Rutrex 10 mg Concentrate for oral solution

Substitution treatment in opiate dependence in conjunction with medical, psychological and social therapy.

Posology
RuTrex 10 mg/ml concentrate for oral solution should be diluted by a health care provider before use. Please refer to section 6.6 for further instructions. RuTrex should always be taken orally with or without food.
RuTrex must not be injected. Dosage should be titrated to individual needs of patients. Substitution treatment with methadone should be prescribed by a doctor with experience of treating opiate/opioid-dependent patients, preferably at centres that are specialised in the treatment of opiate/opioid dependency. The dose is based on the occurrence of withdrawal symptoms and must be adjusted for each patient according to his or her individual situation and the way he or she feels. In general, after adjustment of the dose, the aim is to administer the lowest possible maintenance dose.
Adults:
The standard initial dose is 20 mg methadone once daily. The dose is increased at 10 mg increments 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 per 24 hours, but some individuals may require higher doses. The dosage must be determined based on the clinical evaluation, supported by serum level monitoring. The recommended serum level is 600 to 1200 nmol/L (200 to 400 ng/mL). Great importance is attached to the clinical assessment.
RuTrex is usually 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.
The highest recommended dose, that rarely should be used, is 150 mg/day. The reason for this limitation is an increased frequency of QT-prolongation, Torsades de pointes and cases of cardiac arrest within higher dose ranges (see section 4.4). If the patient has been treated with a combined agonist/antagonist (e.g. buprenorphine), the dose should be reduced gradually when the methadone treatment is initiated. If the methadone treatment is interrupted and a switch to sublingual buprenorphine treatment is planned (especially in combination with naloxone), the methadone dose should be reduced to 30 mg/day initially to avoid withdrawal symptoms caused by buprenorphine/naloxone.
Treatment discontinuation:
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. Treatment discontinuation must always be done gradually by dose reduction in weekly steps of 5 u2013 10 mg over several weeks to months. 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). During this period of gradual dose reduction, it is necessary to pay attention to any recurrence of withdrawal symptoms which would require a return to the previous dosage, and to any resumption of addictive behaviours.
Special populations
Elderly:
Caution must be exercised when treating elderly patients, as they may require a reduced dose (see section 4.4).
Patients with renal or hepatic impairment:
In patients with renal disorders or mild to moderate hepatic disorders it is advisable to reduce the dose (for more information see section 4.4 and also section 4.3).
Patients with hypothyroidism or prostatic hypertrophy:
Patients with hypothyroidism or prostatic hypertrophy must receive a lower initial dose (see section 4.4).
Paediatric population:
There are no data available on the use in patients under 18 years. Therefore, the use of RuTrex is not recommended for children and adolescents (see section 4.4).
Method of administration
For oral administration only. RuTrex may only be used under medical supervision.

• Hypersensitivity to methadone hydrochloride or to any of the excipients (see section 6.1).
• Respiratory depression.
• Use during an acute asthma attack.
• Acute alcoholism.
• Concurrent administration with monoamine oxidase (MAO) inhibitors or within 2 weeks of discontinuation of treatment with them.
• Decreased level of consciousness or head injury.
• Individuals with QT prolongation, including congenital long QT syndrome.
• RuTrex should not be administered to patients with severe hepatic impairment, as it may precipitate portosystemic encephalopathy in patients with severe liver damage.

