Indications

Treatment of moderate to severe pain.

JURNISTA^® should be used in patients requiring continuous analgesia.

Dosage and Administration

As with other opioid analgesics, 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.

As with any strong opioid, appropriate prophylaxis for known adverse reactions (for example constipation), should be considered.

Dosage – Adults

JURNISTA^® should not be taken more than once every 24 hours.

Patients currently not routinely receiving opioids

The initial dose in patients currently not routinely receiving opioids should not exceed 8 mg every 24 hours.  The dose may be titrated upwards, if required, in increments of the lowest available tablet strength, depending on response and supplementary analgesic requirements. The dosage should not be titrated more frequently than every fourth dose (for example, if the first dose is given on a Monday, the dosage could be increased no earlier than the fourth dose, on Thursday).

Because it may be more time consuming to titrate a patient to adequate analgesia using a controlled-release opioid preparation, it may be advisable to begin treatment with conventional immediate-release  preparations  (e.g.  immediate-release  hydromorphone  or  immediate-release morphine) and then convert to the appropriate total daily dose of JURNISTA^®. Use the conversion table provided below to calculate the conversion doses (Table 1).

Patients currently receiving opioids regularly

In patients currently taking opioid analgesics regularly, 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 equivalent total daily dose of morphine, then use Table 1 to determine the equivalent total daily dose of JURNISTA^®.

Table 1: 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^®)   

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^® followed by close patient monitoring and titration is advised.

Dosages should be rounded down to the closest dose of JURNISTA^® available, as clinically indicated.

Discontinue all other around-the-clock opioid analgesic medications when JURNISTA^® therapy is initiated.

JURNISTA^®  can also be safely used with usual doses of non-opioid analgesics and analgesic adjuvants.

Individualization 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 adverse reactions.

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 stabilize, the dosage should be increased no more frequently than every fourth dose (for example, if the first dose is given on a Monday, the dosage could be increased no earlier than the fourth dose, on Thursday). 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 or adjustments in therapy should be reassessed periodically as appropriate.

Missed dose

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.

Stopping treatment

In patients who are physically dependent on opioids and receiving daily administration of hydromorphone, abrupt discontinuation of treatment with JURNISTA^® will result in symptoms of withdrawal syndrome. Therefore, if cessation of therapy with JURNISTA^® is indicated in patients, the dose of JURNISTA^® should be 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.

Special populations

Pediatrics (below age 18)

JURNISTA^® is not recommended for use in children and adolescents below age 18 due to insufficient data on safety and efficacy (see Contraindications).

Elderly

The  medical  status  of  the  elderly  patient  is  often  complex.  Therefore,  treatment  with JURNISTA^® should be initiated cautiously at a reduced initial dose (see Pharmacokinetic Properties – Elderly). Renal impairment

Following single-dose administration of hydromorphone immediate-release tablets, the following results were observed in clinical studies:

•        In patients with moderate renal insufficiency (creatinine clearance of 40-60 mL/min), exposure (plasma AUC) to hydromorphone was approximately 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 moderate renal insufficiency should be started on a reduced dose and closely monitored during dose titration. In patients with severe renal insufficiency an increased dosing interval should also be considered and these patients should in addition be monitored during maintenance therapy for development of opioid-related adverse reactions.

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.

Therefore, patients with moderate hepatic insufficiency should be started on a reduced dose and closely monitored during dose titration.

Administration

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^® may be taken with or without food (see Pharmacokinetic Properties – Absorption).

Hypotension

Opioid analgesics, including hydromorphone, 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.

Paralytic ileus

JURNISTA^® should not be used in situations with risk of paralytic ileus. If during treatment, paralytic ileus is suspected, treatment with JURNISTA^® should be stopped.

Impaired respiration

Respiratory depression is the most important hazard of opioid preparations and 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^®, like all other opioids, should be used with extreme caution in patients with a substantially decreased respiratory reserve or pre-existing respiratory depression and in patients with chronic obstructive pulmonary disease. Severe pain antagonizes the respiratory depressant effects of opioids. However, should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for regional anesthetic 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  opioids  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. Opioids produce effects that 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

Like other opioids, hydromorphone causes a reduction in gastrointestinal motility associated with an increase in smooth muscle tone. Consequently, constipation is a frequent side effect reported with 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 opioids 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 gastrointestinal 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 Contraindications).

