Hydromorphone Hydrochloride Prescribing Information
Hydromorphone Hydrochloride Tablets expose patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Hydromorphone Hydrochloride Tablets, and monitor all patients regularly for the development of these behaviors and conditions
Hydromorphone Hydrochloride Tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hydrochloride Tablets exposes users to the risks of addiction, abuse, and misuse
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydromorphone Hydrochloride Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydromorphone Hydrochloride Tablets, and monitor all patients receiving Hydromorphone Hydrochloride Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hydromorphone Hydrochloride Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hydrochloride Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydromorphone Hydrochloride Tablets. 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
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
- Complete aREMS-compliant education programoffered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
- Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
- Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
- Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
- complete a REMS-compliant education program,
- counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
- emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
- consider other tools to improve patient, household, and community safety.
Serious, life-threatening, or fatal respiratory depression may occur with use of Hydromorphone Hydrochloride Tablets. Monitor for respiratory depression, especially during initiation of Hydromorphone Hydrochloride Tablets or following a dose increase
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Hydromorphone Hydrochloride Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Hydromorphone Hydrochloride Tablets.
To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Tablets are essential
Overestimating the Hydromorphone Hydrochloride Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of Hydromorphone Hydrochloride Tablets, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
Accidental ingestion of even one dose of Hydromorphone Hydrochloride Tablets, especially by children, can result in a fatal overdose of hydromorphone
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, 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
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Hydromorphone Hydrochloride Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of Hydromorphone Hydrochloride Tablets.
To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Tablets are essential
Overestimating the Hydromorphone Hydrochloride Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of Hydromorphone Hydrochloride Tablets, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
Prolonged use of Hydromorphone Hydrochloride Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which 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
Prolonged use of Hydromorphone Hydrochloride Tablets during pregnancy can result in withdrawal 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. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydromorphone Hydrochloride Tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when Hydromorphone Hydrochloride Tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs
Table 1 includes clinically significant drug interactions with Hydromorphone Hydrochloride Tablets.
Benzodiazepines and other Central Nervous System (CNS) Depressants | |
Clinical Impact: | Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
Intervention: | Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ] . |
Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
Serotonergic Drugs | |
Clinical Impact: | The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
Intervention: | If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Hydromorphone Hydrochloride Tablets if serotonin syndrome is suspected. |
Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone),monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
Monoamine Oxidase Inhibitors (MAOIs) | |
Clinical Impact: | MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. |
Intervention: | The use of Hydromorphone Hydrochloride Tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
Examples: | phenelzine, tranylcypromine, linezolid |
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics | |
Clinical Impact: | May reduce the analgesic effect Hydromorphone Hydrochloride Tablets and/or precipitate withdrawal symptoms. |
Intervention: | Avoid concomitant use. |
Examples: | butorphanol, nalbuphine, pentazocine, buprenorphine, |
Muscle Relaxants | |
Clinical Impact: | Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
Intervention: | Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydromorphone Hydrochloride Tablets and/or the muscle relaxant as necessary. |
Diuretics | |
Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
Intervention: | Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
Anticholinergic Drugs | |
Clinical Impact: | The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when Hydromorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs. |
- Serotonergic Drugs:Concomitant use may result in serotonin syndrome. Discontinue Hydromorphone Hydrochloride Tablets if serotonin syndrome is suspected. (7)
- Monoamine Oxidase Inhibitors (MAOIs):Can potentiate the effects of hydromorphone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. (7)
- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics:Avoid use with Hydromorphone Hydrochloride Tablets because they may reduce analgesic effect of Hydromorphone Hydrochloride Tablets or precipitate withdrawal symptoms. (7)
- Reserve concomitant prescribing of Hydromorphone Hydrochloride Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit dosages and durations to the minimum required.
- Follow patients for signs and symptoms of respiratory depression and sedation.
Dosage and Administration (2.5,2.6) 10/2019
Warnings and Precautions (5.4, 5.13) 10/2019
Hydromorphone Hydrochloride Tablets are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses
Hydromorphone Hydrochloride Tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hydrochloride Tablets exposes users to the risks of addiction, abuse, and misuse
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydromorphone Hydrochloride Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydromorphone Hydrochloride Tablets, and monitor all patients receiving Hydromorphone Hydrochloride Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hydromorphone Hydrochloride Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hydrochloride Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydromorphone Hydrochloride Tablets. 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
- Have not been tolerated, or are not expected to be tolerated,
- Have not provided adequate analgesia, or are not expected to provide adequate analgesia
- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
- Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ()
2.1 Important Dosage and Administration Instructions- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals[see Warnings and Precautions ].
- Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse[see Warnings and Precautions ].
- Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Hydromorphone Hydrochloride Tablets and adjust the dosage accordingly[see Warnings and Precautions ].
- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals
- Usual adult starting dose for Hydromorphone Hydrochloride Tablets is 2 mg to 4 mg, orally, every 4 to 6 hours. (
2.2 Initial DosageInitiating Treatment with Hydromorphone Hydrochloride TabletsHydromorphone Hydrochloride Tablets
Initiate treatment with Hydromorphone Hydrochloride Tablets in a dosing range of 2 mg to 4 mg, orally, every 4 to 6 hours.Conversion from Other Opioids to Hydromorphone Hydrochloride Tablets
There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Hydromorphone Hydrochloride Tablets. It is safer to underestimate a patient’s 24-hour Hydromorphone Hydrochloride Tablets dosage than to overestimate the 24-hour dosage and manage an adverse reaction due to overdose.
In general, it is safest to start Hydromorphone Hydrochloride Tablets therapy by administering half of the usual starting dose every 4 to 6 hours for Hydromorphone Hydrochloride Tablets. The dose of Hydromorphone Hydrochloride Tablets can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved[see Dosage and Administration ].Conversion from Hydromorphone Hydrochloride Tablets to Extended-Release Hydromorphone Hydrochloride
The relative bioavailability of Hydromorphone Hydrochloride Tablets compared to extended-release hydromorphone hydrochloride is unknown, so conversion to extended-release tablets must be accompanied by close observation for signs of excessive sedation and respiratory depression. - Hepatic Impairment:Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of hepatic impairment. ()
2.3 Dosage Modifications in Patients with Hepatic ImpairmentInitiate treatment with one-fourth to one-half the usual Hydromorphone Hydrochloride Tablets starting dose depending on the degree of impairment
[see Use in Specific Populations , and Clinical Pharmacology ]. - Renal Impairment:Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of renal impairment. ()
2.4 Dosage Modifications in Patients with Renal ImpairmentInitiate treatment with one-fourth to one-half the usual Hydromorphone Hydrochloride Tablets starting dose depending on the degree of impairment
[see Use in Specific Populations , and Clinical Pharmacology ]. - Do not abruptly discontinue Hydromorphone Hydrochloride Tablets in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide (
2.6 Safe Reduction or Discontinuation of Hydromorphone Hydrochloride TabletDo not abruptly discontinue Hydromorphone Hydrochloride Tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid dependent patient taking Hydromorphone Hydrochloride Tablets, there are a variety of factors that should be considered, including the dose of Hydromorphone Hydrochloride Tablets the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Hydromorphone Hydrochloride Tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic[see Warnings and Precautions , Drug Abuse and Dependence ].
- 2 mg tablets (light orange to orange colored, mottled, round, flat-faced beveled edge tablets debossed with 'U' on one side and '44' on the other side.)
- 4 mg tablets (light yellow to yellow colored, round, flat-faced beveled edge tablets debossed with 'U' on one side and '45' on the other side.
- 8 mg tablets (white to off-white, round, flat-faced beveled edge tablets debossed with 'U46' on one side and bisect on the other side.)
• Pregnancy: May cause fetal harm. (
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome
In animal reproduction studies, reduced postnatal survival of pups, and decreased were noted following oral treatment of pregnant rats with hydromorphone during gestation and through lactation at doses 0.8 times the human daily dose of 24 mg/day (HDD), respectively. In published studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 6.4 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 3 times the HDD to pregnant mice. No malformations were noted at 4 or 40.5 times the HDD in pregnant rats or rabbits, respectively [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
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.
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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydromorphone Hydrochloride Tablets is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Hydromorphone Hydrochloride Tablets, can prolong labor through actions which 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 dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 1, 5, or 10 mg/kg/day (0.4, 2, or 4 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in the two highest dose groups). There was no evidence of malformations or embryotoxicity reported.
Pregnant rabbits were treated with hydromorphone hydrochloride from Gestation Day 7 to 19 via oral gavage doses of 10, 25, or 50 mg/kg/day (8.1, 20.3, or 40.5 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity was noted in the two highest dose groups (reduced food consumption and body weights). There was no evidence of malformations or embryotoxicity reported.
In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation Day 8 to pregnant hamsters (6.4 to 87.2 times the HDD of 24 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. No neural tube defects were noted at 14 mg/kg (4.7 times the human daily dose of 24 mg/day).
In a published study, CF-1 mice were treated subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone hydrochloride (1.5, 3, or 6.1 times the human daily dose of 24 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites) were observed at doses 3 times the human dose of 24 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.
Increased pup mortality and decreased pup body weights were noted at 0.8 and 2 times the human daily dose of 24 mg in a study in which pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 7 to Lactation Day 20 via oral gavage doses of 0, 0.5, 2, or 5 mg/kg/day (0.2, 0.8, or 2 times the HDD of 24 mg based on body surface area, respectively).
Maternal toxicity (decreased food consumption and body weight gain) was also noted at the two highest doses tested.