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MYLOXIFIN 5 MG/2.5 MG PROLONGED-RELEASE TABLETS

Active substance(s): NALOXONE HYDROCHLORIDE DIHYDRATE / OXYCODONE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Myloxifin 5 mg/2.5 mg prolonged-release tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Myloxifin 5 mg/2.5 mg
Each prolonged-release tablet contains 5 mg of oxycodone hydrochloride (equivalent
to 4.5 mg oxycodone) and 2.5 mg of naloxone hydrochloride (as 2.74 mg naloxone
hydrochloride dihydrate, equivalent to 2.25 mg naloxone).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release tablet.
Myloxifin 5 mg/2.5 mg
White, round, biconvex prolonged-release tablet with a diameter of 4.7 mm and a
height of 2.9 - 3.9 mm

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Severe pain, which can be adequately managed only with opioid analgesics.
The opioid antagonist naloxone is added to counteract opioid-induced constipation by
blocking the action of oxycodone at opioid receptors locally in the gut.
Myloxifin is indicated in adults.

4.2

Posology and method of administration
Posology

Analgesia
The analgesic efficacy of Myloxifin is equivalent to oxycodone hydrochloride
prolonged-release formulations.
The dose should be adjusted to the intensity of pain and the sensitivity of the
individual patient. Unless otherwise prescribed, Myloxifin should be administered as
follows:
Adults
The usual starting dose for opioid naive patients is 10 mg/5 mg of oxycodone
hydrochloride/ naloxone hydrochloride at 12 hourly intervals.
Lower strengths are available to facilitate dose titration when initiating opioid therapy
and for individual dose adjustment.
Patients already receiving opioids may be started on higher doses of
Oxycodone/Naloxone Myloxifin depending on their previous opioid experience.
Myloxifin 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy
and individual dose adjustment.
The maximum daily dose of Myloxifin is 160 mg oxycodone hydrochloride and 80
mg naloxone hydrochloride. The maximum daily dose is reserved for patients who
have previously been maintained on a stable daily dose and who have become in need
of an increased dose. Special attention should be given to patients with compromised
renal function and patients with mild hepatic impairment if an increased dose is
considered. For patients requiring higher doses of Myloxifin, administration of
supplemental prolonged-release oxycodone hydrochloride at the same time intervals
should be considered, taking into account the maximum daily dose of 400 mg
prolonged-release oxycodone hydrochloride. In the case of supplemental oxycodone
hydrochloride dosing, the beneficial effect of naloxone hydrochloride on bowel
function may be impaired.
After complete discontinuation of therapy with Myloxifin with a subsequent switch to
another opioid a worsening of the bowel function can be expected.
Some patients taking Myloxifin according to a regular time schedule require
immediate-release analgesics as “rescue” medication for breakthrough pain.
Myloxifin is a prolonged-release formulation and therefore not intended for the
treatment of breakthrough pain. For the treatment of breakthrough pain, a single dose
of “rescue medication” should approximate one sixth of the equivalent daily dose of
oxycodone hydrochloride. The need for more than two “rescues” per day is usually an

indication that the dose of Myloxifin requires upward adjustment. This adjustment
should be made every 1-2 days in steps of twice daily 5 mg/2.5 mg, or where
necessary <2.5 mg/1.25 mg or> 10 mg/5 mg, oxycodone hydrochloride/naloxone
hydrochloride until a stable dose is reached. The aim is to establish a patient-specific
twice daily dose that will maintain adequate analgesia and make use of as little rescue
medication as possible for as long as pain therapy is necessary. (dose corrected) peak plasma concentrations should be taken into account when the
2.5 mg/1.25 mg tablet is used.>
Myloxifin is taken at the determined dose twice daily according to a fixed time
schedule. While symmetric administration (the same dose mornings and evenings)
subject to a fixed time schedule (every 12 hours) is appropriate for the majority of
patients, some patients, depending on the individual pain situation, may benefit from
asymmetric dosing tailored to their pain pattern. In general, the lowest effective
analgesic dose should be selected.
In non-malignant pain therapy, daily doses of up to 40 mg/20 mg oxycodone
hydrochloride/naloxone hydrochloride are usually sufficient, but higher doses may be
needed.
For doses not realisable/practicable with this strength other strengths of this medicinal
product are available.
Analgesia
Paediatric population
The safety and efficacy of Myloxifin in children and adolescents aged below 18 years
has not been established. No data are available.
Elderly patients
As for younger adults the dose should be adjusted to the intensity of the pain and the
sensitivity of the individual patient.

