PACKAGE LEAFLET: INFORMATION FOR THE PATIENT

Lenizak 75 mg/25 mg granules for oral solution in sachet

tramadol hydrochloride/dexketoprofen
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.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
If you experience any side effect, including those not listed in this leaflet, contact your doctor. See section 4.
Contents of this leaflet:

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

1. What Lenizak is and what it is used for

Lenizak contains the active substances tramadol hydrochloride and dexketoprofen.
Tramadol hydrochloride is an analgesic belonging to a group of medicines called opioids, which act on the central nervous system. It relieves pain by acting on specific nerve cells in the brain and spinal cord.
Dexketoprofen is an analgesic belonging to the group of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs).
Lenizak is used for the short-term symptomatic treatment of moderate to severe acute pain in adults.

2. What you should know before taking Lenizak

Do not take Lenizak:
if you are allergic to dexketoprofen, tramadol hydrochloride, or any of the other ingredients of this
medicine (listed in section 6);
if you are allergic to acetylsalicylic acid or to any other NSAID (non-steroidal anti-inflammatory drug);
if you have asthma or have previously experienced asthma attacks, acute allergic rhinitis (short-term inflammation of the
nasal mucosa), nasal polyps (nodules inside the nasal cavity caused by allergy), urticaria
(skin rash), angioedema (swelling of the face, eyes, lips, or tongue, or breathing difficulties), or wheezing
after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs;
if you have previously experienced photoallergic or phototoxic reactions (skin redness and/or blistering
of the skin following exposure to sunlight) during treatment with ketoprofen (an NSAID) or with
fibrates (medicines used to lower blood lipid levels);
if you have peptic ulcer, gastrointestinal or intestinal bleeding, or if you have previously experienced
gastrointestinal or intestinal bleeding, including episodes associated with prior use of NSAIDs;
if you suffer from chronic digestive disorders (e.g., indigestion, heartburn);
if you have an inflammatory bowel disease (Crohn’s disease or ulcerative colitis);
if you have severe heart failure, moderate or severe kidney disease, or severe liver disease;
if you have bleeding disorders, coagulation disorders, or other ongoing bleeding;
if you are severely dehydrated (i.e., if you have lost significant fluids) due to vomiting, diarrhea, or insufficient fluid intake;
if you have recently experienced acute intoxication from alcohol, sedatives, painkillers, or medicines affecting
mood and emotions;
if you are currently taking monoamine oxidase inhibitors (MAOIs) (medicines used to treat depression), or if you have taken them within the last 14 days before starting treatment with this medicine
(see “Other medicines and Lenizak”);
if you have epilepsy or seizures, as the risk of seizures may increase;
if you have difficulty breathing;
if you are pregnant or breastfeeding.

Warnings and precautions
Talk to your doctor before taking Lenizak:
if you have an allergy or have had allergies in the past;
if you have kidney, liver, or heart problems (hypertension and/or heart failure), fluid retention, or if you have previously experienced any of these conditions;
if you are taking diuretics (substances that increase urine production);
if you have heart disease, have had a stroke, or think you may be at risk for such conditions (e.g., if you have high blood pressure, diabetes, high cholesterol levels, or are a smoker); you should speak with your doctor before starting this therapy, as medicines like this may be associated with a slight increase in the risk of heart attacks (myocardial infarction) or stroke. These risks are more likely with higher doses and prolonged treatment; do not exceed the recommended dose or duration of treatment;
if you are elderly, as the risk of adverse effects may be higher (see section 4). If you experience any adverse effect, contact your doctor immediately;
if you are a woman with fertility problems, as this medicine may affect fertility; therefore, you should not take it if you are planning a pregnancy or undergoing fertility investigations;
if you have blood or blood cell formation disorders;
if you have systemic lupus erythematosus or mixed connective tissue disease (immune system disorders affecting connective tissue);
if you have previously suffered from chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease);
if you have or have previously had other gastric or intestinal disorders;
if you have an infection – see section “Infections” below;
if you are taking other medicines that increase the risk of peptic ulcer or bleeding, such as oral steroids, certain antidepressants (e.g., SSRIs, i.e., selective serotonin reuptake inhibitors), antiplatelet agents such as acetylsalicylic acid, or anticoagulants such as warfarin; in such cases, consult your doctor before taking this medicine, as they may prescribe an additional medicine to protect your stomach;
if you suffer from depression and are taking antidepressants, as some of them may interact with
tramadol (see “Other medicines and Lenizak”);
if you are taking other medicines containing the same active substances as this medicine, do not exceed the maximum daily doses of dexketoprofen or tramadol;
if you think you may be dependent on other painkillers (opioids);
if you have disturbances of consciousness (feeling faint);
if you are in shock (a condition that may present with cold sweating);
if you have increased intracranial pressure (after a head injury or brain disease);
if you have breathing difficulties;
if you suffer from porphyria (a disorder characterized by abnormal heme metabolism).

Tolerance, dependence, and substance abuse
This medicine contains tramadol, which is an opioid substance. It may cause dependence and/or substance abuse.
This medicine contains tramadol, which is an opioid substance. Repeated use of opioids may make the medicine less effective (you become accustomed to it, a phenomenon known as drug tolerance). Repeated use of Lenizak may also lead to dependence, abuse, and substance abuse, which can result in a potentially life-threatening overdose. The risk of these adverse effects may increase with higher doses and prolonged use.
Dependence or substance abuse may make you feel that you have lost control over the amount of medicine needed or how often you need to take it.
The risk of developing dependence or substance abuse varies from person to person. You may have a higher risk of becoming dependent or addicted to Lenizak if:

you or a family member has previously suffered from alcohol, prescription drug, or illegal substance abuse or dependence ("substance abuse");
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.

