英文药名： Palexia SR（tapentadol hydrochloride prolonged release tablets）

中文药名：他喷他多缓释片

生产厂家：Grünenthal Ltd
药品介绍
盐酸他喷他多是一种新型的双重作用机制的中枢性镇痛药，它既是阿片μ受体(MOR)激动剂，又是去甲肾上腺素(norepinephrine，NE)重吸收抑制剂，其对急性、炎性和慢性神经病理性疼痛均具有良好的镇痛作用。
本品相对于已上市的中枢性镇痛药物具有以下几个特点：
(1)高效作用：研究显示，盐酸他喷他多相比曲马多(Tramadol，INN)具有更加强效的镇痛作用。他喷他多不依赖代谢活化作用, 没有代谢活化产物，它通过两种作用机制实现更加强效的镇痛效用：一种机制是其激活阿片μ受体，抑制疼痛神经信号的传递，从而影响和控制感知疼痛的大脑皮层部位的活动;另一种机制是其抑制去甲肾上腺素重摄取作用，从而提高大脑中的去甲肾上腺素水平而发挥镇痛作用。
(2)不易成瘾和耐受性良好: 本品与其它阿片类镇痛药如吗啡、曲马多等相比，更不易产生镇痛耐受性和依赖性, 不良反应(如恶心、呕吐等)较轻，副作用小。他喷他多通过两种互补的作用机制实现更加强效的镇痛效用，其双重作用机理可减少对MOR的激活，减少因激活MOR而产生的成瘾性和其他不良反应等。
(3)镇痛谱更广: 研究显示，他喷他多具有广谱的镇痛效能，其不仅对急性疼痛有良好的疗效，并且对于炎性和慢性神经病理性疼痛也有显著地镇痛作用。临床试验结果显示，他喷他多能显著缓解拇囊炎切除术引起的疼痛、末期关节疾病疼痛、腰痛、髋关节或膝关节疼痛等。常规的MOR激动剂如吗啡等对急性疼痛有显著镇痛作用，但对慢性疼痛、神经痛及炎症性疼痛疗效较差。
Palexia SR (for severe chronic pain) is the brand name for tapentadol prolonged release, which is a strong painkiller indicated for management of severe chronic pain in adults, which can be adequately managed with opioid analgesics.
Palexia SR 50, 100, 150, 200, 250 mg prolonged-release tablets
1. Name of the medicinal product
PALEXIA® SR 50 mg prolonged-release tablets
PALEXIA® SR 100 mg prolonged-release tablets
PALEXIA® SR 150 mg prolonged-release tablets
PALEXIA® SR 200 mg prolonged-release tablets
PALEXIA® SR 250 mg prolonged-release tablets
2. Qualitative and quantitative composition
Each prolonged-release tablet contains 50 mg tapentadol (as hydrochloride).
Each prolonged-release tablet contains 100 mg tapentadol (as hydrochloride).
Each prolonged-release tablet contains 150 mg tapentadol (as hydrochloride).
Each prolonged-release tablet contains 200 mg tapentadol (as hydrochloride).
Each prolonged-release tablet contains 250 mg tapentadol (as hydrochloride).
Excipient(s) with known effect:
PALEXIA SR 50 mg contains 3.026 mg lactose.
PALEXIA SR 100 mg contains 3.026 mg lactose.
PALEXIA SR 150 mg contains 3.026 mg lactose.
PALEXIA SR 200 mg contains 3.026 mg lactose.
PALEXIA SR 250 mg contains 3.026 mg lactose.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Prolonged-release tablet
50 mg: White film-coated oblong shaped tablets (6.5 mm x 15 mm) marked with Grünenthal logo on one side and “H1” on the other side.
100 mg: Pale yellow film-coated oblong shaped tablets (6.5 mm x 15 mm) marked with Grünenthal logo on one side and “H2” on the other side.
150 mg: Pale pink film-coated oblong shaped tablets (6.5 mm x 15 mm) marked with Grünenthal logo on one side and “H3” on the other side.
200 mg: Pale orange film-coated oblong shaped tablets (7 mm x 17 mm) marked with Grünenthal logo on one side and “H4” on the other side.
250 mg: Brownish red film-coated oblong shaped tablets (7 mm x 17 mm) marked with Grünenthal logo on one side and “H5” on the other side.
4. Clinical particulars
4.1 Therapeutic indications
PALEXIA SR is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics.
4.2 Posology and method of administration
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.
PALEXIA SR 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 as prolonged-release tablet administered twice daily.
Initiation of therapy in patients currently taking opioid analgesics
When switching from opioids to PALEXIA SR 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 PALEXIA SR for patients currently taking opioids compared to those not having taken opioids before initiating therapy with PALEXIA SR.
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 tapentadol as prolonged-release tablet twice daily every 3 days was appropriate to achieve adequate pain control in most of the patients.
Total daily doses of PALEXIA SR greater than 500 mg 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.
Renal Impairment
In patients with mild or moderate renal impairment a dosage adjustment is not required (see section 5.2).
PALEXIA SR 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 dosage adjustment is not required (see section 5.2).
PALEXIA SR 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. 50 mg tapentadol as prolonged-release tablet, and not be administered more frequently than once every 24 hours. At initiation of therapy a daily dose greater than 50 mg tapentadol as prolonged-release tablet is not recommended. Further treatment should reflect maintenance of analgesia with acceptable tolerability (see sections 4.4 and 5.2).
PALEXIA SR 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 (persons aged 65 years and over)
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 Patients
The safety and efficacy of PALEXIA SR in children and adolescents below 18 years of age has not yet been established. Therefore PALEXIA SR is not recommended for use in this population.
Method of administration
PALEXIA SR has to be taken whole, not divided or chewed, to ensure that the prolonged-release mechanism is maintained. PALEXIA SR should be taken with sufficient liquid. PALEXIA SR can be taken with or without food.
4.3 Contraindications
PALEXIA SR is contraindicated
• in patients with hypersensitivity to tapentadol or to any of the excipients listed in section 6.1.
• in 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
• in any patient who has or is suspected of having paralytic ileus
• in 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
Potential for Abuse and Addiction/ Dependence Syndrome
PALEXIA SR has a potential for abuse and addiction. This should be considered when prescribing or dispensing PALEXIA SR in situations where there is concern about an increased risk of misuse, abuse, addiction, or diversion.
All patients treated with active substances that have mu-opioid receptor agonist activity should be carefully monitored for signs of abuse and addiction.
Respiratory Depression
At high doses or in mu-opioid receptor agonist sensitive patients, PALEXIA SR may produce dose-related respiratory depression. Therefore, PALEXIA SR should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and PALEXIA SR 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
PALEXIA SR 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. PALEXIA SR should be used with caution in patients with head injury and brain tumors.
Seizures
PALEXIA SR 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 agonist activity PALEXIA SR is not recommended in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.
Renal Impairment
PALEXIA SR has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended (see section 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. PALEXIA SR should be used with caution in patients with moderate hepatic impairment (see section 4.2 and 5.2), especially upon initiation of treatment.
PALEXIA SR 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. PALEXIA SR should be used with caution in patients with biliary tract disease, including acute pancreatitis.
Mixed opioid agonists/antagonists
Care should be taken when combining PALEXIA SR 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.
PALEXIA SR prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Medicinal products like benzodiazepines, barbiturates and opioids (analgesics, antitussives or substitution treatments) may enhance the risk of respiratory depression if taken in combination with PALEXIA SR. CNS depressants (e.g. benzodiazepines, antipsychotics, H1-antihistamines, opioids, alcohol) can enhance the sedative effect of tapentadol and impair vigilance. Therefore, when a combined therapy of PALEXIA SR with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both agents should be considered.
Mixed opioid agonists/antagonists
Care should be taken when combining PALEXIA SR with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine) (see also section 4.4).
In isolated cases 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). Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. 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 may lead to increased systemic exposure of tapentadol (see section 5.2).
For patients on tapentadol treatment, caution should be exercised if concomitant drug administration of strong enzyme inducing drugs (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 PALEXIA SR should 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 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).
PALEXIA SR should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Labour and Delivery
The effect of tapentadol on labour and delivery in humans is unknown. PALEXIA SR is not recommended for use in women during and immediately before labour and delivery. 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.
Lactation
There is no information on the excretion of tapentadol in human milk. From a study in rat pups suckled by dams dosed with tapentadol it was concluded that tapentadol is excreted via milk (see section 5.3). Therefore, a risk to the suckling child cannot be excluded. PALEXIA SR should not be used during breast feeding.
4.7 Effects on ability to drive and use machines
PALEXIA SR 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 dosage occur 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 PALEXIA SR 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 PALEXIA SR. 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
Immune system disorders			Drug hypersensitivity including angioedema
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
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

