הודעה על החמרה ( מידע בטיחות) בעלון לצרכן

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)‫בטיחות‬
)‫(מידע בטיחות‬
‫החמרה (מידע‬
‫על החמרה‬
‫הודעה על‬
‫הודעה‬
([email protected] :‫(לשלוח ל‬
2152 ‫ במאי‬51 :‫תאריך‬
Methadone 5% :‫שם תכשיר באנגלית‬
105 67 29097 :‫מספר רישום‬
‫ מעבדות רפא בע"מ‬:‫שם בעל הרישום‬
.‫ כחול=שינוי מקום‬,‫ ירוק=מחיקה‬,‫ צהוב=הוספה‬:‫השינויים בעלון מסומנים בצבע‬
‫לרופא‬
‫עלון לרופא‬
‫בבעלון‬
‫טקסט חדש‬
‫טקסט נוכחי‬
Active ingredient: Methadone HCl Concentrated
Active ingredient: Methadone HCl
Solution 50 mg/ml
Concentrated Solution 50 mg/ml
To be diluted before administration. The solution
To be diluted before administration.
‫פרק בעלון‬
COMPOSITION
should be diluted by the pharmacist to the
requested concentration and volume into a new
Inactive Ingredients: Methyl paraben,
bottle, according to the physician’s instructions.
propyl paraben, purified water.
Inactive Ingredients: Methyl paraben, propyl
paraben, purified water.
Deaths, cardiac and respiratory, have been
Deaths, cardiac and respiratory, have
BLACK BOX
reported during initiation and conversion of pain
been reported during initiation and
WARNING
patients to methadone treatment from treatment
conversion of pain patients to methadone
with other opioid agonists and during initiation of
treatment from treatment with other opioid
methadone treatment for opioid dependence. In
agonists. It is critical to understand the
some cases, drug interactions with other drugs,
pharmacokinetics of methadone when
both licit and illicit, have been suspected.
converting patients from other opioids.
However, in other cases, deaths appear to have
Particular vigilance is necessary during
occurred due to the respiratory or cardiac effects
treatment initiation, during conversion
of methadone and too-rapid titration without
from one opioid to another, and during
appreciation for the accumulation of methadone
dose titration.
over time. It is critical to understand the
Respiratory depression is the chief hazard
pharmacokinetics of methadone when converting
associated with methadone hydrochloride
patients from other opioids. Particular vigilance is
administration. Methadone’s peak
necessary during treatment initiation, during
respiratory depressant effects typically
conversion from one opioid to another, and during
occur later, and persist longer than its
dose titration. Patients must also be strongly
peak analgesic effects, particularly in the
cautioned against self-medicating with CNS
early dosing period. These characteristics
depressants during initiation of methadone
can contribute to cases of iatrogenic
treatment.
overdose, particularly during treatment
Respiratory depression is the chief hazard
initiation and dose titration.
1
associated with methadone hydrochloride
In addition, cases of QT interval
administration. Methadone’s peak respiratory
prolongation and serious arrhythmia
depressant effects typically occur later, and
(torsades de pointes) have been observed
persist longer than its peak analgesic effects,
during treatment with methadone. Most
particularly in the early dosing period. These
cases involve patients being treated for
characteristics can contribute to cases of
pain with large, multiple daily doses of
iatrogenic overdose, particularly during treatment
methadone, although cases have been
initiation and dose titration.
reported in patients receiving doses
In addition, cases of QT interval prolongation and
commonly used for maintenance
serious arrhythmia (torsades de pointes) have
treatment of opioid addiction.
been observed during treatment with methadone.
Methadone treatment for analgesic
Most cases involve patients being treated for pain
therapy in patients with acute or chronic
with large, multiple daily doses of methadone,
pain should only be initiated if the
although cases have been reported in patients
potential analgesic or palliative care
receiving doses commonly used for maintenance
benefit of treatment with methadone is
treatment of opioid addiction.
considered and outweighs the risks.
Methadone treatment for analgesic therapy in
patients with acute or chronic pain should only be
initiated if the potential analgesic or palliative care
benefit of treatment with methadone is considered
and outweighs the risks.
Known hypersensitivity to methadone or to any
Known hypersensitivity to methadone.
CONTRA-
other ingredient in this preparation.
Methadone is contraindicated in any
INDICATIONS
Methadone is contraindicated in any situation
situation where opioids are
where opioids are contraindicated such as:
contraindicated such as: patients with
patients with respiratory depression (in the
respiratory depression (in the absence of
absence of resuscitative equipment or in
resuscitative equipment or in unmonitored
unmonitored settings), and in patients with acute
settings), and in patients with acute
bronchial asthma or hypercardia.
bronchial asthma or hypercardia.
Methadone is contraindicated in any patient who
Methadone is contraindicated in any
has or is suspected of having a paralytic ileus.
patient who has or is suspected of having
a paralytic ileus.
Concentrated solution.
Concentrated solution.
WARNINGS –
Do not dispense the medicine to the patient in this
Do not dispense the medicine to the
(BLACK BOX)
bottle.
patient in this bottle.
The solution should be diluted by the pharmacist
The solution should be diluted by the
to the requested concentration and volume into a
pharmacist to the requested concentration
new bottle, according to the physician’s
and volume into a new bottle, according to
instructions.
the physician’s instructions.
For oral administration only. The preparation must
not be injected.
2
Respiratory depression, Incomplete Cross-
Respiratory depression, Incomplete
tolerance, and Iatrogenic overdose
Cross-tolerance, and Iatrogenic overdose
Respiratory depression is the chief hazard
Respiratory depression is the chief hazard
associated with methadone hydrochloride
associated with methadone hydrochloride
administration. Methadone’s peak respiratory
administration. Methadone’s peak
depressant effects typically occur later, and
respiratory depressant effects typically
persist longer than its peak analgesic effects,
occur later, and persist longer than its
particularly during the initial dosing period. These
peak analgesic effects, particularly during
characteristics can contribute to cases of
the initial dosing period. These
iatrogenic overdose, particularly during treatment
characteristics can contribute to cases of
initiation or dose titration. Respiratory depression
iatrogenic overdose, particularly during
is of particular concern in elderly or debilitated
treatment initiation or dose titration.
patients as well as in those suffering from
conditions accompanied by hypoxia or
Patients tolerant to other opioids may be
hypercapnia when even moderate therapeutic
incompletely tolerant to methadone.
doses may dangerously decrease pulmonary
Incomplete cross-tolerance is of particular
ventilation.
concern for patients tolerant to other mu-
Methadone should be used with extreme caution
opioid agonists who are being converted
in patients with conditions accompanied by
to treatment with methadone, thus making
hypoxia, hypercapnia, or decreased respiratory
determination of dosing during opioid
reserve such as: with acute asthma, chronic
treatment conversion complex. Deaths
obstructive pulmonary disease or cor pulmonale, ,
have been reported during conversion
and with preexisting respiratory depression,
from chronic, high-dose treatment with
severe obesity, sleep apnea syndrome,
other opioid agonists.
myxedema, kyphoscoliasis, and CNS depression
Therefore, it is critical to understand the
or coma. In these patients even usual therapeutic
pharmacokinetics of methadone when
doses of narcoticsmethadone may decrease
converting patients from other opioids. A
respiratory drive while simultaneously increasing
high dose of “opioid tolerance” does not
airway resistance to the point of apnea.
eliminate the possibility of methadone
Alternative, non-opioid analgesics should be
overdose, iatrogenic or otherwise.
considered, and Methadone should be used at the
lowest effective dose and only under careful
Drug abuse and dependence
medical supervision.
