COGNOLIN P Tablets (Citicoline + Piracetam)

Table of Content


Each film-coated tablet contains:
Citicoline Sodium equivalent to
Citicoline ...................... 500 mg
Piracetam ……………   400 mg
Excipients ........................... q.s.

Colour: Titanium Dioxide, IP

Dosage Form

Film-coated bilayered tablet


COGNOLIN P Tablets area fixed-dose combination of citicoline and piracetam



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 cells, re-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 neurodegeneratio 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 the sensitivity of dopaminergic receptors that have been down-regulated during prolonged levodopa therapy. The addition of citicoline to therapy with levodopa (with or without other anti-Parkinsonian agents) has been reported to improve symptoms in patients with Parkinson’s disease in small open and controlled studies.

Piracetam's mode of action in cortical myoclonus is as yet unknown. Piracetam exerts its haemorrheological effects on the platelets, red blood cells, and vessel walls by increasing erythrocyte deformability and by decreasing platelet aggregation, erythrocyte adhesion to vessel walls and capillary vasospasm.

Effects on the Red Blood Cells
In patients with sickle cell anaemia, piracetam improves the deformability of the erythrocyte membrane, decreases blood viscosity, and prevents rouleaux formation.

Effects on Platelets
In open studies in healthy volunteers and in patients with Raynaud's phenomenon, increasing doses of piracetam up to 12 g was associated with a dose-dependent reduction in platelet functions compared with pre-treatment values (tests of aggregation induced by ADP, collagen, epinephrine and beta-TG release), without significant change in platelet count. In these studies, piracetam prolonged the bleeding time.

Effects on Blood Vessels
In animal studies, piracetam inhibited vasospasm and counteracted the effects of various spasmogenic agents. It lacked any vasodilatory action and did not induce “steal”phenomenon, nor low or no reflow, nor hypotensive effects.
In healthy volunteers, piracetam reduced the adhesion of red blood cells (RBCs) to the vascular endothelium and also had a direct stimulant effect on prostacycline synthesis in healthy endothelium.
Effects on Coagulation Factors
In healthy volunteers, compared with pre-treatment values, piracetam up to 9.6 g reduced plasma levels of fibrinogen and von Willebrand's factors (VIII: C; VIII R: AG; VIII R: vW) by 30–40%, and increased bleeding time.
In patients with both primary and secondary Raynaud’s phenomenon, compared with pre-treatment values, piracetam 8 g/dayfor6 months reduced plasma levels of fibrinogen and von Willebrand's factors (VIII: C; VIII R: AG; VIII R: vW (RCF)) by 30–40%, reduced plasma viscosity, and increased bleeding time.



Citicoline is a water-soluble compound, with an absolute bioavailability of 99%. Pharmacokinetic studies on healthy adults show that oral doses of citicoline are rapidly absorbed, with less than 1% excreted in the faeces. Plasma levels peak in a biphasic manner at 1 hour after ingestion, followed by a second larger peak at 24 hours post-dosing.

Two peaks of plasma citicoline equivalents have been reported after oral doses of radiolabelled citicoline (300 mg). An initial peak is observed in approximately 1 hour (1.5 mcg/mL), presumably related to a mixture of unchanged citicoline and its metabolites (choline and cystidinediphosphate). A second peak of approximately 3 mcg/mL is seen at 24 hours post-dose, and may be due to delayed absorption of the drug or continued metabolite accumulation over this period. Brain uptake of citicoline metabolites was demonstrated as early as 30 minutes after administration. When labelled citicoline is administered orally, only about 0.5% of the total radioactivity is incorporated into the brain. Brain uptake increased to about 2% of the total radioactivity when citicoline was administered intravenously. The cerebral levels of citicoline after its administration are unknown. It is not known to what extent brain tissue levels are altered at any given dose.

Following absorption, choline and cytidine are dispersed throughout the body; they enter the systemic circulation for utilization in various biosynthetic pathways and cross the blood–brain barrier for re-synthesis into citicoline in the brain. Choline crosses the blood–brain barrier, presumably serving as a source for acetylcholine and phosphatidylcholine. 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.

