TARGIN 10

Patient leaflet in accordance with the Pharmacists' Regulations (Preparations) –

1986

This medicine is sold with a doctor’s prescription only

Targin 5, Targin 10, Targin 20, Targin 30, Targin 40

Prolonged release tablets

Active ingredients:

Product

Oxycodone hydrochloride

(Oxycodone HCl)

Naloxone hydrochloride

(Naloxone HCl)

Targin 5

5 mg

2.5 mg

Targin 10

10 mg

5 mg

Targin 20

20 mg

10 mg

Targin 30

30 mg

15 mg

Targin 40

40 mg

20 mg

For a list of the other ingredients, see section 6. Also see ‘Important information about some of

the medicine’s ingredients’ in section 2.

Read this entire leaflet carefully before using the medicine. This leaflet contains concise

information about the medicine. If you have any further questions, contact your doctor or

pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

it seems to you that their medical condition is similar to yours.

Medicines of the opioids group may cause addiction, especially with prolonged use and they

have a potential for misuse and overdose. A reaction to an overdose, may be manifested by slow

breathing and may even cause death. Make sure you know the name of the medicine, the

dosage that you take, how often you take it, the duration of treatment, potential side effects and

risks.

Additional information regarding the risk of dependence and addiction can be found at the

following link:

https://www.health.gov.il/UnitsOffice/HD/MTI/Drugs/risk/DocLib/opioids_en.pdf

Taking this medicine along with medicines from the benzodiazepines group, other medicines which

depress the central nervous system (including drugs) or alcohol may cause a feeling of profound

drowsiness, breathing difficulties (respiratory depression), coma and death.

1. What is the medicine intended for?

Targin has two active ingredients. The opioid ingredient of Targin (oxycodone) is intended for the

relief of moderate or severe pain in patients who need constant pain relief throughout the entire day,

for a few days or more. The naloxone ingredient was added to reduce the constipation caused by the

activity of the opioid oxycodone in the gastrointestinal system.

Therapeutic group:

Oxycodone - opioid analgesic (painkiller), Naloxone- opioid antagonist.

2. Before using the medicine

Do not use the medicine if:

You are sensitive (allergic) to the active ingredients or to any of the other ingredients that this tablets

contains (for the list of the other ingredients, see section 6).

You suffer from breathing problems, such as breathing more slowly or weakly than expected

(respiratory depression), severe lung disease associated with narrowing of the airways (COPD),

severe bronchial asthma.

You suffer from cor pulmonale (in this condition, the right side of the heart becomes enlarged due to

increased pressure inside blood vessels in the lung, for instance).

You suffer from bowel obstruction not caused by the use of opioids.

You suffer from moderate to severe liver function impairment.

Special warnings regarding the use of the medicine:

Before treatment with Targin, tell the doctor if:

You are elderly or debilitated (weak) patient.

You suffer from bowel obstruction caused by the use of opioids; impaired kidney function; mild

liver function impairment; severe lung function impairment; breathing stops during the sleep

(which may cause you to be sleepy during the daytime); sleepiness, thyroid gland function

disorder (myxedema or underactivity); gallstones; low or high blood pressure; cardiovascular

heart disease, enlarged prostate gland.

You suffer from insufficient adrenal gland function (adrenal insufficiency, Addison’s disease).

You suffer from a mental problem as a result of a toxic effect from medicines, alcohol or drugs (toxic

psychosis).

You suffer from a head injury (because of the risk of increased brain pressure); inflammation of

the pancreas; epilepsy or spasms (or you have a tendency to seizures).

You suffer or have suffered in the past from addiction to alcohol, medicines or drugs, or from

withdrawal symptoms following discontinuation of their use, such as: agitation, anxiety, tremor or

sweating.

You suffer from cancer associated with metastasis in the peritoneum or beginning of bowel

obstruction following gastrointestinal or pelvic cancer in advanced stages.

Also tell your doctor if you suffered from the above mentioned conditions in the past,

and/or if they are developed while under treatment with the medicine.

The most serious result of opioid overdose is respiratory depression (slow and shallow

breathing), that may also cause blood oxygen levels to fall, resulting in a conditions such as

fainting.

