Ademetionine (Transmetil) 500 mg tablet: One tablet contains ademetionine 1,4-butanedisulfonate equivalent to 500 mg Ademetionine.
Pharmacotherapeutic group: Amino acids and derivatives. ATC-Code: A16AA02.
Pharmacology: Pharmacodynamics: Ademetionine or S-adenosyl-L-methionine, is a derivative of the amino acid methionine. Because of structural instability, stable salt forms of ademetionine are required for its use as an oral drug. The active ingredient is the salt, ademetionine 1,4-butanedisulfonate (ademetionine SD4).
Mechanism of action and Pharmacodynamic effects: S-adenosyl-L-methionine (ademetionine) is a naturally occurring amino acid present in virtually all body tissues and fluids. Ademetionine functions primarily as a coenzyme and donor transfer of the methyl group (transmethylation) is an essential metabolic process in humans and animals. Methyl transfer is also essential to the development of the phospholipid bilayer of cell membranes and contributes to membrane fluidity. Ademetionine can penetrate the blood-brain barrier and ademetionine-mediated 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 in the formation of physiological sulfurated compounds (cysteine, taurine, glutathione, CoA, etc.) via transsulfuration. Glutathione, the most potent antioxidant in the liver, is important in hepatic detoxification. Ademetionine increases hepatic glutathione levels in alcoholic and non-alcoholic liver disease patients. Both folate and vitamin B12 are essential co-nutrients in the metabolism and replenishment of ademetionine.
Clinical efficacy: Intrahepatic cholestasis: The experience accumulated with the oral and parenteral use of ademetionine for more than 20 years has shown that this drug is effective in the treatment of intrahepatic cholestasis of liver disease and of pregnancy and other chronic liver disorders.
Intrahepatic cholestasis is a complication of chronic liver diseases and other causes of hepatocellular damage. In hepatic disease, normal hepatocyte function such as the regulation and clearance of bile acids is compromised, resulting in cholestasis.
The use of ademetionine has been studied in patients with chronic liver diseases that involve intrahepatic cholestasis, including primary biliary cirrhosis, drug-induced liver injury, viral hepatitis, cholestasis induced by total parenteral nutrition, alcoholic liver disease and non-alcoholic fatty liver disease.
More than 2,700 patients affected by intrahepatic cholestasis and/or chronic liver diseases have been included into the clinical trials with ademetionine and 1983 were treated with this drug. In most of these trials, ademetionine was compared with placebo due to the almost total absence of alternative therapies at the point in time. In almost 90% of cases a cholestatic component was associated with chronic liver diseases. The remaining patients were suffering from alcoholic liver disease, acute and chronic hepatitis or intrahepatic cholestasis of pregnancy. The efficacy parameters considered in the clinical studies included the main subjective symptoms of cholestasis (itching, jaundice, fatigue, return to well-being), and biochemical markers of cholestasis and liver damage, such as total and conjugated bilirubin, alkaline phosphatase, bile salts, transaminases, γ-glutamyltransferase. The treatment with ademetionine given IV, IM or orally, improved intrahepatic cholestasis due to chronic liver disease or pregnancy, and alcoholic cirrhosis. The effects of IV or IM treatment are evident after 1-2 weeks of therapy, whereas, oral treatment is suitable for maintenance therapy.
One long-term, double-blind, placebo controlled study of 123 men and women with alcoholic liver cirrhosis found that 1,200 mg/day ademetionine for 2 years may improve survival rates and delay the need for liver transplants more effectively than placebo. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the ademetionine group, although the difference was not statistically significant. Long-term treatment with ademetionine reduced the overall mortality/liver transplantation, especially in patients with less advanced liver disease.
