- Approval Id
- ca4d422ccf0d0dbe
- Drug Approval Emc Name
- Tapentadol Mylan 250 mg prolonged-release tablets
- Drug Name
- Tapentadol Mylan 250 mg prolonged-release tablets
- Company Address
- Building 4, Trident Place, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL
- Company Website
- http://www.mylan.com
- Company Telephone
- +44 (0)1707 853 000
- Company Medical Info Direct Line
- +44 (0)1707 853 000
- Company Medical Info Email
- info@mylan.co.uk
- Company Customer Care Direct Line
- +44 (0)1707 853 000 select option 2
- Company Medical Info Fax
- +44 (0)1707 261 803
- Company Stock Availability
- +44 (0)1707 853 000 select option 2
- Atc Code
- N02AX06
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
UK
- Authorisation Number
- PL 04569/1845
- Authorisation Date
- 24/08/2023
- Instruction Authorisation Holder
- Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
UK
- Instruction Authorisation Number
- PL 04569/1845
- Instruction Authorisation Date
- 24/08/2023
- Instruction Composition
- \*\*Tapentadol Mylan 250 mg prolonged-release tablets\*\*
Each prolonged-release tablet contains 382.848 mg tapentadol phosphate equivalent to 250 mg tapentadol.
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Prolonged-release tablet.
\*\*Tapentadol Mylan 250 mg\*\*
Reddish brown, oblong, biconvex prolonged-release tablets (9 mm x 18 mm) with score lines on both sides.
The score line is not intended for breaking the tablet.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Tapentadol Mylan is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics.
Further in the SmPC 'Tapentadol Mylan' is also stated as 'This medicine'.4.2 Posology and method of administration
\*\*Posology\*\*
The dosing regimen should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient.
This medicine should be taken twice daily, approximately every 12 hours.
\*\*\*Initiation of therapy\*\*\*
\*Initiation of therapy in patients currently not taking opioid analgesics\*
Patients should start treatment with single doses of 50 mg Tapentadol Mylan administered twice daily.
\*Initiation of therapy in patients currently taking opioid analgesics\*
When switching from opioids to Tapentadol Mylan and choosing the initial dose, the nature of the previous medicinal product, administration and the mean daily dose should be taken into account. This may require higher initial doses of Tapentadol Mylan for patients currently taking opioids compared to those not having taken opioids before initiating therapy with Tapentadol Mylan.
\*\*\*Titration and maintenance\*\*\*
After initiation of therapy the dose should be titrated individually to a level that provides adequate analgesia and minimises undesirable effects under the close supervision of the prescribing physician.
Experience from clinical trials has shown that a titration regimen in increments of 50 mg prolonged-release tapentadol twice daily every 3 days was appropriate to achieve adequate pain control in most of the patients.
Total daily doses of more than 500 mg prolonged-release tapentadol have not yet been studied and are therefore not recommended.
\*\*\*Discontinuation of treatment\*\*\*
Withdrawal symptoms could occur after abrupt discontinuation of treatment with tapentadol (see section 4.8). When a patient no longer requires therapy with tapentadol, it is advisable to taper the dose gradually to prevent symptoms of withdrawal.
\*\*Special populations\*\*
\*Renal impairment\*
In patients with mild or moderate renal impairment a dose adjustment is not required (see section 5.2).
Prolonged-release tapentadol has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see sections 4.4 and 5.2).
\*Hepatic impairment\*
In patients with mild hepatic impairment a dose adjustment is not required (see section 5.2).
This medicine should be used with caution in patients with moderate hepatic impairment. Treatment in these patients should be initiated at the lowest available dose strength, i.e. Tapentadol Mylan <25 mg><50 mg> and not be administered more frequently than once every 24 hours. At initiation of therapy a daily dose greater than 50 mg prolonged-release tapentadol is not recommended. Further treatment should reflect maintenance of analgesia with acceptable tolerability (see sections 4.4 and 5.2).
Prolonged-release tapentadol has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.4 and 5.2).
\*Elderly patients (≥65 years)\*
In general, a dose adaptation in elderly patients is not required. However, as elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection as recommended (see sections 4.2 and 5.2).
\*Paediatric population\*
The safety and efficacy of this medicine in children and adolescents below 18 years of age has not yet been established. Therefore this medicine is not recommended for use in this population.
\*\*Method of administration\*\*
This medicine is for oral use.
Tapentadol Mylan has to be taken whole, not divided, crushed or chewed, to ensure that the prolonged-release mechanism is maintained. This medicine should be taken with sufficient liquid.
This medicine can be taken with or without food.
The shell (matrix) of the tablet may not be digested completely and therefore it can be eliminated and seen in the patient's stool. However, this finding has no clinical relevance, since the active substance of the tablet will have already been absorbed.4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Situations where active substances with mu-opioid receptor agonist activity are contraindicated, i.e. patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercapnia
• Any patient who has or is suspected of having paralytic ileus
• Patients with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic active substances (see section 4.5).4.4 Special warnings and precautions for use
\*Do not use for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI).\*
\*Tolerance and Opioid Use Disorder (abuse and dependence)\*
Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids. Abuse or intentional misuse of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).
Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.
\*Risk from concomitant use of sedating medicinal products such as benzodiazepines or related substances\*
Concomitant use of this medicine and sedating medicinal products such as benzodiazepines or related substances may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe this medicine concomitantly with sedating medicinal products, the reduction of dose of one or both medicinal products should be considered and the duration of the concomitant 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).
\*Respiratory depression\*
At high doses or in mu-opioid receptor agonist sensitive patients, this medicine may produce dose-related respiratory depression. Therefore, this medicine' should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and this medicine should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid receptor agonist-induced respiratory depression (see section 4.9).
