Active ingredients: Ademetionine
SAMYR 100 mg / 5ml Powder and solvent for solution for injection
SAMYR 200 mg / 5ml Powder and solvent for solution for injection
SAMYR 200 mg Gastro-resistant tablets
Samyr package inserts are available for pack sizes: - SAMYR 100 mg / 5ml Powder and solvent for solution for injection, SAMYR 200 mg / 5ml Powder and solvent for solution for injection, SAMYR 200 mg Gastro-resistant tablets
- SAMYR 400 mg / 5 ml powder and solvent for solution for injection, SAMYR 400 mg gastro-resistant tablets
Indications Why is Samyr used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Other drugs of the gastrointestinal system and metabolism, amino acids and derivatives
THERAPEUTIC INDICATIONS
Depressive syndromes.
Contraindications When Samyr is not to be used
Hypersensitivity to the active substance or to any of the excipients.
Ademetionine is contraindicated in patients with genetic defects that affect the methionine cycle and / or cause homocystinuria and / or hyperhomocysteinemia (e.g. cystathionine beta-synthase deficiency, vitamin B12 metabolism defects).
Precautions for use What you need to know before taking Samyr
Intravenous injection should be done slowly.
Ammonia levels should be monitored in patients with precyrrotic and cirrhotic states or hyperammonemia following oral administration of ademetionine.
Since vitamin B12 and folate deficiency can decrease ademetionine levels, patients at risk (suffering from anemia, liver disease, pregnant or in case of potential vitamin deficiency due to other pathologies or eating habits such as veganians) they should perform blood tests routinely to check plasma levels. If deficiencies are found, treatment with vitamin B12 and / or folate is recommended before or concurrently with the administration of ademetionine.
Some patients may experience dizziness while taking ademetionine. Patients should be advised not to drive or use machines during treatment until they are reasonably certain that ademetionine therapy does not affect their ability to operate. in such activities (see the paragraph "Special Warnings").
Suicide / Suicidal ideation
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide / related events). This risk persists until specific remission occurs. As improvement may not occur during the first or immediate weeks of treatment, patients should be carefully monitored until improvement occurs.It is generally clinical experience that the risk of suicide may increase in the early stages of improvement.
Drug therapy with antidepressants should always be associated with close surveillance of patients, particularly those at high risk, especially in the initial stages of treatment and after dose changes. Patients (or caregivers) should be advised of the need to monitor and report immediately to their physician any clinical worsening, the onset of suicidal behavior or thoughts, or changes in behavior.
It is not recommended for use in patients with bipolar disease. Cases of transition from depression to hypomania or mania have been reported when treated with ademetionine.
Only one case of serotonin syndrome has been reported in the literature in patients taking ademetionine and clomipramine. Although the potential interaction is suspected, caution is advised when administering ademetionine concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as Clomipramine) and tryptophan medicines and phyto supplements (see section " Interactions ").
The efficacy of ademetionine in the treatment of depression has been studied in short-term clinical trials (duration of 3-6 weeks). The efficacy of ademetionine in the treatment of depression over long periods is not known.
There are many medicines to treat depression and patients should consult with their doctor to determine the optimal therapy. Patients should be encouraged to inform their physicians if their symptoms do not subside or worsen during treatment with ademetionine. Patients with depression are at risk of suicide and other serious events therefore should receive ongoing psychiatric support during ademetionine therapy to ensure that symptoms of depression are adequately considered and treated.
Cases of transient anxiety or exacerbation of anxiety states have been reported in patients receiving ademetionine. In most cases, it was not necessary to stop treatment. In a few cases, the anxiety resolved by reducing the dosage or discontinuing therapy.
Hepatic dysfunction: Pharmacokinetic parameters are similar in healthy volunteers and in patients with chronic liver disease.
Renal dysfunction: No studies have been conducted with patients with impaired renal function. Therefore, caution is recommended when administering ademetionine to such patients.
Elderly patients: Clinical studies conducted with ademetionine did not enroll a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Clinical experience reported did not identify any differences in response between elderly and younger patients.
In general, dose selection for an elderly patient should be done with caution, usually starting with the lowest dose within the therapeutic range, and considering the highest rate of decrease in hepatic, renal or cardiac function, the presence of other concomitant diseases or other drug therapies.
