Denephor 10 mg/5 mg Depottablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

29-09-2017

Produktens egenskaper Produktens egenskaper (SPC)

29-09-2017

Aktiva substanser:
naloxonhydrokloriddihydrat; oxikodonhydroklorid
Tillgänglig från:
Hormosan Pharma GmbH
ATC-kod:
N02AA55
INN (International namn):
naloxone hydrochloride dihydrate; oxycodone hydrochloride
Dos:
10 mg/5 mg
Läkemedelsform:
Depottablett
Sammansättning:
laktosmonohydrat Hjälpämne; stearylalkohol Hjälpämne; naloxonhydrokloriddihydrat 5,5 mg Aktiv substans; oxikodonhydroklorid 10 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
52147
Tillstånd datum:
2016-06-22

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

21-01-2016

Produktens egenskaper Produktens egenskaper - engelska

21-01-2016

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

04-07-2016

Läs hela dokumentet

Package leaflet: Information for the user

Denephor 5 mg/2.5 mg prolonged-release tablets

Denephor 10 mg/5 mg prolonged-release tablets

Denephor 20 mg/10 mg prolonged-release tablets

Denephor 40 mg/20 mg prolonged-release tablets

oxycodone hydrochloride / naloxone hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

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 only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet

What Denephor is and what it is used for

What you need to know before you take Denephor

How to take Denephor

Possible side effects

How to store Denephor

Contents of the pack and other information

1.

What Denephor is and what it is used for

Denephor is a prolonged-release tablet, which means that its active substances are released over an extended

period. Their action lasts for 12 hours.

Pain relief

You have been prescribed Denephor for the treatment of severe pain, which can be adequately managed only

with opioid analgesics. Naloxone is added to counteract constipation.

How Denephor works in pain relief

Denephor tablets contain oxycodone and naloxone as active substances. Oxycodone is responsible for the

painrelieving effect of Denephor. It is a strong analgesic (“painkiller”) that belongs to a group of medicines

called opioids. Naloxone is intended to counteract constipation. Constipation is a typical side effect of

treatment with opioid painkillers.

Restless legs syndrome

You have been prescribed Denephor for the second line symptomatic treatment of severe to very severe

restless legs syndrome in people who can’t be treated with dopamine medicines. People with restless legs

syndrome have unpleasant sensations in their limbs. This can start as soon as they sit or lie down and is only

relieved by an irresistible urge to move the legs, sometimes the arms and other parts of the body. It makes

sitting still and sleeping very difficult. Naloxone hydrochloride is added to counteract constipation.

How Denephor works in restless legs syndrome

These tablets help to relieve the unpleasant sensations and so reduces the urge to move the limbs.

Naloxone is intended to counteract from constipation. Constipation is a typical side effect of treatment with

opioid painkillers.

2.

What you need to know before you take Denephor

Do NOT take Denephor tablets

if you are allergic to oxycodone or naloxone or any of the other ingredients of this medicine

(listed in section 6),

if you have breathing problems, such as breathing more slowly or weakly than expected (respiratory

depression),

if you suffer from a severe lung disease associated with narrowing of the airways (chronic obstructive

pulmonary disease or COPD),

if you suffer from a condition known as cor pulmonale. In this condition the right side of the heart

becomes enlarged, due to increased pressure inside blood vessels in the lung etc. (e.g. as a result of

COPD – see above),

if you suffer from severe bronchial asthma,

if you have a type of bowel obstruction (paralytic ileus) not caused by opioids,

if you have moderate to severe liver problems.

Additionally for restless legs syndrome

if you have a history of opioid abuse.

Warnings and Precautions

Talk to your doctor or pharmacist before taking Denephor:

in the case of elderly or debilitated (weak) patients,

if you have a type of bowel obstruction (paralytic ileus) caused by opioids,

if you have kidney problems,

if you have mild liver

problems,

if you have severe lung problems (i.e. reduced breathing capacity),

if you suffer with a condition characterised by frequent breathing stops during the night, which may make

you feel very sleepy during the daytime (sleep apnoea),

if you have myxoedema (a thyroid disorder, with dryness, coldness and swelling [‘puffiness’] of the skin,

affecting the face and limbs),

if your thyroid gland is not producing enough hormones (underactive thyroid, or hypothyroidism),

if your adrenal glands are not producing enough hormones (adrenal insufficiency, or Addison’s disease),

if you have a mental illness accompanied by a (partial) loss of reality (psychosis), due to alcohol or

intoxication with other substances (substance-induced psychosis),

if you suffer from gallstone problems,

if your prostate gland is abnormally enlarged (prostate hypertrophy),

if you are or ever have been addicted to alcohol or drugs, or have previously suffered from withdrawal

symptoms such as agitation, anxiety, shaking or sweating upon stopping alcohol or drugs (delirium

tremens),

if your pancreas is inflamed (pancreatitis),

if you have low blood pressure (hypotension),

if you have high blood pressure (hypertension),

if you have pre-existing heart disease,

if you have a head injury (due to the risk of increased brain pressure),

if you suffer from epilepsy or are prone to fits,

if you are also taking a type of medicine known as a MAO inhibitor (used to treat depression or

Parkinson’s disease), e.g. medicines containing tranylcypromine, phenelzine, isocarboxazid,

moclobemide and linezolid.

if sleepiness or episodes of suddenly falling asleep occur.

Tell your doctor if any of the above has ever applied to you in the past. Also, please tell your doctor if you

develop any of the above disorders while you are taking Denephor.

These tablets are not recommended for use in patients with advanced digestive or pelvic cancers where bowel

obstruction may be a problem.

