4.1. Therapeutic indications

Symptomatic short term treatment of moderate to severe acute pain in adult patients whose pain is considered to require a combination of tramadol and dexketoprofen.

4.2. Posology and method of administration

Posology

The recommended dosage is one film-coated tablet (corresponding to 75 mg of tramadol hydrochloride and 25 mg of dexketoprofen). Additional doses can be taken as needed, with a minimum dosing interval of 8 hours. The total daily dose should not exceed three film-coated tablets per day (corresponding to 225 mg of tramadol hydrochloride and 75 mg of dexketoprofen).

Skudexa is intended for short term use only and the treatment must be strictly limited to the symptomatic period and in any case not more than 5 days. Switching to a single agent analgesia should be considered according to pain intensity and response of the patient.

Undesirable effects may be minimised by using the lowest number of doses for the shortest duration necessary to control symptoms (see section 4.4).

Elderly:

In elderly patients the starting recommended dosage is one film-coated tablet; additional doses can be taken as needed with the minimum dose interval of 8 hours and not exceeding the total daily dose of 2 film-coated tablets (corresponding to 150 mg of tramadol hydrochloride and 50 mg of dexketoprofen). The dosage may be increased to a maximum of 3 daily film-coated tablets as recommended for the general population only after good general tolerance has been ascertained.

Limited data are available in patients over 75 years, therefore Skudexa should be used with caution in these patients (see section 4.4).

Hepatic impairment:

Patients with mild to moderate hepatic impairment should start therapy at reduced number of doses (total daily dose 2 film-coated tablets Skudexa) and be closely monitored.

Skudexa should not be used in patients with severe hepatic impairment (see section 4.3).

Renal impairment:

The initial total daily dosage should be reduced to 2 film-coated tablets Skudexa in patients with mildly impaired renal function (creatinine clearance 60 - 89 ml / min) (see section 4.4).

Skudexa should not be used in patients with moderate to severe renal impairment (creatinine clearance ≤59 ml / min) (see section 4.3).

Paediatric population:

The safety and efficacy of Skudexa in children and adolescents have not been established. No data are available.

Therefore Skudexa should not be used in children and adolescents.

Method of administration

Oral use.

Skudexa should be swallowed with a sufficient amount of fluid (e.g. one glass of water). Concomitant administration with food delays the absorption rate of the drug (see section 5.2), for a faster effect the tablets may be taken at least 30 minutes before meals.

Treatment goals and discontinuation

Before initiating treatment with Skudexa, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with Skudexa, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

4.3. Contraindications

The contraindications reported for dexketoprofen and tramadol as single agents should be taken into account.

Dexketoprofen must not be administered in the following cases:

• hypersensitivity to dexketoprofen, to any other NSAID, or to any of the excipients listed in section 6.1;

• patients in whom substances with a similar action (e.g. acetylsalicylic acid, or other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema;

• known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates;

• patients with active peptic ulcer/gastrointestinal haemorrhage or any history of gastrointestinal bleeding ulceration or perforation;

• patients with history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy;

• patiens with chronic dyspepsia;

• patients who have other active bleedings or bleeding disorders;

• patients with Crohn's disease or ulcerative colitis;

• patients with severe heart failure;

• patients with moderate to severe renal impairment (creatinine clearance ≤59 ml/min);

• patients with severely impaired hepatic function (Child-Pugh C);

• patients with haemorrhagic diathesis and other coagulation disorders;

• patients with severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake).

Tramadol must not be administered in the following cases:

• hypersensitivity to tramadol or to any of the excipients listed in section 6.1;

• in acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic medicinal products;

• in patients receiving MAO inhibitors, or who have taken them within the last 14 days (see section 4.5);

• in patients with epilepsy not adequately controlled by treatment (see section 4.4);

• severe respiratory depression

Skudexa is contraindicated during pregnancy and lactation (see section 4.6).

4.4. Special warnings and precautions for use

The special warnings and precautions reported for dexketoprofen and tramadol as single agents should be taken into account.

Dexketoprofen

Administer with caution in patients with a history of allergic conditions.

