Jurnista Controlled Release Tablets Biology Essay

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Opioids form part of the oldest generation of drugs ever known; the utilization of the opium poppy as a therapeutic treatment predates recorded history. Opioid analgesics are pain relievers that bind to the specific opioid receptors in the central nervous system in order to produce analgesic effects (Mystakidou et al 2010). Opioid analgesics are used to relieve pain from a variety of conditions (ALZA Corporation 2006).

Therapeutic use and intended patient groups

Jurnista (OROS hydromorphone hydrochloride) is a single-daily formulation of the opioid agonist hydromorphone hydrochloride which uses the OROS (osmotic-controlled release oral delivery system) technology in order to deliver the drug at relatively continuous rate, thus offering constant analgesia to the patient throughout a 24 hour period (Carter & Keating 2010).

Jurnista has been designated to be used by adult (>18 years) and elderly patients suffering of chronic pain, for which it is regarded as an effective alternative to morphine (CCDC 2009). Jurnista's safety and efficacy in children and adolescents (<18 years) has not yet been established, until then, Jurnista should not be administered to this populations (ALZA Corporation 2006). Hydromorphone hydrochloride prolonged release tablets were registered by the Therapeutic Goods Administration on 29 July 2008 for the treatment of moderate to severe pain in patients requiring continuous analgesia (CCDC 2009).

Jurnista is available as a restricted benefit for cancer or non-cancer patients with chronic, round the clock pain that is moderate to severe and expected to be long lasting (CCDC 2009). Jurnista should not usually be the first medicine prescribed for pain, but should be prescribed to patients not responding to non-opioid analgesics. This medication is contraindicated in those with acute or post-operative pain (Binsfeld et al 2010).

Dose forms available

Hydromorphone Hydrochloride is available in various different dosage forms; these dosage forms vary widely and should be titrated according to the patients needs:

Conventional immediate release tablets come in various strengths. Elderly patients require lowers doses.

Tablet

2 mg

Orange

20

Dilaudid

MF

PBS-R1/DPBS-R1

Tablet

4 mg

Yellow

20

Dilaudid

MF

PBS-R1/DPBS-R1

Tablet

8 mg

scored, white

20

Dilaudid

MF

PBS-R1/DPBS-R1

Controlled release tablets come in much higher strengths than conventional tablets and have a longer lasting effect. These tablets should not be used for initial stabilisation.

CR Tablet

4 mg

controlled release, brown

14

Jurnista

JC

PBS-R2/DPBS-R2

CR Tablet

8 mg

controlled release, red

14

Jurnista

JC

PBS-R2/DPBS-R2

CR Tablet

16 mg

controlled release, yellow

14

Jurnista

JC

PBS-R2/DPBS-R2

CR Tablet

32 mg

controlled release, white

14

Jurnista

JC

PBS-R2/DPBS-R2

CR Tablet

64 mg

controlled release, blue

14

Jurnista

JC

PBS-R2/DPBS-R2

Oral liquid formulation exists for patients who have difficulty swallowing

Oral liquid

1 mg/mL

Dilaudid

MF

PBS-R1/DPBS-R1

IV and SC/IM injections are available. A hydromorphone High Potency (HP) injection is also available.

Injection

2 mg/mL

Dilaudid

MF

PBS/DPBS

Injection HP

10 mg/mL

Dilaudid

MF

PBS/DPBS

Injection

10 mg/mL

Dilaudid

MF

PBS

1 severe disabling pain unresponsive to non-narcotic analgesics (Rossi 2009) & (MIMSOnline 2010)

2 chronic severe disabling pain unresponsive to non-narcotic analgesics

Rationale for dose form selection

(Janssen Cilag, 2011)

Hydromorphone is offered as an oral formulation; however the short removal half-life of this drug requires constant dosing approximately every 4-6 hours for effective 24 hour pain management (ALZA Corporation 2006).

