PRESENTATION
APENDOL 50 / 100 mg Tablets
CLINICAL PARTICULARS
Therapeutic Indications
APENDOL 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 individualized 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 APENDOL 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 requirements.
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 minimizes undesirable effects under the close supervision of the prescribing physician. Daily doses greater than 700 mg APENDOL on the first day of treatment and maintenance daily doses greater than 600 mg APENDOL have not been studied and are therefore not recommended.
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 APENDOL, the possibility of switching the patient to therapy with APENDOL prolonged release tablets should be considered. As with all symptomatic treatments, the continued use of APENDOL must be evaluated on an ongoing basis.
Withdrawal symptoms could occur after abrupt discontinuation of treatment with APENDOL.When a patient no longer requires therapy with APENDOL, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
In patients with mild or moderate renal impairment a dosage adjustment is not required APENDOL has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended
In patients with mild hepatic impairment a dosage adjustment is not required. 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 APENDOL 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 APENDOL 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. APENDOL has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended.
In general, a dose adaptation in older people is not required. However, as older people are more likely to have decreased renal and hepatic function, care should be taken in dose selection as recommended.
The safety and efficacy of APENDOL in children and adolescents below 18 years of age has not yet been established. Therefore APENDOL is not recommended for use in this population.
METHOD OF ADMINISTRATION
APENDOL should be taken with sufficient liquid. APENDOL can be taken with or without food.
CONTRAINDICATIONS
APENDOL is contraindicated
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
APENDOL has a potential for abuse and addiction. This should be considered when prescribing or dispensing APENDOL 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.
Risk from concomitant use of sedating medicinal products such as benzodiazepines or related substances. Concomitant use of APENDOL 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 APENDOL concomitantly with sedating medicinal products, the reduction of dose of one or both agents 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.
At high doses or in mu-opioid receptor agonist sensitive patients, APENDOL may produce dose-related respiratory depression. Therefore, APENDOL should be administered with caution to patients with impaired respiratory functions. Alternative non-mu-opioid receptor agonist analgesics should be considered and APENDOL 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.
APENDOL 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. APENDOL should be used with caution in patients with head injury and brain tumors.
APENDOL 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 APENDOL 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, APENDOL may increase the seizure risk in patients taking other medicinal products that lower the seizure threshold.
APENDOL has not been studied in controlled efficacy trials in patients with severe renal impairment, therefore the use in this population is not recommended.
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. APENDOL should be used with caution in patients with moderate hepatic impairment especially upon initiation of treatment.
APENDOL has not been studied in patients with severe hepatic impairment and therefore, use in this population is not recommended.
Active substances with mu-opioid receptor agonist activity may cause spasm of the sphincter of Oddi. APENDOL should be used with caution in patients with biliary tract disease, including acute pancreatitis.
Care should be taken when combining APENDOL 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.
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION
The concomitant use of APENDOL 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 APENDOL with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both agents should be considered and the duration of the concomitant use should be limited.
Care should be taken when combining APENDOL with mixed mu-opioid agonist/antagonists (like pentazocine, nalbuphine) or partial mu-opioid agonists (like buprenorphine) 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 APENDOL 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
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 APENDOL 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 APENDOL. For patients on APENDOL 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 APENDOL 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.
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 embryo toxicity 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. APENDOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The effect of APENDOL on labor and delivery in humans is unknown. APENDOL is not recommended for use in women during and immediately before labour and delivery. Due to the mu-opioid receptor agonist activity of APENDOL, new-born infants whose mothers have been taking APENDOL should be monitored for respiratory depression.
There is no information on the excretion of APENDOL in human milk. From a study in rat pups suckled by dams dosed with APENDOL it was concluded that APENDOL is excreted in milk. Therefore, a risk to the suckling child cannot be excluded. Should not be used during breast feeding.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
APENDOL may have major influence on the ability to drive and use machines, because it may adversely affect central nervous system functions. 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 tranquilizers. Patients should be cautioned as to whether driving or use of machines is permitted.
