PSUR Redaction

PERIODICAL REPORT ON THE SAFETY OF DRUGS
(Citicoline Sodium Oral Drops 100 mg/mL)
NUCLOTEC REMEDIES PVT. LTD.
The holder of the registration certificate:
NUCLOTEC REMEDIES PVT. LTD., India.
14 Milestone, Rudrapur-Kashipur Road,

Gadarpur, U.S.Nagar-263152, Uttarakhand-India.
Reporting period (date) –10th Jan, 2019-25th Feb, 2022

International date of birth: Not Available
DATE OF REPORT: 27th Feb 2022
Periodic report on the safety of the medical product.
(The report was prepared by: Name, position of the responsible officer (s))
Name: Dr. N K Nagrani
Head, Pharmaco-vigilance
Nuclotec Remedies Pvt. Ltd., India.
Other Information:
Data Lock Point of the Next PSUR : 04/06/2025 (Expected)
TO REGULATORY ORGANIZATIONS, CONFIDENTIAL

The information contained in this report is formally vested in right of exclusive use and is protected
unauthorized disclosure in accordance with the current legislation. All pages of this document contain
confidential information. If it is not addressed to you or you are not its authorized recipient, we
strongly recommend not to use, distribute, publish, copy or storing this information electronically
without obtaining written permission from the owner of the copyright rights. Copyright and property
rights:
(20. y.).
Confidential report, generated electronically. PSUR/MPL/001-00

CONTENT
LIST OF TABLES INCLUDED IN THE TEXT
Sr. No. Title
1. INTRODUCTION
2. DATA ON REGISTRATION OF DRUGS ON THE WORLD MARKET
3. ADJUSTMENTS ADOPTED BY REGULATORY ORGANIZATIONS OR HOLDERS
OF REGISTRATION CERTIFICATES, FOR THE CAUSE OF SECURITY
4. CHANGES TO THE SAFETY DATA SHEET
5. VOLUME OF CONSUMPTION OF DRUGS
6. PRESENTATION OF SELECTED CASES OF UNDESIRABLE REACTIONS
6.1 PRESENTATION OF SELECTED CASES OF UNDESIRABLE REACTIONS
6.2 Clinical cases included in this report
6.3 Presentation of lists with a list of reports of adverse events
6.4 Pivot table
6.5 Analysis of individual clinical cases performed by the holder of the registrationcertificate
6.5.1. Deaths
6.5.2 Classes of organ systems by MedDRA
6.5.2.1 Disorders of cardiac activity
6.5.2.2 Congenital, hereditary and genetic disorders
6.5.2.4. Disorders from the musculoskeletal system and connective tissue
6.5.2.6 Disorders from the reproductive system and mammary glands
6.5.2.7 Disturbances from the skin and subcutaneous tissue
7. RESEARCH
7.1. New targeted safety studies
7.2. Published Safety Studies / Literature Review\
7.3. Other studies
8. OTHER INFORMATION
8.1 Performance Information
8.2 Significant information received at the last moment
8.3 Report on the analysis of the relationship between benefit and risk
9. GENERAL SAFETY ASSESSMENT
9.1 Data on increasing the frequency of messages about HP
9.2 Identified symptoms related to drug safety
9.2.1 Vision disorders
9.2.2 Congenital, hereditary and genetic disorders
9.2.3 Disorders from the digestive tract
9.2.4 Disorders from the musculoskeletal system and connective tissue
9.2.5 Neoplasms: benign, malignant and unknown etiology (including cysts and polyps)
9.3 Drug Interactions
9.4 Cases of overdose
9.5 Dependence on medicines and use not for the intended purpose
9.6 Application of drugs during pregnancy and lactation
9.7 Application of drugs in selected categories of patients
9.8 Results of long-term therapy
9.9 Messages received from consumers and other persons (not from health sector)
9.10 Errors in the assignment of the Drugs / Violations of the design scheme
9.11 Other aspects concerning safety
10. CONCLUSION