If you notice any of the following symptoms during use of Lenizak, this may be a sign of dependence or substance abuse:

you feel the need to use the medicine for longer than prescribed by your doctor;
you feel the need to take a higher dose than recommended;
you feel compelled to continue using the medicine, even if it does not help relieve pain;
you use the medicine for reasons other than 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 resume taking it ("withdrawal symptoms").

If you notice any of these symptoms/signs, contact your doctor to discuss the best treatment approach for you, including whether and how to safely discontinue treatment (see section 3, "If you stop taking Lenizak").
Tramadol may cause physical and psychological dependence. When taken for a long period, its effect may decrease, and a higher dose may be needed (development of tolerance). In patients with a tendency to abuse medicines or who are already dependent on medicines, Lenizak should be administered only for short periods and under strict medical supervision.
Talk to your doctor if these problems occur during treatment with Lenizak or if you have had them in the past.
Contact your doctor if you notice any of the following symptoms while taking Lenizak: extreme fatigue, loss of appetite, severe abdominal pain, nausea, vomiting, or low blood pressure. These symptoms may indicate adrenal insufficiency (low cortisol levels). If you experience these symptoms, contact your doctor, who will decide whether hormonal replacement therapy is needed.
Tramadol is metabolized in the liver by an enzyme. Some people have a variation in this enzyme, which may lead to different effects. Some people may not get sufficient pain relief, while others may experience serious adverse effects. If you notice any of the following adverse effects, you must stop taking this medicine and contact a doctor immediately: slow or shallow breathing, confusion, drowsiness, constricted pupils, feeling unwell or malaise, constipation, loss of appetite.
There is a small risk that you may develop serotonin syndrome, which can occur after taking tramadol together with certain antidepressants or tramadol monotherapy. Contact your doctor immediately if you experience any of the symptoms associated with this serious syndrome (see section 4, "Possible side effects").

Sleep-related breathing disorders
Lenizak may cause sleep-related breathing disorders such as sleep apnea (pauses in breathing during sleep) and sleep-related hypoxemia (low blood oxygen levels during sleep). Symptoms may include pauses in breathing during sleep, nighttime awakenings due to gasping for breath, difficulty maintaining sleep, or excessive daytime sleepiness. If you or someone else notices these symptoms, contact your doctor, who may consider reducing the dose.

Infections
Lenizak may mask symptoms of infections such as fever and pain. Therefore, Lenizak may delay appropriate treatment of the infection, increasing the risk of complications. This has been observed in bacterial pneumonia and bacterial skin infections related to chickenpox.
If you take this medicine while having an infection and infection symptoms persist or worsen, contact your doctor immediately.
Use of this medicine during varicella virus infection is not recommended.

Kounis syndrome
With dexketoprofen, manifestations of an allergic reaction to this medicine have been reported, including breathing difficulties, facial and neck swelling (angioedema), and chest pain. If you notice any of these signs, stop taking Lenizak immediately and contact your doctor or emergency medical services immediately.

Children and adolescents
This medicine has not been studied in children and adolescents. Therefore, due to lack of established safety and efficacy, it must not be used in children and adolescents.

Use in children with respiratory problems
Tramadol is not recommended in children with respiratory problems, as symptoms of tramadol toxicity may be worse in these children.

Other medicines and Lenizak
Inform your doctor if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription. Some medicines should not be taken together, while others may require dose adjustments when used concomitantly.
Always inform your doctor if you are using or have been prescribed any of the following medicines in addition to Lenizak.

Use not recommended with Lenizak:
acetylsalicylic acid, corticosteroids, or other anti-inflammatory drugs;
warfarin, heparin, or other anticoagulants;
lithium, used to treat certain types of mood disorders;
methotrexate, used for rheumatoid arthritis and cancer;
phenytoin and phenytoin, used for epilepsy;
sulfamethoxazole, used for bacterial infections and other sulfonamides;
monoamine oxidase inhibitors (MAOIs) (medicines used to treat depression).

Use requiring precautions with Lenizak:
ACE inhibitors, diuretics, and angiotensin II antagonists, used for hypertension and heart conditions;
pentoxifylline, used to treat chronic venous ulcers;
zidovudine, used to treat viral infections;
sulfonylureas such as chlorpropamide and glyburide, used for diabetes;
aminoglycoside antibiotics, used to treat bacterial infections.
Concomitant use of Lenizak and sedative medicines such as benzodiazepines or benzodiazepine-related drugs increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and can be life-threatening. Due to these risks, concomitant use of these medicines should only be considered when no alternative treatments are possible. However, if your doctor prescribes Lenizak together with sedative medicines, the dose and duration of concomitant treatment must be limited by your doctor. Inform your doctor about any sedative medicine you are taking and strictly follow the dose recommended by your doctor. It may be helpful to inform friends and family about the signs and symptoms described above. Inform your doctor if such symptoms occur.

Use requiring caution with Lenizak:
quinolone antibiotics (e.g., ciprofloxacin, levofloxacin) used for bacterial infections;
cyclosporine or tacrolimus, used to treat immune system diseases and in organ transplantation;
streptokinase and other thrombolytic or fibrinolytic medicines, such as medicines used to dissolve blood clots;
probenecid, used to treat gout;
digoxin, used to treat chronic heart failure;
mifepristone, used for medical abortion;
selective serotonin reuptake inhibitor (SSRI) antidepressants;
antiplatelet agents used to reduce platelet aggregation and blood clot formation;
tenofovir, deferasirox, pemetrexed;
beta-blockers, used for high blood pressure and heart problems.

The analgesic effect of tramadol may be reduced and its duration of action shortened if taken together with medicines containing:
carbamazepine (for epileptic seizures);
buprenorphine, nalbuphine, or pentazocine (painkillers);
ondansetron (for nausea).

