Heptral

Heptral

Manufacturer:

Abbott

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ademetionine.
Description
Each enteric-coated tablet contains ademetionine 949 mg equivalent to 500 mg ion. It also contains the following excipients: Microcrystalline cellulose, magnesium stearate, polyethylene glycol 6000, polymethacrillates, polysorbates, colloidal silica, emulsified silicon, sodium-starch glycolate, talc.
Ademetionine is (sulfo-adenosyl-L-methionine)1,4-butanedisulfonate.
Action
Pharmacology: Pharmacodynamics: 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, noradrenalin, 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 detoxificatlon. 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.
Pharmacokinetics: Absorption: Following oral administration of ademetionine, peak plasma concentrations are achieved 3-5 hrs after ingestion of enteric-coated tablets (400-1000 mg). Oral bioavailability is enhanced when ademetionine is administered under fasting conditions. Peak plasma concentrations obtained after administration of enteric-coated tablets are dose related, with peak plasma concentrations of 0.5-1 mg/L achieved 3-5 hrs after single doses ranging from 400-1000 mg. Plasma concentrations decline to baseline within 24 hrs.
Distribution: Volumes of distribution of 0.41 L/kg and 0.44 L/kg have been reported for doses of 100 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 1st 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: Excretion of unmetabollzed ademetionine in humans is split between urinary excretion (15.5±1.5 %) and fecal excretion (23.5±3.5 %).
Toxicology: Preclinical Safety Data: Toxicological studies were performed in multiple animal species (rat, mouse, dog) of both sexes. Chronic toxicity testing did not identify any significant changes to body organs. Single-dose toxicity, repeated-dose toxicity, reproduction toxicity and mutagenicity studies were performed and did not demonstrate any signs of toxic effects.
When administered throughout pregnancy, no adverse effects were observed in the growth and development of the embryo or fetus.
Indications/Uses
Treatment of adults with intrahepatic cholestasis in precirrhotic and cirrhotic states, and intrahepatic cholestasis in pregnancy. Relief of fatigue caused by chronic liver disease.
Dosage/Direction for Use
Treatment can be initiated with parenteral administration and continued or initiated orally.
Adults: Intrahepatic Cholestasis: 10-25 mg/kg/day orally. Usual Starting Dose: 800 mg/day. Total Daily Dose: Not to exceed 1600 mg.
Maintenance Therapy: 800-1600 mg/day.
Administration: Ademetionine tablets should be swallowed whole and not chewed.
For better absorption of ademetionine and complete therapeutic effect, ademetionine tablets should not be taken with meals.
Overdosage
Cases of overdose with ademetionine appear to be rare. Physicians should contact local poison control centers. In general, patients should be monitored and supportive care provided.
Contraindications
Known hypersensitivity to ademetionine or to any of the excipients of Heptral.
Special Precautions
To be used under the supervision of a physician.
Ammonia levels should be monitored in patients with precirrhotic 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 eg, vegans) should have routine blood tests to check the plasma levels. If a deficiency is found, treatment with vitamin 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 (SSRIs), tricyclic antidepressants (eg, clomipramine) and over-the-counter and herbal supplements containing tryptophan (see Interactions).
Renal Impairment: Studies have not been conducted in patients with renal impairment. Therefore, caution is recommended when administering ademetionine to these patients.
Hepatic Impairment: Pharmacokinetic parameters are similar in healthy volunteers and patients with chronic liver disease.
Effects on the Ability to Drive or Operate Machinery: 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 reasonabty certain that ademetionine therapy does not affect their ability to engage in such activities.
Use in pregnancy: The use of high doses of ademetionine in women in the last 3 months of pregnancy did not lead to any adverse effect. It is advisable to administer ademetionine in the first 3 months of pregnancy only if it is absolutely necessary.
Use in lactation: Ademetionine should be used while breastfeeding only if the potential benefit justifies the potential risk to the infant.
Use in children: The safety and efficacy of ademetionine for the use in children has not been established.
Use in the elderly: Clinical studies of ademetionine did not include sufficient numbers of subjects ≥65 years 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.
Use In Pregnancy & Lactation
Use in pregnancy: The use of high doses of ademetionine in women in the last 3 months of pregnancy did not lead to any adverse effect. It is advisable to administer ademetionine in the first 3 months of pregnancy only if it is absolutely necessary.
Use in lactation: Ademetionine should be used while breastfeeding only if the potential benefit justifies the potential risk to the infant.
Adverse Reactions
Clinical Trials: Ademetionine was studied in 2434 patients of whom 1983 were exposed to ademetionine with liver disease and 817 patients with depression, in controlled and open trials for up to 2 years.
The following adverse reactions are based on 1667 patients in 22 clinical trials treated with ademetionine, of whom 121 (7.2%) experienced a total of 188 adverse reactions. Nausea, abdominal pain and diarrhea were the most frequently reported adverse reactions. A causal relationship of the adverse event with the drug was not always assessable.
Infections and Infestations: Urinary tract infection.
Psychiatric Disorders: Confusion, insomnia.
Nervous System Disorders: Dizziness, headache, paresthesia.
Cardiac Disorders: Cardiovascular disorders.
Vascular Disorders: Hot flushes, superficial phlebitis.
Gastrointestinal Disorders: Abdominal distension and pain, diarrhea, dry mouth, dyspepsia, esophagitis, flatulence, gastrointestinal pain and hemorrhage, nausea, vomiting.
Hepatobiliary Disorders: Biliary colic, hepatic cirrhosis.
Skin and Subcutaneous Tissue Disorders: Hypehydrosis, pruritus, skin reactions.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.
General Disorders and Administration Site Conditions: Asthenia, chills, injection site reactions, influenza-like illness, malaise, peripheral edema, pyrexia.
Post-Marketing Experience: Immune System Disorders: Anaphylactic reaction.
Respiratory, Thoracic and Mediastinal Disorders: Laryngeal edema.
Skin and Subcutaneous Tissue Disorders: Injection site reactions (very rarely with skin necrosis), rash, angioedema.
Drug Interactions
Serotonin syndrome has been reported in patients taking ademetionine and clomipramine. Therefore, although a potential interaction is postulated, caution is recommended when administering ademetionine concomitantly with SSRIs, tricyclic antidepressants (eg, clomipramine), and over-the-counter and herbal supplements-containing tryptophan (see Precautions).
Incompatibilities: Not known.
Caution For Usage
Ademetionine tablets should be extracted from the blister package immediately before use. If the tablets appear other than white in color (due to presence of holes in the aluminum wrapper), it is recommended the product not be used.
Storage
Shelf-Life: 36 months.
ATC Classification
A16AA02 - ademetionine ; Belongs to the class of amino acids and derivatives products. Used in treatment of alimentary tract and metabolism problems.
Presentation/Packing
Gastro-resistant tab 500 mg (oval shaped, white to off-white) x 2 x 10's.
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