NABUSER
1g coated tablets
1g granules for oral suspension
NABUMETONE
COMPOSITION
One coated tablet contains:
Active substance: nabumetone 1000 mg.
Excipients: sodium carboxymethylcellulose; sodium lauryl sulfate; magnesium stearate; microcrystalline cellulose; hydroxypropyl-methylcellulose; titanium dioxide (E171); macrogol 400; macrogol 6000.
One sachet contains:
Active substance: nabumetone 1000 mg.
Excipients: hydroxypropylmethylcellulose; colloidal silica; sodium lauryl sulfate; mint flavor; sucrose.
PHARMACEUTICAL FORM AND CONTENT
30 coated tablets of 1 g.
30 sachets of 1 g granules for oral suspension.
PHARMACOTHERAPEUTIC CATEGORY
Non-steroidal anti-inflammatory and anti-rheumatic agent.
MARKETING AUTHORISATION HOLDER, MANUFACTURER AND QUALITY CONTROLLER:
Marketing Authorisation Holder:
PHARMADAY PHARMACEUTICAL S.R.L. Unipersonale – Via Vistarino, 14F -
27010 Copiano (PV).
Tablet Manufacturer and Quality Controller:
Industria Farmaceutica Nova Argentia S.p.a. – Via G. Pascoli, 1 -
20064 – Gorgonzola (Milan)
Sachet Manufacturer and Quality Controller:
La.Fa.Re. S.r.l. – Via Sac. Benedetto Cozzolino, 77 – Ercolano (NA).
THERAPEUTIC INDICATIONS
Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, extra-articular rheumatism.
Periarticular disorders such as bursitis, tendinitis, synovitis and tenosynovitis, periarthritis of the shoulder.
Acute inflammatory conditions including musculoskeletal inflammation, sports injuries.
CONTRAINDICATIONS
Medicinal products containing nabumetone are contraindicated in patients with a history of hypersensitivity to nabumetone or to any of the excipients (see composition). Nabumetone must not be administered to patients who have experienced asthma, urticaria, or allergic reactions after taking acetylsalicylic acid or other NSAIDs.
In such patients, severe anaphylactoid reactions, rarely fatal, have been reported with NSAIDs.

Nabumetone is contraindicated in patients with severe hepatic impairment.
Nabumetone is contraindicated in patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy.
Nabumetone is contraindicated in patients with a history of recurrent or active peptic ulcer/hemorrhage (two or more distinct episodes of confirmed ulceration or bleeding).
Nabumetone is contraindicated during the third trimester of pregnancy and in breastfeeding women.
Nabumetone is contraindicated in patients with severe heart failure, and in patients with active cerebrovascular or other types of bleeding.

The product must not be administered to pediatric patients. The product must not be administered in cases of severe heart failure.
The product must not be administered in cases of significant hematological disorders during anticoagulant therapy, as it may potentiate their action.
PRECAUTIONS FOR USE
NABUSER must be used with caution and under medical supervision in patients with a history of gastrointestinal disorders (gastrointestinal bleeding, peptic ulcer) following therapy with other non-steroidal anti-inflammatory drugs. Due to the occasional tendency of drugs in this therapeutic group to induce fluid retention, nabumetone should be used with caution in patients with incipient or established congestive heart failure and in those with hypertension. As with other non-steroidal anti-inflammatory drugs, occasional visual disturbances may occur. In such cases, consult a physician. Use with caution in patients with renal and/or hepatic impairment, arterial hypertension, heart failure, those undergoing diuretic therapy, and generally in elderly patients, particularly during long-term treatment. It should be noted that administration in asthmatic patients or predisposed subjects may trigger bronchospasm attacks and possibly shock or other allergic phenomena. During prolonged treatment with NABUSER, as with other non-steroidal anti-inflammatory drugs, periodic monitoring of blood parameters and liver and kidney function is recommended as a precautionary measure.
INTERACTIONS WITH OTHER MEDICINES
Inform your doctor or pharmacist if you have recently taken any other medicine, including those without a prescription.
Since this product binds to plasma proteins, this should be taken into account in patients receiving concomitant therapy with drugs that bind to proteins.
No specific studies have been conducted on the interaction between nabumetone and the medicines listed below. Therefore, caution is recommended when using concomitant therapy with the medicines listed below.
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding.
Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin and other anticoagulants; their concomitant administration with nabumetone should be carried out with caution and signs of overdose should be closely monitored.
Antiplatelet agents and serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.
