Methadone Adco 10mg Oral Solution

METHADONE ADCO 10 mg is indicated as substitution treatment in opiate dependence, in conjunction with medical, psychological and social therapy.

Posology
Treatment with METHADONE ADCO 10 mg assumes that the patient is taking part in a programme including drug-assisted rehabilitation for narcotics abuse, approved by a relevant authority. The dose must be tailored for each individual patient.

Adults
The standard initial dose is 20 mg once daily. The dose is increased in steps of 10 mg at a time over a period of three weeks, usually to 70 or 80 mg. After a recommended stabilisation period of four weeks, the dose is adjusted until the patient feels well, does not feel a need for intoxication and is without clinical signs of psychomotor function effects or abstinence symptoms. The normal dose is 60 to 120 mg of METHADONE ADCO 10 mg per 24 hours, but some individuals may require higher doses. Dosage must be determined on the basis of a clinical assessment supported by serum level monitoring. The recommended serum level is 600 to 1 200 nmol/L (200 to 400 ng/mL). Great importance is attached to the clinical assessment. METHADONE ADCO 10 mg is normally administered once daily. More frequent administration carries a risk of accumulation and overdose.

Certain patients develop auto-induction, which leads to the medicine being metabolised more rapidly in the body. In such cases, the dose must be adjusted upwards once or more to maintain the optimum effect. Dose adjustment may be necessary in cases of impaired hepatic function (see section 4.4). Patients with hypothyroidism or prostatic hypertrophy must receive a lower initial dose.

Elderly
Caution must be exercised when this medicine is administered to elderly or ill patients.

Paediatric population
METHADONE ADCO 10 mg must not be administered to children.

Treatment withdrawal
Treatment must be stopped if it is insufficiently effective or if the patient cannot tolerate it. The effect must be evaluated in accordance with national guidelines. If treatment must be stopped, this must be done by gradual dose reduction. The dose may be reduced relatively rapidly to start with, but reduction must be slow in the final phase (from 20 mg daily and downwards).

Method of administration
For oral administration only. The correct dosage should be extracted from the bottle by using a dispenser, measuring cylinder or syringe.

• Hypersensitivity to methadone or to any of the excipients of METHADONE ADCO 10 mg listed in section 6.1
• METHADONE ADCO 10 mg is contraindicated in children
• Respiratory depression, obstructive airways disease and during an acute asthma attack
• Acute alcoholism (see section 4.5)
• Head injury and raised intracranial pressure (further rise in intracranial pressure)
• Concurrent administration of MAOI medicines, including moclobemide, or for 2 weeks after stopping (see section 4.5)
• Use during labour (prolonged duration of action increases the risk of neonatal depression)
• Patients with ulcerative colitis, since METHADONE ADCO 10 mg may precipitate toxic dilation or spasm of the colon
• Patients dependent on non-opioid medicines
• Patients with severe hepatic impairment as it may precipitate encephalopathy; dose adjustment may be necessary in cases of impaired hepatic function (see section 4.4)
• Patients with biliary and renal tract spasm.

At the beginning of the dose increase period, the patient must be observed after administration to record any abnormal/untoward reactions. The patient will have increased serum levels for up to two hours, and it is important that any overdose reactions or other dangerous/severe reactions can be recorded. Great caution must be exercised in the following cases:

• Severe obstructive pulmonary disease, acute asthma attacks, cor pulmonale, lessened respiratory reserve, hypoxia and hypercapnia are relative contraindications; each case must be assessed individually
• A lower initial dose must be administered to patients with hypothyroidism, myxoedema (it can increase the risk of respiratory depression and prolonged CNS depression), renal (increased risk of convulsions) and hepatic impairment (opioids metabolised in liver), asthma or decreased lung volume (it may decrease respiratory drive and increase airway resistance) urethral stricture or prostatic hypertrophy (it may cause urinary retention) (see section 4.2)
• Patients with possible head injury or conditions involving increased intracranial pressure as METHADONE ADCO 10 mg is contraindicated in these group of patients and should be avoided
• METHADONE ADCO 10 mg should not be used in patients with intestinal pseudo-obstruction, acute abdomen and inflammatory bowel disease
• In patients with kidney calculi and in patients with gallstones it may be necessary to administer atropine or other spasmolytic prophylactically
• Elderly patients and patients suffering from cardiovascular diseases; they are at increased risk of hypotension and syncope
• In the case of elderly or ill patients, repeated doses should only be given with extreme caution. Dependence may occur in chronic use. The withdrawal period is longer for METHADONE ADCO 10 mg than for heroin because METHADONE ADCO 10 mg has a longer half-life.
• METHADONE ADCO 10 mg should be given with caution to patients with:
• History of asthma (see section 4.3)
• Convulsive disorders
• Depressed respiratory reserve
• Adrenocortical insufficiency
• Inflammatory or obstructive bowel disorders
• Myasthenia gravis.

