Dolophine

Do not share this medication with others. It is against the law.This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in those cases.

Pregnancy

There are no adequate and well-controlled studies in pregnant women; untreated opioid addiction 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; neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy

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 receiving maintenance treatment of opioid addiction; for women treated with pain severe enough to require daily, around-the-clock, long-term opioid treatment, therapy should be administered during pregnancy only if potential benefit justifies potential risk to fetus

Infertility

• Chronic use of opioids may cause reduced fertility in females and males of reproductive potential; it is not known whether effects on fertility are reversible; 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

Lactation

Methadone present in low levels in human milk; did not show adverse reactions in breastfed infants; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for methadone and any potential adverse effects on the breastfed child from drug or from underlying maternal condition; advise breastfeeding women taking methadone to monitor the infant for increased drowsiness and breathing difficulties

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

• Methadone can cause life-threatening breathing and heart problems which can lead to death.
• Call your doctor or get medical help right away if you:
  • have trouble breathing
  • have extreme drowsiness and breathing slows down
  • have slow shallow breathing (little chest movement with breathing)
  • have fast or slowed heartbeat
  • feel faint, very dizzy, confused, have palpitations (irregular heartbeat) or any other unusual symptoms

These can be symptoms that you have taken too much (overdose of) methadone, or the dose is too high for you. They can also be symptoms of a serious heart reaction. These symptoms can lead to serious problems or death if not treated right away.

• Methadone can cause your blood pressure to drop. This can make you feel dizzy if you get up too fast from sitting or lying down.
• Methadone can cause physical dependence. Do not stop taking methadone or any other opioid without first talking to your doctor. You could become sick with uncomfortable withdrawal symptoms because your body has become used to these medicines. Talk to your doctor about slowly stopping methadone to avoid getting sick with withdrawal symptoms. Physical dependency is not the same as drug addiction.
• For patients using methadone for pain treatment, there is a chance of abuse or addiction with methadone. The chance is higher if you are or have been addicted to or abused other medicines, street drugs, or alcohol, or if you have a history of mental problems.

Some common side effects of methadone are lightheadedness, dizziness, drowsiness, nausea, vomiting and sweating. Other side effects include weakness, headache, constipation, itching, and dry mouth.

Talk to your doctor about any side effects that bother you or that do not go away.

These are not all the possible side effects of methadone. For a complete list, ask your doctor or pharmacist.

• Methadone can cause life-threatening breathing problems which can lead to death. These problems are more likely to happen when methadone is first started or in someone who is not already taking other narcotic (opioid) pain medicines.
• Breathing problems from methadone may not happen right away after taking a dose. Sometimes breathing problems will happen a while after you take a dose, even after pain has returned. It is very important that you take methadone exactly as your doctor has prescribed. Talk to your doctor about your pain. Your doctor can decide if your methadone dose needs to be changed.
• Methadone can cause life-threatening heartbeat problems that can lead to death. Most heartbeat problems have happened in people using large doses of methadone for pain treatment. Some heartbeat problems have happened in people using smaller doses of methadone for treatment of narcotic drug addiction.
• Keep methadone out of the reach of children. Accidental overdose by a child is a medical emergency and can result in death. If a child accidentally takes methadone, get emergency help right away.
• Do not drive, operate heavy machinery, or do other possible dangerous activities until you know how methadone affects you. methadone can make you sleepy. Ask your doctor when it is okay to do these activities.
• Do not drink alcohol while using methadone. It may increase the chance of having dangerous side effects.
• Do not take other medicines with methadone without first talking with your doctor.

Do not take methadone if you:

• have severe asthma or severe lung problems.
• have a blockage or obstruction in your intestines.
• are allergic to methadone or any ingredient in it.

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.

Take methadone exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. Your doctor will determine the best dose for you.

Your doctor may change your dose of methadone during your treatment. Do not stop taking methadone without talking to your doctor. Your dose may be decreased gradually to avoid withdrawal symptoms (restlessness, sweating, chills, muscle pain, tearing eyes, runny nose, widened pupils).

5 mg Tablets: round and white, debossed with tablet identifier “54 162” on one side and scored on the other side.

10 mg Tablets: round and white, debossed with tablet identifier “54 549” on one side and scored on the other side.

Clinical Presentation

Acute overdose with methadone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal-muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, naloxone and nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to methadone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to methadone overdose.

Because the duration of reversal would be expected to be less than the duration of action of methadone in Dolophine Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to opioid antagonists is suboptimal or not sustained, administer additional antagonist as directed in the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Mechanism of Action

Methadone hydrochloride is a mu-agonist; a synthetic opioid with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. The methadone withdrawal syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe.

Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone’s efficacy is unknown.

Pharmacodynamics

Effects on the Central Nervous System

Methadone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Methadone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Some NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Methadone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Methadone produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of methadone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing methadone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

Pharmacokinetics

Absorption

Following oral administration the bioavailability of methadone ranges between 36 to 100% and peak plasma concentrations are achieved between 1 to 7.5 hours. Dose proportionality of methadone pharmacokinetics is not known. However, after administration of daily oral doses ranging from 10 to 225 mg, the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1,255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated.