The use of more than one NSAID is not recommended.
In general, NSAIDs interact with the following medicines, increasing their concentration:

Cardiac glycosides;
Methotrexate;
Lithium. Hyperkalemia may develop, particularly with concomitant administration of potassium-sparing diuretics. Diuretics and other antihypertensive drugs such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARAs) may have reduced efficacy when administered concomitantly with NSAIDs; in some individuals (such as elderly or dehydrated patients), this could lead to further reduction in renal function and, ultimately, acute renal failure (ARF). Consequently, hydration and frequent monitoring of these patients are required. Concomitant administration of nabumetone with other highly protein-bound drugs, such as sulfonamides, sulfonylureas, or hydantoins, should be performed with caution and signs of overdose should be closely monitored. Cyclosporine: NSAIDs increase the risk of nephrotoxicity with this medicine. Mifepristone: Nabumetone must not be used for 8–12 days after administration of mifepristone, as NSAIDs may reduce the effect of mifepristone. Probenecid: reduced metabolism of nabumetone and reduced elimination of nabumetone and its metabolites. Quinolone antibiotics: animal data indicate that NSAIDs increase the risk of seizures associated with quinolone antibiotics. Patients taking nabumetone and quinolones may have an increased risk of developing seizures. Alcohol, bisphosphonates, oxpentifylline (pentoxifylline), and sulfinpyrazone: may potentiate gastrointestinal adverse effects and the risk of bleeding or ulceration. The following commonly available drugs do not affect the metabolism and bioavailability of nabumetone: paracetamol, cimetidine, aluminum hydroxide-based antacids.
SPECIAL WARNINGS
Medicines such as NABUSER may be associated with a modest increase in the risk of heart attack ("myocardial infarction") or stroke. The risk is more likely with high doses and prolonged treatment. Do not exceed the recommended dose or duration of treatment.
If you have heart problems, a history of stroke, or think you may be at risk for these conditions (e.g., if you have high blood pressure, diabetes, high cholesterol, or smoke), discuss your treatment with your doctor or pharmacist. The sachet formulation contains sucrose. This should be taken into account in diabetic patients and in those on a low-calorie diet.
The use of nabumetone with concomitant NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.
Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
Elderly:
Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which can be fatal.
Gastrointestinal bleeding, ulceration, and perforation:
During treatment with all NSAIDs, gastrointestinal bleeding, ulceration, and perforation, which can be fatal, have been reported at any time, with or without warning symptoms or previous history of serious gastrointestinal events. The risk of gastrointestinal bleeding, ulceration, or perforation is higher with increasing NSAID dose, in patients with a history of ulcer, especially if complicated by bleeding or perforation, and in the elderly. These patients should start treatment with the lowest available dose. Combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk. Patients with a history of gastrointestinal peptic disease, especially if elderly, should be alerted to report any unusual gastrointestinal symptoms suggestive of ulceration (especially gastrointestinal bleeding), particularly in the early stages of treatment. Caution should be exercised in patients taking concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents such as acetylsalicylic acid and clopidogrel (see "interactions with other medicines"). When gastrointestinal bleeding or ulceration occurs in patients taking nabumetone, treatment must be discontinued. NSAIDs should be administered with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease), as their condition may worsen.
In an analysis of both pre- and post-marketing clinical trial data with nabumetone, the cumulative average frequencies of gastrointestinal perforations, ulcers, or bleeding (PUBs) in patients treated for 3 to 6 months, 1 year, and 2 years were 0.3%, 0.5%, and 0.8%, respectively. Although these figures appear low, the prescribing physician must be aware that these adverse reactions (ADRs) may occur even in the absence of prior peptic disease.
Cardiovascular and cerebrovascular effects:
Adequate monitoring and appropriate instructions are required for patients with a history of hypertension and/or mild to moderate congestive heart failure, as fluid retention and edema have been reported in association with NSAID therapy. Clinical studies and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and for long-term treatment) may be associated with a modest increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). There are insufficient data to exclude a similar risk for nabumetone. Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with nabumetone only after careful evaluation. Similar considerations should be made before initiating long-term treatment in patients with cardiovascular risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).