Children: The safety and efficacy of ademetionine in children has not been established.
Interference with the homocysteine immunoassay
Ademetionine interferes with homocysteine immunoassays, in patients treated with ademetionine the assay may show distorted elevated plasma homocysteine levels. Therefore, in patients receiving ademetionine, it is recommended that non-immunological assays be used to measure plasma homocysteine levels.
Interactions Which drugs or foods can modify the effect of Samyr
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Serotonin syndrome has been reported in patients taking ademetionine and clomipramine. Therefore, although the potential interaction is supposed, caution is advised when administering ademetionine concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as Clomipramine) and tryptophan medicines and phyto supplements (see "Precautions for use" section).
The combination of SAMYR is compatible with any other antidepressant drug, in particular tricyclics and monoamine oxidase inhibitors. The intake of Ademetionine does not present negative interactions with alcohol intake.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
The intake of therapeutic dosages of Ademetionine in women during the last three months of pregnancy did not result in any adverse events. It is advisable to administer Ademetionine in the first three months of pregnancy only if absolutely necessary.
Feeding time
Ademetionine should only be taken during breastfeeding if the potential benefit justifies the potential risk to the infant.
Effects on ability to drive and use machines
Dizziness has occurred in some patients during treatment with ademetionine. It is recommended that you do not drive or operate machinery during treatment until you are reasonably certain that ademetionine therapy does not affect your ability to drive and perform such activities.
Important information about some of the ingredients
Samyr 100 mg / 5ml powder and solvent for solution for injection contains less than 1 mmol sodium per vial, ie it is essentially "sodium free".
Samyr 200 mg / 5ml powder and solvent for solution for injection contains less than 1 mmol sodium per vial, ie it is essentially "sodium free".
Samyr 200 mg gastro-resistant tablets contain less than 1 mmol sodium per tablet, ie essentially "sodium-free".
Dosage and method of use How to use Samyr: Dosage
Treatment can be initiated by parenteral administration and continued orally or it can be initiated orally.
Powder and solvent for solution for injection
The lyophilized powder must be dissolved using its solvent at the time of use, the unused portion must be discarded. Ademetionine must not be mixed with alkaline solutions or solutions containing calcium ions. If the lyophilisate powder appears other than white / yellowish in color (due to injury to the vial or due to exposure to heat), the product should not be used.
Intravenous administration of ademetionine powder and solvent for solution for injection should be done slowly.
Tablets
Ademetionine tablets should be swallowed whole and not chewed.
For better absorption of the active substance and for a complete therapeutic effect, ademetionine tablets should not be taken with meals.
Ademetionine tablets must be extracted from the blister immediately before use. If the tablets appear brownish in color (due to the presence of holes in the aluminum wrapper), it is recommended not to use the product.
Bottles: 1-2 bottles per day for cycles of 15-20 days, intravenously or intramuscularly (equivalent to 100-200 mg / day or equivalent to 200-400 mg / day).
Tablets: Attack therapy: 400 mg 2-3 times a day for 15-30 days (equivalent to 800-1200 mg / day).
Maintenance therapy: 200 mg 2-3 times a day according to medical prescription.
Instructions for Use
HOW TO OPEN THE SOLVENT VIAL
Safety pre-cut vial
INDICATIONS FOR OPENING:
- position the vial as indicated in figure 1;
- exert pressure with the thumb placed over the colored point as shown in figure 2.
Overdose What to do if you have taken too much Samyr
Cases of overdose with Ademetionine appear to be rare. The physician should contact local poison control centers. In general, patients should be monitored and supportive care provided.
In case of accidental ingestion / intake of an overdose of SAMYR, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of SAMYR, ask your doctor or pharmacist.
Side Effects What are the side effects of Samyr
Like all medicines, SAMYR can cause side effects, although not everybody gets them.
No major side effects are reported even after long-term administration and high dosages. No cases of addiction or drug dependence have been reported. Due to its excellent tolerability, Ademetionine can be safely used in pregnant women, elderly people and chronic liver diseases.
Rarely, and only in particularly sensitive subjects, SAMYR can cause disturbances in the sleep-wake rhythm: in such cases the evening use of a hypno-inducer may be useful.