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.

Special risk patients

JURNISTA^®, like all opioid analgesics, should be administered with caution and in reduced dosages  in  patients  with  moderate  to  severe  renal  or  hepatic  insufficiency,  adrenocortical insufficiency, myxedema, hypothyroidism, prostatic hypertrophy or urethral stricture. Caution should also be exercised in the administration of JURNISTA^®  to patients with central nervous system depression, kyphoscoliosis, toxic psychosis, acute alcoholism, delirium tremens, or convulsive disorders.

JURNISTA^® should not be used during breast-feeding.

Use in renal and hepatic impairment

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 interval should also be considered and these patients should in addition be monitored during maintenance therapy for development of opioid-related adverse reactions (see Dosage and Administration – Special populations).

Use in the elderly

Elderly  patients  are  more  prone  to  central  nervous  system  adverse  effects  (confusion)  and gastrointestinal disturbances, and physiological reduction of 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 considerations emphasize the importance of caution rather than imply a restriction on the use of opioids in the elderly.

Drug dependence, drug abuse, and use with alcohol

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see Dosage and Administration – Stopping treatment).

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 routes, the tablet excipients may cause lethal complications.

Since alcohol increases the sedative effect of hydromorphone concomitant use of JURNISTA^® and alcohol should be avoided.

Lactose

JURNISTA^®  contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp deficiency, or glucose-galactose malabsorption should not take this medicine.

Sulfite allergy

JURNISTA^® may contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) may cause central nervous system excitation or depression, hypotension or hypertension if co-administered with opioids. JURNISTA^® is not intended for patients taking MAOIs or within 14 days of stopping such treatment.

Morphine agonists/antagonists

The concomitant use of hydromorphone with morphine agonists/antagonists (buprenorphine, nalbuphine,  pentazocine)  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 not recommended.

Central nervous system depressants

The concomitant use of central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma may occur. When this combination is indicated, the dose of one or both agents should be reduced. Muscle relaxants

JURNISTA^®, like other opioids, may enhance the neuromuscular blocking action of muscle relaxants and cause an increased degree of respiratory depression.

Alcohol

The concomitant use of alcohol should be avoided. Alcohol increases the sedative effect of hydromorphone.

Pregnancy Category C.  

JURNISTA® has been shown to have an embryocidal effect in rat when given in doses resulting in ~1.5 times the exposure from the median human dose (see Non-Clinical information section). There are no adequate and well-controlled studies in pregnant women. JURNISTA® is contraindicated during pregnancy, labor and delivery.

Hydromorphone has been shown to cross the placental barrier in experimental animals. The potential teratogenic risk for humans from use of hydromorphone and other opioids during pregnancy is unknown.

JURNISTA® should not be used during pregnancy and labor due to impaireduterine contractility and the risk of neonatal respiratory depression. Withdrawal symptoms may be observed in the newborn of mothers undergoing chronic treatment. Breast-feeding

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.

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.

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of hydromorphone hydrochloride based on the comprehensive assessment of the available adverse event information. A causal relationship  with  hydromorphone  hydrochloride  cannot  be  reliably established  in  individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trial Data

Placebo-controlled double-blind data – adverse reactions reported at _≥1% incidence

The safety of JURNISTA^®  was evaluated in 788 patients who participated in 2 multicenter, double-blind, randomized, placebo-controlled clinical trials in patients with osteoarthritis, who received  at  least  one  dose  of  JURNISTA^®   (Studies  M03-644-05  and  42801PAI3001)  and provided safety data. The drug titration phases lasted up to 4 weeks, and maintenance phases were 12 weeks at doses of 8 to 32 mg/day; Study M03-644-05 also included a taper phase of up

to 1 week. Adverse reactions reported for _≥1% of JURNISTA^®-treated patients and with an incidence greater than placebo-treated patients are shown in Table 2.

