Document: Dokument 1 change

• 24.02.2015   Fachinformation (deutsch)
• Dokument 1

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SUMMARY OF PRODUCT CHARACTERISTICS

1. Name of the medicinal product

OxyContin 5 mg capsules, hard

OxyContin 10 mg capsules, hard

OxyContin 20 mg capsules, hard

2. Qualitative and quantitative composition

1 capsule, hard OxyContin 5 mg contains 5 mg of oxycodone hydrochloride equivalent to 4.5 mg of oxycodone.

1 capsule, hard OxyContin 10 mg contains 10 mg of oxycodone hydrochloride equivalent to 9.0 mg of oxycodone.

1 capsule, hard OxyContin 20 mg contains 20 mg of oxycodone hydrochloride equivalent to 17.9 mg of oxycodone.

[only for strength 5 mg:]

Excipients:

OxyContin 5 mg contains sunset yellow FCF (E110).

For a full list of excipients; see section 6.1.

3. Pharmaceutical form

Capsule, hard

OxyContin 5 mg are orange/beige capsules, hard marked “ONR 5”.

OxyContin 10 mg are white/beige capsules, hard marked “ONR 10”.

OxyContin 20 mg are pink/beige capsules, hard marked “ONR 20”.

4. Clinical particulars

4.1. Therapeutic indications

Moderate to severe pain.

4.2. Posology and method of administration

Some patients given prolonged-release oxycodone therapy according to a fixed time schedule will require immediate-release analgesics as “rescue medication” to control breakthrough pain. OxyContin is intended for therapy of breakthrough pain.

OxyContin capsules, hard 5 mg, 10 mg and 20 mg are available for dose initiation and therapy of breakthrough pain (“rescue medication”).

Posology

The dosage should be adjusted to the intensity of the pain and the sensitivity of the individual patient. Generally, the lowest analgesically effective dose should be selected.

Patients already receiving opioids may be initiated on higher doses depending on their previous opioid experience.

A gradual and timely increase in dose may become necessary if pain relief is not sufficient or if pain severity increases.

The following general dosage recommendations apply.

Adults and adolescents (over 12 years)

Dose initiation:

The usual starting dose for an opioid-naive patient is 5 mg oxycodone hydrochloride at 6 hours intervals.

The dose should be titrated with care, if necessary daily, until sufficient relief of pain is achieved. In doing so, the dosing interval of OxyContin may be reduced to 4 hours, if required. On the whole, however, OxyContin should not be taken more than 6 times daily.

If the individually sufficient dose for an analgesic effect is reached, the daily base medication should be changed to prolonged-release OxyContin given twice daily.

Therapy of breakthrough pain:

The single dose of the rescuemedication is to be determined individually. As a rule of thumb, the dose of the rescuemedication can be based on 1/6 of the daily dose of the prolonged-release oxycodone preparation.

If a rescuemedication is used more than twice a day, this is evidence that increasing the dose of a prolonged-release oxycodone preparation (“base medication”) is required. The target is a patient-specific dosagewhich ,a prolonged-release oxycodone preparation given twice daily, displays an adequate analgesic effect and tolerable side effects with as little rescuemedication as possible for pain treatment.

Children under 12 years

OxyContin is not recommended for use in children below the age of 12 years due to insufficient data on safety and efficacy.

Elderly patients

A dose adjustment is usually not necessary in elderly patients without clinically manifest impairment of renal or hepatic function.

Patients at risk

Patients at risk e.g. with renal or hepatic insufficiency, low body weight or slow metabolisers, who are in addition opioid naive should initially be treated with half the dose usually recommended for adults. Therefore the lowest recommended dosage in this SPC of 5 mg oxycodone hydrochloride at 6 hours intervals may not be suitable as a starting dose.

Method of administration

When OxyContin is taken for dose initiation, it should be taken in accordance with a fixed time schedule (e.g. every 6 hours). When OxyContin is taken to treat breakthrough pain, it should be taken as needed.

OxyContin may be swallowed with or without food with sufficient liquid.

OxyContin should not be taken with alcoholic beverages.

Duration of use

OxyContin should not be taken for longer than absolutely necessary. After or during dose initiation, a twice daily prolonged-release oxycodone preparation should be given as early as possible.

If long-term pain treatment is necessary, regular and careful monitoring should be carried out to establish whether and to what extent further treatment is necessary.

When a patient no longer requires opioid therapy, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

4.3. Contraindications

[for strength 5 mg:]

[for strength 10 mg and 20 mg:]

• hypersensitivity to oxycodone hydrochloride or to any of the excipients,

• severe respiratory depression with hypoxia and/or hypercarbia,

• severe chronic obstructive pulmonary disease,

• cor pulmonale,

• severe bronchial asthma,

• paralytic ileus.

4.4. Special warnings and precautions for use

OxyContin is not recommended for use in children below the age of 12 years due to insufficient data on safety and efficacy.

Caution when treating:

• elderly or debilitated patients,

• patients with severe impairment of pulmonary, hepatic or renal function,

• patients with myxedema, hypothyroidism,

• Addison's disease (adrenocortical insufficiency),

• prostatic hypertrophy,

• toxic psychosis (e.g. alcohol), alcoholism, delirium tremens, known opioid dependence,

• pancreatitis, cholelithiasis, obstructive and inflammatory intestinal diseases,

• patients with increased intracranial pressure and those whose ability to maintain blood pressure has been compromised, epileptic disorder or predisposition to convulsions, MAO inhibitor therapy.

With the occurrence or suspicion of paralytic ileus, OxyContin should be immediately discontinued.

Respiratory depression is the chief hazard of an opioid overdose and occurs predominantly in elderly or debilitated patients. The respiratory depressant effects of oxycodone may cause increase of carbon dioxide concentration in the blood and secondarily in the cerebrospinal fluid.

Opioids may cause severe hypotension in susceptible patients.

The patient may develop tolerance to oxycodone with chronic use of OxyContin and require progressively higher doses to maintain pain control. Prolonged use of OxyContin may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Oxycodone has an abuse profile similar to other strong agonist opioids. There is potential for development of psychological dependence (addiction) to opioid analgesics, including OxyContin.

Intake of OxyContin with alcoholic beverages should be avoided because this may lead to more frequent undesirable effects such as somnolence and respiratory depression. Oxycodone hydrochloride containing products should be avoided in patients with a history of or present alcohol and drug abuse.

OxyContin should be used with caution preoperatively and within the first 12-24 hours post-operatively. Depending on the type and extent of surgery, the anaesthetic procedure selected, other co-medication and the individual condition of the patient, the exact timing for initiating postoperative treatment with OxyContin depends on a careful risk-benefit assessment for each individual patient.

Oxygesic is intended for oral use only. Abusive parenteral injections of the capsule constituents may lead to serious, potentially fatal events.

The use of OxyContin may produce positive results in doping controls. Use of Oxy-Contin as a doping agent may become a health hazard.

4.5. Interaction with other medicinal products and other forms of interaction

Centrally acting medicinal products (e.g. sedatives, hypnotics, phenothiazines, neuroleptics, antidepressants, antihistamines, antiemetics) and other opioids or alcohol may enhance the adverse drug reactions of oxycodone, especially the respiratory depression.

Medications with anticholinergic effect (e.g. psychotropic drugs, antihistamines, antiemetics, medicinal products against Morbus Parkinson) may intensify the anticholinergic adverse drug reactions of oxycodone (such as e.g. constipation, dry mouth or dysfunction of urinary excretion).

A clinically relevant decrease or increase of the International Normalized Ratio (INR) has been observed in individual cases with simultaneous use of oxycodone and anticoagulants from coumarin type.

Oxycodone is metabolized in part via the CYP2D6 and CYP3A4 pathways. The activities of these metabolic pathways may be inhibited or induced by various co-administered drugs, which may alter plasma oxycodone concentrations. Oxycodone doses may need to be adjusted accordingly.

4.6. Pregnancy and lactation

There are no adequate data from the use of oxycodone in pregnant women. Studies in animals have shown reproductive toxicity only at maternal toxic doses (see section 5.3). The potential risk for humans is unknown. Oxycodone should not be used in pregnancy unless clearly necessary.

Oxycodon passes the placenta. Following long-term treatment during pregnancy, oxycodone may cause withdrawal in the new-born infant. If oxycodone is used during labour and delivery this may cause respiratory depression in the newborn.

Oxycodone is excreted into breast milk. A milk plasma concentration ratio of 3.4:1 was measured. A risk to the suckling child cannot be excluded in particular following intake of multiple doses of OxyContin by the breast-feeding mother. Breast-feeding should be discontinued during treatment with OxyContin.

4.7. Effects on ability to drive and use machines

OxyContin may impair ability to drive and use machinery. This is particularly likely at the initiation of treatment with OxyContin, after dose increase or changes in medicinal product therapy and if OxyContin is combined with alcohol or other CNS depressant agents.

Patients stabilised on a specific dose will not necessarily be restricted. Therefore, the physician should decide for each individual patient whether the patient is allowed to drive or use machinery.

4.8. Undesirable effects

Due to its pharmacological properties oxycodone may cause respiratory depression, miosis, bronchial spasm and spasm of unstriated muscles and may suppress the cough reflex.

The most frequently reported undesirable effects are nausea (especially at the beginning of treatment) and constipation.

Respiratory depression is the chief hazard of an opioid overdose and occurs predominantly in elderly or debilitated patients.

Opioids may cause severe hypotension in susceptible patients.

The following frequency categories form the basis for classification of the undesirable effects:

Very common: >1/10

Common: >1/100 to < 1/10

Uncommon: >1/1000 to < 1/100

Rare: >1/10000 to < 1/1000

Very rare: < 1/10000

Not known cannot be estimated from the available data

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Rare: Herpes simplex

Immune system disorders

Uncommon: Hypersensitivity

Very rare: Anaphylactic responses

Metabolism and nutrition disorders

Common: Decreased appetite up to loss of appetite

Rare: Dehydration, increased appetite

Psychiatric disorders

Common: Altered mood and personality change (e.g. anxiety, depression, euphoric mood), decreased activity, restlessness, psychomotor hyperactivity, agitation, nervousness, insomnia, abnormal thinking, confusional state

Uncommon: Perception disturbances (e.g. hallucination, derealisation), reduced libido

Not known: Drug dependence

Nervous system disorders

Very common: Sedation (somnolence up to a depressed level of consciousness), dizziness, headache

Common: Syncope, paraesthesia

Uncommon: Concentration impaired, migraine, dysgeusia, hypertonia (increased muscles tension), tremor, involuntary muscle contractions, hypoaesthesia, abnormal coordination

Rare: Convulsions (especially in persons with epileptic disorder or predisposition to convulsions), amnesia

Very rare: Speech disorder

Eye disorders

Uncommon: Visual disturbances

Ear and labyrinth disorders

Uncommon: Hearing impaired, vertigo

Cardiac disorders

Uncommon: Tachycardia

Rare: Palpitations

Vascular disorders

Common: Decrease in blood pressure

Uncommon: Vasodilatation

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea

Uncommon: Dysphonia, cough

Gastrointestinal disorders

Very common: Constipation, vomiting, nausea

Common: Abdominal pain, diarrhoea, dry mouth, hiccups, dyspepsia

Uncommon: Mouth ulceration, stomatitis, flatulence, eructation

Rare: Melaena, tooth disorders such as dental caries, gingival bleeding, dysphagia

Very rare: Ileus

Hepatobiliary disorders

Uncommon: Biliary colic, cholestasis, hepatic enzymes increased

Skin and subcutaneous tissue disorders

Very common: Pruritus

Common: Skin reactions/rash

Rare: Dry skin

Very rare: Urticaria

Renal and urinary disorders

Common: Urinary retention, dysuria, micturition urgency

Reproductive system and breast disorders

Uncommon: Erectile dysfunction

Rare: Amenorrhoea

General disorders and administration site conditions

Common: Hyperhidrosis up to chills, asthenia

Uncommon: Physical dependence with drug withdrawal syndrome, pain (e.g. chest pain), malaise, edema

Rare: Weight increase, weight decrease, thirst

Not known: Drug tolerance

Injury, poisoning and procedural complications

Uncommon: Injuries from accidents

[only for strength 5 mg:]

Sunset yellow FCF (E110) may cause allergic reactions.

4.9. Overdose

Symptoms of intoxication:

Miosis, respiratory depression, somnolence progressing up to stupor, skeletal muscle flaccidity, bradycardia as well as hypotension. Coma, non-cardiogenic pulmonary edema and circulatory failure may occur in more severe cases and may lead to a fatal outcome.

Therapy of intoxication:

Overdose may be treated by the administration of opioid antagonists (e.g. naloxone 0.4-2 mg intravenously). Administration should be repeated at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of 0.9% sodium chloride or 5% dextrose (corresponding to 0.004 mg/ml naloxone). The infusion should be run at a rate related to the previously administered bolus doses and should be in accordance with the patient's response.

Emptying the stomach should be considered.

Supportive measures (including artificial ventilation, oxygen, vasopressors, and fluid infusions) should be employed in the management of circulatory shock accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism should be maintained.

5. Pharmacological properties

5.1. Pharmacodynamic properties

Pharmaco-therapeutic group: natural opium alkaloids

ATC-Code: N02AA05

Oxycodone has affinity for mu, kappa and delta opioid receptors in the brain, spinal cord and peripheral organs. Oxycodone is an opioid agonist at these receptors with no antagonistic effect. The therapeutic effect is mainly analgesic and sedative.

Endocrine System

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.

Other Pharmacologic Effects

In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.

5.2. Pharmacokinetic properties

Maximum plasma levels occur approximately 1 to 1.5 hours after the hard capsules have been taken. In a bioavailability study about another immediate-release oxycodon preparation (solution), the resorption extent (AUC) was increased by 20% after having a fatty meal, whereas the resorption rate (Cmax) was lowered by 20% compared to administration in a fasting state. It is assumed that there are no clinical consequences. Special recommendations regarding meal times when taking OxyContin are not required.

The absolute bioavailability of oxycodone amounts to 42-87% relative to parenteral administration. After absorption, oxycodone is distributed overthe entire body. Oxycodone shows a steady state distribution volume of 2.6 l/ kg, a plasma protein binding of about 45% and an elimination half life of 4 to 6 hours.

Via the P450 cytochrome system, oxycodone is metabolised to noroxycodone, oxymorphone and noroxymorphone and several glucuronide conjugates in the intestines and the liver; CYP2D6 and CYP3A4 play the most important role in that. In-vitro studies suggest that therapeutic doses of cimetidine are not likely to significantly influence the production of noroxycodone. Quinidine reduces the production of oxymorphone in man without substantially influencing the pharmacodynamics of oxycodone Separate published studies in healthy subjects showed that concomitant voriconazole (enzyme inhibitor) and oxycodone administration increases the oxycodone plasma level, whereas concomitant rifampin (enzyme inducer) and oxycodone administration reduces the oxycodone plasma level. The contribution of the metabolites to overall pharmacodynamic effect is insignificant. Oxycodone and its metabolites are excreted in both urine and faeces. Oxycodone also crosses the placenta and may be detected in breast milk.

The plasma concentration of oxycodone is only influenced minimally by the age. In elderly people the plasma concentration is approximately 15% higher than in younger people.

Under consideration of the respective body weight, women have on average a 25% higher plasma concentration than men.

In comparison to healthy subjects, patients with light to severe liver function disorders have a higher plasma concentration of oxycodone and noroxycodone, and a lower plasma concentration of oxymorphone. In comparison to healthy subjects, patients with light to severe renal function disorders have a higher plasma concentration of oxycodone and its metabolites. The elimination half-life of oxycodone may be increased in patients with liver and/or renal function disorders, which can lead to a stronger effect.

5.3. Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

Oxycodone showed 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 fetuses 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.

There were no effects on F2 generation.

Long term carcinogenicity studies have not been performed.

The results of in vitro and in vivo studies indicate that the genotoxic risk of oxycodone to humans is minimal or absent at the systemic oxycodone concentrations that are achieved therapeutically. Oxycodone was not genotoxic in a bacterial mutagenicity assay or in an in vivo micronucleus assay in the mouse. Oxycodone produced a positive response in the in vitro mouse lymphoma assay in the presence of rat liver S9 metabolic activation at dose levels greater than 25 µg/mL. Two in vitro chromosomal aberrations assays with human lymphocytes were conducted. In the first assay, oxycodone was negative without metabolic activation but was positive with S9 metabolic activation at the 24 hour time point but not at 48 hours after exposure. In the second assay, oxycodone did not show any clastogenicity either with or without metabolic activation at any concentration or time point.

6. Pharmaceutical particulars

6.1. List of excipients

Capsule content:

Microcrystalline cellulose (E460i)

Magnesium stearate

Capsule shell:

Gelatin

Sodium laurilsulfate

Titanium dioxide (E171)

Iron oxide (E172)

Indigo carmine (E132),

[only for strength 5 mg:]

sunset yellow FCF (E110)

Black printing ink:

Shellac

Iron oxide (E172)

Propylene glycol

6.2. Incompatibilities

Not applicable.

6.3. Shelf life

3 years

6.4. Special precautions for storage

Do not store above 30°C.

6.5. Nature and contents of container

PVC/PVdC blister packs with aluminium backing foil

[for MRP DE/H/0366/0xx:]

Package sizes: 20 capsules, hard, blister

50 capsules, hard, blister

100 capsules, hard, blister

Xxx?

Hospital pack: xxx

Not all pack sizes may be marketed.

[for MRP DE/H/1026/0xx:]

Package sizes: 20 capsules, hard, blister

50 capsules, hard, blister

Hospital pack: xxx

Not all pack sizes may be marketed.

6.6. Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

[To be completed nationally]

8. Marketing authorisation numbers

[To be completed nationally]

9. Date of first authorisation

[To be completed nationally]

10. Date of revision of the text

[To be completed nationally]