1. Name Of The Medicinal Product
Zomestine 80 mg prolonged-release tablets
2. Qualitative And Quantitative Composition
Each prolonged-release tablet contains 80 mg oxycodone hydrochloride equivalent to 72 mg oxycodone.
Excipient:
The prolonged-release tablets contain a maximum of 48 mg sucrose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Prolonged-release tablet.
Red, oblong, biconvex, tablets with break scores on both sides. The tablet can be divided into equal halves.
4. Clinical Particulars
4.1 Therapeutic Indications
Severe pain, which can be adequately managed only with opioid analgesics.
4.2 Posology And Method Of Administration
The dosage depends on the intensity of pain and the patient's individual susceptibility to the treatment. For doses not realisable/practicable with this medicinal product, other strengths and medicinal products are available.
The following general dosage recommendations apply:
Adults and adolescents (> 12 years)
Dose titration and adjustment
In general, the initial dose for opioid naïve patients is 10 mg oxycodone hydrochloride given at intervals of 12 hours. Some patients may benefit from a starting dose of 5 mg to minimise the incidence of adverse reactions.
Patients already receiving opioids may start treatment with higher dosages taking into account their experience with former opioid therapies.
According to well-controlled clinical studies 10-13 mg oxycodone hydrochloride correspond to approximately 20 mg morphine sulphate, both in the prolonged-release formulation.
Because of individual differences in sensitivity for different opioids, it is recommended that patients should start conservatively with Zomestine prolonged-release tablets after conversion from other opioids, with 50-75% of the calculated oxycodone dose.
Some patients who take Zomestine prolonged-release tablets following a fixed schedule need rapid release analgesics as rescue medication in order to control breakthrough pain. Zomestine prolonged-release tablets are not indicated for the treatment of acute pain and/or breakthrough pain. The single dose of the rescue medication should amount to 1/6 of the equianalgesic daily dose of Zomestine prolonged-release tablets. Use of the rescue medication more than twice daily indicates that the dose of Zomestine prolonged-release tablets needs to be increased.
The dose should not be adjusted more often than once every 1-2 days until a stable twice daily administration has been achieved.
Following a dose increase from 10 mg to 20 mg taken every 12 hours dose adjustments should be made in steps of approximately one third of the daily dose. The aim is a patient specific dosage which, with twice daily administration, allows for adequate analgesia with tolerable undesirable effects and as little rescue medication as possible as long as pain therapy is needed.
Even distribution (the same dose mornings and evenings) following a fixed schedule (every 12 hours) is appropriate for the majority of the patients. For some patients it may be advantageous to distribute the doses unevenly. In general, the lowest effective analgesic dose should be chosen. For the treatment of non malignant pain a daily dose of 40 mg is generally sufficient; but higher dosages may be necessary. Patients with cancer-related pain may require dosages of 80 to 120 mg, which in individual cases can be increased to up to 400 mg. If even higher doses are required, the dose should be decided individually balancing efficacy with the tolerance and risk of undesirable effects.
Method of administration
For oral use.
Zomestine prolonged-release tablets should be taken twice daily based on a fixed schedule at the dosage determined.
The prolonged-release tablets may be taken with or independent of meals with a sufficient amount of liquid. Zomestine prolonged-release tablets must be swallowed whole, not chewed.
Zomestine prolonged-release tablets should not be used with alcoholic beverages.
Duration of administration
Zomestine should not be taken longer than necessary. If long-term treatment is necessary due to the type and severity of the illness careful and regular monitoring is required to determine whether and to what extent treatment should be continued. If opioid therapy is no longer indicated it may be advisable to reduce the daily dose gradually in order to prevent symptoms of a withdrawal syndrome.
Children under 12 years of age
Zomestine prolonged-release tablets are not recommended for children under 12 years of age.
Elderly patients
Elderly patients without clinical manifestation of impaired liver and/or kidney function usually do not require dose adjustments.
Risk patients
Risk patients, for example patients with impaired renal or hepatic function, low body weight or slow metabolism of medicinal products, should initially receive half the recommended adult dose if they are opioid naïve. Therefore the lowest recommended dosage, i.e. 10 mg, may not be suitable as a starting dose. Dose titration should be performed in accordance with the individual clinical situation.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients
• severe respiratory depression with hypoxia and/or hypercapnia
• severe chronic obstructive pulmonary disease
• Cor pulmonale
• severe bronchial asthma
• Paralytic ileus
• acute abdomen, delayed gastric emptying.