Given the acidity of the pH at which, for reasons of stability, the active ingredient in the tablets is maintained, some patients have reported, after oral administration of the product, some cases of heartburn and a sense of epigastric weight, phenomena however, of minor entity and such as not to jeopardize the continuation of therapy.
Suicidal ideation / behavior may rarely occur.
Reactions during Clinical Trials
For more than two years Ademetionine has been studied in 2434 patients in controlled and open clinical trials; of which 1983 suffering from hepatic pathologies and 817 suffering from depression.
The table below is based on 1667 patients enrolled in 22 clinical trials and treated with ademetionine. Of these 121 (7.2%) had evidence of 188 adverse reactions in total. Nausea, abdominal pain and diarrhea were the most frequently reported adverse reactions. It was not always possible to assess the causality between the adverse event and the medicinal product.
Postmarketing Surveillance Reactions or Phase IV Clinical Trials
Disorders of the immune system
Hypersensitivity, anaphylactoid reactions or anaphylactic reactions (i.e. flushing, dyspnoea, bronchospasm, back pain, chest tightness, altered blood pressure (hypotension, hypertension) or heart rate (tachycardia, bradycardia)).
Psychiatric disorders
Anxiety
Respiratory, thoracic and mediastinal disorders
Laryngeal edema
Skin and subcutaneous tissue disorders
Injection site reaction (very rarely with skin necrosis), angioedema, allergic skin reactions (i.e. rash, pruritus, urticaria, erythema).
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
Gastro-resistant tablets: no special storage precautions.
Ampoules and solvent: store at a temperature not exceeding 30 ° C.
From a chemical-physical point of view, the reconstituted product remains stable for 6 hours.
From a microbiological point of view, the product should be used immediately. Otherwise, the storage conditions (after reconstitution) are the responsibility of the user and in any case should not exceed 24 hours at a temperature between 2 and 8 ° C, unless reconstitution takes place under controlled aseptic conditions. and validated.
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
KEEP THIS MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN
Composition and pharmaceutical form
COMPOSITION
One bottle of 100 mg powder contains: ademetionine (Sulfo-Adenosyl-L-Methionine) sulfate p-toluenesulphonate 192 mg equal to 100 mg ion. Excipients: mannitol.
A 5 ml vial of solvent contains: water for injections, L-lysine, sodium hydroxide.
One bottle of 200 mg powder contains: ademetionine 1,4-butanedisulphonate 380 mg equal to ion 200 mg. Excipients: mannitol.
A 5 ml vial of solvent contains: water for injections, L-lysine, sodium hydroxide.
A 200 mg gastro-resistant tablet contains: ademetionine 1,4-butanedisulphonate 380 mg equal to ion 200 mg. Excipients: colloidal silica, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 6000, simethicone, polysorbate 80, sodium hydroxide, talc, iron oxide.
PHARMACEUTICAL FORM AND CONTENT
"100 mg / 5ml powder and solvent for solution for injection" 5 bottles + 5 solvent vials of 5 ml
"200 mg / 5ml powder and solvent for solution for injection" 5 bottles + 5 solvent vials of 5 ml
"200 mg gastro-resistant tablets" 20 tablets
Not all pack sizes may be marketed
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SAMYR
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
• SAMYR 100 mg / 5ml powder and solvent for solution for injection
One bottle of powder contains:
Active principle:
Ademetionine (Sulfo-Adenosyl-L-Methionine) sulfate p-toluenesulfonate 192 mg equal to ion 100 mg
• SAMYR 200 mg / 5ml powder and solvent for solution for injection
One bottle of powder contains:
Active principle:
Ademetionine 1,4-butanedisulfonate 380 mg equal to ion 200 mg
• SAMYR 200 mg gastro-resistant tablets
One gastro-resistant tablet contains:
Active principle:
Ademetionine 1,4-butanedisulfonate 380 mg equal to ion 200 mg
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Powder and solvent for solution for injection
Gastro-resistant tablet
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Depressive syndromes.
04.2 Posology and method of administration
Treatment can be initiated by parenteral administration and continued orally or it can be initiated orally.
Powder and solvent for solution for injection
The lyophilized powder must be dissolved using the relative solvent at the time of use, the unused portion must be discarded.
