Formulation

Each film-coated tablet contains:

Citicoline (as Sodium)….. 500 mg

Description

White-colored film-coated capsule-shaped biconvex tablet.

Indications

For the treatment of patients with serious cerebral injuries of vascular traumatic nature with or without loss of consciousness and for the treatment of degenerative damages and chronic cerebral vascular injuries in senile dementia.

Dosage & Administration

2 tablets daily or as prescribed by the physician.

Citicoline should be taken orally with a glass of water. To prevent an upset stomach you may take it with food. Remember

when taking Citicoline or any prescription drug to always follow the label closely. Do not take more than directed.

Citicoline should only be taken as instructed by a professional physician. Be sure to remember not to stop taking this medicine without consulting your physician first about how to stop safely. If you are researching this medication for your child

keep in mind that children often have special dosage instructions. Ask your physician about these differences prior to starting this medication if this is the case.

In the event that a dose of Citicoline was missed

take one as soon as you can. But if your next scheduled dose is near

wait until that next dose is due and just skip the one you’ve already missed.

Undesirable Effects

Very rare (<1 / 10000) (includes individual reports)

Psychiatric:

Hallucinations

Nervous system disorders: Headache

vertigo

Vascular disorders:

Hypertension

hypotension

Respiratory

thoracic and mediastinal:

Dyspnea

Gastrointestinal disorders: Nausea

vomiting

occasional diarrhea

Skin and subcutaneous tissue disorders:

Flushing

urticaria

rash

purpura

General disorders:

Chills

Interactions with Drugs

 Choline supplementation has been associated with decreasing urinary excretion of carnitine in young adult women.

 A study concluded that chronic treatment with lithium enhances the effects of choline in the brain. A preliminary report of MRI studies did not observe a significant

positive relationship between increases in brain choline and increases in brain lithium.

 CDP-choline can cause an increase in plasma concentrations of dopa.

 Methotrexate may diminish pools of all choline metabolites. Choline supplementation reverses fatty liver caused by methotrexate administration in rats.

 Pentazocine exhibits neuromuscular blocking effects in part through a depressive action on cholinoceptive sites on the nerve motor end terminals

presenting a

possible interaction if administered with choline.

 Although a few studies have linked choline with partially reversing the effects of scopolamine

a later study failed to demonstrate similar effects.

 Choline is a product of the breakdown of succinylcholine. Taking choline with succinylcholine may theoretically intensify effects and/or toxicity.

Interactions with Herbs and Supplements

 Choline

via its metabolism to betaine

works in concert with vitamins B6

B12

and folic acid in the metabolism of the potentially atherogenic substance homocysteine.

Pregnancy and Lactation

During pregnancy

intake of Citicoline by the mother may influence memory and brain development in the growing infant. Studies on citicoline and lecithin supplementation clearly show an increase in blood choline levels following supplementation.

Pregnant and lactating women and children may consume choline within the recommended adequate intake (AI) parameters; supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed.

Warnings and Precautions

Must not be administered in conjunction with medications containing centrophenoxine. In case of persistent intracranial hemorrhage

it is recommended not to exceed the dose of 1000 mg of Citicoline daily.

Cholines are generally regarded as safe and appear to be well-tolerated. High intake of cholines may cause low blood pressure

steatorrhea (undigested fat in stool)

nausea

vomiting

salivation

diarrhea

constipation

anorexia

dizziness (vertigo)

sweating

insomnia and headache. Cholines can possibly trigger existing epilepsy.

Dosages at the upper limit (UL) intake levels are contraindicated for persons suffering from trimethylaminuria

Parkinson’s disease

or kidney or liver disease.

Skin rash has been reported. A cold and cough were noted in patients taking citicoline in a trial. Choline should be used cautiously by people with kidney or liver disorders. Agitation

paranoia and severe depression have been reported. Use cautiously in patients with a history of depression.

Because choline is a product of the breakdown of succinylcholine

it may produce undesirable effects as the drug

like respiratory depression. A “fishy” odor has been associated with choline. Sweating and stunted growth may occur.

Overdosage

Intoxication appearance is unlikely due to low toxicity

even in cases when the therapeutic doses are accidentally exceeded.

In case of accidental overdose a symptomatic therapy is carried out. Contraindications

Must not be administered to patients with hypertonia of the parasympathetic nervous system Citicoline is contraindicated in conditions like unconsciousness

brain surgery.

Pharmacodynamic Properties

Pharmacotherapeutic group:

Psychostimulants and nootropics

ATC code:

N06BX06

Mechanism of Action

Citicoline stimulates the biosynthesis of structural neuronal membrane phospholipids

as demonstrated in studies with magnetic resonance spectroscopy. Citicoline by

this action improves the function of the mechanisms of membrane

such as the operation of pumps and ion exchange receptors embedded in it

whose modulation is

essential for proper neurotransmission. Citicoline by its membrane stabilizing action has properties that favor reabsorption of cerebral edema.