Methadone is, a mu-agonist opioid with an
abuse liability similar to other opioid
Incomplete Cross-tolerance between Methadone
agonists. Methadone and other opioids
and other Opioids
used in analgesia can be abused and are
Patients tolerant to other opioids may be
subject to criminal diversion. Abuse of
incompletely tolerant to methadone. Incomplete
methadone poses a risk of overdose and
cross-tolerance is of particular concern for
death. This risk is increased with
patients tolerant to other mu-opioid agonists who
concurrent abuse of methadone with
are being converted to treatment with methadone,
alcohol and other substances. In addition,
3
WARNINGS
thus making determination of dosing during opioid
parenteral drug abuse is commonly
treatment conversion complex. Deaths have been
associated with transmission of infectious
reported during conversion from chronic, high-
diseases such as hepatitis and HIV.
dose treatment with other opioid agonists.
Drug addiction is characterized by
Therefore, it is critical to understand the
compulsive use, use for non-medical
pharmacokinetics of methadone when converting
purposes, and continued use despite
patients from other opioids. A high dose of “opioid
harm or risk of harm. Drug addiction is a
tolerance” does not eliminate the possibility of
treatable disease, utilizing a multi-
methadone overdose, iatrogenic or otherwise.
disciplinary approach, but relapse is
common.
Drug abuse and dependence
“Drug-seeking” behavior is very common
Methadone is, a mu-agonist opioid with an abuse
in addicts and drug abusers. Drug-
liability similar to other opioid agonists.
seeking tactics include emergency calls or
Methadone and other opioids used in analgesia
visits near the end of office hours, refusal
can be abused and are subject to criminal
to undergo appropriate examination,
diversion. Abuse of methadone poses a risk of
testing or referral, repeated claims of lost
overdose and death. This risk is increased with
prescriptions, tampering with prescriptions
concurrent abuse of methadone with alcohol and
and reluctance to provide prior medical
other substances. In addition, parenteral drug
records or contact information for other
abuse is commonly associated with transmission
treating physician(s). “Doctor shopping”
of infectious diseases such as hepatitis and HIV.
(visiting multiple prescribers) to obtain
Drug addiction is characterized by compulsive
additional prescriptions is common among
use, use for non-medical purposes, and continued
drug abusers and people suffering from
use despite harm or risk of harm. Drug addiction
untreated addiction. However, it should be
is a treatable disease, utilizing a multi-disciplinary
important to note that preoccupation with
approach, but relapse is common.
achieving adequate pain relief can be
“Drug-seeking” behavior is very common in
appropriate behavior in a patient with poor
addicts and drug abusers. Drug-seeking tactics
pain control.
include emergency calls or visits near the end of
office hours, refusal to undergo appropriate
Tolerance and Physical Dependence
examination, testing or referral, repeated claims of
Abuse and addiction are separate and
lost prescriptions, tampering with prescriptions
distinct from physical dependence and
and reluctance to provide prior medical records or
tolerance. Physicians should be aware
contact information for other treating physician(s).
that addiction may not be accompanied by
“Doctor shopping” (visiting multiple prescribers) to
concurrent tolerance and symptoms of
obtain additional prescriptions is common among
physical dependence in all addicts. In
drug abusers and people suffering from untreated
addition, abuse of opioids can occur in the
addiction. However, it should be important to note
absence of true addiction and is
that preoccupation with achieving adequate pain
characterized by misuse for non-medical
relief can be appropriate behavior in a patient with
purposes, often in combination with other
poor pain control.
psychoactive substances. Methadone, like
4
other opioids, has been diverted for nonTolerance and Physical Dependence
medical use. Careful record-keeping of
Tolerance is the need for increasing doses of
prescribing information, including quantity,
opioids to maintain a defined effect such as
frequency, andrenewal requests is
analgesia (in the absence of disease progression
strongly advised.
or other external factors). Physical dependence is
Proper assessment of the patient, proper
manifested by withdrawal symptoms after abrupt
prescribing practices, periodic re-
discontinuation of a drug or upon administration of
evaluation of therapy, and proper
an antagonist.
dispensing and storage are appropriate
Physical dependence is expected during opioid
measures that help to limit abuse of opioid
agonist therapy of opioid addiction.
drugs.
Physical dependence and/or tolerance are not
If methadone is abruptly discontinued in a
unusual during chronic opioid therapy.
physically dependent patient, an
Abuse and addiction are separate and distinct
abstinence syndrome may occur. The
from physical dependence and tolerance.
opioid abstinence or withdrawal syndrome
Physicians should be aware that addiction may
is characterized by some or all of the
not be accompanied by concurrent tolerance and
following: restlessness,
symptoms of physical dependence in all addicts.
lacrimation,rhinorrhea, yawning,
In addition, abuse of opioids can occur in the
perspiration, chills, myalgia, and
absence of true addiction and is characterized by
mydriasis. Other symptoms also may
misuse for non-medical purposes, often in
develop, including irritability, anxiety,
combination with other psychoactive substances.
backache, joint pain, weakness,
Methadone, like other opioids, has been diverted
abdominal cramps, insomnia, nausea,
for non-medical use. Careful record-keeping of
anorexia, vomiting, diarrhea, or increased
prescribing information, including quantity,
blood pressure, respiratory rate, or heart
frequency, andrenewal requests is strongly
rate.
advised.
In general, chronically administered
Proper assessment of the patient, proper
methadone should not be abruptly
prescribing practices, periodic re-evaluation of
discontinued
therapy, and proper dispensing and storage are
However, most patients who receive
appropriate measures that help to limit abuse of
opiates for medical reasons do not
opioid drugs.
develop dependence syndromes.
If methadone is abruptly discontinued in a
Infants born to mothers physically
physically dependent patient, an abstinence
dependent on opioids may also be
syndrome may occur. The opioid abstinence or
physically dependent and may exhibit
withdrawal syndrome is characterized by some or
respiratory difficulties and withdrawal
all of the following: restlessness,
symptoms.
lacrimation,rhinorrhea, yawning, perspiration,
chills, myalgia, and mydriasis. Other symptoms
Asthma and other Respiratory Conditions
also may develop, including irritability, anxiety,
Methadone should be used with extreme
backache, joint pain, weakness, abdominal
caution in patients with acute asthma,
5
cramps, insomnia, nausea, anorexia, vomiting,
chronic obstructive pulmonary disease or
diarrhea, or increased blood pressure, respiratory
cor pulmonale, a substantially decreased
rate, or heart rate.
respiratory reserve, and with preexisting
In general, chronically administered methadone
respiratory depression, hypoxia or
should not be abruptly discontinued
hypercapnia, severe obesity, sleep apnea
However, most patients who receive opiates for
syndrome, myxedema ,kyphoscoliasis,
medical reasons do not develop dependence
and CNS depression or coma. In these
syndromes.
patients even therapeutic doses of
Infants born to mothers physically dependent on
narcotics may decrease respiratory drive
opioids may also be physically dependent and
while simultaneously increasing airway
may exhibit respiratory difficulties and withdrawal
resistance to the point of apnea.
symptoms.