\*Head injury and increased intracranial pressure\*
This medicine should not be used in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Analgesics with mu-opioid receptor agonist activity may obscure the clinical course of patients with head injury. This medicine should be used with caution in patients with head injury and brain tumours.
\*Seizures\*
Prolonged-release tapentadol has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical trials. However, like other analgesics with mu-opioid receptor agonist activity of this medicine is not recommended in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures. In addition, tapentadol may increase the seizure risk in patients taking other medicinal products that lower the seizure threshold (see section 4.5).
\*Renal impairment\*
Prolonged-release tapentadol has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see sections 4.2 and 5.2).
\*Hepatic impairment\*
Subjects with mild and moderate hepatic impairment showed a 2-fold and 4.5-fold increase in systemic exposure, respectively, compared with subjects with normal hepatic function. This medicineshould be used with caution in patients with moderate hepatic impairment (see sections 4.2 and 5.2), especially upon initiation of treatment.
Prolonged-release tapentadol has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.2 and 5.2).
\*Use in pancreatic/biliary tract disease\*
Active substances with mu-opioid receptor agonist activity may cause spasm of the sphincter of Oddi. This medicineshould be used with caution in patients with biliary tract disease, including acute pancreatitis.
\*Sleep-related breathing disorders\*
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxaemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dose.
\*Mixed opioid agonists/antagonists\*
Care should be taken when combining this medicine with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine). In patients maintained on buprenorphine for the treatment of opioid dependence, alternative treatment options (like e.g. temporary buprenorphine discontinuation) should be considered, if administration of full mu-agonists (like tapentadol) becomes necessary in acute pain situations. On combined use with buprenorphine, higher dose requirements for full mu-receptor agonists have been reported and close monitoring of adverse events such as respiratory depression is required in such circumstances.
\*Drug withdrawal syndrome\*
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with tapentadol phosphate.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction.
When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
\*Hyperalgesia\*
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.4.5 Interaction with other medicinal products and other forms of interaction
\*Centrally-acting medicinal products/central nervous system (CNS) depressants, including alcohol and CNS depressant narcotic drugs\*
The concomitant use of this medicine with sedating medicinal products such as benzodiazepines or other respiratory or CNS depressants (other opioids, antitussives or substitution treatments, barbiturates, antipsychotics, H1-antihistamines, alcohol) increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Therefore, when a combined therapy of this medicine with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both medicinal products should be considered and the duration of the concomitant use should be limited (see section 4.4). The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.
\*Mixed opioid agonists/antagonists\*
Care should be taken when combining this medicine with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine) (see also section 4.4).
This medicine can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other medicinal products that lower the seizure threshold to cause convulsions.
There have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs), serotonin- norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants.
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 serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.
The major elimination pathway for tapentadol is conjugation with glucuronic acid mediated via uridine diphosphate transferase (UGT) mainly UGT1A6, UGT1A9 and UGT2B7 isoforms. Thus, concomitant administration with strong inhibitors of these isoenzymes (e.g. ketoconazole, fluconazole, meclofenamic acid) may lead to increased systemic exposure of tapentadol (see section 5.2).
For patients on tapentadol treatment, caution should be exercised if concomitant administration of strong enzyme inducing substances (e.g. rifampicin, phenobarbital, St John's Wort (\*Hypericum perforatum\*)) starts or stops, since this may lead to decreased efficacy or risk for adverse effects, respectively.
Treatment with this medicineshould be avoided in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on synaptic noradrenaline concentrations which may result in adverse cardiovascular events, such as hypertensive crisis.4.6 Fertility, pregnancy and lactation
\*Pregnancy\*
There is very limited amount of data from the use in pregnant women.
Studies in animals have not shown teratogenic effects. However, delayed development and embryotoxicity were observed at doses resulting in exaggerated pharmacology (mu-opioid-related CNS effects related to dosing above the therapeutic range). Effects on the postnatal development were already observed at the maternal NOAEL (see section 5.3).
This medicine should not be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome can be life-threatening if not recognised and treated.
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
\*Labour and delivery\*
The effect of tapentadol on labour and delivery in humans is unknown. This medicine is not recommended for use in women during and immediately before labour and delivery. Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available. Due to the mu-opioid receptor agonist activity of tapentadol, new-born infants whose mothers have been taking tapentadol should be monitored for respiratory depression.
\*Breastfeeding\*
There is no information on the excretion of tapentadol in human milk. Administration to nursing women is not recommended as tapentadol phosphate may be secreted in breast milk and may cause respiratory depression in the infant. From a study in rat pups suckled by dams dosed with tapentadol it was concluded that tapentadol is excreted in milk (see section 5.3). Therefore, a risk to the suckling child cannot be excluded. This medicine should not be used during breastfeeding.
\*Fertility\*
No human data on the effect of this medicine on fertility are available. In a fertility and early embryonic development study, no effects on reproductive parameters were observed in male or female rats (see section 5.3).4.7 Effects on ability to drive and use machines
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called 'statutory defence') if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
o It was not affecting your ability to drive safely.
This medicine may have major influence on the ability to drive and use machines, because it may adversely affect central nervous system functions (see section 4.8). This has to be expected especially at the beginning of treatment, when any change of dose occurs as well as in connection with the use of alcohol or tranquilisers (see section 4.4). Patients should be cautioned as to whether driving or use of machines is permitted.4.8 Undesirable effects
The adverse drug reactions that were experienced by patients in the placebo-controlled trials performed with tapentadol prolonged-release were predominantly of mild and moderate severity. The most frequent adverse drug reactions were in the gastrointestinal and central nervous system (nausea, dizziness, constipation, headache and somnolence).
The table below lists adverse drug reactions that were identified from clinical trials performed with tapentadol prolonged-release and from post-marketing environment. They are listed by class and frequency. Frequencies are defined as 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).