Children and adolescents

This medicine must not be given to children or adolescents under 18 years of age as the safety and benefits

have not been shown yet.

How to use Denephor correctly

If you experience severe diarrhoea at the start of treatment (within the first 3-5 days) this may be due to the

effect of naloxone. It may be a sign that your bowel movements are returning to normal. If diarrhoea persists

after 3-5 days, or it gives you cause for concern, please contact your doctor.

If you have been using high doses of another opioid, withdrawal symptoms (such as restlessness, bouts of

sweating or muscle pain) may occur when you initially switch to taking these tablets. If you experience

withdrawal symptoms, you may need to be specially monitored by your doctor.

If you need to undergo surgery, please tell your doctor that you are taking this medicine.

If you have been taking this medicine for a long time, you may become tolerant. This means you may need a

higher dose to achieve the desired effect. Long-term use of these tablets may also lead to physical dependence.

Medicines containing oxycodone should be avoided in patients with a present or past abuse of alcohol, drugs or

medicines. Withdrawal symptoms may occur if treatment is stopped too suddenly. If you no longer need

treatment, you should reduce your daily dose gradually, in consultation with your doctor.

As with other strong opioid painkillers, there is a risk that you may develop a psychological dependence to

oxycodone.

You may notice remains of the tablet in your stools. Do not be alarmed, as the active substances will have

already been released in the stomach and gut, and absorbed into your body.

Incorrect use of Denephor

Denephor is not suitable for withdrawal treatment.

This medicine should never be abused, particularly if you have a drug addiction. If you are addicted to drugs

such as heroin, morphine or methadone, severe withdrawal symptoms are likely if you abuse this medicine

because it contains the ingredient naloxone. Pre-existing withdrawal symptoms may be made worse.

You should never misuse the tablets by dissolving and injecting them (e.g. into a blood vessel). They contain

talc, which can cause destruction of local tissue (necrosis) and changes in lung tissue (lung granuloma). Misuse

can also have other serious consequences which may be fatal.

Other medicines and Denephor

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The risk of side effects is increased if you take these tablets at the same time as medicines which affect the way

the brain works. For example, you may feel very sleepy, or breathing problems (slow and shallow breathing)

may get worse.

Examples of medicines that affect the way the brain works include:

other strong painkillers (opioids),

sleep medication and tranquilisers (sedatives, hypnotics),

antidepressants,

medicines used to treat allergies, travel sickness or nausea (antihistamines or antiemetics),

other medicines which act on the nervous system (phenothiazines, neuroleptics).

Tell your doctor if you are taking:

medicines that decrease the blood’s clotting ability (coumarin derivatives), this clotting time may be

speeded up or slowed down

antibiotics of the macrolide type (such as clarithromycin)

antifungal medicines of the –azole type (e.g. ketoconazole)

ritonavir or other protease inhibitors (used to treat HIV)

rifampicin (used to treat tuberculosis)

carbamazepine (used to treat seizures, fits or convulsions and certain pain conditions)

phenytoin (used to treat seizures, fits or convulsions).

Denephor with food, drink and alcohol

Drinking alcohol whilst taking Denephor may make you feel more sleepy or increase the risk of serious side

effects such as shallow breathing with a risk of stopping breathing, and loss of consciousness. It is

recommended not to drink alcohol while you are taking Denephor.

You should avoid drinking grapefruit juice while you are taking this medicine.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor

or pharmacist for advice before taking this medicine.

Pregnancy

Use of Denephor during pregnancy should be avoided unless your doctor finds treatment with this medicine

is essential. If used over prolonged periods during pregnancy, oxycodone may lead to withdrawal symptoms

in the newborn baby. If oxycodone is given during childbirth, the baby may have breathing problems such as

slow and shallow breathing (respiratory depression).

Breastfeeding

Breastfeeding should be stopped during treatment with this medicine as oxycodone (one of the active

substances of this medicine) passes into breast milk and it is not known whether naloxone also passes into

breast milk. Therefore, a risk for the breastfed infant cannot be excluded in particular following intake of

multiple doses of this medicine.

Driving and using machines

This medicine can affect your ability to drive or operate machines as it may make you sleepy or dizzy. This is

most likely at the start of your treatment, after a dose increase or after switching from a different medication.

These side effects should disappear once you are on a stable dose.

This medicine has been associated with sleepiness and episodes of suddenly falling asleep. If you experience

these side effects, you must not drive or operate machinery. You should tell your doctor if this occurs.

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

medicine.

Denephor contains lactose

Denephor 5 mg/2.5 mg and 10 mg/5 mg contain lactose (milk sugar). If you have been told by your doctor that

you have an intolerance to some sugars, contact your doctor before taking Denephor 5 mg/2.5 mg and 10 mg/5

3.

How to take Denephor

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you

are not sure.

You must swallow the prolonged-release tablet whole, so as not to affect the slow release of oxycodone from the

tablet. Do not break, chew or crush the prolonged-release tablets. Taking broken, chewed or crushed tablets may

result in your body absorbing a potentially fatal dose of oxycodone (see under “If you take more Denephor than

you should”).

Unless otherwise prescribed by your doctor, the usual dose is:

To treat pain

Adults

The usual starting dose is one Denephor 10 mg/5 mg Depottablett every 12 hours.

Your doctor will decide how much you should to take every day and how to divide the total daily dose into

morning and evening doses. The doctor will also decide on any necessary dose adjustment during treatment

depending on your level of pain and individual sensitivity. You should be given the lowest dose needed for

pain relief. If you have already been treated with opioids, your treatment with this medicine may be started at

a higher dose.