Table 2.          Adverse Reactions Reported by _≥1% of JURNISTA^®-Treated Patient and with    an    Incidence    Greater    than    Placebo-Treated    Patients    in    2 Double-Blind, Placebo-Controlled Clinical Trials of JURNISTA^®

            Contusion                                                                                                   1.1

Comparator-controlled and extension study data – adverse reactions reported at 1% incidence Adverse reactions not reported in Table 2 that were reported by ≥1% of JURNISTA^®-treated patients (N=2340) in 11 clinical trials (including the 2 placebo-controlled trials presented in  Table 3)  and  3 extension  studies  of  JURNISTA^®   in  the  treatment  of  chronic  malignant  or nonmalignant pain are shown in Table 3. All patients received at least one dose of JURNISTA^® and provided safety data.

Table 3.          Adverse Reactions Reported by _≥1% of JURNISTA^®-Treated  Patients in

11 Clinical Trials and 3 Extension Studies of JURNISTA^®

®

Comparator-controlled and extension study data – adverse reactions reported at <1% incidence Adverse reactions reported by <1% of JURNISTA^®-treated patients (N=2340) in the above clinical trial dataset are shown in Table 4.

Table 4. Adverse Reactions Reported by <1% of JURNISTA^®-Treated Patients in 11 Clinical Trials and 3 Extension Studies of JURNISTA^®

Postmarketing data

In  addition  to  the  adverse  reactions  reported  during  clinical  studies  and  listed  above,  the following adverse reactions have been reported during postmarketing experience. In Table 5, adverse reactions are presented by frequency category based on spontaneous reporting rates. The frequencies are provided according to the following convention:

Very common   ≥ 1/10

               Common           ≥ 1/100 and < 1/10

              Uncommon       ≥ 1/ 1000 and < 1/100

              Rare                  ≥ 1/10000 and < 1/1000

                 Very rare          < 1/10000, including isolated reports.

Table 5. Adverse Reactions Identified During Postmarketing Experience with JURNISTA^® by Frequency Category Estimated from Spontaneous Reporting Rates

System Organ Class Adverse Reaction

Immune System Disorders

            Very rare                                    Hypersensitivity

Skin and subcutaneous disorders

            Very rare                                   Angioedema, Urticaria                                                                         

Symptoms and signs

Opioid 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.

Treatment

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.

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 opioid antagonist for details of proper use).  The effect of naloxone is relatively short; therefore, the patient should be carefully monitored until respiration has stabilized. 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   caused   by  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.

Pharmacotherapeutic  group:  Analgesics;  natural  opium  alkaloids,  ATC  code:  N02AA03. Hydromorphone is a semisynthetic morphine derivative.

Mechanism of action

As with all opioid analgesics, hydromorphone exerts its principal pharmacological effects on the central nervous system and smooth muscle, including the gastrointestinal tract. These effects are expressed and modulated by binding to specific opioid receptors. Hydromorphone is principally an agonist of µ-receptors, showing a weak affinity for _κ-receptors. Analgesia occurs as a consequence of the binding of hydromorphone to the _µ-receptors of the central nervous system. Although estimates vary (from 2 to 10 times), oral hydromorphone appears to be approximately 5 times as potent (by weight) as morphine.

Pharmacodynamic effects

Respiratory depression occurs principally by direct action on the cerebral respiratory control centers. Opioids may cause nausea and vomiting due to direct stimulation of the chemoreceptors for emesis in the posterior area of the medulla.

Absorption

Following a single oral dose of JURNISTA^® prolonged-release tablets (OROS^® Push-Pull^TM Technology, developed by ALZA Corporation), plasma concentrations gradually increase over 6 to  8  hours  and  thereafter  concentrations  are  sustained  for  approximately  18  to  24  hours post-dose; the mean T_max values were approximately 13 to 16 hours. This demonstrates that, as intended, hydromorphone is released in a controlled manner, consistent with once-daily dosing. The mean absolute bioavailability of hydromorphone after a single dose of 8, 16 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. At steady state, JURNISTA^®  given once daily maintained hydromorphone plasma concentrations within the same concentration range as the immediate-release tablet given 4 times daily at the same total daily dose and diminishes the periodic fluctuations in plasma levels seen with the immediate-release tablet. The degree of fluctuation in plasma concentration at steady state during a 24-hour period was lower with JURNISTA^® (83%) as compared to the overall fluctuations of the immediate-release tablet (147%). At steady state, hydromorphone AUC for JURNISTA^® is equivalent to that observed for the immediate-release tablet.