Asthma and other Respiratory Conditions
Head Injury and Increased Intracranial
Methadone should be used with extreme caution
Pressure
in patients with acute asthma, chronic obstructive
The respiratory depressant effects of
pulmonary disease or cor pulmonale, a
methadone and its capacity to elevate
substantially decreased respiratory reserve, and
cerebrospinal fluid pressure may be
with preexisting respiratory depression, hypoxia or
markedly exaggerated in the presence of
hypercapnia, severe obesity, sleep apnea
increased intracranial pressure.
syndrome, myxedema ,kyphoscoliasis, and CNS
Furthermore, narcotics produce side
depression or coma. In these patients even
effects that may obscure the clinical
therapeutic doses of narcotics may decrease
course of patients with head injuries. In
respiratory drive while simultaneously increasing
such patients, methadone must be used
airway resistance to the point of apnea.
with caution and only if it is deemed
essential.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of methadone
Acute Abdominal Conditions
and its capacity to elevate cerebrospinal fluid
The administration of opioids may
pressure may be markedly exaggerated in the
obscure the diagnosis or clinical course of
presence of head injury, other intracranial lesions
patients with acute abdominal conditions.
or a pre-existing increased in intracranial
pressure. Furthermore, narcotics produce side
Hypotension
effects that may obscure the clinical course of
Hypotension may result in the
patients with head injuries. In such patients,
postoperative patient, or in any individual
methadone must be used with caution and only if
whose ability to maintain blood pressure
it is deemed essential.
is compromised by hypovolemia or
Acute Abdominal Conditions
concurrent administration of
The administration of opioids may obscure the
phenothiazines or general anesthetics.
diagnosis or clinical course of patients with acute
Narcotics may produce orthostatic
abdominal conditions.
hypotension in ambulatory patients.
Hypotension
6
Hypotension may result in the postoperative
Cardiac Conduction Effects
patient, or in any individual whose ability to
Laboratory studies, both in vivo and in
maintain blood pressure is compromised by
vitro, have demonstrated that methadone
hypovolemia or concurrent administration of
inhibits cardiac potassium channels and
phenothiazines or general anesthetics. Narcotics
prolongs the QT interval. Cases of QT
may produce orthostatic hypotension in
interval prolongation and serious
ambulatory patients.
arrhythmia (torsades de pointes) have
Cardiac Conduction Effects
been observed during treatment with
Laboratory studies, both in vivo and in vitro, have
methadone. These cases appear to be
demonstrated that methadone inhibits cardiac
more commonly associated with, but not
potassium channels and prolongs the QT interval.
limited to, higher dose treatment (> 200
Cases of QT interval prolongation and serious
mg/day). Most cases involve patients
arrhythmia (torsades de pointes) have been
being treated for pain with large, multiple
observed during treatment with methadone.
daily doses of methadone, although cases
These cases appear to be more commonly
have been reported in patients receiving
associated with, but not limited to, higher dose
doses commonly used for maintenance
treatment (> 200 mg/day). Most cases involve
treatment of opioid addiction. In most of
patients being treated for pain with large, multiple
the cases seen at typical maintenance
daily doses of methadone, although cases have
doses, concomitant medications and/or
been reported in patients receiving doses
clinical conditions such as hypokalemia
commonly used for maintenance treatment of
were noted as contributing factors.
opioid addiction. In most of the cases seen at
However, the evidence strongly suggests
typical maintenance doses, concomitant
that methadone possesses the potential
medications and/or clinical conditions such as
for adverse cardiac conduction effects in
hypokalemia were noted as contributing factors.
some patients.
However, the evidence strongly suggests that
Methadone should be administered with
methadone possesses the potential for adverse
particular caution to patients already at
cardiac conduction effects in some patients.
risk for development of prolonged QT
Methadone should be administered with particular
interval (e.g., cardiac hypertrophy,
caution to patients already at risk for development
concomitant diuretic use, hypokalemia,
of prolonged QT interval (e.g., cardiac
hypomagnesemia). Careful monitoring is
hypertrophy, concomitant diuretic use,
recommended when using methadone in
hypokalemia, hypomagnesemia). Careful
patients with a history of cardiac
monitoring is recommended when using
conduction abnormalities, those taking
methadone in patients with a history of cardiac
medications affecting cardiac conduction,
conduction abnormalities, those taking
and in other cases where history or
medications affecting cardiac conduction, and in
physical exam suggest an increased risk
other cases where history or physical exam
of dysrhythmia. QT prolongation has also
suggest an increased risk of dysrhythmia. QT
been reported in patients with no prior
prolongation has also been reported in patients
cardiac history who have received high
with no prior cardiac history who have received
doses of methadone. Patients developing
7
high doses of methadone. Patients developing QT
QT prolongation while on methadone
prolongation while on methadone treatment
treatment should be evaluated for the
should be evaluated for the presence of
presence of modifiable risk factors, such
modifiable risk factors, such as concomitant
as concomitant medications with cardiac
medications with cardiac effects, drugs which
effects, drugs which might cause
might cause electrolyte abnormalities, and drugs
electrolyte abnormalities, and drugs which
which might act as inhibitors of methadone
might act as inhibitors of methadone
metabolism. For use of methadone to treat pain,
metabolism. For use of methadone to
the risk of QT prolongation and development of
treat pain, the risk of QT prolongation and
dysrhythmias should be weighed against the
development of dysrhythmias should be
benefit of adequate pain management and the
weighed against the benefit of adequate
availability of alternative therapies.
pain management and the availability of
Methadone treatment for analgesic therapy in
alternative therapies.
patients with acute or chronic pain should only be
Methadone treatment for analgesic
initiated if the potential analgesic or palliative care
therapy in patients with acute or chronic
benefit of treatment with methadone has been
pain should only be initiated if the
considered to outweigh the risk of QT
potential analgesic or palliative care
prolongation that has been reported with high
benefit of treatment with methadone has
doses of methadone.
been considered to outweigh the risk of
The potential risks of methadone, including the
QT prolongation that has been reported
risk of life-threatening arrhythmias, should be
with high doses of methadone.
weighed against the risks of discontinuing
The use of methadone in patients already
methadone treatment. In the patient being treated
known to have a prolonged QT interval
for opiate dependence with methadone
has not been systematically studied. In
maintenance therapy, these risks include a very
using methadone an individualized benefit
high likelihood of relapse to illicit drug use
to risk assessment should be carried out
following methadone discontinuation.
and should include evaluation of patient
The use of methadone in patients already known
presentation and complete medical
to have a prolonged QT interval has not been
history. For patients judged to be at risk,
systematically studied. The potential risks of
careful monitoring of cardiovascular
methadone should be weighed against the
status, including QT prolongation and
substantial morbidity and mortality associated with
dysrhythmias should be performed.
untreated opioid addiction.
