Zantac - Heads of Medicines Agencies

Updated Public assessment report

EU worksharing project paediatric data

Zantac 150 and 300 mg tablets

Zantac syrup: 150 mg/10 ml

Zantac 50 mg/2 ml solution for injection

[ranitidine]

Marketing authorisation holder: GlaxoSmithKline

Rapporteur Medicines Evaluation Board, The

Netherlands

Co-rapporteur Instituto Nacional da Farmacia e do

Medicamento, Portugal

Start 1st round

Clock-off period

Procedure re-start date

1 February 2007

1 May 2007 – 8 November 2007

8 November 2007

Finalisation procedure 13 March 2008

Date of this updated public assessment

report

18 March 2013

2

Currently approved adult indication(s): Oral formulations:

- Duodenal ulcer and benign gastric ulcer,

including that associated with non-steroidal anti-inflammatory agents.

- Prevention of non-steroidal anti-inflammatory drug (NSAID) (including aspirin) associated duodenal ulcers, especially in patients with a history of peptic ulcer disease.

- Duodenal ulcer associated with Helicobacter pylori infection.

- Post-operative ulcer. - Reflux oesophagitis. - Symptom relief in gastro-oesophageal

reflux disease. - Zollinger-Ellison Syndrome.

- Chronic episodic dyspepsia, characterised by pain (epigastric or retrosternal) which is related to meals or disturbs sleep but not associated with the above conditions.

- Prophylaxis of stress ulceration in seriously ill patients.

- Prophylaxis of recurrent haemorrhage from peptic ulcer.

- Prophylaxis of Mendelson's syndrome.

Injection:

- Duodenal ulcer. - Benign gastric ulcer.

- Post-operative ulcer. - Reflux oesophagitis.

- Zollinger-Ellison Syndrome. - Prophylaxis of stress ulceration in

seriously ill. - Prophylaxis of recurrent haemorrhage

from peptic ulcer.

- Prophylaxis of Mendelson's syndrome.

Pharmaceutical form(s) affected by this

project:

Tablets/Syrup/Solution for injection

Strenght(s) affected by this variation:

Tablets: 150 and 300 mg

Syrup: 150 mg/10 ml

Solution for injection: 50 mg/2 ml

3

Content

I Recommendation............................................................................................ 4

I.1 Scope of the variation ................................................................................... 4

I.2 Supplementary paragraph ............................................................................. 5

I.2.1 Peptic ulcer disease ................................................................................ 5

I.2.2 Gastro-oesophageal reflux disease ........................................................... 5

I.2.3 Prophylaxis of stress ulceration ................................................................ 6

II. Scientific discussion ...................................................................................... 6

II.1 Quality aspects ......................................................................................... 6

II.2 Non-Clinical aspects .................................................................................. 6

II.3 Clinical aspects ......................................................................................... 6

II.3.1 Study RC1 998/00023/00 ........................................................................ 6

II.3.2 Pharmacokinetics ..................................................................................11

II.3.3 Pharmacodynamics and Efficacy ..............................................................13

II.3.4 Efficacy data .........................................................................................13

II.3.5 Safety .................................................................................................15

III OVERALL CONCLUSION ................................................................................22

IV. Final agreed changes in the Smpc’s ...............................................................24

Annex I: The MHRA report on Zantac tablets, Zantac effervescent tablets, 300mg,

150mg, Zantac injection 50mg/2ml, Zantac syrup 75mg/5ml .....................................28

Annex II – Safety data overview.............................................................................50

Annex III: Cited references ....................................................................................53

4

Note for the reader:

This updated public assessment report (March 2013) reflects the discussion in the EU

worksharing project paediatric data (procedure finalised on March 13th 2008) for

ranitidine in the treatment of “short term treatment of peptic ulcer and in treatment of

gastro-oesophageal reflux, including reflux oesophagitis and symptomatic relief of

gastro-oesophageal reflux disease” in paediatric populations”.