4.4 Special Warnings And Precautions For Use
Zomestine prolonged-release tablets have not been studied in children younger than 12 years of age. The safety and efficacy of the tablets have not been demonstrated and the use in children younger than 12 years of age is therefore not recommended.
Caution is required in elderly or debilitated patients, in patients with severe impairment of lung, liver or kidney function, myxoedema, hypothyroidism, Addison's disease (adrenal insufficiency), intoxication psychosis (e.g. alcohol), prostatic hypertrophy, alcoholism, known opioid dependence, delirium tremens, pancreatitis, diseases of the biliary tract, biliary or ureteric colic, conditions with increased brain pressure, disturbances of circulatory regulation, epilepsy or seizure tendency and in patients taking MAO inhibitors.
Special care should be taken when oxycodone is applied in patients undergoing bowel-surgery. Opioids should only be administered post-operatively when the bowel function has been restored.
Patients with severe hepatic impairment should be closely monitored.
Respiratory depression is the most significant risk induced by opioids and is most likely to occur in elderly or debilitated patients. The respiratory depressant effect of oxycodone can lead to increased carbon dioxide concentrations in blood and hence in cerebrospinal fluid. In predisposed patients opioids can cause severe decrease in blood pressure.
Long-term use of Zomestine prolonged-release tablets can cause the development of tolerance which leads to the use of higher doses in order to achieve the desired analgesic effect. There is a cross-tolerance to other opioids. Chronic use of Zomestine prolonged-release tablets can cause physical dependence. Withdrawal symptoms may occur following abrupt discontinuation of therapy. If therapy with oxycodone is no longer required it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of a withdrawal syndrome.
Zomestine prolonged-release tablets have a primary dependence potential. However, when used as directed in patients with chronic pain the risk of developing physical or psychological dependence is markedly reduced or needs to be assessed in a differentiated manner. There are no data available on the actual incidence of psychological dependence in chronic pain patients. In patients with a history of alcohol and drug abuse the medicinal product must be prescribed with special care. The safety of Zomestine prolonged-release tablets used pre-operatively has not been established and cannot be recommended.
In case of abusive parenteral venous injection the tablet excipients may lead to necrosis of the local tissue, granulomas of the lung or other serious, potentially fatal events. To avoid damage to the controlled release properties of the tablets the prolonged-release tablets must not be chewed or crushed. The administration of chewed or crushed tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone (see section 4.9).
Zomestine prolonged-release tablets must not be taken with alcoholic beverages, since this might result in an increased incidence of undesirable effects (e.g. somnolence, respiratory depression).
Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests.
Use of Zomestine as a doping agent may become a health hazard.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Central nervous system depressants (e.g. sedatives, hypnotics, phenothiazines, neuroleptics, anaesthetics, antidepressants, muscle relaxants, antihistamines, antiemetics) and other opioids or alcohol can enhance the adverse reactions of oxycodone, in particular respiratory depression.
Anticholinergics (e.g. neuroleptics, antihistamines, antiemetics, antiparkinson medicinal products) can enhance the anticholinergic undesirable effects of oxycodone (such as constipation, dry mouth or micturition disorders).
Cimetidine can inhibit the metabolism of oxycodone.
MAO inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hyper- or hypotensive crisis (see section 4.4).
The inhibition of cytochrome P450 2D6 and 3A4 has no clinical relevance, however, strong CYP2D6 inhibitors may have an effect on the elimination of oxycodone. The effect of other relevant isoenzyme inhibitors on the metabolism of oxycodone is not known. Potential interactions should be taken into account.
Clinically relevant changes in International Normalised Ratio (INR) in both directions have been observed in individuals if coumarin anticoagulants are co-applied with Zomestine prolonged-release tablets.
There are no studies investigating the effect of oxycodone on CYP catalysed metabolism of other active substances.
4.6 Pregnancy And Lactation
Pregnancy
Limited data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of congenital abnormalities. Oxycodone crosses the placenta. Animal studies with oxycodone have not revealed any teratogenic or embryotoxic effects.
Prolonged use of oxycodone during pregnancy can cause withdrawal symptoms in newborns. Use of oxycodone during labour can cause foetal respiratory depression. Oxycodone should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate.
Lactation
Zomestine prolonged-release tablets should not be taken during lactation (see section 4.3).