Ademetionine must not be mixed with alkaline solutions or solutions containing calcium ions. If the lyophilisate powder appears other than white in color (due to a vial injury or due to exposure to heat), the product should not be used.
Intravenous administration of ademetionine powder and solvent for solution for injection should be done slowly.
Tablets
Ademetionine tablets should be swallowed whole and not chewed.
For better absorption of the active substance and for a complete therapeutic effect, ademetionine tablets should not be taken with meals.
Ademetionine tablets should be removed from the blister immediately before use.If the tablets appear brownish in color (due to the presence of holes in the aluminum wrapper), it is recommended not to use the product.
Bottles: 1-2 bottles per day for cycles of 15-20 days, intravenously or intramuscularly (equivalent to 100-200 mg / day or equivalent to 200-400mg / day).
Tablets: Attack therapy: 400 mg 2-3 times a day for 15-30 days (equivalent to 800-1200 mg / day).
Maintenance therapy: 200 mg 2-3 times a day according to medical prescription.
Elderly patients: Clinical studies conducted with ademetionine did not enroll a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical experience reported did not identify any differences in response between elderly and younger patients.
In general, dose selection for an elderly patient should be done with caution, usually starting with the lowest dose within the therapeutic range, and considering the highest rate of decrease in hepatic, renal or cardiac function, the presence of other concomitant diseases or other drug therapies.
Children: The safety and efficacy of ademetionine in children has not been established.
Hepatic dysfunction: Pharmacokinetic parameters are similar in healthy volunteers and in patients with chronic liver disease.
Renal dysfunction: No studies have been conducted with patients with impaired renal function. Therefore, caution is recommended when administering ademetionine to such patients.
04.3 Contraindications
Ademetionine is contraindicated in patients with genetic defects that affect the methionine cycle and / or cause homocystinuria and / or hyperhomocysteinemia (e.g. cystathionine beta-synthase deficiency, vitamin B12 metabolism defects).
Ademetionine is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.
04.4 Special warnings and appropriate precautions for use
Intravenous injection should be done slowly.
Ammonia levels should be monitored in patients with precyrrotic and cirrhotic states or hyperammonemia following oral administration of ademetionine.
Since vitamin B12 and folate deficiency can decrease ademetionine levels, patients at risk (suffering from anemia, liver disease, pregnant or in case of potential vitamin deficiency due to other pathologies or eating habits such as veganians) they should perform blood tests routinely to check plasma levels. If deficiencies are found, treatment with vitamin B12 and / or folate is recommended before or concurrently with the administration of ademetionine.
Some patients may experience dizziness while taking ademetionine. Patients should be advised not to drive or use machines during treatment until they are reasonably certain that ademetionine therapy does not affect their ability to operate. in such activities (see section 4.7).
Suicide / Suicidal ideation
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide / related events). This risk persists until specific remission occurs. As improvement may not occur during the first or immediate weeks of treatment, patients should be carefully monitored until improvement occurs. It is generally clinical experience that the risk of suicide may increase in the early stages of improvement.
Other psychiatric conditions for which Samyr is prescribed may also be associated with an increased risk of suicidal behavior. Furthermore, these conditions can be associated with major depressive disorder. Therefore, precautions followed when treating patients with other psychiatric disorders should be observed when treating patients with major depressive disorders.
Patients with a history of suicidal behavior or thoughts, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are at increased risk of suicidal thoughts or suicidal thoughts, and should be closely monitored during treatment. of clinical trials conducted with antidepressant drugs in comparison with placebo in the therapy of psychiatric disorders, showed an increased risk of suicidal behavior in the age group below 25 years of patients treated with antidepressants compared to placebo.
Drug therapy with antidepressants should always be associated with close surveillance of patients, particularly those at high risk, especially in the initial stages of treatment and after dose changes. Patients (or caregivers) should be advised of the need to monitor and report immediately to their physician any clinical worsening, the onset of suicidal behavior or thoughts, or changes in behavior.
It is not recommended for use in patients with bipolar disease. Cases of transition from depression to hypomania or mania have been reported when treated with ademetionine.
Only one case of serotonin syndrome has been reported in the literature in patients taking ademetionine and clomipramine. Although the potential interaction is supposed, caution is advised when administering ademetionine concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as Clomipramine) and tryptophan medicines and phyto supplements (see section 4.5 ").
