MS Contin

Package leaflet: Information for the user

MS Contin 10 mg, prolonged-release tablets, 30 mg, prolonged-release tablets, 60 mg, prolonged-release tablets, 100 mg, prolonged-release tablets, 200 mg, prolonged-release tablets

Morphine sulfate
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 yours, because it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What MS Contin is and what it is used for

These prolonged-release tablets have been prescribed by your doctor for the relief of prolonged, severe, and resistant pain requiring long-term use of painkillers, and their effect lasts 12 hours. The prolonged-release tablets contain the active substance morphine, a substance belonging to the class of opioid analgesics (painkillers) that work by reducing pain. For other excipients contained in the prolonged-release tablet, see section 6 of this leaflet.
MS Contin provides 12 hours of therapeutic effect when the prolonged-release tablets are swallowed whole. If a prolonged-release tablet is broken, crushed, dissolved in liquid, or chewed, the entire dose intended to be released over 12 hours is instead rapidly absorbed: this may be harmful and cause serious problems, and overdose is potentially fatal.

2. What you should know before taking MS Contin

Do not take MS Contin:

• if you are allergic (hypersensitive) to the active substance or to any of the other ingredients of this medicine (listed in section 6), or if you have previously experienced an allergic reaction to another opioid analgesic;
• if you have respiratory problems, such as airway obstruction, bronchial asthma, or severe lung disease, or if you are breathing more slowly or weakly than normal (respiratory depression);
• if you have a head injury causing severe headache or malaise. This is because prolonged-release tablets may worsen these symptoms or mask the true severity of the head injury;
• if you have increased pressure in the head (intracranial or cerebrospinal hypertension); if you suffer from alcohol dependence (acute alcoholism, delirium tremens);
• if you suffer from depression of the central nervous system, particularly due to other medicines (hypnotics, sedatives, tranquilizers);
• if you have a condition in which the small intestine does not function properly (paralytic ileus), if your stomach empties more slowly than it should (delayed gastric emptying), or if you have severe abdominal pain;
• if you have heart problems (cardiac arrhythmias) and suffer from heart disorders due to chronic lung diseases;
• if you have a recently developed liver disease (acute hepatopathy);
• if you are currently taking antidepressant medicines called monoamine oxidase inhibitors (e.g. tranylcypromine, phenelzine, isocarboxazid, moclobemide, and linezolid), or if you have taken these medicines within the last two weeks.

Tolerance, dependence
This medicine contains morphine, an opioid medicine. Repeated use of opioids may make the medicine less effective over time (you become accustomed to it, a phenomenon known as tolerance). Repeated use of MS Contin may also lead to dependence and abuse, which can result in potentially fatal overdose. The risk of these adverse effects may increase with higher doses and prolonged duration of use. Dependence may make you feel that you no longer have control over the amount of medicine you need or how often you must take it. The risk of developing dependence varies from person to person. You may have a higher risk of becoming dependent on MS Contin if:

• you or a family member has previously suffered from abuse or dependence on alcohol, prescription medicines, or illegal substances ("addiction");
• you are a smoker;
• you have previously had mood disorders (depression, anxiety, or a personality disorder) or have been treated by a psychiatrist for other mental illnesses.

The appearance of any of the following signs during use of MS Contin could indicate dependence:

• you feel the need to take the medicine for longer than prescribed by your doctor;
• you need to take a higher dose than recommended;
• you use the medicine for reasons other than those prescribed, e.g., "to stay calm" or "to help sleep";
• you have repeatedly tried to stop or control use of this medicine without success;
• when you stop taking the medicine you feel unwell, and feel better when you start taking it again ("withdrawal effects").

If you notice any of these signs, consult your doctor to discuss the best treatment path for you, including cases where it may be appropriate to discontinue treatment and how to do so safely (see section 3 If you stop taking MS Contin).