Distribution

Methadone is a lipophilic drug and the steady-state volume of distribution ranges between 1.0 to 8.0 L/kg. In plasma, methadone is predominantly bound to α1-acid glycoprotein (85% to 90%). Methadone is secreted in saliva, breast milk, amniotic fluid and umbilical cord plasma.

Elimination

Metabolism: Methadone is primarily metabolized by N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene  (EDDP). Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, CYP2C19, CYP2C9 and CYP2D6, are responsible for conversion of methadone to EDDP and other inactive metabolites, which are excreted mainly in the urine. Methadone appears to be a substrate for P-glycoprotein but its pharmacokinetics do not appear to be significantly altered in case of P-glycoprotein polymorphism or inhibition.

Excretion: The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Published reports indicate that after multiple dose administration the apparent plasma clearance of methadone ranged between 1.4 and 126 L/h, and the terminal half-life (T1/2) was highly variable and ranged between 8 to 59 hours in different studies. Methadone is a basic (pKa=9.2) compound and the pH of the urinary tract can alter its disposition in plasma. Also, since methadone is lipophilic, it has been known to persist in the liver and other tissues. The slow release from the liver and other tissues may prolong the duration of methadone action despite low plasma concentrations.

Drug Interaction Studies

Cytochrome P450 Interactions: Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, CYP2C9 and CYP2D6. Co-administration of methadone with CYP inducers may result in more rapid metabolism and potential for decreased effects of methadone, whereas administration with CYP inhibitors may reduce metabolism and potentiate methadone’s effects. Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity [see Drug Interactions (7)].

Cytochrome P450 Inducers: The following drug interactions were reported following co-administration of methadone with known inducers of cytochrome P450 enzymes:

  Rifampin: In patients well-stabilized on methadone, concomitant administration of rifampin resulted in a marked reduction in serum methadone levels and a concurrent appearance of withdrawal symptoms.   Phenytoin:In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg twice daily initially for 1 day followed by 300 mg daily for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. Upon discontinuation of phenytoin, the incidence of withdrawal symptoms decreased and methadone exposure increased to a level comparable to that prior to phenytoin administration.   St. John’s Wort, Phenobarbital, Carbamazepine:Administration of methadone with other CYP3A4 inducers may result in withdrawal symptoms.

Cytochrome P450 Inhibitors:

  Voriconazole: Voriconazole can inhibit the activity of CYP3A4, CYP2C9, and CYP2C19. Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the peak plasma concentration (Cmax) and AUC of (R)-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg daily. The Cmax and AUC of (S)-methadone increased by 65% and 103%, respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during co-administration. Dose reduction of methadone may be needed [see Drug Interactions (7)].

Antiretroviral Drugs: Although antiretroviral drugs such as efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir combination are known to inhibit some CYPs, they are shown to reduce the plasma levels of methadone, possibly due to CYP induction activity.

  Abacavir, Amprenavir, Darunavir+Ritonavir, Efavirenz, Nelfinavir, Nevirapine, Ritonavir, Telaprevir, Lopinavir+Ritonavir, Saquinavir+Ritonavir, Tipranvir+Ritonavir Combination:   Co-administration of these anti-retroviral agents resulted in increased clearance or decreased plasma levels of methadone [see Drug Interactions (7)].     Didanosine and Stavudine: Methadone decreased the AUC and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered [see Drug Interactions (7)].   Zidovudine:Methadone increased the AUC of zidovudine which could result in toxic effects [see Drug Interactions (7)].

Applies to methadone: oral liquid, oral solution, oral tablet, oral tablet for suspension

Along with its needed effects, methadone (the active ingredient contained in Dolophine) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking methadone:

Incidence not known

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• blurred vision
• bulging soft spot on the head of an infant
• change in the ability to see colors, especially blue or yellow
• changes in skin color
• chest discomfort or pain
• confusion
• convulsions
• cough
• coughing that sometimes produces a pink frothy sputum
• decreased urine output
• difficult or troubled breathing
• difficult, fast, noisy breathing, sometimes with wheezing
• difficulty with swallowing
• dilated neck veins
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• extreme fatigue
• fainting
• fast, slow, or irregular heartbeat
• headache
• hives, itching, or skin rash
• increased sweating
• increased thirst
• irregular heartbeat
• irregular, fast or slow, or shallow breathing
• loss of appetite
• muscle pain or cramps
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• pain
• pale or blue lips, fingernails, or skin
• pinpoint red spots on the skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• seizures
• sweating
• swelling of the face, fingers, feet, or lower legs
• tenderness
• trouble sleeping
• trouble urinating
• unusual bleeding or bruising
• unusual tiredness or weakness
• weight gain

Some side effects of methadone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Absent, missed, or irregular menstrual periods
• anxiety
• blurred or loss of vision
• confusion about identity, place, and time
• constipation
• decreased interest in sexual intercourse
• disturbed color perception
• double vision
• false or unusual sense of well-being
• halos around lights
• inability to have or keep an erection
• irritability
• lack or loss of strength
• loss in sexual ability, desire, drive, or performance
• night blindness
• overbright appearance of lights
• redness, swelling, or soreness of the tongue
• restlessness
• stopping of menstrual bleeding
• tunnel vision
• weight changes
• welts