Apo-Methadone Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES...................................................................................... 2

TABLE OF CONTENTS ........................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION ............................................................... 4

1 INDICATIONS ............................................................................................................. 4

1.1 Pediatrics ......................................................................................................... 4

1.2 Geriatrics ......................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................ 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ........................................................... 5

4 DOSAGE AND ADMINISTRATION ............................................................................... 6

4.1 Dosing Considerations ..................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment ................................................. 7

4.4 Administration ................................................................................................. 9

4.5 Missed Dose ..................................................................................................... 9

5 OVERDOSAGE ............................................................................................................ 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................. 10

7 WARNINGS AND PRECAUTIONS ............................................................................... 11

7.1 Special Populations ........................................................................................ 18

7.1.1 Pregnant Women ........................................................................................... 19

7.1.2 Breast-feeding ............................................................................................... 20

7.1.3 Pediatrics (< 18 years of age) ......................................................................... 20

7.1.4 Geriatrics (> 65 years of age) ......................................................................... 20

8 ADVERSE REACTIONS ............................................................................................... 20

8.1 Adverse Reaction Overview ........................................................................... 20

8.5 Post-Market Adverse Reactions ..................................................................... 22

9 DRUG INTERACTIONS .............................................................................................. 22

9.1 Serious Drug Interactions ............................................................................... 22

9.2 Drug Interactions Overview ........................................................................... 23

9.3 Drug-Behavioural Interactions ....................................................................... 26

9.4 Drug-Drug Interactions .................................................................................. 26

9.5 Drug-Food Interactions .................................................................................. 30

9.6 Drug-Herb Interactions .................................................................................. 30

9.7 Drug-Laboratory Test Interactions ................................................................. 30

10 CLINICAL PHARMACOLOGY ................................................................................... 30

10.1 Mechanism of Action ..................................................................................... 30

10.2 Pharmacodynamics ........................................................................................ 31

10.3 Pharmacokinetics ........................................................................................... 32

11 STORAGE, STABILITY AND DISPOSAL ..................................................................... 34

12 SPECIAL HANDLING INSTRUCTIONS ............................................................................ 34

PART II: SCIENTIFIC INFORMATION ................................................................................ 35

13 PHARMACEUTICAL INFORMATION ........................................................................ 35

14 CLINICAL TRIALS .................................................................................................... 35

14.3 Comparative Bioavailability Studies ............................................................... 35

15 MICROBIOLOGY ........................................................................................................... 36

16 NON-CLINICAL TOXICOLOGY ................................................................................. 36

17 SUPPORTING PRODUCT MONOGRAPHS ................................................................ 39

PATIENT MEDICATION INFORMATION ........................................................................... 40

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

APO-METHADONE (methadone hydrochloride tablets) is indicated in adult patients for:

• the relief of severe pain.

In general, APO-METHADONE, as an analgesic, should not be used in opioid naïve patients.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada. Therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (> 65 years of age): The safety and efficacy of methadone hydrochloride tablets in patients 65 years and older have not been established.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy (see 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

2 CONTRAINDICATIONS

• Patients who are hypersensitive to the active substance methadone hydrochloride or other opioid analgesics, to any ingredient in the formulation, or to any component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the Product Monograph.
• In patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type).
• Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
• Patients with mild, intermittent or short duration pain that can be managed with other pain medications.
• The management of acute pain.
• Patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus.
• Patients with acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale.
• Patients with acute alcoholism, delirium tremens, and convulsive disorders.
• Patients with severe CNS (central nervous system) depression, increased cerebrospinal or intracranial pressure, and head injury.
• Patients taking monoamine oxidase inhibitors (MAOIs) (or within 14 days of such therapy).
• Women who are breast-feeding, pregnant or during labour and delivery (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and 7.1 Special Populations).
• Patients with diarrhea, which is associated with pseudomembranous colitis caused by cephalosporins, lincomycins (possibly including topical clindamycin), or penicillins, or to patients having diarrhea caused by poisoning, until toxic material has been eliminated from the gastrointestinal tract.
• Patients naïve to opioids.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

APO-METHADONE (methadone hydrochloride tablets) is for oral administration only. This preparation must not be injected. It is recommended that APO-METHADONE tablets, if dispensed, be packaged in child resistant containers and kept out of the reach and sight of children and pets to prevent accidental ingestion.

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the risks of overdose and death with immediate release opioid formulations, APO-METHADONE should only be used in patients for whom alternative treatment options (e.g., non-opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide appropriate management of pain (see 4 DOSAGE AND ADMINISTRATION).

Addiction, Abuse, and Misuse

APO-METHADONE poses risks of opioid addiction abuse, and misuse, which can lead to overdose and death. Each patient’s risk should be assessed prior to prescribing APO-METHADONE, and all patients should be monitored regularly for the development of these behaviours or conditions (see 7 WARNINGS AND PRECAUTIONS, General, Addiction, Abuse and Misuse). Appropriate security measures should be taken to safeguard stocks of methadone against diversion. APO-METHADONE should be stored securely to avoid theft or misuse.

Life-threatening Respiratory Depression: OVERDOSE

Serious, life-threatening, or fatal respiratory depression may occur with use of APO-METHADONE. Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed. Patients should be monitored for respiratory depression, especially during initiation of APO-METHADONE or following a dose increase.

APO-METHADONE must be swallowed whole. Cutting, breaking, crushing, chewing, or dissolving APO-METHADONE tablets can cause rapid release and absorption of a potentially fatal dose of methadone hydrochloride leading to dangerous adverse events including death (see 7 WARNINGS AND PRECAUTIONS, General, Addiction, Abuse and Misuse). Further, instruct patients of the hazards related to taking opioids including fatal overdose.

Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone’s peak respiratory depressant effects are typically delayed. This characteristic can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.

QT interval prolongation

Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.

Accidental Exposure

Accidental ingestion of even one dose of APO-METHADONE especially by children, can result in a fatal overdose of methadone hydrochloride (see 11 STORAGE, STABILITY AND DISPOSAL).

