"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
Addiction, Abuse, And Misuse
EXALGO contains hydromorphone, a Schedule II controlled substance. As an opioid, EXALGO exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence]. As modified-release products such as EXALGO deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydromorphone present.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed EXALGO and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing EXALGO, and monitor all patients receiving EXALGO for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of EXALGO for the proper management of pain in any given patient.
Patients at increased risk may be prescribed modified-release opioid formulations such as EXALGO, but use in such patients necessitates intensive counseling about the risks and proper use of EXALGO along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of EXALGO by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death [see OVERDOSAGE].
Opioid agonists such as EXALGO are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing EXALGO. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see PATIENT INFORMATION]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of EXALGO, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with EXALGO and following dose increases.
To reduce the risk of respiratory depression, proper dosing and titration of EXALGO are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the EXALGO dose when converting patients from another opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of EXALGO, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of EXALGO during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.
Interactions With Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression, and death may result if EXALGO is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of EXALGO in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin EXALGO is made, start with one third to one half the calculated starting dose, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see DRUG INTERACTIONS].
Use In Elderly, Cachectic, And Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating EXALGO and when EXALGO is given concomitantly with other drugs that depress respiration [see Life-threatening Respiratory Depression].
Use In Patients With Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with EXALGO, as in these patients, even usual therapeutic doses of EXALGO may decrease respiratory drive to the point of apnea [see Life-threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in these patients if possible.
EXALGO may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see DRUG INTERACTIONS]. Monitor these patients for signs of hypotension after initiating or titrating the dose of EXALGO.
Use In Patients With Head Injury Or Increased Intracranial Pressure
Monitor patients taking EXALGO who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with EXALGO. EXALGO may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of EXALGO in patients with impaired consciousness or coma.
Use In Patients With Gastrointestinal Conditions
EXALGO is contraindicated in patients with paralytic ileus. Avoid the use of EXALGO in patients with other GI obstruction.
Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, EXALGO is contraindicated in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.
It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.
EXALGO contains 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 nonasthmatic people.
Use In Patients With Convulsive Or Seizure Disorders
The hydromorphone in EXALGO may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during EXALGO therapy.
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including EXALGO. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see DRUG INTERACTIONS].
When discontinuing EXALGO, gradually taper the dose [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue EXALGO.
Driving And Operating Machinery
EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of EXALGO and know how they will react to the medication.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Addiction, Abuse, and Misuse
Inform patients that the use of EXALGO, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share EXALGO with others and to take steps to protect EXALGO from theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting EXALGO or when the dose is increased, and that it can occur even at recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental Ingestion, especially in children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store EXALGO securely and to dispose of unused EXALGO by flushing the tablets down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of EXALGO during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS AND PRECAUTIONS].
Interactions with Alcohol and other CNS Depressants
Inform patients that potentially serious additive effects may occur if EXALGO is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider.
Important Administration Instructions
Instruct patients how to properly take EXALGO, including the following:
- Swallowing EXALGO whole
- Not crushing, chewing, splitting or dissolving the tablets
- Using EXALGO exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
- Not discontinuing EXALGO without first discussing the need for a tapering regimen with the prescriber
Advise patients that people with certain stomach or intestinal problems such as narrowing of the intestines or previous surgery may be at higher risk of developing a blockage. Symptoms include abdominal distension, abdominal pain, severe constipation, or vomiting. Instruct patients to contact their healthcare provider immediately if they develop these symptoms.
Inform patients that EXALGO may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
Driving or Operating Heavy Machinery
Inform patients that EXALGO may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Inform patients that anaphylaxis has been reported with ingredients contained in EXALGO. Advise patients how to recognize such a reaction and when to seek medical attention.
Advise female patients that EXALGO can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.
Advise patients to flush the unused tablets down the toilet when EXALGO is no longer needed.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies to evaluate the carcinogenic potential of hydromorphone hydrochloride were completed in both Han-Wistar rats and Crl:CD1®(ICR) mice. Hydromorphone HCl was administered to Han-Wistar rats (2, 5, and 15 mg/kg/day for males, and 8, 25 and 75 mg/kg/day for females) for 2 years by oral gavage. In female rats, incidences of hibernoma (tumor of brown fat) were increased at 10.5 times the maximum recommended daily exposure based on AUC at the mid dose (2 tumor, 25 mg/kg/day) and 53.7 times the maximum recommended human daily exposure based on AUC at the maximum dose (4 tumors, 75 mg/kg/day). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in male rats. The systemic drug exposure (AUC, ng·h/mL) at the 15 mg/kg/day in male rats was 7.6 times greater than the human exposure at a single dose of32 mg/day of EXALGO. There was no evidence of carcinogenic potential in Crl:CD1®(ICR) mice administered hydromorphone HCl at doses up to 15 mg/kg/day for 2 years by oral gavage. The systemic drug exposure (AUC, ng•h/mL) at the 15 mg/kg/day in mice was 1.1 (in males) and 1.2 (in females) times greater than the human exposure at a single dose of 32 mg/day of EXALGO.
Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay.
Impairment of Fertility
Hydromorphone given orally to rats during the mating period caused a slight but statistically significant reduction in implantations at 6.25 mg/kg/day (~1.2 times the human exposure following to 32 mg/day).
Use In Specific Populations
Fetal/neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see WARNINGS AND PRECAUTIONS].
Teratogenic Effects – Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations].
Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day).
Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and < one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.
In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).
Labor And Delivery
Opioids cross the placenta and may produce respiratory depression in neonates. EXALGO is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.
Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.
The safety and effectiveness of EXALGO in patients 17 years of age and younger have not been established.
Elderly patients have been shown to be more sensitive to the adverse effects of opioids compared to the younger population. Therefore, closely monitor elderly patients for respiratory and central nervous system depression when prescribing EXALGO, particularly during initiation and titration.
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). Start patients with moderate hepatic impairment on 25% of the EXALGO dose that would be used in patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with EXALGO and during dose titration. The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. As further increases in Cmax and AUC0-∞ of hydromorphone in this group are expected, use of alternate analgesics is recommended [see DOSAGE AND ADMINISTRATION].
Administration of a single 4 mg dose of immediate-release hydromorphone tablets resulted in 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 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on 50% and patients with severe renal impairment on 25% of the EXALGO dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with EXALGO and during dose titration. As EXALGO is 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].
Last reviewed on RxList: 4/30/2014
This monograph has been modified to include the generic and brand name in many instances.
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