The risk of adverse effects increases:
if you are taking gabapentin or pregabalin for epilepsy or nerve-related pain (neuropathic pain);
if you take tranquilizers, sleeping pills, other painkillers such as morphine and codeine (even for cough), or alcohol during treatment with Lenizak. You may experience drowsiness or faintness; if this occurs, discuss it with your doctor;
if you are taking medicines that may cause seizures (epileptic attacks), such as certain antidepressants or antipsychotics. The risk of seizures may increase if you take Lenizak together with these medicines; your doctor will advise whether Lenizak is suitable for you;
if you take certain antidepressants. Lenizak may interact with these medicines and you may develop serotonin syndrome (see section 4, "Possible side effects");
if you take anticoagulants (blood-thinning medicines), e.g., warfarin, together with this medicine; the effect of these medicines on blood clotting may be altered, leading to bleeding.

Lenizak and alcohol
Do not drink alcohol during treatment with Lenizak, as it may increase the medicine’s effects.
For instructions on how to take Lenizak, see section 3.

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before taking this medicine.
Dexketoprofen may cause kidney and heart problems in the fetus. It may also affect your and your baby’s tendency to bleed and may delay or prolong labor beyond expected duration. From week 20 of pregnancy, dexketoprofen may cause kidney problems in the fetus, which may in turn lead to reduced levels of amniotic fluid surrounding the baby (oligohydramnios), or narrowing of a blood vessel (ductus arteriosus) in the baby’s heart.
Tramadol is excreted in breast milk.
Lenizak must not be used during pregnancy or breastfeeding.

Driving and operating machinery
Lenizak may affect your ability to drive or operate machinery, as it may cause dizziness, blurred vision, or drowsiness as side effects of treatment. This is especially true if Lenizak is taken together with medicines affecting mood or with alcoholic beverages.
If you experience these effects, do not drive or operate machinery until symptoms resolve.

Lenizak contains sucrose
Lenizak contains 2.7 g of sucrose per dose. This should be taken into account in patients with diabetes mellitus. If you have been diagnosed with intolerance to certain sugars, contact your doctor before taking this medicine.

For athletes
Using this medicine without therapeutic need constitutes doping and may result in a positive anti-doping test.

3. How to take Lenizak

Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor.
The lowest effective dose for the shortest duration necessary to relieve symptoms should be used. If you have
an infection, contact your doctor immediately if symptoms (such as fever and pain) persist or worsen (see section 2).
The dose of Lenizak you need depends on the type, severity, and duration of your pain.
Before starting treatment and regularly during treatment, your doctor will discuss with you what to expect from using Lenizak, how many sachets to take each day, when and for how long it should be used, when to contact your doctor, and when treatment should be stopped (see also “If you stop taking Lenizak”).
Generally, the recommended dose is 1 sachet (containing 75 mg of tramadol hydrochloride and 25 mg of dexketoprofen) every 8 hours, up to a maximum of 3 sachets per day (corresponding to 225 mg of tramadol hydrochloride and 75 mg of dexketoprofen), without exceeding 5 days of treatment.

Use in children and adolescents
Lenizak is not indicated in children and adolescents.

Elderly patients
If you are 75 years of age or older, your doctor may advise you to extend the interval between doses because your body may eliminate the medicine more slowly.

Severe renal or hepatic impairment/dialysis patients:
Do not take Lenizak if you have severe hepatic impairment and/or moderate to severe renal impairment.
If you have mild renal impairment, your doctor may advise you to extend the dosing interval.
If you have mild to moderate hepatic impairment, your doctor may advise you to extend the dosing interval.

Dissolve the entire contents of each sachet in a glass of water; shake/mix well to aid dissolution.
The resulting solution should be taken immediately after reconstitution.
Concomitant food intake slows the absorption of Lenizak; therefore, for a faster effect, take the oral granules for solution at least 30 minutes before meals.

If you take more Lenizak than you should
If you take an excessive amount of this medicine, inform your doctor immediately or go to the nearest hospital emergency department, remembering to bring the medicine pack or this leaflet with you.
Symptoms of overdose with this medicine include:
vomiting, loss of appetite, stomach pain, dizziness, drowsiness/dizziness (loss of balance sensation), disorientation, headache (due to dexketoprofen);
pupil constriction, vomiting, cardiac failure, loss of consciousness, seizures, and breathing difficulties (due to tramadol).

If you forget to take Lenizak
Do not take a double dose to make up for the missed dose. Take the next dose at the usual time (see section 3 “How to take Lenizak”).

If you stop taking Lenizak
Generally, there are no after-effects following discontinuation of Lenizak treatment.
However, in rare cases, patients who have taken Lenizak oral granules for solution in sachets for some time may feel unwell if they stop taking it suddenly. They may feel restless, anxious, nervous or weak, confused, hyperactive, have difficulty sleeping, and experience gastrointestinal or intestinal disturbances.
Rarely, some individuals may experience panic attacks, hallucinations, illusions, paranoia, or a sense of loss of identity. They may experience unusual sensations such as itching, tingling, numbness, and ringing in the ears (tinnitus). Rarely, other unusual symptoms such as confusion, illusions, a sense of detachment from oneself (depersonalization), altered perception of reality (derealization), and delusions of persecution (paranoia) have been observed.
If you experience any of these symptoms after stopping treatment with Lenizak, consult your doctor.

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

4. Possible side effects

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

The possible side effects are listed below, grouped by their frequency of occurrence.

Seek immediate medical attention if you experience symptoms of an allergic reaction such as swelling of the face, tongue and/or throat and/or difficulty swallowing, or hives together with breathing difficulties.

Stop taking Lenizak if you notice the appearance of a skin rash, lesions inside the mouth or on mucous membranes, or signs of allergy.

Very common (may affect more than 1 in 10 people):
nausea/malaise;
dizziness;

Common side effects (may affect up to 1 in 10 people):
vomiting;
stomach ache;
diarrhoea;
digestive problems;
headache;
drowsiness, fatigue;
constipation;
dry mouth;
increased sweating.