In comparison to conventional immediate-release hydromorphone, Jurnista provides a prolonged and more consistent delivery of hydromorphone with smaller peak concentrati-

ons and with lower variability in the plasma concentrations over time; which allows for sustained therapeutic blood levels of the hydromorphone (Lussier et al. 2010). The development of this long-acting opioid agonist formulation offers patients that suffer from chronic pain, a significant treatment alternative (MIMSOnline 2010). Studies have illustrated that long-acting opioids have the ability of improving pain management and decreasing opioid-related side effects when compared to immediate-release formulations (Gardner-Nix & Mercadante 2009).

Jurnista tablets are distinct from other conventional tablets in that they have been formulated using the OROS technology. The OROS osmotic pump (push-pull) bilayer tablet encompasses a semi-permeable cellulose acetate coating that controls the rate at which water enters the tablet after it has been swallowed. Additionally, the drug side of the tablet comprises of a laser drilled hole which allows the dissolved/suspended drug to be released from the tablet at a prolonged rate as it travels though the GI tract (ALZA Corporation 2006). After oral administration of Jurnista, hydromorphone is released at a controlled rate with plateau concentrations reaching 6-8 hours and later remaining at a relatively constant rate for approximately 24hrs post dose (Gupta et al. 2005).

Jurnista's OROS technology system also allows for a higher rate of patient compliance (a single dose is needed as opposed to multiple daily doses). Furthermore, considering that the dosage interval is longer, the patient's sleep will not be disturbed (patient having to take nightly doses) and the analgesic effect will be continuous throughout day and night (Palangio et al. 2002), therefore also providing a better quality of life to the patient (Lussier et al. 2010).

Novel characteristics of the formulation

Studies suggest that hydromorphone provides a higher therapeutic response when compared to other opioid analgesics. Hydromorphone is said to portray greater solubility, quicker onset rate, fewer and less dramatic side effects, and a lower dependence liability when compared to morphine and diamorphine. It is said to be 5 times more potent than morphine, but with a lower risk of dependency (Drover et al. 2002). Due to its low likelihood of interfering with the metabolism of other medications and low plasma protein, Jurnista may be particularly appropriate for patients on several medications (Lussier et al. 2010).

Hydromorphone is, hence, favoured over morphine in several situations, ranging from the constant management of chronic pain conditions, the emergency ward to the operating theatre.

Hydromorphone is said to cause less nausea than morphine and does not present the toxic metabolites of the various opioids linked to pethidine and methadone. Additionally, hydromorphone frequently demonstrates to be the greatest substitute to morphine and fentanyl in severe chronic pain (Sathyan et al. 2007).

The pharmacokinetics of Jurnista are linear and dose-related, and only minimally affected by the intake of food. Additionally, the sustained release characteristics of Jurnista are kept in the occurrence of alcohol, portraying that the dose release levels of hydromorphone are likely to remain unchanged in an intoxicated person (Gardner-Nix & Mercadante 2009). Moreover, pharmaco-economically, it is suggested that Jurnista presents superior cost effectiveness when compared to other opioids in its intended target population. (Carter & Keating 2010)

Main components in the formulation

http://www.bioportfolio.com/static/images/uploaded/drugs/hydromorphone-01.jpg

Hydromorphone hydrochloride

(Janssen Cilag 2007)

Chemical name: 4,5alpha-epoxy- 3-hydroxy-17- methyl-morphinan-6-one hydrochloride.

Molecular formula: C17H19NO3.HCl.

MW: 321.81.

CAS: 71-68-1.

Jurnista is mainly conformed of two main ingredients hydromorphone and hydrochloride. As a whole, the hydromorphone hydrochloride formulation is freely soluble in water, very faintly soluble in ethanol and basically insoluble in methylene chloride (Janssen Cilag 2007).

Hydromorphone, a semi-synthetic morphine derivative, is a hydrogenated ketone of morphine. Hydromorphone is primarily an agonist of µ-receptors, presenting a weak affinity for κ and δ-receptors. Hydromorphone acts as an opioid agonist, and so its principle therapeutic action is analgesia (Lussier et al. 2010). Analgesia takes place as a result of the binding of hydromorphone to the µ-receptors of the central nervous system. Interaction with the µ-opioid receptor family is thought to be accountable for the majority of hydromorphone's clinical effects (CCDC 2009). Even though approximations differ (from 2 to 10 times), oral hydromorphone shows to be roughly 5 times as potent (by weight) as morphine (Sathyan et al. 2005). Respiratory depression occurs principally by direct action on the cerebral respiratory control centres. Hydromorphone might induce vomiting and nausea as a cause of the stimulation of the chemoreceptor for emesis in the posterior site of the medulla (Bass et al. 2002).