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*ADVERSE DRUG REACTIONS\*\* | | | | | |
| \*\*System Organ Class\*\* | \*\*Frequency\*\* | | | | |
| \*\*Very common\*\* | \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* | \*\*Not known\*\* |
| \*\*Immune system disorders\*\* | | | Drug hypersensitivity\\* | | |
| \*\*Metabolism and nutrition disorders\*\* | | Decreased appetite | Weight decreased | | |
| \*\*Psychiatric disorders\*\* | | Anxiety, Depressed mood, Sleep disorder, Nervousness, Restlessness | Disorientation, Confusional state, Agitation, Perception disturbances, Abnormal dreams, Euphoric mood | Drug dependence, Thinking abnormal | Delirium\\*\\* |
| \*\*Nervous system disorders\*\* | Dizziness, Somnolence, Headache | Disturbance in attention, Tremor, Muscle contractions involuntary | Depressed level of consciousness, Memory impairment, Mental impairment, Syncope, Sedation, Balance disorder, Dysarthria, Hypoaesthesia, Paraesthesia | Convulsion, Presyncope, Coordination abnormal | |
| \*\*Eye disorders\*\* | | | Visual disturbance | | |
| \*\*Cardiac disorders\*\* | | | Heart rate increased, Heart rate decreased, Palpitations | | |
| \*\*Vascular disorders\*\* | | Flushing | Blood pressure decreased | | |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | | Dyspnoea | | Respiratory depression | |
| \*\*Gastrointestinal disorders\*\* | Nausea, Constipation | Vomiting, Diarrhoea, Dyspepsia | Abdominal discomfort | Impaired gastric emptying | |
| \*\*Skin and subcutaneous tissue disorders\*\* | | Pruritus, Hyperhidrosis, Rash | Urticaria | | |
| \*\*Renal and urinary disorders\*\* | | | Urinary hesitation, Pollakiuria | | |
| \*\*Reproductive system and breast disorders\*\* | | | Sexual dysfunction | | |
| \*\*General disorders and administration site conditions\*\* | | Asthenia, Fatigue, Feeling of body temperature change, Mucosal dryness, Oedema | Drug withdrawal syndrome, Feeling abnormal, Irritability | Feeling drunk, Feeling of relaxation | |
| \*\\* Post-marketing rare events of angioedema, anaphylaxis and anaphylactic shock have been reported.\* | | | | | |
| \*\\*\\* Post-marketing cases of delirium were observed in patients with additional risk factors such as cancer and advanced age.\* | | | | | |
Clinical trials performed with tapentadol prolonged-release with patient exposure up to 1 year have shown little evidence of withdrawal symptoms upon abrupt discontinuations and these were generally classified as mild, when they occurred. Nevertheless, physicians should be vigilant for symptoms of withdrawal (see section 4.2) and treat patients accordingly should they occur.
The risk of suicidal ideation and suicides committed is known to be higher in patients suffering from chronic pain. In addition, substances with a pronounced influence on the monoaminergic system have been associated with an increased risk of suicidality in patients suffering from depression, especially at the beginning of treatment. For tapentadol data from clinical trials and post-marketing reports do not provide evidence for an increased risk.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
\*Symptoms\*
Human experience with overdose of tapentadol is very limited. Preclinical data suggest that symptoms similar to those of other centrally acting analgesics with mu-opioid receptor agonist activity are to be expected upon intoxication with tapentadol. In principle, these symptoms include, referring to the clinical setting, in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.
\*Management\*
Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of tapentadol is suspected.
Pure opioid receptor antagonists such as naloxone are specific antidotes to respiratory depression resulting from opioid overdose. Respiratory depression following an overdose may outlast the duration of action of the opioid receptor antagonist. Administration of an opioid receptor antagonist is not a substitute for continuous monitoring of airway, breathing, and circulation following an opioid overdose. If the response to opioid receptor antagonists is suboptimal or only brief in nature, an additional dose of antagonist (e.g. naloxone) should be administered as directed by the manufacturer of the medicinal product.
Gastrointestinal decontamination may be considered in order to eliminate unabsorbed active substance. Gastrointestinal decontamination with activated charcoal or by gastric lavage may be considered within 2 hours after intake. Before attempting gastrointestinal decontamination, care should be taken to secure the airway.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics; opioids; other opioids, ATC code: N02AX06.
Tapentadol is a strong analgesic with µ-agonistic opioid and additional noradrenaline reuptake inhibition properties. Tapentadol exerts its analgesic effects directly without a pharmacologically active metabolite.
Tapentadol demonstrated efficacy in preclinical models of nociceptive, neuropathic, visceral and inflammatory pain; efficacy has been verified in clinical trials with tapentadol prolonged-release formulations in non-malignant nociceptive and neuropathic chronic pain conditions as well as chronic tumour-related pain. The trials in pain due to osteoarthritis and chronic low back pain showed similar analgesic efficacy of tapentadol to a strong opioid used as a comparator. In the trial in painful diabetic peripheral neuropathy tapentadol separated from placebo which was used as comparator.
\*Effects on the cardiovascular system\*
In a thorough human QT trial, no effect of multiple therapeutic and supratherapeutic doses of tapentadol on the QT interval was shown. Similarly, tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).
\*Post-marketing data\*
Two post-marketing studies were performed to address the practical use of tapentadol.
The efficacy of a tapentadol prolonged-release formulation has been verified in a multicentre, randomised, double blind parallel-group trial with patients suffering from low back pain with a neuropathic component (KF5503/58). Reductions in average pain intensity were similar in the tapentadol treatment group and the comparator treatment group i.e. receiving a combination of a tapentadol prolonged-release formulation and pregabalin immediate-release tablets.