The efficacy of ademetionine in the treatment of depression has been studied in short-term clinical trials (duration of 3-6 weeks). The efficacy of ademetionine in the treatment of depression over long periods is not known. There are many medicines to treat depression and patients should consult with their doctor to determine the optimal therapy. Patients should be encouraged to inform their physicians if their symptoms do not reduce or worsen during treatment with ademetionine. Patients with depression are at risk of suicide and other serious events therefore should receive ongoing psychiatric support during ademetionine therapy to ensure that symptoms of depression are adequately considered and treated.
Cases of transient anxiety or exacerbation of anxiety states have been reported in patients receiving ademetionine. In most cases, it was not necessary to stop treatment. In a few cases, the anxiety resolved by reducing the dosage or discontinuing therapy.
Interference with the homocysteine immunoassay
Ademetionine interferes with homocysteine immunoassays, in patients treated with ademetionine the assay may show distorted elevated plasma homocysteine levels. Therefore, in patients receiving ademetionine, it is recommended that non-immunological assays be used to measure plasma homocysteine levels.
04.5 Interactions with other medicinal products and other forms of interaction
Serotonin syndrome has been reported in patients taking ademetionine and clomipramine. Therefore, although the potential interaction is supposed, caution is advised when administering ademetionine concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as Clomipramine) and tryptophan medicines and phyto supplements (see paragraph 4.4 ").
It should also be noted that the association of Ademetionine with any other antidepressant drug (such as tricyclics and MAOIs) is compatible. The intake of Ademetionine does not present negative interactions with the intake of alcohol.
04.6 Pregnancy and lactation
When required by particular clinical conditions (cholestasis, pregnancy vomiting), it can be used safely during pregnancy without undesirable consequences for the mother and the fetus.
Pregnancy
The assumption of therapeutic dosages of Ademetionine in women during the last months of pregnancy has not led to any adverse events. It is advisable to administer Ademetionine in the first three months of pregnancy only if absolutely necessary.
Feeding time
Ademetionine should only be taken during breastfeeding if the potential benefit justifies the potential risk to the infant.
04.7 Effects on ability to drive and use machines
Dizziness has occurred in some patients during treatment with ademetionine. It is recommended that you do not drive or operate machinery during treatment until you are reasonably certain that ademetionine therapy does not affect your ability to drive and perform such activities.
04.8 Undesirable effects
No major undesirable effects have been reported even after long-term administration and high dosages. No cases of addiction or drug dependence have been reported. Due to its excellent tolerability, Ademetionine can be safely used in pregnant women, elderly people and chronic liver diseases.
Rarely, and only in particularly sensitive subjects, SAMYR can cause disturbances in the sleep-wake rhythm: in such cases the evening use of a hypno-inducer may be useful.
Given the acidity of the pH at which, for reasons of stability, the active ingredient in the tablets is maintained, some patients have reported heartburn and a sense of epigastric weight by some patients after administration of the product by mouth. extent and such as not to jeopardize the continuation of therapy.
Rare: suicidal ideation / behavior (see section 4.4).
Reactions during Clinical Trials
For more than two years Ademetionine has been studied in 2434 patients in controlled and open clinical trials; of which 1983 suffering from hepatic pathologies and 817 suffering from depression.
The table below is based on 1667 patients enrolled in 22 clinical trials and treated with ademetionine. Of these 121 (7.2%) had evidence of 188 adverse reactions in total. Nausea, abdominal pain and diarrhea were the most frequently reported adverse reactions. It was not always possible to assess the causality between the adverse event and the medicinal product.
Postmarketing Surveillance Reactions or Phase IV Clinical Trials
Disorders of the immune system
Anaphylactic reactions
Psychiatric disorders
Anxiety
Respiratory, thoracic and mediastinal disorders
Laryngeal edema
Skin and subcutaneous tissue disorders.
Injection site reaction (very rarely with skin necrosis), rash, angioedema.