The maximum daily dose is 160 mg oxycodone hydrochloride and 80 mg naloxone hydrochloride. If you need

a higher dose, your doctor may give you additional oxycodone without naloxone. However, the maximum

daily dose of oxycodone should not exceed 400 mg. The beneficial effect of naloxone on bowel movements

may be affected if additional oxycodone is given without additional naloxone.

If you experience pain between doses of Denephor, you may need to take an additional fast-acting painkiller.

Denephor is not suitable for this. Please talk to your doctor.

If you feel that these tablets are too strong or too weak, please talk to your doctor or pharmacist.

To treat restless legs syndrome

Adults

The usual starting dose is one Denephor 5 mg/2.5 mg Depottablett every 12 hours.

Your doctor will decide how much you should take every day and how to divide your total daily dosage into

morning and evening doses. The doctor will also decide on any necessary dose adjustments during treatment.

Your dose will be adjusted according to your individual sensitivity. You should be given the lowest dose

needed to relieve your restless legs symptoms.

If you feel that these tablets are too strong or too weak, please talk to your doctor or pharmacist.

The maximum daily dose is 60 mg oxycodone hydrochloride and 30 mg naloxone hydrochloride.

To treat pain or restless legs syndrome

Elderly patients

In general, no dose adjustment is necessary for elderly patients with normal kidney and/or liver function.

Liver or kidney problems

If you have kidney or mild liver problems your doctor will prescribe Denephor with special caution. You must

not take these tablets if you have moderate or severe liver problems (see also Section 2 “Do not take

Denephortablets” and “Warnings and Precautions”).

Children and adolescents below 18 years of age

No studies have been carried out to show that this medicinework properly in children and adolescents, or are

safe for them to take. It is therefore not recommended for use in patients under 18 years of age.

Method of administration

Swallow your tablets whole with a glass of water. You can take these tablets with or without food. Take them

every 12 hours, according to a fixed time schedule. For instance, if you take a tablet at 8 o’clock in the morning,

you should take your next tablet at 8 o’clock in the evening. Do not break, chew or crush the tablets.

Opening instructions

This medicinal product is in child-resistant packaging. The tablets cannot be pressed out of the blister. Please

observe the following instructions when opening the blister.

Separate a single dose by carefully tearing along the perforated lines.

An unsealed corner is revealed at the intersection point of the perforated lines.

Slowly peel off the foil at the marked corner to unveil the pocket.

Duration of use

You should not take Denephorfor any longer than you need to. If you have been taking the medicine for a long

time your doctor should regularly check that you still need it.

If you take more Denephor than you should

If you have taken more than the prescribed dose, you must inform your doctor immediately.

An overdose may result in:

small (constricted) pupils,

breathing more slowly or weakly than expected (respiratory depression),

drowsiness or loss of consciousness,

low muscle tone (hypotonia),

reduced pulse rate and

a fall in blood pressure.

In severe cases, loss of consciousness (coma), fluid on the lungs and circulatory collapse may occur, which may

be fatal.

You should avoid situations which require you to be alert, e.g. driving.

If you forget to take Denephor,

If you forget to take Denephor or if you take a lower dose than the one prescribed, you may not feel any effect.

If you should forget to take your dose, please follow the instructions below:

If your next usual dose is due in 8 hours or more: Take the forgotten dose immediately and

continue with your normal dosing schedule.

If your next usual dose is due in less than 8 hours: Take the forgotten dose, then, wait another 8 hours

before taking your next dose. Try to get back in your normal dosing schedule (e.g. 8 o’clock in the

morning and 8 o’clock in the evening).

Do not take more than one dose within any 8-hour period.

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

If you stop taking Denephor

Do not stop taking your treatment without first consulting your doctor.

If you do not require any further treatment, your doctor will advise you how to reduce the daily dose gradually.

In this way, you will avoid withdrawal symptoms, such as restlessness, bouts of sweating and muscle pain.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Important side effects or signs to look out for, and what to do if you are affected:

Stop taking Denephor and contact a doctor or go to your nearest emergency department immediately if you

experience any of the following symptoms:

A more slow or shallow breathing (respiratory depression). This is the most serious side effect with

Denephor and it mostly occurs in elderly and weak patients.

Opioids can also cause a severe drop in blood pressure in susceptible patients.

Swelling of the face, tongue or throat; difficulty swallowing; hives; breathing difficulties and drop in

blood pressure (anaphylactic reaction)

Other side effects that may occur are:

The following side effects have been seen in patients being treated for pain

Common (may affect up to 1 in 10 people)

Abdominal pain, indigestion, constipation, diarrhoea, wind

Dry mouth

Vomit (be sick), feel sick

Decreased appetite up to loss of appetite

A feeling of dizziness or ‘spinning’, vertigo

Headache

Hot flushes, sweating

General weakness, tiredness or exhaustion

Itchy skin, skin reactions/rash

Difficulty in sleeping, drowsiness

Uncommon (may affect up to 1 in 100 people)

Abdominal bloating

Abnormal thoughts

Anxiety, confusion, depression, nervousness, difficulties to concentrate

Chest tightness especially if you already have coronary heart disease, chest pain

Drop in blood pressure, rise in blood pressure

Withdrawal symptoms such as agitation

Fainting

Palpitations

Biliary colic

Generally feeling unwell

Pain

Swelling of the hands, ankles or feet

Impaired speaking

Shaking

Restlessness

Difficulties breathing

Chills

Hepatic enzymes increased

Runny nose

Cough

Hypersensitivity/allergic reactions

Weight loss

Injuries from accidents

Increased urge to urinate

Muscle cramps, muscle twitches, muscle pain

Vision impairment

Epileptic seizures (especially in persons with epileptic disorder or predisposition to seizures)

Rare (may affect up to 1 in 1,000 people)

Increase in pulse rate

Dental changes

Yawning

Weight gain

Not known (cannot be estimated from the available data)

Euphoric mood

Severe drowsiness

Erectile dysfunction

Nightmares

Hallucinations

Shallow breathing

Difficulties in passing urine

Tingling in hands or feet

Belching

The active substance oxycodone hydrochloride, if not combined with naloxone hydrochloride, is known

to have the following differing sideeffects:

Breathing problems, such as breathing more slowly or weakly than expected (respiratory depression), reduction

in size of the pupils in the eye, muscle cramps and decreased cough reflex.

