Targin

Package leaflet: Information for the user

Targin 2.5 mg/1.25 mg prolonged-release tablets, 15 mg/7.5 mg prolonged-release tablets, 30 mg/15 mg prolonged-release tablets

Oxycodone hydrochloride/naloxone hydrochloride
Please read this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What Targin is and what it is used for
2. What you need to know before taking Targin
3. How to take Targin
4. Possible side effects
5. How to store Targin
6. Contents of the pack and other information

1. What Targin is and what it is used for

Targin contains oxycodone hydrochloride and naloxone hydrochloride as active substances.
These tablets are for use in adults only.
Targin is used to treat severe pain that can be adequately managed only with opioid analgesics.

How Targin works
Oxycodone hydrochloride is responsible for the pain-relieving effect of Targin and is a potent analgesic (painkiller) belonging to the opioid group of medicines.

The second active ingredient in Targin, naloxone hydrochloride, counteracts constipation. Gastrointestinal dysfunction (e.g. constipation) is a typical adverse effect of treatment with opioid analgesics.

2. What you must know before taking Targin

Do NOT use Targin:

• if you are allergic to oxycodone hydrochloride, naloxone hydrochloride, or any of the other ingredients of this medicine (listed in section 6),
• if your breathing is unable to provide enough oxygen to the blood and remove the carbon dioxide produced (respiratory depression),
• if you suffer from severe lung disease associated with narrowing of the airways (chronic obstructive pulmonary disease or COPD),
• if you have a condition known as cor pulmonale. In this condition, the right side of the heart enlarges due to increased pressure in the blood vessels of the lung, etc. (e.g. as a consequence of COPD – see above),
• if you have severe bronchial asthma,
• if you have paralytic ileus (a type of intestinal obstruction) not caused by opioids,
• if you have moderate or severe liver dysfunction.

Warnings and precautions
Talk to your doctor or pharmacist before taking Targin:

• if you are elderly or debilitated (weak)
• if you suffer from paralytic ileus (a type of intestinal obstruction) caused by opioids
• if you have impaired kidney function
• if you have mild impairment of liver function
• if you have severe pulmonary impairment (e.g. reduced respiratory capacity)
• if you have myxoedema (a thyroid disorder, with dry, cold and swollen skin in the face and limbs)
• if your thyroid gland does not produce enough hormones (hypothyroidism or thyroid insufficiency)
• if your adrenal glands do not produce enough hormones (adrenal insufficiency or Addison’s disease)
• if you have mental disorders accompanied by (partial) loss of sense of reality (psychosis) due to alcohol or intoxication with other substances (substance-induced psychosis)
• if you suffer from gallstones or any other disorder of the biliary tract (disease affecting the bile ducts, gallbladder, etc.)
• if your prostate gland is abnormally enlarged (prostatic hypertrophy)
• if you suffer from alcoholism or 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 cardiovascular diseases
• if you have a head injury (due to the risk of increased intracranial pressure)
• if you suffer from epilepsy or are prone to seizures
• if you are also taking MAO inhibitors (used to treat depression or Parkinson’s disease), or if you have taken these medicines within the last 2 weeks, e.g. medicines containing tranylcypromine, phenelzine, isocarboxazid, moclobemide, linezolid.

Sleep-related breathing disorders
Targin can cause sleep-related breathing disorders, such as sleep apnoea (pauses in breathing during sleep) and sleep-related hypoxaemia (low levels of oxygen in the blood). Symptoms may include pauses in breathing during sleep, night awakenings due to gasping for breath, difficulty maintaining sleep, or excessive daytime sleepiness. If you or someone else observes these symptoms, consult your doctor. Your doctor may consider reducing the dose.
Inform your doctor if any of the above conditions occurred previously. Also inform your doctor if any of these disorders develop while you are taking Targin.
The most serious effect of an opioid overdose is respiratory depression (slow and shallow breathing). This may also cause reduced oxygen levels in the blood, potentially leading to fainting, etc.
You must swallow the prolonged-release tablets whole, so as not to interfere with the slow release of oxycodone hydrochloride from the prolonged-release tablets. Do not break, chew or crush the tablets. Taking broken, chewed or crushed tablets may result in the absorption of a potentially lethal dose of oxycodone hydrochloride (see section 3 “ If you take more Targin than you should”).