Linear pharmacokinetics has been demonstrated for the prolonged-release tablet over the dose range 4 to 64 mg, with dose proportional increases in plasma concentrations (C_max) and overall exposure (AUC).

Distribution

Plasma protein binding is low (<30%). Metabolism

Glucuronidation is the main metabolic pathway and the principal metabolite is the inactive hydromorphone  3-glucuronide,  which  follows  a  similar  time  course  to  hydromorphone  in plasma. Unlike morphine, no active 6-glucuronide metabolite is produced.

Special populations Elderly

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.

Renal impairment

Renal impairment affected the pharmacokinetics of hydromorphone and its metabolite hydromorphone 3-glucuronide following administration of a single oral dose of the immediate- release tablet. 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 hemodialysis was effective at reducing plasma levels of both hydromorphone and metabolites. See Dosage and Administration – Special populations. Hepatic impairment

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. See Dosage and Administration – Special populations.

Gender

Hydromorphone  plasma  concentrations  and  pharmacokinetic  parameters  following administration of JURNISTA^® are comparable in male and female subjects.

Alcohol

In a study evaluating hydromorphone absorption from 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 12 to 16 h and with 0% alcohol was 16 h. No effect was seen on AUC values both in the fed and fasted state.

Concomitant use of alcohol should be avoided (see Warnings and Precautions). Due to the OROS^®  technology in JURNISTA^®, the prolonged-release properties of JURNISTA^® are maintained in the presence of alcohol. For the pharmacodynamic interactions, see Warnings and Precautions.

Non-clinical  data  from  oral  administration  of  hydromorphone  reveal  no  special  hazard  for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and fertility. The major effects were opioid-related pharmacological activities on the central nervous system and gastrointestinal tract, including dose-related increases in sedation, hyperactivity, sudden death, weight loss and decrease in food consumption.

Carcinogenicity

Long-term studies of hydromorphone showed no evidence of any carcinogenic effects after daily oral dosing for two years in mice and rats.  The steady state plasma exposure (AUC, ng•hr/mL) to hydromorphone in mice was approximately 0.46-times and in rats was greater than 3-times the human exposure following a single 64 mg dose of JURNISTA^®.

Reproductive Toxicology

In  the  rat,  a  slight  but  statistically  significant  reduction  in  implantations  was  observed  at

6.25 mg/kg/day, a dose level that produced maternal toxicity during the mating period. Plasma exposure (AUC) to hydromorphone at this dose level was 135 ng•hr/mL, providing a safety factor of about 1.5 over the human exposure (AUC) based on the median daily dose. Neonatal viability and survival were reduced in rats pre-weaning, at the maternal oral daily dose of 6.25 mg/kg. The latter appears to be a class effect of an opioid analgesic.

Butyl  hydroxytoluene  E321,  Cellulose  acetate,  Glycerol  triacetate,  Iron  oxide  black  E172,

Hypromellose,   Lactose,   Macrogol,   Magnesium   stearate,   Polyethylene   oxide,   Povidone,

Propylene glycol, Sodium chloride, Titanium dioxide E171

Ferric oxide red E172 (8 mg only)

Ferric oxide yellow E172 (16 mg and 32 mg only)

Indigo carmine lake E132 (64 mg only)

Not applicable.

See outer carton.

Keep out of reach of children.

PVC/Aclar aluminum blisters.

Pack sizes of 7, 10, 14, 20, 28, 30, 35, 40, 50, 56, 60, 100 tablets.

Not all pack sizes may be marketed

No special requirements.

Instructions for Disposal

Any  unused  product  or  waste  material  should  be  disposed  of  in  accordance  with  local requirements.

National Pharmacovigilance & Drug Safety Centre (NPC)         Fax: +966-11-205-7662  Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.         

        Toll free phone: 8002490000                                                                                      

        E-mail: npc.drug@sfda.gov.sa                                                                                       

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