DOLESTINE

עבט

מ"עב תויטבצמרפ תוישעת

.

הנאתה בוחר

הישעת קראפ

ן"מח

.ד.ת

םהוש

60850

:לט

6864645

סקפ ,

6864944

www.tevapharm.com

ילוי

2018

ה/דבכנ ת/חקור ,ה/ אפור

,

עבט תרבח

:ןלהל טרופמכ עדימ ינוכדע לע עידוהל תשקבמ

Dolestine

Solution for I.M., I.V. or S.C. Injection

ןיטסלוד הקרזהל הסימת

רירשה ךותל דירוה ךותל ,

וא רועל תחתמ

לש הלופמא לכ

1

הליכמ ל"

מ

:

Pethidine (meperidine) hydrochloride 50 mg

לש הלופמא לכ

2

הליכמ ל"מ

:

Pethidine (meperidine) hydrochloride 100 mg

תפסוה

"Black box"

םייטאיפואה תצובקמ םירישכת ינולעב

---------------------------------------------------------------------------------------------------------------------

יוותה

ה

:םושירה תדועתב הרשואש יפכ

Relief of severe pain, pre-operative medication, support of anesthesia, obstetrical analgesia.

לעב תפסותה :ןלהלכ איה ןו

WARNING: RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR

OTHER CNS DEPRESSANTS

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 (see Precautions and Drug Interactions).

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 for signs and symptoms of respiratory depression and sedation.

ןולעה

ל

אפור

םוסרפל חלשנ

אה רתאבש תופורתה רגאמב

י

תואירבה דרשמ לש טנרטנ

http://www.health.gov.il

לבקל ןתינו

ו

עבט תרבחל הינפ י"ע ספדומ

.

Composition

Active Ingredient

Each ampoule of 1 ml contains:

Pethidine (meperidine) hydrochloride

50 mg

Each ampoule of 2 ml contains:

Pethidine (meperidine) hydrochloride

100 mg

Other Ingredients

Water for injections, sodium hydroxide (q.s.for pH

adjustment).

Mechanism of Action

Dolestine is a powerful narcotic analgesic.

WARNING: RISKS FROM CONCOMITANT USE WITH

BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

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 (see Precautions and Drug Interactions).

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 for signs and symptoms of respiratory depression

and sedation.

Indications

∙ Relief of severe pain.

∙ Pre-operative medication.

∙ Support of anesthesia.

∙ Obstetrical analgesia.

Contraindications

Known hypersensitivity to the preparation.

Pethidine is contraindicated in patients who are receiving

monoamine oxidase inhibitors, or those who have recently

received such agents. Therapeutic doses of pethidine

have occasionally precipitated unpredictable, severe, and

occasionally fatal reactions in patients who have received

monoamine oxidase inhibitors within the last 14 days. The

mechanism of these reactions is unclear, but may be related

to a pre-existing hyperphenylalaninemia. Some have been

characterized by coma, severe respiratory depression, cyanosis

and hypotension, and have resembled the syndrome of

acute narcotic overdose. In other reactions, the predominant

manifestations have been hyperexcitability, convulsions,

tachycardia, hyperpyrexia, and hypertension.

Although it is not known that other narcotics are free of the

risk of such reactions, virtually all of the reported reactions

have occurred with pethidine. If a narcotic is needed in

such patients, a sensitivity test should be performed in

which repeated, small, incremental doses of morphine

are administered over the course of several hours while

the patient’s condition and vital signs are under careful

observation. (Intravenous hydrocortisone or prednisolone

have been used to treat severe reactions, with the addition

of intravenous chlorpromazine in those cases exhibiting

hypertension and hyperpyrexia. The usefulness and safety

of narcotic antagonists in the treatment of these reactions

is unknown).

Pethidine is also contraindicated in the following cases:

Respiratory depression, or where respiratory reserve is depleted

(acute bronchial asthma, chronic airway disease, severe

emphysema, severe chronic bronchitis, kyphoscoliosis).