If severe diarrhoea occurs at the beginning of treatment, this may be due to the effect of naloxone. It may be a sign that intestinal function is returning to normal. Diarrhoea may occur during the first 3–5 days of treatment. If diarrhoea persists beyond 3–5 days, or if it causes you concern, contact your doctor.

When switching to treatment with Targin, if you have been using high doses of another opioid, withdrawal symptoms may initially occur, such as restlessness, episodes of sweating and muscle aches. If such symptoms occur, close medical monitoring may be necessary.

Tolerance, dependence and abuse
This medicine contains oxycodone, which is an opioid. It may cause dependence and/or tolerance.
This medicine contains oxycodone, which is an opioid medicine. Repeated use of opioid analgesics may reduce the effectiveness of the medicine (you become accustomed to the medicine, a phenomenon known as tolerance). Repeated use of Targin may also lead to dependence, abuse, and tolerance, which can result in a potentially fatal overdose. The risk of these adverse effects may increase with higher doses and longer duration of use.
Dependence or abuse may make you feel that you have lost control over how much medicine you take or how often you take it. You may feel compelled to continue taking the medicine, even when it no longer helps relieve pain.
The risk of becoming dependent or tolerant varies from person to person. You may have a higher risk of becoming dependent or tolerant to Targin if:

• you or a member of your family has ever abused or been dependent on alcohol, prescription medicines or illegal drugs (“addiction”);
• you are a smoker;
• you have had mood disorders (depression, anxiety or personality disorders) or have been treated by a psychiatrist for other mental illnesses.

If any of the following signs appear while you are taking Targin, this may indicate that you have become dependent or tolerant:
you need to take the medicine for longer than prescribed by your doctor;

• you need to take a higher dose than recommended;
• you are using the medicine for reasons other than prescribed, e.g. “to stay calm” or “to help sleep”;
• you have repeatedly tried, without success, to stop or control your use of the medicine;
• when you stop taking the medicine, you feel unwell, and feel better after resuming it (“withdrawal effects”). If any of these signs appear, consult your doctor to discuss the best treatment approach for you, including when and how to safely discontinue treatment (see section 3 “If you stop taking Targin”).

Contact your doctor if you experience severe pain in the upper abdomen that may radiate to the back, nausea, vomiting or fever, as these may be symptoms associated with inflammation of the pancreas (pancreatitis) or of the biliary tract.
Inform your doctor if you have cancer with peritoneal metastases or if you are experiencing the onset of intestinal obstruction in advanced stages of gastrointestinal or pelvic tumours.
If you require surgery, inform your doctor that you are taking Targin.
Like other opioids, oxycodone may affect the normal production of body hormones such as cortisol or sex hormones, especially when high doses are taken for prolonged periods. If you experience persistent symptoms such as feeling unwell or malaise (including vomiting), loss of appetite, fatigue, weakness, dizziness, changes in menstrual cycle, impotence, infertility or reduced sexual desire, talk to your doctor, as you may require monitoring of your hormone levels.
This medicine may increase your sensitivity to pain, particularly at high doses. Inform your doctor if this occurs. A dose reduction or change of medicine may be necessary.
Residues of the prolonged-release tablet may be found in the faeces. Do not be alarmed, as the active ingredients (oxycodone hydrochloride and naloxone hydrochloride) have already been released into the stomach and intestine and absorbed into your body.