Intrahepatic cholestasis of pregnancy: The efficacy of treatment with Ademetionine was assessed in 7 clinical trials including 264 women with intrahepatic cholestasis of pregnancy. Of these, 156 were treated with ademetionine, 21 received placebo, 60 an active control (ursodeoxycholic acid) and 27 ademetionine plus ursodeoxycholic acid. The treatment with ademetionine given IV, IM or orally, was effective in treatment of intrahepatic cholestasis of pregnancy with improvement of pruritus and biochemical parameters.
Pharmacokinetics: Absorption: In humans, following intravenous administration, the ademetionine pharmacokinetic profile is bi-exponential and composed of a rapid apparent distribution phase into the tissues and a terminal elimination phase characterized by a half-life of approximately 1.5 hours. When administered intramuscularly, absorption of ademetionine is practically complete (96%); the maximum plasma concentrations of ademetionine are reached after approximately 45 minutes. Following oral administration of ademetionine, peak plasma concentrations obtained after administration of enteric-coated tablets are dose related, with peak plasma concentrations of 0.5 to 1 mg/L achieved 3 to 5 hours after single doses ranging from 400 mg to 1000 mg. Plasma concentrations decline to baseline within 24 hours. Oral bioavailability is enhanced when ademtionine is administered under fasting conditions.
Distribution: Volumes of distribution of 0.41 and 0.44 L/kg have been reported for doses of 100 mg and 500 mg ademetionine, respectively. Binding to plasma proteins is negligible being ≤5%.
Metabolism: The reactions that produce, consume, and regenerate ademetionine are called the ademetionine cycle. In the first step of this cycle, ademetionine-dependent methylases use ademetionine as a substrate and produce S-adenosyl-homocysteine. S-adenosyl-homocysteine is then hydrolyzed to homocysteine and adenosine by S-adenosyl-homocysteine hydrolase. The homocysteine is then recycled back to methionine with the transfer of a methyl group from 5-methyltetrahydrofolate. Finally, methionine can be converted back to ademetionine, completing the cycle.
Excretion: In tracer balance studies using orally administered, radioactive (methyl 14C) SAMe in normal volunteers, urinary excretion of radioactivity was 15.5 ± 1.5% after 48 hours and fecal excretion was 23.5 ± 3.5% after 72 hours, leaving approximately 60% incorporated into stable pools.
Toxicology: Preclinical Safety Data: Toxicology studies were performed as single dose and repeat dose in multiple animal species including mouse, rat, hamster and dog of both sexes by the oral, subcutaneous, intravenous, and intramuscular route.
Repeat dose toxicity testing indicated that the kidney is the target organ in the rat and hamster and to a much lesser extent in the dog. Possibly, the testis is a further target organ in the rat. No other significant changes to body organs were observed. Single dose toxicity, repeated dose toxicity through 104 weeks, reproduction toxicity, and mutagenicity studies did not demonstrate any other notable signs of toxic effects.
Ademetionine is indicated for treatment of adults with: Intrahepatic cholestasis in pre-cirrhotic and cirrhotic states; Intrahepatic cholestasis in pregnancy.
The recommended dosing is 10-25 mg/kg/day orally. The usual starting dose is 400-800 mg/day, total daily dose not to exceed 1600 mg.
Maintenance therapy: 500-1,600 mg/day.
Pediatric Population: The safety and efficacy of ademetionine for the use in children has not been established.
Elderly Population: Clinical studies of ademetionine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal Impairment: There is limited clinical data in patients with renal impairment. Caution is recommended when administering ademetionine to these patients.
Hepatic Impairment: Pharmacokinetic parameters are similar in healthy volunteers and patients with chronic liver disease.
Method of Administration: Ademetionine tablets should be swallowed whole and not chewed.
For better absorption of the active ingredient and complete therapeutic effect, ademetionine tablets should not be taken with meals.
Ademetionine tablets should be extracted from the blister package immediately before use. If the tablets appear other than white to yellowish in color (due to presence of holes in the aluminum wrapper), it is recommended the product not be used.
Cases of overdose with ademetionine appear to be rare. Physicians should contact their local poison control centers. In general, patients should be monitored and supportive care provided.
