Citicoline Injection 500mg Taj Pharma

Name of the medicinal product

Citicoline Injection 125mg Taj Pharma
Citicoline Injection 250mg Taj Pharma
Citicoline Injection 500mg Taj Pharma
Citicoline Injection 1000mg Taj Pharma

Qualitative and quantitative composition

Each ml contains:
Citicoline Sodium equivalent to Citicoline 125 mg
Excipients q.s

Citicoline Sodium equivalent to Citicoline 250 mg
Excipients q.s

Citicoline Sodium equivalent to Citicoline 500 mg
Excipients q.s

Citicoline Sodium equivalent to Citicoline 1000 mg
Excipients q.s.

Pharmaceutical form

Solution for Injection

Dosage Form

Injection for intravenous/intramuscular use

Pharmacology

Pharmacodynamics

Citicoline is a complex organic molecule that functions as an intermediate in the biosynthesis of cell membrane phospholipids. Citicoline is also known as CDP-choline and cytidine diphosphate choline (cytidine 5’-diphosphocholine). Citicoline is composed of two essential moieties, cystidine and choline, linked by a diphosphate bridge, and serves as the phosphocholine donor to 1, 2-diacylglycerol (DAG) to form phosphatidylcholine. It is a pyrimidine 5’-nucleotide, which serves as an essential precursor in the synthesis of lecithin (phosphatidylcholine) and other phospholipids. The extensive damage caused by stroke requires repair and regeneration of the axons and synapses of neurons, so new membrane production is necessary.

Results of various studies have suggested the following actions of citicoline:

Phospholipid Precursor

Evidence of citicoline’s role as a phosphatidylcholine precursor has been found in animal studies. The brain uses choline preferentially for acetylcholine synthesis, which can limit the amount of choline available for phosphatidylcholine production. When the demand for acetylcholine increases or choline stores in the brain are low, phospholipids in the neuronal membrane can be catabolized to supply the needed choline. Exogenous citicoline, thus, helps preserve the structural and functional integrity of the neuronal membrane. In an in vitro study, citicoline at high concentrations stimulated brain acetylcholinesterase (AChE) along with Na+/K+-ATPase. The postulated mechanism involves the bioconversion of citicoline to phosphatidylcholine.

Neuronal Membrane Repair

Citicoline has been investigated as a therapy for stroke patients. Three mechanisms are postulated: (1) ability to repair neuronal membranes via increased synthesis of phosphatidylcholine; (2)repair of damaged cholinergic neurons via potentiation of acetylcholine production; and, (3) reduction of free fatty acid build-up at the site of stroke-induced nerve damage. In addition to phosphatidylcholine, citicoline serves as an intermediate in the synthesis of sphingomyelin, another neuronal membrane phospholipid component. Citicoline has shown the potential to restore post-ischaemic sphingomyelin levels. Citicoline also restores the levels of cardiolipin, a phospholipid component of the inner mitochondrial membrane. The mechanism for this is unknown, but data suggest that citicoline inhibits enzymatic hydrolysis of cardiolipin by phospholipase A2.Citicoline avoids, reduces or reverses the effects of ischaemia and/or hypoxia in the major part of animals and cellular models studied; it also acts in the cranial traumatic forms, reduces and limits the injuries to the membranes of the nerve cellsre-establishes the sensitivity and the function of the regulatory intracellular enzymes and accelerates the re-absorption of cerebral oedema. Thus, considerable evidence accumulated supports the use of citicoline for increasing, maintaining and repairing the membranes and the neuronal function in situations such as ischaemia and traumatic injuries.

Reduction of Free Fatty Acid Build-Up

Citicoline may benefit patients experiencing ischaemia by decreasing the accumulation of free fatty acids at the site of the lesion, which occurs as a result of neuronal cell damage and death. Soon after the initiation of ischaemia, there is a significant increase in pro-inflammatory arachidonic acid, glycerols and free fatty acids caused by the breakdown of neuronal membranes. Toxic metabolites as well as prostaglandins, thromboxanes and free radicals can accumulate, leading to further damage. Animal studies have demonstrated evidence in suppressing free fatty acid build-up. Human data is limited.

Effect on Beta-Amyloid

Evidence has surfaced that citicoline counteracts the deposition of beta-amyloid, a neurotoxic protein believed to play a central role in the pathophysiology of Alzheimer’s disease (AD). The characteristic lesion in AD is the formation of plaques and neurofibrillary tangles in the hippocampus. The degree of cognitive dysfunction and neurodegeneration in AD is proportional to the build-up of beta-amyloid.

Effect on Norepinephrine

Evidence of the ability of citicoline to enhance norepinephrine release in humans was found in a study showing that citicoline raises urinary levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a norepinephrine metabolite. Citicoline increased brain levels of neurotransmitters in rats at a dose of 100 mg/kg, administered daily for 7 days. Norepinephrine increased in the cerebral cortex and hypothalamus, dopamine increased in the corpus striatum, and serotonin increased in the cerebral cortex, striatum and hypothalamus.

Activation of the Dopaminergic System

With respect to dopaminergic activation, citicoline has been reported to exert dopaminergic agonist effects in the corpus striatum, enhance dopamine synthesis in the striate body (by activation of tyrosine hydroxylase), inhibit dopamine uptake by synaptosomes, and increase sensitivity of dopaminergic receptors that have been down-regulated during prolonged levodopa therapy. The addition of citicoline to therapy with levodopa (with orwithout other anti-Parkinsonian agents) has been reported to improve symptoms in patients with Parkinson’s disease in small open and controlled studies.