Swallow the tablet whole, so as not to impair the prolonged release of oxycodone from the

tablet. Do not break, chew, crush or halve the tablet! Taking tablets that are not whole may

cause an absorption of a potentially lethal dose of oxycodone (see section: 'If you have

accidentally taken a higher dosage').

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

to the effect of naloxone. If diarrhea persists more than 3-5 days, or it bothers you, consult with your

doctor.

If you have used another opioid before treatment with Targin, there may be withdrawal symptoms

(such as restlessness, sweating, muscle pains) at the beginning of treatment with Targin. If you

experience withdrawal symptoms, you may need a more closely medical follow-up.

Prolonged use may cause tolerance (need for a higher dose to achieve the desired effect), as well

as addiction. There may be withdrawal symptoms if the treatment suddenly stops. When you no

longer need treatment, the daily dose should be reduced gradually in consultation with your doctor.

As with other opioid analgesics, there is a risk of developing a drug dependence (psychological).

You should avoid oxycodone treatment if you suffer or have suffered in the past from addiction to

alcohol, medicines or drugs.

If you are about to undergo surgery, tell your doctor about taking this medicine.

You may notice the remains of the tablet in the stool. This phenomenon is not a cause for concern,

since the active ingredients in the tablet have already been released in the gastrointestinal system

and absorbed into the body.

Misuse of Targin: Targin is not intended and not suitable to treat withdrawal symptoms.

Do not abuse the tablets; using the tablets not via oral administration and not according to the

doctor’s instructions may cause life-threatening side effects or withdrawal effects.

Use of the medicine may cause positive results in drug tests.

Use in children and adolescents: There is no information about the safety and efficacy of the use

in children and adolescents under the age of 18 years and therefore the use is not recommended.

Tests and follow up: During long-term treatment, you should undergo periodic evaluations to

assess the ongoing need for the medicine.

Drug Interactions: If you are taking or have recently taken any other medicines, including

non-prescription medicines and nutritional supplements, tell the doctor or pharmacist.

Especially if you are taking:

Other strong analgesics (opioids); sedatives and sleep-inducing medicines - including

benzodiazepines; antidepressants; medicines against allergies, nausea/vomiting or travel sickness

(antihistamines or antiemetics); medicines for treatment of mental disorders such as phenothiazines,

antipsychotics or neuroleptics.

Anticoagulants (such as coumarin derivatives); antibiotics of the macrolide group (e.g.

clarithromycin, erythromycin, telithromycin); antifungals medicines of the azole group (such as

ketoconazole).

Protease inhibitors (anti-HIV virus) such as ritonavir; cimetidine (for the treatment of heartburn,

gastric ulcer, indigestion); rifampicin (for the treatment of tuberculosis); carbamazepine (for the

treatment of seizures and certain pain conditions), phenytoin (for the treatment of seizures).

Hypericum plant (also called St. John’s Wort); quinidine (for the treatment of heart rhythm

disturbances).

Medicines of the monoamine oxidase inhibitor group (such as linezolid) also used as

antidepressants or to treat Parkinson's disease.

Medicines with anticholinergic activity (such as medicines for the treatment of Parkinson's disease,

medicines for relaxing the muscles).

Use of this medicine and food: You may take the medicine regardless of mealtime.

Avoid drinking grapefruit juice when using this medicine.

Use of the medicine and alcohol consumption: Do not drink alcohol during the period of

treatment with this medicine.

Drinking alcohol while using this medicine may make you feel more sleepy or increase the risk of

serious side effects, such as breathing difficulties ("shallow breathing") with a risk of breathing

cessation and loss of consciousness.

Pregnancy and breastfeeding: Consult your doctor if you are pregnant, think you are pregnant,

plan to become pregnant or are breastfeeding.

Do not use this medicine if you are pregnant (unless otherwise instructed by the doctor).

Prolonged use during pregnancy may cause withdrawal symptoms in the newborn. Use during

childbirth may cause breathing problems in the newborn (respiratory depression).

The active ingredient oxycodone passes into the mother’s milk, and therefore do not

breastfeed during the treatment period.

