METHADONE HYDROCHLORIDE concentrate

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

METHADONE HYDROCHLORIDE (UNII: 229809935B) (METHADONE - UNII:UC6VBE7V1Z)

Available from:

Hikma Pharmaceuticals USA Inc.

INN (International Name):

METHADONE HYDROCHLORIDE

Composition:

METHADONE HYDROCHLORIDE 10 mg in 1 mL

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Methadone Hydrochloride Oral Concentrate (Intensol ™) contains methadone, an opioid agonist indicated for the: Limitations of Use Limitations of Use Methadone products used for the treatment of opioid addiction in detoxification or maintenance programs are subject to the conditions for distribution and use required under 21 CFR, Title 42, Sec 8 [see Dosage and Administration (2.1)] . Methadone Hydrochloride Intensol ™ is contraindicated in patients with: Risk Summary The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Pregnant women involved in methadone maintenance programs have been reported to have improved prenatal care leading to 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 in these studies appears to occur after the first trimester of pregnancy (see Data ). Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.6)] . 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: Dosage adjustment using higher doses or administering the daily dose in divided doses may be necessary in pregnant women treated with Methadone Hydrochloride Intensol ™. Pregnant women appear to have significantly lower trough plasma methadone concentrations, increased plasma methadone clearance, and shorter methadone half-life than after delivery [see Dosage and Administration (2.9), Clinical Pharmacology (12.3)] . Withdrawal signs and symptoms should be closely monitored and the dose adjusted as necessary. Fetal/Neonatal Adverse Reactions: Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with Methadone Hydrochloride Intensol™ . 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 (5.6)] . Labor or Delivery: Opioid-dependent women on methadone maintenance therapy may require additional analgesia during labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data: The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome have been inconsistent. Children prenatally exposed to methadone have been reported to demonstrate mild but persistent deficits in performance on psychometric and behavioral tests and visual abnormalities. In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy. Among women who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the methadone and buprenorphine groups, the study findings are difficult to interpret. 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 JBT/Jd 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 demonstrate 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. Risk Summary Based on two small clinical studies, methadone was present in low levels in human milk, but the exposed infants in these studies did not show adverse reactions. 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. There have been rare case reports of sedation and respiratory depression in infants exposed to methadone through breast milk (see Data ). Monitor infants exposed to methadone through breast milk for excess sedation and respiratory depression. 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. 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. Peak methadone levels in milk occur approximately 4 to 5 hours after an oral dose. 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. Infertility The effect of Methadone Hydrochloride Intensol ™ on fertility is unknown. 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 Toxicology (13)] . 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)] . The safety, effectiveness, and pharmacokinetics of methadone in pediatric patients below the age of 18 years have not been established. 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 patients 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. 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. 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. 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. Methadone hydrochloride oral concentrate contains methadone, a Schedule II opioid agonist. Methadone Hydrochloride Intensol™ contains methadone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol. Methadone Hydrochloride Intensol™ can be abused and are subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.5)] . All patients treated with opioids for pain management require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. 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 people who abuse opioids 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 people with substance use disorders. In addition, abuse of opioids can occur in the absence of true addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Methadone Hydrochloride Intensol™ , 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 Intensol™ 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 Intensol™ is 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 Intensol ™, 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). 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) 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 Intensol ™ should not be abruptly discontinued [see Dosage and Administration (2.6, 2.7)] . If Methadone Hydrochloride Intensol ™ is 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 [see Dosage and Administration (2.6)] . Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.6)] .

Product summary:

Methadone Hydrochloride Oral Concentrate, USP (Intensol TM ), 10 mg per mL 10 mg per mL oral concentrate is supplied as a clear, colorless solution. NDC 0054-3553-44: Bottle of 30 mL with calibrated syringe [graduations of 0.25 mL (2.5 mg), 0.5 mL (5 mg), 0.75 mL (7.5 mg), and 1 mL (10 mg) on the syringe]. Store at 20° to 25°C (68° to 77°F), with excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Store Methadone Hydrochloride Intensol ™ securely and dispose of properly [see Patient Counseling Information (17)] .