Patients with impaired hepatic function
A clinical trial has shown that plasma concentrations of both oxycodone and naloxone
are elevated in patients with hepatic impairment. Naloxone concentrations were
affected to a higher degree than oxycodone (see section 5.2). The clinical relevance of
a relative high naloxone exposure in hepatic impaired patients is yet not known.
Caution must be exercised when administering Myloxifin to patients with mild
hepatic impairment (see section 4.4). In patients with moderate and severe hepatic
impairment Myloxifin is contraindicated (see section 4.3).

Patients with impaired renal function
A clinical trial has shown that plasma concentrations of both oxycodone and naloxone
are elevated in patients with renal impairment (see section 5.2). Naloxone
concentrations were affected to a higher degree than oxycodone. The clinical
relevance of a relative high naloxone exposure in renal impaired patients is yet not
known. Caution should be exercised when administering Myloxifin to patients with
renal impairment (see section 4.4).
Method of administration
For oral use.
These prolonged-release tablets are taken in the determined dose twice daily in a
fixed time schedule.
The prolonged-release tablets may be taken with or without food with sufficient
liquid.
Myloxifin 5 mg/2.5 mg
Myloxifin must be swallowed whole with sufficient liquid, and must not be divided,
broken, chewed or crushed.
Duration of use
Myloxifin should not be administered for longer than absolutely necessary. If longterm treatment is necessary in view of the nature and severity of the illness, careful
and regular monitoring is required to establish whether and to what extent further
treatment is necessary.

Analgesia
When the patient no longer requires opioid therapy, it may be advisable to taper the
dose gradually (see section 4.4).
If the patient does not require opioid treatment anymore, it is advisable to withdraw
the medicinal product gradually, over about a week, in order to reduce the risk of a
withdrawal reaction (see section 4.4).

4.3

Contraindications


Hypersensitivity to the active substances or to any of the excipients listed in
section 6.1,



severe respiratory depression with hypoxia and/or hypercapnia,



severe chronic obstructive pulmonary disease,



Cor pulmonale,



severe bronchial asthma,



non-opioid induced paralytic ileus,
moderate to severe hepatic impairment.

4.4

Special warnings and precautions for use
Respiratory depression
The major risk of opioid excess is respiratory depression. Caution must be exercised
when administering Myloxifin to elderly or infirm patients, patients with opioidinduced paralytic ileus, patients presenting severely impaired pulmonary function,
patients with sleep apnoea, myxoedema, hypothyroidism, Addison’s disease (adrenal
cortical insufficiency), toxic psychosis, cholelithiasis, prostate hypertrophy,
alcoholism, delirium tremens, pancreatitis, hypotension, hypertension, pre-existing
cardiovascular diseases, head injury (due to the risk of increased intracranial
pressure), epileptic disorder or predisposition to convulsions, or patients taking MAO
inhibitors.
Hepatic or renal impairment
Caution must also be exercised when administering Myloxifin to patients with mild
hepatic or renal impairment. A careful medical monitoring is particularly necessary
for patients with severe renal impairment.
Diarrhoea
Diarrhoea may be considered as a possible effect of naloxone.
Long-term treatment
In patients under long-term opioid treatment with higher doses of opioids, the switch
to Myloxifin can initially provoke withdrawal symptoms. Such patients may require
specific attention.
Myloxifin is not suitable for the treatment of withdrawal symptoms.
During long-term administration, the patient may develop tolerance to the medicinal
product and require higher doses to maintain the desired effect. Chronic
administration of Myloxifin may lead to physical dependence. Withdrawal symptoms
may occur upon the abrupt cessation of therapy. If therapy with Myloxifin is no
longer required, it may be advisable to reduce the daily dose gradually in order to
avoid the occurrence of withdrawal syndrome.
Psychological dependence (addiction)