Drug dependence, tolerance and potential for abuse
Prolonged use of RuTrex may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give RuTrex to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for continuing opioid substitution therapy should be reviewed regularly.
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with methadone. The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the doctor and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).
Tolerance and dependence may occur as with morphine. The risks of dependence are increased in individuals of current or past history of substance misuse disorders e.g., alcohol use disorder, opioid use disorder, drug use disorder.
RuTrex can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.
Drug withdrawal syndrome
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. 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).
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take RuTrex during pregnancy, there is a risk that their new-born infants will experience neonatal withdrawal syndrome. The withdrawal period is longer for RuTrex than for heroin because methadone has a longer half-life.
Respiratory depression
RuTrex should be used with caution in patients with asthma, chronic obstructive pulmonary disease or cor pulmonale and in patients with very limited respiratory reserve, a pre-existing impairment of respiratory function, hypoxia or hypercapnia. Even at the usual therapeutic doses for narcotics, these patients can experience a reduction in respiratory activity with a concomitant increase in airway resistance culminating in apnoea. In patients predisposed to such atopic phenomena, pre-existing asthma, skin eruptions and blood count changes (eosinophilia) can be exacerbated. Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two. Asthma may be exacerbated due to histamine release. Concomitant treatment with other medicines with CNS depressant activity is not advised due to the potential for CNS and respiratory depression (see section 4.5).
The symptoms and signs of overdosage and toxicity of methadone are essentially those for morphine, though it is said that methadone has a greater respiratory depressive effect and a lesser sedative effect than an equianalgesic dose of morphine. Toxic doses are highly variable, regular usage giving tolerance. Pulmonary oedema is a frequent corollary of overdosage whilst the dose-related histamine-releasing property of methadone may account for at least some of the urticaria and pruritus associated with methadone administration.
Head injury and increased intracranial pressure
The respiratory depressant effects of methadone and its capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increased intracranial pressure. Furthermore, opiates/opioids produce side effects that may obscure the clinical course of patients with head injuries. In such patients, RuTrex must be used with caution and only if it is deemed essential. Methadone has the potential to increase intracranial pressure especially where it is already raised.
Hepatic disorders
Caution as RuTrex may precipitate portosystemic encephalopathy in patients with severe liver damage. RuTrex may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.
Renal impairment
Caution should be exercised in the use of RuTrex in patients with renal impairment. The dose interval should be lengthened to a minimum of 32 hours if the glomerular filtration rate (GFR) is 10 u2013 50 mL/min and to a minimum of 36 hours if the GFR is lower than 10 mL/min.
Gastrointestinal motility
Methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.
Adrenal insufficiency
Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.
Decreased sex hormones and increased prolactin
Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.
Hypoglycaemia
Hypoglycaemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation (see section 4.8).
Other warnings
Babies born to mothers receiving RuTrex may suffer withdrawal symptoms. Methadone should be used with caution in patients with history of convulsive disorders, hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis.
RuTrex should be used with caution and in reduced dosage in patients who are concomitantly using other narcotic analgesics, general anaesthetics, phenothiazines, other tranquillisers, sedative hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol) (see section 4.5).
QT prolongation and torsade de pointes have been reported with methadone use, particularly at doses above 100 mg daily. RuTrex 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 or ischemic heart disease
• hepatic disease
• hypokalaemia or other electrolyte imbalances, i.e. hypomagnesaemia
• concomitant treatment with medicines that have a potential for QT-prolongation
• concomitant treatment with substances which may cause electrolyte abnormalities
• concomitant treatment with cytochrome P450 CYP3A4 inhibitors (see section 4.5).