Warnings and precautions
Talk to your doctor or pharmacist before taking MS Contin if:

• you are elderly, very old, or debilitated; in these cases, a dose reduction may be necessary;
• you have reduced thyroid function (hypothyroidism), which may require a reduction in the dose of MS Contin;
• you suffer from severe headache or malaise, symptoms that could indicate increased intracranial pressure;
• you have low blood pressure (hypotension), especially if it is markedly and persistently low (hypovolemic shock);
• you suffer from mental disorders due to infection (toxic psychosis);
• you suffer from inflammation of the pancreas (pancreatitis) or gallbladder disorders;
• you suffer from intestinal obstructive or inflammatory disorders;
• you suffer from constipation;
• you suffer from prostate disorders (prostatic hypertrophy) or urinary tract disorders (urethral stenosis);
• you have reduced adrenal function (adrenal insufficiency);
• you have or have previously had dependence on alcohol or drugs. Also inform your doctor if you feel you are becoming dependent on MS Contin while using it. You may have started thinking frequently about when you can take the next dose, even if you do not need it for pain;
• you have previously experienced withdrawal or dependence symptoms such as agitation, anxiety, palpitations, tremors, or sweating after stopping alcohol or drug use; the most common withdrawal symptoms are mentioned in section 3. If this occurs, your doctor may change the type of medicine or the timing between doses;
• you suffer from epileptic seizures or convulsions;
• you suffer from mental confusion or fainting;
• you have breathing problems such as respiratory failure and chronic lung diseases (particularly if accompanied by increased bronchial mucus secretion), and in all conditions involving airway obstruction (obstructive conditions);
• you suffer from sleep apnea;
• you suffer from acute chest syndrome (ACS) associated with sickle cell disease (SCD);
• you have long-standing kidney or liver problems; you should take MS Contin only if recommended by your doctor;
• you are pregnant;
• you are currently taking central nervous system depressants or benzodiazepines (see also section “Other medicines and MS Contin”);
• you experience increased sensitivity to pain despite taking increasing doses (hyperalgesia). Your doctor will decide whether a dose adjustment or a change in strong analgesic ("painkiller") is needed (see section 2);
• you feel weakness, fatigue, loss of appetite, nausea, vomiting, or low blood pressure. These may be symptoms indicating that your adrenal glands are producing insufficient cortisol hormone, and you may need to take hormonal supplements;
• you experience loss of libido, impotence, or cessation of menstruation. This may be due to decreased production of sex hormones. Contact your doctor if you develop severe pain in the upper abdomen possibly radiating to the back, nausea, vomiting, or fever, as these could be symptoms associated with inflammation of the pancreas (pancreatitis) and bile ducts.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with MS Contin treatment. Symptoms usually appear within the first 10 days of treatment. Inform your doctor if you have previously developed severe skin rashes or skin peeling, or skin rash with blisters and/or mouth ulcers after taking MS Contin or other opioids. Stop using MS Contin and contact your doctor immediately if you notice any of the following symptoms: skin rash with blisters, widespread scaly skin, or pus-filled spots together with fever.

Sleep-related breathing disorders
MS Contin may cause sleep-related breathing disorders, such as sleep apnea (breathing pauses during sleep) and sleep-related hypoxemia (low oxygen levels in the blood), or worsen existing sleep problems. Symptoms may include breathing pauses during sleep, nighttime awakenings due to shortness of breath, difficulty maintaining sleep, or excessive daytime sleepiness. If you or someone else observes these symptoms, contact your doctor. Your doctor may consider reducing the dose.

Before undergoing surgery, inform the hospital doctor that you are taking these prolonged-release tablets. The medicine is not recommended in the preoperative period or within 24 hours after surgery.

The administration of morphine, especially if prolonged, may lead to the development of tolerance and dependence.
Opioids may affect the hypothalamic-pituitary-adrenal or gonadal axis. Some changes that may occur include increased serum prolactin and decreased plasma cortisol and testosterone levels. Clinical symptoms related to these hormonal changes may also appear.

For athletes:
Using this medicine without therapeutic need constitutes doping and may lead to a positive anti-doping test.

Children and adolescents
The use of MS Contin is not recommended in children and adolescents under 18 years of age.

Other medicines and MS Contin
Concomitant use of MS Contin and sedative medicines such as benzodiazepines or similar medicines may increase the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may lead to death. For these reasons, concomitant use of these medicines should only be considered if no alternative treatments are available.
In any case, if your doctor prescribes MS Contin together with sedative medicines such as benzodiazepines or similar medicines, the dose and duration of concomitant treatment must be limited by your doctor. Please inform your doctor about any sedative medicines you are taking and strictly follow the doses recommended by your doctor.
It is advisable to inform friends and family to pay attention to the signs and symptoms listed above. Contact your doctor if you experience such symptoms.