On 26 November 2009 an Article 45 of the Regulation (EC)No 1901/2006, as amended

on medicinal products for paediatric use (SE/W/0007/pdWS/001) was finalised (Date of

public assessment report February 9th 2010). The data submitted within this article 45

worksharing procedure partly overlapped the data as discussed in this public assessment

report. Based on the new available data in combination with the previous art 45

procedure it was concluded that the new data did not alter the conclusions as stated in

the previous report.

I RECOMMENDATION The Rapporteurs conclude that based on the submitted paediatric data on safety and

efficacy for ranitidine (Zantac 150 and 300 mg tablets, Zantac syrup 150 mg/10 ml and

Zantac solution for injection 50 mg/2ml) the paediatric indications (short term treatment

of peptic ulcer and in treatment of gastro-oesophageal reflux, including reflux

oesophagitis and symptomatic relief of gastro-oesophageal reflux disease) and posology

as mentioned in the SmPC’s under section 4.1 and 4.2 are acceptable. In addition

changes to SmPC sections 4.8, 5.1 (i.v. formulation only), 5.2 were agreed upon. Refer

to section III of this report for final agreed SmPC’s texts.

I.1 Scope of the variation Zantac (ranitidine hydrochloride) is a histamine H2-receptor antagonist that inhibits

gastric acid secretion. It was first approved in Italy in 1981 and is now available in over

130 countries. In 1998 paediatric information on Zantac has been submitted to the US

Food and Drugs Administration (FDA), under the paediatric exclusivity rules. Reports of

two pharmacokinetic studies and five controlled clinical studies of the use of ranitidine in

children in an oral and intravenous formulation, together with a list of published

information available at the time of submission were submitted.

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) requested the

paediatric data previously submitted to the FDA in 2001. These data were submitted,

however as a result of the Article 30 procedure which was initiated, a full review of the

data was not completed. In 2004 the MHRA requested re-submission of these data. This

was done in September 2004 and was followed shortly after by a Type II variation

proposing SmPC wording and a clinical overview of the available supporting data,

including clinical studies and published literature. This resulted in additional paediatric

indications being added to the UK SmPCs.

This submission contains paediatric data previously submitted to the FDA and the MHRA

concerning the use of Zantac in paediatric patients. It also contains the information

requested as part of the worksharing assessment procedure.

The MAH proposes to broaden the present paediatric indication for the oral formulations

for the treatment of peptic ulcer (age unspecified), to include indications for the long

term management of peptic ulcer and the treatment of gastro-oesophageal reflux

(including reflux oesophagitis and gastro-oesophageal reflux disease) from 1 month of

age and above. In addition to the above for the injection formulation, the MAH has

applied for the following indications from 1 month onwards: the short term treatment of

peptic ulcer and the prevention of stress ulcers in seriously ill children.

5

I.2 Supplementary paragraph In this paragraph the submitted general literature on ranitidine is summarised. See

Annex III for a list of references.

I.2.1 Peptic ulcer disease

Primary duodenal ulcer occurs in children of all ages but is most often seen in those over

10 years of age (Gryboski, 1991). Peptic ulcers in young children are more unusual and

are typically secondary to systemic illnesses or drugs. Duodenal ulcers in older children

and adolescents have a relapsing course that is increasingly recognized as being related

to coexisting, chronic active antral gastritis and Helicobactor-pylori infection (Sherman,

1994).

Not all primary duodenal ulcers in the paediatric population are related to H. pylori and

their cause remains unknown. Treatment of these patients requires anti-ulcer treatment

and long-term maintenance therapy (Sherman, 1994).

A number of studies are available regarding the use of oral ranitidine in peptic ulcer

disease in children. A few of these are placebo- or cimetidine-controlled. Evaluative

procedures are similar to those used in adults, with therapeutic efficacy defined as

endoscopic proof of ulcer healing. Dosage regimens of up to 5 to 10 mg/kg/day have

been reported in the literature for use of Zantac in the treatment of peptic ulcer disease

(e.g. de Angelis & Banchini, 1989; Scorza et al, 1990; Oderda & Ansaldi, 1988).