Driving and use of machinery:

The use of this medicine may impair driving ability, as it may

cause dizziness or sleepiness (especially at the beginning of treatment, when the dosage is

increased, when changing from another medicine or in combination with other medicines that

affect the central nervous system). If you feel drowsiness and/or any other effect that may affect

driving, do not drive, operate machinery or participate in activities that require alertness. Consult

with your doctor if necessary.

Important information about some of the medicine’s ingredients:

The tablets contain

lactose. If you have been told that you have intolerance to certain sugars, inform the doctor

before taking this medicine (see section 6).

3. How should you use the medicine?

Always use according to the doctors’ instructions. You should check with your doctor or

pharmacist if you are not sure regarding the dosage and the manner of treatment with the

medicine. The dosage and the manner of treatment will be determined by the doctor only.

Targin tablets have a prolonged release mechanism. The active ingredients are released for 12

hours.

Swallow the tablet whole, so as not to impair the prolonged release of oxycodone from the

tablet. Do not break, chew crush or halve the tablet! Taking tablets that are not whole may

cause an absorption of a potentially lethal dose of oxycodone (see section: 'If you have

accidentally taken a higher dosage').

The tablets should be taken at set intervals (usually every 12 hours), as determined by your

attending doctor. The doctor will adjust your dosage according to your condition and the intensity

of your pain. The doctor will prescribe the minimum dose needed to control your pain.

Do not exceed the recommended dose.

If your doctor exchanges Targin with another opioid, your bowel function may worsen.

If you experience pain between the doses, contact your doctor. You may need to get an

analgesic that has fast activity. Targin is not suitable for that.

If you feel that the effect of the tablets is too strong or too weak, contact your doctor.

Elderly patients: If the liver and kidney function are normal, there is usually no need for a special

dose adjustment.

Patients with kidney function problems or mild liver function problems: The doctor may

prescribe a lower dose. The medicine is not intended for patients with moderate to severe liver

problems.

How to use: The tablets should be taken whole with a glass of water every 12 hours, regardless

of mealtime. For example at 8 am and 8 pm.

Duration of use: Do not take the tablets for a longer period than necessary. In prolonged

treatment, the doctor will perform follow-up tests to insure the need for further treatment.

If you have accidentally taken a higher dosage

or if a child or any other person has

accidentally swallowed the medicine, go immediately to a doctor or a hospital emergency room

and take the package of the medicine. Symptoms of overdose may include: constriction of the

pupils in the eye, respiratory depression (slower and weaker breathing than normal), drowsiness

up to unconscious, decrease in muscle tone, decrease in pulse rate, drop in blood pressure. In

severe cases there may be coma, fluid in the lungs, collapse of the blood system (shock). These

symptoms can be life threatening and require urgent medical attention. Do not drive or perform

an activity that requires alertness if an overdose was taken.

If you forgot to take the medicine, follow the below instructions:

If 8 hours or more remain until taking the next dose: Take the forgotten dose immediately. Take the

next dose at the regular time.

If less than 8 hours remain until taking the next dose: Take the forgotten dose and wait 8 hours for the

next dose.

Afterwards try to get back onto your regular dosing routine. Consult a doctor if you are not sure.

Make sure to have an interval of at least 8 hours between doses.

Do not take a double dose to compensate for the forgotten dose.

Adhere to the treatment as recommended by your doctor. Even if your state of health improves, do

not stop the treatment with the medicine without consulting your doctor.

If you stop taking the medicine: If you do not need any further treatment, consult your doctor

whom will guide you how to gradually decrease the daily dose in order to reduce the risk of

withdrawal symptoms such as: restlessness, excessive sweating, muscle pains.

Do not take medicines in the dark! Check the label and the dose each time you take a medicine.

Wear glasses if you need them.

If you have any further questions regarding the use of the medicine, consult with your doctor or

pharmacist.

4. Side effects

Like any medicine, the use of Targin may cause side effects in some users. Do not be alarmed

by reading the list of side effects. You may not suffer from any of them.

Contact a doctor immediately if the following side effects appear:

Respiratory depression - the most serious side effect of the medicine in which breathing

becomes slower and weaker. Mainly may occur in elderly and debilitated/weak patients.

Severe decrease in blood pressure.

