Patient Information Leaflet

TWICE 10 mg, prolonged-release hard capsules
TWICE 30 mg, prolonged-release hard capsules
TWICE 60 mg, prolonged-release hard capsules
TWICE 100 mg, prolonged-release hard capsules
Morphine sulfate

Please read this leaflet carefully before taking this medicine, as 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 pass it on to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet:

What TWICE is and what it is used for
What you need to know before taking TWICE
How to take TWICE
Possible side effects
How to store TWICE
Contents of the pack and other information

1. What TWICE is and what it is used for

TWICE contains the active substance morphine sulfate, which belongs to the group of opioid analgesics.
TWICE is indicated for the management of severe and/or chronic pain that is unresponsive to other analgesics, particularly cancer-related pain (associated with tumour).

2. What you should know before taking TWICE

Do not take TWICE:

if you are allergic to morphine and its derivatives or to any of the other ingredients of this medicine (listed in section 6);
if you have sudden, severe abdominal pain (acute abdomen);
if you suffer from intestinal obstruction (paralytic ileus);
if you have delayed gastric emptying;
if you have acute liver diseases;
if you suffer from severe hepatic insufficiency (impaired liver function);
if you experience symptoms such as drowsiness or difficulty with coordination, blurred vision, difficulty speaking, or loss of contact with reality (signs of central nervous system depression);
if you have abused alcohol (acute alcoholism);
if you are affected by psychosis or a confused state caused by alcohol withdrawal (delirium tremens);
if you have sustained a head injury (cranial trauma) or suffer from a condition causing increased pressure in the head (endocranial hypertension);
if you suffer from seizures (involuntary, sudden, and uncontrolled muscle movements);
if you have severe breathing difficulties (respiratory depression);
if you suffer from bronchial asthma (a disease causing narrowing and inflammation of the bronchi);
if you suffer from right-sided heart failure (inability of the heart to supply adequate blood to the lungs);
if you suffer from arrhythmias (abnormal heart rhythms);
if you are currently taking medicines called MAOIs (monoamine oxidase inhibitors), used as antidepressants or in the treatment of Parkinson's disease (a disease causing tremors, stiffness, and slowness of movement), or if you have discontinued them less than two weeks ago;

Warnings and precautions
Talk to your doctor or pharmacist before taking TWICE.
Inform your doctor:

if you are elderly or debilitated;
if you have chronic lung diseases, especially if associated with increased mucus production, or conditions causing breathing difficulties such as kyphoscoliosis (curvature of the spine) or obesity;
if you suffer from reduced thyroid activity (hypothyroidism);
if you have fluid accumulation under the skin due to severe thyroid disorders (myxedema);
if you suffer from reduced function of the adrenal glands (small glands located above each kidney);
if you suffer from severe hypotension (low blood pressure);
in case of shock (reduced blood flow to organs and tissues due to decreased heart activity);
if you suffer from diseases of the biliary tract (ducts transporting bile from the liver to the intestine);
if you suffer from benign prostatic hyperplasia (enlargement of the prostate);
if you have urethral stenosis (narrowing or blockage of the urethra, the tube carrying urine from the bladder to the outside);
if you suffer from constipation;
if you suffer from a condition causing frequent interruptions in breathing during sleep (sleep apnea syndrome);
if you are being treated with medicines used to prevent thrombotic events (formation of clots blocking blood circulation);
if you suffer from a hereditary genetic blood disorder causing deformation of red blood cells (sickle cell disease);
if you have inflammatory or obstructive intestinal diseases;
if you suffer from low blood pressure (hypotension) associated with hypovolemia (reduced blood volume);
if you have inflammation of the pancreas (pancreatitis);
if you have reduced kidney or liver function;
if you underwent surgery for pain relief within the past 24 hours;
if you have a history of epilepsy (a disease causing loss of consciousness and violent involuntary muscle contractions).
Contact your doctor or pharmacist if you notice the onset of any of the following symptoms while taking TWICE:
Increased sensitivity to pain despite increasing doses (hyperalgesia). Your doctor will decide whether a dose adjustment or change in treatment is necessary.
Weakness, fatigue, loss of appetite, nausea, vomiting, dizziness, or low blood pressure. These may be signs of reduced adrenal activity; this effect is reversible but should be monitored and treated.
Constipation.
Loss of sexual desire (decreased libido), inability to achieve or maintain erection (impotence), interruption of menstrual cycle (amenorrhea). This may be due to decreased levels of certain hormones (prolactin, cortisol, and testosterone).
If you have previously been dependent on drugs, narcotics (psychoactive substances capable of altering physical and mental state), or alcohol. Also inform your doctor if you feel you are becoming dependent on TWICE while using it, or if you find yourself frequently thinking about when you can take the next dose, even when not needed for pain relief.