Common (may affect up to 1 in 10 people)

Altered mood and personality changes (e.g. depression, feeling of extreme happiness)

Decreased activity, increased activity

Difficulties in passing urine

Hiccups

Uncommon (may affect up to 1 in 100 people)

Impaired concentration, agitation

Migraines

Taste anomalies

Increased muscle tension, involuntary muscle contractions

Drug dependence, drug tolerance

Ileus

Dry skin, flushing of skin

Reduced sensitivity to pain or touch

Abnormal coordination

Perception disturbances (e.g. hallucination, derealisation)

Vocal changes (dysphonia)

Water retention

Difficulties in hearing

Difficulties in swallowing

Mouth ulcers, sore gums

Reduced sex drive

Dehydration, thirst

Rare (may affect up to 1 in 1,000 people)

Itching rash (urticaria)

Herpes simplex

Increased appetite

Black (tarry) stools

Gingival bleeding

Not known (frequency cannot be estimated from the available data)

Acute generalised allergic (anaphylactic reactions)

Absence of menstrual periods

Problems with bile flow

The following side effects have been observed in patients treated for restless legs syndrome

Very common (may affect more than 1 in 10 people)

Headache

Drowsiness

Constipation

Feel sick

Sweating

Tiredness or exhaustion

Common (may affect up to 1 in 10 people)

Decreased appetite up to loss of appetite

Difficulty sleeping

Difficulty in concentration

Depression

A feeling of dizziness or ‘spinning, vertigo

Shaking

Tingling in hands or feet

Vision impairment

Hot flushes

Drop in blood pressure, rise in blood pressure

Pain, abdominal pain, chest pain

Dry mouth, thirst

Vomit (be sick)

hepatic enzymes increased (alanine aminotransferase increased, gamma-glutamyltransferase increased)

Itchy skin, skin reactions/rash

Chills

Uncommon (may affect up to 1 in 100 people)

Reduced sexual drive

Episodes of suddenly falling asleep

Altered taste

Difficulties breathing

Wind

Erectile dysfunction

Withdrawal symptoms such as agitation

Swelling of hands, ankles or feet

Injuries from accidents

Not known (cannot be estimated from the available data)

Hypersensitivity/allergic reactions

Abnormal thoughts, hallucinations, nightmares

Anxiety, confusion, nervousness, euphoric mood

Restlessness

Epileptic seizures (especially in persons with epileptic disorder or predisposition to seizures)

Severe drowsiness, fainting

Impaired speaking

Chest tightness especially if you already have coronary heart disease

Palpitations, increase in pulse rate

Shallow breathing, yawning

Cough

Runny nose

Abdominal bloating, diarrhoea, indigestion, belching

Dental changes

Biliary colic

Muscle cramps, muscle twitching, muscle pain

Difficulties in passing urine, increased urge to urinate

Generally feeling unwell

Weight loss, weight increase

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 via the national reporting system listed in Appendix V.

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Denephor

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after “EXP”. The

expiry date refers to the last day of that month.

Do not store above 25 ˚C.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Denephor contains

The active substances are oxycodone hydrochloride and naloxone hydrochloride

5 mg/2.5 mg prolonged-release tablets

Each prolonged-release tablet contains 5 mg oxycodone hydrochloride, equivalent to 4.5 mg oxycodone and

naloxone hydrochloride dihydrate, equivalent to 2.5 mg naloxone hydrochloride or 2.25 mg naloxone.

10 mg/5 mg prolonged-release tablets

Each prolonged-release tablet contains 10 mg oxycodone hydrochloride, equivalent to 9.0 mg oxycodone and

naloxone hydrochloride dihydrate, equivalent to 5.0 mg naloxone hydrochloride or 4.5 mg naloxone.

20 mg/10 mg prolonged-release tablets

Each prolonged-release tablet contains 20 mg oxycodone hydrochloride, equivalent to 18.0 mg oxycodone and

naloxone hydrochloride dihydrate, equivalent to 10.0 mg naloxone hydrochloride or 9.0 mg naloxone.

40 mg/20 mg prolonged-release tablets

Each prolonged-release tablet contains 40 mg oxycodone hydrochloride, equivalent to 36.0 mg oxycodone and

naloxone hydrochloride dihydrate, equivalent to 20.0 mg naloxone hydrochloride or 18.0 mg naloxone.

The other ingredients are:

5 mg/2.5 mg prolonged-release tablets

Tablet core: Microcrystalline cellulose, lactose monohydrate, ammonio methacrylate copolymer, povidone,

talc, triacetin, stearyl alcohol, magnesium stearate, anhydrous colloidal silica.

Tablet coat: Hypromellose, macrogol, talc, titanium dioxide (E171), Brilliant Blue FCF (E133).

10 mg/5 mg prolonged-release tablets

Tablet core: Microcrystalline cellulose, lactose monohydrate, ammonio methacrylate copolymer, povidone, talc,

triacetin, stearyl alcohol, magnesium stearate, anhydrous colloidal silica.

Tablet coat: Hypromellose, macrogol, talc, titanium dioxide (E171).