∙ Head injury, raised intracranial pressure (apart from

introducing monitoring and diagnostic problems,

hypercapnia associated with respiratory depression can itself

result in elevated intracranial pressure), brain tumour.

∙ Cardiac arrhythmias, especially supraventricular tachycardias,

cor pulmonale. Pethidine has a vagolytic action and may

produce a significant increase in the ventricular response

rate.

∙ Pre-eclampsia, eclampsia.

∙ Convulsive states such as status epilepticus, tetanus and

strychnine poisoning, due to the stimulatory effects of

pethidine on the spinal cord.

∙ Diabetic acidosis where there is a danger of coma.

∙ Acute alcoholism or delirium tremens.

∙ Severe liver disease, incipient hepatic encephalopathy.

∙ Patients with a low platelet count, coagulation disorders

or receiving anticoagulant treatment.

Pethidine is not recommended for use in infants under 1

year of age.

Warnings

Intravenous Use

Pethidine should not be administered intravenously unless

a narcotic antagonist and facilities for assisted or controlled

respiration are immediately available. When pethidine is

administered parenterally, especially intravenously, the patient

should be lying down.

If pethidine is to be given intravenously, the injection should

be administered very slowly, preferably in the form of a diluted

solution. Rapid I.V. injection of narcotic analgesics, including

pethidine, increases the incidence of adverse reactions;

severe respiratory depression, apnea, hypotension, peripheral

circulatory collapse, and cardiac arrest have occurred.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of pethidine and its capacity

to elevate cerebrospinal fluid pressure may be markedly

exaggerated in the presence of head injury, other intracranial

lesions, or a pre-existing increase in intracranial pressure.

Furthermore, narcotics produce adverse reactions which may

obscure the clinical course of patients with head injuries. In

such patients, pethidine must be used with extreme caution

and only if its use is deemed essential.

Opioids may obscure the diagnosis and/or mask the clinical

course of patients with head injuries or acute abdominal

conditions and should not be used unless absolutely necessary

in these conditions. The respiratory depressant effects of

pethidine may be markedly exaggerated in the presence

of head injury.

Asthma and Other Respiratory Conditions

Pethidine should be used with extreme caution in patients

undergoing an acute asthmatic attack, patients with chronic

obstructive pulmonary disease or cor pulmonale, patients

having a substantially decreased respiratory reserve, pre-

existing respiratory depression, hypoxia, or hypercapnia. In

such patients, even unusual therapeutic doses of narcotics

may decrease respiratory drive while simultaneously increasing

airway resistance to the point of apnea.

Large doses and/or rapid intravenous administration of

pethidine may produce rapid onset respiratory depression,

apnoea, hypotension, peripheral circulatory collapse,

bradycardia (as a result of stimulation of medullary vagal

nuclei) or even cardiac arrest. Pethidine should not be

administered by intravenous injection unless an opioid

antagonist and facilities for controlled or assisted respiration

are available.

Hypotensive Effect

The administration of pethidine may result in severe

hypotension in the postoperative patient or any individual

whose ability to maintain blood pressure has been

compromised by a depleted blood volume or the concurrent

administration of drugs such as phenothiazines or certain

anesthetics.

Drug Dependence

Pethidine can produce drug dependence of the morphine

type and therefore has the potential for being abused. Psychic

and physical dependence, and tolerance may develop upon

repeated administration of the drug.

Pethidine should be restricted to short-term administration

for the relief of severe pain not responding to non-opioid

analgesics. Abrupt withdrawal of pethidine in those physically

dependent may precipitate withdrawal syndrome, including

convulsions.

Use in Pregnancy

Safe use of pethidine prior to the labor period has not been

established. Therefore, it should not be used at this time,

unless the potential benefits to the mother outweigh the

possible hazards to the fetus.

Use in Labor and Delivery

Pethidine crosses the placental barrier and can produce

depression of respiration and psychophysiologic functions

in the newborn. Resuscitation may be required. Therefore,

pethidine is not recommended during labor.

Other

Cross-tolerance between narcotic analgesics can occur.

Seizures may result from prolonged exposure or high doses

of pethidine due to pethidine-associated neurotoxicity (PAN).