BE CAREFUL:

Prolonged use of TWICE over an extended period may lead to loss of effectiveness, resulting in the need to increase the dose to achieve pain relief. This effect is known as tolerance. Your doctor will determine the most appropriate dose and duration of treatment for you. Treatment should be limited in duration.
This medicine may lead to abuse and physical and psychological dependence (possible need to progressively increase dosage). Therefore, treatment should be short-term. Side effects can be minimized by using the shortest duration of treatment necessary to control symptoms. This risk increases with higher doses and longer treatment duration and is more common if you have a history of drug, narcotic, or alcohol abuse. Once physical dependence has developed, abrupt discontinuation of treatment will result in withdrawal symptoms such as increased sensitivity to pain, pupil dilation, headache, high blood pressure, diarrhea, muscle pain, anxiety, restlessness, confusion, and irritability (see "Possible side effects"). Since the risk of withdrawal symptoms is greater after abrupt discontinuation, your doctor will explain how to gradually reduce the dose before stopping.
Concomitant use of TWICE with sedative medicines such as benzodiazepines, hypnotics (medicines inducing sleep), sedatives (calming agents), or anxiolytics (medicines reducing anxiety) increases the risk of drowsiness, breathing difficulties (respiratory depression), coma (deep unconsciousness), and may be life-threatening. For this reason, concomitant use should only be considered when no other treatment options are available. However, if your doctor prescribes TWICE 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 follow their dosage recommendations carefully. It may be helpful
to inform friends or family members so they are aware of the signs and symptoms described
above. Contact your doctor if you experience these symptoms.

Children and adolescents
Do not use TWICE in children and adolescents.

Other medicines and TWICE
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
TWICE must not be used concurrently with certain antidepressants called monoamine oxidase inhibitors (MAOIs), or if you have taken these medicines within the last two weeks (see also section Do not take TWICE). The combination of these medicines may cause serotonin syndrome, characterized by symptoms such as nausea, low blood pressure, neuromuscular hyperactivity (tremor, involuntary muscle contractions), sweating, fever, rapid heartbeat, increased respiratory rate, pupil dilation, agitation, excitement, confusion, and potentially leading to cardiac arrest and death.
Concomitant use of TWICE with sedative medicines such as benzodiazepines or related drugs increases the risk of drowsiness, breathing difficulties (respiratory depression), coma (deep unconscious state), and may be life-threatening.
The dose and duration of treatment must be limited (see "Warnings and precautions").
Inform your doctor if you are taking:

opioids (painkillers), anesthetics (medicines inducing sedation, reduced pain sensitivity, and muscle relaxation), hypnotics (medicines inducing sleep), sedatives (calming agents), anxiolytics (medicines reducing anxiety), neuroleptics (medicines treating mental disorders, such as chlorpromazine), antidepressants, antihistamines (medicines treating allergies);
procarbazine (an anticancer drug);
methocarbamol (a medicine relieving muscle spasms);
amphetamines (psychostimulants);
diuretics (medicines lowering blood pressure);
muscle relaxants and neuromuscular blockers (medicines causing muscle relaxation);
rifampicin, an antibiotic used to treat bacterial infections;
antithrombotics, medicines used to prevent thrombotic events (formation of clots blocking blood circulation);
anticoagulants (medicines delaying blood coagulation).

TWICE and alcohol
Concomitant use of alcohol and TWICE must be avoided, as it may increase the undesirable effects of TWICE.

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, planning pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy
TWICE is not recommended during pregnancy. Administration of TWICE during pregnancy should only be considered if the expected benefit to the mother outweighs the risk to the fetus or infant. Take this medicine under strict medical supervision.
It may cause respiratory depression and withdrawal syndrome in the newborn, who should therefore be closely monitored.
Use of TWICE should be avoided close to delivery.

Breastfeeding
This medicine is excreted in breast milk. Therefore, if you are breastfeeding, discuss with your doctor whether you should discontinue breastfeeding and continue taking TWICE, or continue breastfeeding while avoiding administration of the medicine.

Fertility
Animal studies have shown that morphine may reduce fertility.

Driving and using machines
TWICE impairs the ability to drive and operate machinery, as the morphine contained in TWICE causes drowsiness and slows reflexes.

TWICE contains sucrose. If your doctor has diagnosed you with an intolerance to certain sugars, contact them before taking this medicine.
This medicine contains less than 1 mmol (23 mg) of sodium per capsule, i.e., essentially "sodium-free".

