LENIZAK Film-coated tablet Ref.[51186] Active ingredients: Dexketoprofen Tramadol

The special warnings and precautions reported for dexketoprofen and tramadol as single medicines, apply to the use of LENIZAK.

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 LENIZAK 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 LENIZAK, 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 LENIZAK. Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding.

LENIZAK should not be given to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s 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 LENIZAK. 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 (see section 4.5).

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 LENIZAK may result in deterioration of renal function, fluid retention and oedema. The risk of nephrotoxicity is increased in pateints on diuretic therapy and patients with hypovolaemia. Adequate fluid intake should be ensured during treatment to prevent dehydration/hypovolaemia.

LENIZAK 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.

LENIZAK 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 LENIZAK. 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. LENIZAK 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 LENIZAK 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 LENIZAK after careful consideration.

LENIZAK can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Therefore, the use of LENIZAK 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 LENIZAK (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy. LENIZAK 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 LENIZAK 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).

Other information

Particular caution is required in patients with:

• congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)
• dehydration/hypovolaemia
• directly after major surgery.

Severe acute hypersensitivity reactions (anaphylactic shock, for example) have been observed. Treatment must be discontinued and appropriate therapy initiated at the first signs of severe hypersensitivity reactions following intake of LENIZAK.

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 LENIZAK can cause asthma attacks or bronchospasm, particularly in subjects allergic to acetylsalicylic acid or NSAIDs (see section 4.3).

Varicella can cause serious cutaneous and soft tissues infectious complications. A contributing role of NSAIDs, such as contained in LENIZAK in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of LENIZAK in case of varicella.

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

LENIZAK can mask the symptoms of infectious diseases. Aggravation of sof tissue infections have been described in temporal connection with the use of NSAIDs, such as contained in LENIZAK.

Paediatric population

The safety and efficacy of LENIZAK in children and adolescents <18 years of age have not been established. Therefore LENIZAK should not be used in children and adolescents <18 years of age.

Tramadol related special warnings and precautions

Due to the tramadol component, LENIZAK 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 LENIZAK should be used with caution.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant medicines are being administered (see section 4.5), or if the recommended dosage is 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 medicines that lower the seizure threshold (see section 4.5). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances (see section 4.3).

Tolerance, psychic and physical addiction may develop with the use of LENIZAK. In patients with a tendency to drug abuse or dependence, treatment with LENIZAK should only be carried out for short periods under strict medical supervision. LENIZAK has a maximum treatment duration of 5 days.

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

Concomitant use of LENIZAK and sedative medicines such as benzodiazepines or related medicines 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 LENIZAK 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).

CYP2D6 metabolism

Tramadol as contained in LENIZAK, 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. 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 fatal.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

Use in children

There have been reports in the published literature that tramadol given post-operatively to children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, or in any child with compromised respiratory function from any cause, led to life threatening adverse events.

LENIZAK is not for use in children or adolescents under 18 years of age (see sections 4.1 and 4.2).

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

No clinical studies have been performed to evaluate the potential impact of interactions on safety profile of LENIZAK. However, those reported for dexketoprofen and tramadol as single medicines apply to the use of LENIZAK.

Dexketoprofen

The following interactions apply to nonsteroidal anti-inflammatory drugs (NSAIDs) such as dexketoprofen in LENIZAK:

Concomitant use not recommended:

• Other NSAIDs (including cyclooxygenase-2 selective inhibitors) and 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 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.
• 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 levels (decreased renal excretion of lithium). Lithium levels should be monitored during the initiation, adjustment and withdrawal of treatment with dexketoprofen as contained in LENIZAK.
• 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 LENIZAK.
• Hydantoines and sulphonamides: The toxic effects of these substances may be increased.

