Methadose

Dosage Forms & Strengths

injectable solution: Schedule II

• 10mg/mL

tablet: Schedule II

• 5mg
• 10mg

dispersible tablet: Schedule II

• 40mg

oral solution: Schedule II

• 5mg/5mL
• 10mg/5mL

oral concentrate solution: Schedule II

• 10mg/mL

Chronic Severe Pain

Indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Opioid-naive patients: 2.5 mg PO q8-12hr; titrate slowly with dose increases no more frequent than every 3-5 days

Opioid-tolerant patients

• Discontinue all other around-the-clock opioids
• Substantial interpatient variability, see prescribing information for guidance

Opioid-tolerant definition

• Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression
• Patients who are opioid tolerant are those receiving, for 1 week or longer, at least 60 mg/day PO morphine, 25 mcg/hr transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, 25 mg/day PO oxymorphone, or an equianalgesic dose of another opioid

Limitations of use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve for patients whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain
• Not indicated for acute pain or as a PRN analgesic

Detoxification

20-30 mg PO once daily or minimum dosage necessary to suppress withdrawal; may be titrated to 40 mg/day in divided doses and continued for 2-3 days, then decreased 20% daily as tolerated

Dosing Modifications

Renal impairment (CrCl <10mL/min): 50-75% of normal dose

Hepatic impairment: Not recommended in severe liver disease:

Dosing Considerations

Conversion from PO to parenteral: Parenteral-to-PO ratio, 1:2 (5 mg parenteral = 10 mg PO)

To convert to methadone from another opioid, use available conversion factors to obtain estimated dose

Do not abruptly discontinue methadone in a physically dependent patient

Dosage Forms & Strengths

injected solution: Schedule II

• 10mg/mL

tablet: Schedule II

• 5mg
• 10mg
• 40mg

dispersible tablet: Schedule II

• 40mg

oral solution: Schedule II

• 5mg/5mL
• 10mg/5mL

Pain (Off-label)

0.7 mg/kg/day PO/SC/IV/IM divided q6hr PRN; not to exceed 10 mg/dose  

Opiate Withdrawal (Off-label)

Neonates: 0.05-0.2 mg/kg PO q12-24hr; reduce dose by 10-20% per week over 4-6 weeks; adjust tapering on signs and symptoms of withdrawal

Pain

2.5 mg PO/IM q8-12hr; titrate slowly with dose increases no more frequent than every 3-5 days

Detoxification

20-30 mg PO once daily or minimum dosage necessary to suppress withdrawal; may be titrated to 40 mg/day in divided doses and continued for 2-3 days, then decreased 20% daily as tolerated

Frequency Not Defined

Agitation

Angina pectoris

Anticholinergic effects (dry mouth, palpitation, tachycardia)

Bradycardia

Cardiac arrest

Coma

Constipation

Dizziness

Dysphoria

Euphoria

Faintness

Mental clouding or depression

Myocardial infarction

Nausea

Pruritus, urticaria

Nervousness

QT-interval prolongation

Respiratory arrest

Respiratory/circulatory depression

Restlessness

Sedation

Seizures

Severe cardiac arrhythmias

Shock

ST-segment elevation

Sweating, flushing, warmness of face/neck/upper thorax

Syncope

Urinary retention, oliguria

Ventricular tachycardia

Visual disturbances

Vomiting

Weakness

Mechanism of Action

Narcotic agonist-analgesic of opiate receptors; inhibits ascending pain pathways, thus altering perception and response to pain; produces analgesia, respiratory depression, and sedation

Absorption

Bioavailability: 36-100%

Onset: PO, 0.5-1 hr; parenteral, 10-20 min

Duration: 4-8 hr; repeated administration, 22-48 hr; overdosage, 36-48 hr

Peak plasma time: 1-7.5 hr

Distribution

Protein bound: 85-90%

Vd: 1-8 L/kg

Metabolism

Metabolized in liver via N-demethylation

Elimination

Half-life: 8-59 hr

Excretion: Urine

Tell your doctor if you are breastfeeding or plan to breastfeed. Methadone passes through your breast milk and may harm your baby. You should choose to use methadone or breastfeed, but not both.

Deaths, cardiac and respiratory, have been reported during initiation and conversion of pain patients to methadone treatment from treatment with other opioid agonists. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration.

Respiratory depression is the chief hazard associated with methadone hydrochloride administration. Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, particularly in the early dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.

In addition, 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.

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.