Citicoline is metabolized in the gut wall and liver. Exogenous citicoline is hydrolysed and absorbed as cytidine and choline. Following absorption, choline and cytidine are re-phosphorylated, and citicoline is synthesized from cytidine triphosphate and choline monophosphate by cytidine triphosphate phosphocholine cytidyl-transferase(PCCT). As the rate-limiting intermediate in phosphatidylcholine biosynthesis, it was believed that citicoline administration would provide benefit in pathological conditions such as central nervous system (CNS) injury where membrane damage contributes to neuronal death. During phosphatidylcholine synthesis, choline monophosphate is incorporated into phosphatidylcholine and cytidine 5′-monophosphate (CMP) is released.

CMP can be utilized for the synthesis of RNA, or of DNA as the deoxyribonucleotide. The choline moiety from citicoline is also acetylated to the neurotransmitter acetylcholine or metabolized to betaine, which serves as a source of methyl groups in the synthesis of methionine and S-adenosyl-Lmethionine. AdoMet is the methyl donor in the methylation of protein and nucleotides, and the conversion of phosphatidyl-ethanolamine (PtdEtn) to phosphatidylcholine. The product, S-adenosyl-Lhomocysteine, can be metabolized further to glutathione (GSH).

Pharmacokinetic studies using 14C-citicoline show that citicoline elimination occurs in two phases mirroring the biphasic plasma peaks, mainly via respiratory carbon dioxide (CO2) and urinary 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 initial rapid decline after the 24-hour plasma peak is similarly followed by a slower elimination rate.

Small amounts of a dose are recovered in the urine (2–3%) and in the faeces (less than 1%). Approximately 12% of a dose is eliminated as respiratoryCO2. Elimination half-life of citicoline is 3.5 hours (first peak concentration), and 125 hours (second peak concentration).

Piracetam is rapidly and almost completely absorbed. Peak plasma levels are reached within 1.5 hours after administration. The extent of oral bioavailability, assessed from the area under the curve (AUC), is close to 100% for capsules, tablets and solution. Peak levels and AUC are proportional to the dose given. The volume of distribution of piracetam is 0.7 L/kg, and the plasma half-life is 5.0 hours, in young adult men. Piracetam crosses the blood–brain and the placental barrier, and diffuses across membranes used in renal dialysis. Up to now, no metabolite of piracetam has been found. Piracetam is excreted almost completely in the urine and the fraction of the dose excreted in urine is independent of the dose given. Excretion half-life values are consistent with those calculated from plasma/blood data. Clearance of the compound is dependent on the renal creatinine clearance and would be expected to diminish with renal impairment.


COGNOLIN P Tablets are indicated as an adjunct in adult patients for the treatment of acute stroke.

Dosage and Administration

Dosage should be individualized; it depends on the severity of the symptoms and the response of the individual patient. The usually recommended dose is one tablet three times a day orally or as directed by the physician.The dose may be increased up to four tablets per day.

Dosage adjustment is required in those with mild-to-moderate renal impairment and in the elderly population with diminished renal function.


COGNOLIN P Tablets are contraindicated in the following conditions:

  • Hypersensitivity to either citicoline or piracetam or any other component of the formulation.
  • Patients with severe renal impairment (renal creatinine clearance of less than 20 ml per minute) and/or hepatic impairment.
  • Patients with cerebral haemorrhage.

Warnings and Precautions


Persistent Intracranial Haemorrhage
COGNOLIN P Tablets are contraindicated in patients with persistent intracranial haemorrhage.

Effects on Platelet Aggregation
Due to the effect of piracetam on platelet aggregation, caution is recommended in patients with severe haemorrhage, patients at risk of bleeding (such as gastrointestinal ulcers), patients with underlying disorders of haemostasis, patients with a history of haemorrhagic CVA, patients undergoing major surgery (including dental surgery), and patients using anticoagulants or platelet anti-aggregant drugs (including low-dose aspirin).