The precautions to be taken in the use of METHADONE ADCO 10 mg are the same as those applying to opiates in general. Hepatic and renal impairment. Great caution must be exercised in patients with impaired hepatic and renal function. The metabolism of METHADONE ADCO 10 mg may be reduced in impaired hepatic function, and dose adjustment may be necessary. Caution as METHADONE ADCO 10 mg may precipitate porto-systemic encephalopathy in patients with severe liver damage.

METHADONE ADCO 10 mg may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.

QT prolongation. QT prolongation and torsade de pointes may occur with METHADONE ADCO 10 mg use, particularly at doses above 100 mg daily. It should be given with caution to patients at risk of developing prolongation of the QT interval including those with:

• Known history of QT prolongation or family history of sudden death
• Advanced heart disease
• Hepatic disease
• Hypokalaemia or other electrolyte imbalance
• Concomitant treatment with medicines that have a potential for QT-prolongation.

It should also be used with caution in patients who are taking other potentially dysrhythmogenic medicines, medicines likely to cause electrolyte imbalance, or medicines that inhibit the cytochrome P450 isoenzyme CYP3A4 (see section 4.5). ECG monitoring is recommended before starting treatment in patients with risk factors for QT prolongation, with a further test at dose stabilisation. ECG monitoring is also recommended before and at 7 days after dose titration above 100 mg daily in patients without recognised risk factors.

METHADONE ADCO 10 mg is metabolised in the liver via the cytochrome P450 isoenzymes. Consequently, use with other medicines that induce or inhibit these isoenzymes may result in changes in plasma concentration of METHADONE ADCO 10 mg and, possibly, adverse reactions.

Medicines inhibiting isoenzyme activity: Methadone is a substrate of CYP3A4 (see section 5.2). By inhibition of CYP3A4, clearance of methadone is lowered. Concomitant administration of CYP3A4 inhibitors (e.g. cannabinoids, clarithromycin, delavirdine, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, fluoxetine, fluvoxamine, nefazodone and telithromycin) may result in increased plasma concentrations of METHADONE ADCO 10 mg. A 40 - 100 % increase of the quote between the serum levels and the METHADONE ADCO 10 mg dose has been shown with concomitant fluvoxamine treatment. If these medicines are prescribed to patients on METHADONE ADCO 10 mg maintenance treatment, one should be aware of the risk of overdose.

Medicines inducing isoenzyme activity: Methadone is a substrate of CYP3A4 (see section 5.2). By induction of CYP3A4, clearance of methadone will increase and the plasma levels of METHADONE ADCO 10 mg decrease. Inducers of this enzyme (barbiturates, carbamazepine, phenytoin, nevirapine, rifampicin, efavirenz, amprenavir, spironolactone, dexamethasone, Hypericum perforatum (St Johnu00b4s wort), may induce hepatic metabolism. The consequences of enzyme induction are more marked if the inducer is administered after treatment with METHADONE ADCO 10 mg has begun. Abstinence symptoms have been reported following such interactions and hence, it may be necessary to increase the METHADONE ADCO 10 mg dose. If treatment with a CYP3A4 inducer is interrupted, the METHADONE ADCO 10 mg dose should be reduced.

P-glycoprotein inhibitors: Methadone is a substrate of p-glycoprotein; all medicines that inhibit P-glycoprotein (e.g. quinidine, verapamil, ciclosporin), may therefore raise the serum concentration of methadone. The pharmacodynamic effect of METHADONE ADCO 10 mg may also increase because of increased blood brain barrier passage.