Additional side effects:

Common side effects (appear in 1-10 users out of 100): abdominal pain, constipation, diarrhea, dry

mouth, indigestion, vomiting, nausea, flatulence, decreased appetite (up to loss of appetite), dizziness

or spinning sensation, headache, hot flash, general weakness, tiredness/exhaustion, skin reactions

such as itching or rash, excessive sweating, vertigo, sleeping difficulties, drowsiness.

Uncommon side effects (appear in 1-10 users out of 1,000): abdominal bloating, abnormal thoughts,

anxiety, confusion, depression, nervousness, chest tightness/pain (especially if you already suffer

from a coronary heart disease), decrease or increase in blood pressure, withdrawal symptoms such

as agitation; fainting, lack of energy, thirst, altered taste, palpitations (strong heartbeat), biliary colic,

angina pectoris, generally feeling unwell, pain, swelling of the hands, ankles or feet; difficulties to

concentrate, speaking difficulties, shaking, shortness of breath or breathing difficulties, restlessness,

chills, hepatic enzymes increased, reduced sexual drive, runny nose, cough, hypersensitivity or

allergic reactions, weight loss, increased risk for injuries from accidents, increased urge to urinate;

muscle pain, muscle cramps or twitches; vision impairment, convulsions (especially in epileptic

patients or patients with tendency to seizures).

Rare side effects (appear in 1-10 users out of 10,000): increase in pulse rate, dental changes, weight

gain, yawning, dependence on the medicine.

Side effects of unknown frequency (effects whose frequency has not yet been determined): feeling of

extreme happiness (euphoria), severe drowsiness (sedation), erectile problems, nightmares,

hallucinations, shallow breathing, difficulty in passing urine (urinary retention), tingling, belching.

Other side effects observed in the use of medicines containing oxycodone only as an active

ingredient:

Reduced eye pupils, decreased cough reflex.

Common side effects (appear in 1-10 users out of 100): changes in behavior or mood, increased or

decreased activity, hiccups.

Uncommon side effects (appear in 1-10 users out of 1,000): migraines, increase in muscle tension,

involuntary muscle contractions, drug dependence, bowel obstruction, dry skin, drug tolerance,

reduced sensitivity to pain or touch, impaired coordination, vocal changes, fluid retention (edema),

hearing impairment, ulcers/inflammation in the mouth, difficulties in swallowing, sore gums,

perception disturbances, flushing of skin, widening of blood vessels, dehydration, agitation, a

decrease in sex hormone levels (which may affect sperm production in men or the menstrual cycle in

women).

Rare side effects (appear in 1-10 users out of 10,000): urticaria (itchy rash), infections such as herpes

or cold sores (which may appear as blisters around the mouth or genitals), increased appetite, black

(bloody) stools, bleeding gums.

Side effects of unknown frequency (effects whose frequency has not yet been determined): severe

generalized allergic reaction (anaphylactic reaction), increase in sensitivity to pain, absence of

menstrual periods in women, withdrawal symptoms in the newborn, aggression, problems with bile

flow, dental caries.

If a side effect appears, if one of the side effects worsens, or if you suffer from a side

effect not mentioned in the leaflet, consult with a doctor.

Side effects can be reported to the Ministry of Health by clicking on the link “Reporting on side

effects following medicinal treatment” found on the homepage of the Ministry of Health website

(www.health.gov.il), which leads to the online form for reporting on side effects or by entering the

link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@

moh.gov.il

5 . How to store the medicine?

Avoid poisoning! This medicine and any other medicine must be kept in a closed place, out of the

reach and sight of children and/or infants in order to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by a doctor.

When you no longer need the tablets, consult the pharmacist about how to discard them.

Do not use the medicine after the expiry date (exp. date) stated on the package. The expiry date

refers to the last day of that month.

Storage conditions: Targin 10, 20, 30 and 40 should be stored below 25°C. Targin 5 should be

stored below 25°C in the original package.

6. Additional Information

In addition to the active ingredients, the tablets also contains:

Lactose

monohydrate,

stearyl

alcohol,

ethylcellulose,

talc,

magnesium

stearate,

polyvinyl

alcohol, titanium dioxide (E171), macrogol 3350.

Each tablet contains about 50-100 mg of lactose.

