PALLADONE 10 MGML

Israel - English - Ministry of Health

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Active ingredient:
HYDROMORPHONE HYDROCHLORIDE
Available from:
RAFA LABORATORIES LTD
ATC code:
N02AA03
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
HYDROMORPHONE HYDROCHLORIDE 20 MG / 2 ML
Administration route:
I.M, I.V, S.C
Prescription type:
Required
Manufactured by:
RAFA LABORATORIES LTD, JERUSALEM
Therapeutic group:
HYDROMORPHONE
Therapeutic area:
HYDROMORPHONE
Therapeutic indications:
Relief of moderate to severe pain such as that due to surgery or cancer.
Authorization number:
105 43 28474 00
Authorization date:
2012-04-30

Doctor Leaflet

Highly Concentrated

Palladone Injection 10 mg/ml

(Preservative Free)

Solution for injection

IM, SC, IV

Narcotic prescription required

Composition

Each 2 ml ampoule contains: Hydromorphone HCl 20 mg (10mg/ml).

Palladone Injection also contains citric acid 2 mg/ml and tri-sodium citrate dihydrate 2.28 mg/ml

Palladone Injection contains no preservatives.

The solution is clear and colorless.

Action

Hydromorphone is a semisynthetic opioid agonist analgesic that acts primarily at the mu opiate

receptor. Opiate receptors in the central nervous system mediate analgesic activity. Opioid

agonists occupy the same receptors as endogenous opioid peptides (enkephalins or endorphins),

and both may alter the central release of neurotransmitters from afferent nerves sensitive to

noxious stimuli. Opioid antagonists block the opiate receptor, inhibit the pharmacological

activity of the agonist and will precipitate withdrawal in dependent patients.

Hydromorphone has similar pharmacological and pharmacokinetic properties to morphine to

which it is chemically related. Hydromorphone is recognized by the World Health Organization

as an alternative opioid to morphine for severe pain. This is important since one of the

cornerstones of severe pain management is opioid rotation. Opioid rotation consists of

switching a patient from one opioid to another in order to achieve adequate analgesia with few

side effects. In particular, hydromorphone may have a better side effect profile than morphine

in some individuals, producing less severe constipation and vomiting. In the post-operative

setting as well, hydromorphone is a suitable alternative to morphine, especially in patients with

a history of an unsatisfactory response to morphine e.g. excessive vomiting.

There are several administration techniques for parenteral delivery of hydromorphone,

including a single or double injection (e.g. post-operative), multiple intermittent bolus injections

(e.g. in the cancer patient), or continuous infusion with or without bolus as-needed injections

(e.g. in the cancer patient requiring exceptionally high doses). Patient controlled analgesia (PCA)

is becoming increasingly widespread using on-demand patient-controlled boluses and a lockout

period, with or without an underlying continuous basal infusion.

Hydromorphone is suitable for either bolus injection or continuous infusion. However, the

10 mg/ml concentrated formulation is only indicated for patients already receiving opioids and

will generally be useful for continuous infusion in patients with chronic pain. For bolus

injections, patients with acute pain, or opioid-naive patients, hydromorphone at a concentration

of 10mg/ml is not generally appropriate.

In patients with chronic pain, parenteral opioid infusions should generally be reserved for

patients in whom oral opioids fail to provide adequate analgesia and/or are associated with

unacceptable side effects. Hydromorphone represents an excellent choice for either continuous

intravenous (IV) or subcutaneous (SC) opioid infusion. Hydromorphone is 5-7 times more potent

than morphine and 5 times more soluble. Therefore, when administering an opioid via SC

infusion, hydromorphone affords potent analgesia using a much smaller volume of infusion.

Hydromorphone delivered SC is also less cumbersome and requires fewer changes in needle

sites, an important practical consideration.

The analgesic action of parenteral hydromorphone administered as a bolus is generally apparent

within 15 minutes. Peak analgesic effect occurs at 15-30 minutes following IV therapy, 30-60

minutes following intramuscular (IM) therapy, and 30-90 minutes following SC therapy.