The use of dexketoprofen with concomitant other NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and gastrointestinal GI and cardiovascular risks below).

Gastrointestinal safety

Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen, the treatment should be withdrawn.

The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in older people.

As with all NSAIDs, any history of oesophagitis, gastritis and/or peptic ulcer must be identified in order to ensure their total cure before starting treatment with dexketoprofen. Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding.

NSAIDs should be used with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see section 4.8).

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5).

Renal safety

Caution should be exercised in patients with impairment of renal functions. In these patients, the use of NSAIDs may result in deterioration of renal function, fluid retention and oedema. Caution is also required in patients receiving diuretic therapy or those who could develop hypovolaemia as there is an increased risk of nephrotoxicity.

Adequate fluid intake should be ensured during treatment to prevent dehydration and possibly associated increased renal toxicity.

As with all NSAIDs, it can increase plasma urea nitrogen and creatinine. As with other inhibitors of prostaglandin synthesis, it can be associated with adverse effects on the renal system which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure.

Liver safety

Caution should be exercised in patients with impairment of hepatic functions. As with other NSAIDs, it can cause transient small increases in some liver parameters, and also significant increases in aspartate transaminase (AST) also known as serum glutamic oxaloacetic transaminase (SGOT) and Alanine transaminase (ALT), also known as serum glutamic-pyruvic transaminase (SGPT). In case of a relevant increase in such parameters, therapy must be discontinued.

Cardiovascular and cerebrovascular safety

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAIDs therapy. Special caution should be exercised in patients with a history of cardiac disease, in particular those with previous episodes of heart failure as there is an increased risk of triggering heart failure.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increase in the risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for dexketoprofen.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with dexketoprofen after careful consideration. Similar consideration should be made before initiating long-term treatment of the patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Cases of Kounis syndrome have been reported in patients treated with dexketoprofen. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

All non-selective NSAIDs can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Therefore, the use of dexketoprofen in patients who are receiving other therapy that interferes with haemostasis, such as warfarin or other coumarins or heparins is not recommended (see section 4.5).

Skin reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Dexketoprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Elderly

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). These patients should commence treatment on the lowest dose available.

Elderly are more likely to be suffering from impaired renal cardiovascular or hepatic function (see section 4.2).

Masking of symptoms of underlying infections

Dexketoprofen can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When this medicine is administered for pain relief in relation to infection, monitoring of infection is advised. In non-hospital settings, the patient should consult a doctor if symptoms persist or worsen.

Exceptionally, varicella can be at the origin of serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of dexketoprofen in case of varicella.

Other information:

Particular caution is required in patients with:

- congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)

- dehydration

- directly after major surgery.

Severe acute hypersensitivity reactions (anaphylactic shock, for example) have been observed on very rare occasions. Treatment must be discontinued at the first signs of severe hypersensitivity reactions following intake of dexketoprofen. Depending on the symptoms, any medically required procedures must be initiated by specialist healthcare professionals.

Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to acetylsalicylic acid and/or NSAIDs than the rest of the population. Administration of this medicinal product can cause asthma attacks or bronchospasm, particularly in subjects allergic to acetylsalicylic acid or NSAIDs (see section 4.3).

Dexketoprofen should be administered with caution to patients suffering from haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue disease.

Paediatric population

The safety and efficacy of Skudexa in children and adolescents have not been established. Therefore Skudexa should not be used in children and adolescents.

Tramadol

Tramadol should be used with particular caution in addicted patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, or increased intracranial pressure.

In patients sensitive to opiates the product should be used with caution.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered (see section 4.5), or if the recommended dosage is significantly exceeded (see section 4.9) as the possibility of respiratory depression cannot be excluded in these situations.

Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg).

In addition tramadol may increase the seizure risk in patients taking other medicinal products that lower the seizure threshold (see section 4.5.). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.

Tolerance and Opioid Use Disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Skudexa. A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Skudexa may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with Skudexa and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Skudexa and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Skudexa concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic agents or tramadol alone (see sections 4.5, 4.8 and 4.9).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations.

Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic drugs usually brings about a rapid improvement.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Adrenal insufficiency

Opioid analgesics may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include e.g. severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss.

CYP2D6 metabolism

Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is a risk of developing of opioid toxicity even at commonly prescribed doses. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

Population

Prevalence %

African/Ethiopian

29%

African American

3.4% to 6.5%

Asian

1.2% to 2%

Caucasian

3.6% to 6.5%

Greek

6.0%

Hungarian

1.9%

Northern European

1% to 2%

Post-operative use in children

There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.

Children with compromised respiratory function

Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.

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

4.5. Interaction with other medicinal products and other forms of interaction

No clinical studies have been performed to evaluate the potential impact of drug-drug interactions on safety profile of Skudexa. However, those reported for dexketoprofen and tramadol as single agents should be taken into account.

Dexketoprofen

The following interactions apply to non-steroidal antiinflammatory drugs (NSAIDs) in general:

Concomitant use not recommended:

• Other NSAIDs (including cyclooxygenase-2 selective inhibitors) including high doses of salicylates (≥ 3 g/day): administration of several NSAIDs together may increase the risk of gastrointestinal ulcers and bleeding, via a synergistic effect.

• Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin, due to the high plasma protein binding of dexketoprofen and the inhibition of platelet function and damage to the gastroduodenal mucosa. If the combination cannot be avoided, close clinical observation and monitoring of laboratory values should be carried out.

• Heparins: increased risk of haemorrhage (due to the inhibition of platelet function and damage to the gastroduodenal mucosa). If the combination cannot be avoided, close clinical observation and monitoring of laboratory values should be carried out.

• Corticosteroids: there is an increased risk of gastrointestinal ulceration or bleeding.

• Lithium (described with several NSAIDs): NSAIDs increase blood lithium levels, which may reach toxic values (decreased renal excretion of lithium). This parameter therefore requires monitoring during the initiation, adjustment and withdrawal of treatment with dexketoprofen.

• Methotrexate, used at high doses of 15 mg/week or more: increased haematological toxicity of methotrexate via a decrease in its renal clearance by antiinflammatory agents in general.

• Hydantoines (including phenytoin) and sulphonamides: the toxic effects of these substances may be increased.

Combinations requiring precautions:

• Diuretics, Angiotensin-converting-enzyme (ACE) inhibitors, antibacterial aminoglycosides and angiotensin II receptor antagonists: dexketoprofen may reduce the effect of diuretics and antihypertensive drugs. In some patients with compromised renal function (e. g. dehydrated patients or elderly patients with compromised renal function), the coadministration of agents that inhibit cyclo-oxygenase and ACE inhibitors, angiotensin II receptor antagonists or antibacterial aminoglycosides may result in further deterioration of renal function, which is usually reversible. In case of combined prescription of dexketoprofen and a diuretic, it is essential to ensure that the patient is adequately hydrated and to monitor renal function at the start of the treatment and periodically thereafter. Co-administration of dexketoprofen and potassium-sparing diuretics can lead to hyperkalaemia. Monitoring of blood potassium concentrations is required (see section 4.4).

• Methotrexate, used at low doses, less than 15 mg/week: increased haematological toxicity of methotrexate via a decrease in its renal clearance by antiinflammatory agents in general. Weekly monitoring of blood count during the first weeks of the combination. Increased surveillance in the presence of even mildly impaired renal function, as well as in the elderly.

• Pentoxyfilline: increased risk of bleeding. Increase clinical monitoring and check bleeding time more often.

• Zidovudine: risk of increased red cell line toxicity via action on reticulocytes, with severe anaemia occurring one week after the NSAID is started. Check complete blood count and reticulocyte count one to two weeks after starting treatment with the NSAID.

• Sulfonylureas: NSAIDs can increase the hypoglycaemic effect of sulfonylureas by displacement from plasma protein binding sites.

Combinations needing to be taken into account:

• Beta-blockers: treatment with a NSAID may decrease their antihypertensive effect via inhibition of prostaglandin synthesis.