Inform your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including those not requiring a prescription.

Taking MS Contin together with certain other medicines may alter the effect of MS Contin or the effect of the other medicines.

MS Contin must not be used concomitantly with certain antidepressant medicines called monoamine oxidase inhibitors (e.g. tranylcypromine, phenelzine, isocarboxazid, moclobemide, and linezolid), or if you have taken these medicines within the last two weeks (see also section "Do not take MS Contin").

Inform your doctor or pharmacist: Many medicines may interact with injectable morphine sulfate, potentially causing significant changes in their effects. These medicines include:

• medicines for sleep (e.g. tranquilizers, hypnotics, or sedatives);
• recent use of an anesthetic;
• medicines for depression (antidepressants);
• central nervous system depressants and/or anxiolytics, including benzodiazepines;
• medicines for psychiatric or mental disorders;
• other strong analgesics or painkillers;
• muscle relaxants;
• medicines for high blood pressure;
• quinidine (a medicine for heart rhythm problems);
• cimetidine (an anti-ulcer or heartburn medicine);
• antibiotics (e.g. erythromycin);
• rifampicin, used for example to treat tuberculosis;
• certain medicines used to treat blood clots (e.g. clopidogrel, prasugrel, ticagrelor), which may have delayed and reduced effect when taken with morphine;
• antifungal medicines (e.g. ketoconazole);
• gabapentin or pregabalin used to treat epilepsy and nerve-related pain (neuropathic pain).

MS Contin with food, drinks, and alcohol
Drinking alcohol while taking MS Contin may cause drowsiness or increase the risk of serious adverse effects such as shortness of breath, respiratory depression, and loss of consciousness. It is recommended not to drink alcohol while taking MS Contin.

Pregnancy, breastfeeding, and fertility
If you are pregnant, think you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
If MS Contin is used for a long time during pregnancy, there is a risk that the newborn may show symptoms of withdrawal (abstinence) from substance use, which must be treated by a doctor.
Animal studies have shown that morphine may reduce fertility.

Driving and using machines
When starting treatment with MS Contin for the first time or when the dose is increased, you may experience drowsiness. If you feel drowsy, you should avoid driving or operating machinery.

MS Contin contains lactose
MS Contin 10 mg, MS Contin 30 mg, and MS Contin 60 mg contain lactose, a sugar. If you have an intolerance to certain sugars, contact your doctor before taking MS Contin.

3. How to take MS Contin

Take this medicine exactly as directed by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist. This patient information leaflet describes how many prolonged-release tablets you should take and how often.

Before starting treatment and regularly during treatment, your doctor will discuss with you what to expect from using MS Contin, when and for how long it should be used, when to contact your doctor, and when treatment should be discontinued (see also Discontinuation of MS Contin treatment in this section).

Treatment of pain with MS Contin usually starts with 1 or 2 prolonged-release 10 mg tablets every 12 hours, except in elderly or debilitated patients, for whom a lower initial dose is recommended. The patented prolonged-release morphine system allows morphine to be readily absorbed in the intestine, maintaining plasma levels for up to 12 hours.

To switch from other oral morphine-containing medicines to MS Contin, the same total daily dose of morphine should be maintained, divided into two administrations: morning and evening (one every 12 hours). When switching from parenteral morphine administration to MS Contin, the MS Contin dose must be increased to compensate for the reduced analgesic effect associated with oral administration. Generally, the dose should be increased by approximately 50% to 100%. However, your doctor will prescribe the dose required to treat your pain. If you continue to experience pain despite treatment with MS Contin, discuss this with your doctor. Do not exceed the dose prescribed by your doctor. If in doubt, consult your doctor or pharmacist.

MS Contin prolonged-release tablets should be swallowed whole with water. The prolonged-release tablets must not be chewed, broken, or dissolved. The patented prolonged-release drug delivery system ensures morphine is readily absorbed in the intestinal tract, maintaining plasma levels for up to 12 hours.

You must take the prolonged-release tablets every 12 hours. For example, if you take a prolonged-release tablet at 8 a.m., you should take the next one at 8 p.m.