Each tablet of Targin 5 contains in addition: hydroxypropylcellulose, brilliant blue FCF (E133); Each

tablet of Targin 10 contains in addition: povidone; Each tablet of Targin 20 contains In addition:

povidone, iron oxide red (E172); Each tablet of Targin 30 contains in addition: povidone, iron oxide

yellow (E172) iron oxide black (E172) iron oxide red (E172); Each tablet of Targin 40 contains in

addition: povidone, iron oxide yellow (E172).

What does the medicine look like and what does the package contain?

Oblong coated tablets (caplets). “OXN” embossed on one side and the tablet strength on the

other side (5, 10, 20, 30 or 40, respectively). The color of the tablets: Targin 5 - blue, Targin 10 -

white, Targin 20 - pink, Targin 30 - brown, Targin 40-yellow.

Each box contains 20 tablets in blisters.

Registration holder: Rafa Laboratories Ltd., P.O.Box 405, Jerusalem 9100301

Registration number of the medicine in the National Drug Registry of the Ministry of

Health:

Targin 5 - 1439833120; Targin 10 - 1399531636; Targin 20 - 1399631637;

Targin 30 - 1604335262; Targin 40 - 1439933122

The format of this leaflet was determined by the Ministry of Heath and its content was checked and

approved by it in October 2018.

I-165008

Targin -DL-Dec 2018-05

The format of this leaflet was determined by the Ministry of Health and its content was checked and approved

by it on December 2018

Doctor Leaflet

1. NAME OF THE MEDICINAL PRODUCT

Targin 5, Targin 10, Targin 20, Targin 30, Targin 40

Prolonged-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Targin 5

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

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

Targin 10

Each prolonged-release tablet contains 10 mg of oxycodone hydrochloride equivalent to 9 mg oxycodone, and

5.45 mg of naloxone hydrochloride dihydrate equivalent to 5 mg naloxone hydrochloride and 4.5 mg naloxone.

Targin 20

Each prolonged-release tablet contains 20 mg of oxycodone hydrochloride equivalent to 18 mg oxycodone, and

10.9 mg of naloxone hydrochloride dihydrate equivalent to 10 mg naloxone hydrochloride and 9 mg naloxone.

Targin 30

Each prolonged-release tablet contains 30 mg of oxycodone hydrochloride equivalent to 27 mg oxycodone, and

16.48 mg of naloxone hydrochloride dihydrate equivalent to 15 mg naloxone hydrochloride and 13.5 mg naloxone.

Targin 40

Each prolonged-release tablet contains 40 mg of oxycodone hydrochloride equivalent to 36 mg oxycodone, and

21.8 mg of naloxone hydrochloride dihydrate equivalent to 20 mg naloxone hydrochloride and 18 mg naloxone.

Each tablet of Targin 5 contains 71.75 mg lactose monohydrate.

Each tablet of Targin 10 contains 64.25 mg lactose monohydrate.

Each tablet of Targin 20 contains 54.5 mg lactose monohydrate.

Each tablet of Targin 30 contains 38.42 mg lactose monohydrate.

Each tablet of Targin 40 contains 109 mg lactose monohydrate.

For the full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Prolonged-release tablets.

Targin 5 are oblong, blue film-coated tablets, unscored and marked “OXN” on one side and “5” on the other side.

Targin 10 are oblong, white film-coated tablets, unscored and marked “OXN” on one side and “10” on the other side.

Targin 20 are oblong, pink film-coated tablets, unscored and marked “OXN” on one side and “20” on the other side.

Targin 30 are oblong, brown film-coated tablets, unscored and marked “OXN” on one side and “30” on the other side.

Targin 40 are oblong, yellow film-coated tablets, unscored and marked “OXN” on one side and “40” on the other side.

Page 2 of 13

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Targin is indicated for the relief of moderate to severe pain

The oxycodone component is indicated for the relief of moderate to severe pain in adults who require continuous around

the- clock opioid analgesia for several days or more.

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

opioid receptors locally in the gut.

4.2 Posology and method of administration

Posology

The analgesic efficacy of Targin 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, Targin 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 (Targin 10).

Lower strength (Targin 5) is 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 Targin, depending on their previous opioid

experience.