1. INTRODUCTION
This Periodic Safety Update Report comprises worldwide safety data on product names Citicoline Sodium
Oral Drops 100 mg/mL, received by Nuclotec Remedies Pvt. Ltd., India in the period from 10th Jan, 2019-
25th Feb, 2022.
This medicine belongs to the category of Ischemic stroke, acute phase and its neurological sequelae (as a part
of complex therapy)
Rehabilitation period of ischerriic and hemorrhagic stroke
Traumatic Brain injury and its neurological sequelae, acute phase (as a part of complex therapy) and
rehabilitation period Cognitive and behavioural impairment secondary to chronic vascular and degenerative
cerebral disorders.
MECHANISM OF ACTION:
Citicoline stimulates the biosynthesis of structural phospholipids of the neuronal membrane as it is
demonstrated in the magnetic resonance spectroscopy studies. Citicoline, through this action, improves the
function of the membrane mechanisms, such as the functioning of the ionic exchange pumps and
receptorsinserted in the latter, the modulation of which is indispensable in the neurotransmission.
Citicoline due to its membrane stabilising activity has properties which favour brainoedema reabsorption.
Pharmacokinetic properties General pharmacokinetics
Citicoline is well absorbed after oral, intramuscular or intravenous administration. Plasma choline levels
significantly increase after the aforementioned routes. Oral absorption is nearly complete and its
bioavailability is approximately the same as the intravenous route. The drug product is metabolized in the
intestine and in the liver to choline and cytidine. The administered citicoline is widely distributed in brain
structures, with a quick incorporation of the choline fraction in structural phospholipids and the cytidine
fraction in cytidinic nucleotides and nucleic acids. Citicoline reaches the brain and it is actively
incorporated to cellular, cytoplasmatic and mitochondrial membranes, taking part of the structural
phospholipids fraction.
Only a small amount of the dose appears in urine and faeces (less than 3 %). Approximately 12 % of the
dose is eliminated via expired C02. In the urinary excretion of the drug, two phases can be distinguished:
a first phase, around 36 hours, where the excretion speed rapidly decreases, and a second phase where
excretion speed decreases much slower. The same happens with expired C02, the elimination speed
rapidlydecreases after approximately 15 hours and later it decreases much slower.

2. DATA ON REGISTRATION OF DRUGS ON THE WORLD MARKET

Citicoline Sodium Oral Drops 100 mg/mL, initially approved in India for the treatment of patients with
many different Attention-Deficit Hyperactivity Disorder (ADHD) and nootropics. Later on, Citicoline
Sodium Oral Drops 100 mg/mL has got approval worldwide i.e. ROW markets.

3. ADJUSTMENTS ADOPTED BY REGULATORY ORGANIZATIONS OR HOLDERS OF

REGISTRATION CERTIFICATES, FOR THE CAUSE OF SECURITY
No, regulatory action was taken during the period of reporting for safety reasons i.e. marketing authorization
withdrawal. No action was taken from marketing authorization holder pertaining tosafety reasons i.e. dosage
modifications, change in the target population, indications, or formulation changes.
4. CHANGES TO THE SAFETY DATA SHEET
The Summary of product characteristics (Refer Appendix 1) is used as reference safety information while
preparing this PSUR.
During the period of reporting no changes were made to package insert with respect to contraindications,
precautions, warnings, adverse drug reactions or interactions,
5. VOLUME OF CONSUMPTION OF DRUGS

The registered 8% year on year growth in 2018, which is expected to rise further by 2028. Rising cases of
glaucoma and retinal neurodegradation among geriatric population will remain a chief growth driver.
Fact.MR in its latest study has predicted impressive growth on card for the market during its forecast period
of 2018 and 2028.
Increasing demand for nutraceuticals to improve cognitive functions due to adverse effects of long working
hours and sleep deficiency will boost the market. Citicoline is increasingly finding usage in nutraceutical
production owing to its neuroprotective properties and negligible toxicity.
They are known to induce phospholipids in the brain required for proper functioning of neural pathways.
Increasing cases of dementia, Alzheimer’s, and other neurological ailments are encouraging governments to
support and increase investment in pharmaceutical sector for research and development activities.
Extensive research to study citicoline’s efficacy in preventing and providing potential recovery from
cognitive dysfunction is expected to provide growth opportunities for market players over the coming years.
6. PRESENTATION OF SELECTED CASES OF UNDESIRABLE REACTIONS
6.1 Presentation of Selected cases of undesirable reactions

Very rare (<1/10,000) (include individual notifications) Psychiatric disorders: hallucinations
Nervous system disorders: cephalea, vertigo, insomnia, excitation, sense of heat, numbness in
paralyzed limbs Vascular disorders: arterial hypertension, arterial hypotension Respiratory, thoracic
and mediastinal disorders:dyspnoea, Gastrointestinal disorders: nausea, vomiting, occasional diarrhea,

anorexia, changes in the activity of hepatic enzymes Skin and subcutaneous tissue disorders: blush,
hives, exanthemas, purple General disorders and administration site conditions: shiver, oedema
6.2 Clinical cases included in this report
During this period, no adverse event in the form of spontaneous notification was received either from health
care professionals or regulatory authorities during the period covered by the report.
6.3 Presentation of lists with a list of reports of adverse events
No study has been undertaken by Nuclotec Remedies Pvt. Ltd., during the period covered by the report.
6.4 Pivot table
Not applicable (as there are no reported cases)
6.5 Analysis of individual clinical cases performed by the holder of the registration certificate
6.5.1 Deaths
6.5.2 Classes of organ systems by MedDRA
6.5.2.1 Disorders of cardiac activity
6.5.2.2 Congenital, hereditary and genetic disorders
6.5.2.4. Disorders from the musculoskeletal system and connective tissue
6.5.2.6 Disorders from the reproductive system and mammary glands