20 mg/10 mg prolonged-release tablets

Tablet core: Microcrystalline cellulose, ammonio methacrylate copolymer, povidone, talc, triacetin, stearyl

alcohol, magnesium stearate, anhydrous colloidal silica.

Tablet coat: Hypromellose, macrogol, talc, titanium dioxide (E171), red iron oxide (E172).

40 mg/20 mg prolonged-release tablets

Tablet core: Microcrystalline cellulose, ammonio methacrylate copolymer, povidone, talc, triacetin, stearyl

alcohol, magnesium stearate, anhydrous colloidal silica.

Tablet coat: Hypromellose, macrogol, talc, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide

(E172).

What Denephor looks like and contents of the pack

5 mg/2.5 mg prolonged-release tablets

Light blue, round, convex, blue film-coated tablets with a diameter of 7.2 mm.

10 mg/5 mg prolonged-release tablets

White to off-white, oval, convex, film-coated tablets with a length of 13.2 mm.

20 mg/10 mg prolonged-release tablets

Pink, oval, convex, film-coated tablets with a length of 10.2 mm.

40 mg/20 mg prolonged-release tablets

Light orange to ochre, oval, convex, film-coated tablets with a length of 13.2 mm.

The prolonged-released tablets are available in child-resistant perforated unit dose peel-off PVC/PVDC/PVC-

Alu blisters.

Pack sizes are 10 x 1, 20 x 1, 28 x 1, 30 x 1, 50 x 1, 56 x 1, 60 x 1, 98 x 1 and 100 x 1.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

<to be completed nationally>

Manufacturer:

Acino AG

Am Windfeld 35

83714 Miesbach

Germany

Tel.:

+49 8025 2867-0

Fax:

+49 8025 2867-28

E-mail: info@acino-pharma.com

This leaflet was last revised in 21

st

January 2016

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Denephor 5 mg/2.5 mg prolonged-release tablets

Denephor 10 mg/5 mg prolonged-release tablets

Denephor 20 mg/10 mg prolonged-release tablets

Denephor 40 mg/20 mg prolonged-release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

5 mg/2.5 mg prolonged-release tablets

Each prolonged-release tablet contains 5 mg of oxycodone hydrochloride equivalent to 4.5 mg oxycodone

and naloxone hydrochloride dihydrate equivalent to 2.5 mg naloxone hydrochloride and 2.25 mg naloxone.

Excipient with known effect: Each prolonged-release tablet contains 16.0 mg lactose.

10 mg/5 mg prolonged-release tablets

Each prolonged-release tablet contains 10 mg of oxycodone hydrochloride equivalent to 9.0 mg oxycodone

and naloxone hydrochloride dihydrate equivalent to 5.0 mg naloxone hydrochloride and 4.5 mg naloxone.

Excipient with known effect: Each prolonged-release tablet contains 32.0 mg lactose.

20 mg/10 mg prolonged-release tablets

Each prolonged-release tablet contains 20 mg of oxycodone hydrochloride equivalent to 18.0 mg oxycodone

and naloxone hydrochloride dihydrate equivalent to 10.0 mg naloxone hydrochloride and 9.0 mg naloxone.

< 40 mg/20 mg prolonged-release tablets

Each prolonged-release tablet contains 40 mg of oxycodone hydrochloride equivalent to 36.0 mg

oxycodone and naloxone hydrochloride dihydrate equivalent to 20.0 mg naloxone hydrochloride and 18.0

mg naloxone.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Prolonged-release tablet

Denephor 5 mg/2.5 mg prolonged-release tablet

Light blue, round, convex, film-coated tablets with a nominal diameter of 7.2 mm.

Denephor 10 mg/5 mg prolonged-release tablet

White to off-white, oval, convex, film-coated tablets with a nominal length of 13.2 mm.

Denephor 20 mg/10 mg prolonged-release tablet

Pink, oval, convex, film-coated tablets with a nominal length of 10.2 mm.

Denephor 40 mg/20 mg prolonged-release tablet

Light orange to ochre, oval, convex, film-coated tablets with a nominal length of 13.2 mm.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Severe pain, which can be adequately managed only with opioid analgesics.

Second-line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome

after failure of dopaminergic therapy.

The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of

oxycodone at opioid receptors locally in the gut.

Denephor is indicated in adults.

4.2

Posology and method of administration

Posology

Analgesia

The analgesic efficacy of Denephor is equivalent to oxycodone hydrochloride prolonged-release

formulations.

The dosage should be adjusted to the intensity of pain and the sensitivity of the individual patient. Unless

otherwise prescribed, Denephor should be administered as follows:

Adults

The usual starting dose for an opioid naïve patient is 10 mg/5 mg of oxycodone hydrochloride/naloxone

hydrochloride at 12 hourly intervals.

Patients already receiving opioids may be started on higher doses of Denephor depending on their previous

opioid experience.

Denephor 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy and individual dose

adjustment.

The maximum daily dose of Denephor 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 of oxycodone/naloxone 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 Denephor,

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 Denephor with a subsequent switch to another opioid a

worsening of the bowel function can be expected.

Some patients taking Denephor according to a regular time schedule require immediate-release analgesics as

“rescue” medication for breakthrough pain. Denephor 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 Denephor requires

upward adjustment. This adjustment should be made every 1-2 days in steps of 5 mg/2.5 mg twice daily, or

where necessary 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.

Denephor is taken at the determined dosage 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.