The maximum daily dose of Targin is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride. For patients

requiring higher doses of Targin, administration of supplemental prolonged-release oxycodone hydrochloride at the same

time intervals should be considered. 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 Targin with a subsequent switch to another opioid a worsening of the bowel

function can be expected.

Some patients taking Targin according to a regular time schedule require immediate release analgesics as "rescue"

medication for breakthrough pain. Targin 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

WARNING: RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS

DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS)

depressants, including alcohol, may result in profound sedation, respiratory depression, coma,

and death [see section 4.5]

Reserve concomitant prescribing of these drugs for use in patients for whom alternative

treatment options are inadequate.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

Page 3 of 13

an indication that the dosage requires upward adjustment. This adjustment should be made every 1-2 days in steps of

Targin 5 twice daily, or where necessary Targin 10 twice daily 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.

Targin 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 40mg/20mg oxycodone hydrochloride/naloxone hydrochloride are

usually sufficient, but higher doses may be needed.

Elderly patients

As for younger adults the dosage 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 Targin to patients with mild hepatic impairment (see section 4.4). In patients with moderate and

severe hepatic impairment Targin 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 Targin to patients with renal impairment (see section 4.4).

Paediatric population

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

Method of administration

Oral use.

Targin 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. Targin must be swallowed whole,

and not broken, chewed or crushed (see section 4.4).

Duration of use

Targin 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.

When the patient no longer requires

opioid therapy, it may be

advisable to taper the dose gradually (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

The major risk of opioid excess is respiratory depression.

Page 4 of 13

Caution must be exercised when administering Targin 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 must also be exercised when administering Targin to patients with mild hepatic or renal impairment. 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, the switch to Targin can initially provoke withdrawal symptoms. Such

patients may require specific attention.

Targin 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 Targin may lead to physical dependence. Withdrawal

symptoms may occur upon the abrupt cessation of therapy. If therapy 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 Targin.

Targin 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 Targin, 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).

Concomitant use of alcohol and Targin may increase the undesirable effects of Targin; concomitant use should be

avoided.

Studies have not been performed on the safety and efficacy of Targin 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 Targin in this population is not

recommended.

Targin 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 Targin depends on a careful risk-benefit

assessment for each individual patient.

Any abuse of Targin by drug addicts is strongly discouraged.

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

methadone, Targin 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).

Targin 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.

The use of Targin may produce positive results in doping controls.The use of Targin as a doping agent may become

a health hazard.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase

deficiency or glucose-galactose malabsorption should not take Targin.

Page 5 of 13

4.5 Interaction with other medicinal products and other forms of interaction

Substances having a CNS-depressant effect (e.g. other opioids, sedatives and hypnotics such as benzodiazepines,

antidepressants, phenothiazines, neuroleptics, antihistamines and antiemetics) may enhance the CNS-depressant

effect (e.g. respiratory depression) of Targin.

Concomitant administration of oxycodone with anticholinergics or medications with anticholinergic activity (e.g.

tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in

increased anticholinergic adverse effects.

Alcohol may enhance the pharmacodynamic effects of

Targin; 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. Targin 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 Targin 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 pain 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 breastfeeding

Pregnancy

There are no data from the use of Targin 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 Targin 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.

Targin 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 taking Targin 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 Targin by the breast-

feeding mother.

Page 6 of 13

Breast-feeding should be discontinued during treatment with Targin.

Fertility

There are no data with respect to fertility.

4.7 Effects on ability to drive and use machines

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

treatment, after dose increase or product rotation and if Targin 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.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely.

When prescribing this medicine,

patients should be told:

The medicine is likely to affect your ability to drive.

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

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.

System organ

class

MedDRA

Common

Uncommon

Rare

Not known

Immune system

disorders

Hypersensitivity

Metabolism and

nutritional

disorders

Decreased

appetite up to

loss of appetite

Psychiatric

disorders

Insomnia

Abnormal

thinking

Anxiety

Confusional

state

Depression

Libido

decreased

Nervousness

Restlessness

Euphoric

mood

Hallucination

Nightmares

Nervous system

disorders

Dizziness

Headache

Somnolence

Convulsions

Disturbance in

attention

Dysgeusia

Speech disorder

Syncope

Tremor

Lethargy

Paraesthesia

Sedation

Eye disorders

Visual

impairment

Ear and labyrinth

disorders

Vertigo

Page 7 of 13

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 disorders

Pruritus

Skin reactions

Hyperhidrosis

Musculoskeletal

and connective

tissue disorders

Muscle spasms

Muscle

twitching,

Myalgia

Renal and urinary

disorders

Micturition

urgency

Urinary

retention

Reproductive

system and breast

disorders

Erectile

dysfunction

General disorders

administration

site conditions

Asthenia

Fatigue

Chest pains

Chills

Drug

withdrawal

syndrome

Malaise

Pain

Peripheral

oedema

Thirst

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.

