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DOLOPHINE is 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.
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 long-acting opioids, reserve DOLOPHINE for use in patients for whom alternative analgesic treatment options (e.g., non-opioid analgesics or immediate-release opioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
DOLOPHINE is not indicated as an as-needed (prn) analgesic.
- 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.
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
Important General Information
- The peak respiratory depressant effect of methadone occurs later and persists longer than its peak therapeutic 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 agonists.
- With repeated dosing, methadone is retained in the liver and then slowly released, prolonging the duration of potential toxicity.
- Methadone has a narrow therapeutic index, especially when combined with other drugs.
Initial Dosing For Management Of Pain
DOLOPHINE should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
Consider the following important factors that differentiate methadone from other opioid analgesics:
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.
- Steady-state plasma concentrations, and full analgesic effects, are not attained until 3 to 5 days after initiation of dosing.
Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see WARNINGS AND PRECAUTIONS]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with DOLOPHINE [see WARNINGS AND PRECAUTIONS].
Use of DOLOPHINE as the First Opioid Analgesic
Initiate treatment with DOLOPHINE with 2.5 mg orally every 8 to 12 hours.
Conversion from Other Oral Opioids to DOLOPHINE
Discontinue all other around-the-clock opioid drugs when DOLOPHINE therapy is initiated. Deaths have occurred in opioid-tolerant patients during conversion to methadone.
While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient's 24-hour oral methadone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral methadone requirements which could result in adverse reactions. With repeated dosing, the potency of methadone increases due to systemic accumulation.
Consider the following when using the information in Table 1:
- This is not a table of equinalgesic doses.
- The conversion factors in this table are only for the conversion from another oral opioid analgesic to DOLOPHINE.
The table cannot be used to convert from DOLOPHINE to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.
Table 1: Conversion Factors to DOLOPHINE
|Total Daily Baseline Oral Morphine Equivalent Dose||Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Equivalent 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 %|
To calculate the estimated DOLOPHINE dose using Table 1:
For patients on a single opioid, sum the current total daily dose of the opioid, convert it to a Morphine Equivalent Dose according to specific conversion factor for that specific opioid, then multiply the Morphine Equivalent Dose by the corresponding percentage in the above table to calculate the approximate oral methadone daily dose. 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).
For patients on a regimen of more than one opioid, calculate the approximate oral methadone dose for each opioid and sum the totals to obtain the approximate total methadone daily dose. 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).
For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Always round the dose down, if necessary, to the appropriate DOLOPHINE strength(s) available.
Example conversion from a single opioid to DOLOPHINE:
Step 1: Sum the total daily dose of the opioid (in this case, Morphine Extended Release Tablets 50 mg twice daily)
50 mg Morphine Extended Release Tablets 2 times daily = 100 mg total daily dose of Morphine
Step 2: Calculate the approximate equivalent dose of DOLOPHINE based on the total daily dose of Morphine using Table 1.
100 mg total daily dose of Morphine x 15% (10% to 20% per Table 1) = 15 mg DOLOPHINE daily
Step 3: Calculate the approximate starting dose of DOLOPHINE to be given every 12 hours. Round down, if necessary, to the appropriate DOLOPHINE tablets strengths available.
15 mg daily / 2 = 7.5 mg DOLOPHINE every 12 hours
Then 7.5 mg is rounded down to 5 mg DOLOPHINE every 12 hours
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to DOLOPHINE.
Conversion from Parenteral Methadone to DOLOPHINE: Use a conversion ratio of 1:2 mg for parenteral to oral methadone (e.g., 5 mg parenteral methadone to 10 mg oral methadone).
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, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.
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 a dose increase of DOLOPHINE, or may need rescue medication with an appropriate dose of an immediate-release medication. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the DOLOPHINE dose.
If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced and/or the dosing interval adjusted (i.e., every 8 hours or every 12 hours). Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
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 5 mg 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].
Dispense in a tight, light-resistant container as defined in the USP/NF.
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. www.Roxane.com, or call 1-800-962-8364. Revised April 2014
Prescribing Document Revised: April 2014This monograph has been modified to include the generic and brand name in many instances.
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