Experimental studies have shown that citicoline inhibits the activation of specific phospholipases (A1

A2

C and D)

reducing free radical formation

avoiding the

destruction of membranes and preserving antioxidant defense systems

such as glutathione. Citicoline protects the reserve neuronal energy; it inhibits and stimulates the

synthesis of acetylcholine. Experiments have shown that citicoline also has prophylactic neuro-protective effect in models of focal cerebral ischemia.

Clinical trials have shown that citicoline significantly improves the functional development in patients with acute ischemic stroke

coinciding with slower growth of cerebral

ischemic injury in brain imaging tests. In patients with head injury

citicoline accelerates recovery in these patients and reduces the duration and intensity of postconcussion

syndrome. Citicoline improves the level of attention and awareness

as well as acts favorably on amnesia and cognitive impairment and neurological disorder

associated with cerebral ischemia.

Pharmacokinetic Properties

Citicoline is a water-soluble compound with greater than 90-percent bioavailability. Pharmacokinetic studies on healthy adults show oral doses of citicoline are rapidly

absorbed

with less than one percent excreted in feces. Plasma levels peak in a biphasic manner

at one hour after ingestion followed by a second larger peak at 24 hours

post-dosing. Citicoline is metabolized in the gut wall and liver. The byproducts of exogenous citicoline formed by hydrolysis in the intestinal wall are choline and cytidine.

Following absorption

choline and cytidine are dispersed throughout the body; enter systemic circulation for utilization in various biosynthetic pathways

and cross the

blood-brain barrier for resynthesis into citicoline in the brain.

Pharmacokinetic studies using 14C citicoline show citicoline elimination occurs in two phases mirroring the biphasic plasma peaks

mainly via respiratory CO and urinary 2

excretion. The initial peak in plasma concentration is followed by a sharp decline

which then slows over the next 4-10 hours. In the second phase

an initially rapid decline

after the 24-hour plasma peak is similarly followed by a slower elimination rate. The elimination half-life is 56 hours for CO and 71 hours for urinary excretion. 2

Endogenous citicoline serves as an intermediate in the biosynthesis of phospholipids

including phosphatidylcholine

the primary phospholipids in cell membranes.

Cytidine

a major component of RNA

undergoes cytoplasmic conversion to cytidine triphosphate (CTP). In the citicoline metabolic pathway

choline is phosphorylated by

the enzyme choline kinase; the resulting phosphorylcholine combines with CTP to form citicoline. Citicoline then combines with diacylglycerol (DAG)

forming

phosphatidylcholine

with choline phosphotransferase serving as the enzyme catalyst in this reaction.

Oral administration of citicoline raises plasma levels of cytidine and choline in rats within six to eight hours. Prolonged administration for 42 and 90 days increases brain

concentrations of phosphatidylcholine

phosphatidylethanolamine

and phosphatidylserine – the three major phospholipids in brain cell membranes. Evidence for the role

of these metabolites as substrates for phosphatidylcholine synthesis was found in a study giving rats daily oral doses of citicoline for 90 days. At a dose of 500 mg/kg per

day phosphatidylcholine levels increased by 25 percent

phosphatidylethanolamine by 17 percent

and phosphatidylserine by 42 percent. Administration of citicoline to

aged rats activates CTP:phosphocholine cytidylyltransferase

the rate-limiting enzyme in the citicoline pathway of phosphatidylcholine synthesis in the brain cell

membrane. Choline and cytidine are the major metabolites released via hydrolysis of citicoline during absorption.

A single oral dose of citicoline raises plasma choline levels in both younger and older subjects. Using protein magnetic resonance spectroscopy

it was found that brain

choline levels in older subjects decreased after citicoline administration

but increased in younger subjects. The postulated explanation is that the cytidine moiety of

citicoline may be taken up by brain cells in older adults more rapidly than choline. Based on this finding

it is suggested that cytidine is the citicoline component primarily

responsible for stimulating phosphatidylcholine synthesis in older subjects. Using protein-decoupled phosphorus magnetic resonance spectroscopy

it has been shown

that citicoline administration to older subjects for six weeks increases brain levels of phosphodiesters

byproducts of phospholipid metabolism. This is seen as evidence

that citicoline increases phospholipids synthesis and turnover

which may help reverse cognitive functional deficits associated with aging. In clinical trials

citicoline has

been administered orally and by intramuscular injection.

Storage Condition

Store at temperatures not exceeding 30°C.

Caution

Foods

Drugs

Devices and Cosmetics Act prohibits dispensing without prescription.

Availability

Alu-Alu Blister Pack of 10 tablets (Box of 10’s)

Manufactured by

Kusum Healthcare Private Limited

SP-289(A) RIICO Indl. Area Chopanki (Bhiwadi)

Distt-Alwar

Rajasthan

INDIA

Imported and Distributed by

S.M.H.P. Marketing & Consultancy

G/F Manor Bldg.

2629 Taft Avenue

Malate

Manila

PHILIPPINES