Page 8 of 13

System organ

class

MedDRA

Common

Uncommon

Rare

Not known

Infections and

infestations

Herpes

simplex

Immune system

disorders

Anaphylactic

responses

Metabolism and

nutritional

disorders

Dehydration

Increased

appetite

Psychiatric

disorders

Altered mood

personality

changes

Decreased

activity

Psychomotor

hyperactivity

Agitation

Perception

disturbances

(e.g.

derealisation)

Drug

dependence

Aggression

Nervous system

disorders

Concentration

impaired

Migraine

Hypertonia

Involuntary

muscle

contractions

Hypoaesthesia

Abnormal

co-ordination

Hyperalgesia

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

Dental caries

Hepatobiliary

disorders

Cholestasis

Skin and

subcutaneous

tissue disorders

Dry skin

Urticaria

Renal and

urinary

disorders

Dysuria

Reproductive

system and

breast disorders

Hypogonadism

Amenorrhoea

General

disorders and

administration

site conditions

Oedema

Drug tolerance

Drug

withdrawal

syndrome

neonatal

Page 9 of 13

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by

using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

4.9 Overdose

Symptoms of intoxication

Depending on the history of the patient, an overdose of Targin 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 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 affects pain relief

by binding 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

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

Page 10 of 13

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.

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.

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, 6

Naloxol and its glucuronide.

Oxycodone hydrochloride/naloxone hydrochloride combination (Targin)

Pharmacokinetic/pharmacodynamic relationships

The pharmacokinetic characteristics of oxycodone from Targin is equivalent to those of prolonged-release oxycodone

hydrochloride tablets administered together with prolonged-release naloxone hydrochloride tablets.

All dosage strengths of Targin are interchangeable.

After the oral administration of Targin in 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 (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 Targin 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 Targin

is unlikely.

Page 11 of 13

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

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

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

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 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:

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:

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

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 t

1/2Z

and the

Page 12 of 13

corresponding

of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore

based on

values. The ratios may have been influenced by the inability to fully characterize the naloxone plasma

profiles for the healthy subjects.

Naloxone-3-glucuronide:

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

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 t

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, Targin 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 Targin 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 oxycodone 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 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

Targin to humans at therapeutic concentrations may be ruled out with adequate certainty.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethylcellulose, stearyl alcohol, lactose monohydrate, talc, magnesium stearate, polyvinylalcohol, titanium dioxide

(E171), macrogol 3350.

Targin 5 also contains hydroxypropylcellulose and brilliant blue FCF aluminium lake (E133).

Targin 10 also contains povidone K30.

Targin 20 also contains povidone K30 and iron oxide red (E172).

Targin 30 also contains povidone K30 and iron oxide red, iron oxide yellow & iron oxide black (E172).

Targin 40 also contains povidone K30 and iron oxide yellow (E172).

6.2 Incompatibilities

Not applicable.

Page 13 of 13

6.3 Special precautions for storage

Store below 25°C.

Targin 5: Store below 25°C in the original package.

6.4 Nature of container

Polyvinylchloride/aluminium foil blisters.

7. MARKETING AUTHORISATION NUMBER

Targin 5, 20 prolonged-release tablets

Licence no. 143 98 33120

Targin 10, 20 prolonged-release tablets

Licence no. 139 95 31636

Targin 20, 20 prolonged-release tablets Licence no. 139 96 31637

Targin 30, 20 prolonged-release tablets Licence no. 160 43 35262

Targin 40, 20 prolonged-release tablets

Licence no. 143 99 33122

8. REGISTRATION HOLDER: Rafa Laboratories Ltd. POB 405 Jerusalem 9100301