Restless legs syndrome

Denephor is indicated for patients suffering from RLS for at least 6 months. RLS symptoms should be

present daily and during daytime (≥ 4 days/week). Denephor should be used after failure of previous

dopaminergic treatment. Dopaminergic treatment failure is defined as inadequate initial response, a response

that has become inadequate with time, occurrence of augmentation or unacceptable tolerability despite

adequate doses. Previous treatment with at least one dopaminergic medicinal product should have lasted in

general 4 weeks. A shorter period might be acceptable in case of unacceptable tolerability with dopaminergic

therapy.

The dosage should be adjusted to the sensitivity of the individual patient.

Treatment of patients with restless legs syndrome with Denephor should be under the supervision of a

clinician with experience in the management of restless legs syndrome.

Unless otherwise prescribed, Denephor should be administered as follows:

Adults

The usual starting dose is 5 mg/2.5 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly

intervals.

Titration on a weekly basis is recommended in case higher doses are required. The mean daily dose in the

pivotal study was 20 mg/10 mg oxycodone hydrochloride/naloxone hydrochloride. Some patients may

benefit from higher daily doses up to a maximum of 60 mg/30 mg oxycodone hydrochloride/naloxone

hydrochloride.

Denephor is taken at the determined dosage 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 situation, may benefit

from asymmetric dosing tailored to the individual patient. In general, the lowest effective dose should be

selected.

Analgesia / Restless legs syndrome

Elderly patients

As for younger adults the dosage should be adjusted to the intensity of the pain or RLS symptoms 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 Denephor to patients with mild hepatic

impairment (see section 4.4). In patients with moderate and severe hepatic impairment Denephor 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 Denephor to patients with renal impairment (see

section 4.4).

Paediatric population

The safety and efficacy of Denephor in children aged below 18 years has not been established. No data are

available.

Method of administration

Oral use.

Denephor is taken in the determined dosage twice daily in a fixed time schedule.

The prolonged-release tablets may be taken with or without food with sufficient liquid. The prolonged-

release tablets must be swallowed whole, and not broken, chewed or crushed.

Duration of use

Denephor should not be administered for longer than absolutely necessary. If long-term 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).

Restless legs syndrome

At least every three months during therapy with Denephor patients should be clinically evaluated. Treatment

should only be continued if Denephor is considered effective and the benefit is considered to outweigh

adverse effects and potential harms in individual patients. Prior to continuation of RLS treatment beyond 1

year a discharge regimen by gradually tapering down of Denephor over a period of approximately one week

should be considered to establish if continued treatment with Denephor is indicated.

When a patient no longer requires opioid therapy cessation of treatment by tapering down over a period of

approximately one week is recommended 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,

Any situation where opioids are contraindicated,

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.

Additionally, for restless legs syndrome:

History of opioid abuse.

4.4

Special warnings and precautions for use

The major risk of opioid excess is respiratory depression.

Caution must be exercised when administering Denephor to elderly or infirm patients, patients with opioid-

induced 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.

Caution is advised in treating restless legs syndrome patients with additional sleep apnoea syndrome with

oxycodone/naloxone due to the additive risk of respiratory depression. No data about the risk exist because

in the clinical trial patients with sleep apnoea syndrome were excluded.

Caution must also be exercised when administering Denephor to patients with mild hepatic or renal

impairment. A careful medical monitoring is particularly necessary for patients with severe renal

impairment.

Diarrhoea may be considered as a possible effect of naloxone.

In patients under long-term opioid treatment with higher doses of opioids, the switch to Denephor can

initially provoke withdrawal symptoms. Such patients may require specific attention.

Denephor 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 Denephor may lead to physical

dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with

Denephor is no longer required, it may be advisable to reduce the daily dose gradually in order to avoid the

occurrence of withdrawal syndrome (see section 4.2).

There is potential for development of psychological dependence (addiction) to opioid analgesics, including

Denephor. Denephor 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 be taken whole and 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 Denephor (see sections 4.5 and 4.7).

Concomitant use of alcohol and Denephor may increase the undesirable effects of Denephor. Concomitant

use should be avoided

Studies have not been performed on the safety and efficacy of oxycodone/naloxone 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.

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 Denephor in

this population is not recommended

Denephor 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 Denephor

depends on a careful risk-benefit assessment for each individual patient.

Any abuse of Denephor by drug addicts is strongly discouraged.

If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin,

morphine, or methadone, the broken, chewed or crushed tablet 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).

Denephor consists of a dual-polymer matrix, 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.

Denephor 5 mg/2.5 mg and 10 mg/5 mg prolonged-release tablets contain lactose. Patients with rare

hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

should not take Denephor 5 mg/2.5 mg and 10 mg/5 mg.

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 Denephor.

Alcohol may enhance the pharmacodynamic effects of Denephor; concomitant use should be avoided.

Clinically relevant changes in International Normalized 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. Denephor 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

Denephor 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 oxycodone/naloxone 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 oxycodone/naloxone prolonged-release

tablets 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.

Denephor 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 prolonged-release tablets 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 Denephor by the breastfeeding mother. Breastfeeding should be

discontinued during treatment with Denephor.

Fertility

There are no data with respect to fertility.

4.7

Effects on ability to drive and use machines

Denephor has moderate influence on the ability to drive and use machines. This is particularly likely at the

beginning of treatment with Denephor, after dose increase or product rotation and if Denephor is combined

with other CNS-depressant agents. Patients stabilised on a specific dosage 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 withDenephor 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 also sections 4.4 and 4.5).

