Skudexa 75 mg FC tablet.

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.

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, with a maximum duration of 5 days. Switching to a single component medicine for 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 patients (u2265 65 years of age)
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 two 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 for adults < 65 years of age 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 dysfunction should not exceed a total daily dose of two 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 total daily dosage should be reduced to two film-coated tablets SKUDEXA in patients with mildly impaired renal function (creatinine clearance 60 u2013 89 mL/min) (see section 4.4). SKUDEXA should not be used in patients with moderate to severe renal impairment (creatinine clearance u2264 59 mL/min) (see section 4.3).
Paediatric population
The safety and efficacy of SKUDEXA in children and adolescents < 18 years of age have not been established. No data are available. Therefore SKUDEXA should not be used in children and adolescents < 18 years of age.
Method of administration
Oral use. SKUDEXA should be swallowed with a sufficient amount of fluid (e.g. one glass of water) at least 30 minutes before a meal as concomitant administration with food delays the absorption rate of SKUDEXA (see section 5.2).

The contraindications reported for dexketoprofen and tramadol as single medicines, are contraindications for the use of SKUDEXA. Dexketoprofen must not be administered in the following cases:
u2022 Hypersensitivity to dexketoprofen, to any other NSAID, or to any of the excipients listed in section 6.1.
u2022 Patients in whom medicines with a similar action (e.g. acetylsalicylic acid, or other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioedema.
u2022 Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates.
u2022 Patients with active peptic ulcer/gastrointestinal haemorrhage or any history of gastrointestinal bleeding, ulceration or perforation.
u2022 Patients with history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
u2022 Patients with chronic dyspepsia.
u2022 Patients who have other active bleedings or bleeding disorders.
u2022 Patients with Crohnu2019s disease or ulcerative colitis.
u2022 Patients with severe heart failure.
u2022 Patients with moderate to severe renal dysfunction (creatinine clearance u2264 59 mL/min).
u2022 Patients with severe hepatic impairment (Child-Pugh score 10 u2013 15).
u2022 Patients with haemorrhagic diathesis and other coagulation disorders.
u2022 Patients with severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake).
Tramadol must not be administered in the following cases:
u2022 Hypersensitivity to tramadol or to any of the excipients listed in section 6.1.
u2022 In acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic medicines.
u2022 In patients receiving MAO inhibitors, or who have taken them within the last 14 days (see section 4.5).
u2022 In patients with epilepsy not adequately controlled by treatment (see section 4.4).
u2022 Severe respiratory depression.
u2022 In patients with a head injury and a decreased level of consciousness. SKUDEXA is contraindicated during pregnancy and lactation (see section 4.6).

The special warnings and precautions reported for dexketoprofen and tramadol as single medicines, apply to the use of SKUDEXA.
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 and cardiovascular risks below).
Gastrointestinal safety
Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been reported with NSAIDs such as contained in SKUDEXA at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding or ulceration occurs in patients receiving SKUDEXA, the treatment should be discontinued. The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in older people. Any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with SKUDEXA. Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding. SKUDEXA should not be given to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohnu2019s disease) (see section 4.3) as their condition may be exacerbated (see section 4.8). Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any abdominal symptoms (especially gastrointestinal bleeding) during treatment with SKUDEXA.
Renal safety
Severe hypokalaemia and renal tubular acidosis have been reported due to prolonged use of NSAIDs at higher than recommended doses (see sections 4.8 and 4.9). Presenting signs and symptoms included reduced level of consciousness and generalised weakness. NSAID-induced renal tubular acidosis should be considered in patients with unexplained hypokalaemia and metabolic acidosis. Caution should be exercised in patients with impairment of renal function. In these patients, the use of SKUDEXA may result in deterioration of renal function, fluid retention and oedema. The risk of nephrotoxicity is increased in patients on diuretic therapy and patients with hypovolaemia. Adequate fluid intake should be ensured during treatment to prevent dehydration/hypovolaemia. SKUDEXA can increase plasma urea and creatinine and is associated with nephrotoxicity which may present as glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute kidney injury (AKI) (acute renal failure). Elderly patients are more likely to be suffering from impaired renal function (see section 4.2).
Liver safety
Caution should be exercised in patients with impairment of hepatic function. SKUDEXA can cause increases in liver function parameters, such as 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). Progressive significant increases in liver function parameters indicate deterioration of liver function, necessitating discontinuation of treatment.
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 such as contained in SKUDEXA. 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 precipitating heart failure. SKUDEXA should not be used in patients with severe cardiac failure (see section 4.3). Clinical trial and epidemiological data suggest that use of NSAIDs such as contained in SKUDEXA may be associated with an increased 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 SKUDEXA after careful consideration. SKUDEXA can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Therefore, the use of SKUDEXA in patients who are receiving other therapy that interferes with haemostasis, such as warfarin, other anticoagulants 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 in association with the use of NSAIDs, such as contained in SKUDEXA (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy. SKUDEXA should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Elderly patients
The elderly has an increased frequency of adverse reactions to NSAIDs, such as contained in SKUDEXA especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). These patients should commence treatment on the lowest dose available. Elderly patients are more likely to be suffering from impaired renal cardiovascular or hepatic function (see section 4.2).