6.5.2.7 Disturbances from the skin and subcutaneous tissue

7. RESEARCH
7.1 New targeted safety studies
No new safety study has been planned over the period covered by the report.
7.2 Published Safety Studies / Literature Review
No published studies are available with Citicoline Sodium Oral Drops 100 mg/mL of Nuclotec Remedies
Pvt. Ltd. because product safety and efficacy is already proven but Post marketing surveillance was done as a
PSUR to evaluate its safety and efficacy
7.3 Other studies
Not applicable.

8. OTHER INFORMATION
8.1 Performance Information

[Neonatal hypoxic ischemic encephalopathy treated with acupuncture combined with
acupoint injection: a randomized controlled trial].
Tang Y, Shang Q.
Abstract
OBJECTIVE:
To observe the clinical efficacy difference in the treatment of neonatal hypoxic ischemic
encephalopathy (NHIE) between the combined therapy of acupuncture land acupoint injection of
nerve growth fac-tor (NGF) and the combined therapy of the intravenous drop of citicoline sodium
and intramuscular injection of NGF.
METHODS:
Sixty-one cases of NHIE were randomized into an observation group (32 cases) and a control group
(29 cases). In the observation group, acupuncture combined with acupint injection of NGF was
adopted. The acupoints were Baihui (GV 20), Dazhui (GV 14) and Fengfu (GV 16), 0. 5 mL each
acupoint, once a day. In the control group, the intravenous drop of citicoline sodium and
intramuscular injection of NGF were used. The, treatment of 7 days made one session and 3 sessions
were required. Separately, in 7, 14 and 21 days of treatment, the clinical efficacy, behavior nerve
determination score and adverse reaction were observed in the two groups.
RESULTS:
In 7, 14 and 21 days of treatment, the total effective rates were 50. 0% (16/32), 68. 8% (22/32) and
78. 1% (25/32) in the observation group and were 69. 0% (20/29), 72. 4% (21/29) and 82. 8% (24/29)
in the control group. The result in the control group was better than that in the observation group in
the 7 days (P< 0. 05). The behavior determination scores in 7, 14 and 21 days were all improved
obviously as compared with those before treatment in the two groups (P<0. 05, P<0. 01). The score in
the control group was better than that in the, observation group in the 7 days (P<0. 05). The
differences were not significant in the scores between the two groups in 14 and 21 days (both P>0.
05). The incidence of adverse reaction in the observation group was lower than that in, the control
group [14. 3% (5/35) vs 31. 4% (11/35), P<0. 05] and the severity was mild.

CONCLUSION:
In the treatment of NHIE with the combined therapy of acupuncture and acupint injection, the overall
efficacy in 1 week; is inferior to that of the combined therapy of the intravenous drop
of citicolinesodium and intramuscular injection of NGF. But the efficacy is improved gradually along
with the treatment progression and the adverse reaction is less.

8.2 Significant information received at the last moment
No new information received after the database is frozen for review and report preparation.
8.3 Report on the analysis of the relationship between benefit and risk
Citicoline in the treatment of acute ischaemic stroke: an international, randomised,

multicentre, placebo-controlled study (ICTUS trial).
Dávalos A1, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, Serena J, Segura
T, Cruz VT, Masjuan J, Cobo E, Secades JJ; International Citicoline Trial on acUte Stroke (ICTUS)
trial investigators.
Abstract
BACKGROUND:
Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has
shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy
of citicoline in a larger trial.
METHODS:
We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe
acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a
centralised minimisation process, patients were randomly assigned in a 1:1 ratio to
receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h
intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral
tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at
90 days measured by a global test combining three measures of success: National Institutes of Health
Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included
symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen
activator, neurological deterioration, and mortality.
RESULTS:
2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain,
11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed
consent and underwent randomisation, 1148 were assigned to citicolineand 1150 to placebo. The trial
was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients.
The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150
in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25;
p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse
events.

