Dexketoprofen Trometamol

Registered South African indications:

• Symptomatic short-term treatment of pain of mild to moderate intensity, such as musculoskeletal pain, dysmenorrhoea, dental pain

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to any other nonsteroidal anti-inflammatory drug (NSAID)
• 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
• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment (creatinine clearance ≤59ml/min)
• Severely impaired hepatic function (Child-Pugh score 10-15)
• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates
• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy
• Active peptic ulcer/gastrointestinal haemorrhage or any history of gastrointestinal bleeding, ulceration or perforation
• Chronic dyspepsia
• Patients who have other active bleedings or bleeding disorders
• Crohn’s disease or ulcerative colitis
• Severe heart failure
• Haemorrhagic diathesis and other coagulation disorders
• Severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake)
• Congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)

South African recommendations

Caution in the following patient groups

• Mild renal impairment
• Mild to moderate hepatic impairment
• Elderly
• History of allergic conditions
• Dehydration
• Directly after a major surgery
• Haematopoietic disorders
• Systemic lupus erythematosus
• Mixed connective tissue disease

Concomitant nonsteroidal anti-inflammatory drug (NSAID) use

• Avoid concurrent use with other NSAIDs, including COX-2 inhibitors

Dosing and duration

• Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms

Gastrointestinal safety

• Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been reported with NSAIDs such as dexketoprofen trometamol 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gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen trometamol , the treatment should be withdrawn
• 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, 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 dexketoprofen
• Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding
• Dexketoprofen trometamol, should be given with care to patients with a history of gastrointestinal disease as their condition may be exacerbated
• Combination therapy with protective medicines (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 medicines likely to increase gastrointestinal risk
• 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 medicines which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet medicines such as acetylsalicylic acid
• The elderly has an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal
• These patients should commence treatment on the lowest dose available

Renal safety

• Severe hypokalaemia and renal tubular acidosis have been reported due to prolonged use of NSAIDS at higher than recommended doses
• 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
• In patients with renal impairment, dexketoprofen trometamol 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
• Dexketoprofen trometamol can increase plasma urea nitrogen and creatinine. 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
• Elderly patients are more likely to be suffering from impaired renal function
• Dexketoprofen trometamol is contraindicated in patients with moderate to severe renal dysfunction (creatinine clearance ≤59ml/min), see Contraindications

Hepatic safety

• Use with caution as dexketoprofen may cause significant increases in liver enzymes (serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT)), requiring discontinuation if levels remain elevated
• Elderly patients are more likely to be suffering from impaired hepatic function
• Dexketoprofen trometamol is contraindicated in patients with severely impaired hepatic function (Child-Pugh score 10-15), see Contraindications

Cardiovascular and cerebrovascular disease

• Appropriate monitoring and advice are required for patients with history of hypertension and/or mild to moderate heart failure
• 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, since fluid retention and oedema have been reported in association with NSAIDs therapy
• 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 increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for dexketoprofen
• Consequently, patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should not receive dexketoprofen trometamol
• Elderly patients are more likely to be suffering from impaired cardiovascular function

Haemostasis and coagulation

• Dexketoprofen trometamol can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Therefore, its use in patients who are receiving other therapy that interferes with haemostasis, such as warfarin or other coumarins or heparins is not recommended

Severe skin reactions

• Risk of fatal exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, typically occurring within the first month of treatment
• Dexketoprofen trometamol should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity

Hypersensitivity and respiratory conditions

• Severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed. Treatment must be discontinued at the first signs of severe hypersensitivity reactions following intake of dexketoprofen trometamol
• Depending on the symptoms, any medically required procedures must be initiated by specialist health care providers. 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 dexketoprofen trometamol can cause asthma attacks or bronchospasm, particularly in subjects allergic to acetylsalicylic acid or NSAIDs

Infections and varicella

• 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 trometamol in case of varicella
• Dexketoprofen trometamol can mask the symptoms of infectious diseases

Paediatric population

• The safe use in children and adolescents has not been established

Effects on ability to drive and use machines

• Dexketoprofen trometamol may cause undesirable effects such as dizziness, visual disturbances or drowsiness. The ability to react and the ability to take part actively in road traffic and to operate machines may be impaired in these cases

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Symptomatic short-term treatment of pain of mild to moderate intensity, such as musculoskeletal pain, dysmenorrhoea, dental pain

• Oral (fct): According to the nature and severity of pain; Recommended dosage: 12.5mg, every 4-6hrs OR 25mg, every 8hrs; Max: 75mg/24hrs; Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms

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Dexketoprofen trometamol are not intended for long term use and the treatment must be limited to the symptomatic period

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Method of administration: The tablet 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 medicine thus in case of acute pain it is recommended that administration is at least 30 minutes before meals

Not established for use in children and adolescents

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Dexketoprofen trometamol has not been studied in children and adolescents. Therefore, the safety and efficacy in children and adolescents have not been established and dexketoprofen trometamol should not be used in children and adolescents

Pregnancy

South African recommendations

• Contraindicated
• Dexketoprofen trometamol is contraindicated during third trimester of pregnancy
• 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
• During pregnancy, dexketoprofen trometamol should not be given. During the third trimester of pregnancy, dexketoprofen trometamol may expose the foetus to:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction, which may progress to renal failure with oligohydramnios;
• the mother and the neonate, at the end of pregnancy, to:
  • possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
  • inhibition of uterine contractions resulting in delayed or prolonged labour