Neonatal Opioid Withdrawal Syndrome

Prolonged maternal use of APO-METHADONE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening (see 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance, Neonatal Opioid Withdrawal Syndrome (NOWS)).

Interaction with Alcohol

The co-ingestion of alcohol with APO-METHADONE should be avoided as it may result in dangerous additive effects, due to increased plasma levels of methadone hydrochloride, which can result in overdose, serious injury or death (see 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance, Use in Drug and Alcohol Addiction and 9.3 Drug-Behavioural Interactions).

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 7 WARNINGS AND PRECAUTIONS, Neurologic, Interactions with CNS Depressants and 9.2 Drug Interactions Overview).

• Reserve concomitant prescribing of APO-METHADONE and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

For the management of chronic non-cancer, non-palliative pain, consider the benefits and the risks of higher doses as they are associated with an increased risk of adverse events and overdose. The level of pain should be assessed regularly to evaluate the need for further use of APO-METHADONE.

Patients prescribed methadone should be carefully monitored and provided appropriate supportive psychological and social services.

APO-METHADONE should only be used in patients for whom alternative treatment options are ineffective or not tolerated (e.g., non-opioid analgesics), or would be otherwise inadequate to provide sufficient management of pain (e.g., immediate-release opioids).

Dosing is to be determined by the physician. Methadone differs from many other opioid agonists in several important ways. Methadone’s pharmacokinetic properties, coupled with high inter-patient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration.

APO-METHADONE is not indicated for injection or rectal administration.

4.2 Recommended Dose and Dosage Adjustment

Adults (over 18 years):

Dosage should be carefully titrated and adjusted according to the severity of the pain and response of the patient. The usual adult oral dose is 2.5 to 10 mg every 4 hours during the first 3 to 5 days, followed by a fixed dose every 8 to 12 hours depending on the patient’s requirements. In geriatric patients the dosage schedule could be given on a once daily basis.

Patients Not Receiving Opioids at the Time of Initiation of methadone hydrochloride Treatment:

APO-METHADONE should not be used in opioid naïve patients.

Switching Patients from an Alternate Opioid Product:

When switching from an alternate opioid product to methadone, there is significant risk of respiratory depression if the patient is switched abruptly (see 7 WARNINGS and PRECAUTIONS, Dependence/Tolerance, Incomplete Cross-Tolerance Between Methadone and Other Opioids). Conversion to methadone should be undertaken with caution.

Dose Titration:

Dose titration is the key to success with opioid analgesic therapy. Proper optimization of doses scaled to the relief of the individual's pain should aim at administration of the lowest dose which will achieve the overall treatment goal of satisfactory pain relief with acceptable side effects.

Dosage adjustments should be based on the patient's clinical response. Dose adjustment should be cautious; deaths have occurred in early treatment due to the cumulative effects of the first several days’ dosing. Patients should be reminded that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.

Use with Non-Opioid Medications:

If a non-opioid analgesic is being provided, it may be continued. APO-METHADONE can be safely used concomitantly with usual doses of other non-opioid analgesics.

Patients with Hepatic Impairment:

Dosage adjustments should be based on the patient’s clinical response (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Patients with Renal Impairment:

Dosage adjustments should be based on the patient’s clinical response (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Pediatrics (< 18 years of age):

Health Canada has not authorized an indication for pediatric use (see 1.1 Pediatrics).

Geriatrics (> 65 years of age):

Respiratory depression has occurred in the elderly following administration of large initial doses of opioids to patients who were not opioid-tolerant or when opioids were co-administered with other agents that can depress respiration. APO-METHADONE should be initiated at a low dose and slowly titrated to effect (see 7.1.4 Geriatrics and 10.3 Pharmacokinetics, Special Populations and Conditions, Geriatrics).

Adjustment or Reduction of Dosage:

Physical dependence with or without psychological dependence tends to occur with chronic administration of opioids, including APO-METHADONE. Withdrawal (abstinence) symptoms may occur following abrupt discontinuation of therapy. These symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.

Following successful relief of severe pain, periodic attempts to reduce the opioid dose should be made. Smaller doses or complete discontinuation may become feasible due to a change in the patient's condition or mental state. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. In patients who are appropriately treated with opioid analgesics and who undergo gradual withdrawal of the drug, these symptoms are usually mild (see 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance ). Tapering should be individualized and carried out under medical supervision.

After interruption of chronic dosing, if methadone treatment is to be continued, starting doses should be low and patients should be titrated slowly to effect in order to avoid severe toxicity and respiratory depression.

Patients should be informed that reducing and/or discontinuing opioids decreases their tolerance to these drugs. If treatment needs to be re-initiated, the patient must start at the lowest dose and titrate up to avoid overdose.

4.4 Administration

APO-METHADONE tablets must be swallowed whole. Cutting, breaking, crushing, chewing, or dissolving APO-METHADONE can lead to dangerous adverse events including death (see 7 WARNINGS AND PRECAUTIONS).

4.5 Missed Dose

If the patient forgets to take one or more doses, they should take their next dose at the next scheduled time and in the normal amount.

5 OVERDOSAGE

Signs and Symptoms: Serious overdosage of methadone hydrochloride is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal-muscle flaccidity, cold and clammy skin and, sometimes, bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.

Other important adverse events reported with methadone overdose include toxic leukoencephalopathy, delayed post-hypoxic leukoencephalopathy, sudden sensorial hearing loss, rhabdomyolysis progressing to renal failure, serotonin syndrome and hypoglycemia.

Treatment: Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. If a non-tolerant person, especially a child, takes a large dose of methadone, effective narcotic antagonists are available to counteract the potentially lethal respiratory depression. The physician must remember, however, that methadone is a long-acting depressant (thirty-six to forty-eight hours), whereas the antagonist act for much shorter periods (one to three hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and may need to be treated repeatedly with the narcotic antagonist as needed. If the diagnosis is correct and respiratory depression is due only to overdosage of methadone, the use of respiratory stimulants is not indicated.