UNDESIRABLE EFFECTS
The adverse drug reactions that were experienced by patients in the placebo controlled trials performed with APENDOL 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 Tapentadol and from post-marketing environment. They are listed by class and frequency. Frequencies are defined as very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Adverse Drug Reactions
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ADVERSE DRUG REACTIONS |
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System Organ Class |
Frequency |
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Very common
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Common |
Uncommon |
Rare |
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Immune system disorders |
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Drug Hypersensitivity |
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Metabolism and nutrition disorders |
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Decreased appetite |
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Psychiatric disorders |
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anxiety, Confusional state, Hallucination, Sleep disorder, Abnormal dreams |
Depressed mood, Disorientation, Agitation, Nervousness, Restlessness, Euphoric mood |
Thinking abnormal |
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Nervous system disorders |
Dizziness, Somnolence, Headache |
Tremor |
Disturbance in attention, Memory impairment, Presyncope, Sedation, Ataxia, Dysarthria, Hypo aesthesia, Paresthesia, Muscle contractions involuntary |
Convulsion, Depressed level of consciousness, Coordination abnormal |
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Eye disorders |
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Visual disturbance |
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Cardiac disorders |
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Heart rate increased, Palpitations |
Heart rate decreased |
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Vascular disorders
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Flushing |
Blood pressure decreased
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Respiratory, thoracic and mediastinal disorders |
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Respiratory depression, Oxygen saturation decreased, Dyspnea, |
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Gastrointestinal disorders |
Nausea, Vomiting |
Constipation, Diarrhea, Dyspepsia, Dry mouth |
Abdominal discomfort |
Impaired gastric emptying |
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Musculoskeletal and connective tissue disorder |
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Muscle spasms |
Sensation of heaviness |
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Renal and urinary disorders |
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Urinary hesitation, Pollakiuria |
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General disorders and administration site conditions |
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Asthenia, Fatigue, Feeling of body temperature change |
Drug withdrawal syndrome, Edema, Feeling abnormal, Feeling drunk, Irritability, Feeling of relaxation |
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*Post-marketing rare events of angioedema, anaphylaxis and anaphylactic shock have been reported. |
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Overdose
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, and 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 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.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamics Properties
APENDOL is a strong analgesic with µ-agonistic opioid and additional noradrenaline reuptake inhibition properties. APENDOL exerts its analgesic effects directly without a pharmacologically active metabolite.
APENDOL 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 orthopedic and abdominal pain as well as chronic pain due to osteoarthritis of the hip or knee. In general the analgesic effect of APENDOL in nociceptive pain trials was similar to that observed with a strong opioid used as comparator.
The European Medicines Agency has deferred the obligation to submit the results of studies with Tapentadol in all subsets of the pediatrics population in moderate to severe acute pain
Pharmacokinetic Properties
APENDOL is rapidly and completely absorbed after oral administration of APENDOL. Mean absolute bioavailability after single-dose administration (fasting) is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of APENDOL are typically observed at around 1.25 hours after administration of film-coated tablets. Dose-proportional increases in the Cmax and AUC values of APENDOL 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 APENDOL 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.
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 Tapentadol 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 metabolized. 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 metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxyl tapentadol (2%) by CYP2D6, which are further metabolized 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.
APENDOL 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 APENDOL was similar in a trial with older subjects (65-78 years of age) compared to young adults (19-43 years of age), with a 16% lower mean Cmax observed in the older subject group compared to young adult subjects.
AUC and Cmax of APENDOL were comparable in subjects with varying degrees of renal function (from normal to severely imp aired). In contrast, increasing exposure (AUC) to APENDOL -O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of APENDOL -O-glucuronide are 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.
Administration of tapentadol resulted in higher exposures and serum levels to APENDOL in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of APENDOL 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 APENDOL -O-glucuronide was lower in subjects with increased liver impairment.
Pharmacokinetic Interactions
APENDOL is mainly metabolized by Phase 2 glucuronidation, and only a small amount is metabolized 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 APENDOL 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 APENDOL 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 APENDOL. These trials also showed no clinically relevant effects on APENDOL serum concentrations. In vitro studies did not reveal any potential of APENDOL 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 APENDOL is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.
Preclinical Safety Data
APENDOL 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. APENDOL 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.
APENDOL 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. APENDOL showed no teratogenic effects in rats and rabbits following intravenous and subcutaneous exposure. However, delayed development and embryo toxicity 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 APENDOL. Pups were dose-dependently exposed to APENDOL and APENDOL O-glucuronide. It was concluded that APENDOL is excreted in milk.
SPECIAL PRECAUTIONS FOR STORAGE
This medicinal product does not require any special storage conditions.