Dolophine Hydrochloride

Dolophine Hydrochloride

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Questions & Answers

Side Effects & Adverse Reactions

Respiratory Depression, Incomplete Cross-tolerance, and Iatrogenic Overdose

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 during the initial dosing period. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation or dose titration.

Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other mu-opioid agonists who are being converted to treatment with methadone, thus making determination of dosing during opioid treatment 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 DOSAGE AND ADMINISTRATION, Table 1, for appropriate conversion schedules). A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise.

Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.

Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be used at the lowest effective dose and only under careful medical supervision.

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. In most of the cases seen at typical maintenance doses, concomitant medications and/or clinical conditions such as hypokalemia were noted as contributing factors. However, the evidence strongly suggests that methadone possesses the potential for adverse cardiac conduction effects in some patients.

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 a prolonged QT interval has not been systematically 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.

Misuse, Abuse, and Diversion of Opioids

Methadone is a mu-agonist opioid with an abuse liability similar to that of morphine and is a Schedule II controlled substance. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion.

Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing DOLOPHINE in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Interactions with other CNS Depressants

Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics or other CNS depressants (including alcohol) concomitantly with methadone may experience respiratory depression, hypotension, profound sedation, or coma (see PRECAUTIONS).

Interactions with Alcohol and Drugs of Abuse

Methadone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Deaths associated with illicit use of methadone frequently have involved concomitant benzodiazepine abuse.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential.

Acute Abdominal Conditions

The administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Hypotensive Effect

The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion).

Legal Issues

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FDA Safety Alerts

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Manufacturer Warnings

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FDA Labeling Changes

There are currently no FDA labeling changes available for this drug.

Uses

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History

There is currently no drug history available for this drug.

Other Information

DOLOPHINE® HYDROCHLORIDE (Methadone Hydrochloride Tablets, USP), for oral administration, each contain 5 mg or 10 mg of methadone hydrochloride.

Methadone hydrochloride is a white, crystalline material that is water-soluble.

Methadone hydrochloride is chemically described as 6-(dimethylamino)-4,4-diphenyl-3-hepatanone hydrochloride. Its molecular formula is C21H27NO · HCl and it has a molecular weight of 345.91. Methadone hydrochloride has a melting point of 235°C, and a pKa of 8.25 in water at 20°C. Its octanol/water partition coefficient at pH 7.4 is 117. A solution (1:100) in water has a pH between 4.5 and 6.5.

It has the following structural formula:

Structural Formula

Other ingredients of DOLOPHINE include: magnesium stearate, microcrystalline cellulose, and starch.

Dolophine Hydrochloride Manufacturers


  • Pd-rx Pharmaceuticals, Inc.
    Dolophine Hydrochloride (Methadone Hydrochloride) Tablet [Pd-rx Pharmaceuticals, Inc.]

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