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YANTIL® 50 mg film-coated tablets



Each film-coated tablet contains 50 mg tapentadol (as hydrochloride).
Excipient(s) with known effect:
YANTIL 50 mg contains 24.74 mg lactose.
For the full list of excipients, see section 6.1.


Film-coated tablet (tablet)
White round shaped film-coated tablets of 7 mm diameter, marked with Grünenthal
logo on one side and “H6” on the other side.



Therapeutic indications
YANTIL is indicated for the relief of moderate to severe acute pain in adults, which
can be adequately managed only with opioid analgesics.
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.
Patients should start treatment with single doses of 50 mg tapentadol as film-coated
tablet administered every 4 to 6 hours. Higher starting doses may be necessary
depending on the pain intensity and the patient’s previous history of analgesic
On the first day of dosing, an additional dose may be taken as soon as one hour after
the initial dose, if pain control is not achieved. The dose should then be titrated
individually to a level that provides adequate analgesia and minimises undesirable
effects under the close supervision of the prescribing physician.
Daily doses greater than 700 mg tapentadol on the first day of treatment and
maintenance daily doses greater than 600 mg tapentadol have not been studied and are
therefore not recommended.

Duration of treatment
The film-coated tablets are intended for acute pain situations. If longer term treatment
is anticipated or becomes necessary and effective pain relief in the absence of
intolerable adverse events was achieved with YANTIL, the possibility of switching
the patient to therapy with YANTIL prolonged release tablets should be considered.
As with all symptomatic treatments, the continued use of tapentadol must be
evaluated on an ongoing basis.
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 may be advisable to taper the dose gradually to prevent symptoms of
Renal Impairment
In patients with mild or moderate renal impairment a dosage adjustment is not
required (see section 5.2).
YANTIL 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).
YANTIL 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 film-coated tablet, and not be administered more frequently
than once every 8 hours. At initiation of therapy a daily dose greater than 150 mg
tapentadol as film-coated tablet is not recommended. Further treatment should reflect
maintenance of analgesia with acceptable tolerability, to be achieved by either
shortening or lengthening the dosing interval (see sections 4.4 and 5.2).
YANTIL 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 YANTIL in children and adolescents below 18 years of age
has not yet been established. Therefore YANTIL is not recommended for use in this
Method of administration
YANTIL should be taken with sufficient liquid. YANTIL can be taken with or
without food.
YANTIL 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)

Special warnings and precautions for use
Potential for Abuse and Addiction/ Dependence Syndrome
YANTIL has a potential for abuse and addiction. This should be considered when
prescribing or dispensing YANTIL 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, YANTIL may
produce dose-related respiratory depression. Therefore, YANTIL should be
administered with caution to patients with impaired respiratory functions. Alternative
non-mu-opioid receptor agonist analgesics should be considered and YANTIL 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
YANTIL 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. YANTIL should be used with caution in patients with head injury and
brain tumors.
YANTIL 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 YANTIL is not recommended in patients with a
history of a seizure disorder or any condition that would put the patient at risk of
Renal Impairment
YANTIL 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. YANTIL should be used with caution in patients with moderate
hepatic impairment (see section 4.2 and 5.2), especially upon initiation of treatment.
YANTIL 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. YANTIL should be used with caution in patients with biliary tract
disease, including acute pancreatitis.
Mixed opioid agonists/antagonists
Care should be taken when combining YANTIL 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.
YANTIL film-coated 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.
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 YANTIL. 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 YANTIL
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 YANTIL 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 (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 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 YANTIL 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.
Fertility, pregnancy and lactation
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).
YANTIL 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. YANTIL 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.
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 in
milk (see section 5.3). Therefore, a risk to the suckling child cannot be excluded. YANTIL
should not be used during breast feeding.

Effects on ability to drive and use machines
YANTIL 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 changes of dosage
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

Undesirable effects
The adverse drug reactions that were experienced by patients in the placebo controlled
trials performed with YANTIL were predominantly of mild and moderate severity.
The most frequent adverse drug reactions were in the gastrointestinal and central
nervous system (nausea, vomiting, somnolence, dizziness and headache).
The table below lists adverse drug reactions that were identified from clinical trials
performed with YANTIL. 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).