There is potential for development of psychological dependence (addiction) to opioid
analgesics, including Myloxifin. Myloxifin should be used with particular care in
patients with a history of alcohol and drug abuse. Oxycodone alone has an abuse
profile similar to other strong agonist opioids.
In order not to impair the prolonged-release characteristic of the prolonged-release
tablets, the prolonged-release tablets must not be broken, chewed or crushed.
Breaking, chewing or crushing the prolonged-release tablets for ingestion leads to a
faster release of the active substances and the absorption of a possibly fatal dose of
oxycodone (see section 4.9).
Patients who have experienced somnolence and/or an episode of sudden sleep onset
must refrain from driving or operating machines. Furthermore, a reduction of the dose
or termination of therapy may be considered. Because of possible additive effects,
caution should be advised when patients are taking other sedating medicinal products
in combination with Myloxifin (see sections 4.5 and 4.7).
Alcohol
Concomitant use of alcohol and Myloxifin may increase the undesirable effects of
Myloxifin; concomitant use should be avoided.
Paediatric population
Studies have not been performed on the safety and efficacy of Myloxifin in children
and adolescents below the age of 18 years. Therefore, their use in children and
adolescents under 18 years of age is not recommended.
Cancer
There is no clinical experience in patients with cancer associated to peritoneal
carcinomatosis or with sub-occlusive syndrome in advanced stages of digestive and
pelvic cancers. Therefore, the use of Myloxifin in this population is not
recommended.
Surgery
Myloxifin is not recommended for pre-operative use or within the first 12-24 hours
post-operatively. Depending on the type and extent of surgery, the anaesthetic
procedure selected, other co-medication and the individual condition of the patient,
the exact timing for initiating post-operative treatment with Myloxifin depends on a
careful risk-benefit assessment for each individual patient.
Abuse
Any abuse of Myloxifin by drug addicts is strongly discouraged.
If abused parenterally, intranasally or orally by individuals dependent on opioid
agonists, such as heroin, morphine, or methadone, Myloxifin is expected to produce
marked withdrawal symptoms - because of the opioid receptor antagonist

characteristics of naloxone - or to intensify withdrawal symptoms already present (see
section 4.9).
These tablets intended for oral use only. Abusive parenteral injections of the
prolonged-release tablet constituents (especially talc) can be expected to result in
local tissue necrosis and pulmonary granulomas or may lead to other serious,
potentially fatal undesirable effects.
The empty prolonged-release tablet matrix may be visible in the stool.
Doping
Athletes must be aware that this medicine may cause a positive reaction to ‘antidoping’ tests. The use of Myloxifin as a doping agent may become a health hazard.

4.5

Interaction with other medicinal products and other forms of interaction
Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics,
antidepressants, phenothiazines, neuroleptics, antihistamines and antiemetics) may
enhance the CNS-depressant effect (e.g. respiratory depression) of Myloxifin.
Alcohol may enhance the pharmacodynamic effects of Myloxifin; concomitant use
should be avoided.
Clinically relevant changes in International Normalised Ratio (INR or Quick-value)
in both directions have been observed in individuals if oxycodone and coumarin
anticoagulants are co-applied.
Oxycodone is metabolised primarily via the CYP3A4 pathways and partly via the
CYP2D6 pathway (see section 5.2). The activities of these metabolic pathways may
be inhibited or induced by various co-administered drugs or dietary elements.
Myloxifin doses may need to be adjusted accordingly.
CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin,
telithromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole, itraconazole,
posaconazole), protease inhibitors (e.g. ritonavir, indinavir, nelfinavir, saquinavir),
cimetidine and grapefruit juice may cause decreased clearance of oxycodone which
could lead to an increase in oxycodone plasma concentrations. A reduction in the
dose of Myloxifin and subsequent re-titration may be necessary.
CYP3A4 inducers, such as rifampicin, carbamazepine, phenytoin and St. John's Wort,
may induce the metabolism of oxycodone and cause increased clearance of the drug,
resulting in a decrease in oxycodone plasma concentrations. Caution is advised and
further titration may be necessary to reach an adequate level of symptom control.

Theoretically, medicinal products that inhibit CYP2D6 activity, such as paroxetine,
fluoxetine and quinidine, may cause decreased clearance of oxycodone which could
lead to an increase in oxycodone plasma concentrations. Concomitant administration
with CYP2D6 inhibitors had an insignificant effect on the elimination of oxycodone
and also had no influence on the pharmacodynamic effects of oxycodone.
In vitro metabolism studies indicate that no clinically relevant interactions are to be
expected between oxycodone and naloxone. The likelihood of clinically relevant
interactions between paracetamol, acetylsalicylic acid or naltrexone and the
combination of oxycodone and naloxone in therapeutic concentrations is minimal.