Incorrect use of Targin
Targin is not suitable for the treatment of withdrawal.
You must never abuse Targin, especially if you are drug-dependent. If you are dependent on substances such as heroin, morphine or methadone, severe withdrawal symptoms are likely if you abuse Targin because it contains naloxone. Pre-existing withdrawal symptoms may be worsened.
You must not misuse the prolonged-release tablets by dissolving and injecting them (e.g. into a blood vessel). In particular, they contain talc, which may cause local tissue destruction (necrosis) and changes in lung tissue (pulmonary granuloma). Such abuse may also have other serious consequences and may be fatal.
The use of Targin may yield positive results in anti-doping tests.
The use of Targin as a doping agent may pose a health risk.
For athletes: using the medicine without therapeutic need constitutes doping and may result in a positive anti-doping test.

Other medicines and Targin
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
The risk of adverse effects increases if you take antidepressants (such as citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine). These medicines may interact with oxycodone, and you may experience symptoms such as involuntary rhythmic muscle contractions, including muscles controlling eye movement, agitation, excessive sweating, tremor, exaggerated reflexes, increased muscle tension, body temperature above 38°C. Contact your doctor if these symptoms occur.
Concomitant use of opioids, including oxycodone hydrochloride, and sedative medicines such as benzodiazepines or similar medicines, increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be life-threatening. For this reason, concomitant use should only be considered if no alternative treatments are available.
However, if your doctor prescribes Targin together with sedative medicines, the dose and duration of concomitant treatment must be limited by your doctor.
Inform your doctor about all sedative medicines you are taking and strictly follow the doses recommended by your doctor. It may be helpful to inform friends and family to watch for the signs and symptoms listed above. Contact your doctor if you experience such symptoms. Examples of sedative or similar medicines include:

• other strong painkillers (opioids);
• medicines for epilepsy, pain and anxiety such as gabapentin and pregabalin;
• sleeping pills and tranquillisers (sedatives including benzodiazepines, hypnotics, anxiolytics);
• medicines for depression;
• medicines used to treat allergies, motion sickness or nausea (antiemetics or antihistamines);
• other medicines for psychiatric or mental disorders (antipsychotics including phenothiazines and neuroleptics);
• muscle relaxants;
• medicines for Parkinson’s disease.

If you take these tablets together with other medicines, the effect of these tablets or the other medicines may vary, as described below.
Inform your doctor if you are taking:

• medicines that reduce blood clotting ability (coumarin derivatives): clotting time may be accelerated or slowed;
• macrolide antibiotics (such as clarithromycin, erythromycin or telithromycin);
• azole antifungals (such as ketoconazole, voriconazole, itraconazole or posaconazole);
• a specific type of medicine known as a protease inhibitor used to treat HIV (examples include ritonavir, indinavir, nelfinavir or saquinavir);
• cimetidine (a medicine used to treat stomach ulcers, indigestion or heartburn);
• rifampicin (used to treat tuberculosis);
• carbamazepine (used to treat epileptic seizures, fits or convulsions and in some pain conditions);
• phenytoin (used to treat epileptic seizures, fits or convulsions);
• a herbal remedy known as St. John’s wort (also known as Hypericum perforatum);
• quinidine (a medicine used to treat irregular heartbeat). No interactions between Targin and paracetamol, acetylsalicylic acid or naltrexone are expected.

Targin with food, drinks and alcohol
Drinking alcohol while taking Targin may cause drowsiness or increase the risk of serious adverse effects such as shortness of breath, risk of respiratory depression and loss of consciousness. It is recommended not to drink alcohol while taking Targin.
You should avoid drinking grapefruit juice when taking Targin.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
The use of Targin should be avoided as much as possible during pregnancy. If used for prolonged periods during pregnancy, oxycodone hydrochloride may cause withdrawal symptoms in newborns. If oxycodone hydrochloride is administered during childbirth, respiratory depression (slow and shallow breathing) may occur in the newborn.
Breastfeeding
Breastfeeding must be discontinued during treatment with Targin. Oxycodone hydrochloride passes into breast milk. It is not known whether naloxone hydrochloride also passes into breast milk. Therefore, a risk to the breastfed infant cannot be excluded, particularly after multiple doses of Targin.