• Cyclosporin and tacrolimus: nephrotoxicity may be enhanced by NSAIDs via renal prostaglandin mediated effects. During combination therapy, renal function has to be measured.

• Thrombolytics: increased risk of bleeding.

• Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

• Probenecid: plasma concentrations of dexketoprofen may be increased; this interaction can be due to an inhibitory mechanism at the site of renal tubular secretion and of glucuronoconjugation and requires adjustment of the dose of dexketoprofen.

• Cardiac glycosides: NSAIDS may increase plasma glycoside concentration.

• Mifepristone: because of a theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of mifepristone, NSAIDS should not be used for 8-12 days after mifepristone administration.

Limited evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

• Quinolone antibiotics: animal data indicate that high doses of quinolones in combination with NSAIDS can increase the risk of developing convulsions.

• Tenofovir: concomitant use with NSAID can increase plasma urea nitrogen and creatinine, renal function should be monitored in order to control a potential synergic influence on renal function.

• Deferasirox: concomitant use with NSAIDs can increase the risk of gastrointestinal toxicity. Close clinical monitoring is required when deferasirox is combined with these substances.

• Pemetrexed: concomitant use with NSAIDs may decrease pemetrexed elimination, therefore caution should be made when administering higher doses of NSAIDs. In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), the concomitant administration of pemetrexed with NSAIDs doses should be avoided for 2 days before and 2 days following pemetrexed administration.

Tramadol

Concomitant use not recommended:

• Tramadol should not be combined with Monoamine Oxidase (MAO) inhibitors (see section 4.3). In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with tramadol.

• Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of elevated International Normalized Ratio (INR) with major bleeding and ecchymoses in some patients.

• The combination of mixed agonists/antagonists opioid receptors (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.

Combinations requiring precautions:

• Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal product (such as bupropion, mirtazapine, tethrahydrocannabinol) to cause convulsions.

• Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin syndrome, a potentially life-threatening condition (see sections 4.4 and 4.8).

• The concomitant use of opioids with sedative medicines such as gabapentinoids (gabapentin and pregabalin), benzodiazepines or related drugs may result in respiratory depression, hypotension, profound sedation, coma or death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Combinations needing to be taken into account:

• Concomitant administration of tramadol with other centrally depressant medicinal products or alcohol may potentiate the central nervous system effects (see section 4.8).

• The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur.

• Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

• In a limited number of studies the pre- or postoperative administration of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

• Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.

4.6. Fertility, pregnancy and lactation

Pregnancy

No cases of pregnancy occurred during the Skudexa clinical development. The safety profile of Skudexa during pregnancy has not been established in the clinical studies included in this section. Data reported for dexketoprofen and tramadol as single agents should be taken into account.

Dexketoprofen

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. Nevertheless, animal studies with dexketoprofen haven't shown reproductive toxicity (see section 5.3). From the 20th week of pregnancy onward, dexketoprofen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

• renal dysfunction (see above) ;

At the end of pregnancy, the mother and the neonate may be exposed to:

• possible prolongation of bleeding time, an anti-platelet effect which may occur even at very low doses;

• inhibition of uterine contractions resulting in delayed or prolonged labour.

Tramadol

Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Teratogenic effects were not observed. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy.

Tramadol – administered before or during birth – does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.

Considering the above Skudexa is contraindicated in pregnancy (see section 4.3).

Breastfeeding

No controlled trials have been conducted to study the excretion of Skudexa in human milk. Data reported for dexketoprofen and tramadol as single agents should be taken into account.

Dexketoprofen

It is not known whether dexketoprofen is excreted in human milk.

Tramadol

Tramadol and its metabolites are found in small amounts in human breast milk.

Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason tramadol should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.Considering the above Skudexa is contraindicated during breastfeeding (see section 4.3).

Fertility

As with other NSAIDs, the use of dexketoprofen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of dexketoprofen should be considered.

4.7. Effects on ability to drive and use machines

The effects known for the single components of Skudexa apply to the fixed combination.

Dexketoprofen

Dexketoprofen has minor or moderate influence on the ability to drive and use machines, due to possible occurrence of dizziness or somnolence.