In using methadone an individualized benefit to
GENERAL
risk assessment should be carried out and should
When treating pain, methadone given on
include evaluation of patient presentation and
a fixed-dose schedule may have a narrow
complete medical history. For patients judged to
therapeutic index in certain patient
be at risk, careful monitoring of cardiovascular
populations, especially when combined
status, including QT prolongation and
with other drugs, and should be reserved
dysrhythmias should be performed.
for cases where the benefits of opioid
analgesia with methadone outweigh the
8
GENERAL
known potential risks of cardiac
When treating pain, methadone given on a fixed-
conduction abnormalities, respiratory
dose schedule may have a narrow therapeutic
depression, altered mental states and
index in certain patient populations, especially
postural hypotension. Methadone should
when combined with other drugs, and should be
be used with caution in elderly and
reserved for cases where the benefits of opioid
debilitated patients; patients who are
analgesia with methadone outweigh the known
known to be sensitive to central nervous
potential risks of cardiac conduction
system depressants, such as those with
abnormalities, respiratory depression, altered
cardiovascular, pulmonary, renal, or
mental states and postural hypotension.
hepatic disease; and in patients with
Methadone should be used with caution in elderly
comorbid conditions or concomitant
and debilitated patients; patients who are known
medications which may predispose to
to be sensitive to central nervous system
dysrhythmia.
depressants, such as those with cardiovascular,
pulmonary, renal, or hepatic disease; and in
Interactions with other CNS Depressants
patients with comorbid conditions or concomitant
Patients receiving other opioid analgesics,
medications which may predispose to dysrhythmia
general anesthetics, phenothiazines,
or reduced ventilatory drive.
other tranquilizers, sedatives, hypnotics or
Interactions with other CNS Depressants
other CNS depressants (including alcohol)
Patients receiving other opioid analgesics, general
concomitantly with methadone may
anesthetics, phenothiazines, other tranquilizers,
experience respiratory depression
sedatives, hypnotics or other CNS depressants
,hypotension, profound sedation, or coma.
(including alcohol) concomitantly with methadone
may experience respiratory depression,
Anxiety – Since methadone as used by
hypotension, profound sedation, or coma.
tolerant patients at a constant
Interactions with Alcohol and Drugs of Abuse
maintenance dosage does not act as a
Methadone may be expected to have additive
tranquilizer, patients who are maintained
effects when used in conjunction with alcohol,
on this drug will react to life problems and
other opioids, or with illicit drugs that cause
stresses with the same symptoms of
central nervous system depression. Deaths have
anxiety as do other individuals. The
been reported when methadone has been abused
physician should not confuse such
in conjunction with benzodiazepines.
symptoms with those of narcotic
Anxiety – Since methadone as used by tolerant
abstinence and should not attempt to treat
patients at a constant maintenance dosage does
anxiety by increasing the dose of
not act as a tranquilizer, patients who are
methadone. The action of methadone in
maintained on this drug will react to life problems
maintenance treatment is limited to the
and stresses with the same symptoms of anxiety
control of narcotic withdrawal symptoms
as do other individuals. The physician should not
and is ineffective for relief of general
confuse such symptoms with those of narcotic
anxiety.
abstinence and should not attempt to treat anxiety
Acute Pain – Maintenance patients on a
by increasing the dose of methadone. The action
stable dose of methadone who
9
of methadone in maintenance treatment is limited
experience physical trauma, postoperative
to the control of narcotic withdrawal symptoms
pain or other acute pain cannot be
and is ineffective for relief of general anxiety.
expected to derive analgesia from their
Acute Pain – Maintenance patients on a stable
existing dose of methadone. Such
dose of methadone who experience physical
patients should be administered
trauma, postoperative pain or other acute pain
analgesics, including opioids, in doses
cannot be expected to derive analgesia from their
that would otherwise be indicated for non-
existing dose of methadone. Such patients should
methadone-treated patients with similar
be administered analgesics, including opioids, in
painful conditions. Due to the opioid
doses that would otherwise be indicated for non-
tolerance induced by methadone, when
methadone-treated patients with similar painful
opioids are required for management of
conditions. Due to the opioid tolerance induced by
acute pain in methadone patients,
methadone, when opioids are required for
somewhat higher and/or more frequent
management of acute pain in methadone patients,
doses will often be required than would be
somewhat higher and/or more frequent doses will
the case for non-tolerant patients.
often be required than would be the case for nontolerant patients.
Special-Risk Patients
Special-Risk Patients
Methadone should be given with caution
Methadone should be given with caution and the
and the initial dose reduced in certain
initial dose reduced in certain patients, such as
patients, such as the elderly and
the elderly and debilitated and those with severe
debilitated and those with severe
impairment of hepatic or renal function,
impairment of hepatic or renal function,
hypothyroidism, Addison’s disease, prostatic
hypothyroidism, Addison’s disease,
hypertrophy, or urethral stricture. The usual
prostatic hypertrophy, or urethral stricture.
precautions should be observed and the
The usual precautions should be
possibility of respiratory depression requires
observed and the possibility of respiratory
added vigilance.
depression requires added vigilance.
Use in Pregnancy
Safety of use in pregnancy has not been
Use in Pregnancy
established. The placental transfer of narcotics is
Safety of use in pregnancy has not been
very rapid. Maternal addiction with subsequent
established. The placental transfer of
neonatal withdrawal is well documented following
narcotics is very rapid. Maternal addiction
illicit use. Withdrawal symptoms include
with subsequent neonatal withdrawal is
irritability, excessive crying, yawning, sneezing,
well documented following illicit use.
increased respiratory rate, tremors, hyperreflexia,
Withdrawal symptoms include irritability,
fever, vomiting, increased stools and diarrhea.
excessive crying, yawning, sneezing,
Symptoms usually appear during the first days of
increased respiratory rate, tremors,
life.
hyperreflexia, fever, vomiting, increased
Labor and Delivery
stools and diarrhea. Symptoms usually
As with all opioids, administration of this product
appear during the first days of life.
to the mother shortly before delivery may result in
10
some degree of respiratory depression in the
Labor and Delivery
newborn, especially if higher doses are used.
As with all opioids, administration of this
Methadone is not recommended for obstetric
product to the mother shortly before
analgesia because its long duration of action
delivery may result in some degree of
increases the probability of respiratory depression
respiratory depression in the newborn,
in the newborn. Narcotics with mixed agonist-
especially if higher doses are used.
antagonist properties should not be used for pain
Methadone is not recommended for
control during labor in patients chronically treated
obstetric analgesia because its long
with methadone as they may precipitate acute
duration of action increases the probability
withdrawal.
of respiratory depression in the newborn.
Nursing Mothers
Narcotics with mixed agonist-antagonist
Methadone is secreted into human milk. The
properties should not be used for pain
safety of breastfeeding while taking oral
control during labor in patients chronically
methadone is controversial. At maternal oral
treated with methadone as they may
doses of 10 to 80 mg/day, methadone
precipitate acute withdrawal.
concentrations from 50 to 570 mcg/L in milk have
been reported, which, in the majority of samples,
Nursing Mothers
were lower than maternal serum drug
Methadone is secreted into human milk.
concentrations at steady state.
