Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Menarini International Operations Luxembourg S.A., 1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg
The contraindications reported for dexketoprofen and tramadol as single agents should be taken into account.
Dexketoprofen must not be administered in the following cases:
Tramadol must not be administered in the following cases:
Skudexa is contraindicated during pregnancy and lactation (see section 4.6).
The special warnings and precautions reported for dexketoprofen and tramadol as single agents should be taken into account.
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 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 When gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen, the treatment should be withdrawn.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 antiplatelet agents such as acetylsalicylic acid (see section 4.5).
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.
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.
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).
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).
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.
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).
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.
Particular caution is required in patients with:
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.
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.
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 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, psychic and physical addiction may develop, especially after long-term use. In patients with a tendency to drug abuse or dependence, treatment with tramadol should only be carried out for short periods under strict medical supervision.
When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
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, 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.
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.
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.
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% |
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.
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”.
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.
The following interactions apply to non-steroidal antiinflammatory drugs (NSAIDs) in general:
Concomitant use not recommended:
Combinations requiring precautions:
Combinations needing to be taken into account:
Concomitant use not recommended:
Combinations requiring precautions:
Combinations needing to be taken into account:
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.
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:
At the end of pregnancy, the mother and the neonate may be exposed to:
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).
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.
It is not known whether dexketoprofen is excreted in human milk.
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).
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.
The effects known for the single components of Skudexa apply to the fixed combination.
Dexketoprofen has minor or moderate influence on the ability to drive and use machines, due to possible occurrence of dizziness or somnolence.
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.
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 | ||
| 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 | Uncommon | 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 | ||
| 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 | ||
| 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 | |
| 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 | |||
| Oedema peripheral | Rare | |||
| Pain | Uncommon | |||
| Investigations | Blood pressure increased | Uncommon | Rare | Rare |
| Blood alkaline phosphatase increased | Uncommon | |||
| Blood lactate dehydrogenase increased | Uncommon | |||
In clinical studies the most commonly observed adverse reactions were vomiting, nausea and dizziness (2.9%, 2.7% and 1.1% of patients, respectively).
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).
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 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.
Not applicable.
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