In an open-label, multicentre, randomised trial with patients having severe chronic low back pain with a neuropathic component (KF5503/60), a tapentadol prolonged-release formulation was associated with significant reductions in average pain intensity.
\*Paediatric population\*
The European Medicines Agency has deferred the obligation to submit the results of studies with the reference medicinal product containing tapentadol in all subsets of the paediatric population in severe chronic pain (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties
\*Absorption\*
Mean absolute bioavailability after single-dose administration (fasting) of tapentadol prolonged-release tablets is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are observed at between 3 and 6 hours after administration of prolonged-release tablets.
Dose proportional increases for AUC have been observed after administration of the prolonged-release tablets over the therapeutic dose range.
A multiple dose trial with twice daily dosing using 86 mg and 172 mg tapentadol administered as prolonged-release tablets showed an accumulation ratio of about 1.5 for the parent active substance which is primarily determined by the dosing interval and apparent half-life of tapentadol. Steady state serum concentrations of tapentadol are reached on the second day of the treatment regimen.
\*Food effect\*
The AUC and Cmax increased by 8% and 18%, respectively, when prolonged-release tablets were administered after a high-fat, high-calorie breakfast. This was judged to be without clinical relevance as it falls into the normal inter-subject variability of tapentadol PK parameters. This medicinemay be given with or without food.
\*Distribution\*
Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 l. The serum protein binding is low and amounts to approximately 20 %.
\*Biotransformation\*
In humans, the metabolism of tapentadol is extensive. About 97 % of the parent compound is metabolised. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70 % of the dose is excreted in urine as conjugated forms (55 % glucuronide and 15 % sulfate of tapentadol). Uridine diphosphate glucuronyl transferase (UGT) is the primary enzyme involved in the glucuronidation (mainly UGT1A6, UGT1A9 and UGT2B7 isoforms). A total of 3 % of active substance is excreted in urine as unchanged active substance. Tapentadol is additionally metabolised to N-desmethyl tapentadol (13 %) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2 %) by CYP2D6, which are further metabolised by conjugation. Therefore, active substance metabolism mediated by cytochrome P450 system is of less importance than glucuronidation.
None of the metabolites contributes to the analgesic activity.
\*Elimination\*
Tapentadol and its metabolites are excreted almost exclusively (99 %) via the kidneys. The total clearance after intravenous administration is 1530 +/- 177 ml/min. Terminal half-life is on average 5-6 hours after oral administration.
\*\*\*Special populations\*\*\*
\*Elderly patients\*
The mean exposure (AUC) to tapentadol was similar in a trial with elderly subjects (65-78 years of age) compared to young adults (19-43 years of age), with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.
\*Renal impairment\*
AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O- glucuronide are 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.
\*Hepatic impairment\*
Administration of tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild and moderate hepatic impairment groups in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.
\*\*\*Pharmacokinetic interactions\*\*\*
Tapentadol is mainly metabolised by glucuronidation, and only a small amount is metabolised by oxidative pathways.
As glucuronidation is a high capacity/low affinity system, which is not easily saturated even in disease, and as therapeutic concentrations of active substances are generally well below the concentrations needed for potential inhibition of glucuronidation, any clinically relevant interactions caused by glucuronidation are unlikely to occur. In a set of drug-drug interaction trials using paracetamol, naproxen, acetylsalicylic acid and probenecid, a possible influence of these active substances on the glucuronidation of tapentadol was investigated. The trials with probe active substances naproxen (500 mg twice daily for 2 days) and probenecid (500 mg twice daily for 2 days) showed increases in AUC of tapentadol by 17 % and 57 %, respectively. Overall, no clinically relevant effects on the serum concentrations of tapentadol were observed in these trials.
Furthermore, interaction trials of tapentadol with metoclopramide and omeprazole were conducted to investigate a possible influence of these active substances on the absorption of tapentadol. These trials also showed no clinically relevant effects on tapentadol serum concentrations.
\*In vitro\* studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.
Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic interactions by displacement from the protein binding site is low.5.3 Preclinical safety data
Tapentadol was not genotoxic in bacteria in the Ames test. Equivocal findings were observed in an \*in vitro\* chromosomal aberration test, but when the test was repeated the results were clearly negative. Tapentadol was not genotoxic \*in vivo\*, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. Long-term animal studies did not identify a potential carcinogenic risk relevant to humans.
Tapentadol had no influence on male or female fertility in rats but there was reduced \*in utero\* survival at the high dose. It is not known whether this was mediated via the male or the female. Tapentadol showed no teratogenic effects in rats and rabbits following intravenous and subcutaneous exposure. However, delayed development and embryotoxicity were observed after administration of doses resulting in exaggerated pharmacology (mu-opioid related CNS effects related to dosing above the therapeutic range). After intravenous dosing in rats reduced in utero survival was seen. In rats tapentadol caused increased mortality of the F1 pups that were directly exposed via milk between days 1 and 4 postpartum already at doses that did not provoke maternal toxicities. There were no effects on neurobehavioral parameters.
Excretion into breast milk was investigated in rat pups suckled by dams dosed with tapentadol. Pups were dose-dependently exposed to tapentadol and tapentadol O-glucuronide. It was concluded that tapentadol is excreted in milk.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
\*\*Tablet core\*\*
Microcrystalline cellulose (E460)
Hypromellose (E464)
Silica, colloidal anhydrous (E551)
Magnesium stearate
\*\*Tablet coating\*\*
Hypromellose (E464)
Glycerol (E422)
Talc (E553b)
Microcrystalline cellulose (E460)
Titanium dioxide (E171)
Red iron oxide (E172)
Black iron oxide (E172)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Child resistant aluminium PVC/PE/PVDC perforated unit dose blisters.