Duration of action is 4-5 hours following IM or SC administration and 2-3 hours following IV

administration. A 10 mg IM injection of morphine is approximately equivalent to a 1.5 mg IM

injection of hydromorphone.

Indications

Relief of moderate to severe pain such as that due to surgery or cancer.

Contraindications

Hypersensitivity to hydromorphone or to any of the other ingredients.

Respiratory depression with hypoxia or elevated carbon dioxide levels in the blood in the

absence of resuscitative equipment, status asthmaticus , upper airway obstruction.

Paralytic ileus.

Concurrent monoamine oxidase inhibitors (MAOIs) or within 14 days of such therapy.

Due to the high concentration, this formulation is contraindicated:

In all patients who are not already receiving large amounts of opioids.

For use during obstetric labor.

For use during Pregnancy.

In children and in all other patients who cannot reliably participate in the correct

assessment of their own pain relief.

Warnings and precautions

Palladone Injection 10 mg/ml is a highly concentrated solution of hydromorphone intended for

use in patients already receiving opioids.

Drug Dependence

Like other opioids, continuing use of hydromorphone may result in physical dependence,

tolerance, and, in susceptible individuals, psychological dependence.

Physical dependence and tolerance are expected to occur with chronic opioid therapy, but both

are distinct entities from psychological (psychogenic) dependence.

Physical Dependence

Physical dependence is the adaptation of the body to the presence of an opioid drug. This

involves physiological changes that explain two phenomena frequently seen with long-term

opioid treatment: tolerance and the withdrawal syndrome.

Tolerance is defined as the need to administer a higher dose of the opioid to maintain the same

level of analgesia. For most patients, the first indication of tolerance is a decrease in the

duration of analgesia for a given dose and the appearance of breakthrough pain. Tolerance may

be confused with an increase in the pain intensity of the disease itself (which is the most

common reason an increase in dosage is indicated). Irrespective of the underlying cause, it is

recommended that the dose be increased and the patient re-titrated until the pain is again

controlled.

Withdrawal symptoms, sometimes called the opioid abstinence syndrome, are those manifested

by a patient upon cessation of treatment or rapid reduction of dosage. In its mildest form, the

opioid abstinence syndrome may be confused with viral, influenza-like syndromes.

In severe withdrawal, early symptoms include yawning, lacrimation, rhinorrhea, restless or "yen

sleep", and perspiration. These may be followed by mydriasis, piloerection, flushing,

tachycardia, twitching, tremor, restlessness, instability, and anorexia. Ultimately, symptoms

include muscle spasm, fever, nausea, diarrhea, vomiting, and spontaneous orgasm.

Opioid abstinence syndrome has been well described in the literature and the severity of the

syndrome in a particular patient can vary from mild discomfort to potential cardiovascular

collapse.

Without treatment most observable symptoms resolve in 5-14 days. A period of “subacute

withdrawal” lasting up to 6 months has also been described in which previously dependent

patients experience difficulty concentrating, insomnia, irritability, myalgias and autonomic

instability.

The severity of the abstinence syndrome is related to the degree of dependence, the abruptness

of withdrawal, and the drug used. In general, withdrawal symptoms develop at the time the

next dose would originally have been given. For hydromorphone, they gradually increase in

intensity, reaching a maximum at 24-72 hours and subsiding over 5-10 days.

If a reduction in dosage is required, the opioid abstinence syndrome can usually be avoided by

gradually decreasing the dosage in the following fashion. Half the prior daily dosage should be

given for the first 2 days. This should be reduced by 25% every 2 days thereafter, until the daily

dosage is 1.5 mg parenteral hydromorphone. The drug may be discontinued after 2 days on this

dose.

Various regimens have been described for treatment of severe abstinence syndrome, including

but not limited to methadone substitution, clonidine, benzodiazepines, and phenothiazines.

Supportive care is essential and associated symptoms, such as dehydration and gastrointestinal

(GI) disturbances, should be treated accordingly.

Withdrawal precipitated by the administration of an opioid antagonist is manifested by the

onset of symptoms within minutes, reaching maximum intensity within 30 minutes. Do not

administer an opioid antagonist as a means of detecting dependence. If an opioid antagonist

must be used to treat serious respiratory depression in a physically dependent patient,

administer with extreme care.