Conditions for Distribution and Use of Methadone Products for the Treatment of Opioid Addiction

Code of Federal Regulations, Title 42, Sec 8

Methadone products when used for the treatment of opioid addiction in detoxification or maintenance programs, shall be dispensed only by opioid treatment programs (and agencies, practitioners or institutions by formal agreement with the program sponsor) certified by the Substance Abuse and Mental Health Services Administration and approved by the designated state authority. Certified treatment programs shall dispense and use methadone in oral form only and according to the treatment requirements stipulated in the Federal Opioid Treatment Standards (42 CFR 8.12). See below for important regulatory exceptions to the general requirement for certification to provide opioid agonist treatment.

Failure to abide by the requirements in these regulations may result in criminal prosecution, seizure of the drug supply, revocation of the program approval, and injunction precluding operation of the program.

Regulatory Exceptions to the General Requirement for Certification to Provide Opioid Agonist Treatment:

1. During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21 CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis.
2. During an emergency period of no longer than 3 days while definitive care for the addiction is being sought in an appropriately licensed facility (pursuant to 21 CFR 1306.07(b)).

This section provides information on the proper use of a number of products that contain methadone. It may not be specific to Methadose. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines.

This medicine comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Swallow the tablet whole. Do not crush, break, chew, or dissolve it.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For pain:
    • For patients taking Dolophine® as the first pain medicine:
      • Adults—At first, 2.5 milligrams (mg) every 8 to 12 hours. Your doctor may adjust your dose as needed. Do not take more than your prescribed dose in 24 hours.
      • Children—Use and dose must be determined by your doctor.
    • For patients switching from other opioids to Dolophine®:
      • Adults—The dose must be determined by your doctor based on the previous dose of opioid medicine. The dose is given every 8 or 12 hours. Your doctor may adjust your dose as needed. Do not take more than your prescribed dose in 24 hours.
      • Children—Use and dose must be determined by your doctor.
  • For opioid addiction:
    • Adults—At first, 20 to 30 milligrams (mg) taken as a single dose per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 40 mg per day. Do not take more than your prescribed dose in 24 hours.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you are taking this medicine for opioid addiction and miss a dose, take your next dose the following day as scheduled.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Methadone can cause serious unwanted effects if taken by adults who are not used to strong narcotic pain medicines, children, or pets. Make sure you store the medicine in a safe and secure place to prevent others from getting it.

Methadose™ Dispersible Tablet for oral administration following dispersion in a liquid: 40 mg of methadone hydrochloride and is a white round dispersible tablet.            

Methadone Hydrochloride Tablets USP (dispersible, orange flavored) for oral administration following dispersion in a liquid: 40 mg of methadone hydrochloride and is an orange rectangular dispersible tablet.

Methadone hydrochloride tablets for oral suspension are cross-scored, allowing for flexible dosage adjustment. Each tablet may be broken or cut in half to yield two 20 mg doses, or in quarters to yield four 10 mg doses.

Methadone hydrochloride tablets for oral suspension are contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.1)]

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7)]

• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)]

• Hypersensitivity (e.g., anaphylaxis) to methadone or any other ingredient in methadone hydrochloride tablets for oral suspension [see Adverse Reactions (6)]

Pregnancy

Risk Summary

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.5)].

Pregnant women in methadone maintenance programs may have reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes and risk of continued or relapsing illicit opioid use. These risks should be considered in women treated with methadone hydrochloride tablets for oral suspension for maintenance treatment of opioid addiction. There are no adequate and well-controlled studies in pregnant women.

In published animal reproduction studies, methadone administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) in the hamster at doses 2 times the human daily oral dose of 120 mg/day on a mg/m2 basis (HDD) and in mice at doses equivalent to the HDD. Administration of methadone to pregnant animals during organogenesis and through lactation resulted decreased litter size, increased pup mortality, decreased pup body weights, developmental delays, and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD. Administration of methadone to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in behavioral tests in the offspring at exposures comparable to and less than the HDD [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and Embryo-Fetal Risk: Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dosage Adjustment During Pregnancy: The disposition of oral methadone has been studied in approximately 30 pregnant patients in 2nd and 3rd trimesters. Total body clearance of methadone was increased in pregnant patients compared to the same patients postpartum or to non-pregnant opioid-dependent women. The terminal half-life of methadone is decreased during 2nd and 3rd trimesters. The decrease in plasma half-life and increased clearance of methadone resulting in lower methadone trough levels during pregnancy can lead to withdrawal symptoms in some pregnant patients. The dosage may need to be increased or the dosing interval decreased in pregnant patients receiving methadone hydrochloride tablets for oral suspension to achieve therapeutic effect [see Dosage and Administration (2.8)].