No clinical studies have been performed to evaluate the potential impact of interactions on safety profile of SKUDEXA. However, those reported for dexketoprofen and tramadol as single medicines apply to the use of SKUDEXA.
Dexketoprofen
The following interactions apply to nonsteroidal anti-inflammatory drugs (NSAIDs) such as dexketoprofen in SKUDEXA:
Concomitant use not recommended
u2022 Other NSAIDs (including cyclooxygenase-2 selective inhibitors) and high doses of salicylates (u2265 3 g/day): Administration of several NSAIDs together may increase the risk of gastrointestinal ulcers and bleeding, via a synergistic effect.
u2022 Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4), 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 appropriate laboratory indicators should be carried out.
u2022 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.
u2022 Corticosteroids: There is an increased risk of gastrointestinal ulceration or bleeding.
u2022 Lithium (described with several NSAIDs): NSAIDs increase blood lithium levels, which may reach toxic levels (decreased renal excretion of lithium). Lithium levels should be monitored during the initiation, adjustment and withdrawal of treatment with dexketoprofen as contained in SKUDEXA.
u2022 Methotrexate, used at high doses of 15 mg/week or more: Increased haematological toxicity of methotrexate may occur due to a decrease in its renal clearance by anti-inflammatory medicines such as dexketoprofen contained in SKUDEXA.
u2022 Hydantoines and sulphonamides: The toxic effects of these substances may be increased.
Combinations requiring precautions
u2022 Diuretics, ACE inhibitors, antibacterial aminoglycosides and angiotensin II receptor antagonists: Dexketoprofen may reduce the effect of diuretics and antihypertensive medicines. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the coadministration of medicines 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 SKUDEXA 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 (see section 4.4).
u2022 Methotrexate, used at low doses, less than 15 mg/week: Increased haematological toxicity of methotrexate may occur due to a decrease in its renal clearance by anti-inflammatory medicines, such as dexketoprofen contained in SKUDEXA. Frequent monitoring of the full blood count and renal function is indicated especially in elderly patients.
u2022 Pentoxifylline: An increased risk of bleeding. Frequent clinical monitoring and checking of the bleeding time are required.
u2022 Zidovudine: An increased risk of red cell line toxicity via action on reticulocytes, with severe anaemia during treatment with SKUDEXA. Check complete blood count and reticulocyte count during treatment with SKUDEXA.
Combinations needing to be taken into account
u2022 Beta-blockers: Treatment with SKUDEXA may decrease their antihypertensive effect via inhibition of prostaglandin synthesis.
u2022 Ciclosporin and tacrolimus: Nephrotoxicity may be enhanced by SKUDEXA via renal prostaglandin mediated effects. During combination therapy, renal function should be monitored.
u2022 Thrombolytics: Increased risk of bleeding.
u2022 Antiplatelet medicines and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).
u2022 Probenecid: Plasma concentrations of dexketoprofen may be increased due to an inhibitory mechanism at the site of renal tubular secretion and of glucurono-conjugation. This may require adjustment of the dose of SKUDEXA.
u2022 Cardiac glycosides (digoxin): SKUDEXA may increase plasma digoxin concentration.
u2022 Mifepristone: Because of a theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of mifepristone, NSAIDs such as dexketoprofen in SKUDEXA 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.
u2022 Quinolone antibiotics: Animal data indicate that high doses of quinolones in combination with NSAIDs such as contained in SKUDEXA can increase the risk of developing convulsions.
u2022 Tenofovir: Concomitant use with SKUDEXA, may increase plasma urea and creatinine, renal function should be monitored in order to detect impairment of renal function or deterioration thereof.
u2022 Deferasirox: Concomitant use with SKUDEXA can increase the risk of gastrointestinal toxicity. Close clinical monitoring is required when deferasirox is combined with NSAID containing medicines such as SKUDEXA.
u2022 Pemetrexed: Concomitant use with NSAIDs such as dexketoprofen may decrease pemetrexed elimination, therefore caution is advised when administering higher doses of SKUDEXA. In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min), the concomitant administration of pemetrexed with SKUDEXA should be avoided for 2 days before and 2 days following pemetrexed administration.