The safety of breastfeeding while taking
Peak methadone levels in milk occur
oral methadone is controversial. At
approximately 4 to 5 hours after an oral dose.
maternal oral doses of 10 to 80 mg/day,
Based on an average milk consumption of 150
methadone concentrations from 50 to 570
mL/kg/day, an infant would consume
mcg/L in milk have been reported, which,
approximately 17.4 mcg/kg/day which is
in the majority of samples, were lower
approximately 2 to 3% of the oral maternal dose.
than maternal serum drug concentrations
Methadone has been detected in very low plasma
at steady state.
concentrations in some infants whose mothers
Peak methadone levels in milk occur
were taking methadone. Caution should be
approximately 4 to 5 hours after an oral
exercised when methadone is administered to a
dose. Based on an average milk
nursing woman. There have been rare cases of
consumption of 150 mL/kg/day, an infant
sedation and respiratory depression in infants
would consume approximately 17.4
exposed to methadone through breast milk.
mcg/kg/day which is approximately 2 to
Mothers using methadone should receive specific
3% of the oral maternal dose. Methadone
information about how to identify respiratory
has been detected in very low plasma
depression and sedation in their babies. They
concentrations in some infants whose
should know when to contact their healthcare
mothers were taking methadone.
provider or seek immediate medical care. A
Women on high dose methadone
healthcare provider should weigh the benefits of
maintenance, who are already breast
breastfeeding against the risks of infant exposure
feeding, should be counseled to wean
to methadone and possible exposure to other
breast-feeding gradually in order to
medicines.
prevent neonatal abstinence syndrome.
11
Women on high dose methadone maintenance,
Methadone-treated mothers considering
who are already breast feeding, should be
nursing an opioid-naïve infant should be
counseled to wean breast-feeding gradually in
counseled regarding the presence of
order to prevent neonatal abstinence syndrome.
methadone in breast milk.
Methadone-treated mothers considering nursing
Because of the potential for serious
an opioid-naïve infant should be counseled
adverse reactions in nursing infants from
regarding the presence of methadone in breast
methadone, a decision should be made
milk.
whether to discontinue nursing or to
Because of the potential for serious adverse
discontinue the drug, taking into account
reactions in nursing infants from methadone, a
the importance of the drug to the mother.
decision should be made whether to discontinue
In patients being treated for opioid
nursing or to discontinue the drug, taking into
dependence, this should include weighing
account the importance of the drug to the mother.
the risk of methadone against the risk of
In patients being treated for opioid dependence,
maternal illicit drug use.
this should include weighing the risk of
methadone against the risk of maternal illicit drug
Pediatric Use
use.
Safety and effectiveness in pediatric
Pediatric Use
patients below the age of 18 years have
Safety and effectiveness in pediatric patients
not been established. Accidental or
below the age of 18 years have not been
deliberate ingestion by a child may cause
established. Accidental or deliberate ingestion by
respiratory depression that can result in
a child may cause respiratory depression that can
death. Patients and caregivers should be
result in death. Patients and caregivers should be
instructed to keep methadone in a secure
instructed to keep methadone in a secure place
place out of the reach of children and to
out of the reach of children and to discard unused
discard unused methadone in such a way
methadone in such a way that individuals other
that individuals other than the patient for
than the patient for whom it was originally
whom it was originally prescribed will not
prescribed will not come in contact with the drug.
come in contact with the drug.
Heroin Withdrawal
Heroin Withdrawal
ADVERSE
During the induction phase of methadone
During the induction phase of methadone
REACTIONS
maintenance treatment, patients are being
maintenance treatment, patients are being
withdrawn from heroin and may therefore show
withdrawn from heroin and may therefore
typical withdrawal symptoms, which should be
show typical withdrawal symptoms, which
differentiated from methadone-induced side
should be differentiated from methadone-
effects.They may exhibit some or all of the
induced side effects.They may exhibit
following signs and symptoms associated with
some or all of the following signs and
acute withdrawal from heroin or other opiates:
symptoms associated with acute
lacrimation, rhinorrhea, sneezing, yawning,
withdrawal from heroin or other opiates:
excessive perspiration, goose-flesh, fever,
lacrimation, rhinorrhea, sneezing,
chilliness alternating with flushing, restlessness,
yawning, excessive perspiration, goose-
12
irritability, weakness, anxiety, depression, dilated
flesh, fever, chilliness alternating with
pupils, tremors, tachycardia, abdominal cramps,
flushing, restlessness, irritability,
body aches, involuntary twitching and kicking
weakness, anxiety, depression, dilated
movements, anorexia, nausea, vomiting, diarrhea,
pupils, tremors, tachycardia, abdominal
intestinal spasms, and weight loss.
cramps, body aches, involuntary twitching
and kicking movements, anorexia,
Initial Administration
nausea, vomiting, diarrhea, intestinal
The initial methadone dose should be carefully
spasms, and weight loss.
titrated to the individual. Too rapid titration for the
patient's sensitivity is more likely to produce
Major Hazards
adverse effects.
Respiratory depression, apnea, and to a
lesser degree, systemic hypotension,
Major Hazards
circulatory depression, respiratory arrest,
Respiratory depression, apnea, and to a lesser
shock and cardiac arrest, and death have
degree, systemic hypotension, circulatory
occurred.
depression, respiratory arrest, shock and cardiac
arrest, and death have occurred.
Most Frequent
Lightheadedness, dizziness, sedation,
Most Frequent
nausea, vomiting, and sweating. These
Lightheadedness, dizziness, sedation, nausea,
effects are more prominent in ambulatory
vomiting, and sweating. These effects are more
patients and in those not experiencing
prominent in ambulatory patients and in those not
severe pain. They can be alleviated by
experiencing severe pain. They can be alleviated
lowering the dosage.
by lowering the dosage.
Allergic
Allergic
Pruritis, urticaria, other skin rashes,
Pruritis, urticaria, other skin rashes, diaphoresis,
diaphoresis, laryngospasm, edema, and
laryngospasm, edema, and rarely, haemorrhagic
rarely, haemorrhagic urticaria.
urticaria.
Central Nervous System
Central Nervous System
Euphoria, dysphoria, delirium, weakness,
Euphoria, dysphoria, delirium, weakness,
headache, edema, drowsiness, miosis,
headache, edema, drowsiness, miosis, coma,
coma, insomnia, agitation, tremor,
insomnia, agitation, tremor, seizures, impairment
impairment of mental and physical
of mental and physical performance, lethargy,
performance, lethargy, anxiety fear,
anxiety fear, psychic dependence, mood changes,
psychic dependence, mood changes,
hallucinations, disorientation, confusion, and
hallucinations, disorientation, confusion,
visual disturbances. Choreic movements have
and visual disturbances. Choreic
been induced by methadone.
movements have been induced by
methadone.
Cardiovascular
13
Facial flushing, peripheral circulatory collapse,
Cardiovascular
arrhythmias, bigeminal rhythms, cardiomyopathy,
Facial flushing, peripheral circulatory
ECG abnormalities, extrasystoles, heart failure,
collapse, arrhythmias, bigeminal rhythms,
phlebitis, QT interval prolongation, T-wave
cardiomyopathy, ECG abnormalities,
inversion, torsade de pointes, tachycardia,
extrasystoles, heart failure, phlebitis, QT
bradycardia, palpitations, hypotension, syncope,
interval prolongation, T-wave inversion,
ventricular fibrillation.
torsade de pointes, tachycardia,
bradycardia, palpitations, hypotension,
Gastrointestinal
syncope.