TWICE 60 mg contains: Orange Yellow S (E 110). May cause allergic reactions.

For individuals engaged in sports: using this medicine without therapeutic need constitutes doping and may result in a positive anti-doping test.

3. How to use TWICE

Take this medicine exactly as directed by your doctor or pharmacist.
If you have any doubts, consult your doctor or pharmacist.
Your doctor will determine the correct dose and duration of treatment based on the severity of your symptoms and the type of illness.

Adults
The initial dose is 1 or 2 capsules of 10 mg twice daily.
Two administrations per day are recommended, with an interval of 12 hours between doses.
In elderly patients, the initial dose is lower.
If persistent pain occurs or if tolerance to the medicine develops, your doctor may adjust the dosing regimen as needed to achieve the optimal dosage.

Patients previously treated with other morphine-containing medicines administered by parenteral route (intramuscularly or intravenously):

If you were receiving morphine injections and are switching to TWICE therapy, your doctor will prescribe a higher dose. The increase may range from approximately 50% to 100%.
Do not exceed the recommended dose.
If you have any doubts, consult your doctor or pharmacist.

Children and adolescents
Do not use TWICE in children and adolescents.

Method of administration
Capsules must be swallowed whole and must not be broken, chewed, or crushed. For patients with swallowing difficulties, the contents of the capsules may be administered via gastric tube (a small tube inserted into the stomach, used to provide artificial nutrition to patients who are unable or refuse to eat normally).

If you take more TWICE than you should
In case of overdose, the following symptoms may occur:
constriction of the pupil (miosis), reduced heart rate, severe breathing difficulties (respiratory depression) up to respiratory arrest, ab ingestis pneumonia (lung inflammation caused by aspiration of foreign material into the bronchi due to improper swallowing), drowsiness which may progress to deep stupor or coma (a state of complete unconsciousness, absence of any sensitivity and voluntary movement), hypothermia (reduced body temperature), rhabdomyolysis (muscle damage) leading to renal failure (impaired kidney function), low blood pressure, collapse (sudden loss of consciousness), circulatory failure (inability of the heart to supply adequate blood to the body), and death.
In deep coma, dilation of the pupils (mydriasis) may occur.
Using broken, chewed, or crushed capsules causes immediate release of morphine, which may result in a fatal overdose.

If you forget to take TWICE
Do not take a double dose to make up for a missed dose.

If you stop taking TWICE
Treatment with TWICE must not be stopped abruptly.
Your doctor will explain how to gradually reduce the dose until discontinuation.
Sudden discontinuation of treatment may lead to withdrawal symptoms (see "Warnings and precautions").

If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Immediately inform your doctor if you experience breathing difficulties, wheezing, swelling of the face, lips, mouth, tongue or throat, which may cause difficulty in breathing or swallowing, skin rash or itching, especially if widespread throughout your body, as these are signs and symptoms of severe allergic reactions (anaphylactic and anaphylactoid reactions).

The following side effects have been reported:

Common (may affect up to 1 in 10 people):

Confusion, drowsiness,
involuntary muscle contractions,
dizziness (sensation of movement or spinning),
abdominal pain,
anorexia (reduced or loss of appetite),
vomiting,
itching,
malaise,
fatigue.

Uncommon (may affect up to 1 in 100 people):

allergic reaction,
hallucinations (perception of things that are not real),
mood changes,
convulsions (uncontrolled body movements),
hypertonia (increased muscle tone),
paresthesia (numbness, tingling sensation),
dizziness,
facial flushing (sensation of warmth),
low blood pressure,
pulmonary edema (fluid accumulation in the lungs),
bronchospasm (contraction of bronchial muscles),
ileus (intestinal obstruction),
taste disturbances,
dyspepsia (indigestion),
increased liver enzymes (proteins that rise in case of liver damage),
urinary retention (inability to urinate or empty the bladder),
peripheral edema (fluid accumulation),
neonatal abstinence syndrome (manifesting as irritability, high-pitched crying, tremors, difficulty sucking, breathing problems, sleep disturbances, sweating and diarrhea).