PAN is a recognised clinical entity which is mainly due to

the metabolite norpethidine. Norpethidine concentrations

are enhanced by reduction in renal excretion as in the

elderly and the very young and by increased conversion of

pethidine to norpethidine due to the effects of drugs such

as phenobarbitone and phenytoin. Furthermore, pethidine-

associated neurotoxicity is dose-related, so pethidine should

not be used for periods greater than 24 to 36 hours.

Because of the spasmogenic properties of pethidine on the

biliary tract and sphincter of Oddi, it should be used only when

necessary and then with caution in biliary colic, operations on

the biliary tract and acute pancreatitis. Pethidine may render

surgical exploration of the common bile duct difficult.

Decreased gastric emptying associated with pethidine may be

expected to increase the risks of aspiration either associated

with pethidine induced CNS depression/coma or during or

after general anaesthesia, e.g., a labouring patient going

on the cesarean section.

Inadvertent intra-arterial administration can produce severe

necrosis and gangrene.

Use in Breastfeeding

Pethidine is secreted in breast milk. Therefore, having taken

into account the importance of the drug to the mother, either

discontinue nursing or discontinue the drug.

Use in Patients with Hepatic Impairment

Accumulation of pethidine and/or its active metabolite,

norpethidine, can occur in patients with hepatic impairment.

Pethidine should therefore be used with caution in patients

with hepatic impairment.

Use in Patients with Renal Impairment

Accumulation of pethidine and/or its active metabolite,

norpethidine, can also occur in patients with renal impairment.

Pethidine should therefore be used with caution in patients

with renal impairment.

Use in Geriatrics

Clinical studies of pethidine during product development

did not include sufficient numbers of subjects aged 65 and

over to evaluate age-related differences in safety or efficacy.

Literature reports indicate that geriatric patients have a slower

elimination rate compared to young patients and they may

be more susceptible to the effects of pethidine. A reduction

in the total daily dose of pethidine may be required in elderly

patients, and the potential benefits of the drug weighed

against the relative risk to a geriatric patient.

Adverse Reactions

As with other opioid analgesics, respiratory depression

is the major hazard associated with parenteral pethidine

therapy.

Other adverse reactions include:

More Common Reactions

Central Nervous System

Lightheadedness, dizziness, sedation, sweating, bizarre

feelings, disorientation, hallucinations, psychosis. Some of

these effects seem to be more prominent in ambulatory

patients and those not experiencing severe pain, and may

be relieved by reducing the dose slightly and lying down.

Gastrointestinal

Nausea and vomiting, constipation.

Less Common Reactions

Cardiovascular

Hypotension, vasodilation, hypertension, tachycardia,

bradycardia, gangrene, following inadvertent intra-arterial

administration.

Dermatological

Rash, pruritus, urticaria, erythema, injection site complications

e.g., local irritation and induration, fibrosis of muscle tissue

with frequent repetition of intramuscular injection.

Gastrointestinal

Decreased gastric emptying.

Genito-urinary

Urinary retention and anuria.

Hepatic

Increased biliary tract pressure, choledochoduodenal sphincter

spasm.

Nervous System

Pethidine associated neurotoxicity (see Warnings and

Precautions), or neuropsychiatric toxicity, i.e., auditory

and visual hallucinations, irritability, agitation, hypomania,

paranoia, delirium and complex partial seizures, vertigo,

dizziness, coma, headache, convulsions or tremor, respiratory

depression, cold clammy skin, sweating and pallor. Inadvertent

injection around a nerve trunk may cause sensory-neural

effects, which is usually, but not always transitory.

Psychiatric

Neuropsychiatric toxicity, hyperactivity or agitation, depression,

mental clouding, dysphoria.

General

Dry mouth, weakness, hypersensitivity.

Pain at injection site; local tissue irritation and induration

following subcutaneous injection (particularly when repeated)

and antidiuretic effect.

Reporting of suspected adverse reactions

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

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“This leaflet format has been determined by the Ministry of Health and the content thereof has been checked and

approved.” Date of approval: July 2011.