04.9 Overdose
Cases of overdose with Ademetionine appear to be rare. The physician should contact local poison control centers. In general, patients should be monitored and supportive care provided.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antidepressant, ATC code: N06AX49
S-Adenosyl L-methionine (Ademetionine) is a physiologically present amino acid with an almost ubiquitous distribution in the tissues and fluids of the body, where it intervenes in important biological processes in humans and animals mainly as a coenzyme and as a methyl donor (reactions of Transmethylation). Transmethylation is also essential in the development of the phospholipid bilayer of cell membranes and contributes to membrane fluidity. Ademetionine can penetrate the blood brain barrier and mediated ademetionine transmethylation is critical in the formation of neurotransmitters in the central nervous system including catecholamines (dopamine, noradrenaline, adrenaline), serotonin, melatonin and histamine. Ademetionine is also a precursor of physiological sulfur compounds (cysteine, taurine, glutathione, CoA, etc.) in transulfuration reactions. Glutathione, the most powerful antioxidant in the liver, is important in liver detoxification. Ademetionine increases liver levels. of glutathione in patients with liver disease caused by alcohol and not. Both folate and vitamin B12 are essential co-factors in the metabolism and restoration of Ademetionine.
The transfer of the methyl group (transmethylation) from ademetionine to biological molecules such as hormones, neurotransmitters, nucleic acids, proteins, phospholipids constitutes a fundamental step in the metabolic processes of the organism.
In childhood and adolescence the levels of ademetionine are elevated, in adults they decrease appreciably and are further reduced in old age.
Transmethylation processes take on particular value in the brain as they intervene in the metabolism of catecholamine neurotransmitters (dopamine, noradrenaline, adrenaline), indolamines (serotonin and melatonin) and imidazoles (histamine).
Exogenous ademetionine crosses the blood brain barrier, increases the concentration of CSF ademetionine and increases the turnover of serotonin and noradrenaline in the brain.
Furthermore, chronic treatment with Ademetionine allows to prevent the reduction of phospholipid methylation that occurs during senescence; consequently, the fluidity of the synaptosomal membranes and the efficiency of the b-adrenergic receptors are preserved. These data have suggested the use of ademetionine in depressive syndromes, characterized by a reduced turnover of serotonin and / or noradrenaline and by an inadequate b- sensitivity. receptor.
The clinical results show that SAMYR exerts a marked antidepressant activity and that the pharmacological action is rapid, within 2-6 days, and without unwanted side effects.
The association with any other antidepressant drug is compatible, in particular tricyclics and monoamine oxidase inhibitors.
05.2 Pharmacokinetic properties
Absorption
In man, after intravenous administration, the pharmacokinetic profile of SAMYR is of the bi-exponential type and is composed of a phase of apparent rapid distribution in the tissues and a purification phase characterized by a half-life of about 80 minutes. By intramuscular route the absorption of the drug is practically complete (93%); the maximum plasma values of Ademetionine are reached approximately 30-45 minutes after administration and the product has a half-life similar to that observed with the intravenous route.
Orally, peak plasma concentrations are reached 3 to 5 hours after ingestion of fat-resistant tablets (400-1000 mg). Oral bioavailability is increased when ademetionine is administered under fasted conditions. The peak plasma concentration obtained after administration of the gastro-resistant tablets is dose correlated with peak plasma concentrations of 0.5 to 1 mg / l reached 3 to 5 hours after a single administration ranging from 400 mg to 1000 mg. Plasma concentrations decrease to baseline within 24 hours.
SAMYR binds only poorly to plasma proteins (5%) and is rapidly distributed in tissues and cells.
Most of the drug is part of the metabolic pathways characteristic of ademetionine (transmethylation, transulfuration, decarboxylation, etc.); the remainder of the drug is excreted unchanged in the urine.
SAMYR administered orally is absorbed from the intestinal tract and induces significant increases in plasma concentrations of Sulfo-Adenosyl-L-Methionine.
The remainder is absorbed and enters the metabolic pathways characteristic of Ademetionine. Urinary excretion occurs mainly in the form of metabolites and amounts to 15% of the dose in the 48 hours following administration.
Distribution
Distribution volumes of 0.41 and 0.44 L / kg have been reported for doses of 100 mg and 500 mg of ademetionine, respectively. Plasma protein binding is underestimated as it is greater than 5%.