Dry mouth, glossitis, abdominal pain, anorexia,
constipation, and biliary tract spasm. Patients
Gastrointestinal
with chronic ulcerative colitis may experience
Dry mouth, glossitis, abdominal pain,
increased colonic motility and toxic dilation.
anorexia, constipation, and biliary tract
Concomitant administration of laxatives may
spasm. Patients with chronic ulcerative
counteract narcotic-induced constipation.
colitis may experience increased colonic
motility and toxic dilation. Concomitant
Genitourinary
administration of laxatives may counteract
Ureteral spasm and spasm of vesical sphincters,
narcotic-induced constipation.
urinary retention or hesitancy, oliguria, antidiuretic
effect, reduced libido or potency, amenorrhea.
Genitourinary
Ureteral spasm and spasm of vesical
Haematologic and Lymphatic
sphincters, urinary retention or hesitancy,
Reversible thrombocytopenia has been described
oliguria, antidiuretic effect, reduced libido
in opioid addicts with chronic hepatitis.
or potency, amenorrhea.
Metabolic and Nutritional
Haematologic and Lymphatic
Hypokalaemia, hypomagnesemia, weight gain.
Reversible thrombocytopenia has been
described in opioid addicts with chronic
Respiratory
hepatitis.
Pulmonary edema, respiratory depression.
Metabolic and Nutritional
Other
Hypokalaemia, hypomagnesemia, weight
Muscular rigidity.
gain.
Maintenance on a stabilized dose- during
prolonged administration of methadone, as in a
Respiratory
methadone maintenance treatment program,
Pulmonary edema, respiratory
there is usually a gradual, yet progressive,
depression.
disappearance of side effects over a period of
several weeks. However, constipation and
Other
sweating often persist.
Muscular rigidity.
Maintenance on a stabilized dose- during
14
prolonged administration of methadone,
as in a methadone maintenance treatment
program, there is usually a gradual, yet
progressive, disappearance of side effects
over a period of several weeks. However,
constipation and sweating often persist.
Methadone/Alcohol/General Anesthetics/Tricyclic
Methadone/Alcohol/General
DRUG INTER-
Antidepressants/CNS Depressants
Anesthetics/Tricyclic
ACTIONS
Concomitant use may result in increased CNS
Antidepressants/CNS Depressants
depression, respiratory depression, and
Concomitant use may result in increased
hypotensive effects. Caution is recommended,
CNS depression, respiratory depression,
and the dosage of one or both agents should be
and hypotensive effects. Caution is
reduced. Deaths have been reported when
recommended, and the dosage of one or
methadone has been abused in conjunction with
both agents should be reduced. Deaths
benzodiazepines. In addition, some
have been reported when methadone has
phenothiazines increase, while others decrease,
been abused in conjunction with
methadone-induced analgesia.
benzodiazepines. In addition, some
phenothiazines increase, while others
Methadone/Anticholinergics
decrease, methadone-induced analgesia.
Concomitant use may result in increased risk of
severe constipation and/or urinary retention.
Methadone/Anticholinergics
Concomitant use may result in increased
Methadone/ Anti-retroviral agents
risk of severe constipation and/or urinary
Abacavir, amprenavir, efavirenz, nelfinavir,
retention.
nevirapine, ritonavir,lopinavir+ritonavir
combination
Methadone/ Anti-retroviral agents
Concomitant use of these anti retroviral agents as
Concomitant use of anti retroviral agents
abacavir, amprenavir, efavirenz, nelfinavir,
as abacavir, amprenavir, efavirenz,
nevirapine, ritonavir, lopinavir+ritonavir
nelfinavir, nevirapine, ritonavir,
combination, resulted in increased clearance or
lopinavir+ritonavir combination, resulted in
decreased plasma levels of methadone.
increased clearance or decreased plasma
Methadone-maintained patients beginning
levels of methadone. Methadone-
treatment with these anti-retroviral drugs should
maintained patients should be monitored
be monitored for evidence of withdrawal effects
for evidence of withdrawal effects and
and methadone dose should be adjusted
methadone dose should be adjusted
accordingly.
accordingly.
Methadone/ Didanosine and Stavudine
Experimental evidence demonstrated that
Methadone/ Cytochrome P450
methadone decreased the AUC and peak levels
In vitro results suggest that methadone
15
for didanosine and stavudine, with a more
undergoes hepatic N-demethylation by
significant decrease for didanosine. Methadone
cytochrome P450 enzymes, principally
disposition was not substantially altered.
CYP3A4, CYP2B6, CYP2C19 and to a
Methadone/Zidovudine
lesser extent by CYP2C9 and CYP2D6.
Experimental evidence demonstrated that
Coadministration ofmethadone with CYP
methadone increased the AUC of zidovudine
inducers of these enzymes may result in a
which could result in toxic effects.
more rapid metabolism and potential for
decreased effects of methadone, whereas
Methadone/ Cytochrome P450
administration with CYP inhibitors may
In vitro results suggest that methadone undergoes
reduce metabolism and potentiate
hepatic N-demethylation by cytochrome P450
methadone’s effects. Although
enzymes, principally CYP3A4, CYP2B6,
antiretroviral drugs such as efavirenz,
CYP2C19 and to a lesser extent by CYP2C9 and
nelfinavir, nevirapine, ritonavir,
CYP2D6. Coadministration ofmethadone with
lopinavir+ritonavir combination are known
CYP inducers of these enzymes may result in a
to inhibit CYPs, they are shown to reduce
more rapid metabolism and potential for
the plasma levels of methadone, possibly
decreased effects of methadone, whereas
due to their CYP induction activity.
administration with CYP inhibitors may reduce
Therefore, drugs administered
metabolism and potentiate methadone’s effects.
concomitantly with methadone should be
Although antiretroviral drugs such as efavirenz,
evaluated for interaction potential;
nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir
clinicians are advised to evaluate
combination are known to inhibit CYPs, they are
individual response to drug therapy
shown to reduce the plasma levels of methadone,
possibly due to their CYP induction activity.
Cytochrome P450 Inducers
Therefore, drugs administered concomitantly with
Methadone-maintained patients beginning
methadone should be evaluated for interaction
treatment with CYP3A4 inducers should
potential; clinicians are advised to evaluate
be monitored for evidence of withdrawal
individual response to drug therapy.
effects and methadone dose should be
adjusted accordingly. The following drug
Cytochrome P450 Inducers
interactions were reported following co-
Methadone-maintained patients beginning
administration of methadone with inducers
treatment with CYP3A4 inducers should be
of cytochrome P450 enzymes:
monitored for evidence of withdrawal effects and
Rifampin – In patients well-stabilized on
methadone dose should be adjusted accordingly.
methadone, concomitant administration of
The following drug interactions were reported
rifampin resulted in a marked reduction in
following co-administration of methadone with
serum methadone levels and a concurrent
inducers of cytochrome P450 enzymes:
appearance of withdrawal symptoms.
