UNITE DES SOINS PALLIATIFS
Zahle et Bekaa. LIBAN
PALLIATIVE CARE UNIT
Zahle and Bekaa. LEBANON
Tuesday, March 31, 2015
Hydromorphone Hydrochloride Extended-Release (Page 7 of 10)
By Mallinckrodt, Inc. | Last revised:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Hydromorphone, a semi-synthetic morphine derivative, is a hydrogenated ketone of morphine. Hydromorphone is principally an agonist of mu-receptors, showing a weak affinity for κ-receptors. Comparing relative binding affinity for mu- and κ-opioid receptors, hydromorphone binds more specifically to mu-receptors than structurally related morphine. As an opioid agonist, the principle therapeutic action of hydromorphone is analgesia. The precise mechanism of action of opioid analgesics is not known but the effects are thought to be mediated through opioid-specific receptors located predominantly in the central nervous system (CNS). Interaction with the mu-opioid receptor subtype is believed to be responsible for most of hydromorphone’s clinical effects. There is no intrinsic limit to the analgesic effect of hydromorphone. Clinically, however, dosage limitations are imposed by the adverse effects, primarily respiratory depression, sedation, nausea, and vomiting, which can result from high doses.
CNS Depressant/Alcohol Interaction
Additive pharmacodynamic effects may be expected when hydromorphone hydrochloride extended-release tablets are used in conjunction with alcohol, other opioids, legal or illicit drugs that cause central nervous system depression.
Effects on the Central Nervous System
Hydromorphone produces dose-related respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.
Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla.
Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic. Marked mydriasis, rather than miosis, may be seen due to severe hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Gastric, biliary and pancreatic secretions are decreased by hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm. The end result is constipation. Hydromorphone also can cause an increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.
Effects on the Cardiovascular System
Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by hydromorphone and can contribute to opioid-induced hypotension. Manifestations of histamine release or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.
Effects on the Endocrine System
Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Hydromorphone hydrochloride extended-release tablets are an extended-release formulation of hydromorphone that produces a gradual increase in hydromorphone concentrations. Following a single-dose administration of hydromorphone hydrochloride extended-release tablets, plasma concentrations gradually increase over 6 to 8 hours, and thereafter concentrations are sustained for approximately 18 to 24 hours post-dose. The median Tmax values ranged from 12 to 16 hours. The mean half-life was approximately 11 hours, ranging from 8 to 15 hours in most individual subjects. Linear pharmacokinetics has been demonstrated for hydromorphone hydrochloride extended-release tablets over the dose range 8 to 64 mg, with a dose-proportional increase in Cmax and overall exposure (AUC0-∞ ) (see Table 4). Steady-state plasma concentrations are approximately twice those observed following the first dose, and steady state is reached after 3 to 4 days of once-daily dosing of hydromorphone hydrochloride extended-release tablets. At steady state, hydromorphone hydrochloride extended-release tablets 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 diminished the fluctuations between peak and trough concentrations seen with the immediate-release tablet (see Figure 1). The bioavailability of hydromorphone hydrochloride extended-release tablets once daily and immediate-release hydromorphone four times daily in adults is comparable, as presented inTable 4.
Figure 1. Mean Steady-State Plasma Concentration Profile
NA = not applicable * Median (range) reported for Tmax † Steady-state results on Day 5 (0-24 hours) ‡ Cmin 2.15 (0.87) ng/mL § Cmin 1.47 (0.42) ng/mL
The pharmacokinetics of hydromorphone hydrochloride extended-release tablets are not affected by food as indicated by bioequivalence when administered under fed and fasting conditions. Therefore, hydromorphone hydrochloride extended-release tablets may be administered without regard to meals. When a 16 mg dose of hydromorphone hydrochloride extended-release tablets was administered to healthy volunteers immediately following a high-fat meal, the median time to Cmax (Tmax ) was minimally affected by the high-fat meal occurring at 16 hours compared to 18 hours while fasting.
Following intravenous administration of hydromorphone to healthy volunteers, the mean volume of distribution was 2.9 (±1.3) L/kg, suggesting extensive tissue distribution. The mean extent of binding of hydromorphone to human plasma proteins was determined to be 27% in an in vitro study.
After oral administration of an immediate-release formulation, hydromorphone undergoes extensive first-pass metabolism and is metabolized primarily in the liver by glucuronidation to hydromorphone-3-glucuronide, which follows a similar time course to hydromorphone in plasma. Exposure to the glucuronide metabolite is 35 to 40 times higher than exposure to the parent drug. In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.
Approximately 75% of the administered dose is excreted in urine. Most of the administered hydromorphone dose is excreted as metabolites. Approximately 7% and 1% of the dose are excreted as unchanged hydromorphone in urine and feces, respectively.
Based on data obtained from a study using immediate-release hydromorphone, the pharmacokinetics of hydromorphone in healthy elderly subjects (65 to 74 years old) are similar to the pharmacokinetics in healthy young subjects.
The pharmacokinetics of hydromorphone hydrochloride extended-release tablets were not evaluated in a pediatric population.
Females appeared to have approximately 10% higher mean systemic exposure in terms of Cmax and AUC values.
The effect of race on hydromorphone hydrochloride extended-release tablets pharmacokinetics has not been studied.
In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-∞ ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied. Further increase in Cmax and AUC0-∞ of hydromorphone in this group is expected. Start patients with moderate hepatic impairment on 25% of the usual dose of hydromorphone hydrochloride extended-release tablets and closely monitor for respiratory and central nervous system depression during dose titration. Consider alternate analgesic therapy for patients with severe hepatic impairment [see Dosage and Administration (2.4) and Specific Populations (8.6)].
Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h ) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hr) compared to subjects with normal renal function (15 hr). Start patients with moderate renal impairment on 50% of the usual hydromorphone hydrochloride extended-release tablets dose for patients with normal renal function and closely monitor for respiratory and central nervous system depression during dose titration. As hydromorphone hydrochloride extended-release tablets are only intended for once-daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.5) and Use in Specific Populations (8.7)].
Drug Interaction/Alcohol Interaction
An in vivo study examined the effect of alcohol (40%, 20%, 4% and 0%) on the bioavailability of a single dose of 16 mg of hydromorphone hydrochloride extended-release tablets in healthy, fasted or fed volunteers. The results showed that the hydromorphone mean AUC0-∞ was 5% higher and 4% lower (not statistically significant) in the fasted and fed groups respectively after co-administration of 240 mL of 40% alcohol. The AUC0-∞ was similarly unaffected in subjects following the co-administration of hydromorphone hydrochloride extended-release tablets and alcohol (240 mL of 20% or 4% alcohol).
The change in geometric mean Cmax with concomitant administration of alcohol and hydromorphone hydrochloride extended-release tablets ranged from an increase of 10% to 31% across all conditions studied. The change in mean Cmax was greater in the fasted group of subjects. Following concomitant administration of 240 mL of 40% alcohol while fasting, the mean Cmax increased by 37% and up to 151% in an individual subject. Following the concomitant administration of 240 mL of 20% alcohol while fasting, the mean Cmax increased by 35% and up to 139% in an individual subject. Following the concomitant administration of 240 mL of 4% alcohol while fasting, the mean Cmax increased by 19% on average and as much as 73% for an individual subject. The range of median Tmax for the fed and fasted treatments with 4%, 20% and 40% alcohol was 12 to 16 hours compared to 16 hours for the 0% alcohol treatments.
The University of Texas MD Anderson Cancer Center, Houston, TX
Corresponding author: Akhila Reddy, MD, Department of Palliative Care and Rehabilitation Medicine, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1414, Houston, TX 77030; e-mail: firstname.lastname@example.org.
During opioid rotation, one opioid is substituted for another using equianalgesic tables, mainly to alleviate uncontrolled pain or opioid-related adverse effects.1 Herein, we describe a case in which opioid rotation was administered for an unusual reason.
Our patient, a 62-year-old man, was diagnosed with metastatic appendiceal cancer at our institute 3 years ago. Despite multiple abdominal surgeries and chemotherapy regimens, his disease progressed and he developed chronic partial small bowel obstruction. However, he was able to take oral medications, occasional nausea and vomiting notwithstanding. Total parenteral nutrition was initiated. Oral extended-release morphine sulfate was initially prescribed for his abdominal pain and was later changed to a fentanyl transdermal patch because of opioid-induced neurotoxicity.1Given that his pain persisted, fentanyl was subsequently switched to three 12-mg extended-release hydromorphone (HMER) tablets (36 mg) twice per day plus immediate-release hydromorphone at a dose of 4 mg taken orally every 4 hours as needed for breakthrough pain. The morphine equivalent daily dose (MEDD) was 440 mg.
The patient's nausea and vomiting worsened and necessitated the placement of a venting gastrostomy tube.
The patient also experienced uncontrolled pain. During the endoscopic procedure, numerous empty casings of HMER were extracted from the gastric region.
Figure 1 shows the endoscopic extraction of HMER casings via a Roth Net (US Endoscopy, Mentor, OH) from the stomach.
After extensive discussions with the patient and the primary team, opioid rotation to oral methadone was initiated, and the venting gastrostomy tube was clamped for 30 minutes after the administration of each oral medication.
It is long acting because of its preparation rather than because of its innate nature.2,3 Given that the casings did not pass beyond the stomach region, the nature of drug delivery in this patient was difficult to understand.
The equivalent dose of methadone for an MEDD of 440 mg is approximately 30 to 40 mg. However, because HMER absorption was likely unreliable in this patient, we initiated a starting dose of oral methadone of 5 mg twice per day. At a follow-up visit to the clinic a month later, the patient had excellent and sustained pain control and was receiving a total MEDD of about 100 mg in the form of methadone 5 mg twice per day and one to two doses of immediate-release hydromorphone 4 mg taken for breakthrough pain. This strongly suggests that the absorption of HMER was profoundly impaired in this patient with a partial bowel obstruction. An opioid rotation that was conducted assuming good bioavailability of HMER would have resulted in severe toxicity to methadone.
The package inserts for extended-release preparations of morphine, oxycodone, and hydromorphone state that use in patients with a bowel blockage or GI narrowing should be avoided.2,4,5 However, it is important to attempt pain control with an oral regimen of long-acting pain medications, given that the ease of administration ensures a better quality of life for our patients. HMER is delivered via an oral osmotic system, which consists of a semipermeable membrane with the drug and an active push compartment. As water passes through the membrane and the active push is expanded, the drug is released slowly through the GI tract. This system allows for the continuous slow release of the drug without noticeable peaks and troughs.2,3However, methadone is long acting because of the pharmacokinetic properties of the drug rather than the delivery formulation.
On the basis of the findings described herein, methadone, which has a long half-life and is rapidly absorbed higher in the GI tract, and transdermal formulations such as fentanyl, may be preferred over oral extended-release formulations of opioids in patients with a partial bowel obstruction. Our patient case emphasizes the importance of understanding the pharmacologic intricacies of opioids, not only to benefit our patients but also to avoid causing iatrogenic harm. Our patient was able to enjoy a weeklong vacation with his wife shortly after the follow-up clinic visit.