\*\*Tapentadol Mylan 250 mg prolonged tablets\*\*
20x1, 24x1, 28x1, 30x1, 40x1, 50x1, 54x1, 56x1, 60x1 or 100x1
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
\*\*Tapentadol Mylan 250 mg prolonged-release tablets\*\*
Each prolonged-release tablet contains 382.848 mg tapentadol phosphate equivalent to 250 mg tapentadol.
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Prolonged-release tablet.
\*\*Tapentadol Mylan 250 mg\*\*
Reddish brown, oblong, biconvex prolonged-release tablets (9 mm x 18 mm) with score lines on both sides.
The score line is not intended for breaking the tablet.
## Clinical Particulars
4.1 Therapeutic indications
Tapentadol Mylan is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics.
Further in the SmPC 'Tapentadol Mylan' is also stated as 'This medicine'.4.2 Posology and method of administration
\*\*Posology\*\*
The dosing regimen should be individualised according to the severity of pain being treated, the previous treatment experience and the ability to monitor the patient.
This medicine should be taken twice daily, approximately every 12 hours.
\*\*\*Initiation of therapy\*\*\*
\*Initiation of therapy in patients currently not taking opioid analgesics\*
Patients should start treatment with single doses of 50 mg Tapentadol Mylan administered twice daily.
\*Initiation of therapy in patients currently taking opioid analgesics\*
When switching from opioids to Tapentadol Mylan and choosing the initial dose, the nature of the previous medicinal product, administration and the mean daily dose should be taken into account. This may require higher initial doses of Tapentadol Mylan for patients currently taking opioids compared to those not having taken opioids before initiating therapy with Tapentadol Mylan.
\*\*\*Titration and maintenance\*\*\*
After initiation of therapy the dose should be titrated individually to a level that provides adequate analgesia and minimises undesirable effects under the close supervision of the prescribing physician.
Experience from clinical trials has shown that a titration regimen in increments of 50 mg prolonged-release tapentadol twice daily every 3 days was appropriate to achieve adequate pain control in most of the patients.
Total daily doses of more than 500 mg prolonged-release tapentadol have not yet been studied and are therefore not recommended.
\*\*\*Discontinuation of treatment\*\*\*
Withdrawal symptoms could occur after abrupt discontinuation of treatment with tapentadol (see section 4.8). When a patient no longer requires therapy with tapentadol, it is advisable to taper the dose gradually to prevent symptoms of withdrawal.
\*\*Special populations\*\*
\*Renal impairment\*
In patients with mild or moderate renal impairment a dose adjustment is not required (see section 5.2).
Prolonged-release tapentadol has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see sections 4.4 and 5.2).
\*Hepatic impairment\*
In patients with mild hepatic impairment a dose adjustment is not required (see section 5.2).
This medicine should be used with caution in patients with moderate hepatic impairment. Treatment in these patients should be initiated at the lowest available dose strength, i.e. Tapentadol Mylan <25 mg><50 mg> and not be administered more frequently than once every 24 hours. At initiation of therapy a daily dose greater than 50 mg prolonged-release tapentadol is not recommended. Further treatment should reflect maintenance of analgesia with acceptable tolerability (see sections 4.4 and 5.2).
Prolonged-release tapentadol has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.4 and 5.2).
\*Elderly patients (≥65 years)\*
In general, a dose adaptation in elderly patients is not required. However, as elderly patients are more likely to have decreased renal and hepatic function, care should be taken in dose selection as recommended (see sections 4.2 and 5.2).
\*Paediatric population\*
The safety and efficacy of this medicine in children and adolescents below 18 years of age has not yet been established. Therefore this medicine is not recommended for use in this population.
\*\*Method of administration\*\*
This medicine is for oral use.
Tapentadol Mylan has to be taken whole, not divided, crushed or chewed, to ensure that the prolonged-release mechanism is maintained. This medicine should be taken with sufficient liquid.
This medicine can be taken with or without food.
The shell (matrix) of the tablet may not be digested completely and therefore it can be eliminated and seen in the patient's stool. However, this finding has no clinical relevance, since the active substance of the tablet will have already been absorbed.4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Situations where active substances with mu-opioid receptor agonist activity are contraindicated, i.e. patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment), and patients with acute or severe bronchial asthma or hypercapnia
• Any patient who has or is suspected of having paralytic ileus
• Patients with acute intoxication with alcohol, hypnotics, centrally acting analgesics, or psychotropic active substances (see section 4.5).4.4 Special warnings and precautions for use
\*Do not use for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI).\*
\*Tolerance and Opioid Use Disorder (abuse and dependence)\*
Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids. Abuse or intentional misuse of opioids may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).
Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.
\*Risk from concomitant use of sedating medicinal products such as benzodiazepines or related substances\*
Concomitant use of this medicine and sedating medicinal products such as benzodiazepines or related substances may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe this medicine concomitantly with sedating medicinal products, the reduction of dose of one or both medicinal products should be considered and the duration of the concomitant 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).
\*Respiratory depression\*
At high doses or in mu-opioid receptor agonist sensitive patients, this medicine may produce dose-related respiratory depression. Therefore, this medicine' should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and this medicine should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid receptor agonist-induced respiratory depression (see section 4.9).
\*Head injury and increased intracranial pressure\*
This medicine should not be used in patients who may be particularly susceptible to the intracranial effects of carbon dioxide retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Analgesics with mu-opioid receptor agonist activity may obscure the clinical course of patients with head injury. This medicine should be used with caution in patients with head injury and brain tumours.
\*Seizures\*
Prolonged-release tapentadol has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical trials. However, like other analgesics with mu-opioid receptor agonist activity of this medicine is not recommended in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures. In addition, tapentadol may increase the seizure risk in patients taking other medicinal products that lower the seizure threshold (see section 4.5).