Opioid antagonists should not be administered in the absence of clinically significant respiratory or cardiovascular depression. In an individual physically dependant on opioids, the administration of the usual dose of an opioid antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. If antagonists must be used to treat serious respiratory depression in the physically dependant patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Intravenously administered naloxone or nalmefene may be used to reverse signs of intoxication. Because of the relatively short half-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.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated.

Note: In an individual physically dependent on opioids, the administration of the usual dose of 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 the antagonist administered. The use of an opioid antagonist in such a person should be avoided if possible. If it must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist (10 to 20% of the usual recommended initial dose of the antagonist).

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

This tromethamine-based APO-METHADONE tablet formulation was studied in vitro in different solution media to observe the solubility of its methadone content. The new formulation showed a methadone solubility reduced by 70% to 100% in an aqueous solution. Methadone solubility in alcoholic solutions (ethanol or isopropyl alcohol) or in simulated gastric fluid was not affected by tromethamine. However, its solubility in water after evaporation of such an alcoholic solution was reduced by close to 100%.

APO-METHADONE is available in the following dosage forms: tablet.

1 mg: Blue, round shape, flat face, beveled-edge tablet. Engraved “APO” over “1” on one side, plain with bisect on the other side.

5 mg: Peach, round shape, flat face, beveled-edge tablet. Engraved “APO” over “5” on one side, plain with bisect on the other side.

10 mg: Pale green, round shape, flat face, beveled edge tablet. Engraved “APO” over “10” on one side, plain with bisect on the other side.

25 mg: White to off-white, capsule shape, biconvex tablet. Engraved “APO 25” on one side, plain with bisect on the other side.

The tablet formulation cannot be dissolved in water.

Packaging:

Available in HDPE bottles of 100.

7 WARNINGS AND PRECAUTIONS

MAY BE HABIT FORMING.

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Methadone hydrochloride, a synthetic opioid, is a controlled substance listed in Schedule I of the Controlled Drugs and Substances Act (CDSA). Appropriate security measures should be taken to safeguard stock of methadone against diversion.

Patients should be instructed not to give APO-METHADONE (methadone hydrochloride) to anyone other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. APO-METHADONE should be stored securely to avoid theft or misuse.

APO-METHADONE should only be prescribed by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists.

Patients should be cautioned not to consume alcohol while taking APO-METHADONE as it may increase the chance of experiencing serious adverse events, including death.

Hyperalgesia that will not respond to a further dose increase of methadone hydrochloride can occur at particularly high doses. A methadone hydrochloride dose reduction or change in opioid may be required (see 7 WARNINGS AND PRECAUTIONS, Neurologic, Opioid Induced Hyperalgesia).

Addiction, Abuse and Misuse

Like all opioids, APO-METHADONE is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, APO-METHADONE should be prescribed and handled with caution.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse.

Opioids, such as APO-METHADONE, should be used with particular care in patients with a history of alcohol and illicit/prescription drug abuse and other mental health disorders including, but not limited to, major depression and anxiety. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

APO-METHADONE is intended for oral use only. The tablets should be swallowed whole, and not chewed or crushed. Abuse of oral dosage forms can be expected to result in serious adverse events, including death.

Like morphine, methadone is a μ-agonist opioid agonist with an abuse liability and is subject to criminal diversion.

Carcinogenesis and Genotoxicity

See 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity and Genotoxicity sections.

Cardiovascular

Methadone administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of APO-METHADONE.

Cardiac Conduction Effects: Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (>200 mg/day). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.

Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction abnormalities, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia. QT prolongation has also been reported in patients with no prior cardiac history who have received high doses of methadone. Patients developing QT prolongation while on methadone treatment should be evaluated for the presence of modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism. For use of methadone to treat pain, the risk of QT prolongation and development of dysrhythmias should be weighed against the benefit of adequate pain management and the availability of alternative therapies.

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 has been considered to outweigh the risk of QT prolongation that has been reported with high doses of methadone.

The use of methadone in patients already known to have prolonged QT interval has not been systemically studied.

In using methadone an individualized benefit to risk assessment should be carried out and should include evaluation of patient presentation and complete medical history. For patients judged to be at risk, careful monitoring of cardiovascular status, including QT prolongation and dysrhythmias and those described previously should be performed.

If a patient taking APO-METHADONE experiences symptoms suggestive of an arrhythmia (such as palpitations, dizziness, light-headedness, or syncope), that patient should seek immediate medical attention.

Methadone, like other opioids, may produce orthostatic hypotension in ambulatory patients.

The use of APO-METHADONE in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure (see 10.2 Pharmacodynamics).

Dependence/Tolerance

As with other opioids, tolerance, physical and psychological dependence and opioid use disorder (OUD) may develop upon repeated administration of APO-METHADONE.

Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid, and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Abuse or intentional misuse of methadone may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g., major depression, anxiety and personality disorders).

Patients will require monitoring for signs of drug-seeking behaviour (e.g., too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist (see 4.2 Recommended Dose and Dosage, Adjustment or Reduction of Dosage). Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see 8 ADVERSE REACTIONS).

Incomplete Cross-Tolerance between Methadone and Other Opioids: Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is a particular concern for patients tolerant to other μ-opioid agonists when converting to methadone, making determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high dose treatment with other opioid agonists. Therefore, it is critical to understand the pharmacokinetics of methadone when converting patients from other opioids (see 7 WARNINGS AND PRECAUTIONS, Respiratory and 4 DOSAGE AND ADMINISTRATION). A high degree of “opioid tolerance” does not eliminate the possibility of methadone toxicity.

Use in Drug and Alcohol Addiction: APO-METHADONE is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of pain requiring opioid analgesia.

Patients with a history of addiction to drugs or alcohol may be at higher risk of becoming addicted to APO-METHADONE unless used under extreme caution and awareness.

Neonatal Opioid Withdrawal Syndrome (NOWS): Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Use of APO-METHADONE for analgesia is contraindicated in pregnant women (see 2 CONTRAINDICATIONS).

Driving and Operating Machinery

APO-METHADONE may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of methadone hydrochloride with other CNS depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol.