Cutaneous reactions:
Severe skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been rarely reported in association with the use of non-steroidal anti-inflammatory drugs (NSAIDs), including nabumetone. At the time of prescription, patients should be informed about the signs and symptoms, and careful monitoring should be implemented to detect the onset of skin reactions. If signs and symptoms suggestive of these reactions occur, nabumetone administration must be immediately discontinued and alternative treatment should be considered (if appropriate). Patients appear to be at higher risk in the early stages of therapy; the reaction typically occurs within the first two months of treatment. Treatment with nabumetone must be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. If a patient has developed a severe skin reaction such as SJS, TEN, or DRESS associated with nabumetone use, treatment with nabumetone must never be resumed in this patient.
Impairment of female fertility
The use of nabumetone may alter fertility and is not recommended in women attempting to conceive. In women experiencing difficulty conceiving or undergoing fertility investigations, discontinuation of nabumetone should be considered.
Others:
NSAIDs may mask signs or symptoms of infection (fever, pain, swelling).
Cases of blurred vision or reduced visual acuity have been reported with the use of NSAIDs, including nabumetone. Patients experiencing these events should undergo an ophthalmological examination.
Caution is required when administering nabumetone to patients with:
Asthma, urticaria, or other previous allergic-type reactions induced by acetylsalicylic acid or other NSAIDs. Since fatal asthma attacks have been reported in such patients during administration of other NSAIDs, the first administration of nabumetone should be supervised by a physician.
Systemic lupus erythematosus (SLE) and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis (see section "undesirable effects").
Severe hepatic impairment. As with other NSAIDs, abnormalities in liver function tests, rare cases of jaundice and hepatic failure (some of which were fatal) have been reported. A patient with signs/symptoms suggesting hepatic dysfunction, or who has shown abnormal liver function tests during nabumetone therapy, should be evaluated for the risk of developing a more severe hepatic reaction. Nabumetone must be discontinued if such a reaction occurs.
Severe renal impairment (creatinine clearance less than 30 ml/min): laboratory tests should be performed before starting treatment and within a few weeks of starting therapy. Further tests should be performed if necessary; if impairment worsens, discontinuation of therapy may be required. In cases of moderate renal impairment (creatinine clearance from 30 to 49 ml/min), there is a 50% increase in free plasma 6-MNA and dose reduction may be necessary.
Pregnancy and lactation.
NABUSER must not be administered during pregnancy and breastfeeding.
Pregnancy.
There is no clinical experience with the use of nabumetone during human pregnancy.
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest an increased risk of spontaneous abortion and cardiac malformations and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk of cardiac malformations increases from less than 1% to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of prostaglandin synthesis inhibitors has been shown to cause increased pre- and post-implantation loss and embryofetal mortality. Furthermore, an increased incidence of various malformations, including cardiovascular ones, has been reported in animals administered prostaglandin synthesis inhibitors during the organogenesis period.
Do not take Nabuser during the last three months of pregnancy, as it may harm the fetus or cause problems during delivery. It may cause kidney and heart problems in the fetus. It may affect your and your baby's tendency to bleed and delay or prolong labor more than expected.
You should not take NABUSER during the first six months of pregnancy unless absolutely necessary and under medical advice.
Where treatment is required during this period or during attempts to conceive, the lowest possible dose for the shortest possible time should be used.
From the 20th week of pregnancy, NABUSER may cause kidney problems in the fetus if taken for more than a few days, thereby reducing the levels of amniotic fluid surrounding the baby (oligohydramnios) or causing narrowing of a blood vessel (ductus arteriosus) in the baby's heart. Where treatment is required for more than a few days, your doctor may recommend additional monitoring.
Therefore, Nabuser is contraindicated during the third trimester of pregnancy.
Lactation
There is no clinical experience with the use of nabumetone during lactation. It is not known whether nabumetone is excreted in human milk; however, 6-MNA is excreted in the milk of lactating rats. Due to the risk of serious adverse reactions in breastfed infants from nabumetone, a decision must be made whether to discontinue breastfeeding or to suspend the drug, taking into account the importance of the drug for the mother.
Fertility
See the section "Special Warnings" regarding female fertility.
Driving and use of machinery: dizziness and confusion have been reported after administration of nabumetone. If these symptoms occur, the patient must not drive or operate machinery.
Keep out of reach and sight of children
DOSAGE, ADMINISTRATION AND DURATION OF TREATMENT
Adults:
One tablet or one sachet of 1 g in the evening.
In severe and persistent cases or during acute exacerbations, an additional half tablet or half sachet, or one tablet or one sachet of 1 g in the morning may be added.
In cases of acute conditions, such as sports injuries, a loading dose of one tablet or one sachet followed by standard dosing is recommended.