Physician’s Package Insert

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DOLESTINE

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SOLUTION FOR I.M., I.V. or S.C. INJECTION

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Precautions

Some adverse reactions have been reported more frequently

after intravenous administration. Pethidine should only be

administered I.V. if a narcotic antagonist and facilities for

assisted or controlled respiration are available.

Pethidine should always be administered with caution,

and in reduced dosage, to elderly and debilitated patients

and patients with head injuries, severe hepatic or renal

impairment, biliary tract disorders, hypothyroidism,

adrenocortical insufficiency, shock, prostatic hypertrophy,

urethral stricture and Addison's disease.

Supraventricular Tachycardia

Pethidine should be used with caution in patients with atrial

flutter and other supraventricular tachycardias because of

a possible vagolytic action which may produce a significant

increase in the ventricular response rate.

Acute Abdominal Conditions

As with other narcotics, pethidine may obscure the

diagnosis or clinical course in patients with acute abdominal

conditions.

Convulsions

Pethidine may aggravate pre-existing convulsions in patients

with convulsive disorders.

Convulsions may occur in individuals without a history

of convulsive disorders, following use of a higher than

recommended dosage of the drug.

Other Precautions

Caution is also required in patients exhibiting acute alcoholism,

raised intracranial pressure or convulsive disorders.

Serious or life-threatening reactions such as respiratory

depression, coma, convulsions, possibly due to elevated

levels of norpethidine and hypotension have been associated

with the use of pethidine.

Pethidine should be used with caution in patients taking

other CNS depressant drugs such as hypnotics and

sedatives including barbiturates and benzodiazepines,

phenothiazines, and other tranquillisers, anaesthetics, alcohol

and antidepressants.

Patients with severe pain may tolerate very high doses of

pethidine but may exhibit respiratory depression should

their pain suddenly subside.

The elderly demonstrate an increased sensitivity to opioids

relative to younger patients. Reduced liver function, renal

function and plasma protein binding may contribute to the

elevated plasma levels found in elderly subjects.

Since pethidine is metabolized in the liver and excreted via

the kidneys, the possibility of accumulation of the toxic

metabolic norpethidine should be considered in patients

with hepatic and/or renal impairment.

Reduced cardiac output may lead to reduced hepatic

perfusion and diminished metabolism of pethidine, leading

to accumulation of pethidine with possible toxic results.

Pethidine may cause a transient rise in blood pressure

and systemic vascular resistance and increased heart rate.

Therefore, it is not recommended for pain relief in cardiac

infarction.

Pethidine in patients with pheochromocytoma may result

in a hypertensive crisis.

In an individual physically dependent on opioids, the

administration of the usual dose of an opioid antagonist

will precipitate an acute withdrawal syndrome. The severity

of this syndrome will depend on the degree of physical

dependence and the dose of antagonist administered. The

use of opioid antagonists in such individuals should be

avoided if possible. If an opioid antagonist must be used

to treat serious respiratory depression in the physically

dependent patient, the antagonist should be administered

with extreme care and only 10 to 20% of the usual initial

dose administered.

In eclampsia the combination of pethidine with phenothiazines

has been reported to induce recurrence of seizures rather

than stopping them. Therefore, the use of pethidine in

eclampsia and pre-eclampsia is not recommended (see

Contraindications).

Pethidine, while commonly used for pain relief in obstetrics,

is known to pass the placenta and may cause neonatal

depression, including respiratory depression. An opioid

antagonist such as naloxone may be required to reverse

such depression. In the neonate, pethidine is excreted and

metabolized at a significantly reduced rate compared to

adults.

Orthostatic hypotension has been reported in ambulatory

patients administered pethidine.

Pethidine should be given with caution and the initial

dose should be reduced in patients with hypothyroidism

or Addison’s disease.

Pethidine should be used with caution in patients with

prostatic hypertrophy or urethral stricture.

As opiate agonists may produce hyperglycemia, this effect

should be considered when diabetics require pethidine.