Driving and using machines
Targin may affect your ability to drive vehicles or operate machinery. This is particularly likely at the beginning of Targin therapy, after a dose increase, or after switching from a different medicine. However, these adverse effects usually disappear once the Targin dose has been stabilised.
Ask your doctor whether you can drive or operate machinery.

Targin contains lactose
This medicine contains lactose (milk sugar). If your doctor has diagnosed you with an intolerance to certain sugars, contact them before taking this medicine.

3. How to take Targin

Take this medicine exactly as directed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.
Before starting treatment and regularly during treatment, your doctor will discuss with you what to expect from using Targin, when and for how long you should take it, when to contact your doctor, and when you should stop taking it (see also "If you stop taking Targin").

In the absence of specific medical instructions, the recommended dose is:

Adults
The usual starting dose is 10 mg of oxycodone hydrochloride / 5 mg of naloxone hydrochloride every 12 hours.
Your doctor will decide how much Targin you should take each day and how to divide the daily dose between morning and evening. Your doctor will also determine any necessary dose adjustments during treatment. The dose will be adjusted according to the level of pain and individual sensitivity. You should be given the lowest dose necessary to relieve your pain. If you have previously been treated with opioids, Targin may be started at a higher dose.

The maximum daily dose of Targin is 160 mg of oxycodone hydrochloride and 80 mg of naloxone hydrochloride. If you require a higher dose, your doctor may prescribe additional oxycodone hydrochloride without naloxone hydrochloride. However, the total daily dose of oxycodone hydrochloride should not exceed 400 mg. The beneficial effect of naloxone hydrochloride on intestinal function may decrease when higher doses of oxycodone hydrochloride are administered without additional naloxone hydrochloride.

If you switch from Targin to another opioid medicine for pain treatment, your bowel function will likely worsen.

If you experience pain between doses of Targin, you may need a fast-acting painkiller. Targin is not suitable for this purpose. In such cases, consult your doctor.

If you feel that the effect of Targin is too strong or too weak, talk to your doctor or pharmacist.

Elderly patients
In general, dose adjustment is not necessary in elderly patients with normal kidney and/or liver function.

Renal or hepatic impairment
If you have impaired kidney function or mild impairment of liver function, your doctor will prescribe Targin with particular caution. If you have moderate or severe impairment of liver function, Targin must not be used (see also section 2 "Do not take Targin" and "Warnings and Precautions").

Children and adolescents under 18 years of age
Targin has not yet been studied in children and adolescents under 18 years of age. Its safety and efficacy have not been established in this population. Therefore, the use of Targin in children and adolescents under 18 years of age is not recommended.

Method of administration
Targin is for oral use.
Swallow the prolonged-release tablets whole (without chewing) with an adequate amount of liquid (½ glass of water). You may take the prolonged-release tablets with or without food. Take the tablets every 12 hours according to a fixed schedule (e.g., 8 a.m. and 8 p.m.).

You must swallow the prolonged-release tablet whole to ensure the slow release of oxycodone hydrochloride from the tablet is not disrupted.

The tablets must not be broken, chewed, or crushed.
Swallowing broken, chewed, or crushed tablets may result in the absorption of a potentially lethal dose of oxycodone hydrochloride (see section 3 “If you take more Targin than you should”).

Duration of use
In general, you should not take Targin for longer than necessary. If you are on long-term treatment, your doctor should regularly assess whether you still need Targin.

If you take more Targin than you should
If you have taken more than the prescribed dose of Targin, inform your doctor immediately.
An overdose may cause:

• constricted pupils
• slow and shallow breathing (respiratory depression)
• drowsiness (up to loss of consciousness)
• reduced muscle tone (hypotonia)
• reduced pulse rate
• low blood pressure
• a brain disorder (known as toxic leukoencephalopathy).

