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Published on: 27 Oct 2015
COGNOLIN P Tablets (Citicoline + Piracetam)
Composition
COGNOLIN P Tablets
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
Description
COGNOLIN P Tablets area fixed-dose combination of citicoline and piracetam
Pharmacology
Pharmacodynamics
Citicoline
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 1,2diacylglycerol (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
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.
Pharmacokinetics
Citicoline
Absorption
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.
Distribution
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.
Metabolism
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-adenosy-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-adenosy-Lhomocysteine, can be metabolized further to glutathione (GSH).
Elimination
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
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.
Indications
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.
Contraindications
COGNOLIN P Tablets are contraindicated in the following conditions:
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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
General
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.
Acenocoumarol
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 antiepileptic 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).
Pregnancy
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.
Lactation
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.
Discontinuation
Abrupt discontinuation of treatment should be avoided as this may induce myoclonic or generalized
seizures in some myoclonic patients.
Undesirable Effects
Citicoline
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.
Piracetam
Common undesirable effects reported are nervousness, hyperkinesia, and weight increased.
Uncommon undesirable effects reported are depression, somnolence, and asthenia.
Overdosage
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
COGNOLIN P Tablets
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