4.6

Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of Myloxifin in pregnant women and during
childbirth. Limited data on the use of oxycodone during pregnancy in humans reveal
no evidence of an increased risk of congenital abnormalities. For naloxone,
insufficient clinical data on exposed pregnancies are available. However, systemic
exposure of the women to naloxone after use of Myloxifin is relatively low (see
section 5.2).
Both oxycodone and naloxone pass into the placenta. Animal studies have not been
performed with oxycodone and naloxone in combination (see section 5.3). Animal
studies with oxycodone or naloxone administered as single drugs have not revealed
any teratogenic or embryotoxic effects.
Long-term administration of oxycodone during pregnancy may lead to withdrawal
symptoms in the newborn. If administered during childbirth, oxycodone may evoke
respiratory depression in the newborn.
Myloxifin should only be used during pregnancy if the benefit outweighs the possible
risks to the unborn child or neonate.
Breastfeeding
Oxycodone passes into the breast milk. A milk-plasma concentration ratio of 3.4:1
was measured and oxycodone effects in the suckling infant are therefore conceivable.
It is not known whether naloxone also passes into the breast milk. However, after use
of oxycodone/naloxone systemic naloxone levels are very low (see section 5.2).
A risk to the suckling child cannot be excluded in particular following intake of
multiple doses of Myloxifin by the breastfeeding mother.
Breastfeeding should be discontinued during treatment with Myloxifin.
Fertility
There are no data with respect to fertility.

4.7

Effects on ability to drive and use machines
Myloxifin has moderate influence on the ability to drive and use machines. This is
particularly likely at the beginning of treatment with Myloxifin, after dose increase or
product rotation and if Myloxifin is combined with other CNS depressant agents.
Patients stabilised on a specific dose will not necessarily be restricted. Therefore,
patients should consult with their physician as to whether driving or the use of
machinery is permitted.
Patients being treated with Myloxifin and presenting with somnolence and/or sudden
sleep episodes must be informed to refrain from driving or engaging in activities
where impaired alertness may put themselves or others at risk of serious injury or
death (e.g. operating machines) until such recurrent episodes and somnolence have
resolved (see sections 4.5 and 4.7).

4.8
Undesirable effects
Undesirable effects are presented below in three sections: the treatment of pain, the
active substance oxycodone hydrochloride.
The following frequencies are the basis for assessing undesirable effects:
Very common ≥1/10
Common
≥1/100 to <1/10
Uncommon
≥1/1,000 to <1/100
Rare
≥1/10,000 to <1/1,000
Very rare
<1/10,000
Not known
cannot be estimated from the available data
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Undesirable effects for treatment of pain
System organ class
MedDRA
Immune system
disorders

Common

Metabolism and
nutrition disorders

Decreased appetite
up to loss of
appetite

Psychiatric disorders

Insomnia

Uncommon

Rare

Very rare

Not known

Hyper-sensitivity

Restlessness,
Abnormal
thinking,
Anxiety,
Confusion state,
Depression,
libido decreased,

Euphoric mood,
Hallucination,
Nightmares

System organ class
MedDRA

Common

Uncommon

Rare

Very rare

Not known

Nervousness
Nervous system
disorders

Dizziness,
Headache,
Somnolence,

Eye disorders

Ear and labyrinth
disorders

Vertigo

Angina pectoris2,
Palpitations
Hot flush

Respiratory, thoracic
and mediastinal
disorders
Gastrointestinal
disorders

Abdominal pain,
Constipation,
Diarrhoea,
Dry mouth,
Dyspepsia,
Vomiting,
Nausea,
Flatulence

Hepatobiliary disorders

Skin and subcutaneous
tissue disorders

Tachycardia

Decrease in blood
pressure,
Increase in blood
pressure
Dyspnoea,
Rhinorrhoea,
Cough

Yawning

Respiratory
depression

Abdominal
distention

Tooth
disorder

Eructation

Hepatic enzymes
increased,
Biliary colic
Pruritus,
Skin reactions,
Hyperhidrosis

Musculo-skeletal and
connective tissue
disorders

Muscle spasms,
Muscle twitching,
Myalgia

Renal and urinary
disorders

Micturition
urgency

Reproductive system
and breast disorders

Paraesthesia,
Sedation

Visual
impairment

Cardiac disorders

Vascular disorders

Convulsions1
Disturbance in
attention
dysgeusia
Speech disorder
Syncope
Tremor
lethargy

Urinary retention

Erectile
dysfunction

System organ class
MedDRA
General disorders and
administration site
conditions

Common

Uncommon

Asthenic,
fatigue

Drug withdrawal
syndrome,
Chest pain,
Chills,
Malaise,
Pain,
Peripheral,
oedema,
thirst
Weight decreased