9. GENERAL SAFETY ASSESSMENT

9.1 Data on increasing the frequency of messages about HP
9.2 Identified symptoms related to drug safety
9.2.1. Vision disorders

A comparative study of free plasma choline levels following intramuscular administration of L-
alpha-glycerylphosphorylcholine and citicoline in normal volunteers.
Gatti G1, Barzaghi N, Acuto G, Abbiati G, Fossati T, Perucca E.
Abstract
L-alpha-glycerylphosphorylcholine (alpha-GPC) is a recently developed cognitive enhancer whose
mode of action is considered to involve the release of free choline, which is then utilized for
acetylcholine and phosphatidylcholine biosynthesis in the brain. The purpose of this studywas to
evaluate the profile of free plasma choline levels following a single i.m. dose of alpha-GPC in 12
normal volunteers. Citicoline (CTC), which also acts as a choline precursor, was included for
comparison purposes. Each subject was studied on three randomized occasions, (i) in a control day in
the absence of drug administration (to evaluate the plasma level profile of endogenous choline), (ii)
after i.m. alpha-GPC (1,000 mg) and (iii) after i.m. CTC (1,000 mg) respectively, with a wash-out
period of at least 1-week between sessions. Blood samples for plasma choline HPLC determinations
were collected at regular intervals over a 6 h period. In the control session, plasma choline levels
remained stable during the sampling period. The administration of alpha-GPC was associated with a
rapid rise in plasma choline, peak levels being usually observed at the first (0.25 h) or second (0.5 h)
sampling time after the injection. Thereafter, the concentration of cholinedeclined gradually and
returned to near baseline values at the end of the observation period. After the administration of
CTC, plasma cholinelevels showed a similar time course but were considerably lower than those
observed after the administration of alpha-GPC.

9.2.2 Congenital, hereditary and genetic disorders

9.2.3 Disorders from the digestive tract
Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis

jirovecii
Christine Robin 1 2, Minh Patrick Lê 3 4, Giovanna Melica 5, Laurent Massias 3 4, Rabah Redjoul 1, Nihel
Khoudour 6, Mathieu Leclerc 1 2, Florence Beckerich 1 2, Sébastien Maury 1 2, Anne Hulin 6, Catherine
Cordonnier 1 2
Abstract
Objectives: Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of

Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients. In volunteers, there was wide inter-
individual variability in atovaquone bioavailability. The aim of this study was to assess the plasma
concentrations of atovaquone in immunocompromised patients under PCP prophylaxis.
Methods: Adult haematology or HIV-positive patients receiving atovaquone (750 mg oral suspension twice a
day) for PCP prophylaxis were included. Plasma concentrations were assessed using UV-HPLC, around 12 h
after the evening dose (Cmin) and 1-5 h after the morning dose (Cmax).
Results: A total of 82 measurements were performed in 33 patients. This included 19 HSCT recipients, 7
haematology non-transplant patients and 7 HIV-positive patients. The median Cmin (IQR) was 11.3 µg/mL
(6.2-27.8) and the median Cmax was 13.4 µg/mL (6.0-28.3). The Cmin and Cmax of atovaquone were not
different between HIV-negative and HIV-positive patients, or between HSCT and non-HSCT patients.
Atovaquone concentrations were not influenced by the co-administration of valaciclovir (n = 20) or
ciclosporin (n = 11), by gut graft-versus-host disease (n = 7) or by the intake of atovaquone with food.
Nineteen of the 33 (58%) patients had Cmin <15 µg/mL, a threshold associated with a low rate of clinical
response in PCP treatment.
Conclusions: Atovaquone is poorly absorbed in more than half of immunocompromised patients and its
bioavailability varies between individuals. These unpredictable variations raise the question of therapeutic
drug monitoring, in order to identify patients with low concentrations and those who could benefit from
regimen adaptation or from alternatives.