Breastfeeding

South African recommendations

• Contraindicated
• It is not known whether dexketoprofen is excreted in human milk. Dexketoprofen trometamol is contraindicated during breastfeeding

Fertility

South African recommendations

• The use of dexketoprofen trometamol may impair female fertility and is not recommended in women attempting to conceive

South African recommendations

• Mild (CrCl 60-89ml/min): Caution; dose adjustment recommended
  The initial dosage should be reduced to 50mg total daily dose in patients with mildly impaired renal function
• Moderate to severe (CrCl≤59ml/min): Contraindicated
  Dexketoprofen trometamol should not be used in patients with moderate to severe renal dysfunction

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  Patients with mild to moderate hepatic dysfunction should start therapy at reduced doses (50mg total daily dose) and be closely monitored
• Severe: Contraindicated

South African recommendations

• Caution; dose adjustment recommended
  In elderly patients it is recommended to start the therapy at the lower end of the dosage range (50mg total daily dose)
  The dosage may be increased to that recommended for the general population only after good general tolerance has been ascertained

Blood And Lymphatic System Disorders

Very rare

• Neutropenia
• Thrombocytopenia

Immune System Disorders

Rare

• Laryngeal oedema

Very rare

• Anaphylactic reaction, including anaphylactic shock

Metabolism And Nutrition Disorders

Rare

• Anorexia

Not known

• Hypokalaemia (typically following prolonged use at higher than recommended doses)

Psychiatric Disorders

Uncommon

• Insomnia
• Anxiety

Nervous System Disorders

Uncommon

• Headache
• Dizziness
• Somnolence

Rare

• Paraesthesia
• Syncope

Eye Disorders

Rare

• Blurred vision

Ear And Labyrinth Disorders

Uncommon

• Vertigo

Rare

• Tinnitus

Cardiac Disorders

Uncommon

• Palpitations

Rare

• Tachycardia

Vascular Disorders

Uncommon

• Flushing

Rare

• Hypertension

Very rare

• Hypotension

Respiratory, Thoracic And Mediastinal Disorders

Rare

• Bradypnoea

Very rare

• Bronchospasm
• Dyspnoea

Gastrointestinal Disorders

Common

• Nausea and/or vomiting
• Abdominal pain
• Diarrhoea
• Dyspepsia

Uncommon

• Gastritis
• Constipation
• Dry mouth
• Flatulence

Rare

• Peptic ulcer
• Peptic ulcer haemorrhage or peptic ulcer perforation

Very rare

• Pancreatitis

Hepatobiliary Disorders

Rare

• Hepatocellular injury

Skin And Subcutaneous Tissue Disorders

Uncommon

• Rash

Rare

• Urticaria
• Acne
• Sweating increase

Very rare

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis (Lyell’s syndrome)
• Angioedema
• Facial oedema
• Photosensitivity reaction
• Pruritus

Musculoskeletal And Connective Tissue Disorders

Rare

• Back pain

Renal And Urinary Disorders

Rare

• Acute renal failure
• Polyuria

Very rare

• Nephritis or nephrotic syndrome

Not known

• Renal tubular acidosis (typically following prolonged use at higher than recommended doses)

Reproductive System And Breast Disorders

Rare

• Menstrual disorder
• Prostatic disorder

General Disorders And Administration Site Conditions

Uncommon

• Fatigue
• Pain
• Asthenia
• Rigors
• Malaise

Rare

• Peripheral oedema

Investigations

Rare

• Abnormal liver function test

• Other nonsteroidal anti-inflammatory drugs (NSAIDs)
• Cyclooxygenase-2 selective inhibitors
• High doses of salicylates (≥3 g/day)
• Anticoagulants
• Warfarin
• Heparins
• Corticosteroids
• Lithium
• Methotrexate
• Hydantoins
• Sulphonamides
• Diuretics
• ACE inhibitors
• Antibacterial aminoglycosides
• Angiotensin II receptor antagonists
• Pentoxifylline
• Zidovudine
• Sulfonylureas
• Beta-blockers
• Ciclosporin
• Tacrolimus
• Thrombolytics
• Antiplatelet medicines
• Selective serotonin reuptake inhibitors (SSRIs)
• Probenecid
• Cardiac glycosides
• Mifepristone
• Quinolone antibiotics
• Tenofovir
• Deferasirox
• Pemetrexed

Specific cases may require

• Renal function
• Hepatic impairment
• Blood pressure
• Cardiac function
• Laboratory levels (for warfarin and heparins, when coadministered)
• Lithium levels (when coadministered)
• Full blood count (when coadministered with methotrexate)

Additional observations

• Digestive disturbances, especially gastrointestinal bleeding
• Bleeding time (when coadministered with pentoxifylline)
• Skin reactions

Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3-benzoylphenyl) propionic acid, an analgesic, anti-inflammatory and antipyretic medicine, which belongs to the nonsteroidal antiinflammatory group of medicines. Dexketoprofen has been demonstrated to be an inhibitor for COX-1 and COX-2 activities in experimental animals and humans. Clinical studies performed on several pain models demonstrated effective analgesic activity of dexketoprofen. The onset of the analgesic activity was obtained in some studies at 30 minutes post-administration. The analgesic effect persists for 4 to 6 hours.