Uncommon side effects (may affect up to 1 in 100 people):
increased platelet count;
effects on the heart and blood circulation (palpitations, tachycardia, feeling faint or collapse), low blood pressure. These adverse effects may occur especially when patients are in an upright position or under physical exertion;
high or very high blood pressure;
swelling (oedema) of the larynx;
reduced levels of potassium in the blood;
psychotic disorders;
swelling around the eyes;
slow and/or shallow breathing;
discomfort, abnormal sensations;
blood in the urine;
feeling of dizziness;
insomnia or difficulty falling asleep;
nervousness/anxiety;
flushing;
flatulence;
tiredness;
pain;
feeling feverish and chills, general feeling of malaise;
abnormal blood tests;
nausea and urge to vomit;
feeling of pressure in the stomach, abdominal bloating;
gastritis;
skin reactions (e.g. itching, rash);
amnesia;
facial swelling.

Rare side effects (may affect up to 1 in 1,000 people):
swelling of the lips and throat;
peptic ulcer, perforation or bleeding from peptic ulcer, which may be indicated by blood in vomit or black stools;
prostate disorders;
inflammation of the liver (hepatitis), liver damage;
acute kidney failure;
slow heartbeat (bradycardia);
seizures;
allergic/anaphylactic reactions (e.g. breathing difficulties, wheezing, skin swelling) and anaphylactic shock (sudden circulatory failure);
transient loss of consciousness (syncope);
hallucinations;
fluid retention or swollen ankles;
loss of appetite, changes in appetite;
acne;
back pain;
frequent or less frequent urination than normal, with difficulty or pain;
menstrual disorders;
abnormal sensations (such as itching, tingling, numbness);
tremor, muscle spasms, uncoordinated movements, muscle weakness;
confusion;
sleep disturbances and nightmares;
perception disorders;
blurred vision, constricted pupils;
laboured breathing.

After treatment with Lenizak, you may experience psychological side effects. These may vary in intensity and nature (depending on the patient's personality and duration of therapy):
mood changes (mainly elevated mood, occasionally irritability);
changes in activity (slowing down, but sometimes increased activity);
reduced awareness;
reduced ability to make decisions, which may lead to poor judgment.

Worsening of asthma has been reported.

When treatment is stopped abruptly, withdrawal symptoms may occur (see "If you stop taking Lenizak").

Seizures have been observed, particularly with high doses of tramadol or when tramadol was taken together with other medicines that may trigger such seizures.

Very rare (may affect up to 1 in 10,000 people):
inflammation of the pancreas;
kidney problems;
reduced number of white blood cells (neutropenia);
reduced number of platelets in the blood (thrombocytopenia);
skin, mouth, eye and genital lesions (Stevens-Johnson syndrome and Lyell’s syndrome);
shortness of breath due to narrowing of the airways;
ringing in the ears (tinnitus);
sensitive skin;
photosensitivity.

Not known (frequency cannot be estimated from the available data):
chest pain, which may be a sign of a severe allergic reaction called Kounis syndrome;
drug-induced fixed eruption. An allergic skin reaction known as fixed drug eruption, which may appear as round or oval patches with redness and swelling of the skin, blistering rash and itching. Darkening of the skin in the affected areas may also occur, which could persist even after healing. Upon re-exposure to the medicine, the fixed drug eruption usually recurs at the same site (or sites);
serotonin syndrome, which may present as changes in mental status (e.g. agitation, hallucinations, coma) and other effects such as fever, increased heart rate, unstable blood pressure, involuntary muscle contractions, muscle rigidity, lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea) (see section 2, "What you need to know before taking Lenizak");
speech disorders;
extreme dilation of the pupil;
reduced levels of glucose in the blood;
hiccups.

Contact your doctor immediately if you experience gastrointestinal side effects at the beginning of therapy (such as stomach ache, burning or bleeding), especially if you have previously suffered from such side effects due to prolonged use of anti-inflammatory medicines, and particularly if you are elderly.

The most common side effects during treatment with Lenizak are nausea and drowsiness, occurring in more than 1 in 10 patients.

During treatment with NSAIDs, fluid retention and swelling (especially in the ankles and legs), increased blood pressure and heart failure have been observed.

Medicines such as Lenizak may be associated with a slightly increased risk of heart attack or stroke.

In patients with immune system disorders affecting connective tissue (systemic lupus erythematosus or mixed connective tissue disease), anti-inflammatory medicines may rarely cause fever, headache and neck stiffness.

Reporting of side effects

If you experience any side effects, including those not listed in this leaflet, talk to your doctor. 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 Lenizak

Keep this medicine out of the sight and reach of children.
Store this medicine in a safe and secure place, inaccessible to other people.
Taking this medicine by other people to whom it has not been prescribed may cause serious harm and can be fatal.
Do not use this medicine after the expiry date stated on the packaging and sachet after "Exp.".
The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions or temperature.
Keep in the original packaging to protect the medicine from light.
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 Lenizak contains

The active substances are tramadol hydrochloride and dexketoprofen. Each sachet contains: 75 mg of tramadol hydrochloride and 25 mg of dexketoprofen (as dexketoprofen trometamol).
The other components are Sucrose, Lemon flavour, Acesulfame potassium (E-950).