Postoperative pain: Your doctor will instruct you not to take MS Contin prolonged-release tablets during the first 24 hours after surgery. After this period, your doctor will prescribe MS Contin according to the following dosage regimen:
a) MS Contin 20 mg every 12 hours for patients weighing less than 70 kg;
b) MS Contin 30 mg every 12 hours for patients weighing more than 70 kg.

If necessary, supplementary parenteral morphine doses may be administered, but particular attention must be paid to the total morphine dose, bearing in mind the prolonged effect of morphine in the MS Contin formulation.

As with all morphine-containing medicines, MS Contin should be used with caution after surgical procedures, especially in cases of acute abdomen or following abdominal surgery.

Use in children and adolescents
The use of MS Contin is not recommended in children and adolescents under 18 years of age.

You must take MS Contin by mouth only
Prolonged-release tablets must not be broken or injected, as this could result in serious, potentially fatal, adverse effects.

If you take more MS Contin than you should
Contact your doctor or the nearest hospital immediately. In case of overdose, drowsiness and malaise may occur. Individuals who have taken an excessive dose may develop a brain disorder (known as toxic leukoencephalopathy), or aspiration pneumonia due to vomiting or foreign body inhalation, with symptoms possibly including dyspnea, cough, and fever. Respiratory difficulties may also occur, potentially leading to unconsciousness or even death, and emergency hospital treatment may be required. When seeking medical help, bring this patient information leaflet with you and show your doctor any remaining prolonged-release tablets in the used packaging.

If you forget to take MS Contin
If less than 4 hours have passed since the time you were supposed to take the prolonged-release tablet, take it immediately. Then take the next prolonged-release tablet at the usual scheduled time. If more than 4 hours have passed, contact your doctor or pharmacist for advice. Do not take a double dose to make up for a missed prolonged-release tablet.

If you stop taking MS Contin
Do not stop taking the prolonged-release tablets abruptly unless instructed by your doctor. If you wish to discontinue treatment, discuss this first with your doctor. Your doctor will advise you on how to stop treatment, usually by gradually reducing the dose to avoid unpleasant adverse effects and withdrawal symptoms. Withdrawal symptoms may include muscle aches, tremors, diarrhea, stomach pain, nausea, flu-like symptoms, rapid heartbeat, and dilated pupils. Psychological symptoms may include intense feelings of dissatisfaction, anxiety, and irritability.

If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine may cause side effects, although not everyone experiences them.
Stop using MS Contin and contact your doctor immediately if you notice any of the following symptoms:

• All medicines can cause allergic reactions, although serious allergic reactions are rare. Inform your doctor immediately if you experience difficulty breathing, sudden wheezing, swelling of the eyelids, face or lips, skin rash or itching, especially if it spreads over your entire body.
• Severe skin reaction with blisters, widespread scaly skin, pus-filled spots together with fever. This could be a condition called acute generalized exanthematous pustulosis (AGEP).
• Slow and shallow breathing (respiratory depression) is the main danger of an opioid overdose. This mainly occurs in elderly and debilitated patients. Opioids may also cause a severe drop in blood pressure in predisposed patients. As with other opioids, there is a risk of developing physical or psychological dependence on MS Contin. The following frequency categories are used to assess side effects: Very common: affects more than 1 in 10 people - Common: affects 1 to 10 in 100 people - Uncommon: affects 1 to 10 in 1,000 people - Rare: affects 1 to 10 in 10,000 people - Very rare: affects less than 1 in 10,000 people - Not known: frequency cannot be estimated from available data.

Very common side effects:

• Nausea: these problems usually tend to improve after a few days. However, your doctor may prescribe an antiemetic medicine if the problem persists.
• Constipation: your doctor may prescribe a laxative to manage this problem. You may also feel unusually drowsy at the beginning of treatment or after dose increases. This effect usually resolves spontaneously after a few days.