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

Hikma Pharmaceuticals USA Inc.
----------
MEDICATION GUIDE
Methadone Hydrochloride Oral Concentrate, USP, CII
(Intensol™)
(METH-a-done)
Rx Only
Methadone Hydrochloride Intensol™ is:
•
A strong prescription pain medicine that contains an opioid (narcotic)
that is used to manage pain
severe enough to require daily around-the-clock, long-term treatment
with an opioid, when other
pain treatments such as non-opioid pain medicines or immediate-release
opioid medicines do not
treat your pain well enough or you cannot tolerate them.
•
A long-acting opioid pain medicine that can put you at risk for
overdose and death. Even if you
take your dose correctly as prescribed you are at risk for opioid
addiction, abuse, and misuse that
can lead to death.
•
Not for use to treat pain that is not around-the-clock.
•
Also used to manage drug addiction.
Important information about Methadone Hydrochloride Intensol™:
•
Get emergency help or call 911 right away if you take too much
Methadone Hydrochloride
Intensol™(overdose). When you first start taking Methadone
Hydrochloride Intensol™, when your
dose is changed, or if you take too much (overdose), serious or
life-threatening breathing problems
that can lead to death may occur. Talk to your healthcare provider
about naloxone, a medicine for
emergency treatment of opioid overdose.
•
Taking Methadone Hydrochloride Intensol™ with other opioid
medicines, benzodiazepines,
alcohol, or other central nervous system depressants (including street
drugs) can cause severe
drowsiness, decreased awareness, breathing problems, coma, and death.
•
Never give anyone else your Methadone Hydrochloride Intensol™. They
could die from taking it.
Selling or giving away Methadone Hydrochloride Intensol™ is against
the law.
•
Store Methadone Hydrochloride Intensol™ securely, out of sight and
reach of children, and in a
location not accessible by others, including visitors to the home.
Do not take Methadone Hydrochloride Intensol™ if you have:
•
Severe asthma, trouble breathi

Summary of Product characteristics

METHADONE HYDROCHLORIDE- METHADONE HYDROCHLORIDE CONCENTRATE
HIKMA PHARMACEUTICALS USA INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
METHADONE
HYDROCHLORIDE ORAL CONCENTRATE SAFELY AND EFFECTIVELY. SEE FULL
PRESCRIBING
INFORMATION FOR METHADONE HYDROCHLORIDE ORAL CONCENTRATE.
METHADONE HYDROCHLORIDE ORAL CONCENTRATE, CII
INITIAL U.S. APPROVAL: 1947
WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION, LIFE-THREATENING QT
PROLONGATION, ACCIDENTAL INGESTION, ABUSE POTENTIAL, INTERACTIONS WITH
DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES, TREATMENT FOR OPIOID
ADDICTION, AND RISK EVALUATION AND MITIGATION STRATEGY (REMS)
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING_
•
•
•
•
•
•
•
•
RECENT MAJOR CHANGES
Dosage and Administration (2.3) 06/2021
Warnings and Precautions (5.1, 5.2) 06/2021
INDICATIONS AND USAGE
Methadone Hydrochloride Oral Concentrate (_Intensol_™) is an opioid
agonist indicated for the:
•
Limitations of Use
•
FATAL RESPIRATORY DEPRESSION MAY OCCUR, WITH HIGHEST RISK AT
INITIATION AND WITH
DOSE INCREASES. INSTRUCT PATIENTS ON PROPER ADMINISTRATION OF
METHADONE TO REDUCE
THE RISK. (5.1)
CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CENTRAL NERVOUS SYSTEM
(CNS)
DEPRESSANTS, INCLUDING ALCOHOL, MAY RESULT IN PROFOUND SEDATION,
RESPIRATORY
DEPRESSION, AND DEATH. (5.2, 7)
QT INTERVAL PROLONGATION AND SERIOUS ARRHYTHMIA (_TORSADES DE
POINTES_) HAVE
OCCURRED WITH TREATMENT WITH METHADONE. (5.3)
ACCIDENTAL INGESTION OF METHADONE CAN RESULT IN FATAL OVERDOSE OF
METHADONE,
ESPECIALLY IN CHILDREN. (5.4)
METHADONE CONTAINS METHADONE, A SCHEDULE II CONTROLLED SUBSTANCE AND
CAN BE
ABUSED AND CRIMINALLY DIVERTED. (5.5)
CONCOMITANT USE WITH CYP3A4, 2B6, 2C19, 2C9 OR 2D6 INHIBITORS OR
DISCONTINUATION
OF CONCOMITANTLY USED CYP3A4, 2B6, 2C19, OR 2C9 INDUCERS CAN RESULT IN
A FATAL
OVERDOSE OF METHADONE. (5.7, 7)
METHADONE PRODUCTS, WHEN USED FOR THE TREATMENT OF OPIOID ADDICTION IN
DETOXIFICATION OR MAINTENANCE PROGRAMS,