Physical dependence does not imply psychological dependence.

Psychological Dependence

Psychological dependence is a pattern of compulsive drug use characterized by a craving for an

opioid and the need to use the opioid for effects other than pain relief.

This type of dependence is extremely rare in patients taking opioids for the relief of severe pain.

It is very occasionally seen in patients who have previously used psychoactive substances for

recreational purposes. This must not be confused with the behavior of patients whose pain is

inadequately treated, who will also manifest drug-seeking behavior. For these patients titration

to pain-controlling dosage is required.

Use in drug and alcohol-dependent patients

Hydromorphone has an abuse profile similar to other strong opioids. Hydromorphone may be

sought and abused by people with latent or manifest addiction disorders. Hydromorphone

should be used with caution in patients with alcoholism and other drug dependencies due to the

increased frequency of opioid tolerance, physical and psychological dependence observed in

these patient populations. Abuse of hydromorphone in combination with other CNS depressant

drugs can result in serious risks to the patient.

Head Injury

Because of the tendency of hydromorphone to produce respiratory depression and its capacity

to elevate cerebrospinal fluid pressure, it should be used with extreme caution, if at all, in the

presence of head injury, other intracranial lesions or a pre-existing increase in intracranial

pressure, since both of these adverse reactions may be markedly exaggerated. Opioid agonists

like hydromorphone may interfere with evaluation of CNS functions, especially relative to

consciousness levels, pupillary changes, and respiratory depression, thereby masking the

clinical course and neurologic signs of further increase in intracranial pressure

in patients with

head injuries. In such cases, hydromorphone must be used with extreme caution and only

when it is absolutely essential.

Respiratory Conditions

The major risk of opioid excess is respiratory depression. Respiratory depression occurs most

frequently in overdose situations, in the elderly, in the debilitated, and in those suffering from

conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may

dangerously decrease pulmonary ventilation.

Hydromorphone should be used with extreme caution, if at all, in patients with

severe

impairment of pulmonary function, acute asthma, chronic obstructive pulmonary disease or cor-

pulmonale, a decreased respiratory reserve (as in emphysema, kyphoscoliosis or severe obesity),

pre-existing respiratory depression, hypoxia or hypercapnia. In such patients even therapeutic

doses of opioids may decrease respiratory drive while simultaneously increasing airway

resistance to the point of apnea.

Cardiovascular Effects

Opioids may cause severe hypotension in the postoperative patient, or in those whose ability to

maintain blood pressure is compromised by hypovolemia or concurrent administration of

phenothiazines or general anesthetics. Opioids may produce orthostatic hypotension in

ambulatory patients.

Hydromorphone, like all opioid analgesics, should be administered with caution to patients in

circulatory shock since vasodilation produced by the drug may further reduce cardiac output and

blood pressure.

Hyperalgesia

Hyperalgesia that will not respond to a further dose increase of hydromorphone may occur, in

particular, at high doses. A hydromorphone dose reduction or change in opioid may be required.

Other Effects

Patients receiving opioids on a chronic basis and who undergo cordotomy or any other pain-

relieving surgical procedure should be monitored closely for respiratory depression, and the

hydromorphone dosage should be titrated to the new post-operative requirement.

Carcinogenicity

Long term carcinogenicity studies have not been performed.

Genotoxicity

Hydromorphone was non-genotoxic in the Ames test and the in vivo mouse micronucleus assay

but positive in mouse lymphoma assay with metabolic activation. Similar findings have been

reported with other opioid analgesics such as codeine and oxycodone.

Effects on fertility

No effects have been observed on male or female fertility or sperm parameters in rats.

Use in Pregnancy

Safety of use in pregnancy has not been established. The placental transfer of opioids is rapid.

Maternal addiction following illicit use, resulting in withdrawal symptoms in the neonate, is well

documented. Withdrawal symptoms include irritability, excessive crying, yawning, sneezing,

increased respiratory rate, tremors, hyperreflexia, fever, vomiting, increased stools and diarrhea.

These symptoms usually appear during the first days of life. Palladone injection 10 mg/ml is

contraindicated during pregnancy.