9.2.4 Disorders from the musculoskeletal system and connective tissue
In vivo susceptibility of Campylobacter pylori

D Y Graham 1, P D Klein, A R Opekun, K E Smith, R R Polasani, D J Evans Jr, D G Evans, L C Alpert, P A
Michaletz, H H Yoshimura, et al.
Abstract
Campylobacter pylori infection has been associated with duodenal ulcer, gastric ulcer, and non-ulcer
dyspepsia. Although in vitro studies have shown that C. pylori is susceptible to most commonly used
antibiotics, predictions from in vitro sensitivity studies have not led to a safe and generally effective therapy;
C. pylori has proved to be very difficult to eradicate in vivo. We used the urea breath test to assess the
susceptibility of C. pylori in vivo to various drugs. C. pylori was susceptible to bismuth subsalicylate, bismuth
subnitrate, and furazolidone. C. pylori was not susceptible (i.e., urease activity remained despite
administration of the drug) to the following drugs: 1) antiulcer agents (cimetidine, ranitidine, famotidine,
omeprazole, misoprostol, sucralfate, liquid antacids); 2) NSAIDs (aspirin, indomethacin, ibuprofen, naproxen,
tolmetin); 3) antibiotics (oral penicillin V, trimethoprim-sulfamethoxazole, dicloxacillin); 4) salts (lithium,
ferrous sulfate, gold); 5) miscellaneous (acetaminophen, phenytoin, hydrochlorothiazide, propranolol,
metoprolol, metoclopramide, ursodeoxycholic acid). Oral antimicrobials can be administered directly onto the
site of infection, so that a very low oral dose will provide many multiples of the in vitro minimal inhibitory
concentration. Furazolidone suspension (7 mg) was administered seven times daily (daily dose 49 mg) to
three individuals infected by C. pylori during suppression of gastric acid secretion with famotidine (40 mg
bid). After 4 days, all subjects had significant reductions in urease activity (two to normal and one to a
borderline value). This response suggested that very low-dose therapy may be useful either alone or combined
with bismuth. Conclusive establishment of an etiologic (or major contributory) relationship of C. pylori to
ulcer disease will require a safe and reliable method to eradicate the organism from the stomach and
duodenum.

9.2.5 Neoplasms: benign, malignant and unknown etiology (including cysts and polyps)
Citicoline in the treatment of acute ischaemic stroke: an international, randomised,
multicentre, placebo-controlled study (ICTUS trial).
Dávalos A1, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, Serena J, Segura
T, Cruz VT, Masjuan J, Cobo E, Secades JJ; International Citicoline Trial on acUte Stroke (ICTUS)
trial investigators.
Abstract
BACKGROUND:
Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has
shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy
of citicoline in a larger trial.
METHODS:
We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe
acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a
centralised minimisation process, patients were randomly assigned in a 1:1 ratio to
receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h
intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral
tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at
90 days measured by a global test combining three measures of success: National Institutes of Health
Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included
symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen
activator, neurological deterioration, and mortality. This trial is registered, NCT00331890.
RESULTS:
2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain,
11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed
consent and underwent randomisation, 1148 were assigned to citicolineand 1150 to placebo. The trial
was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients.
The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and
1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-
1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of
adverse events.

9.3 Drug Interactions

Levodopa
Citicoline may enhance the effects of levodopa. 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 to 1200 mg/day) allowed for lower dosages of levodopa to be used with stable or
improved therapeutic efficacy and reduced side effects in some patients. However, data are limited.
Coadministration with meclofenoxate

Citicoline must not be administered in conjunction with medication containing meclofenoxate (also known as
Clophenoxate).
9.4 Cases of overdose

No case of overdose has been reported

9.5 Dependence on medicines and usc not for the intended purpose

9.6 Application of drugs during pregnancy and lactation
There are no adequate data from the use of Citicoline in pregnant women .
Citicoline Sodium Oral Drops 100 mg/mL should not be used during pregnancy unless clearly necessary. That
is, only when the expected therapeutic benefit is higher than any possible risk (see section 5.3).
If Citicoline is prescribed in lactation period, the breastfeeding must be stopped, as the allocation data of
Citicoline with human milk are absent.

9.7 Application of drugs in selected categories of patients

Effect of citicoline on visual acuity in amblyopia: preliminary results.
Campos EC1, Schiavi C, Benedetti P, Bolzani R, Porciatti V.
Abstract
BACKGROUND:
Citicoline has been used to improve consciousness levels in cerebral trauma and as a complement for
levodopa in Parkinson's disease. It has also been shown that severe glaucomatous visual field deficits
improve for at least 4 months with the use of citicoline. In this paper, preliminary results are
presented of an open and a double-blind study on the effect of citicoline in amblyopia.
METHODS:
The open study was started in 1991. Fifty patients with amblyopia were treated with citicoline (1000
mg i.m. daily for 15 days). They were selected from an age group beyond the plastic period of the
visual system. Occlusion or other types of anti-amblyopic treatment were never used at the same
time as citicoline. A double-blind study was conducted on 10 more patients, randomly assigned to a
treatment or placebo group and followed for 6 months. A statistical test for repeated measures was
performed on all the results.
RESULTS:
A statistically significant improvement in visual acuity was found both for the amblyopic and the
sound eye in 46 of the 50 patients (92%). The behaviour was different for normal and amblyopic
eyes. The improvement remained stable for at least 4 months. These results have been substantiated
by the double-blind study. No side effects were observed.
CONCLUSION:
Citicoline improves visual acuity, at least temporarily, in amblyopic patients beyond the plastic
period of the visual system. Our results suggest that trials of citicoline as a medical treatment of
amblyopia are warranted.