Hypersensitivity to the active substance or to any of the excipients; Patients with genetic defects affecting the methionine cycle and/or causing homocystinuria and/or hyperhomocysteinemia (e.g. cystathionine beta-synthase deficiency, Vitamin B12 metabolism defect).
Ammonia levels should be monitored in patients with pre-cirrhotic and cirrhotic states of hyperammonemia taking oral ademetionine.
Because vitamin B12 and folate deficiencies may decrease ademetionine levels, at risk patients (anemia, liver disease, pregnancy or potential for vitamin deficiencies due to other illnesses or eating habits such as vegans) should have routine blood tests to check the plasma levels. If a deficiency is found, treatment with B12 and/or folate is recommended prior to or concurrently with administration of ademetionine (see Pharmacology: Pharmacokinetics under Actions).
Ademetionine is not recommended for use in patients with bipolar disease. There have been reports of patients switching from depression to hypomania or mania when treated with ademetionine. There has been a single literature report of serotonin syndrome in a patient taking ademetionine and clomipramine. Although a potential interaction is postulated, caution is recommended when administering ademetionine concomitantly with selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (such as clomipramine), and over-the-counter and herbal supplements containing tryptophan (see Interactions).
The efficacy of ademetionine in the treatment of depression was studied in short-term clinical trials (3-6 weeks in duration). The effectiveness of ademetionine in the treatment of depression over longer periods is unknown. There are many medications to treat depression, and patients should consult with their physicians to determine optimal therapy. Patients should be encouraged to inform their physicians if their symptoms do not abate or worsen during ademetionine therapy.
Patients with depression are at risk for suicide and other serious events and therefore should receive continuous psychiatric support during therapy with ademetionine to ensure that the symptoms of depression are adequately addressed and treated.
There have been reports of transient or worsening anxiety in patients treated with ademetionine. In most cases, interruption of therapy was not required. In a few cases, the anxiety resolved after a reduction in dosage or discontinuation of therapy.
Interference with homocysteine immunoassays: Ademetionine interferes with homocysteine immunoassays, which may show falsely elevated levels of plasma homocysteine in patients treated with ademetionine. In patients treated with ademetionine, it is therefore recommended to use non-immunological methods to measure plasma homocysteine.
Effects on Ability to Drive and Use Machines: Some patients may experience dizziness with the use of ademetionine. Patients should be advised not to drive or operate machinery during treatment until they are reasonably certain that ademetionine therapy does not affect their ability to engage in such activities.
Use in Pregnancy: In clinical studies, no adverse reactions were observed in women in the last three months of pregnancy treated with ademetionine. It is advisable to administer ademetionine in the first three months of pregnancy only if it is absolutely necessary.
Use in Lactation: Ademetionine should be used while breast-feeding only if the potential benefit justifies the potential risk to the infant.
In clinical trials, more than 2100 patients were exposed to Ademetionine. The most frequently reported events with Ademetionine treatment were Headache, Diarrhea and Nausea.
The following undesirable effects have been observed with the frequencies indicated as follows during clinical trials using Ademetionine (n=2115) and from spontaneous reporting.
Adverse reactions listed by System Organ Class. Frequencies are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000). (See Table.)
Click on icon to see table/diagram/image
Serotonin syndrome has been reported in a patient taking ademetionine and clomipramine. Therefore, although a potential interaction is postulated, caution is recommended when administering ademetionine concomitantly with selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (such as clomipramine), and over-the-counter and herbal supplements containing tryptophan (see Precautions).
Incompatibilities: See Dosage & Administration.
Store at temperatures not exceeding 30°C.
Shelf Life: 24 Months.
A16AA02 - ademetionine ; Belongs to the class of amino acids and derivatives products. Used in treatment of alimentary tract and metabolism problems.
Tab 500 mg (white to yellowish, oval) x 10's.