In severe cases, loss of consciousness (coma), fluid accumulation in the lungs, and circulatory collapse may occur, which in some cases can be fatal.
Avoid situations requiring high alertness, such as driving.

If you forget to take Targin
If you miss a dose or take a lower dose than prescribed, you may not experience any analgesic effect.
If you forget to take your dose, follow the instructions below:

• If your next scheduled dose is 8 hours or more away: take the missed dose immediately, then continue with your regular dosing schedule.
• If your next scheduled dose is less than 8 hours away: take the missed dose, then wait at least 8 hours before taking your next dose. Try to return to your original dosing schedule (e.g., 8 a.m. and 8 p.m.). Do not take more than one dose within an 8-hour period.

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

If you stop taking Targin
Do not stop treatment without consulting your doctor.
If further treatment is no longer needed, you must gradually reduce the daily dose after discussing it with your doctor. This will help you avoid withdrawal symptoms such as restlessness, episodes of sweating, and muscle pain.

If you have any questions about 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 everyone will experience them.
Important side effects or signs to watch for, and what to do if they occur:
If you notice any of the following important side effects, contact your doctor immediately.
Slow and shallow breathing (respiratory depression) is the main danger of an opioid overdose. This occurs especially in elderly and debilitated (weakened) patients. Opioids may also cause a severe drop in blood pressure in predisposed patients.

Common (may affect up to 1 in 10 people)

• abdominal pain • nausea • unusual weakness
• constipation • flatulence • fatigue or exhaustion
• diarrhoea • reduced appetite or loss of appetite • itching of the skin
• dry mouth • dizziness or vertigo • skin reactions/rash
• indigestion • headache
• vomiting (feeling sick) • sweating
• hot flushes • dizziness
• difficulty sleeping
• drowsiness

Uncommon (may affect up to 1 in 100 people)

• abdominal swelling • palpitations • runny nose
• unusual thoughts • biliary colic • cough
• anxiety • chest pain • hypersensitivity/allergic reactions
• confusion • general malaise • accidental injuries
• depression • pain • increased urge to urinate, especially if you already suffer from coronary heart disease
• nervousness • swelling of hands, ankles or feet • muscle cramps
• weight loss • muscle spasms
• difficulty concentrating • muscle pain
• reduced blood pressure • impaired speech • vision problems
• tremors • seizures
• withdrawal symptoms such as agitation • shortness of breath (especially in people with epilepsy or predisposition to convulsions)
• restlessness • chills
• lack of energy • increased liver enzymes
• altered taste • increased blood pressure

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

• increased heart rate • dental abnormalities • yawning
• weight gain
• drug dependence

Not known (frequency cannot be estimated from available data)

• euphoric mood • hallucinations • skin tingling
• severe drowsiness • shallow breathing • belching
• erectile dysfunction • difficulty urinating • sleep apnoea (pauses in breathing during sleep)

The active substance, oxycodone hydrochloride, when not combined with naloxone hydrochloride, has the following side effects:
Oxycodone may cause breathing problems (respiratory depression), reduction in pupil size (miosis), bronchial muscle spasms, spasms of smooth muscle, and suppression of the cough reflex.

Common (may affect up to 1 in 10 people)

• mood changes and • decreased activity • difficulty urinating personality changes • increased activity • hiccup (e.g., depression, feeling of extreme happiness)

Uncommon (may affect up to 1 in 100 people)

• reduced ability to • reduced sensitivity to • gum pain concentrate pain or touch • perception disorders
• headache • changes in voice (e.g., hallucinations, derealisation)
• increased muscle tension • fluid retention • skin redness
• involuntary muscle contractions • hearing difficulties • dehydration
• mouth ulcers • agitation
• difficulty swallowing • decreased levels of sex hormones which may alter sperm production in men or the menstrual cycle in women
• dry skin
• drug tolerance

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

• itchy skin rash (urticaria) • increased appetite • bleeding gums
• black (tarry) stools
• infections such as herpes (which may cause blisters around the mouth or genitals)

Not known (frequency cannot be estimated from available data)

• acute generalized allergic reactions (anaphylactic reactions) • absence of menstruation • bile flow problems
• increased sensitivity to pain • tooth decay
• neonatal withdrawal syndrome
• a condition affecting a valve in the intestine that may cause severe upper abdominal pain (Oddi sphincter dysfunction)

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report the adverse reaction directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting adverse reactions, you help provide more information on the safety of this medicine.