Use in Labor

Due to the high concentration, this formulation is contraindicated for use during labor (see

Contraindications).

Use in Breastfeeding

Ordinarily, nursing should not be undertaken while a patient is receiving Palladone Injection

since hydromorphone may be excreted in maternal milk.

Use in Pediatrics

Due to the high concentration of the 10mg/ml injection, this formulation is contraindicated in

children and in all other patients who cannot reliably participate in the correct assessment of

their own pain relief (see Contraindications). Safety and effectiveness in children have not been

established. Paradoxical excitation is more likely to occur in pediatric patients receiving opioid

therapy.

Use in the Elderly

Elderly subjects have been shown to have at least twice the sensitivity (as measured by EEG

changes) of young adults to some opioids.

Hydromorphone should be used with caution in the elderly, and the initial dose should be

reduced. The elderly may require a lower dosage than adults to achieve adequate analgesia.

Some elderly patients may be sensitive to the respiratory depressant effect of hydromorphone

and should be monitored closely during therapy initiation and any subsequent dosage increase.

The diagnosis or clinical course of acute abdominal conditions may be obscured by opioids.

Exercise caution (and reduced initial dose) in elderly and debilitated patients and in patients

sensitive to CNS depressants, including those with cardiovascular disease, myxoedema or

hypothyroidism, acute alcoholism, delirium tremens, cerebral arteriosclerosis, fever,

kyphoscoliosis,

adrenocortical insufficiency e.g. Addison's disease, prostatic hypertrophy or

urethral stricture, toxic psychosis, CNS depression, coma, gallbladder/biliary tract/pancreas

dysfunction including pancreatitis, or a history of drug abuse.

Renal and hepatic dysfunction may cause a prolonged duration of action and a cumulative

effect. Hence, care should be exercised in these conditions, particularly with repeated dosing.

Seizures may become aggravated, or may occur in individuals without a history of convulsive

disorders. Patients with known seizure disorders should be carefully observed.

The cough reflex is suppressed.

Exercise caution when using opioid analgesics in patients with pulmonary disease.

Use with caution in patients with atrial flutter and other supraventricular tachycardias. Vagolytic

action may increase the ventricular response rate.

Use in surgery: Palladone should be used with caution pre- or intra- operatively and within the

first 24 hours post-operatively.

Exercise caution when using opioid analgesics especially following gastrointestinal tract surgery

as opioids are known to impair intestinal motility and should not be used until the physician is

assured of normal bowel function. Should paralytic ileus be suspected or occur during use,

Palladone should be discontinued immediately).

Opioid

analgesics

including

hydromorphone

should

also

used with caution in patients

requiring biliary tract procedures since it may cause spasm of the sphincter of Oddi.

Driving and operating dangerous machinery

Hydromorphone may impair mental and/or physical ability required for the performance of

potentially hazardous tasks (e.g. the drug may produce drowsiness or dizziness).Therefore,

patients should be warned that their ability to perform potentially hazardous tasks requiring

mental alertness or physical coordination, such as driving a vehicle or operating machinery,

may be impaired.

Drug Interactions

Hydromorphone should not be given to patients taking non-selective MAOIs or within 14 days

of stopping such treatment.

Administration of an opioid antagonist such as naloxone or naltrexone will block the therapeutic

effect of hydromorphone, and will precipitate withdrawal symptoms in patients physically

dependent on opioids; such symptoms may persist for up to 48 hours and be difficult to reverse.

Similarly, administration of a mixed agonist/antagonist opioid analgesic (e.g. pentazocine,

buprenorphine) to a patient receiving therapy with a pure agonist opioid such as

hydromorphone may reduce the analgesic effect, or precipitate withdrawal.

Use with caution and in reduced dosage in patients concurrently receiving other opioid

analgesics, general anesthetics, antihistamines, phenothiazines, barbiturates,

neuroleptics, other

tranquilizers, sedative-hypnotics, antidepressants, antiemetics and other CNS depressants

including alcohol, anticholinergics or neuromuscular blocking agents. Concurrent therapy may

increase the risk of respiratory depression, hypotension, profound sedation, coma, severe

constipation, or urinary retention.