Endocrine and Metabolism

Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Gastrointestinal

Methadone hydrochloride and other morphine-like opioids have been shown to decrease bowel motility. The administration of methadone hydrochloride or other narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions (see 2 CONTRAINDICATIONS).

Hepatic/Biliary/Pancreatic

The use of methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating methadone after multiple dosing.

Neurologic

Head Injury: The respiratory depressant effects of methadone hydrochloride, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Also, methadone hydrochloride may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, methadone hydrochloride must be used with extreme caution and only if it is deemed essential (see 2 CONTRAINDICATIONS).

Interactions with CNS Depressants (including benzodiazepines and alcohol): APO-METHADONE should be used with caution and in a reduced dosage during concomitant administration of other opioids analgesics, general anesthetics, phenothiazines and other tranquilizers, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, gabapentinoids, baclofen, centrally-active anti-emetics and other CNS depressants including alcohol. Respiratory depression, hypotension and profound sedation, coma or death may result.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see 9.2 Drug Interactions Overview). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when APO-METHADONE is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see 9 DRUG INTERACTIONS).

APO-METHADONE should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see 2 CONTRAINDICATIONS, 8 ADVERSE REACTIONS, Sedation and 9 DRUG INTERACTIONS).

Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest.

Opioid Induced Hyperalgesia: Opioid induced hyperalgesia (OIH) is a paradoxical response to an opioid in which there is an increase in pain perception despite stable or increased opioid exposure. It differs from tolerance, in which higher opioid doses are required to achieve the same analgesic effect or treat recurring pain. Clinically, OIH may be associated with high opioid doses, long term opioid treatment, and intraoperative opioid use. OIH may manifest as an unexplained increase in pain, more diffuse pain than pre-existing, or as pain from ordinary (i.e., non-painful) stimuli (allodynia) in the absence of disease progression. When OIH is suspected, the dose of opioid should be reduced or tapered off, if possible. It is reasonable to consider opioid rotation, or the use of a non-opioid strategy for pain control. There is currently no well-established treatment for OIH.

Serotonin Toxicity / Serotonin Syndrome: Serotonin toxicity also known as serotonin syndrome is a potentially life-threatening condition and has been reported with methadone, including methadone hydrochloride tablets particularly during combined use with other serotonergic drugs (see 9.2 Drug Interactions Overview, Serotonergic Drugs).

Serotonin toxicity is characterized by neuromuscular excitation, autonomic stimulation (e.g. tachycardia, flushing) and altered mental state (e.g. anxiety, agitation, hypomania). In accordance with the Hunter Criteria, serotonin toxicity diagnosis is likely when, in the presence of at least one serotonergic agent, one of the following is observed:

• Spontaneous clonus
• Inducible clonus or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature >38°C and ocular clonus or inducible clonus.

If concomitant treatment with APO-METHADONE and other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see 9.2 Drug Interactions Overview, Serotonergic Drugs). If serotonin toxicity is suspected, discontinuation of the serotonergic agents should be considered.

Renal

The use of methadone has not been extensively evaluated in patients with renal insufficiency.

Reproductive Health: Female and Male Potential

• Fertility

  Long term use of opioids may be associated with symptoms such as infertility (see 8.5 Post-Market Adverse Reactions, Androgen deficiency).

• Function

  Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido or erectile dysfunction (see 8.5 Post-Market Adverse Reactions, Androgen deficiency).

Respiratory

Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Methadone hydrochloride should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia (see 2 CONTRAINDICATIONS).

There is significant risk of respiratory depression if the patient is switched abruptly from other opioids to methadone. Conversion to methadone should be undertaken with caution.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of APO-METHADONE, the risk is greatest during the initiation of therapy or following a dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with APO-METHADONE and following dose increases.

Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

To reduce the risk of respiratory depression, proper dosing and titration of APO-METHADONE are essential (see 4 DOSAGE AND ADMINISTRATION). Overestimating the APO-METHADONE dose when converting patients from another opioid product can result in a fatal overdose with the first dose. In these patients, the use of non-opioid analgesics should be considered, if feasible (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, Special Risk Groups, and 4 DOSAGE AND ADMINISTRATION).

Sleep Apnea: Opioids can cause sleep-related breathing disorders such as sleep apnea syndromes (including central sleep apnea [CSA]) and hypoxia (including sleep-related hypoxia). Opioid use increases the risk of CSA in a dose-dependent fashion. Evaluate patients on an ongoing basis for the onset of a new sleep apnea, or a worsening of an existing sleep apnea. In these patients, consider reducing or stopping the opioid treatment if appropriate, using best practices for tapering of opioids (see 4.2 Recommended Dose and Dosage Adjustment, Adjustment or Reduction of Dosage; 7 WARNINGS AND PRECAUTIONS; Dependence/Tolerance).

Use in Patients with Chronic Pulmonary Disease: APO-METHADONE should be administered with extreme caution to patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve (such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma), hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with APO-METHADONE, as in these patients, even usual therapeutic doses of APO-METHADONE may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. These patients should be monitored and use of alternative non-opioid analgesics should be considered, if possible, and APO-METHADONE should be employed only under careful medical supervision at the lowest effective dose. The use of APO-METHADONE is contraindicated in patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see 2 CONTRAINDICATIONS).

7.1 Special Populations

Special Risk Groups: Methadone hydrochloride given on a fixed-dose schedule may have a narrow therapeutic index in certain patient populations, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known potential risks of cardiac conduction abnormalities, respiratory depression, altered mental states and postural hypotension.

APO-METHADONE (methadone hydrochloride tablets) should be given with caution and the initial dose should be reduced in certain patients, such as the elderly or debilitated; those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, myxedema, toxic psychosis, prostatic hypertrophy, or urethral stricture; patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease; and in patients with comorbid conditions or concomitant medications which may predispose to dysrhythmia. The usual precautions appropriate to the use of parenteral opioids should be observed and the possibility of respiratory depression should always be kept in mind.