Description of the appearance of Lenizak and the contents of the pack
White to almost white oral granules for solution, supplied in heat-sealed paper/aluminium/multilayer polyethylene foil sachets (as copolymer with vinyl acetate) contained in a cardboard box.
Lenizak is available in packs containing 2, 3, 10, 15, 20, 50, 100 and 500 sachets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 – Luxembourg
Concessionaire for sale:
A. Menarini Industrie Farmaceutiche Riunite s.r.l.
Via Sette Santi, 3 – 50131 Florence, Italy
Manufacturer:
E-Pharma Trento S.p.A.
Frazione Ravina, Via Provina, 2
Trento, 38123
Italy

This medicinal product is authorised in the European Economic Area countries under the following names:
Belgium, Croatia, Cyprus, Estonia, Finland, Greece, Ireland, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Czech Republic, Slovak Republic, Romania, Slovenia, Hungary: Skudexa
Italy: Lenizak
Spain: Enanplus

PATIENT INFORMATION LEAFLET: INFORMATION FOR THE PATIENT

Lenizak 75 mg/25 mg film-coated tablets

tramadol hydrochloride/dexketoprofen
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, consult your doctor.
This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor. See section 4.
Contents of this leaflet:

What Lenizak is and what it is used for
What you need to know before taking Lenizak
How to take Lenizak
Possible side effects
How to store Lenizak
Package contents and other information

2. What Lenizak is and what it is used for

4. What you need to know before taking Lenizak

Do not take Lenizak:
if you are allergic to dexketoprofen, tramadol hydrochloride, or any of the other ingredients of this
medicinal product (listed in section 6);
if you are allergic to acetylsalicylic acid or to another NSAID (non-steroidal anti-inflammatory drug);
if you have previously experienced asthma attacks, acute allergic rhinitis (short-term inflammation of the nasal
mucosa), nasal polyps (nodules inside the nasal cavity caused by allergy), urticaria (skin rash), angioedema (swelling of the face, eyes, lips, or tongue, or breathing difficulties), or
dyspnoea after taking acetylsalicylic acid or other non-steroidal anti-inflammatory drugs;
if you have previously experienced photoallergic or phototoxic reactions (skin redness and/or blistering of the
skin following exposure to sunlight) during treatment with ketoprofen (an NSAID) or with fibrates (medicines used to lower blood lipid levels);
if you suffer from peptic ulcer, gastric or intestinal bleeding, or have previously experienced gastric or
intestinal bleeding, including episodes associated with prior use of NSAIDs;
if you have chronic digestive disorders (e.g. indigestion, heartburn);
if you suffer from an inflammatory bowel disease (Crohn’s disease or ulcerative colitis);
if you suffer from severe heart failure, moderate or severe kidney disease, or severe liver disease;
if you have bleeding or coagulation disorders;
if you are severely dehydrated (i.e. if you have lost a lot of fluids) due to vomiting, diarrhoea, or insufficient
fluid intake;
if you have recently experienced acute alcohol intoxication, sedative, analgesic, or medicines affecting mood
and emotions;
if you are currently taking monoamine oxidase inhibitors (MAOIs) (medicines used to treat depression) or
have taken them within the last 14 days before starting treatment with this medicine (see “Other medicines and Lenizak”);
if you suffer from epilepsy or seizures, as the risk of seizures may increase;
if you have difficulty breathing;
if you are pregnant or breastfeeding.

Warnings and precautions
Talk to your doctor before taking Lenizak:
if you have an allergy or have previously experienced allergic reactions;
if you suffer from kidney, liver, or heart disorders (hypertension and/or heart failure), fluid retention, or if you
have previously experienced any of these conditions;
if you are taking diuretics;
if you suffer from heart disease, have had a stroke, or think you may be at risk for such conditions (e.g. if you
have high blood pressure, diabetes, high cholesterol levels, or are a smoker); you should talk to your doctor
before starting this treatment, as medicines like this may be associated with a slight increase in the risk of
heart attacks (myocardial infarction) or stroke. These risks are more likely with high doses and prolonged
treatment; do not exceed the recommended dose or duration of treatment;
if you are elderly, as the risk of adverse effects may be higher (see section 4). If any adverse effect occurs,
contact your doctor immediately;
if you are a woman with fertility problems, as this medicine may affect fertility; therefore, you should not take
it if you are planning a pregnancy or undergoing fertility investigations;
if you suffer from blood and blood cell formation disorders;
if you suffer from systemic lupus erythematosus or mixed connective tissue disease (immune system disorders
affecting connective tissue);
if you have previously suffered from chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease);
if you have or have previously had other gastric or intestinal disorders;
if you have an infection – see section “Infections” below;
if you are taking other medicines that increase the risk of peptic ulcer or bleeding, such as oral steroids,
certain antidepressants (e.g. SSRIs, i.e. selective serotonin reuptake inhibitors), antiplatelet agents such as
acetylsalicylic acid, or anticoagulants such as warfarin; in such cases, consult your doctor before taking this
medicine, as they may prescribe an additional medicine to protect your stomach;
if you suffer from depression and are taking antidepressants, as some of them may interact with tramadol (see
“Other medicines and Lenizak”);
if you are taking other medicines containing the same active substances as this medicine, do not exceed the
maximum daily doses of dexketoprofen or tramadol;
if you think you are addicted to other painkillers (opioids);
if you suffer from disorders of consciousness (feeling faint);
if you are in shock (a condition that may present with cold sweating);
if you have increased intracranial pressure (after a head injury or brain disease);
if you have breathing difficulties;
if you suffer from porphyria.

Tolerance, dependence and substance abuse
This medicine contains tramadol, which is an opioid substance. It may cause dependence and/or
substance abuse.
This medicine contains tramadol, which is an opioid substance. Repeated use of opioids may make the medicine
less effective (you become accustomed to it, a phenomenon known as drug tolerance). Repeated use of Lenizak
may also lead to dependence, abuse, and substance abuse, which may result in a life-threatening overdose. The
risk of these adverse effects may increase with higher doses and prolonged duration of use.
Dependence or substance abuse may make you feel that you have lost control over the amount of medicine needed
or the frequency with which you must take it.
The risk of developing dependence or substance abuse varies from person to person. You may have a higher risk
of becoming dependent on or abusing Lenizak if:

you or a family member have previously suffered from alcohol, prescription drug, or illegal substance abuse or dependence (substance abuse);
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.