When such combined therapy is contemplated, the dose of one or both agents should be

reduced, however hydromorphone should not be taken with alcohol.

Concurrent use of opioid analgesics with antidiarrheals may increase the risk of severe

constipation, as well as CNS depression.

Patients receiving concurrent antihypertensive medication and opioid analgesics should be

monitored closely, due to the increased risk of orthostatic hypotension.

Case reports have described CNS toxicity (confusion, disorientation, respiratory depression,

apnea, seizures) following concurrent administration of cimetidine and opioid analgesics, though

no clear-cut cause and effect relationship has been established.

Diagnostic Interference

Because opioids may increase biliary tract pressure with resultant increases in plasma amylase

or lipase, measurements of these enzymes may be unreliable for 24 hours following

administration.

Adverse Reactions

The adverse effects of hydromorphone are similar to those of other opioid agonist analgesics,

and represent established pharmacological effects of the drug class. The major hazards include

respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory

arrest, shock and cardiac arrest have occurred.

Adverse effects reported commonly (frequency > 1%) seem to be more prominent in

ambulatory patients and in those not experiencing severe pain. Syncopal reactions and related

symptoms in ambulatory patients may be alleviated if the patient lies down.

Key:

Very common (≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to <1/100)

Rare

(≥ 1/10,000 to < 1/1,000)

Very rare

(<1/10,000)

Not known

(cannot be estimated from the available data)

Cardiovascular disorders

Common

hypotension

Uncommon

bradycardia, hypertension, palpitation, tachycardia

Unknown

flushing

Eye disorders

Uncommon

blurred vision, diplopia, miosis, visual impairment

Gastrointestinal disorders

Very common

constipation, nausea

Common

abdominal pain, dry mouth, vomiting

Uncommon

cramps, diarrhea, dysgeusia (taste alteration), paralytic ileus

General disorders and administration site conditions

Common

asthenia, injection site reactions (following parenteral administration)

Uncommon

chills, drug tolerance, drug withdrawal syndrome, peripheral

oedema, fatigue, malaise

Hepatobiliary disorders

Uncommon

biliary colic, increased hepatic enzymes

Immune system disorders

Uncommon

anaphylactic reactions, hypersensitivity reactions (including

oropharyngeal swelling)

Metabolism and nutrition disorders

Common

anorexia

Nervous system disorders

Very common

dizziness, somnolence

Common

headache, light-headedness, sedation

Uncommon

convulsions, dyskinesia, faintness, hyperalgesia, increased intracranial

pressure, myoclonus, uncoordinated muscle movement, muscle rigidity,

paraesthesia, syncope, tremor, weakness

Rare

lethargy

Psychiatric disorders

Common

anxiety, confusional state, dysphoria, euphoria, insomnia, nervousness

Uncommon

agitation, drug dependence, alterations of mood (apprehension,

depression, floating feelings), transient hallucinations, disorientation,

nightmares

Renal and urinary disorders

Common

urinary retention

Uncommon

antidiuretic effects, urinary hesitancy

Reproductive system and breast disorders

Uncommon

erectile dysfunction

Respiratory, thoracic and mediastinal disorders

Uncommon

bronchospasm, dyspnoea, laryngospasm, respiratory depression

Skin and subcutaneous tissue disorders

Common

hyperhidrosis (sweating), pruritus, rash

Uncommon

urticaria and other skin rashes

Other

In clinical trials, neither local tissue irritation nor induration was observed at the site of

subcutaneous injection; pain at the injection site was rarely observed.

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.gov.il

Dosage and Administration

Because of its high concentration, the delivery of precise doses of Palladone Injection 10 mg/ml

may be difficult if low doses of hydromorphone are required. Therefore, Palladone Injection

10mg/ml should be used only if the amount of hydromorphone required can be delivered

accurately with this formulation. Similarly, Palladone Injection 10mg/ml is not generally

recommended for single-dose administration due to the very large amount of hydromorphone

in the ampoule and the associated risk of overdosage.