Rifampin – In patients well-stabilized on
Phenytoin – In a pharmacokinetic study
methadone, concomitant administration of
with patients on methadone maintenance
rifampin resulted in a marked reduction in serum
therapy, phenytoin administration (250 mg
methadone levels and a concurrent appearance of
b.i.d. initially for 1 day followed by 300 mg
16
withdrawal symptoms.
QD for 3 to 4 days) resulted in an
Phenytoin – In a pharmacokinetic study with
approximately 50%reduction in
patients on methadone maintenance therapy,
methadone exposure and withdrawal
phenytoin administration (250 mg b.i.d. initially for
symptoms occurred concurrently. Upon
1 day followed by 300 mg QD for 3 to 4 days)
discontinuation of phenytoin, the
resulted in an approximately 50%reduction in
incidence of withdrawal symptoms
methadone exposure and withdrawal symptoms
decreased and methadone exposure
occurred concurrently. Upon discontinuation of
increased to a level comparable to that
phenytoin, the incidence of withdrawal symptoms
prior to phenytoin administration.
decreased and methadone exposure increased to
St. John’s Wort, Phenobarbital,
a level comparable to that prior to phenytoin
Carbamazepine - Administration of
administration.
methadone along with other CYP3A4
St. John’s Wort, Phenobarbital, Carbamazepine -
inducers may result in withdrawal
Administration of methadone along with other
symptoms.
CYP3A4 inducers may result in withdrawal
symptoms.
Cytochrome P450 Inhibitors
Since the metabolism of methadone is
Cytochrome P450 Inhibitors
mediated primarily by CYP3A4 isozyme,
Since the metabolism of methadone is mediated
coadministration of drugs that inhibit
primarily by CYP3A4 isozyme, coadministration of
CYP3A4 activity may cause decreased
drugs that inhibit CYP3A4 activity may cause
clearance of methadone. The expected
decreased clearance of methadone. The expected
clinical results would be increased or
clinical results would be increased or prolonged
prolonged opioid effects. Thus,
opioid effects. Thus, methadone-treated patients
methadone-treated patients
coadministered strong inhibitors of CYP3A4, such
coadministered strong inhibitors of
as azole antifungal agents (e.g., ketoconazole)
CYP3A4, such as azole antifungal agents
and macrolide antibiotics (e.g., erythromycin), with
(e.g., ketoconazole) and macrolide
methadone should be carefully monitored and
antibiotics (e.g., erythromycin), with
dosage adjustment should be undertaken if
methadone should be carefully monitored
warranted. Some selective serotonin reuptake
and dosage adjustment should be
inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
undertaken if warranted. Some selective
may increase methadone plasma levels up on
serotonin reuptake inhibitors (SSRIs)
coadministration with methadone and result in
(e.g., sertraline, fluvoxamine) may
increased opiate effects and/or toxicity.
increase methadone plasma levels up on
Methadone/ Didanosine and Stavudine
coadministration with methadone and
Experimental evidence demonstrated that
result in increased opiate effects and/or
methadone decreased the AUC and peak levels
toxicity.
for didanosine and stavudine, with a more
Methadone/ Didanosine and Stavudine
significant decrease for didanosine. Methadone
Experimental evidence demonstrated that
disposition was not substantially altered.
methadone decreased the AUC and peak
Methadone/Zidovudine
levels for didanosine and stavudine, with
17
Experimental evidence demonstrated that
a more significant decrease for
methadone increased the AUC of zidovudine
didanosine. Methadone disposition was
which could result in toxic effects.
not substantially altered.
Methadone/ Voriconazole
Methadone/Zidovudine
Repeat dose administration of oral voriconazole
Experimental evidence demonstrated that
(400mg Q12h for 1 day, then 200mg Q12h for 4
methadone increased the AUC of
days) increased the Cmax and AUC of (R)-
zidovudine which could result in toxic
methadone by 31% and 47%, respectively, in
effects.
subjects receiving a methadone maintenance
Methadone/ Voriconazole
dose (30 to 100 mg QD). The Cmax and AUC of
Repeat dose administration of oral
(S)-methadone increased by 65% and 103%,
voriconazole (400mg Q12h for 1 day, then
respectively. Increased plasma concentrations of
200mg Q12h for 4
methadone have been associated with toxicity
days) increased the Cmax and AUC of
including QT prolongation. Frequent monitoring
(R)-methadone by 31% and 47%,
for adverse events and toxicity related to
respectively, in subjects receiving a
methadone is recommended during
methadone maintenance dose (30 to 100
coadministration. Dose reduction of methadone
mg QD). The Cmax and AUC of (S)-
may be needed.
methadone increased by 65% and 103%,
Methadone/ Hydroxyzine
respectively. Increased plasma
Concomitant use may result in increased
concentrations of methadone have been
analgesia and sedation.
associated with toxicity including QT
prolongation. Frequent monitoring for
Methadone/ Levallorphan/ Naloxone
adverse events and toxicity related to
Antagonism of the analgesic, CNS, and
methadone is recommended during
respiratory depressant effects of methadone may
coadministration. Dose reduction of
occur, and may precipitate withdrawal symptoms
methadone may be needed.
in physically dependent patients. The dosage of
Methadone/ Hydroxyzine
levallorphan, naloxone, naltrexone should be
Concomitant use may result in increased
carefully titrated when used to treat overdosage in
analgesia and sedation.
dependent patients.
Methadone/ Levallorphan/ Naloxone
Methadone/ Other Opioid Drugs
Antagonism of the analgesic, CNS, and
Additive CNS depressant, respiratory depressant,
respiratory depressant effects of
and hypotensive effects may occur if two or more
methadone may occur, and may
opioid agonist analgesics are used concurrently.
precipitate withdrawal symptoms in
Patients who are addicted to heroin or who are on
physically dependent patients. The
a methadone maintenance program may
dosage of levallorphan, naloxone,
experience withdrawal symptoms when given
naltrexone should be carefully titrated
pentazocine, butorphanol, nalbuphine or
when used to treat overdosage in
buprenorphine.
dependent patients.
18
Methadone/Monoamine Oxidase Inhibitors/
Methadone/ Other Opioid Drugs
Furazolidone Desipramine
Additive CNS depressant, respiratory
Methadone should be used cautiously, and in
depressant, and hypotensive effects may
reduced dosage, in patients receiving monoamine
occur if two or more opioid agonist
oxidase inhibitors or furazolidone. It is
analgesics are used concurrently.
recommended that a small test dose, or several
Patients who are addicted to heroin or
incremental test doses over a period of several
who are on a methadone maintenance
hours, should first be administered to permit
program may experience withdrawal
observation of any interaction.
symptoms when given pentazocine,
Methadone /Desipramine
butorphanol, nalbuphine or
Blood levels of desipramine have increased with
buprenorphine.
concurrent methadone administration.
Methadone/Monoamine Oxidase
Methadone/ Arrythmogenic agents
Inhibitors/ Furazolidone/ Desipramine
Extreme caution is necessary when any drug
Methadone should be used cautiously,
known to have the potential to prolong the QT
and in reduced dosage, in patients
interval is prescribed in conjunction with
receiving monoamine oxidase inhibitors or
methadone. Pharmacodynamic interactions may
furazolidone. It is recommended that a
occur with concomitant use of methadone and
small test dose, or several incremental
potentially arrythmogenic agents such as class I
test doses over a period of several hours,
and III antiarrhythmics, some neuroleptics and
should first be administered to permit
tricyclic antidepressants, and calcium channel
observation of any interaction.
blockers.