9.8 Results of long-term therapy

Citicoline in the treatment of Parkinson's disease.
Martí Massó JF1, Urtasun M.
Abstract
The subjects were 20 patients with Parkinson's disease. They were aged 52 to 76 years and the
duration of the disease ranged from four to 25 years (mean, 12.5 years). All the patients were
receiving levodopa alone or in combination with tricyclic antidepressants, amantadine,
bromocriptine, anticholinergic agents, or lisuride. Each patient received 1,000 mg
of citicoline intramuscularly daily for 15 days and then 500 mg daily for 15 days. After 30 days of
treatment, the scores on the Columbia rating scale improved 7.3%; rigidity was improved 18.8%;
times to walk 10 m and turn over were reduced 17.5% and 37.4%; and the handwriting test scores
improved 19.7%. No side effects were reported. Four patients with advanced parkinsonian symptoms
and psychotic side effects received 2,000 mg of citicoline subcutaneously or intravenously for seven
days. No improvements in symptoms or treatment side effects were noted.

9.9 Messages received from consumers and other persons not involved in the Health sector
9.10 Errors in the assignment of the Drugs / Violations of the design scheme
9.11 Other aspects concerning safety

10. CONCLUSION
This PSUR covers safety information pertaining to Citicoline Sodium Oral Drops 100 mg/mL from 10th Jan,
2019- 25th Feb, 2022. There was no spontaneous report of adverse events reported during this period.
Literature search also did not yield any safety information. Hence no changes are recommended for
Company Core Safety Information or Package Insert Citicoline Sodium Oral Drops 100 mg/mL will
continue to be closely monitored for safety related issues.

Appendix 1
SUMMARY OF PRODUCT CHARACTERISTICS

1. Name of the medicinal product
Citicoline Sodium Oral Drops 100 mg/mL
2. Qualitative and quantitative composition
Each mL contains:
Citicoline Sodium
Eq. to Citicoline ................... 100 mg
In a Flavoured Syrup ........................... q.s.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Oral Drops.
Citicoline Sodium Oral Drops 100 mg/mL
Orange colour suspension filled in 15 mL amber coloured round PET bottles.
4. Clinical particulars
4.1 Therapeutic indications
Ischemic stroke, acute phase and its neurological sequelae (as a part of complex therapy)
Rehabilitation period of ischerriic and hemorrhagic stroke
Traumatic Brain injury and its neurological sequelae, acute phase (as a part of complex therapy) and
rehabilitation period Cognitive and behavioural impairment secondary to chronic vascular and
degenerative cerebral disorders.
4.2 Posology and method of administration
Adults:
The recommended dose is from 500 to 2,000 mg/day, dependi ng on the severity of the symptoms to
be treated.
It may be taken directly or dissolved in half a glass of water ( 120 ml), with the meals or between
them.
The dosage recommendations
The acute phase of Ischemic stroke and Traumatic Brain injury:

1000 mg (10 ml) every 12 hours. Treatment duration of at least 6 weeks.

Rehabilitation period of ischemic and hemorrhagic stroke, rehabilitation period of Traumatic Brain
injury, Cognitive and behavioural impairment secondary to chronic vascular and degenerative
cerebral disorders:
500-2000mg daily (5-lOml). The dosage and duration of treatment depend on the severity of
symptoms.
See the instructions for preparation in section 6.6
Elderly:
Citicoline Sodium Oral Drops 100 mg/mL does not need any specific dose adjustment for this age
group.
Children:
The experience in children is limited; therefore it may only be admi nistered when the expected
therapeutical benefit is higher than any possi ble risk.
4.3 Contraindications
Hypersensitivity to any component
Expressed vagotonia
Rare inherited diseases associated with fructose intolerance
Because of the absence of sufficient clinical data Citicoline Sodium Oral Drops 100 mg/mL is not
recommended for use in children under 18 years
4.4 Special warnings and precautions for use
It is possible a formation of slight number of crystals in the cold, due to a temporary partial
crystallizationof preserving agent. With further storage under recommended conditions the crystals
are dissolved in for several months. The presence of crystals does not affect the qual ity of the
product.
In case of performing of potentially dangerous activities, requiring special attention and fast
reactions the caution should be kept during the treatment.
4.5 Interaction with other medicinal products and other forms of interaction
Citicoline potentiates the effects of L-Dopa.
It must not be administered in conjunction with medicaments containi ng Meclofenoxate.
4.6 Fertility, pregnancy and lactation
There are no adequate data from the use of Citicoline in pregnant women .

