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Palladone (Hydromorphone Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

 
 



CNS Depressants

Hydromorphone should be dosed with caution in patients who are concurrently taking other central nervous system depressants that may cause respiratory depression, hypotension, profound sedation or potentially result in coma. Such agents include barbiturates, other sedatives or hypnotics, general anesthetics, other opioid analgesics, phenothiazines and other neuroleptics, centrally acting anti-emetics, benzodiazepines or other tranquilizers, and alcohol.

Muscle Relaxants

Hydromorphone may interact with skeletal muscle relaxants to enhance neuromuscular blocking action to increase respiratory depression.

Mixed Agonist-Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as hydromorphone. In this situation, significant doses of mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs)

No specific interaction between hydromorphone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate. MAOI therapy should be discontinued for at least two weeks prior to the initiation of therapy with Palladone™ Capsules.

H2 Antagonists/Proton Pump Inhibitors

In the patients enrolled in the clinical trials, Palladone™ exposure and effects on pain were comparable when administered with or without various H2 antagonists/proton pump inhibitors.

Drug/Laboratory Test Interactions

There is no known interference of this drug with laboratory tests.

Food

The bioavailability of Palladone™ Capsules is not significantly affected by food.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted in animals.

Hydromorphone was negative in the in vitro  bacterial reverse mutation assay and in the in vivo  mouse micronucleus assay. Hydromorphone was negative in the mouse lymphoma assay in the absence of metabolic activation, but was positive in the mouse lymphoma assay in the presence of metabolic activation. Morphinone, an impurity, tested as a besylate salt was negative in the in vitro  bacterial reverse mutation assay and negative in the in vivo  mouse micronucleus assay. Morphinone was positive in the Chinese Hamster Ovary Cell Chromosomal Aberration test in the absence and presence of metabolic activation.

Hydromorphone did not affect fertility in rats at oral doses up to 5 mg/kg which is equivalent to a 32 mg human daily oral dose on a body surface area basis.

Pregnancy

Pregnancy Category C

Hydromorphone was not teratogenic in female rats given oral doses up to 10 mg/kg or female rabbits given oral doses up to 50 mg/kg during the major period of organ development. Estimated exposures in the female rat and rabbit were approximately 3-fold and 6-fold higher than a 32 mg human daily oral dose based on exposure (AUC0-24h). In a rat pre- and post-natal study, an increase in pup mortality and a decrease in pup body weight which was associated with maternal toxicity was observed at doses of 2 and 5 mg/kg/day. The maternal no effect level for hydromorphone was 0.5 mg/kg/day which is <1-fold lower than a 32 mg human daily oral dose on a body surface area basis. Hydromorphone had no effect on pup development or reproduction when given to female rats during the pre-natal and postnatal periods up to a dose of 5 mg/kg which is equivalent to a 32 mg human daily oral dose on a body surface area basis.

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 278 mg/kg during organogenesis (gestation days 8-10), 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 7-10) 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 3-fold higher and <1-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. Palladone™ Capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Labor and Delivery).

Labor and Delivery

Palladone™ Capsules are not recommended to be initiated prior to or during labor or in the immediate post-partum period. Women who are taking opioids during pregnancy should not be withdrawn abruptly during labor and delivery, but maintained on their current dose of medication since abrupt withdrawal can precipitate delivery. Neonates whose mothers have been taking hydromorphone chronically may exhibit respiratory depression and/or withdrawal symptoms, at birth and/or in the post-delivery period.

Neonatal Withdrawal Syndrome

Chronic use of opioids during pregnancy can affect the fetus with subsequent withdrawal symptoms. Neonatal withdrawal syndrome presents as irritability, hyperactivity and loss of sleep pattern, abnormal crying, tremor, vomiting, diarrhea and subsequent weight loss or failure to gain weight and may result in death. The duration and severity of neonatal withdrawal syndrome varies based on the drug used, duration of use, the time and dose of last maternal use, and rate of elimination by the newborn. Use standard care as medically appropriate.

Nursing Mothers

Low concentrations of opioid analgesics have been detected in breast milk with the potential for withdrawal symptoms when administration of opioid analgesics to the mother is stopped. The distribution of hydromorphone has not been studied. It is prudent to assume that hydromorphone would also distribute into breast milk. Ordinarily, nursing should not be undertaken while a patient is receiving Palladone™ Capsules because of the possibility of sedation and/or respiratory depression in the infant.

Pediatric Use

The safety and effectiveness of Palladone™ Capsules have not been established in patients below the age of 18 years.

Geriatric Use

Of the total number of subjects in clinical studies of Palladone™ Capsules, 22% were 65 and over, and 6% were 75 and over. Dosages should be adjusted according to the clinical situation. As with all opioids, the starting dose should be reduced to 1/3 to 1/2 of the usual dosage in debilitated patients. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.

Laboratory Monitoring

Due to the broad range of plasma concentrations that are associated with individual daily dose requirements to achieve adequate pain relief, the varying degrees of pain, and the development of tolerance seen in patient populations, plasma hydromorphone measurements are usually not helpful in clinical management.

Hepatic Impairment

Palladone™ Capsules were not studied in patients with severe hepatic impairment and are not recommended for use in such patients. Care in initial dose selection and careful observation are recommended in patients with evidence of mild to moderate hepatic impairment.

Renal Impairment

In patients with mild to moderate renal impairment, based on calculated creatinine clearance, the concentrations of hydromorphone in plasma were slightly higher than in subjects with normal renal function. Dosages should always be adjusted according to the clinical situation.

Gender

There were no male/female differences detected for efficacy, pharmacokinetic metrics or adverse events in clinical trials.

Race

Analgesia and adverse events were similar in the various ethnic groups included in the clinical program.

OVERDOSAGE

Acute overdosage with hydromorphone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.

The nature of extended-release hydromorphone should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects. Deaths due to overdose may occur with abuse and misuse of Palladone™ Capsules.

In the treatment of hydromorphone overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

The pure opioid antagonists, such as naloxone or nalmefene, are specific antidotes against respiratory depression from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including Palladone™ Capsules, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

CONTRAINDICATIONS

Palladone™ Capsules are contraindicated:

  • for use on an as needed basis (i.e. prn).
  • in situations of significant respiratory depression, especially in unmonitored settings where there is a lack of resuscitative equipment.
  • in patients who have acute or severe bronchial asthma.
  • in patients who have or are suspected of having paralytic ileus.
  • in patients with known hypersensitivity to any of its components or the active ingredient, hydromorphone.

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