If you notice any of the following symptoms during treatment with Lenizak, this may be a sign of dependence or
substance abuse:

you feel the need to use the medicine for longer than prescribed by your doctor;
you feel the need to take a higher dose than recommended;
you feel compelled to continue taking the medicine, even if it does not help relieve pain;
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 the use of this medicine without success;
when you stop taking the medicine, you feel unwell, and feel better when you resume taking it (withdrawal effects).

If you notice any of these symptoms/signs, talk to your doctor to discuss the best treatment approach for you,
including whether it is appropriate to discontinue treatment and how to do so safely (see section 3, If you stop
taking Lenizak).
Contact your doctor if you experience any of the following symptoms while taking Lenizak: extreme fatigue,
loss of appetite, severe abdominal pain, nausea, vomiting, or low blood pressure. These symptoms may indicate
adrenal insufficiency (low cortisol levels). If you experience these symptoms, contact your doctor, who will
decide whether hormone replacement therapy is needed.
Tramadol is metabolized in the liver by an enzyme. Some people have variations in this enzyme, which may lead
to different effects. Some people may not get sufficient pain relief, while others may experience serious adverse
effects. If you notice any of the following adverse effects, you must stop taking this medicine and consult a
doctor immediately: slowed or shallow breathing, confusion, drowsiness, constricted pupils, feeling unwell or
malaise, constipation, loss of appetite.
There is a small risk that you may develop serotonin syndrome, which may occur after taking tramadol together
with certain antidepressants or tramadol used as monotherapy. Consult your doctor immediately if you develop
any of the symptoms associated with this serious syndrome (see section 4 “Possible side effects”).

Sleep-related breathing disorders
Lenizak may cause sleep-related breathing disorders such as sleep apnoea (pauses in breathing during sleep) and
sleep-related hypoxaemia (low blood oxygen levels during sleep). Symptoms may include pauses in breathing
during sleep, nocturnal awakenings due to shortness of breath, difficulty maintaining sleep, or excessive daytime
sleepiness. If you or someone else observes these symptoms, contact your doctor, who may consider reducing
the dose.

Infections
Lenizak may mask symptoms of infections such as fever and pain. Therefore, Lenizak may delay appropriate
treatment of the infection, which could increase the risk of complications. This has been observed in bacterial
pneumonia and bacterial skin infections related to chickenpox.
If you take this medicine while having an infection and the symptoms of infection persist or worsen, contact your
doctor immediately.
The use of this medicine is not recommended during chickenpox virus infection.

Kounis syndrome
With dexketoprofen, manifestations of an allergic reaction to this medicine have been reported, including
breathing problems, swelling of the face and neck area (angioedema), and chest pain. If you notice any of these
signs, stop taking Lenizak immediately and contact your doctor or emergency medical services immediately.

Children and adolescents
This medicine has not been studied in children and adolescents. Therefore, as neither safety nor efficacy has been
established, it should not be used in children and adolescents.

Use in children with respiratory problems
Tramadol is not recommended in children with respiratory problems, as symptoms of tramadol toxicity may be
worse in these children.

Other medicines and Lenizak
Tell your doctor if you are taking, have recently taken, or might take any other medicine, including medicines
obtained without a prescription. Some medicines should not be taken together, while others may require dose
adjustment when used concomitantly.
Always inform your doctor if you are using or have been prescribed any of the following medicines in addition to
Lenizak.

Use not recommended with Lenizak:
acetylsalicylic acid, corticosteroids, or other anti-inflammatory drugs;
warfarin, heparin, or other anticoagulant medicines;
lithium, used to treat certain types of mood disorders;
methotrexate, used for rheumatoid arthritis and cancer;
ethotoin and phenytoin, used for epilepsy;
sulfamethoxazole, used for bacterial infections;
monoamine oxidase inhibitors (MAOIs) (medicines used to treat depression).

Use requiring certain precautions with Lenizak:
ACE inhibitors, diuretics, beta-blockers, and angiotensin II antagonists, used for hypertension and cardiac
diseases;
pentoxifylline, used to treat chronic venous ulcers;
zidovudine, used to treat viral infections;
chlorpropamide and glibenclamide, used for diabetes;
aminoglycoside antibiotics, used to treat bacterial infections;
concomitant use of Lenizak and sedative medicines such as benzodiazepines or benzodiazepine-related drugs
increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be life-threatening. Due to these risks, concomitant use of these medicines should only be considered when no alternative treatments are possible. However, if your doctor prescribes Lenizak together with sedative medicines, the dose and duration of concomitant treatment must be limited by your doctor. Inform your doctor about any sedative medicine you are taking and strictly follow the dose recommended by your doctor. It may be helpful to inform friends and family about the signs and symptoms described above. Inform your doctor if such symptoms occur.

Use requiring caution with Lenizak:
quinolone antibiotics (e.g. ciprofloxacin, levofloxacin) used for bacterial infections;
cyclosporine or tacrolimus, used to treat immune system diseases and in organ transplantation;
streptokinase and other thrombolytic or fibrinolytic medicines, such as medicines used to break up blood clots;
probenecid, used to treat gout;
digoxin, used to treat chronic heart failure;
mifepristone, used for termination of pregnancy;
selective serotonin reuptake inhibitor (SSRI) antidepressants;
antiplatelet agents used to reduce platelet aggregation and blood clot formation;
tenofovir, deferasirox, pemetrexed.

The analgesic effect of tramadol may be reduced and the duration of action may be shorter if you also take
medicines containing:
carbamazepine (for epileptic seizures);
buprenorphine, nalbuphine, or pentazocine (analgesics);
ondansetron (for nausea).