Citicoline Sodium Oral Drops 100 mg/mL should not be used during pregnancy unless clearly
necessary. That is, only when the expected therapeutic benefit is higher than any possible risk (see
section 5.3).
If Citicoline is prescribed in lactation period, the breastfeeding must be stopped, as the allocation
data of Citicoline with human milk are absent.
4.7 Effects on ability to drive and use machines
Citicoline Sodium Oral Drops 100 mg/mL affects on the ability to drive and use of machines.
4.8 Undesirable effects
Very rare (<1/10,000) (include individual notifications) Psychiatric disorders: hallucinations
Nervous system disorders: cephalea, vertigo, insomnia, excitation, sense of heat, numbness in
paralyzed limbs Vascular disorders: arterial hypertension, arterial hypotension Respiratory,
thoracic and mediastinal disorders:dyspnoea, Gastrointestinal disorders: nausea, vomiting,
occasional diarrhea, anorexia, changes in the activity of hepatic enzymes Skin and subcutaneous
tissue disorders: blush, hives, exanthemas, purple General disorders and administration site
conditions: shiver, oedema
4.9 Overdose
No case of overdose has been reported
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psychostimulants, agents used for Attention-Deficit Hyperactivity
Disorder(ADHD) and nootropics.
ATC code: N06BX06
Citicoline stimulates the biosynthesis of structural phospholipids of the neuronal membrane as it is
demonstrated in the magnetic resonance spectroscopy studies. Citicoline, through this action,
improves the function of the membrane mechanisms, such as the functioning of the ionic
exchange pumps and receptors inserted in the latter, the modulation of which is indispensable in
the neurotransmission.
Citicoline due to its membrane stabilising activity has properties which favour brainoedema
reabsorption.
Experimental studies have shown that Citicoline inhibits the activation of some phospholipases
(Al, A2, C and D), reducing the formation of free radicals, avoiding the destruction of membranous

systems and preserving antioxidant defence systems as glutation.

Citicoline preserves the neuronal energetic reserve, inhibits apoptosis and stimulates acetylcholine
synthesis
It has been experimentally shown that Citicoline also exerts a prophylactic neuroprotective effect
in focal brain ischemic models.
Clinical trials have shown that Citicoline significantly increases the fupctional evolution of
patients with acute ischemic cerebrovascular accident, coinciding with a lower growth of the brain
ischemic injury in neuroimagen tests.
In patients with craniocerebral traumatisms, citicoline speeds up their recuperation and reduces the
duration and intensity of the post-concussional syndrome.
Citicoline improves the level of attention and consciousness and acts favourably over amnesia
and cognitive and neurological disorders associated to brain ischemia.
5.2 Pharmacokinetic properties
Citicoline is well absorbed after oral, intramuscular or intravenous administration. Plasma choline
levelssignificantly increase after the aforementioned routes. Oral absorption is nearly complete and
its bioavailability is approximately the same as the intravenous route. The drug product is
metabolized in the intestine and in the liver to choline and cytidine. The administered citicoline is
widely distributed in brain structures, with a quick incorporation of the choline fraction in structural
phospholipids and the cytidine fraction in cytidinic nucleotides and nucleic acids. Citicoline
reaches the brain and it is actively incorporated to cellular, cytoplasmatic and mitochondrial
membranes, taking part of the structural phospholipids fraction.
Only a small amount of the dose appears in urine and faeces (less than 3 %). Approximately 12
% of thedose is eliminated via expired C02. In the urinary excretion of the drug, two phases can
be distinguished: afirst phase, around 36 hours, where the excretion speed rapidly decreases, and a
second phase where excretion speed decreases much slower. The same happens with expired
C02, the elimination speed rapidly decreases after approximately 15 hours and later it decreases
much slower.
5.3 Preclinical safety data
Oral and intraperitoneal chronic toxicity studies (1.5 g/kg/day during 6 months in dogs) did not
show significant abnormalities related with the administration of the drug. Intravenous

administration of 300-500 mg/kg/day of citicoline during 3 months i n dogs, only produced toxic
signs immediately after the injection, such as occasional vomiting, diarrhoea and hyper-salivation.
800 mg/kg of Citicoline was administered to albino rabbits during the organogenesis phase, from lh
to 18th gestation day. The animals were sacrificed the 29th day and a detailed exam of foetus and
their mothers was carried out. No toxicity sign were observed neither maternal nor embryo-foetal.
The effects over organogenesis were inappreciable, only 10 % of the treated foetus has a slight
delay in brain osteogenesis.
6. Pharmaceutical particulars
6.1 List of excipients
Sorbitol Solution
Glycerin
Sodium Benzoate
Sodium Methylparaben
Sodium Propylparaben
Aspartame
Saccharine Sodium
Flavour Mixed Fruit
Colour Ponceau-4R Supra
Citric Acid Monohydrate