Drug Interactions

General Interactions
The drug interaction potential, resulting in changes in the piracetam pharmacokinetics, is expected to be low because approximately 90% of the dose of piracetam is excreted in the urine as unchanged drug.
In vitro, piracetam does not inhibit the human liver cytochrome (CY) P450 isoforms, CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 4A9/11 at concentrations of 142, 426 and 1,422 µg/ml.
At 1,422 µg/ml, minor inhibitory effects on CYP 2A6 (21%) and 3A4/5 (11%) were observed. However, the Ki values for the inhibition of these two CYP isoforms are likely to be well in excess of 1,422 µg/ml. Therefore, metabolic interaction of piracetam with other drugs is unlikely.

Carbidopa, Levodopa and Entacapone
Citicoline may enhance the effects of levodopa, carbidopa and entacapone. The exact mechanism is unknown, but animal models suggest that citicoline may increase dopamine levels in the 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. Hence,COGNOLIN P Tablets  may increase the effect of levodopa, carbidopa and entacapone.

Co-administration with Centrophenoxine
COGNOLIN P Tablets must not be administered in conjunction with medications containing centrophenoxine.

In a published single-blind study on patients with severe recurrent venous thrombosis, piracetam 9.6 g/day did not modify the doses of acenocoumarol necessary to reach the international normalized ratio (INR) of 2.5–3.5, but compared with the effects of acenocoumarol alone, the addition of piracetam 9.6 g/day significantly decreased platelet aggregation, beta-thromboglobulin release, levels of fibrinogen and von Willebrand's factors (VIII: C; VIII: vW: Ag; VIII: vW: RCo), and whole blood and plasma viscosity. Hence,COGNOLIN P Tablets should be administered with caution with such drugs.

Anti-Epileptic Drugs
A 20 g daily dose of piracetam over 4 weeks did not modify the peak and trough serum levels of anti-epileptic drugs (carbamazepine, phenytoin, phenobarbitone, and valproate) in epileptic patients who were receiving stable doses.

Thyroid Hormones
Confusion, irritability and sleep disorder have been reported during concomitant treatment with thyroid extract (T3 + T4).


There are no adequate and well-controlled studies of citicoline plus piracetam during pregnancy and lactation. COGNOLIN P Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.


COGNOLIN P Tablets should not be used during breastfeeding or breastfeeding should be discontinued, while receiving treatment with COGNOLIN P Tablets as piracetam is excreted in human breast milk. A decision must be made whether to discontinue breastfeeding or to discontinue COGNOLIN P Tablet’s therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Geriatric Use

Adjustment of the dose is recommended in elderly patients with compromised renal function. For long-term treatment in the elderly, regular evaluation of the creatinine clearance is required to allow dosage adaptation if needed.

Renal Impairment

Piracetam is eliminated via the kidneys and, thus, care should be taken in cases of renal impairment.


Abrupt discontinuation of treatment should be avoided as this may induce myoclonic or generalized seizures in some myoclonic patients.

Undesirable Effects


Citicoline is a safe and effective nutraceutical, and toxicological tests have shown no serious side effects even after prolonged treatment. The most commonly seen undesirable effects on the administration of citicoline are anxiety, leg oedema, agitation, coughing, diarrhoea, dizziness, ECG abnormality, fever, auricular fibrillation, headache, haematuria, hypertension, hypokalaemia, hypotension, urinary tract infection, insomnia, joint pain, nausea, vomiting, pain (back/chest/shoulders), rash, and restlessness. Citicoline may cause hypotension; in case it is necessary, the hypotensive effect can be treated with corticosteroids or sympathomimetics. In a short-term, placebo-controlled, crossover study, 12 healthy adults took citicoline at daily doses of 600 and 1,000 mg or placebo for consecutive 5-day periods. Transient headaches occurred in 4 subjects on the 600mg dose, 5 on the 1,000mg 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.


Common undesirable effects reported are nervousness, hyperkinesia, and weight increased.

Uncommon undesirable effects reported are depression, somnolence, and asthenia. 


There are no known cases of overdose in humans reported for COGNOLIN P Tablets.

Storage and Handling Instructions

Store in a cool anddry place. Protect from light and moisture.

Packaging Information

COGNOLIN P Tablets.........................Strip pack of 10 tablets

Last Updated: Aug 2013
Last Reviewed: Jul 2015