Pharmacokinetic interactions
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 may also increase because of increased blood brain barrier passage.
CYP3A4-enzyme inducers:
Methadone is a substrate of CYP3A4 (see section 5.2). By induction of CYP3A4, clearance of methadone will increase, and the plasma levels decrease. Inducers of this enzyme (barbiturates, carbamazepine, phenytoin, nevirapine, rifampicin, efavirenz, amprenavir, spironolactone, dexamethasone, Hypericum perforatum (St John's wort)), may induce hepatic metabolism. For instance, after three weeksu2019 treatment with 600 mg efavirenz daily, the mean maximal plasma concentration and AUC decreased by 48 % and 57 % respectively, in patients treated with methadone (35 u2013 100 mg daily). The consequences of enzyme induction are more marked if the inducer is administered after treatment with methadone has begun. Abstinence symptoms have been reported following such interactions and hence, it may be necessary to increase the RuTrex dose. If treatment with a CYP3A4 inducer is interrupted, the RuTrex dose should be reduced.
Co-administration of RuTrex with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of methadone with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and RuTrex are administered concurrently; clinical response and/or medicine levels should be monitored as appropriate.
CYP3A4-enzyme inhibitors:
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, ciprofloxacin, fluconazole, grapefruit juice, cimetidine, itraconazole, ketoconazole, fluoxetine, fluvoxamine, nefazodone and telithromycin) may result in increased plasma concentrations of methadone. A 40 u2013 100 % increase of the quote between the serum levels and the methadone dose has been shown with concomitant fluvoxamine treatment. If these medicines are prescribed to patients on RuTrex maintenance treatment, one should be aware of the risk of overdose. Dose adjustment may be necessary.
Products that affect the acidity of the urine:
Methadone is a weak base. Acidifiers of the urine (such as ammonium chloride and ascorbic acid) may increase the renal clearance of methadone. Patients that are treated with RuTrex are recommended to avoid products containing ammonium chloride.
Concomitant HIV infection treatment:
Some protease inhibitors (amprenavir, nelfinavir, abacavir, lopinavir/ritonavir and ritonavir/saquinavir) seem to decrease the serum levels of methadone. When ritonavir is administered alone, a two-fold AUC of methadone has been observed. The plasma levels of zidovudine (a nucleoside analogue) increase with methadone use after both oral and intravenous administration of zidovudine. This is more noticeable after oral than after intravenous use of zidovudine. These observations are likely caused by inhibition of zidovudine glucuronidation, and therefore decreased clearance of zidovudine. During treatment with RuTrex, patients must be carefully monitored for signs of toxicity caused by zidovudine, which may require a reduction in the zidovudine dose. Because of mutual interactions between zidovudine and methadone (zidovudine is a CYP3A4 inducer), typical opiate/opioid abstinence symptoms may develop during concomitant use (headache, myalgia, fatigue and irritability).
Didanosine and stavudine:
Methadone delays the absorption and increases the first pass metabolism of stavudine and didanosine, which results in a decreased bioavailability of stavudine and didanosine.
Desipramine:
RuTrex may double the serum levels of desipramine.
Pharmacodynamic interactions
Opiate/opioid antagonists:
Naloxone and naltrexone counteract the effects of methadone and induces abstinence. Similarly, buprenorphine and pentazocine may precipitate withdrawal symptoms.
CNS depressants:
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 RuTrex treatment, the slowly eliminated substance methadone, gives rise to a slow tolerance development, and every dose increase may after 1 u2013 2 weeks give rise to symptoms of respiratory depression. The dose adjustments must therefore be made with caution and the dose increased gradually and with careful observation. Anaesthetics, sedative-hypnotics (including barbiturates, chloral hydrate and chlormethiazole), anxiolytics phenothiazines, antipsychotics and tricyclic antidepressants may increase the general depressant effects of RuTrex when used concomitantly (see section 4.4). Antipsychotics may enhance the sedative effects and hypotensive effects of RuTrex.
Sedative medicines such as benzodiazepines or related medicines:
The concomitant use of opiates/opioids with sedative medicines such as benzodiazepines or related medicines increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4)
Peristalsis inhibition:
Concomitant use of RuTrex and peristalsis inhibiting medicines (loperamide and diphenoxylate) may result in severe obstipation and increase the CNS depressant effects. Opiate/opioid analgesics, in combination with antimuscarinics, may result in severe obstipation or paralytic ileus, especially in long-term use.
QT-prolongation:
RuTrex should not be combined with medicines that may prolong the QT interval such as antidysrhythmics (sotalol, amiodarone, and flecainide), antipsychotics (thioridazine, haloperidol, sertindole, and phenothiazines), antidepressants (paroxetine, sertraline) or antibiotics (erythromycin, clarithromycin).
Serotonergic medicines:
Serotonergic syndrome may occur with concomitant administration of RuTrex with pethidine, monoamine oxidase (MAO) inhibitors and serotonin medicines such as selective serotonin re- uptake inhibitor (SSRI), serotonin norepinephrine re-uptake inhibitor (SNRI) and tricyclic antidepressants (TCAs). The symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
MAO-inhibitors:
Concomitant administration of MAO-inhibitors may result in reinforced CNS-inhibition, serious hypotonia and or apnoea. RuTrex should not be combined with MAO-inhibitors and two weeks after such treatment (see section 4.3).