6.2 Incompatibilities
None known
6.3 Shelf life
24 Months.
6.4 Special precautions for storage
Store at a temperature not exceeding 25°C. Protect from light.
6.5 Nature and contents of container
Amber colour PET bottles.
Pack size: 15 ml

7. Marketing authorisation holder

MAATR HEALTHCARE PVT. LTD.
B-64, 3rd Floor, Nehru Ground,
Nit, Near Passport Office,
Faridabad, Haryana-121001-INDIA.
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text

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PERIODICAL REPORT ON THE SAFETY OF DRUGS

(Citicoline Sodium Oral Drops 100 mg/mL)

NUCLOTEC REMEDIES PVT. LTD.

The holder of the registration certificate:

NUCLOTEC REMEDIES PVT. LTD., India.

14 Milestone, Rudrapur-Kashipur Road,

Reporting period (date) –10th Jan, 2019-25th Feb, 2022

Name: Dr. N K Nagrani

Nuclotec Remedies Pvt. Ltd., India.

TO REGULATORY ORGANIZATIONS, CONFIDENTIAL

Confidential report, generated electronically. PSUR/MPL/001-00

Confidential report, generated electronically. PSUR/MPL/001-00

Rehabilitation period of ischerriic and hemorrhagic stroke

Confidential report, generated electronically. PSUR/MPL/001-00

2. DATA ON REGISTRATION OF DRUGS ON THE WORLD MARKET

Confidential report, generated electronically. PSUR/MPL/001-00

3. ADJUSTMENTS ADOPTED BY REGULATORY ORGANIZATIONS OR HOLDERS OF

5. VOLUME OF CONSUMPTION OF DRUGS

6. PRESENTATION OF SELECTED CASES OF UNDESIRABLE REACTIONS

6.1 Presentation of Selected cases of undesirable reactions

Confidential report, generated electronically. PSUR/MPL/001-00

6.2 Clinical cases included in this report

6.3 Presentation of lists with a list of reports of adverse events

6.4 Pivot table

Not applicable (as there are no reported cases)

Not applicable (as there are no reported cases)

6.5.2 Classes of organ systems by MedDRA

Not applicable (as there are no reported cases)

6.5.2.1 Disorders of cardiac activity

Not applicable (as there are no reported cases)

6.5.2.2 Congenital, hereditary and genetic disorders

Not applicable (as there are no reported cases)

6.5.2.4. Disorders from the musculoskeletal system and connective tissue

Not applicable (as there are no reported cases)

6.5.2.6 Disorders from the reproductive system and mammary glands

Not applicable (as there are no reported cases)

Confidential report, generated electronically. PSUR/MPL/001-00

6.5.2.7 Disturbances from the skin and subcutaneous tissue

Not applicable (as there are no reported cases)

Confidential report, generated electronically. PSUR/MPL/001-00

7.2 Published Safety Studies / Literature Review

7.3 Other studies

Confidential report, generated electronically. PSUR/MPL/001-00

8.1 Performance Information

Confidential report, generated electronically. PSUR/MPL/001-00

Confidential report, generated electronically. PSUR/MPL/001-00

8.2 Significant information received at the last moment

Citicoline in the treatment of acute ischaemic stroke: an international, randomised,

Confidential report, generated electronically. PSUR/MPL/001-00

9. GENERAL SAFETY ASSESSMENT

9.2.1. Vision disorders

Confidential report, generated electronically. PSUR/MPL/001-00

9.2.2 Congenital, hereditary and genetic disorders

Not applicable (as there are no reported cases)

Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis

Objectives: Atovaquone is one of the alternatives to trimethoprim/sulfamethoxazole for prophylaxis of

Confidential report, generated electronically. PSUR/MPL/001-00

9.2.4 Disorders from the musculoskeletal system and connective tissue

In vivo susceptibility of Campylobacter pylori

Confidential report, generated electronically. PSUR/MPL/001-00

Confidential report, generated electronically. PSUR/MPL/001-00

9.3 Drug Interactions

Coadministration with meclofenoxate