because
ORAMORPH can affect the way some other medicines work. Also
some other medicines can affect the way ORAMORPH works.

{ny particular tell your doctor or pharmacist if you are taking any of the

following medicines:

+ Medicines to help you sleep, make you feel less anxious or calm you
down such as tranquilisers, hypnotics, sedatives, antipsychotics or
uricyelic antidepressants

+ Anaesthetics - used during operations

+ Domperidone, metoclopramide or phenothiazine - medicines for
feeling sick (nausea) and being sick (vomiting)

+ Mexiletine and esmolol - for controlling heart rhythm

+ Ritonavir - for HIV infections

+ Cimetidine - for stomach ulcers, indigestion o heartburn

+ Monoamine oxidase Inhibitors (MAOIs) ~ for depression

+ Rifamplcin - used to treat tuberculosis and other infections

+ Gabapentin - for epilepsy and long lasting pain caused by damage ta
the nerves

Taking ORAMORPH with food and drink
You should avoid alcohol whilst taking this inedicine.

Pregnancy and breast-feeding

‘Talk to your doctor before taking this medicine if you are pregnant,
trying to become pregnant or if you are breast-feeding. If you take this
medicine during pregnancy or while breast-feeding, it may slow down
the baby’s breathing. If you take this medicine for a tong time whilst
pregnant, it may mean that the baby will be born showing signs of
withdrawal.

Operations and anaesthetics

Tell your doctor or pharmacist if you are due to have an operation
‘or an anaesthetic or If you have had an operation or an anaesthetic
within the last 24 hours.

Driving and using machines
You may feel drowsy while taking this medicine. If this happens,
do not drive or use any tools or machines,

Additional information for patients in the UK:
+ Do not drive while taking this medicine until you know how it
affects you,
+ Itisan offence to drive if this medicine affects your ability to drive.
* However, you would not be committing an offence if:
~The medicine has been prescribed to treat a medical or dental
problem and
= You have taken it according to the instructions given by the
prescriber or in the Information provided with the medicine and
~ Itwas not affecting your ability to drive safely

Talk to your doctor or pharmacist if you are not sure whether itis sale
fof you to drive while taking this medicine.

Important information about some of the ingredients of ORAMORPH
This medicine contains:

+ Ethanol (Alcohol): This product contains 10 volume % ethanol
(alcohol). Each dose contains up to 0.81 g of alcohol which is
equivalent to 20 ml beer or 8.3 ml wine. This medicine fs harmful it
you are addicted to alcohol, The amount of alcohol should also be
considered if you are pregnant or breast-feeding, have long term
(chronic) liver problems or epilepsy, or you are a child

+ Sucrose: This product contains 30 g of suctose in the 100 m! bottle,
‘90 g of sucrose in the 300 ml bottle, and 150 of sucrose In the
500 ml bottle. When taken according to the dosage recommendations
each dose supplies up to 3 g of sucrose, You should not take this
product if you have a bowel condition that makes you intolerant to
some sugars such as fructose, glucose, galactose or sucrose

+ Methyl parahydroxybenzoate (E218) and propy!
parahydroxybenzoate (E216) These may cause allergic reactions in
some people that could occur some time after taking this medicine,
The signs may include swelling of the mouth and face, sudden
breathing difficulties and your blood pressure being lower than
normal

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3 HOWTO TAKE ORAMORPH ORAL SOLUTION

Always take this medicine exactly as your doctor has told you
You should check with your doctor or pharmacist If you are not sure

‘Taking this medicine

+ Take this medicine by mouth only

+ Use a 5 ml plastic spoon to measure your dose
+ They ate available from your pharmacist

How much to take
Your doctor will decide the amount of medicine to give you

Adults
The most that should be taken 1s 5 to 18 ml (one to two teaspoons)
every four hours

Paediatric population

Children 13 to 18 years
+ The most that should be taken 1s 2 5 to 10 ml (half to two
teaspoons) every four hours

Children 6 to 12 years
+ The most that should be taken Is 2 5 to 5 ml (half to one
teaspoon) every four hours

Children 1 to 5 years
+ The most that should be taken 1s 2 5 ml (half a teaspoon) every
four hours