\*Renal impairment\*
Prolonged-release tapentadol has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see sections 4.2 and 5.2).
\*Hepatic impairment\*
Subjects with mild and moderate hepatic impairment showed a 2-fold and 4.5-fold increase in systemic exposure, respectively, compared with subjects with normal hepatic function. This medicineshould be used with caution in patients with moderate hepatic impairment (see sections 4.2 and 5.2), especially upon initiation of treatment.
Prolonged-release tapentadol has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended (see sections 4.2 and 5.2).
\*Use in pancreatic/biliary tract disease\*
Active substances with mu-opioid receptor agonist activity may cause spasm of the sphincter of Oddi. This medicineshould be used with caution in patients with biliary tract disease, including acute pancreatitis.
\*Sleep-related breathing disorders\*
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxaemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dose.
\*Mixed opioid agonists/antagonists\*
Care should be taken when combining this medicine with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine). In patients maintained on buprenorphine for the treatment of opioid dependence, alternative treatment options (like e.g. temporary buprenorphine discontinuation) should be considered, if administration of full mu-agonists (like tapentadol) becomes necessary in acute pain situations. On combined use with buprenorphine, higher dose requirements for full mu-receptor agonists have been reported and close monitoring of adverse events such as respiratory depression is required in such circumstances.
\*Drug withdrawal syndrome\*
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with tapentadol phosphate.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction.
When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
\*Hyperalgesia\*
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.4.5 Interaction with other medicinal products and other forms of interaction
\*Centrally-acting medicinal products/central nervous system (CNS) depressants, including alcohol and CNS depressant narcotic drugs\*
The concomitant use of this medicine with sedating medicinal products such as benzodiazepines or other respiratory or CNS depressants (other opioids, antitussives or substitution treatments, barbiturates, antipsychotics, H1-antihistamines, alcohol) increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Therefore, when a combined therapy of this medicine with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both medicinal products should be considered and the duration of the concomitant use should be limited (see section 4.4). The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.
\*Mixed opioid agonists/antagonists\*
Care should be taken when combining this medicine with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine) (see also section 4.4).
This medicine can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other medicinal products that lower the seizure threshold to cause convulsions.
There have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs), serotonin- norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants.
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 serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.
The major elimination pathway for tapentadol is conjugation with glucuronic acid mediated via uridine diphosphate transferase (UGT) mainly UGT1A6, UGT1A9 and UGT2B7 isoforms. Thus, concomitant administration with strong inhibitors of these isoenzymes (e.g. ketoconazole, fluconazole, meclofenamic acid) may lead to increased systemic exposure of tapentadol (see section 5.2).
For patients on tapentadol treatment, caution should be exercised if concomitant administration of strong enzyme inducing substances (e.g. rifampicin, phenobarbital, St John's Wort (\*Hypericum perforatum\*)) starts or stops, since this may lead to decreased efficacy or risk for adverse effects, respectively.
Treatment with this medicineshould be avoided in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on synaptic noradrenaline concentrations which may result in adverse cardiovascular events, such as hypertensive crisis.4.6 Fertility, pregnancy and lactation
\*Pregnancy\*
There is very limited amount of data from the use in pregnant women.
Studies in animals have not shown teratogenic effects. However, delayed development and embryotoxicity were observed at doses resulting in exaggerated pharmacology (mu-opioid-related CNS effects related to dosing above the therapeutic range). Effects on the postnatal development were already observed at the maternal NOAEL (see section 5.3).
This medicine should not be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome can be life-threatening if not recognised and treated.
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
\*Labour and delivery\*
The effect of tapentadol on labour and delivery in humans is unknown. This medicine is not recommended for use in women during and immediately before labour and delivery. Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available. Due to the mu-opioid receptor agonist activity of tapentadol, new-born infants whose mothers have been taking tapentadol should be monitored for respiratory depression.
\*Breastfeeding\*
There is no information on the excretion of tapentadol in human milk. Administration to nursing women is not recommended as tapentadol phosphate may be secreted in breast milk and may cause respiratory depression in the infant. From a study in rat pups suckled by dams dosed with tapentadol it was concluded that tapentadol is excreted in milk (see section 5.3). Therefore, a risk to the suckling child cannot be excluded. This medicine should not be used during breastfeeding.
\*Fertility\*
No human data on the effect of this medicine on fertility are available. In a fertility and early embryonic development study, no effects on reproductive parameters were observed in male or female rats (see section 5.3).4.7 Effects on ability to drive and use machines
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called 'statutory defence') if:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
o It was not affecting your ability to drive safely.
This medicine may have major influence on the ability to drive and use machines, because it may adversely affect central nervous system functions (see section 4.8). This has to be expected especially at the beginning of treatment, when any change of dose occurs as well as in connection with the use of alcohol or tranquilisers (see section 4.4). Patients should be cautioned as to whether driving or use of machines is permitted.4.8 Undesirable effects
The adverse drug reactions that were experienced by patients in the placebo-controlled trials performed with tapentadol prolonged-release were predominantly of mild and moderate severity. The most frequent adverse drug reactions were in the gastrointestinal and central nervous system (nausea, dizziness, constipation, headache and somnolence).
The table below lists adverse drug reactions that were identified from clinical trials performed with tapentadol prolonged-release and from post-marketing environment. They are listed by class and frequency. Frequencies are defined as 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).