Tramadol

Even when taken according to instructions, tramadol may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators.

This applies particularly in conjunction with other psychotropic substances and alcohol.

4.8. Undesirable effects

The adverse events at least possibly related reported in the clinical trials performed with Skudexa and the adverse reactions reported in dexketoprofen and tramadol oral formulations SmPCs are tabulated below, classified by system organ class.

The frequencies are defined as follows:

Very common: ≥ 1/10

Common: ≥ 1/100 to <1/10

Uncommon: ≥1/1000 to <1/100

Rare: ≥ 1/10 000 to <1/1000

Very rare (< 1/10,000)

Not known: cannot be estimated from the available data

MedDRA SYSTEM ORGAN CLASS

Adverse Reaction

Frequency

Skudexa

Dexketoprofen

Tramadol

Blood and lymphatic system disorders

Thrombocytosis

Uncommon

Neutropenia

-

Very rare

-

Thrombocytopenia

-

Very rare

-

Immune system disorders

Hypersensitivity (e.g. dyspnoea, bronchospasm, wheezing, Angioedema)

-

Very rare

Rare

Anaphylactic reaction, including anaphylactic shock

-

Very rare

Rare

Laryngeal oedema

Uncommon

Rare

-

Metabolism and nutrition disorders

Appetite disorder

Rare

Decreased appetite

-

Rare

-

Hypoglycaemia

not known

Hypokalaemia

Uncommon

Psychiatric disorders

Anxiety

Uncommon

Rare

Cognitive disorder

Rare

Confusional state

Rare

Dependence

Rare

Hallucination

Rare

Insomnia

Uncommon

Mood altered

Rare

Nightmare

Rare

Psychotic disorder

Uncommon

Sleep disorder

Rare

Nervous system disorders

Coordination abnormal

Rare

Amnesia

Uncommon

Dizziness

Common

Uncommon

Very common

Epilepsy

Rare

Headache

Uncommon

Uncommon

Common

Muscle contractions involuntary

Rare

Paraesthesia

Rare

Rare

Sensory disturbance

Rare

Serotonin syndrome

Not known

Somnolence

Common

Uncommon

Common

Speech disorder

Not known

Syncope

Rare

Rare

Tremor

Rare

Eye disorders

Blurred vision

Very rare

Rare

Mydriasis

Not known

Miosis

Rare

Periorbital oedema

Uncommon

Ear and labyrinth disorders

Tinnitus

Very rare

Vertigo

Uncommon

Uncommon

Cardiac disorders

Bradycardia

Rare

Palpitations

Uncommon

Uncommon

Kounis syndrome

Not known

Tachycardia

Uncommon

Very rare

Uncommon

Vascular disorders

Circulatory collapse

Uncommon

Flushing

Uncommon

Hypertensive crisis

Uncommon

Hypotension

Uncommon

Very rare

Orthostatic hypotension

Uncommon

Respiratory, thoracic and mediastinal disorders

Bradypnoea,

Rare

Bronchospasm

Very rare

Dyspnoea

Very rare

Rare

Respiratory depression

Uncommon

Hiccups

Not known

Gastrointestinal disorders

Abdominal discomfort

Uncommon

Uncommon

Abdominal distension

Uncommon

Uncommon

Abdominal pain

Common

Constipation

Uncommon

Uncommon

Common

Diarrhoea

Common

Uncommon

Dry mouth

Uncommon

Common

Dyspepsia

Uncommon

Common

Flatulence

Uncommon

Gastritis

Uncommon

Gastrointestinal tract irritation

Uncommon

Nausea

Common

Common

Very common

Pancreatitis

Very rare

Peptic ulcer haemorrhage

Rare

Peptic ulcer perforation

Rare

Peptic ulcer,

Rare

Retching

Uncommon

Vomiting

Common

Common

Common

Hepatobiliary disorders

Hepatitis

Rare

Hepatocellular injury

Rare

Hepatic enzyme increased including Liver function test abnormal and Gamma-glutamyl transferase increased)