CNS depressants: Alcohol, anaesthetics, hypnotics and sedatives, barbiturates, phenothiazines, some other major tranquillisers and tricyclic antidepressants may increase the general depressant effects of METHADONE ADCO 10 mg when used concomitantly. There are reports that antidepressant medicines (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone. Medicines with a sedative effect on the central nervous system may result in increased respiratory depression, hypotension, strong sedation or coma, therefore it may be necessary to reduce the dose of one or both of the medicines. With METHADONE ADCO 10 mg treatment, the slowly eliminated substance methadone, gives rise to a slow tolerance development and every dose increase may after 1 - 2 weeks give rise to symptoms of respiratory depression. The dose adjustments must therefore be made with caution and the dose increased gradually with careful observation.

Peristalsis inhibition: Concomitant use of METHADONE ADCO 10 mg and peristalsis inhibiting medicines (loperamide and diphenoxylate) may result in severe obstipation and increase the CNS depressant effects. Opioid analgesics, in combination with antimuscarinics, may result in severe obstipation or paralytic ileus, especially in long-term use.

QT prolongation: Cardiac events may occur in cases of co-administration with medicines affecting cardiac conduction (prolong QT interval) or electrolyte balance such as antidysrhythmic (sotalol, amiodarone, flecainide), antipsychotics (thioridazine, haloperidol, sertindole, phenothiazines), antidepressants (paroxetine, sertraline) or antibiotics (erythromycin, clarithromycin).

Histamine H2 antagonists: Histamine H2 antagonists such as cimetidine, can reduce the protein binding of methadone resulting in increased opiate action.

MAOIs: The concurrent use of MAOIs is contraindicated as they may prolong and enhance the respiratory depressant effects of METHADONE ADCO 10 mg. METHADONE ADCO 10 mg should not be given for two weeks after treatment with MAOIs (see section 4.3).

pH of urine: Medicines that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH. Patients that are treated with METHADONE ADCO 10 mg are recommended to avoid medicines containing ammonium chloride.

Opioid agonist analgesics: Additive CNS depression, respiratory depression and hypotension.

Opioid antagonists: Naloxone and naltrexone antagonise the analgesic, CNS and respiratory depressant effects of METHADONE ADCO 10 mg and can rapidly precipitate withdrawal symptoms. Similarly, buprenorphine and pentazocine may precipitate withdrawal symptoms.

Antiretroviral medicines such as nevirapine, efavirenz, nelfinavir, ritonavir: Based on the known metabolism of methadone, these medicines may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with some retroviral medicines and METHADONE ADCO 10 mg concomitantly. METHADONE ADCO 10 mg maintained patients beginning antiretroviral therapy should be monitored for evidence of withdrawal and METHADONE ADCO 10 mg dose should be adjusted accordingly. Some protease inhibitors (amprenavir, nelfinavir, lopinavir/ritonavir and ritonavir/saquinavir) seem to decrease the serum levels of METHADONE ADCO 10 mg. When ritonavir is administered alone, a two-fold AUC of methadone has been observed. Methadone may increase the plasma concentration of zidovudine. During treatment with METHADONE ADCO 10 mg, patients must be carefully monitored for signs of toxicity caused by zidovudine, hence it may be necessary to reduce the dose of zidovudine. Because of mutual interactions between zidovudine and METHADONE ADCO 10 mg (zidovudine is a CYP3A4 inducer), typical opioid abstinence symptoms may develop during concomitant use (headache, myalgia, fatigue and irritability). METHADONE ADCO 10 mg delays the absorption and increases the first pass metabolism of stavudine and didanosine which results in a decreased bioavailability of stavudine and didanosine. Ciprofloxacin: Concomitant use may lead to sedation, confusion and respiratory depression.

Pregnancy
Neonatal abstinence syndrome, respiratory depression and low birth weight have been reported in neonates after METHADONE ADCO 10 mg treatment during pregnancy. METHADONE ADCO 10 mg should not be administered during pregnancy.

Breastfeeding
METHADONE ADCO 10 mg is distributed into breast milk and should not be used during lactation.