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*ADVERSE DRUG REACTIONS\*\* | | | | | |
| \*\*System Organ Class\*\* | \*\*Frequency\*\* | | | | |
| \*\*Very common\*\* | \*\*Common\*\* | \*\*Uncommon\*\* | \*\*Rare\*\* | \*\*Not known\*\* |
| \*\*Immune system disorders\*\* | | | Drug hypersensitivity\\* | | |
| \*\*Metabolism and nutrition disorders\*\* | | Decreased appetite | Weight decreased | | |
| \*\*Psychiatric disorders\*\* | | Anxiety, Depressed mood, Sleep disorder, Nervousness, Restlessness | Disorientation, Confusional state, Agitation, Perception disturbances, Abnormal dreams, Euphoric mood | Drug dependence, Thinking abnormal | Delirium\\*\\* |
| \*\*Nervous system disorders\*\* | Dizziness, Somnolence, Headache | Disturbance in attention, Tremor, Muscle contractions involuntary | Depressed level of consciousness, Memory impairment, Mental impairment, Syncope, Sedation, Balance disorder, Dysarthria, Hypoaesthesia, Paraesthesia | Convulsion, Presyncope, Coordination abnormal | |
| \*\*Eye disorders\*\* | | | Visual disturbance | | |
| \*\*Cardiac disorders\*\* | | | Heart rate increased, Heart rate decreased, Palpitations | | |
| \*\*Vascular disorders\*\* | | Flushing | Blood pressure decreased | | |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | | Dyspnoea | | Respiratory depression | |
| \*\*Gastrointestinal disorders\*\* | Nausea, Constipation | Vomiting, Diarrhoea, Dyspepsia | Abdominal discomfort | Impaired gastric emptying | |
| \*\*Skin and subcutaneous tissue disorders\*\* | | Pruritus, Hyperhidrosis, Rash | Urticaria | | |
| \*\*Renal and urinary disorders\*\* | | | Urinary hesitation, Pollakiuria | | |
| \*\*Reproductive system and breast disorders\*\* | | | Sexual dysfunction | | |
| \*\*General disorders and administration site conditions\*\* | | Asthenia, Fatigue, Feeling of body temperature change, Mucosal dryness, Oedema | Drug withdrawal syndrome, Feeling abnormal, Irritability | Feeling drunk, Feeling of relaxation | |
| \*\\* Post-marketing rare events of angioedema, anaphylaxis and anaphylactic shock have been reported.\* | | | | | |
| \*\\*\\* Post-marketing cases of delirium were observed in patients with additional risk factors such as cancer and advanced age.\* | | | | | |
Clinical trials performed with tapentadol prolonged-release with patient exposure up to 1 year have shown little evidence of withdrawal symptoms upon abrupt discontinuations and these were generally classified as mild, when they occurred. Nevertheless, physicians should be vigilant for symptoms of withdrawal (see section 4.2) and treat patients accordingly should they occur.
The risk of suicidal ideation and suicides committed is known to be higher in patients suffering from chronic pain. In addition, substances with a pronounced influence on the monoaminergic system have been associated with an increased risk of suicidality in patients suffering from depression, especially at the beginning of treatment. For tapentadol data from clinical trials and post-marketing reports do not provide evidence for an increased risk.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
\*Symptoms\*
Human experience with overdose of tapentadol is very limited. Preclinical data suggest that symptoms similar to those of other centrally acting analgesics with mu-opioid receptor agonist activity are to be expected upon intoxication with tapentadol. In principle, these symptoms include, referring to the clinical setting, in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.
\*Management\*
Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of tapentadol is suspected.
Pure opioid receptor antagonists such as naloxone are specific antidotes to respiratory depression resulting from opioid overdose. Respiratory depression following an overdose may outlast the duration of action of the opioid receptor antagonist. Administration of an opioid receptor antagonist is not a substitute for continuous monitoring of airway, breathing, and circulation following an opioid overdose. If the response to opioid receptor antagonists is suboptimal or only brief in nature, an additional dose of antagonist (e.g. naloxone) should be administered as directed by the manufacturer of the medicinal product.
Gastrointestinal decontamination may be considered in order to eliminate unabsorbed active substance. Gastrointestinal decontamination with activated charcoal or by gastric lavage may be considered within 2 hours after intake. Before attempting gastrointestinal decontamination, care should be taken to secure the airway.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics; opioids; other opioids, ATC code: N02AX06.
Tapentadol is a strong analgesic with µ-agonistic opioid and additional noradrenaline reuptake inhibition properties. Tapentadol exerts its analgesic effects directly without a pharmacologically active metabolite.
Tapentadol demonstrated efficacy in preclinical models of nociceptive, neuropathic, visceral and inflammatory pain; efficacy has been verified in clinical trials with tapentadol prolonged-release formulations in non-malignant nociceptive and neuropathic chronic pain conditions as well as chronic tumour-related pain. The trials in pain due to osteoarthritis and chronic low back pain showed similar analgesic efficacy of tapentadol to a strong opioid used as a comparator. In the trial in painful diabetic peripheral neuropathy tapentadol separated from placebo which was used as comparator.
\*Effects on the cardiovascular system\*
In a thorough human QT trial, no effect of multiple therapeutic and supratherapeutic doses of tapentadol on the QT interval was shown. Similarly, tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).
\*Post-marketing data\*
Two post-marketing studies were performed to address the practical use of tapentadol.
The efficacy of a tapentadol prolonged-release formulation has been verified in a multicentre, randomised, double blind parallel-group trial with patients suffering from low back pain with a neuropathic component (KF5503/58). Reductions in average pain intensity were similar in the tapentadol treatment group and the comparator treatment group i.e. receiving a combination of a tapentadol prolonged-release formulation and pregabalin immediate-release tablets.
In an open-label, multicentre, randomised trial with patients having severe chronic low back pain with a neuropathic component (KF5503/60), a tapentadol prolonged-release formulation was associated with significant reductions in average pain intensity.