7.1.1 Pregnant Women

No controlled studies of methadone use in pregnant women have been conducted. APO-METHADONE crosses the placental barrier and is contraindicated in pregnant women.

Prolonged maternal use of opioids during pregnancy can result in respiratory difficulties and withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening (see 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance, Neonatal Opioid Withdrawal Syndrome).

Studies show methadone exposure to be associated with an increased risk of very pre-term birth (< 32 weeks of gestation), being small for gestational age (< 10^th percentile), admission to the neonatal unit, and diagnosis of a major congenital anomaly.

Several studies have suggested that infants prenatally exposed to methadone present decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. Moreover it has been suggested that prenatally exposed infants are at a higher risk of presenting neurodevelopmental and neuropsychological impairments, as well as visual (see 7.1.1 Pregnant Women, Neonate Growth and Development).

Additional information on the potential risks of methadone with pre-natal opioid exposure may be derived from animal data (see 16 NON-CLINICAL TOXICOLOGY, Teratogenicity).

Neonate Growth and Development: Exposure to opioids in utero can result in the development of the life-threatening, Neonatal Opioid Withdrawal Syndrome (see 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance, Neonatal Opioid Withdrawal Syndrome).

There are conflicting reports on whether the risk of sudden infant death syndrome (SIDS) is increased in infants born to women treated with methadone during pregnancy.

Prenatal opioid exposure, including to methadone, is suggested to have an effect on the visual system and on brain development.

Lower performance on tests of cognitive function and neurodevelopmental abnormalities have been found in some, although not all, studies and children have been shown to demonstrate mild, but persistent deficits in performance on psychometric and behavioral tests. It is unclear whether these differences in performance are caused by the direct effects of in-utero exposure to methadone or indirectly by genetic and environmental risk factors, or are a consequence of pre-term birth.

Ophthalmic Abnormalities: Infants prenatally exposed to methadone are at risk of a range of visual problems, the underlying causes of which are not clear. Ophthalmic abnormalities included reduced acuity, nystagmus, delayed visual maturation, strabismus, refractive errors, and cerebral visual impairment. Those infants with NOWS severe enough to receive pharmaceutical treatment may be at particular risk of developing nystagmus. Delayed visual development has also been reported. Exposure to opioid including methadone, during pregnancy may result in permanently reduced vision and nystagmus.

Labour and Delivery: Since methadone has a long duration of action, can cross the placental barrier and is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma, APO-METHADONE is contraindicated for obstetric analgesia, during labour and delivery. As with all opioids, administration of methadone to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Naloxone, a drug that counters the effects of opiates, should be readily available if APO-METHADONE is used in this population.

7.1.2 Breast-feeding

Since methadone has a long duration of action, can cross the placental barrier and is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma, APO-METHADONE is contraindicated for obstetric analgesia in nursing mothers. Cases of death have been reported in association with methadone in children less than one year of age exposed through breast milk.

Women being treated with methadone, who are already breast feeding, should be counselled to wean breast-feeding gradually in order to prevent neonatal abstinence syndrome. Methadone-treated mothers considering nursing an opioid-naïve infant should be counselled of the presence of methadone in breast milk.

7.1.3 Pediatrics (< 18 years of age)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics (> 65 years of age)

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrate slowly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see 4.2 Recommended Dose and Dosage Adjustment, Geriatrics and 10.3 Pharmacokinetics, Special Populations and Conditions, Geriatrics).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Adverse effects of APO-METHADONE are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class.

The major hazards of methadone are respiratory and central nervous system depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock and cardiac arrest and death have occurred.

The most frequently observed adverse effects of APO-METHADONE include light-headedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe pain. In such individuals, lower doses of methadone are advisable.

Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.

Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.

Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.

Other adverse reactions that have been reported in patients receiving methadone include the following:

Body as a Whole: Asthenia (weakness), edema, headache

Cardiovascular: Arrhythmias, bigeminal rhythms, bradycardia, extrasystoles, tachycardia, Torsade de Pointes, ventricular fibrillation, ventricular tachycardia. ECG abnormalities, prolonged QT interval, T-wave inversion, cardiomyopathy, flushing, heart failure, hypotension, palpitations, phlebitis, syncope

Digestive: Abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis

Metabolic and Nutritional: Hypokalemia, hypomagnesemia, weight gain

Nervous: Agitation, confusion, seizures, disorientation, dysphoria, euphoria, insomnia

Ocular: Visual disturbances

Respiratory: Pulmonary edema

Special senses: Visual disturbances

Urogenital: Antidiuretic effect, amenorrhea, urinary retention or hesitancy, reduced libido and/or potency

Abnormal Hematologic and Clinical Chemistry Findings: Reversible thrombocytopenia has been described in patients with chronic hepatitis.

8.5 Post-Market Adverse Reactions

Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Metabolic and Nutritional: Hypoglycemia

Nervous system Disorders: Serotonin toxicity/Serotonin syndrome

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

• Risks from concomitant use of opioids and benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see 7 WARNINGS AND PRECAUTIONS, Neurologic, Interactions with CNS Depressants (including benzodiazepines and alcohol)).

  • Reserve concomitant prescribing of APO-METHADONE and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate
  • Consider dose reduction of CNS depressants in situations of concomitant prescribing
  • Follow patients for signs and symptoms of respiratory depression and sedation
• MAO inhibitors intensify the effects of opioid drugs which can cause anxiety, confusion and decreased respiration. APO-METHADONE is contraindicated in patients receiving MAO inhibitors or who have used them within the previous 14 days.

9.2 Drug Interactions Overview

Interactions with CNS Depressants (including benzodiazepines and alcohol):

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids; sedatives; gabapentinoids such as pregabalin, baclofen; hypnotics; antidepressants; anxiolytics; tranquilizers; muscle relaxants; general anesthetics; antipsychotics; phenothiazines; neuroleptics; antihistamines; antiemetics; and alcohol) and beta-blockers, increases the risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see 7 WARNINGS AND PRECAUTIONS, Neurologic, Interactions with CNS Depressants (including benzodiazepines and alcohol) and Driving and Operating Machinery). APO-METHADONE should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.