Investigations
Injury, poisoning and
procedural
complications
1
2

Rare

Very rare

Not known

Weight
increased

Injury from
accidents

particularly in persons with epileptic disorder or predisposition to convulsions
particular in patients with history of coronary artery disease

For the active substance oxycodone hydrochloride, the following additional
undesirable effects are known
Due to its pharmacological properties, oxycodone hydrochloride may cause
respiratory depression, miosis, bronchial spasm and spasms of nonstriated muscles as
well as suppress the cough reflex.
System organ
class
MedDRA
Infections and
infestations

Common

Uncommon

Rare

Anaphylact
ic reactions

Metabolism and
nutrition disorders

Nervous system
disorders

Not
known

Herpes
simplex

Immune system
disorders

Psychiatric
disorders

Very
rare

Dehydration

Altered
mood and
personality
changes
Decreased activity
Psychomotor
hyperactivity

Increased
appetite

Agitation,
Perception
disturbances (e.g.
derealisation),
Drug dependence

Aggression

Concentration
impaired,
Migraine,

Hyperalgesia

Hypertonia ,
Involuntary
muscle
contractions,
Hypoaesthesia,
Abnormal co-

ordination
Ear and labyrinth
disorders

Hearing
impaired

Vascular disorders

Vasodilation

Respiratory, thoracic
and mediastinal
disorders

Dysphonia

Gastrointestinal
disorders

Hiccups

Dysphagia,
Ileus,
Mouth
ulceration,
Stomatitis

Melaena,
Gingival
bleeding

Hepatobiliary
disorders

Cholestasis

Skin and
subcutaneous
tissue disorders
Renal and urinary
disorders

Dental caries

Dry skin

Urticaria

Dysuria

Reproductive
system and breast
disorders

Hypogonadism

Amenorrhoe

General disorders
and administration
site conditions

Oedema,

Drug withdrawal
syndrome
neonatal

Drug tolerance

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 the MHRA Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms of intoxication
Depending on the history of the patient, an overdose of Oxycodone/Naloxone
Myloxifin may be manifested by symptoms that are either triggered by oxycodone
(opioid receptor agonist) or by naloxone (opioid receptor antagonist).

Symptoms of oxycodone overdose include miosis, respiratory depression,
somnolence progressing to stupor, hypotonia, bradycardia as well as hypotension.
Coma, non-cardiogenic pulmonary oedema and circulatory failure may occur in more
severe cases and may lead to a fatal outcome.
Symptoms of a naloxone overdose alone are unlikely.
Therapy of intoxication
Withdrawal symptoms due to an overdose of naloxone should be treated
symptomatically in a closely-supervised environment.
Clinical symptoms suggestive of an oxycodone overdose may be treated by the
administration of opioid antagonists (e.g. naloxone hydrochloride 0.4-2 mg
intravenously). Administration should be repeated at 2-3 minute intervals, as
clinically necessary. It is also possible to apply an infusion of 2 mg naloxone
hydrochloride in 500 ml of 0.9% sodium chloride or 5% dextrose (0.004 mg/ml
naloxone). The infusion should be run at a rate aligned to the previously administered
bolus doses and to the patient's response.
Consideration may be given to gastric lavage.
Supportive measure (artificial ventilation, oxygen, vasopressors and fluid infusions)
should be employed as necessary, to manage the circulatory shock accompanying an
overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism
should be maintained.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Nervous system; Analgesics; opioids; natural opium
alkaloids
ATC code: N02AA55
Mechanism of action
Oxycodone and naloxone have an affinity for kappa, mu and delta opiate receptors in
the brain, spinal cord and peripheral organs (e.g. intestine). Oxycodone acts as opioid-