Children under 1 year
Do not give this medicine to children under 1 year

Being given more of less of this medicine

+ For some people, it may be necessary for the doctor to give a higher dose

+ For other people (for example the elderly, people with kidney or hver
problems, an underactive adrenal or thyroid gland or prostate
problems, and people that should not be sedated) the doctor
may decide to use a lower dose

Your body may get used to the medicine (tolerance)

+ Do not take more than your doctor has prescribed

+ Ifyou have been taking your medicine for some time you may find
that it does not seem to be working as well as it did If this happens,
talk to your doctor

If you take more ORAMORPH than you should

Ifyou take more of this medicine than you should, talk to.a doctor or
go to a hospital straight away Take the medicine pack with you This
Is so the doctor knows what you have taken

Ifyou take more than you should, the follovang effects may happen
‘The black circte in the centre of your eyes (pupil) gets smaller

+ You breathe more slowly.

+ You have low blood pressure

In more severe cases, very high doses could cause your blood
circulation to slow down and cause unconscrousness fora long time,
‘or even death In children a high dose may cause fits (convulsions)

If you forget to take ORAMORPH
Hf you forget a dose, take it as soon as you remember it and take
your next dose at the usual time
If ts neatly time for the next dose, skip the missed dose This is
because the time between doses should be at feast 4 hours

+ Donot take a double dose to inake up for a forgotten dose

you stop takang ORAMORPH

Its important to talk to your doctor if you want to stop taking your
medicine Do not stop taking your medicine suddenly This 1s because
your body may have got used to it Also, you may need to have your
dose lowered slowly

4 POSSIBLE SIDE EFFECTS

Like all medicines, ORAMORPH can cause side effects, although not
everybody gets them The following side effects may happen with this
medicine

Allergic reactions

Ifyou have a severe allergic reaction, stop talang this medicine and see

a doctor straight away Signs may include swelling of the inouth and face,
difficulty breathing, dizziness and skin reactions such as rash and itching.

Tell your doctor straight away if you notice the following side effects

You may need urgent medical treatment

+ Having aheadache This could be a sign of increased pressure inside
your skull

+ Feeling dizzy or unsteady when you stand up This could be a sign of
a temporary fall in blood pressure {orthostatic hypotension)

+ Shallow breathing, with a stow heartbeat (bradycardia) and cold
clammy skin
Feehng restless, writable of having changes in your mood

+ Stomach pain caused by spasin (cramps) of the tubes that carry
unne to the bladder or bite to the intestines

+ Difficulty breathing (not linked to an allergic reaction)

Other side effects

+ Feeling sick (nausea) or being sick (vomiting)
Constipation, which can be treated with appropnate laxatives

+ Difficulty in passing water (uane}

+ Feeling drowsy

+ Dry mouth, sweating and flushing of your face
Your heart rate getting faster (tachycardia) or slower (bradycardia) or
fast and uneven (palpitations)

+ Lower body temperature (hypothettnta)

+ Lowered sex dnve or erection problems

+ Seeing or heanng things that ate not there (hallucinations) or
feeling confused
Muscles feehng tense

+ The black circle in the centee of your eyes (pupil) getting smaller
(mosis)
Dependence on ORAMORPH This can happen with any morphine
product

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse
This includes any possible side effects not hsted in this leaflet You
can also report side effects directly (see details below) By reporting
side effects you can help provide more information on the safety of
this medicine

United Kingdom
Yellow Card Scheme
Website www mhra gov uk/yellowcard

Ireland

HPRA Pharinacovglance
Earlsfort Terrace

IRL~ Dubhn 2

Tel +353 16764971

Fax +353 16762517
Website www hpra te
e-mail medsafety@hpra te

5 HOWTO STORE ORAMORPH ORAL SOLUTION

Keep out of the reach and sight of children

Do not use this medicine after the expiry date whichis stated on the
bottle label and the outer carton The expiry date refers to the last day
of the month

Do not store ORAMORPH above 25°C Store in the onginal container
im order to protect from hght

Please return any remaining medicine to your pharmacist 3 months
after first opening

Medicines should not be disposed of ia wastewater or household
waste Ask your pharmacist how to dispose of methcines no longer
required These measures will help to protect the environment.