4.8

Undesirable effects

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 in the treatment of pain

System organ

class MedDRA

Common

Uncommon

Rare

Not known

Immune system

disorders

Hypersensitivity

Metabolism and

nutritional

disorders

Appetite decreased

up to loss of

appetite

Psychiatric

disorders

Insomnia

Abnormal

thinking

Anxiety

Confusion

Depression

Nervousness

Restlessness

Euphoric mood

Hallucination

Nightmares

Nervous system

disorders

Dizziness

Headache

Somnolence

Convulsions

Disturbance in

attention

Speech disorder

Syncope

Tremor

Paraesthesia

Sedation

Eye disorder

Visual impairment

Ear and labyrinth

disorder

Vertigo

Cardiac disorders

Angina pectoris

Palpitations

Tachycardia

Vascular

disorders

Hot flush

Blood pressure

decreased Blood

pressure increased

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea

Rhinorrhoea

Cough

Yawning

Respiratory

depression

Gastrointestinal

disorders

Abdominal pain

Constipation

Diarrhoea

Dry mouth

Dyspepsia

Vomiting

Nausea

Flatulence

Abdominal

distention

Tooth disorder

Eructation

Hepatobiliary

disorders

Hepatic enzymes

increased

Biliary colic

Skin and

subcutaneous

tissue disorder

Pruritus

Skin reactions

Hyperhidrosis

Musculoskeletal

and connective

tissue disorder

Muscle spasms

Muscle twitching

Myalgia

Renal and urinary

disorders

Micturition

urgency

Urinary retention

Reproductive

system and breast

disorders

Erectile

dysfunction

General disorders

and administration

site conditions

Asthenic

conditions

Fatigue

Chest pain

Chills

Drug withdrawal

syndrome

Malaise

Pain

Oedema

peripheral

Investigations

Weight decreased

Weight increased

Injury, poisoning,

and procedural

complications

Injuries from

accidents

particularly in persons with epileptic disorder or predisposition to convulsions

particularly 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

Common

Uncommon

Rare

Not known

Infections and

infestations

Herpes simplex

Immune system

disorders

Anaphylactic

responses

Metabolism and

nutritional

disorders

Dehydration

Appetite

increased

Psychiatric

disorders

Altered mood

and personality

changes

Decreased

activity

Psychomotor

hyperactivity

Agitation

Perception

disturbances (e.g.

derealisation)

Libido reduced

Drug dependence

Nervous system

disorders

Impaired

concentration

Migraine

Dysgeusia

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

Dry skin

Urticaria

Renal and urinary

disorders

Dysuria

Reproductive

system and breast

disorders

Amenorrhoea

General disorders

and administration

site conditions

Oedema

Thirst

Drug tolerance

Undesirable effects in the treatment of restless legs syndrome

The list below reflects the adverse drug reactions seen with oxycodone hydrochloride/naloxone

hydrochloride in a 12-week, randomised, placebo-controlled clinical trial comprising a total of 150 patients

on oxycodone hydrochloride/naloxone hydrochloride and 154 patients on placebo with daily dosages

between 10 mg/5 mg and 80 mg/40 mg oxycodone hydrochloride/naloxone hydrochloride. Adverse drug

reactions associated with oxycodone/naloxone prolonged-release tablets in pain not observed in RLS study

population were added with the frequency of not known.

System organ

class MedDRA

Very Common

Common

Uncommon

Not known

Immune system

disorders

Hypersensitivity

Metabolism and

nutrition disorders

Appetite decreased

up to loss of

appetite

Psychiatric

disorders

Insomnia

Depression

Libido

Decreased

Sleep attacks

Abnormal

thinking Anxiety

Confusion

Nervousness

Restlessness

Euphoric mood

Hallucination

Nightmares

Nervous system

disorders

Headache

Somnolence

Dizziness,

Disturbance in

attention Tremor

Paraesthesia

Dysgeusia

Convulsions

Sedation Speech

disorder Syncope

Eye disorders

Visual

impairment

Ear and labyrinth

disorders

Vertigo

Cardiac disorders

Angina pectoris

Palpitations

Tachycardia

Vascular

disorders

Hot flush

Blood pressure

decreased

Blood pressure

increased

Respiratory

thoracic and

mediastinal

disorders

Dyspnoea

Cough

Rhinorrhoea

Respiratory

depression

Yawning

Gastrointestinal

disorders

Constipation

Nausea

Abdominal pain

Dry mouth

Vomiting

Flatulence

Abdominal

Distention

Diarrhoea

Dyspepsia

Eructation

Tooth disorder

Hepatobiliary

disorders

Hepatic enzymes

increased

Biliary colic

Skin and

subcutaneous

tissue disorders

Hyperhidorosis

Pruritus

Skin reactions

Musculoskeletal

and connective

tissue disorders

Muscle spasms

Muscle twitching

Myalgia

Renal and urinary

disorders

Micturition

urgency

Urinary retention

Reproductive

systems and breast

disorders

Erectile

dysfunction

General disorders

and administration

site conditions

Fatigue

Chest pain

Chills

Thirst Pain

Drug withdrawal

syndrome

Oedema

peripheral

Malaise

Investigation

Weight decreased

Weight increased

Injury, poisoning

and procedural

complications

Injuries from

accidents

particularly in persons with epileptic disorder or predisposition to convulsions

particularly in patients with history of coronary artery disease

alanine aminotransferase increased, gamma-glutamyl transferease increased

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 national reporting system listed in Appendix V.

4.9

Overdose

Symptoms of intoxication

Depending on the history of the patient, an overdose of Denephor 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,

skeletal muscle flaccidity, 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 measures (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: 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 opioid-induced 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.