There are conflicting reports about the effect of pethidine on

the eye. Some reports state that pethidine and its congeners

produce miosis, whereas others indicate that these drugs tend

to produce mydriasis or no pupillary change. Until the effects

are better defined, intraocular tension should be monitored

in patients with glaucoma who received pethidine.

Patients may experience drowsiness while receiving pethidine

and should therefore be cautioned not to engage in

potentially-hazardous activities requiring mental alertness,

such as driving a car or operating machinery.

Drug Interactions

Pethidine has been found to interact with the following

drugs:

Barbiturates, Chloral Hydrate, Benzodiazepines:

Pethidine enhances the CNS depressant effects of these drugs.

In addition, the combination of pethidine and phenobarbitone

may reduce the analgesic effect of pethidine in part due to

the increased conversion of pethidine to the toxic metabolite,

norpethidine.

Phenothiazines: CNS toxicity and hypotension including

respiratory depression may occur when given together. In

eclampsia the combination has been reported to induce

recurrence of seizures (see Precautions).

Butyrophenones: The CNS depressant effect of tranquillisers

may be increased by pethidine.

Monoamine Oxidase Inhibitors (see Contraindications):

Excitation, sweating, rigidity, hypertension or hypotension,

coma have occurred with combination. Interaction with

furazolidone is not likely until it has been taken for five days.

Interaction with selegiline, a MAOI Type B, has been reported

as causing delirium, restlessness, sweating and rigidity.

Paracetamol: Absorption may be reduced due to delayed

gastric emptying caused by pethidine.

CNS Depressants (Including Alcohol): Depressant effects

may be enhanced by pethidine.

Phenytoin: Increased metabolism of pethidine and generation

of norpethidine resulting in the possibility of increased CNS

effects of norpethidine and reduced analgesia.

Coumarin/Indandione-Derivative: The effects of

coumarin or indandione-derivative anticoagulants may be

increased.

Amphetamines: Concurrent use with amphetamines, which

have some MAO inhibiting activity, is not recommended

because of the risk of serious reactions similar to those

reported with other MAO inhibitors.

Cimetidine: Cimetidine inhibits metabolism of pethidine

and therefore increases plasma concentration.

Anticholinergics: Use of pethidine in prolonged increasing

dosage or concomitantly with anticholinergics may result

in neurotoxicity in patients with renal failure, cancer or

sickle cell anemia.

Acyclovir: Plasma concentrations of pethidine and its

metabolite, norpethidine, may be increased by acyclovir, thus

caution should be used with concomitant administration.

Ritonavir: Plasma concentrations of the active metabolite

norpethidine may be increased by ritonavir, thus concomitant

administration should be avoided.

Skeletal Muscle Relaxants: Opioid analgesics, including

pethidine, may enhance the neuromuscular blocking action

of skeletal muscle relaxants and produce an increased degree

of respiratory depression.

Diagnostic Interference

Narcotic analgesics may produce increases in plasma

amylase and plasma lipase levels; the diagnostic utility of

determinations of these enzymes may be compromised for up

to 24 hours after the medication has been administered.

Information for Patients

CNS depression is increased when pethidine is co-

administered with alcohol, butyrophenones, hypnotics,

sedatives, phenothiazines, tricyclics, antihistamines and

other CNS depressant agents.

Driving and operating dangerous machinery should not

be contemplated until the day following the last dose of

pethidine.

Dosage and Administration

Parenteral drug products should be inspected visually for

particulate matter and discoloration prior to administration,

whenever solution and container permit.

Relief of Pain

Dosage should be adjusted according to the severity of the

pain and the response of the patient.

Adults

The usual dosage is 50-100 mg, administered intramuscularly

or subcutaneously every 3 or 4 hours as necessary.

Children

The usual dosage is 1-1.8 mg/kg body weight, administered

intramuscularly or subcutaneously every 3 or 4 hours as

necessary. Irrespective of body weight, the adult dose should

not be exceeded.

Pre-operative Medication

Adults

The usual dosage is 50-100 mg, administered intramuscularly

or subcutaneously, 30 to 90 minutes before anesthesia is

started.

Children

The usual dosage is 1-2 mg/kg body weight, administered

intramuscularly or subcutaneously 30-90 minutes before

the start of anesthesia.

Irrespective of body weight, the adult dosage should not

be exceeded.

Support of Anesthesia

The dose should be titrated to the needs of the patient,

according to the premedication and type of anesthetic being

employed, the characteristics of the particular patient, and

the nature and duration of the operative procedure.

Dolestine may be administered intravenously, either by

repeated slow injection of fractional doses of a solution

diluted to 10 mg/ml, or by infusion as a solution diluted

to 1 mg/ml.

Dosage may be individualized up to a maximum of

50 mg.

Obstetrical Analgesia

The usual dosage is 50-100 mg, administered intramuscularly

or subcutaneously when pain becomes regular. It may be

repeated at 1-3 hour intervals.

Incompatibilities

The mixing of thiopentone solutions with pethidine results

in the formation of a pharmacologically inactive complex.

A loss of clarity of solution was noted when solutions of

pethidine hydrochloride were mixed with the following:

aminophylline, heparin, amylobarbitone sodium, methicillin

sodium, morphine sulphate, phenobarbitone sodium,

phenytoin sodium, sodium bicarbonate or sodium iodide.

Pethidine is also incompatible with alkalis, iodine and

iodides.

Overdosage

Manifestations

Opioid analgesic overdosage usually produces central nervous

system depression ranging from stupor to a profound coma,

respiratory depression which may progress to Cheyne-

Stokes respiration and/or cyanosis, cold clammy skin and/

or hypothermia, flaccid skeletal muscles, bradycardia and

hypotension. In patients with severe overdosage, particularly

following rapid intravenous administration of an opioid,

apnoea, circulatory collapse, cardiac arrest, respiratory arrest

and death may occur.

Complications such as pneumonia, shock and/or pulmonary

oedema may also prove fatal. Although miosis (pupillary

constriction) is characteristic of overdosage with morphine

derivatives and methadone, mydriasis may occur in terminal

narcosis or severe hypoxia. Overdosage of pethidine may

produce mydriasis rather than miosis.

Toxic effects of pethidine may be excitatory, especially in

patients who have developed tolerance to the depressant

effects of the drug. These patients may exhibit dry mouth,

increased muscular activity, muscle tremors and twitches,

tachycardia, delirium with disorientation, hallucinations and,

occasionally, grand mal seizures.

Treatment

In overdosage, if necessary, establish an airway and institute

assisted or controlled ventilation.

Circulation should be maintained with infusions of plasma

or suitable electrolyte solution. If consciousness is impaired

and respiration depressed, an opioid antagonist should

be administered. Naloxone, a pure antagonist, is now the

treatment of choice. Consult naloxone (or nalorphine) product

information. Administer I.V. naloxone (e.g., 0.4 mg) which

may be repeated at 2 to 3 minute intervals.

For children, the initial dose recommended is 0.01 mg/kg

naloxone. In neonates, a more rapid and improved antagonism

was noted after 0.02 mg/kg was administered. A response

should be seen after 2 or 3 doses. Note the duration of action

of naloxone is usually shorter than that of pethidine and thus

the patient should be carefully observed for signs of CNS

depression returning. An opioid antagonist should not be

administered in the absence of clinical signs of respiratory

or cardiovascular depression.

Note: In an individual physically dependent on opioids, the

administration of the usual dose of an opioid antagonist

will precipitate an acute withdrawal syndrome. The severity

of this syndrome will depend on the degree of physical

dependence and the dose of antagonist administered. The

use of opioid antagonists in such individuals should be

avoided if possible. If an opioid antagonist must be used

to treat serious respiratory depression in the physically

dependent patient, the antagonist should be administered

with extreme care and only 10 to 20% of the usual initial

dose administered.

Storage

Store below 25°C.

Drug Registration No.:

021.04.21091

Manufacturer and Licence Holder

Teva Pharmaceutical Industries Ltd.,

P.O.Box 3190, Petah-Tikva, Israel.

DOLE SOL PHY SH 280118

59462

281494.01-IL