Blood levels of desipramine have
Caution should also be exercised when
increased with concurrent methadone
prescribing methadone concomitantly with drugs
administration.
capable of inducing electrolyte disturbances
(hypomagnesemia, hypokalemia) that may
Methadone/ Arrythmogenic agents
prolong the QT interval. These drugs include
Extreme caution is necessary when any
diuretics, laxatives, and, in rare cases,
drug known to have the potential to
mineralocorticoid hormones.
prolong the QT interval is prescribed in
conjunction with methadone.
Methadone/ Neuromuscular Blocking Agents
Pharmacodynamic interactions may occur
Respiratory depressant effects of neuromuscular
with concomitant use of methadone and
blocking agents may be additive to central
potentially arrythmogenic agents such as
respiratory depressant effects of opioid
class I and III antiarrhythmics, some
analgesics. Caution is recommended when
neuroleptics and tricyclic antidepressants,
methadone is administered in the immediate post-
and calcium channel blockers.
operative period to patients who have received a
Caution should also be exercised when
neuromuscular blocking agent.
prescribing methadone concomitantly with
Methadone/ Rifampicin/ Phenytoin
drugs capable of inducing electrolyte
The concurrent administration of rifampicin or
disturbances (hypomagnesemia,
19
phenytoin may reduce the plasma levels of
hypokalemia) that may prolong the QT
methadone to a degree sufficient to produce
interval. These drugs include diuretics,
withdrawal symptoms. The mechanism is not fully
laxatives, and, in rare cases,
understood, but may be due to increased hepatic
mineralocorticoid hormones.
metabolism of methadone.
Diagnostic Interference
Methadone/ Neuromuscular Blocking
Because narcotics may increase biliary tract
Agents
pressure with resultant increases in plasma
Respiratory depressant effects of
amylase or lipase, levels may be unreliable for 24
neuromuscular blocking agents may be
hours after narcotic administration.
additive to central respiratory depressant
effects of opioid analgesics. Caution is
recommended when methadone is
administered in the immediate postoperative period to patients who have
received a neuromuscular blocking agent.
Methadone/ Rifampicin/ Phenytoin
The concurrent administration of
rifampicin or phenytoin may reduce the
plasma levels of methadone to a degree
sufficient to produce withdrawal
symptoms. The mechanism is not fully
understood, but may be due to increased
hepatic metabolism of methadone.
Diagnostic Interference
Because narcotics may increase biliary
tract pressure with resultant increases in
plasma amylase or lipase, levels may be
unreliable for 24 hours after narcotic
administration.
Manifestations
Manifestations
In severe overdosage, apnea, circulatory collapse,
In severe overdosage, apnea, circulatory
convulsions, cardiopulmonary arrest, and even
collapse, convulsions, cardiopulmonary
death may occur. The less severely poisoned
arrest, and even death may occur. The
patient often presents the triad of central nervous
less severely poisoned patient often
system depression, miosis and respiratory
presents the triad of central nervous
depression.
system depression, miosis and respiratory
Serious overdosage is characterized by
depression.
respiratory depression (a decrease in respiratory
Serious overdosage is characterized by
20
OVERDOSAGE
rate and/or tidal volume, Cheyne-Stokes
respiratory depression, extreme
respiration, cyanosis) , extreme somnolence
somnolence progressing to stupor or
progressing to stupor or coma, constricted pupils,
coma, constricted pupils, skeletal muscle
skeletal muscle flaccidity, and cold and clammy
flaccidity, and cold and clammy skin.
skin. Hypotension, bradycardia, hypothermia,
Hypotension, bradycardia, hypothermia,
pulmonary edema, pneumonia, or shock occurs in
pulmonary edema, pneumonia, or shock
up to 40% of patients.
occurs in up to 40% of patients.
Treatment
Treatment
Primary attention should be given to the
Primary attention should be given to the
maintenance of adequate respiratory exchange
maintenance of adequate respiratory
through provision of a patent airway and institution
exchange through provision of a patent
of assisted or controlled ventilation. If depressed
airway and institution of assisted or
respiration is associated with muscular rigidity, an
controlled ventilation. If depressed
intravenous neuromuscular blocking agent may
respiration is associated with muscular
be required.
rigidity, an intravenous neuromuscular
After assessing the pulmonary status of the
blocking agent may be required.
patient, administer a narcotic antagonist
After assessing the pulmonary status of
(naloxone is the antagonist of choice). Narcotic
the patient, administer a narcotic
antagonists are specific antidotes for overdosage.
antagonist (naloxone is the antagonist of
The physician must remember, however, that
choice). Narcotic antagonists are specific
methadone is a long-acting depressant (36 to 48
antidotes for overdosage. The physician
hours), where opioid antagonist act for much
must remember, however, that
shorter periods (one to three hours).
methadone is a long-acting depressant
Since the duration of action of most narcotics
(36 to 48 hours), where opioid antagonist
exceeds that of narcotic antagonists,
act for much shorter periods (one to three
administration of the antagonist should be
hours).
repeated to maintain adequate respiration and the
Since the duration of action of most
patient should be kept under surveillance. Do not
narcotics exceeds that of narcotic
administer an antagonist in the absence of
antagonists, administration of the
clinically-significant respiratory or cardiovascular
antagonist should be repeated to maintain
depression.
adequate respiration and the patient
In an individual physically dependent on opioids,
should be kept under surveillance. Do not
the administration of the usual dose of an opioid
administer an antagonist in the absence
antagonist may precipitate an acute withdrawal
of clinically-significant respiratory or
syndrome. The severity of this syndrome will
cardiovascular depression.
depend on the degree of physical dependence
Employ oxygen, intravenous fluids,
and the dose of the antagonist administered. If
vasopressors, and other supportive
antagonists must be used to treat serious
measures as indicated. In cases of oral
respiratory depression in the physically dependent
overdose, and where treatment can be
patient, the antagonist should be administered
instituted within 2 hours following
with extreme care and by titration with smaller
ingestion, evacuate the stomach by
21
than usual doses of the antagonist.
emesis or gastric lavage. Closely observe
Intravenously administered naloxone or
the patient for a rise in temperature or
nalmefene may be used to reverse signs of
pulmonary complications that may require
intoxication. Because of the relatively short half-
institution of antibiotic therapy.
life of naloxone as compared with methadone,
repeated injections may be required until the
status of the patient remains satisfactory.
Naloxone may also be administered by
continuous intravenous infusion.
Employ oxygen, intravenous fluids, vasopressors,
and other supportive measures as indicated. In
cases of oral overdose, and where treatment can
be instituted within 2 hours following ingestion,
evacuate the stomach by emesis or gastric
lavage. Closely observe the patient for a rise in
temperature or pulmonary complications that may
require institution of antibiotic therapy.
Store below 25°C.
SPECIAL
Once the bottle is opened, it should be stored
PRECAUTIONS
below 25°C and the solution can be used within 6
FOR STORAGE
months, but no later than the expiration date
printed on the package.
Bottles of 90 and 200 ml.
Bottles of 90 and 200 ml.
PRESENTATION
22
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