The risk of adverse effects increases
if you are taking gabapentin or pregabalin for the treatment of epilepsy or nerve-related pain (neuropathic pain);
if you take tranquillisers, sleeping pills, other analgesics such as morphine and codeine (even for cough) or
alcohol during treatment with Lenizak. You may experience drowsiness or feel faint; if this happens, discuss it with your doctor;
if you are taking medicines that may cause seizures (epileptic attacks), such as certain antidepressants or
antipsychotics. The risk of having a seizure may increase if you take Lenizak together with these medicines;
your doctor will tell you whether Lenizak is suitable for you;
if you take certain antidepressants. Lenizak may interact with these medicines and you may develop serotonin
syndrome (see section 4 “Possible side effects”);
if you take anticoagulants (medicines that thin the blood), e.g. warfarin, together with this medicine; the effect
of these medicines on blood clotting may be altered, and you may experience bleeding.

Lenizak and alcohol
Do not drink alcohol during treatment with Lenizak, as it may increase the effect of the medicine.
For instructions on how to take Lenizak, see section 3.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor
before taking this medicine.
Dexketoprofen may cause kidney and heart problems in the fetus. In addition, it may affect your and your baby’s
tendency to bleed and may delay or prolong labour more than expected. From week 20 of pregnancy, dexketoprofen may cause kidney problems in the fetus, which may in turn lead to reduced levels of amniotic fluid surrounding the baby (oligohydramnios), or narrowing of a blood vessel (ductus arteriosus) in the baby’s heart.
Tramadol is excreted in breast milk.
Lenizak is contraindicated during pregnancy and breastfeeding.

Driving and using machines
Lenizak may affect your ability to drive and use machines, as it may cause dizziness, drowsiness, and visual disturbances as side effects of treatment. This is especially true if Lenizak is taken together with medicines that affect mood or together with alcohol.
If you notice these effects, do not drive or use machines until the symptoms have disappeared.

This medicine contains less than 1 mmol of sodium (23 mg) per dose, i.e. essentially “sodium-free”.

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

5. How to take Lenizak

Always use this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor.
The lowest effective dose for the shortest duration necessary to relieve symptoms should be used. If you have
an infection, contact your doctor immediately should symptoms (e.g. fever and pain) persist or worsen (see section 2).
The dose of Lenizak you need depends on the type, severity, and duration of your pain.
Before starting treatment and regularly during treatment, your doctor will discuss with you what to expect from using Lenizak, how many tablets to take each day, when and for how long it should be used, when to contact your doctor, and when treatment should be discontinued (see also “If you stop taking Lenizak”).
Generally, the recommended dose is 1 film-coated tablet (corresponding to 75 mg of tramadol hydrochloride and 25 mg of dexketoprofen) every 8 hours, up to a maximum of 3 film-coated tablets per day (corresponding to 225 mg of tramadol hydrochloride and 75 mg of dexketoprofen), without exceeding 5 days of treatment.
Use in children and adolescents
Lenizak is not indicated in children and adolescents.
Elderly patients
If you are 75 years of age or older, your doctor may advise you to extend the interval between doses, as your body may eliminate the medicine more slowly.
Severe renal or hepatic impairment/dialysis patients:
Patients with severe renal or hepatic impairment must not take Lenizak.
In case of mild renal impairment, your doctor may advise you to extend the interval between doses.
In case of mild-to-moderate hepatic impairment, your doctor may advise you to extend the interval between doses.
Swallow the tablet with sufficient liquid (preferably with a glass of water).
Concomitant food intake slows the absorption of Lenizak; therefore, for a faster effect, take the tablet at least 30 minutes before meals. The score line on the tablet is intended to facilitate splitting if you have difficulty swallowing it whole.
If you take more Lenizak than you should
If you take an excessive amount of this medicine, inform your doctor immediately or go to the nearest hospital emergency department, remembering to bring the medicine pack or this leaflet with you.
Symptoms of overdose with this medicine include:
vomiting, loss of appetite, stomach pain, dizziness, drowsiness/dizziness (for dexketoprofen);
pupil constriction, vomiting, cardiac failure, loss of consciousness, seizures, and breathing difficulties (for tramadol).
If you forget to take Lenizak
Do not take a double dose to make up for the missed dose. Take the next dose at the regular time (see section 3 “How to take Lenizak”).
If you stop taking Lenizak
Generally, there are no sequelae following discontinuation of Lenizak therapy.
However, in rare cases, patients who have taken Lenizak tablets for some time may feel unwell if they stop taking it suddenly. They may feel agitated, anxious, nervous, or weak, confused, hyperactive, have difficulty sleeping, and experience gastrointestinal or intestinal disturbances. Rarely, some individuals may experience panic attacks, hallucinations, illusions, paranoia, or a sense of loss of identity. They may experience unusual sensations such as itching, tingling, numbness, and ringing in the ears (tinnitus).
Rarely, other unusual symptoms have been observed, such as confusion, illusions, a sense of detachment from oneself (depersonalization), a distorted perception of reality (derealization), and delusions of persecution (paranoia). If you experience any of these symptoms after stopping Lenizak treatment, consult your doctor.
If you have any doubts about how to use this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
The possible side effects are listed below according to their frequency of occurrence.
You must consult a doctor immediately if you experience symptoms of an allergic reaction such as swelling of the face, tongue and/or throat and/or difficulty swallowing or hives together with breathing difficulties.
Stop taking Lenizak if you notice the appearance of a skin rash or lesions inside the mouth or on mucous membranes, or signs of allergy.

Very common (may affect more than 1 in 10 people):
nausea/malaise;
dizziness.

Common side effects (may affect up to 1 in 10 people):
vomiting;
stomach ache;
diarrhoea;
digestive problems;
headache;
drowsiness, fatigue;
constipation;
dry mouth;
increased sweating.