5. How to store Targin

Keep this medicine out of the sight and reach of children. Store this medicine in a secure place, not accessible to others. It may cause serious harm or be fatal to people for whom it has not been prescribed.

Do not use this medicine after the expiry date 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 dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Targin contains
The active substances are: oxycodone hydrochloride and naloxone hydrochloride
{Targin 2.5 mg/1.25 mg}
Each prolonged-release tablet contains 2.5 mg of oxycodone hydrochloride equivalent to 2.25 mg of oxycodone and 1.25 mg of naloxone hydrochloride equivalent to 1.37 mg of dihydrate naloxone hydrochloride, and 1.13 mg of naloxone
{Targin 15 mg/7.5 mg}
Each prolonged-release tablet contains 15 mg of oxycodone hydrochloride equivalent to 13.5 mg of oxycodone and 7.5 mg of naloxone hydrochloride equivalent to 8.24 mg of dihydrate naloxone hydrochloride, corresponding to 6.75 mg of naloxone
{Targin 30 mg/15 mg}
Each prolonged-release tablet contains 30 mg of oxycodone hydrochloride equivalent to 27 mg of oxycodone and 15 mg of naloxone hydrochloride equivalent to 16.48 mg of dihydrate naloxone hydrochloride, corresponding to 13.5 mg of naloxone

The other components are:
{Targin 2.5 mg/1.25 mg}
Tablet core:
Ethylcellulose, stearyl alcohol, lactose monohydrate, talc, magnesium stearate.
Tablet coating:
Partially hydrolysed polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc, iron oxide red (E172), iron oxide yellow (E172).
{Targin 15 mg/7.5 mg}
Tablet core:
Hydroxypropylcellulose, ethylcellulose, stearyl alcohol, lactose monohydrate, talc, magnesium stearate.
Tablet coating:
Partially hydrolysed polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc, iron oxide black (E172), iron oxide red (E172), iron oxide yellow (E172).
{Targin 30 mg/15 mg}
Tablet core:
Povidone K30, ethylcellulose, stearyl alcohol, lactose monohydrate, talc, magnesium stearate.
Tablet coating:
Partially hydrolysed polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc, iron oxide black (E172), iron oxide red (E172), iron oxide yellow (E172).

Description of the appearance of Targin and contents of the pack
Targin is available as a prolonged-release tablet, meaning its active substances are released over an extended period of time. Its effect lasts for 12 hours.
{Targin 2.5 mg/1.25 mg}
Light yellow, round tablets with a film coating, nominal length 5 mm.
{Targin 15 mg/7.5 mg}
Grey, oval-shaped tablets with a film coating, nominal length 9.5 mm, marked "OXN" on one side and "15" on the other.
{Targin 30 mg/15 mg}
Brown, oval-shaped tablets with a film coating, nominal length 9.5 mm, marked "OXN" on one side and "30" on the other.

Prolonged-release tablets of Targin are available in packs containing 10, 14, 20, 28, 30, 50, 56, 60, 98 and 100 tablets, or in hospital packs containing 100 tablets (10 x 10).
Not all pack sizes may be marketed.

Marketing Authorisation Holder
MUNDIPHARMA PHARMACEUTICALS SRL – Viale Restelli 3/7, 20124 Milano, Italy

Manufacturer:
Mundipharma DC B.V.
Leusderend 16
3832 RC Leusden
The Netherlands

This medicinal product is authorised in the European Economic Area countries under the following names: