PACKAGE INSERT. Each JURNISTA 4 mg extended-release tablet contains 4,36 mg and delivers 4 mg hydromorphone

Transcription

1 PACKAGE INSERT SCHEDULING STATUS Schedule 6 PROPRIETARY NAME AND DOSAGE FORM JURNISTA JURNISTA 4 mg extended-release tablets 8 mg extended-release tablets JURNISTA 16 mg extended-release tablets Contains the antioxidant, butylated hydroxytoluene. COMPOSITION Each JURNISTA 4 mg extended-release tablet contains 4,36 mg and delivers 4 mg hydromorphone hydrochloride, equivalent to 3,56 mg hydromorphone base. Each JURNISTA 8 mg extended-release tablet contains 8,72 mg and delivers 8 mg hydromorphone hydrochloride, equivalent to 7,12 mg hydromorphone base. Each JURNISTA 16 mg extended-release tablet contains 16,35 mg and delivers 16 mg hydromorphone hydrochloride, equivalent to 14,24 mg hydromorphone base. PHARMACOLOGICAL CLASSIFICATION A.2.9 Other Analgesics PHARMACOLOGICAL ACTION Pharmacodynamic Properties Hydromorphone is a semi-synthetic morphine derivative. Hydromorphone exerts its principal pharmacological effects on the CNS and smooth muscle. These effects are expressed and modulated by binding to specific opioid receptors. Hydromorphone is principally an agonist of -receptors, showing a weak affinity for -receptors. Analgesia occurs as a consequence of the binding of hydromorphone to the -receptors of the CNS. CCDS: 20 April 2009 Page 1 of 37

2 Although estimates vary (from 2 to 10 times), hydromorphone appears to be approximately 5 times as potent (by weight) as morphine and has a shorter duration of effect. Respiratory depression occurs principally by direct action on the cerebral respiratory control centers. Hydromorphone may cause nausea and vomiting due to direct stimulation of the chemoreceptors for emesis in the posterior area of the medulla. Pharmacokinetic Properties Following a single oral dose of JURNISTA extended-release tablets, plasma concentrations gradually increase over 6 to 8 hours thereafter concentrations are sustained for approximately hours postdose; the mean Tmax values were approximately hours. Hydromorphone is released in a consistent manner from the dosage form, with drug absorption continuing throughout the intestinal tract for approximately 24 hours, consistent with once-daily dosing. The mean absolute bioavailability of hydromorphone after a single dose of 8 mg, 16 mg or 32 mg of JURNISTA ranged from 22 % to 26 %. The concomitant administration of JURNISTA with a high fat meal has no effect on the absorption of hydromorphone. Steady state plasma concentrations are approximately twice those observed following the first dose, and steady state is reached by the fourth dose of JURNISTA. No time dependent change in pharmacokinetics was seen with multiple dosing. Plasma protein binding is low (< 30 %). Glucuronidation is the main metabolic pathway and the principal metabolite is hydromorphone 3-glucuronide, which follows a similar time course to hydromorphone in plasma. Unlike morphine, no 6-glucuronide is produced. Linear pharmacokinetics has been demonstrated for the (extended release) tablet over the dose range 4 to 64 mg, with dose proportional increase in plasma concentrations (C max ) and overall exposure (AUC). CCDS: 20 April 2009 Page 2 of 37

3 The effect of age on the single-dose pharmacokinetics of hydromorphone immediate-release resulted in a 14 % decrease in C max and a modest increase (11 %) in AUC in the elderly compared to the young. No difference in T max was observed. Greater sensitivity of older individuals cannot be excluded. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population. JURNISTA plasma concentrations and pharmacokinetic parameters are comparable in male and female subjects. Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of hydromorphone. In studies, that used single oral dosing with conventional (immediate release) tablets, hepatic impairment reduces the first-pass metabolism of hydromorphone such that four-fold higher plasma levels of hydromorphone are seen in subjects with moderate hepatic dysfunction. Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites hydromorphone 3-glucuronide and 3-sulphate. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in hydromorphone bioavailability in moderate and severe impairment, respectively. There were also substantial changes in hydromorphone 3-glucuronide elimination kinetics for the severe impairment group, although haemodialysis was effective at reducing plasma levels of both hydromorphone and metabolites. See section DOSAGE AND DIRECTIONS FOR USE for recommendations on dosage. In a study comparing hydromorphone absorption with JURNISTA when taken with 240 ml of 4 %, 20 % and 40 % alcohol, C max increased on average by 17, 31, and 28 % respectively in the fasting state and was less affected in the fed state with increases of 14, 14, and 10 %, respectively. Median T max (fasted and fed) with 4, 20 and 40 % alcohol was h and with 0 % alcohol was 16 h. No effect was seen on AUC values both in the fed and fasted state. Due to the OROS technology in JURNISTA, the extendedrelease properties of JURNISTA are maintained in the presence of alcohol. For the pharmacodynamic interactions (see Special Warnings and Precautions for use). CCDS: 20 April 2009 Page 3 of 37

4 INDICATIONS Treatment of severe chronic intractable pain. CONTRA-INDICATIONS JURNISTA is contraindicated in: Patients with a known hypersensitivity to hydromorphone or to any of the excipients. Patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have blind loops of the gastrointestinal tract or gastrointestinal obstruction. The management of acute or post-operative pain. Patients with severely decreased liver function. Patients with respiratory insufficiency. Patients with acute abdominal pain of unknown origin. Patients with status asthmaticus. Concomitant treatment with MAO-inhibitors or within 14 days of stopping such treatment. Concomitant treatment with buprenorphine, nalbuphine or pentazocine. Patients in a coma state. Children, pre-term newborn infants, or during labour for delivery of pre-term newborn infants. WARNINGS JURNISTA may cause severe hypotension in an individual whose ability to maintain blood pressure is compromised by a depleted blood volume or concomitant administration of drugs such as phenothiazines or general anesthetics. JURNISTA should not be used in situations with risk of paralytic ileus. If during treatment, paralytic ileus is suspected, the treatment should be stopped. CCDS: 20 April 2009 Page 4 of 37

5 In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with JURNISTA within 24 hours after the operation. Thereafter, a new dose should be used in accordance with the change needed for pain relief, if needed. Impaired respiration: Respiratory depression is the most important hazard of hydromorphone preparations but occurs most frequently in overdose situations, in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate doses may dangerously decrease respiration. JURNISTA should be used with extreme caution in patients having a substantially decreased respiratory reserve or pre-existing respiratory depression and in patients with chronic obstructive pulmonary disease. Severe pain antagonises the respiratory depressant effects of opioids. However, should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for regional anaesthetic procedures or other interruptions of pain transmission pathways should not receive JURNISTA within 24 hours of the procedure. Concomitant administration of hydromorphone with other opioid analgesics is associated with an increased risk of respiratory failure. Therefore, it is important to reduce the dose of hydromorphone, when other analgesics are given concomitantly. Head injury and increased intracranial pressure: The respiratory depressant effects of JURNISTA with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury or raised intracranial pressure. JURNISTA produces effects, which may obscure neurological signs of further increases in intracranial pressure in patients with head injuries. JURNISTA should only be administered under such circumstances when considered essential and then with extreme caution. Gastrointestinal tract and other smooth muscle: CCDS: 20 April 2009 Page 5 of 37

6 Hydromorphone causes a reduction in gastrointestinal motility associated with an increase in smooth muscle tone. Constipation is a frequent side effect reported with the treatment with opioids. Patients should be advised on measures to prevent constipation and prophylactic laxative use should be considered. Extra caution should be used in patients with chronic constipation. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with JURNISTA and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids. The administration of JURNISTA may obscure the diagnosis or clinical course of acute abdominal conditions. Therefore it is important to make sure that the patient is not suffering from intestinal occlusion, especially of the ileus before initiation of treatment. Hydromorphone also can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should therefore be exercised in the administration of JURNISTA to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery. The JURNISTA tablet is non deformable and does not appreciably change in shape in the GI tract. There have been very rare reports of obstructive symptoms in patients with known strictures in association with ingestion of medicinal products in non deformable controlled-release formulations (see CONTRA- INDICATIONS). Patients should be advised not to be alarmed if they notice what appears to be the JURNISTA tablet in their stools, as it is simply the non-dissolvable shell. INTERACTIONS Monoamine oxidase inhibitors (MAOIs) may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids. JURNISTA is contraindicated for patients taking MAOIs. The concomitant use of hydromorphone with morphine agonist/antagonists (buprenorphine, nalbuphine, petazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms, therefore this combination is contraindicated. CCDS: 20 April 2009 Page 6 of 37

7 The concomitant use of central nervous system depressants such as hypnotics, sedatives, general anaesthetics, antipsychotics and alcohol may cause additive depressant effects, and respiratory depression, hypotension and profound sedation or coma may occur. When this combination is indicated, the dose of one or both agents should be reduced. JURNISTA may enhance the neuromuscular blocking action of muscle relaxants and cause an increased degree of respiratory depression. The concomitant use of alcohol should be avoided. Alcohol increases the sedative effect of hydromorphone. PREGNANCY AND LACTATION Pregnancy: No clinical data on exposed pregnancies are available. While animal studies have revealed no teratogenic effects, reproductive toxicity has been observed. Hydromorphone has been shown to cross the placental barrier in experimental animals. The potential risk for humans from use of opiates during pregnancy is unknown. JURNISTA should not be used during pregnancy and labour due to impaired uterine contractility and the risk of neonatal respiratory depression. Withdrawal symptoms may be observed in the newborn of mothers undergoing chronic treatment. Lactation: Low concentrations of hydromorphone and other opioid analgesics have been detected in human milk in clinical studies. Preclinical studies have shown that hydromorphone can be detected in milk of lactating rats. JURNISTA should not be used during breast-feeding. DOSAGE AND DIRECTIONS FOR USE CCDS: 20 April 2009 Page 7 of 37

8 Safe and effective administration of JURNISTA to patients with pain depends upon a comprehensive assessment of the patient. The nature of the pain as well as the concurrent medical status of the patient will affect selection of the dose. Owing to the varied response observed to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose of opioid therapy and titrated to an adequate level of analgesia, balanced against an acceptable frequency of adverse reactions. Appropriate prophylaxis for known adverse reactions (for example constipation), should be instituted with initiation of therapy. Patients should be instructed to swallow the JURNISTA tablet whole with a glass of water, at approximately the same time each day, and never to chew, divide, or crush it. JURNISTA should not be taken more than once every 24 hours. If the patient did not take the regularly scheduled dose of JURNISTA, the patient should be instructed to take the next dose immediately and start a new 24-hour regimen. Patients currently not routinely receiving opioids: The initial dose in patients currently not routinely receiving opioids should not exceed 8 mg every 24 hours. Some patients may benefit from an initial titration dose of 4 mg every 24 hours to improve tolerability. The dose may be titrated upwards, if required, in increments of either 4 or 8 mg depending on response and supplementary analgesic requirements. Dose should not be titrated more frequently than every 2 days. Patients currently receiving opioids regularly: In patients currently taking opioid analgesics, the starting dose of JURNISTA should be based on the prior daily opioid dose, using standard equianalgesic ratios. For opioids other than morphine, first estimate the CCDS: 20 April 2009 Page 8 of 37

9 equivalent total daily dose of morphine, then use the table (1a) below to determine the equivalent total daily dose of JURNISTA. Table 1a: Conversion Table: Multiplication Factors for Converting the Daily Dose of Prior Opioids to the Daily Dose of JURNISTA (mg/day Prior Opioid x Factor = mg/day JURNISTA): Prior Opioid Oral Prior Opioid (factor) Parenteral Prior Opioid (factor) Morphine 0,2 0,6 Hydromorphone 1 4 No fixed conversion ratio is likely to be satisfactory in all patients, due to individual patient and formulation differences. Therefore conversion to the recommended starting dose of JURNISTA should be followed by close patient monitoring and titration. Dosages should be rounded down to the closest dose of JURNISTA available in 4 mg increments (4, 8, 16, 32, 64 mg tablets), as clinically indicated. Discontinue all other around-the-clock opioid analgesic medications when JURNISTA therapy is initiated. Supplemental Analgesia: In addition to once daily JURNISTA therapy, supplemental breakthrough pain medication in the form of immediate release preparations (e.g. immediate release morphine) could be made available to all patients with chronic pain. For conversion, the conversion table should be used. Individual supplemental doses of immediate release morphine should generally not exceed 10 % to 25 % of the JURNISTA dose. Individualisation of Dosage and Maintenance of Therapy: After initiation of therapy with JURNISTA, dose adjustments may be necessary to obtain the patient s best balance between pain relief and opioid-related side effects. If the pain increases in severity or analgesia is inadequate, a gradual increase in dosage may be required. In order to allow the effects of the dose change to stabilise, the dosage should be increased no more CCDS: 20 April 2009 Page 9 of 37

10 frequently than every two days. As a guideline, dosage increases of 25 %-100 % of the current daily dose of JURNISTA should be considered for each titration step. Once patients become stable on once-daily JURNISTA therapy, the dose may be continued for as long as pain relief is necessary. The continued need for around-the-clock opioid therapy and adjustments in therapy should be reassessed periodically as appropriate. Use in children: JURNISTA is not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy. Use in the elderly: The medical setting of the elderly is often complex. Therefore, treatment with JURNISTA should be initiated cautiously, and the initial dose should be reduced. Renal and hepatic impairment: Following single dose administration of hydromorphone immediate release tablets, the following results were observed in clinical studies: In patients with moderate hepatic insufficiency (scoring 7-9 on Child-Pugh rating scale) both exposure (plasma AUC) and peak plasma concentrations of hydromorphone were approximately 4-times higher compared with healthy controls and elimination half-life was unaltered. In patients with moderate renal insufficiency (creatinine clearance of ml/min), exposure (plasma AUC) to hydromorphone was 2-times higher than in those with normal renal function and elimination half-life was unaltered. In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), exposure (plasma AUC) to hydromorphone was approximately 4-times greater than in those with normal renal function and elimination half-life 3-times longer. Therefore, patients with either moderate hepatic or renal insufficiency should be started on a reduced dose and closely monitored during dose titration. In patients with severe renal insufficiency an increased dosing CCDS: 20 April 2009 Page 10 of 37

11 interval should also be considered and these patients should in addition be monitored during maintenance therapy for development of opioid-related adverse reactions. Cessation of Therapy: In patients who are physically dependent and receiving daily administration of hydromorphone, abrupt discontinuation of treatment with JURNISTA will result in symptoms of withdrawal syndrome. If cessation of therapy with JURNISTA is indicated, patients should therefore have their JURNISTA dose reduced by 50 % every 2 days until the lowest possible dose is reached, at which time therapy may be safely discontinued. If symptoms of withdrawal appear, tapering should be stopped. The dose should be slightly increased until the signs and symptoms of opioid withdrawal disappear. Tapering should then begin again but with longer periods of time between each JURNISTA dose reduction, or before converting to an equianalgesic dose of another opioid to continue tapering. SIDE-EFFECTS AND SPECIAL PRECAUTIONS Side-effects Adverse Drug Reactions In clinical trials with JURNISTA (n = 1684), the most commonly reported ADRs were opioid-related GI events of constipation, nausea, and vomiting. They can usually be managed by dose reduction, laxatives or anti-emetics, as appropriate. The table below shows the adverse drug reactions (ADRs) observed with JURNISTA and those that have been reported with other hydromorphone hydrochloride formulations. If the JURNISTA and hydromorphone hydrochloride frequencies were different, the higher frequency of both databases was used. Table 2: Adverse Drug Reactions in JURNISTA treated patients. System Organ Adverse Drug Reaction Frequency Class Very Common (> 1/10) Common (1/100 to <1/10) Uncommon (1/1000 to <1/100) Rare ( 1/10,000 to <1/1000) CCDS: 20 April 2009 Page 11 of 37

12 Table 2: Adverse Drug Reactions in JURNISTA treated patients. System Organ Adverse Drug Reaction Frequency Class Very Common (> 1/10) Common (1/100 to <1/10) Uncommon (1/1000 to <1/100) Infections and Diverticulitis, Gastroenteritis infestations Endocrine disorders Metabolism and Anorexia appetite nutrition disorders Dehydration Fluid retention Hyperuricaemia Psychiatric Insomnia Decreased libido disorders Anxiety Panic attack Confusional state Paranoia Nervousness Aggression Abnormal dreams Crying Depression Listless Mood alterations Drug tolerance* Restlessness Dysphoria Hallucination Euphoric mood Nervous system Somnolence Memory impairment Myoclonus disorders Dizziness Hypoaesthesia Abnormal coordination Headache Paraesthesia Dyskinesia Tremor or involuntary Syncope muscle contractions Dysarthria Sedation Balance disorder Disturbance in Depressed level of attention consciousness Dysgeusia Hyperaesthesia Encephalopathy Cognitive disorder Psychomotor hyperactivity Fits/convulsions Eye disorders Visual disorders s.a. Miosis, blurred vision Diplopia Dry eye Ear and labyrinth Vertigo Tinnitus disorders Cardiac Disorders Tachycardia Palpitations Extrasystoles Vascular disorders Hypotension Flushing Hypertension Rare ( 1/10,000 to <1/1000) Hypogonadism Dependence* Hyperreflexia Bradycardia CCDS: 20 April 2009 Page 12 of 37

13 Table 2: Adverse Drug Reactions in JURNISTA treated patients. System Organ Adverse Drug Reaction Frequency Class Very Common (> 1/10) Common (1/100 to <1/10) Uncommon (1/1000 to <1/100) Respiratory, Dyspnoea Respiratory distress thoracic and Rhinorrhoea mediastinal Hypoxia disorders Bronchospasm Hyperventilation Sneezing Gastrointestinal Constipation Dry mouth Abdominal distension, disorders Nausea Diarrhoea Haemorrhoids Vomiting Abdominal pain Haematochezia Dyspepsia Abnormal faeces Dysphagia Intestinal obstruction Flatulence Diverticulum Eructation Gastrointestinal motility disorder Large intestine perforation Hepatobiliary disorders Skin and Hyperhidrosis Eczema* subcutaneous Pruritus tissue disorders Rash Musculoskeletal Muscle spasms Myalgia and connective Back pain tissue disorders Arthralgia Pain in extremity Renal and urinary Urinary retention Urinary hesitation disorders Dysuria Pollakiuria Micturition disorder Reproductive Erectile dysfunction / system and breast impotence disorders Sexual dysfunction General disorders Asthenia Oedema Feeling abnormal and administration Drug withdrawal Malaise site conditions syndrome Difficulty in walking Pyrexia Feeling jittery Pain Hangover Chest discomfort Chills Rare ( 1/10,000 to <1/1000) in pancreatic enzymes* Anal fissure Bezoar Duodenitis Ileus Impaired gastric emptying Painful defaecation Biliary colic Reddening of face/erythema Feeling drunk Feeling hot and cold Hypothermia CCDS: 20 April 2009 Page 13 of 37

14 Table 2: Adverse Drug Reactions in JURNISTA treated patients. System Organ Adverse Drug Reaction Frequency Class Very Common (> 1/10) Common (1/100 to <1/10) Uncommon (1/1000 to <1/100) Rare ( 1/10,000 to <1/1000) Investigations Weight decreased Oxygen saturation Blood potassium Blood testosterone Hepatic enzyme Blood amylase Injury, poisoning and procedural complications Fall Contusion Overdose * Adverse drug reaction (ADR) reported with other hydromorphone HCl formulations. The following terms of unknown frequencies have been reported in the literature: Respiratory failure; delirium and amenorrhea. Respiratory depression may be more likely in certain subgroups of patients (see WARNINGS). Special Precautions Special risk patients: JURNISTA should be administered with caution and in reduced dosages in patients with moderate to severe renal or mild to moderate hepatic insufficiency, adrenocortical insufficiency, myxedema, hypothyroidism, prostatic hypertrophy or urethral stricture. Caution should also be exercised in the administration of JURNISTA to patients with CNS depression, kyphoscoliosis, toxic psychosis, acute alcoholism, delirium tremens, or convulsive disorders. Use in the Elderly: Elderly are more prone to CNS adverse effects (confusion) and gastrointestinal disturbances, and physiological reduction of the renal function. Therefore, extra caution should be shown, and the initial dose should be reduced. Concomitant use of other medications, especially tricyclic antidepressants, increases the risk of confusion and constipation. Diseases of the prostate gland and the urinary tract are often seen in the elderly. This contributes to the increased risk of urinary retention. The above CCDS: 20 April 2009 Page 14 of 37

15 considerations should stress the importance of caution rather than imply a restriction of the use of hydromorphone in the elderly. Drug dependence: JURNISTA should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance and psychological dependence observed in these patient populations. With abuse by parenteral route, the tablet excipients may be fatal. With the continued use of JURNISTA, the development of tolerance and physical dependence may be expected. The deliberate abuse of JURNISTA may occur and is characterized by changes in behaviour, which are not seen in patients whose pain is treated appropriately with JURNISTA. The development of psychological dependence or an addictive effect is believed to occur only in individuals who may be predisposed in some way and is not a normal or expected response to the appropriate administration of opioids for pain management. However, even if a patient has misused opioids in the past, JURNISTA or other opioids could still be indicated in the treatment of moderate to severe pain in the patient. A requirement for an increase in dose may be due to the underlying pathology and should be re-evaluated. In most cases the request for higher doses reflects a real need for pain relief and should not be mistaken for inappropriate medication use. Use of JURNISTA in connection with sporting will imply disqualification. Since alcohol increases the sedative effect of hydromorphone concomitant use of JURNISTA and alcohol should be avoided. Reactions to Excipients CCDS: 20 April 2009 Page 15 of 37

16 An excipient of JURNISTA, butylated hydroxytoluene, is known to be an irritant to the eyes, skin and mucous membranes. Effects on Ability to Drive and Use Machines JURNISTA can have a major influence on the ability to drive and use machines. This is particularly likely at the start of therapy, following an increase in dose or change of preparation. KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT JURNISTA overdose is characterized by respiratory depression, drowsiness which progresses to stupor and coma, musculoskeletal flaccidity, cold skin, contracted pupils and, at times, tachycardia and hypotension. In cases of severe overdose, apnoea, circulatory collapse, cardiac arrest and death may occur. In the treatment of overdose, primary attention should be given to the reestablishment of adequate respiratory exchange keeping the airway open and instituting assisted or controlled ventilation. If the oral ingestion was recent, gastric contents may be emptied by gastric lavage, as indicated. Supportive measures (including oxygen and, vasopressors) should be used to manage the shock and pulmonary edema, which potentially accompany overdose. Cardiac arrest and arrhythmias may require cardiac massage or defibrillation. In cases of severe overdose, specific antidotes such as naloxone and nalmefene should be used to manage respiratory depression (see the prescribing information for the specific opioids antagonist for details of proper use). The effect of naloxone is relatively short, therefore, the patient should be carefully monitored until respiration has stabilised. CCDS: 20 April 2009 Page 16 of 37

17 JURNISTA will release hydromorphone for approximately 24 hours. This should be taken into account in determining the treatment. Opioid antagonists should not be given in the absence of clinically significant respiratory depression, or circulatory depression because of opioids. Opioid antagonists should be administered with caution to patients suspected to be physically dependent on hydromorphone, since rapid reversal of an opioid, including hydromorphone, may precipitate symptoms of withdrawal. IDENTIFICATION JURNISTA 4 mg extended-release tablet: pale beige, round, biconvex tablet, with HM 4 printed in black ink on one side. JURNISTA 8 mg extended-release tablet: red, round, biconvex tablet, with HM 8 printed in black ink on one side. JURNISTA 16 mg extended-release tablet: yellow, round, biconvex tablet, with HM 16 printed in black ink on one side. PRESENTATION JURNISTA extended-release tablets are packed in opaque PVC/Aclar blisters, heat-sealed to aluminium foil. One or more blisters are packed into an outer carton. Each carton contains 14 or 28 tablets. STORAGE INSTRUCTIONS Store below 25 C. Blisters must be kept in the cartons until required for use. KEEP OUT OF REACH OF CHILDREN. REGISTRATION NUMBER(s) JURNISTA 4 mg: 41/2.9/1136 JURNISTA 8 mg: 41/2.9/1130 JURNISTA 16 mg: 41/2.9/1131 CCDS: 20 April 2009 Page 17 of 37

18 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION JANSSEN PHARMACEUTICA (PTY) LTD (Reg. No. 1980/011122/07) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, DATE OF PUBLICATION OF THE PACKAGE INSERT October 2010 CCDS: 20 April 2009 Page 18 of 37

19 VOUBILJET SKEDULERINGSTATUS Skedule 6 EIENDOMSNAAM EN DOSEERVORM JURNISTA JURNISTA 4 mg verlengde-vrystelling tablette 8 mg verlengde-vrystelling tablette JURNISTA 16 mg verlengde-vrystelling tablette Bevat die antioksidant, gebutileerde hidroksietolueen. SAMESTELLING Elke JURNISTA 4 mg verlengde-vrystelling tablet bevat 4,36 mg en lewer 4 mg hidromorfoonhidrochloried, ekwivalent aan 3,56 mg hidromorfoon basis. Elke JURNISTA 8 mg verlengde-vrystelling tablet bevat 8,72 mg en lewer 8 mg hidromorfoonhidrochloried, ekwivalent aan 7,12 mg hidromorfoon basis. Elke JURNISTA 16 mg verlengde-vrystelling tablet bevat 16,35 mg en lewer 16 mg hidromorfoonhidrochloried, ekwivalent aan 14,24 mg hidromorfoon basis. FARMAKOLOGIESE KLASSIFIKASIE A.2.9 Ander Analgetika FARMAKOLOGIESE WERKING Farmakodinamiese eienskappe Hidromorfoon is n semi-sintetiese morfienderivaat. Die belangrikste farmakologiese werking van hidromorfoon vind plaas in die SSS en gladde spiere. Hierdie werksaamhede word uitgedruk en gemoduleer deur binding aan spesifieke opioïedreseptore. Hidromorfoon is hoofsaaklik n agonis van - reseptors en toon n swak affiniteit vir -reseptore. Analgesie ontstaan as n gevolg van die binding van hidromorfoon aan die -reseptore van die SSS. CCDS: 20 April 2009 Page 19 of 37

20 Alhoewel skattings wissel (van 2 tot 10 keer), wil dit voorkom asof JURNISTA ongeveer 5 keer so kragtig is (volgens massa) as morfien en n korter duur van werking het. Respiratoriese onderdrukking kom hoofsaaklik voor deur direkte werking op die serebrale respiratoriese beheersentrum. Hidromorfoon kan naarheid en braking veroorsaak as gevolg van direkte stimulasie van die chemoreseptore vir emese in die posterior streek van die medulla. Farmakokinetiese eienskappe Na n enkele orale dosis JURNISTA verlengde-vrystelling tablette neem plasmakonsentrasies geleidelik toe vir 6 tot 8 uur daarna en word volgehou vir ongeveer uur na dosering; die gemiddelde Tmaks waardes was ongeveer uur. Hidromorfoon word bestendig vrygestel uit die doseringsvorm, met volgehoue geneesmiddel-absorpsie regdeur die dermkanaal vir ongeveer 24 uur, wat steekhoudend is met een-keer-daaglikse dosering. Die gemiddelde absolute biobeskikbaarheid van hidromorfoon na n enkele dosis van 8 mg, 16 mg of 32 mg JURNISTA het gereik van 22 % tot 26 %. Die gesamentlike toediening van JURNISTA met n hoëvet maaltyd het geen effek op die absorpsie van hidromorfoon nie. Bestendige toestand plasmakonsentrasies is ongeveer twee keer soveel as wat waargeneem is met die eerste dosis en bestendige toestand word bereik teen die vierde dosis van JURNISTA. Geen tydsafhanklike verandering in farmakokinetika is met veelvuldige dosisse waargeneem nie. Plasma proteïenbinding is gering (< 30 %). Glukuronidasie is die belangrikste metaboliese weg en die belangrikste metaboliet is hidromorfoon 3-glukuronied, wat n soortgelyke tydsverloop het as hidromorfoon in plasma. In teenstelling met morfien, word geen 6-glukuronied geproduseer nie. Lineêre farmakokinetika is aangetoon vir die ER ( Extended Release ) tablet oor die dosis reikwydte 4 tot 64 mg, met dosis-proporsionele toename in plasmakonsentrasie (K maks ) en algehele blootstelling (AOK). CCDS: 20 April 2009 Page 20 of 37

21 Die effek van ouderdom op die enkeldosis farmakokinetika van hidromorfoon onmiddellike-vrystelling het gelei tot n 14 % afname in K maks en n matige toename (11 %) in AOK by die bejaarde, vergeleke met jongmense. Geen verskil in T maks is waargeneem nie. Verhoogde gevoeligheid by ouer individue kan nie uitgesluit word nie. Oor die algemeen moet die keuse van n dosis vir n bejaarde pasiënt versigtig geskied, gewoonlik deur te begin aan die lae kant van die doseringsreeks, wat die hoër frekwensie van verminderde lewer, nier of hartfunksie en/of gesamentlike siekte of ander geneesmiddelterapie by hierdie populasie weerspieël. JURNISTA plasmakonsentrasies en farmakokinetiese parameters is vergelykbaar by manlike en vroulike pasiënte. Populasie farmakokinetiese analise het geen bewys opgelewer van rasverwante verskille in die farmakokinetika van hidromorfoon na toediening nie. In navorsingstudies waar enkele orale dosering met konvensionele (onmiddellike vrystelling) tablette gebruik is, verminder lewerinkorting die eerste-deurgangsmetabolisme van hidromorfoon tot so n mate dat viervoudige hoër plasmavlakke van hidromorfoon by pasiënte met matige lewerdisfunksie waargeneem word. Nierinkorting affekteer die farmakokinetika van hidromorfoon en die metaboliete daarvan, hidromorfoon 3-glukuronied en 3-sulfaat. Die effekte van nierinkorting op hidromorfoon farmakokinetika was onderskeidelik tweevoudige en viervoudige toenames in hidromorfoon biobeskikbaarheid by matige en ernstige inkorting. Daar was ook aansienlike veranderinge in die hidromorfoon 3-glukuronied eliminasie-kinetika vir die groep met ernstige inkorting, alhoewel hemodialise doeltreffend was om plasmavlakke van beide hidromorfoon en metaboliete te verlaag. Sien afdeling DOSIS EN GEBRUIKSAANWYSINGS vir aanbevelings oor die dosering. In n navorsingstudie waar absorpsie van hidromorfoon met JURNISTA vergelyk is toe dit geneem is met 240 ml alkohol 4 %, 20 % en 40 %, het die K maks gemiddeld toegeneem met onderskeidelik 17, 31 en 28 % in die vastende toestand en was dit minder aangetas in die gevoede toestand met onderskeidelike toenames van 14, 14 en 10 %. Die mediane T max (vastend en gevoed) met 4, 20 en 40 % alkohol was h en met 0 % alkohol was 16 h. Geen effek is waargeneem op AOK waardes by sowel die gevoede as die vastende toestand nie. Te danke aan die OROS -tegnologie van JURNISTA word die uitgebreide- CCDS: 20 April 2009 Page 21 of 37

22 vrystellingseienskappe JURNISTA volgehou in die teenwoordigheid van alkohol. Vir die farmakodinamiese interaksies (sien Waarskuwings en Spesiale voorsorgmaatreëls vir gebruik). INDIKASIES Behandeling van ernstige chroniese halsstarrige pyn. KONTRAÏNDIKASIES JURNISTA word teenaangedui by: Pasiënte met n bekende hipersensitiwiteit vir hidromorfoon of vir enige van die bestanddele. Pasiënte wat chirurgiese prosedures ondergaan het en/of n onderliggende siekte het wat kan lei tot vernouing van die gastroïntestinale weg, stagnante derms of gastroïntestinale obstruksie. Die beheer van akute of post-operatiewe pyn. Pasiënte met ernstige verminderde lewerfunksie. Pasiënte met respiratoriese ontoereikendheid. Pasiënte met akute abdominale pyn van onbekende oorsprong. Pasiënte met langdurige bronchospasma (status asthmaticus). Gesamentlike behandeling met MAO-remmers of binne 14 dae wat sodanige behandeling gestaak is. Gesamentlike behandeling met buprenorfien, nalbufien of pentasoksien. Pasiënte in n komateuse toestand. Kinders, vroeggebore babas, of tydens kraam vir die verlossing van voortydige pasgebore babas. WAARSKUWINGS JURNISTA kan ernstige hipotensie veroorsaak by n individu by wie die vermoë om die bloeddruk te reguleer deur n verminderde bloedvolume of gesamentlike toediening van geneesmiddels soos fenotiasiene of algemene narkosemiddels aangetas is. JURNISTA moet nie gebruik word by situasies waar daar n risiko vir paralitiese ileus is nie. Indien daar tydens behandeling paralitiese ileus vermoed word, moet die behandeling gestaak word. CCDS: 20 April 2009 Page 22 of 37

23 In die geval van beplande chordotomie of ander pynverligtende operasies moet pasiënte nie binne 24 uur van die operasie met JURNISTA behandel word nie. Daarna kan n nuwe dosis vir pynverligting gebruik word, in ooreenstemming met die behoefte aan verandering, indien nodig. Belemmerde asemhaling: Respiratoriese onderdrukking is die belangrikste gevaar van hidromorfoon preparate, maar dit kom meestal by oordoseringsituasies voor, by die bejaarde, by die verswakte persoon en by diegene wat ly aan toestande wat gepaard gaan met hipoksie of hiperkapnie, wanneer selfs matige dosisse die respirasie gevaarlik kan laat afneem. JURNISTA moet met uiterste versigtigheid gebruik word by pasiënte met n aansienlik verlaagde respiratoriese reserwe of voorafbestaande respiratoriese onderdrukking en by pasiënte met chroniese obstruktiewe pulmonêre siekte. Erge pyn antagoniseer die respiratoriese onderdrukkende effekte van opioïede. Indien pyn egter skielik opklaar, kan hierdie effek skielik na vore tree. Pasiënte wat geskeduleer word vir streeks-narkotiese prosedures of ander onderbrekings van pyn-oordrag weë moet nie JURNISTA binne 24 uur van die prosedure ontvang nie. Gesamentlike toediening van hidromorfoon met ander opioïed-analgetika word geassosieer met n verhoogde risiko vir respiratoriese versaking. Gevolglik is dit belangrik om die hidromorfoon dosis te verminder wanneer ander analgetika gesamentlik gegee word. Kopbesering en verhoogde intrakraniale druk: Die respiratories onderdrukkende effekte van JURNISTA met koolsuurgas-retensie en sekondêre verhoging van serebrospinale vloeistofdruk kan aansienlik sterker word in die teenwoordigheid van kopbesering of verhoogde intrakraniale drukking. JURNISTA produseer effekte wat neurologiese tekens kan verbloem of wat intrakraniale druk meer kan verhoog by pasiënte met hoofbeserings. JURNISTA moet slegs toegedien word onder sodanige omstandighede waar dit noodsaaklik geag word en dan slegs met buitengewone versigtigheid. CCDS: 20 April 2009 Page 23 of 37

24 Gastroïntestinale weg en ander gladde spiere: Hidromorfoon veroorsaak n afname in gastroïntestinale motiliteit, geassosieer met n toename in gladdespier tonus. Hardlywigheid is n gereelde newe-effek wat aangemeld word by behandeling met opioïede. Pasiënte moet geadviseer word oor maatreëls om hardlywigheid te voorkom en die gebruik van voorkomende lakseermiddels moet oorweeg word. Spesiale voorsorg moet gebruik word by pasiënte met chroniese hardlywigheid. Kliniese toestande of medisinale produkte wat n skielike en beduidende verkorting van gastroïntestinale deurgangstyd veroorsaak, kan lei tot verminderde hidromorfoon absorpsie met JURNISTA en kan potensieel lei tot onttrekkingsimptome by pasiënte met n fisiese afhanklikheid van opioïede. Die toediening van JURNISTA kan die diagnose of kliniese verloop van akute abdominale toestande aantas. Dit is gevolglik belangrik om voor aanvang van behandeling te verseker dat die pasiënt nie aan inwendige verstopping, veral van die ileus, ly nie. Hidromorfoon kan ook n toename in galbuisdruk veroorsaak as gevolg van spasma in die sfinkter van Oddi. Versigtigheid moet gevolglik uitgeoefen word by die toediening van JURNISTA aan pasiënte met inflammatoriese of obstruktiewe dermsiektes, akute pankreatitis sekondêr tot galbuis siekte en by pasiënte wat op die punt staan om gal-chirurgie te ondergaan. Die JURNISTA tablet is nie vervormbaar nie en verander nie veel van vorm in die SVK nie. Daar was baie seldsame berigte van obstruktiewe simptome by pasiënte met bekende strikture in assosiasie met die inname van medisinale produkte by nie-vervormbare beheerde-vrystelling formulerings (sien KONTRAÏNDIKASIES). Pasiënte moet aangeraai word om nie te skrik as hulle in hul stoelgang iets gewaar wat soos n JURNISTA tablet lyk nie, aangesien dit slegs die onoplosbare dop is. INTERAKSIES CCDS: 20 April 2009 Page 24 of 37

25 Monoamien-oksidase inhibeerders (MAOIs) kan SSS prikkeling of depressie veroorsaak, hipotensie of hipertensie, indien saam met opioïede toegedien. JURNISTA word teenaangedui by pasiënte wat MAOIs neem. Die gesamentlike gebruik van hidromorfoon met morfien agoniste/antagoniste (buprenorfien, nalbufien, pentasosien) kan lei tot n afname in die analgetiese effek deur kompetitiewe blokkering van die reseptore en sodoende n risiko van onttrekkingsimptome laat ontstaan; gevolglik word hierdie kombinasie teenaangedui. Die gesamentlike gebruik van sentrale senuweestelsel onderdrukkers soos hipnotika, bedaarmiddels, algemene narkosemiddels, antipsigotiese middels en alkohol kan additiewe onderdrukkende effekte en respiratoriese onderdrukking, hipotensie veroorsaak en intense kalmering of koma kan voorkom. Indien hierdie kombinasie aangedui word, moet die dosis van een of albei middels verminder word. JURNISTA kan die neuromuskulêre blokkeringswerking van spierverslappers versterk en n verhoogde graad van respiratoriese onderdrukking veroorsaak. Die gesamentlike gebruik van alkohol moet vermy word. Alkohol verhoog die kalmerende effek van hidromorfoon. SWANGERSKAP EN LAKTASIE Swangerskap: Geen kliniese data is beskikbaar oor swangerskappe wat blootgestel is nie. Alhoewel daar nie met dierestudies enige teratogeniese effekte getoon is nie, is reproduktiewe toksisiteit waargeneem. Daar is aangetoon dat hidromorfoon die plasentale skans kruis by proefdiere. Die potensiële risiko vir die mens met die gebruik van opiate tydens swangerskap is onbekend. CCDS: 20 April 2009 Page 25 of 37

26 JURNISTA moet nie tydens swangerskap en geboorte gebruik word nie as gevolg van belemmerde kontraktiliteit van die uterus en die risiko vir neonatale respiratoriese onderdrukking. Onttrekkingsimptome kan waargeneem word by die pasgeborenes van moeders wat chroniese behandeling ondergaan. Laktasie: Lae konsentrasies hidromorfoon en ander opioïede analgetika is in mens melk tydens kliniese navorsingstudies waargeneem. Pre-kliniese navorsingstudies het getoon dat hidromorfoon in borsmelk van lakterende rotte waargeneem kan word. JURNISTA moet nie tydens borsvoeding gebruik word nie. DOSIS EN GEBRUIKSAANWYSINGS Veilige en doeltreffende toediening van JURNISTA aan pasiënte met pyn hang af van n omvattende evaluering van die pasiënt. Die aard van die pyn sowel as die gelyktydige mediese status van die pasiënt sal die seleksie van die dosis bepaal. As gevolg van die verskil in respons tussen individue op opioïede, word dit aanbeveel dat alle pasiënte begin met die laagste toepaslike dosis opioïed-behandeling en getitreer word tot by n voldoende vlak van analgesie, gebalanseer ten opsigte van n aanvaarbare frekwensie van newe-effekte. Geskikte profilakse vir bekende newe-effekte (byvoorbeeld konstipasie) moet met aanvang van behandeling ingestel word. Pasiënte moet ingelig word om die JURNISTA tablet heel in te sluk met n glas water, ongeveer dieselfde tyd elke dag en om dit nooit te kou, deel of breek nie. JURNISTA moet nie meer as een keer elke 24 uur geneem word nie Indien die pasiënt nie gereeld die geskeduleerde dosis JURNISTA geneem het nie, moet die pasiënt die volgende dosis dadelik neem en n nuwe 24-uur regimen begin. CCDS: 20 April 2009 Page 26 of 37

27 Pasiënte wat tans nie gereeld opioïede middels gebruik nie: Die aanvanklike dosis vir pasiënte wat tans nie gereeld opioïede ontvang nie, moet nie meer wees as 8 mg elke 24 uur nie. Sommige pasiënte kan voordeel trek uit n aanvanklike titrasiedosis van 4 mg elke 24 uur om verdraagsaamheid te verbeter. Die dosis kan indien nodig opwaarts getitreer word, met inkremente van 4 mg of 8 mg, afhangende van die respons en aanvullende analgetiese behoeftes. Die dosis moet nie meer dikwels as elke 2 dae getitreer word nie. Pasiënte wat tans gereeld opioïede ontvang: By pasiënte wat tans n opioïed-analgetikum neem, moet die aanvangsdosis van JURNISTA gebaseer word op die vorige daaglikse opioïed dosis, met behulp van standaard equianalgesic ratios (gelykwaardige analgesie-verhoudings). Vir opioïede, behalwe morfien, bepaal eers die ekwivalente daaglikse dosis van morfien, gebruik dan die tabel (1a) hieronder om die ekwivalente daaglikse dosis JURNISTA te bepaal. Tabel 1a: Omskakelingstabel: Vermenigvuldigingsfaktore vir die omskakeling van daaglikse dosis van vorige opioïed na daaglikse dosis JURNISTA (mg/dag Vorige Opioïed x Faktor = mg/dag JURNISTA) Vorige Opioïed Orale Vorige Opioïed (faktor) Parenterale Vorige Opioïed (faktor) Morfien 0,2 0,6 Hidromorfoon 1 4 Geen vaste omrekeningsverhouding sal waarskynlik by alle pasiënte bevredigend wees nie, te wyte aan die individuele pasiënt en formuleringsverskille. Gevolglik moet omskakeling na die aanbevole aanvangsdosis van JURNISTA gevolg word deur sorgvuldige pasiënt-monitering en titrasie. Dosisse moet afgerond word tot die naaste dosis van JURNISTA wat beskikbaar is in 4 mg inkremente (4, 8, 16, 32, 64 mg tablette), soos klinies aangedui. Staak alle ander deurlopende opioïed analgetiese medikasies wanneer daar met JURNISTA behandeling begin word. CCDS: 20 April 2009 Page 27 of 37

28 Aanvullende Analgesie: Bo en behalwe een keer daaglikse JURNISTA behandeling, kan aanvullende deurbraak pynmedikasie in die vorm van onmiddellik-vrygestelde preparate (bv. onmiddellike vrystelling morfien) beskikbaar gemaak word aan alle pasiënte met chroniese pyn. Die omrekeningstabel moet gebruik word vir omskakeling. Individuele aanvullende dosisse van onmiddellik vrystelling morfien moet gewoonlik nie 10 % tot 25 % van die JURNISTA dosis oorskry nie. Individualisering van dosering en instandhoudingsterapie: Na aanvang van behandeling met JURNISTA kan dosis aanpassings nodig wees om die pasiënt se beste balans tussen verligting van pyn en opioïed-verwante newe-effekte te bereik. Indien die pyn toeneem in erns of analgesie onvoldoende is, kan n geleidelik verhoging van dosis benodig word. Ten einde die effek van die verandering in dosis toe te laat om te stabiliseer, moet die dosis nie meer dikwels as elke twee dae verhoog word nie. As n riglyn kan dosisverhogings van 25 %-100 % van die huidige daaglikse dosis van JURNISTA oorweeg word met elke titrasiestap. Sodra pasiënte gestabiliseer is op een-keer-daaglikse JURNISTA terapie, kan die dosis volgehou word solank as wat pynverligting nodig is. Die voortgesette behoefte aan deurlopende opioïed behandeling en aanpassings in terapie moet periodiek revalueer word, soos toepaslik. Gebruik by kinders: JURNISTA word nie aanbeveel vir gebruik by kinders en adolessente onder 18 jaar oud nie, as gevolg van onvoldoende data oor veiligheid en doeltreffendheid. Gebruik by bejaardes: Die mediese opset van die bejaarde is dikwels kompleks. Gevolglik moet behandeling met JURNISTA versigtig begin word en die aanvanklike dosis moet verminder word. Nier- en lewerinkorting: CCDS: 20 April 2009 Page 28 of 37

29 Na enkel dosis toediening van hidromorfoon onmiddellike vrystelling tablette, is die volgende resultate in kliniese proewe waargeneem: By pasiënte met matige lewerinkorting (telling 7-9 op Child-Pugh taksering skaal) was beide blootstelling (plasma AOK) en piek plasmakonsentrasies van hidromorfoon ongeveer 4-keer hoër vergeleke met gesonde kontroles en die eliminasie-halfleeftyd was onveranderd. By pasiënte met matige nierinkorting (kreatinienopklaring ml/min), was die blootstelling (plasma AOK) aan hidromorfoon 2-keer hoër as by diegene met n normale nierfunksie en eliminasie-halfleeftyd was onveranderd. By pasiënte met ernstige nierinkorting (kreatinien-opklaring < 30 ml/min), was blootstelling (plasma AOK) aan hidromorfoon ongeveer 4-keer hoër as by diegene met normale nierfunksie en eliminasie-halfleeftyd 3-keer langer. Gevolglik moet pasiënte met matige lewer- of nierinkorting begin word met n verminderde dosis en noukeurige monitering tydens dosistitrasie. By pasiënte met ernstige nierinkorting moet n verhoogde dosis interval ook oorweeg word en hierdie pasiënte moet ook tydens instandhoudingsterapie gemoniteer word vir die ontwikkeling van opioïed-verwante newe-effekte. Staking van behandeling: By pasiënte wat fisies afhanklik is en daaglikse toediening van hidromorfoon ontvang, sal skielike onttrekking van behandeling met JURNISTA aanleiding gee tot simptome van onttrekkingsindroom. Indien staking van behandeling met JURNISTA aangedui word, moet pasiënte dus hulle JURNISTA dosis elke 2 dae met 50 % verminder totdat die laagste moontlike dosis bereik word, wanneer terapie veilig gestaak kan word. Indien simptome van onttrekking voorkom, moet afskaling gestaak word. Die dosis moet dan effens verhoog word totdat die tekens en simptome van opioïed-onttrekking verdwyn. Afskaling moet dan weer begin maar met langer tydperke tussen elke JURNISTA dosis-vermindering, of voordat oorgeskakel word na n gelykwaardige analgetiese dosis van n ander opioïed, waarmee dan aangegaan word met afskaling. CCDS: 20 April 2009 Page 29 of 37

30 NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS Newe-effekte Ongunstige Geneesmiddelreaksies (OGRs) In kliniese proewe met JURNISTA (n = 1684), was die mees algemeen aangemelde OGRs opioïedverwante GI voorvalle van hardlywigheid, naarheid en braking. Dit kan gewoonlik beheer word deur die dosis te verlaag, lakseermiddels of anti-emetika, soos van toepassing. Die onderstaande tabel dui die ongunstige geneesmiddelreaksies (OGRs) wat met JURNISTA waargeneem is aan en die wat met ander hidromorfoonhidrochloried formulerings aangemeld is. Indien JURNISTA en hidromorfoonhidrochloried frekwensies verskil, was die hoogste frekwensie van elke databasis gebruik. Tabel 2: Ongunstige Geneesmiddelreaksies by JURNISTA behandelde pasiënte. Orgaan Sisteemklas Ongunstige Geneesmiddelreaksie Frekwensie Baie Algemeen Algemeen Ongewoon Seldsaam ( 1/10) (1/100 tot <1/10) (1/1000 tot <1/100) ( 1/10,000 tot <1/1000) Infeksies en infestasies Divertikulitis, Gastroënteritis Endokriensiektes Hipogonadisme Metabolisme en Anoreksie eetlus voedingsiektes Dehidrasie Vloeistof retensie Hiperurisemie Psigiatriese siektes Slaaploosheid Afname in libido Afhanklikheid* Angs Paniek aanval Verwarde toestand Paranoia Senuweeagtigheid Aggressie Abnormale drome Huil Depressie Lusteloosheid Gemoed skommeling Geneesmiddel toleransie* Rusteloosheid Disforie Hallusinasie Euforiese bui CCDS: 20 April 2009 Page 30 of 37