receptor agonist at these receptors and binds to the endogenous opioid receptors in
the CNS. By contrast, naloxone is a pure antagonist acting on all types of opioid
receptors.
Pharmacodynamic effects
Because of the pronounced first-pass metabolism, the bioavailability of naloxone
upon oral administration is <3%, therefore a clinically relevant systemic effect is
unlikely. Due to the local competitive antagonism of the opioid receptor mediated
oxycodone effect by naloxone in the gut, naloxone reduces the bowel function
disorders that are typical for opioid treatment.
Clinical efficacy and safety
Opioids can influence the hypothalamic-pituitary-adrenal or gonadal axes. Among the
changes observed are an increase of prolactin in the serum and a reduced level of
cortisol and testosterone in the plasma. Clinical symptoms may occur because of
these hormone changes.
Preclinical studies show differing effects of natural opioids on components of the
immune system. The clinical significance of these findings is not known. It is not
known whether oxycodone, a semi-synthetic opioid, has similar effects on the
immune system to natural opioids.
Analgesia
In a 12 weeks parallel group double-blinded study in 322 patients with opioidinduced constipation, patients who were treated with oxycodone
hydrochloride/naloxone hydrochloride had on average one extra complete
spontaneous (without laxatives) bowel movement in the last week of treatment,
compared to patients who continued using similar doses of oxycodone hydrochloride
prolonged release tablets (p<0.0001). The use of laxatives in the first four weeks was
significantly lower in the oxycodone-naloxone group compared to the oxycodone
monotherapy group (31% versus 55%, respectively, p<0.0001). Similar results were
shown in a study with 265 non-cancer patients comparing daily doses of oxycodone
hydrochloride/naloxone hydrochloride of 60 mg/30 mg to up to 80 mg/40 mg with
oxycodone hydrochloride monotherapy in the same dose range.

5.2

Pharmacokinetic properties
Oxycodone hydrochloride
Absorption
Oxycodone has a high absolute bioavailability of up to 87% following oral
administration.

Distribution
Following absorption, oxycodone is distributed throughout the entire body.
Approximately 45% is bound to plasma protein. Oxycodone crosses the placenta and
may be detected in breast milk.
Biotransformation
Oxycodone is metabolised in the gut and the liver to noroxycodone and oxymorphone
and to various glucuronide conjugates. Noroxycodone, oxymorphone and
noroxymorphone are produced via the cytochrome P450 system. Quinidine reduces
the production of oxymorphone in man without substantially influencing the
pharmacodynamics of oxycodone. The contribution of the metabolites to overall
pharmacodynamic effect is insignificant.
Elimination
Oxycodone and its metabolites are excreted in both urine and faeces.
Naloxone hydrochloride
Absorption
Following oral administration, naloxone has a very low systemic availability of <3%.
Distribution
Naloxone passes into the placenta. It is not known, whether naloxone also passes into
breast milk.
Biotransformation and elimination
After parenteral administration, the plasma half-life is approximately one hour. The
duration of action depends upon the dose and route of administration, intramuscular
injection producing a more prolonged effect than intravenous doses. It is metabolised
in the liver and excreted in the urine. The principal metabolites are naloxone
glucuronide, 6β-naloxol and its glucuronide.
Oxycodone hydrochloride/naloxone hydrochloride combination (Myloxifin)
Pharmacokinetic/pharmacodynamic relationships
The pharmacokinetic characteristics of oxycodone from oxycodone
hydrochloride/naloxone hydrochloride is equivalent to those of prolonged-release
oxycodone hydrochloride tablets administered together with prolonged-release
naloxone hydrochloride tablets.
All dose strengths of Myloxifin are interchangeable.
After the oral administration of oxycodone hydrochloride/naloxone hydrochloride in
maximum dose to healthy subjects, the plasma concentrations of naloxone are so low
that it is not feasible to carry out a valid pharmacokinetic analysis. To conduct a

pharmacokinetic analysis naloxone-3-glucuronide as surrogate marker is used, since
its plasma concentration is high enough to measure.
Overall, following ingestion of a high-fat breakfast, the bioavailability and peak
plasma concentration (Cmax) of oxycodone were increased by an average of 16% and
30% respectively compared to administration in the fasting state. This was evaluated
as clinically not relevant, therefore oxycodone hydrochloride/naloxone hydrochloride
prolonged-release tablets may be taken with or without food (see section 4.2).
In vitro drug metabolism studies have indicated that the occurrence of clinically
relevant interactions involving oxycodone hydrochloride/naloxone hydrochloride is
unlikely.
Elderly patients
Oxycodone
For AUC of oxycodone, on average there was an increase to 118% (90% C.I.: 103,
135), for elderly compared with younger volunteers. For Cmax of oxycodone, on
average there was an increase to 114% (90% C.I.: 102, 127). For Cmin of oxycodone,
on average there was an increase to 128% (90% C.I.: 107, 152).
Naloxone
For AUC of naloxone, on average there was an increase to 182% (90% C.I.: 123,
270), for elderly compared with younger volunteers. For Cmax of naloxone, on average
there was an increase to 173% (90% C.I.: 107, 280). For Cmin of naloxone, on average
there was an increase to 317% (90% C.I.: 142, 708).
Naloxone-3-glucuronide
For AUC of naloxone-3-glucuronide, on average there was an increase to 128%
(90% C.I.: 113, 147), for elderly compared with younger volunteers. For Cmax of
naloxone-3-glucuronide, on average there was an increase to 127% (90% C.I.: 112,
144). For Cmin of naloxone-3-glucuronide, on average there was an increase to 125%
(90% C.I.: 105, 148).
Patients with impaired hepatic function
Oxycodone
For AUCINF of oxycodone, on average there was an increase to 143% (90% C.I : 111,
184), 319% (90% C.I.: 248, 411) and 310% (90% C.I.: 241, 398) for mild, moderate
and severe hepatically impaired subjects, respectively, compared with healthy
volunteers. For Cmax of oxycodone, on average there was an increase to 120% (90%
C.I.: 99, 144), 201% (90% C.I.: 166, 242) and 191% (90% C.I.: 158, 231) for mild,
moderate and severe hepatically impaired subjects, respectively, compared with
healthy volunteers. For t1/2Z of oxycodone, on average there was an increase to 108%
(90% C.I.: 70, 146), 176% (90% C.I.: 138, 215) and 183% (90% C.I.: 145, 221) for
mild, moderate and severe hepatically impaired subjects, respectively, compared with
healthy volunteers.