Pregnancy
RuTrex administered to pregnant women for the management of opiate/opioid addiction has the potential for several adverse effects on the foetus and the neonate. Withdrawal symptoms/respiratory depression may occur in neonates of mothers who were treated with RuTrex chronically during pregnancy. RuTrex should not be administered to pregnant women, because of possible adverse effects on the foetus and neonate including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. However, if maternal RuTrex substitution therapy is strongly indicated, careful monitoring is required. It may be necessary to increase the dose of RuTrex if withdrawal symptoms develop. Increased clearance and reduced plasma levels have been reported during pregnancy. Considering the well-being of the foetus, it may be advisable to split up the daily dose in order to prevent high peak plasma concentrations and to compensate the accelerated degradation of methadone, thus preventing withdrawal symptoms. Dose reduction or withdrawal during pregnancy must always be carried out under careful monitoring of the mother and only after a stringent risk/benefit assessment. Medicine withdrawal of the neonate must be carried out at an adequate intensive care unit for children, as treatment with RuTrex may lead to habituation and addiction of the foetus as well as to withdrawal symptoms in the neonate, which require treatment. Approximately 60 u2013 80 % of the neonates require hospitalised treatment due to the neonatal abstinence syndrome. Dose adjustment (especially dose reduction) may be necessary within 1 u2013 2 weeks postnatal. The use of RuTrex just before and during birth is advised against, because of the risk of neonatal respiratory depression.
Breastfeeding
RuTrex is distributed into breast milk and should not be used during lactation.
Fertility
Methadone does not appear to impair human female fertility. Studies in men on methadone maintenance programmes have shown that methadone reduces serum testosterone and markedly depresses the ejaculate volume and sperm motility. The sperm counts of methadone subjects were twice that of controls, but this reflected the lack of dilution from seminal secretions.

RuTrex may 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 a doctor.

Blood and lymphatic system disorders
Frequency unknown: Reversible thrombocytopenia has been reported in opioid-dependent patients with chronic hepatitis.
Metabolism and nutrition disorders
Frequent: Fluid retention. Frequency unknown: Anorexia, hypokalaemia, hypomagnesaemia, hypoglycaemia.
Psychiatric disorders
Frequent: Euphoria, hallucinations. Less frequent: Dysphoria, dependence, agitation, insomnia, disorientation. Frequency unknown: Drug dependence (see section 4.4).
Nervous system disorders
Frequent: Dizziness, euphoria, sedation, confusion, headache, sleep disturbances, sweating. Less frequent: Syncope.
Eye disorders
Frequent: Blurred vision, dry eyes. Frequency unknown: Nystagmus, strabismus, reduced visual acuity. Less frequent: Visual disturbances, miosis.
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: Facial flush, hypotension.
Respiratory, thoracic and mediastinal disorders
Less frequent: Pulmonary oedema, exacerbation of asthma, dry nose, respiratory depression (at high doses).
Gastrointestinal disorders
Frequent: Nausea, vomiting, constipation. Less frequent: Dry mouth, glossitis.
Hepatobiliary disorders
Less frequent: Bile duct dyskinesia.
Skin and subcutaneous tissue disorders
Frequent: Transient rash, sweating. Less frequent: Pruritis, urticaria, bleeding urticaria, tendency to oedema.
Endocrine disorders
Less frequent: Hypothyroidism. Frequency unknown: Raised prolactin levels with long-term administration, hypoadrenalism, hypogonadism.
Renal and urinary disorders
Less frequent: Urinary retention, anti-diuretic effect.
Reproductive system and breast disorders
Frequent: Reduced libido. Less frequent: Galactorrhoea, dysmenorrhoea and amenorrhoea.
The undesirable effects are usually moderate in patients receiving long-term treatment.
General disorders and administration site conditions
Frequent: Fatigue, drowsiness. Less frequent: Oedema of the lower extremities, asthenia, oedema, hypothermia, drug withdrawal syndrome.
Investigations
Frequent: Weight increase.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.
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.
Treatment: Secure the airways by assisted or controlled ventilation. It may prove necessary to use opioid antagonists, but since the effect of RuTrex 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 withdrawal 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.