Anti-retroviral agents:

Nevirapine: Based on the known metabolism of methadone, nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Opioid withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Efavirenz: Coadministration of efavirenz in HIV-infected methadone-maintenance patients has resulted in decreased methadone plasma concentrations associated with signs of opioid withdrawal, and necessitating increases in methadone dose.

Ritonavir and Ritonavir/lopinavir: Reduced plasma methadone levels have been observed after administration of ritanovir alone or ritanovir/lopinavir combination. Withdrawal symptoms were however, inconsistently observed. Caution is warranted when administering methadone to patients receiving ritonavir-containing regimens in addition to other drugs known to decrease methadone plasma levels.

Zidovudine: Experimental evidence suggests that methadone increases the area under the concentration-time curve (AUC) of zidovudine with possible toxic effects.

Didanosine and Stavudine: Experimental evidence suggests that methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.

Cytochrome P450 inhibitors:

Since the metabolism of methadone is mediated by the CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opioid effects. Thus patients coadministered with inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), while receiving methadone should be carefully monitored and dosage adjustment made if warranted. Some selective serotonin reuptake inhibitors (SSRI’s) (i.e. sertraline, fluvoxamine) upon coadministration may increase methadone plasma levels and result in increased opiate effects or toxicity.

Specifically, repeat dose administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 4 days) increased the C_max and AUC of pharmacologically active R-methadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg QD). Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.

Cytochrome P450 inducers: The following drug interactions were reported following coadministration of methadone with inducers of cytochrome P450 enzymes:

Rifampin/Rifampicin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in marked reduction in serum methadone levels and concurrent appearance of withdrawal symptoms.

Phenytoin: In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i.d. initially for 1 day followed by 300 mg QD for 3 to 4 days) resulted in ~50% reduction in methadone exposure and concurrently withdrawal symptoms occurred. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and the methadone exposure increased and was comparable to pre-phenytoin dose scenario.

Phenobarbital, carbamazepine: Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms (see also 9.6 Drug-Herb Interactions).

Potentially Arrhythmogenic Agents:

Extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Caution should also be exercised when prescribing concomitant drugs capable of inducing electrolyte disturbances that may prolong the QT interval (hypomagnesemia, hypokalemia). These include diuretics, laxatives, and in rare cases mineralocorticoid hormones.

Monoamine Oxidase Inhibitors (MAOIs):

Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Since the safety of methadone in this regard has not been established, the use of methadone in patients who have received MAO inhibitors during the previous 14-day period is contraindicated. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small incremental doses are administered over the course of several hours while the patient's condition and vital signs are under careful observation.

Opioid antagonist, mixed agonist/antagonist, and partial agonists drugs:

Agonist/ antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) when administered concomitantly with a pure opioid agonist, such as methadone hydrochloride may reduce the analgesic effect of methadone hydrochloride and/or may precipitate withdrawal symptoms, the latter being a particular risk to patients on prolonged methadone therapy.

Protease inhibitors:

Agenerase: Coadministration of methadone with Agenerase resulted in a decrease in the C_max and AUC of the active methadone enantiomer (R-enantiomer) of 25% and 13% respectively, while the C_max, AUC and C_min of the inactive methadone enantiomer (S- enantiomer) were decreased by 48%, 40% and 23% respective. When methadone is coadministered with Agenerase, patients should be monitored for methadone underdosing, in particular if low-dose ritonavir is also given. As compared to a non-matched historical control group, coadministration of methadone and Agenerase resulted in a 30%, 27% and 25% decrease in serum Agenerase AUC, C_max and C_min respectively. No recommendations can be made regarding adjustment of Agenerase dose when Agenerase is coadministered with methadone.

Viracept: When coadministered with Viracept, changes are reported for total plasma methadone; changes for the individual R-enantiomer and S-enantiomer were similar. Dosage of methadone may need to be increased.

Non-nucleoside reverse transcriptase inhibitors:

Rescriptor: Dosage of methadone may need to be decreased when coadministered with Rescriptor.

Desipramine:

Blood levels of desipramine have increased with concurrent methadone therapy.

Serotonergic Drugs:

Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) may increase methadone plasma levels upon co-administration with APO-METHADONE and result in increased opioid effects and/or toxicity.

Coadministration of APO-METHADONE with serotonergic drugs, such as a Selective Serotonin Re-uptake Inhibitor, a Serotonin Norepinephrine Re-uptake Inhibitor or other serotonergic drug, may increase the risk of serotonin syndrome, a potentially life-threatening condition (see 7 WARNINGS AND PRECAUTIONS, Neurologic, Serotonin toxicity / Serotonin syndrome). If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue APO-METHADONE if serotonin syndrome is suspected.

9.3 Drug-Behavioural Interactions

The concomitant use of alcohol should be avoided (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX).

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 – Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Administration of methadone along with other CYP3A4 inducers, such as St. John’s Wort, may result in withdrawal symptoms.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Methadone is an opioid agonist with actions predominantly at the μ receptor. The analgesic activity of the racemate is almost entirely due to the l-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have antitussive effects. Methadone also has some agonist actions at the κ and σ opioid receptors. These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect on the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the oculomotor nerve, and perhaps on opioid receptors in the pupillary muscles causes pupillary constriction. All these effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine. Like many basic drugs, methadone enters mast cells and releases histamine by a nonimmunological mechanism. Similar to morphine, both isomers are 5-HT(3) receptor antagonists, although l-methadone producing greater inhibition than d-methadone. Methadone causes a dependence syndrome of the morphine type. Cross-tolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls.

Some data indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown. Other NMDA receptor antagonists have been shown to product neurotoxic effects in animals.

10.2 Pharmacodynamics

Prolongation of the QT interval associated with methadone can lead to potentially fatal ventricular arrhythmias and is caused by block of the rapid component of the cardiac delayed rectifier K(+) current (I(Kr)), which is encoded by hERG related gene. In vitro effects of methadone have been compared to heroin in human embryonic kidney cells expressing hERG currents, with methadone exhibiting 100-fold higher potency (IC50 4.8 microM) at inhibiting hERG than heroin (IC50 427 microM) (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Cardiac Conduction Effects).