Naloxone
For AUCt of naloxone, on average there was an increase to 411% (90% C.I.: 152,
1112), 11518% (90% C.I.: 4259, 31149) and 10666% (90% C.I.: 3944, 28847) for
mild, moderate and severe hepatically impaired subjects, respectively, compared with
healthy volunteers. For Cmax of naloxone, on average there was an increase to 193%
(90% C.I.: 115, 324), 5292% (90% C.I: 3148, 8896) and 5252% (90% C.I.: 3124,
8830) for mild, moderate and severe hepatically impaired subjects, respectively,
compared with healthy volunteers. Due to insufficient amount of data available t1/2Z
and the corresponding AUCINF of naloxone were not calculated. The bioavailability
comparisons for naloxone were therefore based on AUCt values.
Naloxone-3-glucuronide
For AUCINF of naloxone-3-glucuronide, on average there was an increase to 157%
(90% C.I.: 89, 279), 128% (90% C.I.: 72, 227) and 125% (90% C.I.: 71, 222) for
mild, moderate and severe hepatically impaired subjects, respectively, compared with
healthy volunteers. For Cmax of naloxone-3-glucuronide, on average there was an
increase to 141% (90% C.I.: 100, 197), 118% (90% C.I.: 84, 166) and a decrease to
98% (90% C.I.: 70, 137) for mild, moderate and severe hepatically impaired subjects,
respectively, compared with healthy volunteers. For t1/2Z of naloxone-3-glucuronide,
on average there was an increase to 117% (90% C.I.: 72, 161), a decrease to 77%
(90% C.I.: 32, 121) and a decrease to 94% (90% C.I.: 49, 139) for mild, moderate and
severe hepatically impaired subjects, respectively, compared with healthy volunteers.
Patients with impaired renal function
Oxycodone
For AUCINF of oxycodone, on average there was an increase to 153% (90% C.I.: 130,
182), 166% (90% C.I.: 140, 196) and 224% (90% C.I.: 190, 266) for mild, moderate
and severe renally impaired subjects, respectively, compared with healthy volunteers.
For Cmax of oxycodone, on average there was an increase to 110% (90% C.I.: 94,
129), 135% (90% C.I.: 115, 159) and 167% (90% C.I.: 142, 196) for mild, moderate
and severe renally impaired subjects, respectively, compared with healthy volunteers.
For t1/2Z of oxycodone, on average there was an increase to 149%, 123% and 142%
for mild, moderate and severe renally impaired subjects, respectively, compared with
healthy volunteers.
Naloxone
For AUCt of naloxone, on average there was an increase to 2850% (90% C.I.: 369,
22042), 3910% (90% C.I.: 506, 30243) and 7612% (90% C.I.: 984, 58871) for mild,
moderate and severe renally impaired subjects, respectively, compared with healthy
volunteers. For Cmax of naloxone, on average there was an increase to 1076% (90%
C.l.: 154, 7502), 858% (90% C.I.: 123, 5981) and 1675% (90% C.I.: 240, 11676) for
mild, moderate and severe renally impaired subjects, respectively, compared with
healthy volunteers. Due to insufficient amount of data available t1/2Z and the
corresponding AUCINF of naloxone were not calculated. The bioavailability
comparisons for naloxone were therefore based on AUCt values. The ratios may have
been influenced by the inability to fully characterise the naloxone plasma profiles for
the healthy subjects.
Naloxone-3-glucuronide