Uncommon

Rare

Very rare

Skin and subcutaneous tissue disorders

Acne

Rare

Face oedema

Uncommon

Very rare

Hyperhidrosis

Uncommon

Rare

Common

Photosensitivity reaction

Very rare

Pruritus

Very rare

Uncommon

Rash

Uncommon

Uncommon

Stevens Johnson syndrome

Very rare

Toxic epidermal necrolysis (Lyell's syndrome)

Very rare

Urticaria

Uncommon

Rare

Uncommon

Fixed drug eruption

Not known

Musculoskeletal and connective tissue disorders

Back pain

Rare

Weakness

Rare

Renal and urinary disorders

Dysuria

Rare

Haematuria

Uncommon

Micturition disorder

Rare

Nephritis

Very rare

Nephrotic syndrome

Very rare

Polyuria

Rare

Renal failure acute

Rare

Urinary retention

Rare

Reproductive system and breast disorders

Menstrual disorder

Rare

Prostatic disorder

Rare

General disorders and administration site conditions

Asthenia

Uncommon

Uncommon

Chills

Uncommon

Uncommon

Discomfort

Uncommon

Feeling abnormal

Uncommon

Drug withdrawal syndrome (agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms: rare; panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus, and unusual CNS symptoms i.e. confusion, delusions, depersonalisation, derealisation, paranoia)

Rare/very rare

Fatigue

Uncommon

Common

Malaise

Uncommon

Uncommon

Oedema peripheral

Rare

Pain

Uncommon

Investigations

Blood pressure increased

Uncommon

Rare

Rare

Blood alkaline phosphatase increased

Uncommon

Blood lactate dehydrogenase increased

Uncommon

Dexketoprofen-tramadol

In clinical studies the most commonly observed adverse reactions were vomiting, nausea and dizziness (2.9%, 2.7% and 1.1% of patients, respectively).

Drug dependence

Repeated use of Skudexa can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

Dexketoprofen

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4 Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed. Oedema, hypertension and cardiac failure have been reported in association with NSAIDs treatment.

As with other NSAIDs the following undesirable effects may appear: aseptic meningitis, which might predominantly occur in patients with systemic lupus erythematosus or mixed connective tissue disease; haematological reactions (purpura, aplastic and haemolytic anaemia, and rarely agranulocytosis and medullar hypoplasia).

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare).

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increase in the risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Tramadol

The most commonly reported adverse reactions due to tramadol are nausea and dizziness, both occurring in more than 10% of patients.

If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5) respiratory depression may occur.

Worsening of asthma has been reported, though a causal relationship has not been established.

Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with drugs, which can lower the seizure threshold or themselves induce cerebral convulsions (see section 4.4 and section 4.5).

Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows; agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Other symptoms that have very rarely been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus, and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation, paranoia).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No cases of overdose have been reported in the clinical studies. Data reported for dexketoprofen and tramadol as single agents should be taken into account.

Symptoms

Dexketoprofen

The symptomatology following overdose due to dexketoprofen is not known.

Medicinal products containing dexketoprofen have produced gastrointestinal (vomiting, anorexia, abdominal pain) and neurological (somnolence, vertigo, disorientation, headache) disorders.

Tramadol

In tramadol overdose, in principle, the same symptoms occur as for all other central acting analgesics (opioids). In particular, these include miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest. Serotonin syndrome has also been reported.

Management

Dexketoprofen

In case of accidental or excessive intake, immediately initiate symptomatic therapy according to the patient's clinical condition.

If more than 5 mg/kg has been ingested by an adult or a child, activated charcoal should be administered within the first hour after ingestion. Dexketoprofen may be removed by dialysis.

Tramadol

Keep the respiratory tract open (and avoid aspiration), maintain respiration and circulation depending on the symptoms. The antidote for respiratory depression is naloxone. In animal experiments naloxone had no effect on convulsions. In such case diazepam should be given intravenously.

In case of orally intoxication, gastrointestinal decontamination with activated charcoal is recommended within two hours after tramadol intake.

Tramadol may be removed by dialysis, but it is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.