In the elderly, the total daily dose must not exceed 1 g (in some cases, 500 mg, half a tablet or half a sachet may provide satisfactory results).
Sachets must always be dissolved in half a glass of water before use.
The resulting suspension should be stirred with a teaspoon and taken immediately.
Sachets are particularly suitable for use in all patients who have difficulty swallowing.
Currently, there are no data on use in patients under 14 years of age.
Concomitant food intake does not affect the absorption of NABUSER.
OVERDOSE
Symptoms and signs
There is no information on overdose.
Symptoms include nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhea, disorientation, excitement, coma, drowsiness, dizziness, and occasionally seizures. In cases of significant intoxication, acute renal failure and liver damage are possible.
Treatment
There is no specific antidote and the active metabolite 6-MNA is not dialyzable.
Accidental overdose should be treated with gastric lavage followed by activated charcoal and appropriate supportive therapy.
UNDESIRABLE EFFECTS
Like all medicines, Nabuser can cause undesirable effects, although not everyone will experience them
Widespread skin rash, elevated body temperature, increased liver enzymes, reduced number of eosinophils in the blood (a type of white blood cell), lymph node enlargement and involvement of other organs (drug reaction with eosinophilia and systemic symptoms also known as DRESS or drug-induced hypersensitivity syndrome).
Stop using Nabuser if you develop any of these symptoms and contact your doctor immediately. See also section 2.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000) and very rare (<1/10,000), including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo and comparator groups was not considered in the assessment of these frequencies. Rare and very rare events were generally determined from spontaneous reports.
Hematopoietic and lymphatic system disorders:
Very rare: thrombocytopenia.
Not known: Anemia (including aplastic anemia and hemolytic anemia).
Immune system disorders
Very rare: anaphylaxis, anaphylactoid reaction.
Psychiatric disorders
Uncommon: confusion, nervousness, insomnia.
Not known: hallucinations.
Nervous system disorders
Uncommon: drowsiness, dizziness, headache, paresthesia.
Not known: aseptic meningitis (especially in patients with existing autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see special warnings).
Eye disorders
Uncommon: altered vision, eye disorders.
Ear and labyrinth disorders
Common: tinnitus, ear disorder.
Vascular disorders
Common: increased blood pressure.
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnea, respiratory disorders, epistaxis.
Very rare: interstitial pneumonia.
Gastrointestinal disorders
Common: diarrhea, constipation, dyspepsia, gastritis, nausea, abdominal pain, flatulence.
Uncommon: duodenal ulcer, gastrointestinal bleeding, gastric ulcer, gastrointestinal disorder, melena, vomiting, stomatitis, dry mouth.
Gastrointestinal: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or bleeding, sometimes fatal, occur predominantly in the elderly (see special warnings). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section special warnings) have been reported following administration. Gastritis has been observed less frequently.
Hepatobiliary disorders
Very rare: hepatic failure, jaundice.
Skin and subcutaneous tissue disorders
Common: rash, pruritus.
Uncommon: photosensitivity, urticaria, sweating.
Very rare: bullous reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms, erythema multiforme, angioedema, pseudoporphyria, alopecia.
Musculoskeletal and connective tissue disorders
Uncommon: myopathy.
Renal and urinary disorders
Uncommon: urinary tract disorders.
Very rare: renal failure, nephrotic syndrome.
Reproductive system and breast disorders
Very rare: menorrhagia.
Systemic disorders and administration site conditions
Common: edema.
Uncommon: asthenia, fatigue.
Investigations
Uncommon: elevated liver function tests.
Edema, hypertension and heart failure have been reported in association with NSAID treatment.
Clinical studies and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and long-term treatment) may be associated with an increased risk of arterial thrombotic events (e.g., myocardial infarction, stroke and death) (see special warnings section).
Reporting of adverse effects:
If you experience any adverse effect, including those not listed in this leaflet, contact your doctor or pharmacist. You may also report adverse effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting adverse effects, you can help provide more information on the safety of this medicine.
Inform your doctor or pharmacist if any adverse effects not described in this patient information leaflet occur.
Following the instructions contained in the leaflet reduces the risk of adverse effects. If any of the adverse effects worsen, or if you notice any adverse effect not listed in this leaflet, inform your doctor or pharmacist.
EXPIRY DATE
The expiry date stated on the packaging refers to the product in intact packaging, correctly stored.
WARNING
Caution: do not use the medicine after the expiry date stated on the packaging.
No special precautions for storage are required.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

Nabuser