Pregnancy
SKUDEXA is contraindicated during pregnancy and lactation (see section 4.3).
Dexketoprofen
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal 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 %. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-fetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the third trimester of pregnancy, prostaglandin synthesis inhibitors such as contained in SKUDEXA may expose the fetus to:
u2022 cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
u2022 renal dysfunction, which may progress to renal failure with oligohydramnios;
At the end of pregnancy, the mother and the neonate may be exposed to:
u2022 possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
u2022 inhibition of uterine contractions resulting in delayed or prolonged labour.
Tramadol
Animal studies with tramadol as contained in SKUDEXA revealed at high doses effects on organ development, ossification and neonatal mortality. Teratogenic effects were not observed. Tramadol crosses the placenta and may induce respiratory depression in the neonate. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.
Breastfeeding
SKUDEXA is contraindicated during breastfeeding (see section 4.3)
Dexketoprofen
It is not known whether dexketoprofen is excreted in human milk.
Tramadol
Tramadol and its metabolites are found in human breast milk. For this reason, tramadol should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol.
Fertility
The use of SKUDEXA may impair female fertility and is not recommended in women attempting to conceive.

The effects known for the single components of SKUDEXA apply to the fixed combination.
Dexketoprofen
Dexketoprofen may cause dizziness and somnolence which impair the patientu2019s ability to drive or to use machines.
Tramadol
Tramadol may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators.

The adverse events reported in the clinical trials performed with SKUDEXA and the adverse reactions reported in dexketoprofen and tramadol oral formulations are tabulated below, classified by system organ class. The frequencies are defined as follows:
Very common: u2265 1/10
Common: u2265 1/100 to < 1/10
Uncommon: u2265 1/1 000 to < 1/100
Rare: u2265 1/10 000 to < 1/1 000
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 Rare involuntary Paraesthesia Rare Rare
Sensory disturbance Rare
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 Uncommon
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 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 e.g. confusion, delusions, depersonalisation, derealisation, paranoia) Rare/very rare
Fatigue Uncommon Common
Malaise Uncommon
Oedema peripheral Rare
Pain Uncommon
Investigations Increased blood pressure Uncommon Rare Rare
Increased blood alkaline phosphatase Uncommon
Increased blood lactate dehydrogenase Uncommon
Dexketoprofen-tramadol combination SKUDEXA In clinical studies the most commonly observed adverse reactions were vomiting, nausea and dizziness (2,9 %, 2,7 % and 1,1 % of patients, respectively).
Dexketoprofen Gastrointestinal: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in elderly patients, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of ulcerative colitis and Crohnu2019s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Oedema, hypertension and cardiac failure have been reported in association with NSAIDs such as contained in SKUDEXA. 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 NSAIDs such as contained in SKUDEXA (particularly at high doses and in long-term treatment) may be associated with an increased 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 exceeded or if 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 have occurred especially after administration of high doses of tramadol or after concomitant treatment with medicines, 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).
Post-marketing experience
The following side effects with frequency not known (cannot be estimated from the available data), have been reported for NSAIDs, as contained in SKUDEXA: Hypokalaemia*. Renal and urinary disorders: Renal tubular acidosis*. * See sections 4.4 and 4.9. Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of NSAIDs at higher than recommended doses.
The following side effects have been reported for opioid containing medicines as contained in SKUDEXA: Gastrointestinal disorders: Increased risk of abdominal pain, including pancreatitis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of SKUDEXA is important. It allows continued monitoring of the benefit/risk balance of SKUDEXA. Health care providers are asked to report any suspected adverse reactions via the 6.04 Adverse Drug Reaction Reporting Form, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Data reported for dexketoprofen and tramadol as single medicines should be taken into account.
Symptoms
Dexketoprofen
In dexketoprofen overdose symptoms included gastrointestinal (vomiting, anorexia, abdominal pain) and neurological (somnolence, vertigo, disorientation, headache) adverse events. Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see sections 4.4 and section 4.8).
Tramadol
In tramadol overdose, symptoms included miosis, vomiting, cardiovascular collapse, consciousness disorders, coma, convulsions, respiratory depression and respiratory arrest.
Management
Dexketoprofen
In case of accidental or excessive intake, immediately initiate symptomatic and supportive therapy according to the patientu2019s 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. When convulsions occur, a benzodiazepine such as 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, haemodialysis or haemofiltration alone is not suitable for detoxification.