6 FURTHER INFORMATION

What ORAMORPH contains

+ Each 5 mi contains 10 mg of morphine sulfate as the active
ingredient

+ The other ingredients are alcohol (ethanol), corn syrup, sucrose,
methyl parahydroxybenzoate (E218), propyl
patahydroxybenzoate (E216) and punfied water

What ORAMORPH looks like and content of the pack

ORAMORPH 1s a Solution and is available in bottles of 100, 250,

300 and 500 ml The bottles come mn cartons

Not ail pack sizes may be marketed

Marketing Authonsation Holder and Manufacturer
The Marketing Authonsation for ORAMORPH 1s held by

Boehnnger Ingelheim Limited, Ellesfield Avenue,
Bracknell, Berkshore, RG12 8YS, United Kingdom

and the solution 1s manufactured by

Istituto de Ange S r| at
Localita Prulli Si Sotto n 103/C, 50066 Reggello (Fl), Italy

This leaflet was revised in June 2015

© Boehringer Ingelheim Limited 2015.

sara7Gens

+ You have an under:
insufficiency)
+ You are very overweight

= Package Leaflet: Information for the User.

Oramorphe Oral Solution
10 mg/5 ml

(morphine sulfate)

Read all of this leaflet carefully before you start taking thls medicine.

« Keep this leaflet. You may need to read {t again.

+ you have any further questions, ask your doctor ot pharmacist.

+ This medicine has been prescribed for you. Do not pass It on to
others, It may harm them, even if their symptoms are the same as

yours,

+ If any of the side effects gets troublesome or serious, or if you
notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist.

In this teaflet:

1, What ORAMORPH Oral Solution is and what itis used for
2. Before you take ORAMORPH Oral Solution

3. How to take ORAMORPH Oral Solution

4, Possible side effects,

5, How to store ORAMORPH Oral Solution

6. Further Information

1. WHAT ORAMORPH ORAL SOLUTION IS AND WHATIT 1S USED FOR

The name of your medicine is ORAMORPH Oral Solution 10 mg/S mt

(called ORAMORPH In this teafled)

+ It contains a medicine called morphine sulfate. This belongs toa
group of medicines called ‘oplold analgesics!

+ Its Used (o relieve severe pain

2, BEFORE YOU TAKE ORAMORPH ORAL SOLUTION

Do not take ORAMORPH ift

+ You are allergic (hypersensitive) to morphine sulfate or any of the
‘other ingredients of ORAMORPH (listed in Section 6 below)

+ You have problems with your lungs or breathing such as
‘hypoventilation’ or ‘Chronic Obstructive Pulmonary Disease’ (COPD)

+ You are having an asthma attack

+ You have sudden or recent liver problems

+ You have recently had a head injury

+ You have something called ‘pheochromocytoma’. This Isa rare
tumour which fs not malignant

+ You have fits (convulsions) or increased pressure inside your skull

+ The person taking the medicine \s in a deep and prolonged
unconscious state (coma)

+ You are addicted to alcohol or have recently consumed large
amounts of alcoho!

+ You are taking or have in the last two weeks taken medication to
‘teat depression such as monoamine-oxidase inhibitors (MAOIs)

+ You have paralytic ileus (loss of intestinal movement)

Do not take this medicine if any of the above apply to you. If you
are not sure, talk to your doctor or pharmacist.

Take special care with ORAMORPH

Check with your doctor ot pharmacist before taking your medicin

+ You are pregnant, trylng to become pregnant orf you are
breast-feeding

+ You have had an operation within the last 24 hours

+ You have @ particular lung problem that causes shortness of breath
called emphysema or you have heart failure

+ You have shock (circulatory failure)

+ You have asthma

+ You have gall bladder problems

+ You have long term (chronic) liver or kidney problems

+ You are a man who has prostate problems

+ You have an under-active thyroid gland or swelling of your skin
(myxoedema)

+ Your spine is unusually curved (kyphoscoliosis)

+ You have bowel problems.

tive adrenal gland (adrenocortical

Ityou ate not sure if any of the above apply to you, talk to your
doctor or phatmatist before taking ORAMORPH

ce

File information

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Taking other medicines

Please tell your doctor or pharmacist if you are taking ot have recently
taken any other medicines. This Includes medicines that you buy
without a prescription and herbal medicines. This is because
ORAMORPH can affect the way some other medicines work. Also
some other medicines can affect the vray ORAMORPH Works.

In particular tell your doctor or pharmacist If you are ta