Fertility
No data on male and female fertility is available. (Please refer to section 4.5)

METHADONE ADCO 10 mg will affect the psychomotor functions until the patient has been stabilised at a suitable level, so he/she should not drive or use machines until stabilisation has been achieved and there have been no symptoms of abuse for six months. When driving and use of machines can be resumed is largely dependent on the individual patient and must be determined by the medical practitioner.

a. Summary of the safety profile
The side effects of METHADONE ADCO 10 mg treatment are in general the same as those in treatment with other opiates. The most serious side effect of methadone as contained in METHADONE ADCO 10 mg is respiratory depression, which may emerge during the stabilisation phase. Apnoea, shock and cardiac arrest may occur.

b. Tabulated list of adverse reactions
The following side effects have been reported and may occur with METHADONE ADCO 10 mg:

System Organ Class Frequency Adverse Event
Blood and lymphatic system disorders Frequency unknown Reversible thrombocytopenia has been reported in opioid patients with chronic hepatitis
Endocrine disorders Less frequent Hypothyroidism Frequency unknown Raised prolactin levels with long-term administration.
Metabolism and nutrition disorders Frequent Fluid retention Less frequent Anorexia Frequency unknown Hypokalaemia, hypomagnesemia, hypoglycaemia
Psychiatric disorders Frequent Euphoria, hallucinations Less frequent Dysphoria, agitation, insomnia, disorientation Frequency unknown Dependence, confusion particularly at the start of the treatment, changes of mood
Nervous system disorders Frequent Dizziness, sedation, confusion, headache, sleep disturbances, sweating Less frequent Visual disturbances, syncope Frequency unknown METHADONE ADCO 10 mg has the potential to increase intracranial pressure, particularly in circumstances where it is already raised
Eye disorders Frequent Miosis, blurred vision Frequency unknown Dry eyes
Ear and labyrinth disorders Frequent Vertigo
Cardiac disorders Less frequent Bradycardia, palpitations, drop in blood pressure (at high doses), QT prolongation and torsade de pointes.
Vascular disorders Less frequent Orthostatic hypotension, facial flushing
Respiratory, thoracic and mediastinal disorders Less frequent Respiratory depression (at high doses), pulmonary oedema Frequency unknown Exacerbation of existing asthma, dry nose, central sleep apnoea syndrome
Gastrointestinal disorders Frequent Nausea, vomiting, constipation (obstipation) Less frequent Dry mouth (xerostomia), glossitis, acute pancreatitis*
Hepatobiliary disorders Less frequent Bile duct dyskinesia
Skin and subcutaneous tissue disorders Frequent Transient rash, sweating Less frequent Pruritus, urticaria, other rash, bleeding urticaria, tendency to oedema
Renal and urinary disorders Less frequent Urinary retention and antidiuretic effect, micturition
Reproductive system and breast disorders Frequent Reduced libido Less frequent Reduced potency and amenorrhea Frequency unknown Galactorrhoea, dysmenorrhea
General disorders and administration site conditions Frequent Fatigue Less frequent Oedema of the lower extremities, asthenia, oedema Frequency unknown Hypothermia, drug withdrawal syndrome
Investigations Frequent Weight increase
* Post-marketing experience: Less frequent increased risk of abdominal pain, including pancreatitis has been reported.

c. Description of selected adverse reactions
In long term use of METHADONE ADCO 10 mg, as for maintenance treatment, the undesirable effects diminish successively and progressively during a period of several weeks. However, obstipation and perspiration often remain. Long-term use of METHADONE ADCO 10 mg may lead to morphine-like dependence. The abstinence syndromes are similar to the ones observed with morphine and heroine, however less intense, but more long-lasting.

Symptoms
Severe overdose is characterised by respiratory failure, extreme drowsiness that develops into stupor or coma, maximum miosis, slack musculature, cold and clammy skin and occasionally bradycardia and hypotension. Apnoea, cardiovascular failure, cardiac arrest and death may occur in cases of severe overdose. Toxic leukoencephalopathy has been observed with methadone overdose.

Treatment
Secure the airways by assisted or controlled ventilation. It may prove necessary to use opioid antagonists, but since the effect of METHADONE ADCO 10 mg is long-lasting (36 to 48 hours) and that of antagonists is only 1 to 3 hours, antagonist treatment must be repeated as necessary. Antagonists must not be used if there is any sign of respiratory failure or loss of consciousness. If the patient is physically dependent on narcotics, administration of an antagonist may lead to acute abstinence symptoms. If possible, the use of antagonists should be avoided in such patients, but if it nevertheless proves necessary to administer antagonists because of severe respiratory depression, great caution must be exercised. In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).