Restless legs syndrome

In a 12-week double-blind efficacy study, 150 patients with severe to very severe idiopathic restless legs

syndrome at randomisation were treated with oxycodone hydrochloride/naloxone hydrochloride. Severe

syndrome is defined as IRLS score between 21 and 30 and very severe as score between 31 and 40. Patients

showed a clinically relevant and a statistically significant improvement in mean IRLS score compared to

placebo during the entire treatment period with a decrease in the mean IRLS score of 5.9 points compared to

placebo at week 12 (assuming an effect similar to placebo completers for patients who discontinued the

study representing a very conservative approach). The onset of efficacy was demonstrated from as early as

week 1 of treatment. Similar results were shown for the RLS symptom severity improvement (as measured

by the RLS-6-Rating scale), in quality of life as measured by a QoL-RLS questionnaire, in sleep quality

(measured by MOS sleep scale), and for the proportion of IRLS score remitters. No subject had a confirmed

case of augmentation during the study.

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 (Denephor)

Pharmacokinetic/pharmacodynamic relationships

The pharmacokinetic characteristics of oxycodone from oxycodone/naloxone hydrochloride prolonged-

release tablets is equivalent to those of prolonged-release oxycodone hydrochloride tablets administered

together with prolonged-release naloxone hydrochloride tablets.

All dosage strengths of Denephor are interchangeable.

After the oral administration of oxycodone/naloxone hydrochloride prolonged-release tablets at the

maximum dose to healthy subjects, the plasma concentrations of naloxone are so low that it is not feasible to

carry out a 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 (C

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/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/naloxone hydrochloride prolonged-release tablets 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 C

of oxycodone, on average there was an increase to 114% (90%

C.I.: 102, 127). For C

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 C

of naloxone, on average there was an increase to 173% (90% C.I.: 107,

280). For C

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 C

of naloxone-3-glucuronide, on average there was an

increase to 127% (90% C.I.: 112, 144). For C

of naloxone-3-glucuronide, on average there was an increase

to 125% (90% C.I.: 105, 148).

Patients with impaired hepatic function

Oxycodone

For AUC

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 C

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 t

1/2Z

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 AUC

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 C

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 t

1/2Z

and the corresponding AUC

of naloxone were not

calculated. The bioavailability comparisons for naloxone were therefore based on AUC

values.

Naloxone-3-glucuronide

For AUC

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 C

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 t

1/2Z

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 AUC

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 C

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 t

1/2Z

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 AUC

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 C

of naloxone, on average there was an

increase to 1076% (90% C.I.: 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 t

1/2Z

and the corresponding AUC

of naloxone were not

calculated. The bioavailability comparisons for naloxone were therefore based on AUC

values. The ratios

may have been influenced by the inability to fully characterize the naloxone plasma profiles for the healthy

subjects.

Naloxone-3-glucuronide

For AUC

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 C

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

1/2Z

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, Denephor 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 Denephor will not have

the effect intended. In oxycodone-dependent 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 fetuses were used in statistical evaluation, a dose-related increase in developmental variations was

observed (increased incidence of 27 presacral vertebrae, extra pairs of ribs). When these parameters were

statistically evaluated using litters, only the incidences 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/fetotoxic, 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 dosages 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 oxycodone/naloxone hydrochloride prolonged-release tablets to humans at therapeutic

concentrations may be ruled out with adequate certainty.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

5 mg/2.5 mg prolonged-release tablets

Tablet core:

Microcrystalline cellulose,

Lactose monohydrate,

Ammonio methacrylate copolymer,

Povidone,

Talc,

Triacetin,

Stearyl alcohol,

Magnesium stearate,

Anhydrous colloidal silica

Tablet coat:

Hypromellose,

Macrogol,

Talc,

Titanium dioxide (E171),

Brilliant Blue FCF (E133)

10 mg/5 mg prolonged-release tablets

Tablet core:

Microcrystalline cellulose,

Lactose monohydrate,

Ammonio methacrylate copolymer,

Povidone,

Talc,

Triacetin,

Stearyl alcohol,

Magnesium stearate,

Anhydrous colloidal silica

Tablet coat:

Hypromellose,

Macrogol,

Talc,

Titanium dioxide (E171)

20 mg/10 mg prolonged-release tablets

Tablet core:

Microcrystalline cellulose,

Ammonio methacrylate copolymer,

Povidone,

Talc,

Triacetin,

Stearyl alcohol,

Magnesium stearate,

Anhydrous colloidal silica

Tablet coat:

Hypromellose,

Macrogol,

Talc,

Titanium dioxide (E171),

Red iron oxide (E172)

40 mg/20 mg prolonged-release tablets

Tablet core:

Microcrystalline cellulose,

Ammonio methacrylate copolymer,

Povidone,

Talc,

Triacetin,

Stearyl alcohol,

Magnesium stearate,

Tablet coat:

Hypromellose,

Macrogol,

Talc,

Titanium dioxide (E171),

Red iron oxide (E172),

Yellow iron oxide (E172)

Anhydrous colloidal silica

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years for the 40 mg/20 mg and 20 mg/10 mg prolonged-release tablets in PVC/PVDC/PVC-Alu blisters.

1 year for the 10 mg/5 mg prolonged-release tablets in PVC/PVDC/PVC-Alu blisters.

9 months for the 5 mg/2.5 mg prolonged-release tablets in PVC/PVDC/PVC-Alu blisters.

6.4

Special precautions for storage

Do not store above 25 °C.

6.5

Nature and contents of container

The prolonged-released tablets are available in child-resistant, perforated unit dose peel-off

PVC/PVDC/PVC-Alu blisters in packs of 10 x 1, 20 x 1, 28 x 1, 30 x 1, 50 x 1, 56 x 1, 60 x 1, 98 x 1 and

100 x 1.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

<to be completed nationally>

8.

MARKETING AUTHORISATION NUMBER(S)

<to be completed nationally>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<to be completed nationally>

10.

DATE OF REVISION OF THE TEXT

January 2016

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