Combinations requiring precautions:

• 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 LENIZAK 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).
• 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 LENIZAK. Frequent monitoring of the full blood count and renal function is indicated especially in elderly patients.
• Pentoxifylline: An increased risk of bleeding. Frequent clinical monitoring and checking of the bleeding time are required.
• Zidovudine: An increased risk of red cell line toxicity via action on reticulocytes, with severe anaemia during treatment with LENIZAK. Check complete blood count and reticulocyte count during treatment with LENIZAK.
• Sulfonylureas: LENIZAK 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 LENIZAK may decrease their antihypertensive effect via inhibition of prostaglandin synthesis.
• Ciclosporin and tacrolimus: Nephrotoxicity may be enhanced by LENIZAK via renal prostaglandin mediated effects. During combination therapy, renal function should be monitored.
• Thrombolytics: Increased risk of bleeding.
• Antiplatelet medicines and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).
• 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 LENIZAK.
• Cardiac glycosides (digoxin): LENIZAK may increase plasma digoxin concentration.
• Mifepristone: Because of a theoretical risk that prostaglandin synthetase inhibitors may alter the efficacy of mifepristone, NSAIDs such as dexketoprofen in LENIZAK should not be used for 8-12 days after mifepristone administration. Limited evidence suggests that coadministration 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 such as contained in LENIZAK can increase the risk of developing convulsions.
• Tenofovir: Concomitant use with LENIZAK, may increase plasma urea and creatinine, renal function should be monitored in order to detect impairment of renal function or deterioration thereof.
• Deferasirox: Concomitant use with LENIZAK can increase the risk of gastrointestinal toxicity. Close clinical monitoring is required when deferasirox is combined with NSAID containing medicines such as LENIZAK.
• Pemetrexed: Concomitant use with NSAIDs such as dexketoprofen may decrease pemetrexed elimination, therefore caution is advised when administering higher doses of LENIZAK. In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min), the concomitant administration of pemetrexed with LENIZAK should be avoided for 2 days before and 2 days following pemetrexed administration.

Tramadol

Concomitant use not recommended:

• Due to the tramadol component LENIZAK 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 opioid receptor agonist/antagonist medicines (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable because the analgesic effect of a pure agonist may theoretically be reduced in such circumstances.

Combinations requiring precautions:

• Tramadol as contained in LENIZAK 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 medicines (such as bupropion and mirtazapine) and including substances such as tetrahydrocannabinol to cause convulsions.
• Concomitant use of tramadol as contained in LENIZAK and serotonergic medicines, 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 toxicity. Serotonin syndrome is likely when one of the following is observed: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, hypertonia and body temperature >38°C and inducible ocular clonus. Withdrawal of the serotonergic medicines usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.
• The concomitant use of opioids with sedative medicines such as benzodiazepines or related medicines increases the risk of sedation, respiratory depression, coma and 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 as contained in LENIZAK with other centrally depressant medicines or alcohol may potentiate the central nervous system effects (see section 4.8).
• The results of pharmacokinetic studies have shown no clinically relevant interactions relating to previous administration or concomitant administration with cimetidine (enzyme inhibitor).
• 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) and probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.

Pregnancy

LENIZAK 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 LENIZAK may expose the fetus to:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios;

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

Tramadol

Animal studies with tramadol as contained in LENIZAK 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

LENIZAK 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 LENIZAK may impair female fertility and is not recommended in women attempting to conceive.

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

Dexketoprofen

Dexketoprofen may cause dizziness and somnolence which impair the patient’s 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 LENIZAK 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 ≥1/10, Common ≥1/100 to <1/10, Uncommon ≥1/1 000 to <1/100, Rare ≥1/10 000 to <1/1 000, Very rare (<1/10 000), Not known cannot be estimated from the available data.

Dexketoprofen-tramadol combination LENIZAK

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 Crohn’s 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 LENIZAK. 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 LENIZAK (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 LENIZAK:

Metabolism and nutrition disorders: 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 LENIZAK:

Gastrointestinal disorders: Increased risk of abdominal pain, including pancreatitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of LENIZAK is important. It allows continued monitoring of the benefit/risk balance of LENIZAK. Health care providers are asked to report any suspected adverse reactions via the 6.04 Adverse Drug Reaction Reporting Form, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.