Oxycodone passes into breast milk. The milk/plasma concentration ratio was 3.4:1 and oxycodone effects in the suckling infant are therefore conceivable. A risk to the suckling child cannot be excluded in particular following intake of multiple doses of oxycodone by the breast-feeding mother. Breast-feeding should be discontinued during treatment with oxycodone.
4.7 Effects On Ability To Drive And Use Machines
Oxycodone can impair alertness and reactivity to such an extent that the ability to drive and operate machinery is affected or ceases altogether. With stable therapy, a general ban on driving a vehicle is not necessary. The treating physician must assess the individual situation.
4.8 Undesirable Effects
Oxycodone can cause respiratory depression, miosis, bronchial spasms and spasms of the smooth muscles and can suppress the cough reflex.
The adverse reactions considered at least possibly related to treatment are listed below by system organ class and absolute frequency. Frequencies are defined as:
Very common (
Common (
Uncommon (
Rare (
Very rare (< 1/10,000)
Not known (cannot be estimated from the available data)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Blood and lymphatic system disorders
Rare: lymphadenopathy
Endocrine disorders
Uncommon: syndrome of inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders
Common: anorexia
Rare: dehydration
Psychiatric disorders
Common: various psychological adverse reactions including changes in mood (e.g. anxiety, depression, euphoria), changes in activity (mostly supression sometimes associated with lethargy, occasionally increase with agitation, nervousness and insomnia) and changes in cognitive performance (abnormal thinking, confusion, amnesia, isolated cases of speech disorders)
Uncommon: change in perception such as depersonalisation, hallucinations, change in taste, visual disturbances, hyperacousis
Nervous system disorders
Very common: somnolence, dizziness, headache
Common: asthenia, paraesthesia
Uncommon: both increased and decreased muscle tone, tremor, involuntary muscle contractions, hypaesthesia, coordination disturbances, malaise, vertigo
Rare: seizures, in particular in epileptic patients or patients with tendency to convulsions, muscle spasm
Eye disorders
Uncommon: lacrimation disorder, miosis
Cardiac and vascular disorders
Common: lowering of blood pressure, rarely accompanied by secondary symptoms such as palpitations, syncope, bronchospasm
Uncommon: supraventricular tachycardia, vasodilatation
Respiratory, thoracic and mediastinal disorders
Common: respiratory depression
Uncommon: increased coughing, pharyngitis, rhinitis, voice changes
Gastrointestinal disorders
Very common: constipation, nausea, vomiting
Common: dry mouth, rarely accompanied by thirst and difficulty swallowing; gastrointestinal disorders such as abdominal pain, diarrhoea, eructation, dyspepsia, loss of appetite
Uncommon: biliary colics, oral ulcers, gingivitis, stomatitis, flatulence
Rare: gum bleeding, increased appetite, tarry stool, tooth staining and damage, ileus
Skin and subcutaneous tissue disorders
Very common: itching
Common: skin eruptions including rash, in rare cases increased photosensitivity, in isolated cases urticaria or exfoliative dermatitis
Rare: dry skin, herpes simplex
Renal and urinary disorders
Common: micturition disturbances (urinary retention, but also increased urge to urinate)
Rare: haematuria
Reproductive system and breast disorders
Uncommon: reduced libido, impotence
Rare: amenorrhoea
General disorders and administration site conditions
Common: sweating and even chills
Uncommon: accidental injuries, pain (e.g. chest pain), oedema, migraine, physical dependence with withdrawal symptoms, allergic reactions
Rare: weight changes (increase or decrease), cellulitis
Very rare: anaphylactic reactions
Tolerance and dependence may develop.
4.9 Overdose
Symptoms of overdose
Miosis, respiratory depression, somnolence, reduced skeletal muscle tone and drop in blood pressure. In severe cases circulatory collapse, stupor, coma, bradycardia and non-cardiogenic lung oedema may occur; abuse of high doses of strong opioids such as oxycodone can be fatal.
Therapy of overdose
Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation
In the event of overdosing intravenous administration of an opiate antagonist (e.g. 0.4-2 mg intravenous naloxone) may be indicated. Administration of single doses must be repeated depending on the clinical situation at intervals of 2 to 3 minutes. Intravenous infusion of 2 mg of naloxone in 500 ml isotonic saline or 5% dextrose solution (corresponding to 0.004 mg naloxone/ml) is possible. The rate of infusion should be adjusted to the previous bolus injections and the response of the patient. Gastric lavage can be taken into consideration. Consider activated charcoal (50 g for adults, 10 -15 g for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected. It may be reasonable to assume that late administration of activated charcoal may be beneficial for prolonged-release preparations; however there is no evidence to support this.