General Recommendations

Palladone concentrated preservative-free Injection 10 mg/ml is intended for IV, SC (and rarely

IM) administration only in patients already receiving opioids. In most cases, these patients will

have chronic, not acute pain. Patients with severe chronic pain should receive opioids on a

regular time schedule (round-the-clock) so that they remain free of pain, rather than on an as-

needed basis after pain recurs.

Because this formulation of hydromorphone is highly concentrated, a smaller injection volume

can be used than with other parenteral opioid formulations. Discomfort associated with the SC

(or IM) injection of an unusually large volume of solution can therefore be avoided.

For the correct and effective use of hydromorphone it is critical to adjust the dosing regimen for

each patient individually, according to the severity of pain, the patient's metabolism, previous

history of analgesic therapy, concurrent medications and response to hydromorphone. The

following dosage recommendations are, therefore, only suggested approaches to what is

actually a series of clinical decisions in the management of pain of an individual patient.

Continuous Infusions

For patients with severe chronic pain in whom the oral route is not feasible, parenteral opioids

are needed. Since intermittent injections are expensive, uncomfortable, induce "clock

watching" and are associated with the "bolus effect" (peak levels associated with intolerable

adverse effects and trough levels associated with inadequate analgesia), continuous IV or SC

infusions are preferable. Continuous IV infusions (CIVI) are suitable for patients who already

require IV access and maintenance for other reasons. In home-based patients in particular, it is

rarely feasible to maintain peripheral IV access for continuous IV infusions. Thus, continuous IV

infusions are usually considered when patients have an indwelling central venous port or other

long-term venous access device. In most other patients, continuous SC infusions (CSCI) using

relatively small, portable programmable infusion pumps attached to a 27-gauge butterfly needle

placed SC, are an excellent alternative to CIVI. CSCI does not require IV access or the need for

continuous nursing care, enhances patient mobility and is not associated with potentially

dangerous complications, e.g. sepsis. However, in CSCI, skin irritation at the infusion site must be

monitored and the infusion site rotated accordingly, e.g. every 7 days. The anterior chest wall,

abdominal wall and subclavicular region are popular sites for the SC infusion.

A. Initial Dosage and Rescue Medication

For patients transferring from morphine or oral hydromorphone to Palladone Injection,

conversion factors should be used to convert the previous 24-hour opioid use to a parenteral

hydromorphone equivalent. (For patients receiving opioids other than morphine or

hydromorphone, standard equianalgesic tables should be consulted to determine the equivalent

24-hour opioid dose in parenteral morphine equivalents. Then follow the steps below for

parenteral morphine.)

Calculate the total daily dosage (mg) of each opioid (around-the-clock plus rescue doses).

Multiply the daily dose of each prior opioid by the appropriate multiplication factor from the

table for oral and/or parenteral forms, adding the results to obtain the equivalent total daily

hydromorphone parenteral dose. For CIVI, the daily parenteral hydromorphone dose should be

added to solution (e.g. 500 ml saline) and delivered over the ensuing 24 hours (e.g. 20 ml/hour).

A loading bolus of 2 mg may be given by slow IV injection at the start of the infusion. For CSCI,

the daily parenteral hydromorphone dose should be divided into 24 to obtain the initial hourly

infusion rate and the pump/infusion device set accordingly.

An hourly volume of 5 ml, and preferably 2 ml, should not be exceeded.

Multiplication Factors for Converting to Parenteral Hydromorphone

(mg/day prior opioid X factor = mg/day parenteral hydromorphone)

Prior Opioid

Oral

Parenteral

Hydromorphone

Morphine

0.05

0.13

For example, a patient receiving 240 mg oral morphine daily (120 mg twice daily) who is being

switched to Palladone Injection:

240 mg X 0.05 = 12 mg daily parenteral hydromorphone

12 mg ÷ 24 hr = 0.5 mg/hr hydromorphone

The conversion table is only meant to serve as a guide. It should be noted that the above table is

based on a hydromorphone:morphine ratio of 7.5:1. However, recent studies have indicated

that in some patients the ratio may approximate 4:1. Therefore, the above table presents a

conservative starting dose, and consideration should be given to early upward titration in a

significant portion of patients. In the rare patient receiving very large opioid doses,

consideration should be given to the potential for incomplete cross tolerance. When converting

these patients to hydromorphone therapy, the starting dose estimated by the conversion ratio

may need to be decreased. For patients who have experienced intolerable side effects on their

previous opioid, consideration should be given to decreasing the initial hydromorphone infusion

rate by 50%. In all circumstances, the patient's response following conversion from other opioids

must be carefully monitored and the dosage of Palladone Injection adjusted accordingly. (Note:

The table should not be used for converting patients from hydromorphone to other opioids.)