Fetal/Neonatal Adverse Reactions: Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with methadone hydrochloride tablets for oral suspension.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5)].

Labor or Delivery: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including methadone hydrochloride tablets for oral suspension can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.

Human Data

Reported studies have generally compared the benefit of methadone to the risk of untreated addiction to illicit drugs. Pregnant women involved in methadone maintenance programs have been reported to have significantly improved prenatal care leading to significantly reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality when compared to women using illicit drugs. Several factors, including maternal use of illicit drugs, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children of women who take methadone during pregnancy. Information is limited regarding dose and duration of methadone use during pregnancy, and most maternal exposure appears to occur after the first trimester of pregnancy.

A review of published data on experiences with methadone use during pregnancy by the Teratogen Information System (TERIS) concluded that maternal use of methadone during pregnancy as part of a supervised, therapeutic regimen is unlikely to pose a substantial teratogenic risk (quantity and quality of data assessed as “limited to fair”). However, the data are insufficient to state that there is no risk (TERIS, last reviewed October, 2002). A retrospective case series of 101 pregnant, opioid-dependent women who underwent inpatient opiate detoxification with methadone did not demonstrate any increased risk of miscarriage in the 2nd trimester or premature delivery in the 3rd trimester. Recent studies suggest an increased risk of premature delivery in opioid-dependent women exposed to methadone during pregnancy, although the presence of confounding factors makes it difficult to determine a causal relationship. Several studies have suggested that infants born to narcotic-addicted women treated with methadone during all or part of pregnancy have been found to have decreased fetal growth with reduced birth weight, length, and/or head circumference compared to controls. This growth deficit does not appear to persist into later childhood. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests. In addition, several studies suggest that children born to opioid-dependent women exposed to methadone during pregnancy may have an increased risk of visual development anomalies; however, a causal relationship has not been assigned.

There are conflicting reports on whether Sudden Infant Death Syndrome occurs with an increased incidence in infants born to women treated with methadone during pregnancy. Abnormal fetal non-stress tests 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.

Animal Data: Formal reproductive and developmental toxicology studies for methadone have not been conducted. Exposure margins for the following published study reports are based on a human daily dose (HDD) of 120 mg methadone using a body surface area comparison.

In a published study in pregnant hamsters, a single subcutaneous dose of methadone ranging from 31 mg/kg (2 times the HDD) to 185 mg/kg on Gestation Day 8 resulted in a decrease in the number of fetuses per litter and an increase in the percentage of fetuses exhibiting neural tube defects including exencephaly, cranioschisis, and “various other lesions.” The majority of the doses tested also resulted in maternal death. In a study in pregnant mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11% of the embryos. In another study in pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone (equivalent to the HDD) administered from Gestation Day 6 to 15 resulted in no malformations, but there were increased postimplantation loss and decreased live fetuses at 10 mg/kg/day or greater (0.4 times the HDD) and decreased ossification and fetal body weight at 20 mg/kg/day or greater (0.8 times the HDD). In a second study of pregnant mice dosed with subcutaneous doses up to 28 mg/kg/day methadone from Gestation Day 6 to 15, there was decreased pup viability, delayed onset of development of negative phototaxis and eye opening, increased righting reflexes at 5 mg/kg/day or greater (0.2 times the HDD), and decreased number of live pups at birth and decreased pup weight gain at 20 mg/kg/day or greater (0.8 times the HDD).

No effects were reported in a study of pregnant rats and rabbits at oral doses up to 40 mg/kg (3 and 6 times, respectively, the HDD) administered from Gestation Days 6 to 15 and 6 to 18, respectively.

When pregnant rats were treated with intraperitoneal doses of 2.5, 5, or 7.5 mg/kg methadone from one week prior to mating, through gestation until the end of lactation period, 5 mg/kg or greater (0.4 times the HDD) methadone resulted in decreases in litter size and live pups born and 7.5 mg/kg (0.6 times the HDD) resulted in decreased birth weights. Furthermore, decreased pup viability and pup body weight gain at 2.5 mg/kg or greater (0.2 times the HDD) were noted during the preweaning period.

Additional animal data demonstrates evidence for neurochemical changes in the brains of offspring from methadone-treated pregnant rats, including changes to the cholinergic, dopaminergic, noradrenergic and serotonergic systems at doses below the HDD. Other animal studies have reported that prenatal and/or postnatal exposure to opioids including methadone alters neuronal development and behavior in the offspring including alterations in learning ability, motor activity, thermal regulation, nociceptive responses, and sensitivity to drugs at doses below the HDD. Treatment of pregnant rats subcutaneously with 5 mg/kg methadone from Gestation Day 14 to 19 (0.4 times the HDD) reduced fetal blood testosterone and androstenedione in males.