Pharmacokinetics

Absorption

Citicoline is well absorbed following intramuscular administration. After intramuscular doses of citicoline 1,000 mg, peak increases in plasma choline levels were seen in 0.4 hours, with levels increasing from 11 micromol/L (baseline) to 25 micromol/L.

Distribution

Choline derived from citicoline crosses the blood–brain barrier, presumably serving as a source of acetylcholine and phosphatidylcholine (lecithin) synthesis. The major portion of a dose of citicoline appears to be incorporated into tissues and/or used in biosynthetic/ biodegradation pathways, including lecithin/lipid membrane synthesis.

Metabolism

Citicoline is metabolized in the liver to free choline. The liver is capable of synthesizing lecithin from choline. The half-life of free choline is of 2 hours after intramuscular administration.

Excretion

Only small amounts of dose are recovered in the urine andfaeces (less than 3% each). Approximately 12% of a dose is eliminated through the lungs as carbon dioxide.

Indications

Citicoline Injection is indicated for the treatment of patients with disturbance of consciousness resulting from a head injury or brain operation, and in the acute stage of cerebral infarction.

Dosage and Administration

Disturbance of Consciousness Resulting from Head Injury or Brain Operation

Usually, for adults, a dose of 100–500 mg of Citicoline Injection is administered once or twice a day, by intravenous drip infusion, intravenous injection or intramuscular injection. The dose may be adjusted according to the patient’s age and condition.

Disturbance of Consciousness in the Acute Stage of Cerebral Infarction

Usually, a dose of 1,000 mg of Citicoline Injection is administered once a day, by intravenous injection, for 2 consecutive weeks.

Contraindications

Hypersensitivity to Citicoline Injection or any other component of the formulation.

Warnings and Precautions

General

For patients with acute, severe and progressive disturbance of consciousness resulting from a head injury or brain operation, citicoline injection should be administered in conjunction with haemostatics and an intracranial pressure relieving drug, or a treatment such as hypothermia. For patients with disturbance of consciousness in the acute stage of cerebral infarction, it is recommended to start the administration of citicoline injection within 2 weeks after an apoplectic stroke.

In administering citicoline injection intramuscularly, caution should be exercised so as not to affect the tissues, nerves, etc. Intramuscular injection should be given only when indispensable, and should be restricted to the minimum to be required. In particular, repeated injection at the same site should be avoided. Care should be exercised to avoid injection at sites along the course of the nerves. In case of intense pain or backflow of blood upon insertion of the injection needle, the needle should be withdrawn immediately and injected at a different site.In intravenous administration, inject as slowly as possible. Since shock may occur, a close observation should be maintained. If any such abnormalities such as drop in blood pressure, distressed feeling of the chest or dyspnoea are observed, citicoline injection should be discontinued and appropriate measures taken.

Persistent Intracranial Haemorrhage

In case of persistent intracranial haemorrhage, it is recommended not to exceed the dose of 1,000mg of citicoline daily, given through very slow intravenous administration (30 drops/minute)

Drug Interactions

Carbidopa, Levodopa and Entacapone

Citicoline may enhance the effects of levodopa, carbidopa and entacapone. The exact mechanism is unknown, but animalmodels suggest that citicoline may increase dopamine levels inthe brain and/or improve dopaminergic cell survival. In patients with Parkinson’s disease, a few studies have demonstrated levodopa-saving effects, whereby the addition of citicoline(500–1,200 mg/day) allowed for lower dosages of levodopa to be used with stable or improved therapeutic efficacy and reduced the side effects in some patients. However, data are limited.

Co-administration with Centrophenoxine

Must not be administered in conjunction with medications containing centrophenoxine.

Pregnancy

There are no adequate and well-controlled studies of citicoline during pregnancy. Citicoline should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Lactation

Caution should be exercised during breastfeeding because it is not known whether citicoline is excreted in breast milk.

Geriatric Use

No dosage adjustment is required in this patient population and the usually recommended adult dose can be administered.

Undesirable Effects

The commonly observed adverse effects (0.1–5%) with intravenous use of citicoline were rash, insomnia, occurrence or intensification of numbness of paralyzed extremities (when usedin patients with post-apopleptic hemiplegia), nausea, abnormal laboratory values for function of the liver, and feeling of warmth.

The other adverse reactions (<0.1%) were excitation, convulsions, anorexia, transient diplopia, transient blood pressure changes, malaise, shock, distressed feeling of the chest, and dyspnoea. In a short-term, placebo-controlled, crossover study, 12 healthy adults took citicoline at daily doses of 600 mg and 1,000 mg or placebo for consecutive 5-day periods. Transient headaches occurred in 4 subjects on the 600 mg dose, 5 on the 1,000 mg dose, and 1 on placebo. No changes or abnormalities were observed in haematology, clinical biochemistry or neurological tests. A large drug surveillance study analysed the results of citicoline treatment in 2,817 patients aged 60 to 80 years, suffering from senility and cerebral vascular insufficiency. A total of 151 incidents of side effects were recorded, representing 5% of the patient sample. The most common adverse effects were transient in nature and included stomach pain and diarrhoea in 102 cases. Vascular symptoms of hypotension, tachycardia or bradycardia occurred in 16 cases.

Overdosage

There are no known cases of overdose in humans available for citicoline.

Incompatibility

Citicoline must not be administered in conjunction with medicaments containing meclofenoxate (also known asclophenoxate).

Storage and Handling Instructions

Store in a cool place. Protect from light.

Packaging Information

Citicoline Injection: Ampoule of 2 ml and 4 ml

MANUFACTURED IN INDIA BY:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com