Metabolism
The reactions that produce, consume and regenerate ademetionine are called the ademetionine cycle. In the first step of this cycle, an ademetionine dependent methylase uses ademetionine as a substrate to produce S-adenosyl homocysteine. S-adenosyl homocysteine is then hydrolyzed into homocysteine and adenosine from S-Adenosyl homocysteine hydrolase. Homocysteine is then converted back into methionine with the transfer of a methyl group from 5-methyltetrahydrofolate. Eventually, methionine can be converted to ademetionine, completing the cycle.
Excretion
The excretion of unmetabolized ademetionine in men is divided between urinary excretion (15.5 ± 1.5%) and faecal excretion (23.5 ± 3.5%)
05.3 Preclinical safety data
Toxicological studies were performed in multiple animal species (rats, mice, dogs) of both sexes. Chronic toxicity tests did not identify any significant organ changes.
Single toxicity, repeated dose, reproductive toxicity and mutagenicity studies have been conducted which did not demonstrate any signs of toxicity. When administered during pregnancy, no adverse events were observed in the growth and development of the embryo or fetus.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
• SAMYR 100 mg / 5ml powder and solvent for solution for injection
Mannitol. A 5 ml vial of solvent contains: water for injections, L-lysine, sodium hydroxide.
• SAMYR 200 mg / 5ml powder and solvent for solution for injection
Mannitol. A 5 ml vial of solvent contains: water for injections, L-lysine, sodium hydroxide.
• SAMYR 200 mg gastro-resistant tablets
Colloidal silica, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 6000, simethicone, polysorbate 80, sodium hydroxide, talc, iron oxide.
06.2 Incompatibility
SAMYR 100 mg / 5 ml and 200 mg / 5 ml powder and solvent for solution for injection must not be mixed with alkaline solutions or solutions containing calcium ions.
06.3 Period of validity
• SAMYR 100 mg / 5ml and 200 mg / 5ml powder and solvent for solution for injection: 3 years
• SAMYR 200 mg gastro-resistant tablets: 3 years
06.4 Special precautions for storage
Gastro-resistant tablets: no special storage precautions.
Ampoules and solvent: store at a temperature not exceeding 30 ° C.
From a chemical-physical point of view, the reconstituted product remains stable for 6 hours.
From a microbiological point of view, the product should be used immediately. Otherwise, the storage conditions (after reconstitution) are the responsibility of the user and in any case should not exceed 24 hours at a temperature between 2 and 8 ° C, unless reconstitution takes place under controlled aseptic conditions. and validated.
06.5 Nature of the immediate packaging and contents of the package
• Box containing 5 hermetically sealed glass bottles (rubber stopper and aluminum metal cap) of 100 mg + 5 glass vials containing 5 ml of solvent.
• Box containing 5 hermetically sealed glass bottles (rubber stopper and aluminum metal cap) of 200 mg + 5 glass vials containing 5 ml of solvent.
• Carton containing 2 blisters (aluminum / aluminum) of 10 gastro-resistant tablets of 200 mg.
Not all pack sizes may be marketed
06.6 Instructions for use and handling
How to open the solvent vial:
INDICATIONS FOR OPENING:
• place the vial;
• exert pressure with the thumb placed over the colored point.
07.0 MARKETING AUTHORIZATION HOLDER
ABBOTT S.r.l. S.R. 148 Pontina km 52 snc - 04011 Campoverde di Aprilia (LT)
08.0 MARKETING AUTHORIZATION NUMBER
"100 mg / 5ml powder and solvent for solution for injection" 5 vials powder + 5 solvent vials of 5 ml - A.I.C .: n. 022865149
"200mg / 5ml powder and solvent for solution for injection" 5 vials powder + 5 solvent vials 5 ml - A.I.C .: n. 022865190
20 gastro-resistant tablets of 200 mg - A.I.C .: n. 022865202
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
• "100 mg / 5 ml powder and solvent for solution for injection" 5 vials of powder + 5 vials of 5 ml solvent: 16.08.1983
• "200 mg / 5 ml powder and solvent for solution for injection" 5 vials powder +5 5 ml solvent ampoules: 21.06.1984
• 20 gastro-resistant tablets of 200 mg: 09.07.1982
Authorization renewal: 01.06.2010
10.0 DATE OF REVISION OF THE TEXT
June 2012