Following initiation of the infusion and after any subsequent changes in the infusion rate that

are substantial, the patient should be monitored closely for several hours in a setting where an

opioid antagonist, oxygen and resuscitative equipment, and personnel trained in their use, are

available.

Arrangements for rescue medication for breakthrough pain should always be ensured.

Rescue medication should always preferably consist of the same opioid administered through

the same route of administration. For continuous infusions, the size of the rescue dose should

be 50-100% of the hourly dose, and rescue doses should be available every 60 minutes. An initial

loading dose equivalent to the rescue dose should be given at the start of the infusion to reduce

the time before reaching steady state. Both the initial bolus and the rescue doses can be

administered using the same site of infusion via a three-way stopcock or via a PCA device with a

bolus feature.

B. Titration to Pain Control

Adjustments of the initial dosage should be made to obtain an appropriate balance between

pain relief and opioid adverse experiences. The optimal dose is that which maintains adequate

analgesia with no or controllable side effects. Adequate analgesia is generally considered to be

mild or no pain with the regular use of no more than two doses of supplemental analgesia per

24 hours. If the initial dose provides inadequate analgesia, the dose should be titrated upwards

and the patient should be assessed.

The number of daily rescue doses required by the patient is a useful guide for the escalation of

the baseline continuous infusion. For example, a patient receiving hydromorphone 4 mg/hr by

continuous infusion who requires 6 supplemental doses of 4 mg should have the infusion

increased to 5 mg/h with a concurrent increase in the rescue dose to 5 mg.

4 mg/h X 24 hours = 96 mg via continuous infusion

96 mg + 24 mg rescue medication = 120 mg total daily dose

120 mg/day ÷ 24 hours = 5 mg/h

If significant adverse events occur before the therapeutic goal of mild or no pain is achieved, the

events should be treated aggressively. Once adverse events are under control, upward titration

can continue to an acceptable level of pain control. Patients with good pain relief who develop

intolerable side effects should have the infusion decreased by 25-50% with further titration up

or down depending on the response. Whenever the adverse experiences cannot be controlled

or tolerated, opioid rotation should be considered.

C. Maintenance of Therapy

During the course of treatment the patient may experience a recurrence of pain due to an

increase in the level of pain because of disease progression or due to the development of

tolerance. Regardless of the reason, the hydromorphone dose should be increased and the

patient re-titrated as outlined above in order to re-establish pain control. As there is no upper

limit to the amount of hydromorphone that may be given in intractable oncologic pain, the

quantity administered should be that which produces adequate analgesia.

Patients who undergo pain-relieving procedures (e.g. nerve blocks, cordotomy) should be

reassessed following the procedure to determine whether further treatment with Palladone

Injection is indicated. If so, the dosage should be adjusted to the new post-operative

requirement.

Bolus Injections

Hydromorphone 10 mg/ml should not generally be used for bolus injections. In the occasional

patient in whom this therapy is appropriate, bolus injections should preferably be administered

either IV or SC. Repeated IM injections are painful and should be avoided. Repeated bolus IV or

SC injections can be considered if the oral route becomes unavailable for a short period.

However, for longer periods, continuous infusions are preferable to repeated bolus injections

(see above). (Note: If an infusion device is not available, hydromorphone can be administered SC

as intermittent four-hourly injections via a 27-gauge butterfly needle left in situ for several

days.)

Since rapid IV injections of opioids can cause serious adverse reactions, IV injections should be

administered in a dilute solution slowly, over a period of several minutes. An opioid antagonist

and equipment for artificial ventilation should be available.