\*Paediatric population\*
The European Medicines Agency has deferred the obligation to submit the results of studies with the reference medicinal product containing tapentadol in all subsets of the paediatric population in severe chronic pain (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic properties
\*Absorption\*
Mean absolute bioavailability after single-dose administration (fasting) of tapentadol prolonged-release tablets is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are observed at between 3 and 6 hours after administration of prolonged-release tablets.
Dose proportional increases for AUC have been observed after administration of the prolonged-release tablets over the therapeutic dose range.
A multiple dose trial with twice daily dosing using 86 mg and 172 mg tapentadol administered as prolonged-release tablets showed an accumulation ratio of about 1.5 for the parent active substance which is primarily determined by the dosing interval and apparent half-life of tapentadol. Steady state serum concentrations of tapentadol are reached on the second day of the treatment regimen.
\*Food effect\*
The AUC and Cmax increased by 8% and 18%, respectively, when prolonged-release tablets were administered after a high-fat, high-calorie breakfast. This was judged to be without clinical relevance as it falls into the normal inter-subject variability of tapentadol PK parameters. This medicinemay be given with or without food.
\*Distribution\*
Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 l. The serum protein binding is low and amounts to approximately 20 %.
\*Biotransformation\*
In humans, the metabolism of tapentadol is extensive. About 97 % of the parent compound is metabolised. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70 % of the dose is excreted in urine as conjugated forms (55 % glucuronide and 15 % sulfate of tapentadol). Uridine diphosphate glucuronyl transferase (UGT) is the primary enzyme involved in the glucuronidation (mainly UGT1A6, UGT1A9 and UGT2B7 isoforms). A total of 3 % of active substance is excreted in urine as unchanged active substance. Tapentadol is additionally metabolised to N-desmethyl tapentadol (13 %) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2 %) by CYP2D6, which are further metabolised by conjugation. Therefore, active substance metabolism mediated by cytochrome P450 system is of less importance than glucuronidation.
None of the metabolites contributes to the analgesic activity.
\*Elimination\*
Tapentadol and its metabolites are excreted almost exclusively (99 %) via the kidneys. The total clearance after intravenous administration is 1530 +/- 177 ml/min. Terminal half-life is on average 5-6 hours after oral administration.
\*\*\*Special populations\*\*\*
\*Elderly patients\*
The mean exposure (AUC) to tapentadol was similar in a trial with elderly subjects (65-78 years of age) compared to young adults (19-43 years of age), with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.
\*Renal impairment\*
AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O- glucuronide are 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.
\*Hepatic impairment\*
Administration of tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild and moderate hepatic impairment groups in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.
\*\*\*Pharmacokinetic interactions\*\*\*
Tapentadol is mainly metabolised by glucuronidation, and only a small amount is metabolised by oxidative pathways.
As glucuronidation is a high capacity/low affinity system, which is not easily saturated even in disease, and as therapeutic concentrations of active substances are generally well below the concentrations needed for potential inhibition of glucuronidation, any clinically relevant interactions caused by glucuronidation are unlikely to occur. In a set of drug-drug interaction trials using paracetamol, naproxen, acetylsalicylic acid and probenecid, a possible influence of these active substances on the glucuronidation of tapentadol was investigated. The trials with probe active substances naproxen (500 mg twice daily for 2 days) and probenecid (500 mg twice daily for 2 days) showed increases in AUC of tapentadol by 17 % and 57 %, respectively. Overall, no clinically relevant effects on the serum concentrations of tapentadol were observed in these trials.
Furthermore, interaction trials of tapentadol with metoclopramide and omeprazole were conducted to investigate a possible influence of these active substances on the absorption of tapentadol. These trials also showed no clinically relevant effects on tapentadol serum concentrations.
\*In vitro\* studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.
Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic interactions by displacement from the protein binding site is low.5.3 Preclinical safety data
Tapentadol was not genotoxic in bacteria in the Ames test. Equivocal findings were observed in an \*in vitro\* chromosomal aberration test, but when the test was repeated the results were clearly negative. Tapentadol was not genotoxic \*in vivo\*, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. Long-term animal studies did not identify a potential carcinogenic risk relevant to humans.
Tapentadol had no influence on male or female fertility in rats but there was reduced \*in utero\* survival at the high dose. It is not known whether this was mediated via the male or the female. Tapentadol showed no teratogenic effects in rats and rabbits following intravenous and subcutaneous exposure. However, delayed development and embryotoxicity were observed after administration of doses resulting in exaggerated pharmacology (mu-opioid related CNS effects related to dosing above the therapeutic range). After intravenous dosing in rats reduced in utero survival was seen. In rats tapentadol caused increased mortality of the F1 pups that were directly exposed via milk between days 1 and 4 postpartum already at doses that did not provoke maternal toxicities. There were no effects on neurobehavioral parameters.
Excretion into breast milk was investigated in rat pups suckled by dams dosed with tapentadol. Pups were dose-dependently exposed to tapentadol and tapentadol O-glucuronide. It was concluded that tapentadol is excreted in milk.
## Pharmaceutical Particulars
6.1 List of excipients
\*\*Tablet core\*\*
Microcrystalline cellulose (E460)
Hypromellose (E464)
Silica, colloidal anhydrous (E551)
Magnesium stearate
\*\*Tablet coating\*\*
Hypromellose (E464)
Glycerol (E422)
Talc (E553b)
Microcrystalline cellulose (E460)
Titanium dioxide (E171)
Red iron oxide (E172)
Black iron oxide (E172)6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Child resistant aluminium PVC/PE/PVDC perforated unit dose blisters.
\*\*Tapentadol Mylan 250 mg prolonged tablets\*\*
20x1, 24x1, 28x1, 30x1, 40x1, 50x1, 54x1, 56x1, 60x1 or 100x1
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Company Detail Path
- /organization/mylan-laboratories-limited