Jurnista's second main ingredient is hydrochloride (HCl). HCl is a salt resulting from the reaction of hydrochloric acid with an organic base (mostly an amine). Jurnista's hydrochloride compound gives the formulation the ability of being easily and more efficiently released in the gastrointestinal tract; hydrochloride is often absorbed by the body within 15 or 30 minutes (Sathyan et al. 2005).

Pre-formulation, rheological and other pharmaceutical manufacturing concerns

Jurnista is obtainable in 8 mg, 16 mg, 32 mg and 64 mg strengths. The 32 mg and 64 mg tablets would be appropriate only for patients that are extremely opioid tolerant. Prescribers ought to be reminded of the risks of intoxication that Jurnista upholds with unsuitable use or unintentional overdose (Janssen Cilag, 2008). Jurnista tablets have a non-dissolvable cellulose acetate external coating that may cause concern to patients when it appears visible in their stool (Carter & Keating 2010).

The PBAC has recognized that Jurnista has a very high toxicity potential when being misused and abused (CCDC 2009). The excipients that conform the Jurnista tablets can result in fatal complications when crushed and injected intravenously. Studies demonstrated that in animals, the intravenous administration of Jurnista caused anaemia, damage to myocardial and renal tubular cells and death (Gardner-Nix& Mercadante, 2009).

Being an opioid analgesic, Jurnista has an increased risk of causing impaired respiration. The most common type of impaired respiration caused by Jurnista is respiratory depression. This is more likely to occur with patients in overdose situations, in the elderly, in the debilitated and in those suffering from conditions characterised by hercapnia or hypoxia when even small doses might severely diminish respiration (Sathyan et al. 2007). Concomitant administration of hydromorphone with other opioid analgesics, sedatives or alcohol has been linked with increased risks of adverse effects, including sedation, hypotension, an augmented danger of respiratory failure and coma (MIMSOnline 2010).

Bioavailability data

The bioavailability of hydromorphone from Jurnista has proven to be virtually unaffected by food. Hydromorphone primarily undergoes hepatic metabolism and is then excreted in the urine (Weinstein et al. 2006). Hydromorphone does not present an active 6-glucuronide metabolite (metabolite of morphine). Active 6-glucuronide can gather in the existence of renal failure; thus, the absence of an active 6-glucuronide metabolite presents hydromorphone as a practical substitute to morphine in elderly patients suffering of renal failure. Nonetheless, hydromorphone alike morphine, metabolises to hydromorphone-3-glucuronide, which may be neuroexcitatory. (Lussier et al. 2010)

Studies indicate that overall, following a single dose of Jurnista, plasma concentrations reach a broad, somewhat plateau region in 6 to 8 hours, and thereafter sustain this concentrations for approximately 18 to 24 hours post-dose (CCDC 2009). Results have also illustrated, that beginning 24 to 30 hours post-dose, plasma hydromorphone concentrations start to decline slowly, with an apparent mean half-life of approximately 11 hours, varying from 8 to 15 hours in most individual subjects; the mean Tmax values appear to range approximately from 13-16 hours. This proves that, as anticipated, all the strength of Jurnista tablets release hydromorphone at a controlled rate, encompassing a continuous 24 hour drug absorption rate while travelling through the intestinal tract, which is consistent with the behaviour of a once-daily dosing formulation (CCDC 2009). Jurnista's mean absolute bioavailability has been established to range from 22 to 26% (Weinstein et al. 2006).

Studies have also indicated that the plasma hydromorphone concentrations and the general exposure to hydromorphone are relative to the strength of the Jurnista dose being administered. This therefore, serves to emphasize the clinical effectiveness and essentiality of Jurnista in the treatment of chronic, ongoing intense pain. (Sabatowski & Giesecke 2007)

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