Overdosage

Symptoms

Serious overdosage with hydromorphone is characterised by respiratory depression

(reduced respiratory rate and/or tidal volume, cyanosis), extreme somnolence, progressing

to stupor or coma, skeletal muscle flaccidity, cold and/or clammy skin, pupillary constriction,

and possibly bradycardia, hypotension and death. Severe overdose may result in apnoea,

pulmonary oedema, circulatory collapse and death.

Treatment

The primary concern in the treatment of opioid overdose is immediate supportive therapy with

the establishment of adequate respiratory exchanges through the provision of, and

maintenance of, adequate ventilation - patients may need ventilatory support up to and

including endotracheal intubation and controlled ventilation. Adequate body temperature and

fluid balance should be maintained. Oxygen, intravenous fluids, vasopressors and other

supportive measures should be used as indicated.

Tolerance to the respiratory and CNS-depressant effects of opioids develops concomitantly

with tolerance to the analgesic effects, therefore making respiratory depression unlikely in an

opioid-tolerant patient taking the usual therapeutic doses of hydromorphone. Activated

charcoal may reduce absorption of the drug if given within one to two hours after ingestion.

A potentially serious recent oral ingestion of hydromorphone, if suspected, may be treated

with activated charcoal in a patient who is fully conscious with an intact gag reflex or a secured

airway. Initial dose of charcoal is 30 to 100 g in adults and 1 - 2 g/kg in children and is given as

a slurry via nasogastric tube. In patients who are not fully conscious or have an impaired gag

reflex, consideration should be given to administering activated charcoal via a nasogastric tube,

once the airway is protected.

If there are signs of clinically significant respiratory or cardiovascular depression, the use of

an opioid antagonist such as naloxone should be considered.

Caution should always be observed when using an opioid antagonist for the treatment of

suspected hydromorphone overdose as the duration of action of hydromorphone may exceed

that of the antagonist. Continuing surveillance is mandatory to prevent recurrence of

respiratory depression and supportive care - including ventilatory and circulatory

resuscitation/support when indicated - should always be provided. Additional doses of

antagonist may be given as indicated by the clinical situation.

Opioid antagonists such as naloxone may precipitate an acute abstinence syndrome in opioid-

dependent patients and should be carefully titrated to the desired degree of reversal. The

severity of an abstinence syndrome precipitated by administration of an opioid antagonist is

contingent upon the degree of dependence and the dose of antagonist given. Too rapid or

complete reversal may induce nausea, vomiting, sweating and circulatory stress and may

reverse the desirable therapeutic effects (analgesia) as well.

Toxicity

Toxicity may result from overdosage but because of the great interindividual variation in

sensitivity to opioids it is difficult to determine an exact dose of any opioid that is toxic or

lethal. The toxic effects and signs of overdosage may be less pronounced than expected, when

pain and /or tolerance are manifest.

Pharmaceutical Precautions

Protect from light and store below 25

C. Discard any unused portion. Do not autoclave. Protect

from freezing.

Parenteral solutions should be inspected visually for particulate matter and discoloration prior

to administration whenever container and solution permit. Do not use if the solution is not clear

and colorless or if it contains a precipitate.

Hydromorphone has been reported to be physically or chemically incompatible with solutions

containing cefazolin, cloxacillin sodium, diazepam, dimenhydrinate, gallium nitrate, haloperidol,

heparin sodium, hyaluronidase, soluble barbiturates, phenobarbitol sodium, phenytoin sodium,

prochlorperazine edisylate, sodium bicarbonate, sargramostim, or thiopental sodium.

Each ampoule of Palladone Injection 10mg/ml contains a large amount of potent narcotic that

may be potentially abused. Due to the limited indications for this product, the risk of overdosage

and risk of its diversion and abuse, it is recommended that special measures be taken to control

this product within the hospital or clinic. Accidental dermal exposure should be treated by the

removal of any contaminated clothing and rinsing the affected area with water.

Presentation

2 ml amber ampoules.

Each box contains 5 ampoules.

Rafa Laboratories Ltd. P.O.Box 405, Jerusalem 9100301

Registration number: 105 43 28474

The format of this leaflet was determined by the Ministry of Health and its content was checked and approved in

March 2016.

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