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DOLOPHINE is indicated for the:
- Management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.
- Detoxification treatment of opioid addiction (heroin or other morphine-like drugs).
- Maintenance treatment of opioid addiction (heroin or other morphine-like drugs), in conjunction with appropriate social and medical services.
Limitations of Use
DOLOPHINE is not for use:
- As an as-needed (prn) analgesic
- For pain that is mild or not expected to persist for an extended period of time
- For acute pain
- For postoperative pain
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: During inpatient care, when the patient was admitted for any condition other than concurrent opioid addiction (pursuant to 21CFR 1306.07(c)), to facilitate the treatment of the primary admitting diagnosis).
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 21CFR 1306.07(b)).
DOSAGE AND ADMINISTRATION
Initial Dosing for Management of Pain
Consider the following factors when selecting an initial dose of DOLOPHINE:
- Total daily dose, potency, and prior opioid the patient has been taking previously;
- Patient's degree of opioid experience and opioid tolerance;
- General condition and medical status of the patient;
- Concurrent medication;
- Type and severity of the patient's pain
In addition, consider the following important factors that differentiate methadone from other opioid analgesics:
- The peak respiratory depressant effect of methadone occurs later and persists longer than its peak analgesic effect.
- A high degree of opioid tolerance does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists and during initiation of methadone treatment of addiction in subjects previously abusing high doses of other opioid agonists.
- There is high interpatient variability in absorption, metabolism, and relative analgesic potency. Population-based equianalgesic conversion ratios between methadone and other opioids are not accurate when applied to individuals.
- The duration of analgesic action of methadone is 4 to 8 hours (based on single-dose studies) but the plasma elimination half-life is 8 to 59 hours.
- With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.
- Steady-state plasma concentrations, and full analgesic effects, are not attained until 3 to 5 days after initiation of dosing.
- Methadone has a narrow therapeutic index, especially when combined with other drugs.
DOLOPHINE is administered at a frequency of every 8 to 12 hours.
Use of DOLOPHINE as the First Opioid Analgesic
Initiate DOLOPHINE therapy with small doses, no more than 2.5 mg to 10 mg every 8 to 12 hours. To maintain adequate analgesia, more frequent administration may be required. Monitor patients closely for signs of respiratory and central nervous system depression.
Conversion from Parenteral Methadone
Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).
Conversion from Other Opioids
Published conversion ratios for other opioids to methadone may overestimate the dose of methadone. Deaths have occurred in opioid-tolerant patients during conversion to methadone.
Conversion ratios in many commonly used equianalgesic dosing tables are based on single-dose comparisons in patients not tolerant to the effects of opioid and do not apply in the setting of conversion of opioid tolerant patients to methadone for chronic use. In the case of a single-dose administration, the onset, duration, and potency of analgesic action of methadone are comparable to those of morphine. Incomplete cross tolerance can result in greater than expected toxicity. In addition, with repeated dosing, the potency of methadone increases due to systemic accumulation.
The conversion ratio between methadone and other opioids varies dramatically depending on baseline opioid (morphine equivalent) use as shown in the table below.
The dose conversion scheme below (Table 1) is derived from various consensus guidelines for converting chronic pain patients to methadone from morphine. Consult published conversion guidelines to determine the equivalent morphine dose for patients converting from other opioids.
Table 1: Oral Morphine to Oral Methadone Conversion for
|Total Daily Baseline Oral Morphine Dose||Estimated Daily Oral Methadone Requirementas Percent of Total Daily Morphine Dose|
|< 100 mg||20% to 30%|
|100 to 300 mg||10% to 20%|
|300 to 600 mg||8% to 12%|
|600 mg to 1000 mg||5% to 10%|
|> 1000 mg||< 5 %|
Divide the total daily methadone dose derived from the table above to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
Equianalgesic methadone dosing varies not only between patients, but also within the same patient, depending on baseline morphine (or other opioid) dose. Table 1 has been included in order to illustrate this concept and to provide a recommendation for a starting point for opioid conversion.
In addition to these recommendations, take into consideration the patient's:
- prior opioid exposure
- general medical condition
- concomitant medication
- anticipated breakthrough medication use
Titration and Maintenance of Therapy for Pain
Individually titrate DOLOPHINE to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving DOLOPHINE to assess the maintenance of pain control and the relative incidence of adverse reactions. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.
If the level of pain increases, attempt to identify the source of increased pain, while adjusting the DOLOPHINE dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 24 to 36 hours, DOLOPHINE dosage adjustments may be done every 1 to 2 days. Patients who experience breakthrough pain may require dosage adjustment or rescue medication with a small dose of an immediate-release medication.
If signs of excessive opioid-related adverse reactions are observed, the next dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions. The endpoint of titration is achievement of adequate pain relief, balanced against tolerability of opioid adverse reactions.
If a patient develops intolerable opioid related adverse reactions, the methadone dose, or dosing interval, may need to be adjusted.
Discontinuation of DOLOPHINE for Pain
When a patient no longer requires therapy with DOLOPHINE for pain, use a gradual downward titration, of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue DOLOPHINE.