Uncommon side effects (may affect up to 1 in 100 people):
increase in platelet count;
effects on the heart and blood circulation (palpitations, tachycardia, weakness or collapse), low blood pressure. These adverse effects may occur especially when patients are in an upright position or under physical exertion;
high or very high blood pressure;
swelling (edema) of the larynx;
reduced levels of potassium in the blood;
psychotic disorders;
swelling around the eye area;
slow and/or shallow breathing;
discomfort, abnormal sensations;
blood in urine;
sensation of dizziness;
insomnia or difficulty falling asleep;
nervousness/anxiety;
hot flushes;
flatulence;
tiredness;
pain;
feverish feeling and chills, general feeling of malaise;
abnormal blood tests;
nausea;
feeling of pressure in the stomach, abdominal bloating;
gastritis;
skin reactions (e.g. itching, rash);
amnesia;
facial swelling.

Rare side effects (may affect up to 1 in 1,000 people):
swelling of the lips and throat;
peptic ulcer, perforation or bleeding from peptic ulcer, which may be indicated by blood in vomit or black stools;
prostate disorders;
inflammation of the liver (hepatitis), liver damage;
acute kidney failure;
bradycardia;
epileptic seizures;
allergic/anaphylactic reactions (e.g. breathing difficulties, wheezing, skin swelling) and anaphylactic shock (sudden circulatory failure);
transient loss of consciousness (syncope);
hallucinations;
fluid retention or swollen ankles;
loss of appetite, changes in appetite;
acne;
back pain;
frequent or less frequent urination than normal, with difficulty or pain;
menstrual disorders;
abnormal sensations (such as itching, numbness, tinnitus);
tremor, muscle spasms, uncoordinated movement, muscle weakness;
confusion;
sleep disturbances and nightmares;
perceptual disturbances;
visual disturbances, pupil constriction;
shortness of breath.

After treatment with Lenizak, you may experience psychological side effects. These may vary in intensity and nature (depending on the patient's personality and duration of therapy):
mood changes (mainly increased mood tone, occasionally irritability);
changes in activity (slowing down, but sometimes increased activity);
reduced awareness;
reduced decision-making ability, which may lead to poor judgment.

Worsening of asthma has been reported.
When treatment is stopped abruptly, withdrawal symptoms may occur (see "If you stop taking Lenizak").
Epileptic seizures have been observed especially with high doses of tramadol or when tramadol was taken together with other medicines that may induce such seizures.

Very rare (may affect up to 1 in 10,000 people):
inflammation of the pancreas;
kidney problems;
reduced number of white blood cells (neutropenia);
reduced number of platelets in the blood (thrombocytopenia);
skin, mouth, eye and genital lesions (Stevens-Johnson syndrome and Lyell syndrome);
shortness of breath due to narrowing of the airways;
ringing in the ears (tinnitus);
tender skin;
photosensitivity.

Not known (frequency cannot be estimated from available data):
chest pain, which may be a sign of a severe allergic reaction called Kounis syndrome;
drug-induced fixed drug eruption. An allergic skin reaction, known as fixed drug eruption, which may appear as round or oval patches with redness and skin swelling, skin rash with blisters and itching. Darkening of the skin in affected areas may also occur, which could persist even after healing. Upon re-exposure to the medicine, fixed drug eruption usually recurs at the same site (or sites);
serotonin syndrome, which may present as changes in mental status (e.g. agitation, hallucinations, coma) and other effects such as fever, increased heart rate, unstable blood pressure, involuntary muscle contractions, muscle rigidity, lack of coordination and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea) (see section 2 “What you should know before taking Lenizak”);
speech disorders;
extreme dilation of the pupil;
reduction in blood glucose levels;
hiccups.

Contact your doctor immediately if you experience gastrointestinal/intestinal side effects at the beginning of therapy (such as stomach ache, burning or bleeding), especially if you have previously suffered from these side effects due to prolonged use of anti-inflammatory medicines and particularly if you are elderly.

The most common side effects during treatment with Lenizak are nausea and drowsiness, which occur in more than 1 in 10 patients.

During treatment with NSAIDs, fluid retention and swelling (especially in the ankles and legs), increased blood pressure and heart failure have been observed.

Medicines such as Lenizak may be associated with a slightly increased risk of heart attack or stroke.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor. 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 Lenizak

Keep this medicine out of the sight and reach of children.
Store this medicine in a safe and secure place, inaccessible to other people.
Taking this medicine by other people for whom it has not been prescribed may cause serious harm and can be fatal.
Do not use this medicine after the expiry date stated on the packaging and on the blister after Exp.
The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions or temperature.
Keep it in the original packaging to protect the medicine from light.
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 Lenizak contains

The active substances are tramadol hydrochloride and dexketoprofen. Each tablet contains: 75 mg of tramadol hydrochloride and 25 mg of dexketoprofen.
The other components are: Tablet core: microcrystalline cellulose, pregelatinized corn starch, sodium croscarmellose, sodium stearyl fumarate, anhydrous colloidal silica. Film coating: Opadry II White 85F18422 composed of polyvinyl alcohol, titanium dioxide, Macrogol/PEG 3350, talc.

Description of the appearance of Lenizak and package contents
Film-coated, oval tablets, almost white to slightly yellow in colour, with a score line on one side to allow tablet division and an engraved "M" on the other side, packed in plastic/aluminum blister packs.
Lenizak is available in packs containing 2, 4, 10, 15, 20, 30, 50, 100 film-coated tablets and in multipacks containing 5 boxes, each box containing 100 film-coated tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 - Luxembourg
Concessionaire for sale:
A. Menarini Industrie Farmaceutiche Riunite s.r.l.
Via Sette Santi, 3 – 50131 Florence, Italy
Manufacturer:
Menarini – Von Heyden GmbH
Leipziger Strasse 7-13
01097 Dresden, Germany

This medicinal product is authorised in the European Economic Area countries under the following names:
Belgium, Bulgaria, Croatia, Cyprus, Estonia, Finland, Greece, Ireland, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, United Kingdom (Northern Ireland), Czech Republic, Slovak Republic, Romania, Slovenia, Sweden, Hungary: Skudexa
France: Skudexum
Italy: Lenizak
Spain: Enanplus