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

anaphylactic and anaphylactoid reactions (severe allergic reactions),
thought disturbances,
dysphoria (mood disturbance),
dependence (see “Warnings and precautions”),
excitement,
insomnia (altered quantity and quality of sleep),
agitation,
euphoria,
depressed mood,
indifference,
irritability,
headache,
hyperalgesia (increased sensitivity to pain),
increased intracranial pressure (high pressure in the head),
allodynia (pain caused by a stimulus that normally does not provoke pain),
hyperhidrosis (excessive sweating),
sleep apnoea syndrome (frequent interruptions in breathing during sleep),
sedation,
mental obtundation (reduced level of consciousness),
syncope (sudden, transient loss of consciousness),
miosis (constriction of the pupils),
visual disturbances,
vertigo (sensation of movement or spinning),
low blood pressure,
vasodilation in the extremities,
orthostatic hypotension (drop in blood pressure upon standing),
cardiovascular collapse (rapid drop in blood pressure),
reduced cough reflex,
respiratory depression (severe difficulty in breathing),
atelectasis (collapse of lung alveoli),
respiratory arrest,
dry mouth,
nausea,
vomiting urge (feeling of needing to vomit),
constipation,
epigastric discomfort ("sensation in the upper stomach"),
reduced gastric acidity,
intestinal motility disorders,
biliary tract pain,
increased biliary tract pressure,
spasm of the sphincter of Oddi (contraction of a muscle that opens and closes to allow digestive juices to pass),
biliary colic (acute, intermittent pain in the upper right abdomen),
facial flushing,
erythema (skin redness),
sweating,
pruritus,
urticaria (skin rash),
rash (skin irritation),
oliguria (decreased urine output),
difficulty emptying the bladder,
amenorrhea (cessation of menstrual periods),
decreased libido (sexual desire),
erectile dysfunction (erection problems),
tolerance (see “Warnings and precautions”),
withdrawal syndrome,
asthenia (weakness),
reduced levels of certain hormones in the blood (ACTH, cortisol, LH, FSH and testosterone),
increased levels of certain hormones (ADH and prolactin).

Description of some side effects:

Respiratory depression is mild or moderate and without consequences in healthy individuals; however, it may be severe in patients with bronchopulmonary diseases.
Intestinal motility disorders may slow down fecal transit.
Increased biliary tract pressure may worsen nausea and epigastric discomfort and may exacerbate or trigger biliary colic (acute, intermittent pain in the upper right abdomen).
Withdrawal syndrome manifests as muscle aches, tremors, restless legs syndrome (a sleep disorder characterized by tingling, itching or pain in the legs, associated with an irresistible urge to move the legs), diarrhea, abdominal colic (acute, intermittent abdominal pain), nausea, flu-like symptoms, tachycardia (increased heart rate), mydriasis (dilation of the pupils), mood disturbances, anxiety and irritability.
In men, increased prolactin levels may worsen symptoms related to reduced testosterone production.

Reporting of side effects

If you experience any side effect, including those not listed in this leaflet, talk to 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.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store TWICE

Keep this medicine out of the sight and reach of children.
Do not store above 25°C.
Do not use this medicine after the expiry date stated on the pack. The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What TWICE contains
The active substance is morphine sulfate.
TWICE 10 mg
Each 10 mg capsule contains: 10 mg of morphine sulfate equivalent to 7.5 mg of morphine.
The other components are: sucrose and maize starch microgranules, macrogol 4000, aquacoat ECD 30, dibutyl sebacate, talc, gelatin, quinoline yellow E 104, titanium dioxide E 171, iron oxide black.
TWICE 30 mg
Each 30 mg capsule contains: 30 mg of morphine sulfate equivalent to 22.5 mg of morphine.
The other components are: sucrose and maize starch microgranules, macrogol 4000, aquacoat ECD 30, dibutyl sebacate, talc, gelatin, titanium dioxide E 171, erythrosine E 127, iron oxide black.
TWICE 60 mg
Each 60 mg capsule contains: 60 mg of morphine sulfate equivalent to 45 mg of morphine.
The other components are: sucrose and maize starch microgranules, macrogol 4000, aquacoat ECD 30, dibutyl sebacate, talc, gelatin, titanium dioxide E 171, orange yellow S E 110, iron oxide black.
TWICE 100 mg
Each 100 mg capsule contains: 100 mg of morphine sulfate equivalent to 75 mg of morphine.
The other components are: sucrose and maize starch microgranules, macrogol 4000, aquacoat ECD 30, dibutyl sebacate, talc, gelatin, titanium dioxide E 171, iron oxide black.

Description of the appearance of TWICE and package contents
Prolonged-release hard capsules of 10 mg, 30 mg, 60 mg and 100 mg in Al/PVC blisters.

Marketing Authorization Holder
Ethypharm, 194 Bureaux de la Colline, Bâtiment D, 92213 Saint Cloud cedex – France.

Manufacturer
Ethypharm – Chemin de la Poudrière – 76120 Grand-Quevilly (France).