Induction/Initial Dosing for Detoxification and Maintenance Treatment of Opioid Addiction
For detoxification and maintenance of opioid dependence methadone should be administered in accordance with the treatment standards cited in 42 CFR Section 8.12, including limitations on unsupervised administration.
Administer the initial methadone dose under supervision, when there are no signs of sedation or intoxication, and the patient shows symptoms of withdrawal. An initial single dose of 20 to 30 mg of DOLOPHINE will often be sufficient to suppress withdrawal symptoms. The initial dose should not exceed 30 mg.
To make same-day dosing adjustments, have the patient wait 2 to 4 hours for further evaluation, when peak levels have been reached. Provide an additional 5 to 10 mg of DOLOPHINE if withdrawal symptoms have not been suppressed or if symptoms reappear.
The total daily dose of DOLOPHINE on the first day of treatment should not ordinarily exceed 40 mg. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at the time of expected peak activity (e.g., 2 to 4 hours after dosing). When adjusting the dose, keep in mind that methadone levels will accumulate over the first several days of dosing; deaths have occurred in early treatment due to the cumulative effects. Instruct patients that the dose will “hold” for a longer period of time as tissue stores of methadone accumulate.
Use lower initial doses for patients whose tolerance is expected to be low at treatment entry. Any patient who has not taken opioids for more than 5 days may no longer be tolerant. Do not determine initial doses based on previous treatment episodes or dollars spent per day on illicit drug use.
For a brief course of stabilization followed by a period of medically supervised withdrawal, titrate the patient to a total daily dose of about 40 mg in divided doses to achieve an adequate stabilizing level. After 2 to 3 days of stabilization, gradually decrease the dose of DOLOPHINE. Decrease the dose of DOLOPHINE on a daily basis or at 2-day intervals, keeping the amount of DOLOPHINE sufficient to keep withdrawal symptoms at a tolerable level. Hospitalized patients may tolerate a daily reduction of 20% of the total daily dose. Ambulatory patients may need a slower schedule.
Titration and Maintenance Treatment of Opioid Dependence Detoxification
Titrate patients in maintenance treatment to a dose that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring that the patient is tolerant to the sedative effects of methadone. Most commonly, clinical stability is achieved at doses between 80 to 120 mg/day.
Medically Supervised Withdrawal After a Period of Maintenance Treatment for Opioid Addiction
There is considerable variability in the appropriate rate of methadone taper in patients choosing medically supervised withdrawal from methadone treatment. Dose reductions should generally be less than 10% of the established tolerance or maintenance dose, and 10 to 14-day intervals should elapse between dose reductions. Apprise patients of the high risk of relapse to illicit drug use associated with discontinuation of methadone maintenance treatment.
Risk of Relapse in Patients on Methadone Maintenance Treatment of Opioid Addiction
Abrupt opioid discontinuation can lead to development of opioid withdrawal symptoms [see Drug Abuse and Dependence]. Opioid withdrawal symptoms have been associated with an increased risk of relapse to illicit drug use in susceptible patients.
Considerations for Management of Acute Pain During Methadone Maintenance Treatment
Patients in methadone maintenance treatment for opioid dependence who experience physical trauma, postoperative pain or other acute pain cannot be expected to derive analgesia from their existing dose of methadone. Such patients should be administered analgesics, including opioids, in doses that would otherwise be indicated for non-methadone-treated patients with similar painful conditions. When opioids are required for management of acute pain in methadone maintenance patients, somewhat higher and/or more frequent doses will often be required than would be the case for non-tolerant patients due to the opioid tolerance induced by methadone.
Dosage Adjustment During Pregnancy
Methadone clearance may be increased during pregnancy. During pregnancy, a woman's methadone dose may need to be increased or the dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations].
Dosage Forms And Strengths
DOLOPHINE Tablets are available in 5mg and 10 mg dosage strengths. The 5 mg tablets are round, white and are debossed with tablet identifier “54 162” on one side and scored on the other side. The 10 mg tablets are round, white and are debossed with tablet identifier “54 549” on one side and scored on the other side.
Storage And Handling
DOLOPHINE contains methadone which is a controlled substance. Like fentanyl, morphine, oxycodone, hydromorphone, and oxymorphone, methadone is controlled under Schedule II of the Federal Controlled Substances Act. DOLOPHINE may be targeted for theft and diversion by criminals [see WARNINGS AND PRECAUTIONS].
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
DOLOPHINE Tablets, USP
5 mg Tablets: round, white tablets debossed with tablet identifier 54 162 on one side and scored on the other side. NDC 0054-4218-25: Bottles of 100 tablets.
10 mg Tablets: round, white tablet debossed with tablet identifier 54 549 on one side and scored on the other side. NDC 0054-4219-25: Bottles of 100 tablets.
DEA order form required.
Roxane Laboratories, Inc., Columbus, Ohio 43216. Revised: 07/2012
Last reviewed on RxList: 7/19/2012
This monograph has been modified to include the generic and brand name in many instances.
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