Clinical trials performed with PALEXIA SR 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
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 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.
5. 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 tablets 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).
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with PALEXIA SR 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 PALEXIA SR 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. PALEXIA SR may 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%.
Metabolism
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 phase 2 conjugation.
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
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 Phase 2 glucuronidation, and only a small amount is metabolised by Phase 1 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 Phase 2 metabolism 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 drug-drug 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 dosages 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.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core (all doses):
Hypromellose
Microcrystalline cellulose
Colloidal anhydrous silica
Magnesium stearate
Tablet coat:
Hypromellose
Lactose monohydrate
Talc
Macrogol 6000
Propylene glycol
Titanium dioxide (E 171) – 50mg, 100mg, 150mg
Yellow iron oxide (E 172) – 100mg, 150mg
Red iron oxide (E 172) – 150mg, 200mg
Black iron oxide (E 172) – 250mg
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
PVC/PVDC-aluminium/paper/PET blisters
Packs with 7, 10, 14, 20, 24, 28, 30, 40, 50, 54, 56, 60, 90, 100 prolonged-release tablets.
PVC/PVDC aluminium/paper/PET perforated unit-dose blisters
Packs with 10, 14, 20, 28, 30, 50, 56, 60, 90, 100 prolonged-release tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Grünenthal Ltd
Regus Lakeside House
1 Furzeground Way
Stockley Park East
Uxbridge
Middlesex UB11 1BD
United Kingdom
8. Marketing authorisation number(s)
PALEXIA® SR 50 mg prolonged-release tablets: PL 21727/0041
PALEXIA® SR 100 mg prolonged-release tablets: PL 21727/0042
PALEXIA® SR 150 mg prolonged-release tablets: PL 21727/0043
PALEXIA® SR 200 mg prolonged-release tablets: PL 21727/0044
PALEXIA® SR 250 mg prolonged-release tablets: PL 21727/0045
9. Date of first authorisation/renewal of the authorisation
04 February 2011
10. Date of revision of the text
November 2013