Central Nervous System: Methadone hydrochloride produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO₂ tension and to electrical stimulation.

Methadone hydrochloride depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Methadone hydrochloride causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings).

Gastrointestinal Tract and Other Smooth Muscle: Methadone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System: Methadone hydrochloride may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, hyperhidrosis and/or orthostatic hypotension.

Endocrine System: Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.

Immune System: In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.

Many of the actions of methadone, in various animal species, are characteristic of those seen with other opioid agonists which exert their activity primarily at the mu receptor. The analgesic effect and other morphine-like properties of methadone are exhibited chiefly by the l-form.

The effect of methadone in common laboratory animal paradigms is qualitatively the same as that of morphine, e.g., the Straub reaction in mice, purposeless excitement in cats, and effects on behaviour and reflex activity in decorticate, decerebrate and spinal dogs and cats.

Methadone has an effect similar to that of morphine on circulation and respiration and on smooth muscle. In rats or dogs chronically injected, tolerance to the analgesic effect of methadone develops at nearly the same rate as for morphine. However, dogs rendered only moderately tolerant to methadone are even more tolerant to other opioids than they are to methadone itself.

The heightened activity and increased lability found for methadone in the rat may be related to the persistence of pharmacologically active concentrations of the drug. Exposure to the prenatal period produces a significant delay in postnatal brain growth associated with a reduction in brain DNA content measured at 21 days of age. Studies of plasma drug concentrations indicate a plasma half-life in the rat of only a few hours, but studies using titrated methadone indicate that following prenatal administration, methadone accumulates and persists in neonatal brain and liver for long periods and may alter the maturation of the cholinergic-adrenergic or catecholamine systems.

10.3 Pharmacokinetics

When administered orally, methadone is approximately one half as potent as when given parenterally. Oral administration results in a delay of the onset, a lowering of the peak, and an increase in the duration of analgesic effect. The steady-state elimination half-life of methadone is approximately 25 hours. Large inter-individual variability in elimination half-life may necessitate 2 to 9 days for steady-state serum levels.

Acutely, methadone has similar effects to other opioids; however, its pharmacological properties are significantly different from other opioid agonists in that it is extremely long-acting (36 to 48 hours) in humans.

After interruption of chronic dosing, if methadone treatment is to be continued, starting doses should be low and patients should be titrated slowly to effect in order to avoid severe toxicity and respiratory depression.

The pharmacokinetic parameters of methadone following the administration of a single methadone hydrochloride tablet 10 mg dose, under fasting conditions, to twenty-four (24) healthy male and female subjects are presented in the table below.

Table 3 - Mean (CV%) Methadone Pharmacokinetic Parameters after Administration of a Single 10 mg dose of methadone hydrochloride tablet to Healthy Subjects (n=24)

^a median (range)

Absorption

Methadone is one of the more lipid soluble opioids, and is well absorbed from the gastrointestinal tract. Following oral administration, the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 and 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated.

Distribution

Methadone undergoes fairly extensive first pass metabolism. It is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in lung, liver and kidneys being much higher than in the blood. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to a1-acid glycoprotein (85% to 90%). Marked variations in plasma levels occur in dependent persons on a stable dose of oral methadone, without any relation to symptoms. Methadone is secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels.

Metabolism

Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, CYP2C19, and to a lesser extent CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine.

Elimination

The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, and the terminal half-life (T½) was highly variable and ranged between 8 and 59 hours in different studies. Since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations.

Special Populations and Conditions

• Pediatrics (< 18 years of age): The pharmacokinetics of methadone hydrochloride tablets have not been evaluated in the pediatric population. Individuals under 18 years of age should not take APO-METHADONE.
• Geriatrics (> 65 years of age): The pharmacokinetics of methadone hydrochloride tablets have not been evaluated in the geriatric population. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy.
• Hepatic Insufficiency: The use of methadone has not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized in the liver and patients with liver impairment may be at risk of accumulating methadone after multiple dosing.
• Renal Insufficiency: The use of methadone has not been extensively evaluated in patients with renal insufficiency.

11 STORAGE, STABILITY AND DISPOSAL

Dispense in tight containers, protect from light, store at 15°C - 30°C.

Disposal

APO-METHADONE should be kept in a safe place, out of the sight and reach of children before, during and after use. APO-METHADONE should not be used in front of children, since they may copy these actions.

APO-METHADONE should never be disposed of in household trash. Disposal via a pharmacy take back program is recommended. Unused or expired APO-METHADONE should be properly disposed of as soon as it is no longer needed to prevent accidental exposure to others, including children or pets. If temporary storage is required before disposal, a sealed child-proof container, such as a biohazard waste container or a lockable medication box could be obtained from a pharmacy.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Methadone Hydrochloride

Chemical name: 6-Dimethylamino-4,4-diphenyl-3-heptanone hydrochloride

Molecular formula and molecular mass: C₂₁H₂₇NO·HCl; 345.91 g/mol

Structural formula:

Physicochemical Properties:

Description: White or almost white powder

Solubility: Soluble in water, freely soluble in ethanol (96 %). Insoluble in n-hexane, toluene, diethyl ether, chloroform, ethyl acetate, and acetone

pKa and pH: 8.25 (water, 20°C) and 4.5 to 6.5 (1% w/w, water)

Partition co-efficient: Log P = 2.1 (octanol/water, pH 7.4)

Melting point: 235°C (DSC)

14 CLINICAL TRIALS

14.3 Comparative Bioavailability Studies

A randomized, two-treatment, two-period, single oral dose, cross-over, comparative bioavailability study of APO-METHADONE 10 mg tablets (Apotex Inc.) and METADOL^® 10 mg tablets (Paladin Labs Inc.) was conducted in healthy, adult, male and female subjects under fasting conditions. A summary of the comparative bioavailability data from 20 subjects included in the statistical analysis is presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ APO-METHADONE (methadone hydrochloride) tablets, 10 mg (Apotex Inc.)