Common side effects:

• Dry mouth, loss of appetite, slow digestion, abdominal pain, vomiting
• Itching
• Headache, confusion, drowsiness, feeling of unusual weakness or fainting (especially when standing), insomnia (difficulty sleeping), general malaise, fatigue
• Involuntary muscle contractions
• Dizziness or vertigo
• Excessive sweating, skin flushing
• Dry mouth

Uncommon side effects:

• Bloating, abdominal swelling, gastrointestinal disturbances (e.g. abdominal pain or cramps), altered taste
• Itching (urticaria) or skin rash due to allergic reaction
• A condition causing abnormal production of antidiuretic hormone, characterized by intense thirst and urine retention (syndrome of inappropriate antidiuretic hormone secretion, SIADH)
• Increased liver enzymes (transaminases)
• Hallucinations, mood changes (e.g. depression or euphoria), unusual hyperactivity, agitation
• Dizziness or vertigo, fainting, widespread muscle stiffness, seizures, reduced level of consciousness, reduced sensitivity to pain or touch, tingling
• Blurred vision
• Facial flushing, low blood pressure
• Pulmonary edema, difficulty breathing, shortness of breath, wheezing
• Slowed or shallow breathing, sudden breathlessness
• Thirst
• Peripheral edema (swelling of hands, ankles or feet)
• Allergic reaction
• Neonatal withdrawal syndrome

Side effects with unknown frequency:

• Generalized acute allergic reaction (anaphylactic reaction)
• Impotence, decreased libido, absence of menstrual periods
• Increased sensitivity to pain
• Excessive sweating
• Abnormal thoughts or dreams, mood changes, increased intracranial pressure
• Constricted pupils
• Biliary colic
• Reduced cough reflex
• Withdrawal symptoms or dependence (e.g. agitation, anxiety, palpitations, tremors, and sweating) occurring when treatment with MS Contin is stopped. (For symptoms, see section 3: If you stop taking MS Contin)
• Persistent urge to take the medicine even when not needed (dependence)
• Need to take increasingly higher doses of the medicine to achieve the same pain-relieving effect (tolerance)
• Hyperalgesia (increased pain sensitivity)
• Sleep apnea (breathing pauses during sleep)
• Symptoms associated with inflammation of the pancreas (pancreatitis) or bile ducts, such as severe pain in the upper abdomen possibly radiating to the back, nausea, vomiting or fever.

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

5. How to store MS Contin

Keep MS Contin out of the sight and reach of children. Accidental overdose in a child is
extremely dangerous and potentially fatal.
Do not use this medicine after the expiry date which is stated on the blister and the carton after Exp. The expiry date refers to the last day of that month. Store below 25°C.
Do not take broken or crushed prolonged-release tablets, as this may be dangerous and cause serious problems such as overdose.
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. Package contents and other information

What MS Contin contains
The active substance is morphine sulfate. Each prolonged-release tablet contains 10 mg, 30 mg, 60 mg, 100 mg, or 200 mg of morphine sulfate.
The other components are:
• MS Contin 10 mg: Anhydrous lactose, hydroxyethylcellulose, cetostearyl alcohol, magnesium stearate, talc, Opadry.
• MS Contin 30 mg: Anhydrous lactose, hydroxyethylcellulose, cetostearyl alcohol, magnesium stearate, talc, Opadry OY-6708.
• MS Contin 60 mg: Anhydrous lactose, hydroxyethylcellulose, cetostearyl alcohol, magnesium stearate, talc, Opadry OY-3508.
• MS Contin 100 mg: Hydroxyethylcellulose, cetostearyl alcohol, magnesium stearate, talc, Opadry OY-8215.
• MS Contin 200 mg: Hydroxyethylcellulose, cetostearyl alcohol, magnesium stearate, talc, Opadry OY-5970, polyethylene glycol 400.

Description of the appearance of MS Contin and package contents
On one side of each MS Contin prolonged-release tablet, the drug dosage (10, 30, 60, 100, 200) is printed. Depending on the dosage, the prolonged-release tablets are coated in the following colors: morphine 10 mg – ochre, 30 mg – purple-red, 60 mg – orange, 100 mg – grey, 200 mg – turquoise. Each package contains 16 prolonged-release tablets.
It is possible that not all pack sizes are marketed.

Marketing Authorization Holder and Manufacturer
Mundipharma Pharmaceuticals S.r.t.
Via F. Turati, 40
20121 Milano, Italy
Mundipharma DC B.V.
Leusderend 16
3832 RC Leusden
The Netherlands