Published animal data have reported increased neonatal mortality in the offspring of male rodents that were treated with methadone at doses comparable to and less than the HDD for 1 to 12 days before and/or during mating (with more pronounced effects in the first 4 days). In these studies, the female rodents were not treated with methadone, indicating paternally-mediated developmental toxicity. Specifically, methadone administered to the male rat prior to mating with methadone-naïve females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals, suggesting that paternal methadone exposure can produce physiological and behavioral changes in progeny in this model.  Examination of uterine contents of methadone-naïve female mice bred to methadone-treated male mice (once a day for three consecutive days) indicated that methadone treatment produced an increase in the rate of preimplantation deaths in all post-meiotic states at 1 mg/kg/day or greater (0.04 times the HDD). Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater.

Studies demonstrated that methadone treatment of male rats for 21 to 32 days prior to mating with methadone-naïve females did not produce any adverse effects, suggesting that prolonged methadone treatment of the male rat resulted in tolerance to the developmental toxicities noted in the progeny. Mechanistic studies in this rat model suggest that the developmental effects of “paternal” methadone on the progeny appear to be due to decreased testosterone production. These animal data mirror the reported clinical findings of decreased testosterone levels in human males on methadone maintenance therapy for opioid addiction and in males receiving chronic intraspinal opioids.

Lactation

Risk Summary

Based on two studies in 22 breastfeeding women maintained on methadone treatment, methadone was present in low levels in human milk, and did not show adverse reactions in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methadone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise breastfeeding women taking methadone to monitor the infant for increased drowsiness and breathing difficulties.

Data

In a study of ten breastfeeding women maintained on oral methadone doses of 10 to 80 mg/day, methadone concentrations from 50 to 570 mcg/L in milk were reported, which, in the majority of samples, were lower than maternal serum drug concentrations at steady state.

In a study of twelve breastfeeding women maintained on oral methadone doses of 20 to 80 mg/day, methadone concentrations from 39 to 232 mcg/L in milk were reported. Based on an average milk consumption of 150 mL/kg/day, an infant would consume approximately 17.4 mcg/kg/day which is approximately 2 to 3% of the oral maternal dose. Methadone has been detected in very low plasma concentrations in some infants whose mothers were taking methadone.

There have been rare cases of sedation and respiratory depression in infants exposed to methadone through breast milk.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2), Nonclinical Pharmacology (13.1)].  Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported.

In published animal studies, methadone produces a significant regression of sex accessory organs and testes of male mice and rats and administration of methadone to pregnant rats reduced fetal blood testosterone and androstenedione in male offspring [see Nonclinical Toxicology (13)].

Pediatric Use

The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established.

Geriatric Use

Clinical studies of methadone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, start elderly at the low end of the dosing range, taking into account the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients. Closely monitor elderly patients for signs of respiratory and central nervous system depression.

Methadone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Impairment

Methadone pharmacokinetics have not been extensively evaluated in patients with hepatic insufficiency. Methadone is metabolized by hepatic pathways; therefore, patients with liver impairment may be at risk of increased systemic exposure to methadone after multiple dosing. Start these patients on lower doses and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression.

Renal Impairment

Methadone pharmacokinetics have not been extensively evaluated in patients with renal insufficiency. Since unmetabolized methadone and its metabolites are excreted in urine to a variable degree, start these patients on lower doses and with longer dosing intervals and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression.

Controlled Substance

Methadone hydrochloride tablets for oral suspension contain methadone, a Schedule II controlled substance.

Abuse

Methadone hydrochloride tablets for oral suspension contain methadone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. Methadone hydrochloride tablets for oral suspension can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.4)].

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Methadone hydrochloride tablets for oral suspension, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity and frequency as required by state and federal law, is strongly advised.

Proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Methadone Hydrochloride Tablets for Oral Suspension

Abuse of methadone poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone with alcohol and other substances. Methadone hydrochloride tablets for oral suspension are intended for oral use only and must not be injected. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Methadone hydrochloride tablets for oral suspension, when used for the treatment of opioid addiction in detoxification or maintenance programs, may be dispensed only by opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (and agencies, practitioners, and institutions by formal agreements with the program sponsor).

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or significant dose reduction of a drug. Withdrawal is also precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene) or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Physical dependence is expected during opioid agonist therapy of opioid addiction.

Methadone hydrochloride tablets for oral suspension should not be abruptly discontinued [see Dosage and Administration (2.4), (2.5)]. If methadone hydrochloride tablets for oral suspension are abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.5)].