System Organ





ity, including

Immune system


Decreased appetite

Metabolism and
nutrition disorders

Nervous system

Anxiety, Confusional state,
Hallucination, Sleep disorder,
Abnormal dreams


Eye disorders
Cardiac disorders

Vascular disorders
thoracic and
Skin and
subcutaneous tissue
Musculoskeletal and
connective tissue
Renal and urinary
General disorders
and administration
site conditions

Depressed mood,
Disorientation, Agitation,
Nervousness, Restlessness,
Euphoric mood
Disturbance in attention,
Memory impairment,
level of
Presyncope, Sedation, Ataxia,
Dysarthria, Hypoaesthesia, consciousness
Paraesthesia, Muscle
contractions involuntary
Visual disturbance
Heart rate increased,
Blood pressure decreased

Heart rate

Respiratory depression,
Oxygen saturation decreased,

Constipation, Diarrhoea, ,
Dyspepsia, Dry mouth

Abdominal discomfort

Pruritus, Hyperhidrosis, Rash


Muscle spasms

Sensation of heaviness

Asthenia, Fatigue, Feeling of
body temperature change

Urinary hesitation,
Drug withdrawal syndrome,
Oedema, Feeling abnormal,
Feeling drunk, Irritability,
Feeling of relaxation


Clinical trials performed with YANTIL with patient exposure up to 90 days 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

Human experience with overdose of tapentadol is very limited. Preclinical data
suggest that symptoms similar to those of other centrally acting analgesics with muopioid 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 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
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.



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 film-coated tablets covering nociceptive pain conditions including
postoperative orthopaedic and abdominal pain as well as chronic pain due to
osteoarthritis of the hip or knee. In general the analgesic effect of tapentadol in
nociceptive pain trials was similar to that observed with a strong opioid used as
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 YANTIL in all subsets of the paediatric population in moderate to severe
acute pain (see section 4.2 for information on paediatric use).
Pharmacokinetic properties
Tapentadol is rapidly and completely absorbed after oral administration of YANTIL.
Mean absolute bioavailability after single-dose administration (fasting) is
approximately 32% due to extensive first-pass metabolism. Maximum serum
concentrations of tapentadol are typically observed at around 1.25 hours after
administration of film-coated tablets. Dose-proportional increases in the Cmax and
AUC values of tapentadol have been observed after administration of film-coated
tablets over the oral therapeutic dose range.
A multiple (every 6 hour) dose trial with doses ranging from 75 to 175 mg tapentadol
administered as film-coated tablets showed an accumulation ratio between 1.4 and 1.7
for the parent active substance and between 1.7 and 2.0 for the major metabolite
tapentadol-O-glucuronide, which are primarily determined by the dosing interval and
apparent half-life of tapentadol and its metabolite. Steady state serum concentrations
of tapentadol are reached on the second day of the treatment regimen.
Food Effect
The AUC and Cmax increased by 25% and 16%, respectively, when film-coated tablets
were administered after a high-fat, high-calorie breakfast. The time to maximum
plasma concentration was delayed by 1.5 hours under these conditions. Based on
efficacy data obtained at early assessment time points during phase II/III trials, the
food effect does not appear to be of clinical relevance YANTIL may be given with or
without food.
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%.
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.
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 4 hours after oral administration.
Special populations
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-Oglucuronide 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.

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 Oglucuronide. It was concluded that tapentadol is excreted in milk.




List of excipients
Tablet core:
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Povidone K30
Magnesium stearate
Tablet coat :

Titanium dioxide (E 171)
Macrogol 3350


Not applicable


Shelf life
3 years


Special precautions for storage
This medicinal product does not require any special storage conditions.


Nature and contents of container
PVC/PVDC aluminium blisters
Packs with 5, 10, 14, 20, 28, 30, 40, 50, 56, 60, 90, 100 film-coated tablets.
PVC/PVDC aluminium perforated unit-dose blisters
Packs with 10x1, 14x1, 20x1, 28x1, 30x1, 50x1, 56x1, 60x1, 90x1, 100x1 film-coated
Not all pack sizes may be marketed.


Special precautions for disposal
No special requirements.


Grünenthal Ltd
Regus Lakeside House
1 Furzeground Way
Stockley Park East
Middlesex UB11 1BD
United Kingdom


PL 21727/0035





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