For AUCINF of naloxone-3-glucuronide, on average there was an increase to 220%
(90% C.I.: 148, 327), 370% (90% C.I.: 249, 550) and 525% (90% C.I.: 354, 781) for
mild, moderate and severe renally impaired subjects, respectively, compared with
healthy subjects. For Cmax of naloxone-3-glucuronide, on average there was an
increase to 148% (90% C.I.: 110, 197), 202% (90% C.I.: 151, 271) and 239% (90%
C.I.: 179, 320) for mild, moderate and severe renally impaired subjects, respectively,
compared with healthy subjects. For t1/2Z of naloxone-3-glucuronide, on average there
was no significant change between the renally impaired subjects and the healthy
subjects.
Abuse
To avoid damage to the prolonged-release properties of the tablets,
Oxycodone/Naloxone Myloxifin must not be broken, crushed or chewed, as this leads
to a rapid release of the active substances. In addition, naloxone has a slower
elimination rate when administered intranasally. Both properties mean that abuse of
Oxycodone/Naloxone Myloxifin will not have the effect intended. In oxycodonedependent rats, the intravenous administration of oxycodone hydrochloride/ naloxone
hydrochloride at a ratio of 2:1 resulted in withdrawal symptoms.

5.3

Preclinical safety data
There are no data from studies on reproductive toxicity of the combination of
oxycodone and naloxone. Studies with the single components showed that oyxcodone
had no effect on fertility and early embryonic development in male and female rats in
doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of
up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits,
when individual foetuses were used in statistical evaluation, a dose related increase in
developmental variations was observed (increased incidences of 27 presacral
vertebrae, extra pairs of ribs). When these parameters were statistically evaluated
using litters, only the incidence of 27 presacral vertebrae was increased and only in
the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the
pregnant animals. In a study on pre- and postnatal development in rats F1 body
weights were lower at 6 mg/kg/d when compared to body weights of the control
group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg
body weight). There were neither effects on physical, reflexological, and sensory
developmental parameters nor on behavioural and reproductive indices. The standard
oral reproduction toxicity studies with naloxone show that at high oral doses naloxone
was not teratogenic and/or embryo/foetotoxic, and does not affect perinatal/postnatal
development. At very high doses (800 mg/kg/day) naloxone produced increased pup
deaths in the immediate post-partum period at doses that produced significant toxicity
in maternal rats (e.g. body weight loss, convulsions). However, in surviving pups, no
effects on development or behaviour were observed.
Long-term carcinogenicity studies with oxycodone/naloxone in combination or
oxycodone as a single entity have not been performed. For naloxone, a 24-months
oral carcinogenicity study was performed in rats with naloxone doses up to 100
mg/kg/day. The results indicate that naloxone is not carcinogenic under these
conditions.

Oxycodone and naloxone as single entities show a clastogenic potential in in vitro
assays. No similar effects were observed, however, under in vivo conditions, even at
toxic doses. The results indicate that the mutagenic risk of Myloxifin to humans at
therapeutic concentrations may be ruled out with adequate certainty.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core
Myloxifin 5 mg/2.5 mg
Polyvinyl acetate
Povidone K30
Sodium lauryl sulphate
Silica, colloidal anhydrous
Cellulose, microcrystalline
Magnesium stearate

Tablet coating
Myloxifin 5 mg/2.5 mg
Polyvinyl alcohol,
Titanium dioxide (E171),
Macrogol 3350,
Talc

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
Blister:
2 years

Bottles:
2 years
Shelf life after first opening: 3 months.

6.4

Special precautions for storage
Blister:
Do not store above 25°C.
Bottles:
Do not store above 30°C.

6.5

Nature and contents of container
Blister
Child resistant aluminium/PVC/PE/PVDC blisters.
Bottles
White HDPE bottles with white, child-resistant, tamper-evident screw cap made of
PP.
Pack sizes
Blister: 10, 14, 20, 28, 30, 50, 56, 60, 90, 98, 100 prolonged-release tablets
Bottle: 50, 100, 250 prolonged-release tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Amneal Pharma Europe Limited
70 Sir John Rogerson’s Quay
Dublin 2
Ireland

8

MARKETING AUTHORISATION NUMBER(S)
PL 42357/0252

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/08/2017

10

DATE OF REVISION OF THE TEXT
10/08/2017

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