For speeding up the passage a suitable laxative (e.g. a PEG based solution) may be useful.
Supportive measures (artificial respiration, oxygen supply, administration of vasopressors and infusion therapy) should, if necessary, be applied in the treatment of accompanying circulatory shock. Upon cardiac arrest or cardiac arrhythmias cardiac massage or defibrillation may be indicated. If necessary, assisted ventilation as well as maintenance of water and electrolyte balance.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Natural opium alkaloids, ATC-Code: N02AA05
Oxycodone shows an affinity to kappa, mu and delta opioid receptors in the brain and spinal cord. It acts at these receptors as an opioid agonist without an antagonistic effect. The therapeutic effect is mainly analgesic and sedative. Compared to rapid- release oxycodone, given alone or in combination with other substances, the prolonged-release tablets provide pain relief for a markedly longer period without increased occurrence of undesirable effects.
5.2 Pharmacokinetic Properties
Absorption
The relative bioavailability of Zomestine prolonged-release tablets is comparable to that of rapid release oxycodone with maximum plasma concentrations being achieved after approximately 3 hours after intake of the prolonged-release tablets compared to 1 to 1.5 hours. Peak plasma concentrations and oscillations of the concentrations of oxycodone from the prolonged-release and rapid-release formulations are comparable when given at the same daily dose at intervals of 12 and 6 hours, respectively. A fat-rich meal before the intake of the tablets does not affect the maximum concentration or the extent of absorption of oxycodone.
The tablets must not be crushed or chewed as this leads to rapid oxycodone release due to the damage of the prolonged-release properties.
Distribution
The absolute bioavailability of oxycodone is approximately two thirds relative to parenteral administration. In steady state, the volume of distribution of oxycodone amounts to 2.6 l/kg; plasma protein binding to 38-45%; the elimination half-life to 4 to 6 hours and plasma clearance to 0.8 l/min. The elimination half-life of oxycodone from prolonged-release tablets is 4-5 hours with steady state values being achieved after a mean of 1 day.
Metabolism
Oxycodone is metabolised in the intestine and liver via the P450 cytochrome system to noroxycodone and oxymorphone as well as to several glucuronide conjugates. In vitro studies suggest that therapeutic doses of cimetidine probably have no relevant effect on the formation of noroxycodone. In man, quinidine reduces the production of oxymorphone while the pharmacodynamic properties of oxycodone remain largely unaffected. The contribution of the metabolites to the overall pharmacodynamic effect is irrelevant.
Elimination
Oxycodone and its metabolites are excreted via urine and faeces. Oxycodone crosses the placenta and is found in breast milk.
Linearity/non-linearity
The 5, 10, 20, 40 and 80 mg prolonged-release tablets are bioequivalent in a dose proportional manner with regard to the amount of active substance absorbed as well as comparable with regard to the rate of absorption.
5.3 Preclinical Safety Data
Oyxcodone had no effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual foetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices.
Long-term carcinogenicity studies were not performed.
Oxycodone shows a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the mutagenic risk of oxycodone to humans at therapeutic concentrations may be ruled out with adequate certainty.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core:Sugar spheres (sucrose, maize starch)
Hypromellose
Talc
Ethylcellulose
Hyprolose
Propylene glycol
Carmellose sodium
Microcrystalline cellulose
Magnesium stearate
Colloidal anhydrous silica
Tablet coating:
Titanium dioxide (E171)
Hypromellose
Macrogol 6000
Talc
Red iron oxide (E 172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
2 year
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 PVC/PE/PVDC-aluminium blisters consisting of a white opaque PVC/PE/PVDC laminated foil and an aluminium foil.
HDPE bottles with child-resistant PP twist-off caps.
Pack sizes:
10, 14, 20, 28, 30, 50, 56, 98, 100 prolonged-release tablets in blister.
10, 20, 30, 50, 100 prolonged-release tablets in HDPE bottles.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Accord Healthcare Limited,
Sage house, 319 Pinner road,
North Harrow, Middlesex, HA1 4HF
United Kingdom
8. Marketing Authorisation Number(S)
PL20075/0330
9. Date Of First Authorisation/Renewal Of The Authorisation
21/09/2011
10. Date Of Revision Of The Text
21/09/2011
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