² METADOL^® (methadone hydrochloride) tablets, 10 mg (Paladin Labs Inc., Canada)

³ n=18 subjects

⁴ Expressed as median (range) only

Due to the long elimination half-life of methadone, AUC_I and T_1/2 could not be accurately calculated from the data obtained in this study.

APO-METHADONE 1 mg tablets have satisfied the criteria for a Biopharmaceutics Classification System (BCS)-based biowaiver in comparison to METADOL^® 1 mg tablets (methadone, as methadone hydrochloride), Paladin Labs Inc.

15 MICROBIOLOGY

No data available.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

In animals, methadone is three to ten times more toxic than morphine, according to the species, and two to three times more toxic than meperidine.

In comparative acute toxicity studies in rats, methadone on a weight-for weight basis is about 10 times more toxic than morphine orally, about 6 times more toxic subcutaneously, and about 25 times more toxic intravenously. The l-isomer of methadone, which accounts for nearly all the analgesic activity of the racemic mixture, is little if any more toxic than dl-methadone.

The following Table summarizes the acute toxicity data for dl-methadone obtained in rats and mice:

A single dog injected subcutaneously with 50 mg/kg of dl-methadone suffered violent convulsions and died 4 hours after injection.

Rats administered a daily dose of 4 mg/kg methadone hydrochloride subcutaneously for ten weeks showed retarded growth. At autopsy, the only gross change noted was a slight increase in liver weight to body weight ratio. Considerable local subcutaneous irritation was observed at the injection sites.

Young adult mongrel female dogs (n=8) injected twice daily on weekdays, and once daily on weekends, with a dose of 2 mg/kg of methadone for up to 16 weeks, exhibited the following extreme side effects: general depression, narcosis, and sedation. Tolerance to these effects was shown to develop much more slowly with methadone than with morphine. Other long-term effects were bradycardia to which no tolerance developed, vomiting, and reduction in voltages of P and R waves on the electrocardiogram. Signs observed after withdrawal of methadone included increase in resting respiratory rate, tachycardia, loss of appetite, and pronounced muscular tremors, with twitching and rigidity.

Carcinogenicity:

Data from published reports of carcinogenicity studies indicate that there was a significant increase in pituitary adenomas in female B6C2F1 mice consuming 15 mg/kg/day methadone for two years. This dose was approximately 0.6 times a human daily oral dose of 120 mg/day, on a body surface area basis. However, this finding was not seen in mice consuming 60 mg/kg/day (approximately 2.5 times a human daily oral dose of 120 mg/day). Furthermore, in a two-year study of dietary administration of methadone to Fischer 344 rats, there was no clear evidence for treatment related increase in the incidence of neoplasms, at doses as high as 28 mg/kg/day in males and 88 mg/kg/day in females (approximately 2.3 times and 7.1 times, respectively, a human daily oral dose of 120 mg/day) based on body surface area comparison.

Genotoxicity:

In published reports, methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures. Methadone treatment of male mice increased sex chromosome and autosome univalent chromosomes and translocations in multivalent chromosomes. Methadone tested positive in the E.coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays.

Reproductive and Developmental Toxicology:

Methadone, like morphine, blocks ovulation in the rat but only at doses approaching toxicity.

Teratogenicity:

Methadone does not appear to be teratogenic or embryotoxic in the rat or rabbit models. However, following large doses, methadone produced teratogenic effects in the guinea pig, hamster and mouse.

One published study found that in hamster fetuses, subcutaneous methadone doses of 31 mg/kg or greater (estimated exposure was approximately 2 times a human daily oral dose of 120 mg/day on a mg/m² basis, or equivalent to a human daily intravenous dose of 120 mg/day) on day 8 of gestation produced exencephaly and neurological effects. Some of the reported effects were observed at doses that were maternally toxic. In another study, a single subcutaneous dose of 22 to 24 mg/kg methadone (estimated exposure was approximately equivalent to a human daily oral dose of 120 mg/day on a mg/m² basis; or half a human daily intravenous dose of 120 mg/day) on day 9 of gestation in mice also produced exencephaly in 11% of the embryos. However, no effects were reported in rats and rabbits at oral doses up to 40 mg/kg (estimated exposure was approximately 3 and 6 times, respectively, a human daily oral dose of 120 mg/day on a mg/m² basis; or 1.5 and 3 times a human daily intravenous dose of 120 mg/day) during days 6 to 15 and 6 to 18, respectively.

Abnormal fetal nonstress tests (NSTs) have been reported to occur more frequently when the test is performed 1 to 2 hours after a maintenance dose of methadone in late pregnancy compared to controls. Published animal studies suggest that perinatal exposure to opioids including methadone may alter neuronal development and behaviour in the offspring. Perinatal methadone exposure in rats has been linked to alterations in learning ability, motor activity, thermal regulation, nociception responses and sensitivity to other drugs. Additional animal data demonstrates evidence for neurochemical changes in the brains of methadone-treated offspring, including the cholinergic, dopaminergic noradrenergic and serotonergic systems.

Administration of a 5, 10, 15 or 20 mg/kg regimen of methadone to gravid rats on the last two weeks of gestation showed a dose-related increase in resorptions and stillbirths, but no teratogenicity. The two intermediate dose levels produced body weights that were reduced at birth but similar to controls by weaning.

Behavioral teratology studies have suggested that dose levels producing a relatively high maternal and offspring mortality may yield survivors that are more resistant to the toxic effects of the drug and thus not show effects seen among the lower dose-level groups.

Gravid rats administered a 5, 10, or 15 mg/kg regimen of methadone on the last two weeks of gestation showed blood levels of methadone which were dose-related, corresponding to the levels found in human subjects receiving daily maintenance doses of approximately 30, 60 and 100 mg, respectively.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. METADOL,tablets, 1 mg, 5 mg, 10 mg and 25 mg, solution, 1 mg / mL and 10 mg / mL, control number: 288381, Product Monograph, Endo Operations Ltd., MAR 18, 2025.