The general consensus for maintenance therapy seems to be a single night time dose of

3- 5mg/kg for one month (de Angelis & Banchini, 1989; Scorza et al, 1990; Oderda

& Ansaldi, 1988).

Ranitidine has also been used as a component of multi-drug regimens to eradicate H.

pylori in children. Scherbakov et al (2001) evaluated the efficacy of triple therapy

regimens comprising amoxicillin (750 mg/day) and metronidazole (30-40mg/kg/day)

with one of proprietary omeprazole (20-40mgday), generic omeprazole (20-40mg/day)

or ranitidine (150 mg twice daily) in 106 children aged 5 to 15 years. The H. pylori

eradication rate in the ranitidine group (n=35) was 74.3%, whilst the ulcer healing rate

at 7 days was 100%. Two patients relapsed 4 weeks after the start of treatment, thus

the 6 week ulcer healing rate with ranitidine was 94.3%. The regimen containing

proprietary omeprazole was more effective than the ranitidine.

There are limited published data on the clinical use of parenteral ranitidine in children

with peptic ulcer disease. Blumer investigated the pharmacokinetics and

pharmacodynamics of intravenous and oral ranitidine in paediatric patients with duodenal

or gastric ulcer (Blumer et al, 1985). This study involved three phases, two of which

involved parenteral administration: a dose ranging phase designed to determine the dose

of ranitidine required to inhibit gastric acid secretion by ≥ 90%, and intravenous bolus

regimen in which the drug was administered every 6 hours at a dose designed to yield

the average serum concentration required to inhibit gastric acid secretion by ≥ 90%. The

patient received oral ranitidine therapy once their nasogastric tubes were removed. Bolus

doses of between 0.13 and 0.80 mg/kg were administered every 6 hours for an

unspecified therapy. All ulcers were healed on repeat endoscopy at the end of the 6 week

study period.

I.2.2 Gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GORD) is a common motility disorder in infancy and

childhood but in the majority of neurologically normal infants symptoms resolve by age

one. Many infants are successfully managed by conservative treatment such as dietary

management and attention to posture. The rationale for medical treatment will be

influenced by signs of more serious disease such as oesophagitis, excessive irritability,

failure to thrive, apnoea, or chronic pulmonary disease (Cezard, 2004). Oral

administration of ranitidine (5-10 mg/kg/day) has been shown to produce symptomatic

and endoscopic improvement in children. Endoscopic examination reported the frequency

of erosive oesophagitis healing of 75-85% at week 8 and 100% at week 12. Patients with

refractory erosive oesophagitis have received doses up to 20 mg/kg/day.

De Angelis and Banchini (1989) reported their experience of the use of ranitidine in

the treatment and prophylaxis of gastro-intestinal disorders in 391 children aged from 72

6

hours to 16 years. The children received oral ranitidine at a dose of 6-8 mg/kg/day

initially, followed by maintenance therapy of 3-4mg/kg/day. Intravenous administration

was used in appropriate cases, such as those with upper gastrointestinal haemorrhage or

in severe oesophagitis due to the ingestion of caustic substances. Reflux oesophagitis

was treated in 185 patients; in 25 severe cases, endoscopy revealed re-epithelialisation

in all patients. In those children with less severe oesophagitis, 95% showed at endoscopy

disappearance or marked improvement of lesions, both macroscopically and

histologically.

In an open label prospective study, Karjoo and Kane (1995) found visual and/or

histologic evidence of peptic oesophagitis in 84% of 153 patients 6-18 years of age

(mean 9.9 years) with chronic abdominal pain lasting more than 3 weeks. These 129

children were initially treated with 4mg/kg ranitidine twice daily for 2 weeks, increasing

to 4mg three times daily for a further 2 weeks. If symptoms persisted patients were

switched to omeprazole. Seventy percent of patients had symptom improvement with

ranitidine.

The effect of high dose ranitidine (10mg/kg twice daily) has been compared with

omeprazole (40mg/day/1.73m2) in 25 paediatric patients (aged 6 months to 13.4 years)

who had previously not responded to 8 weeks of ranitidine at 8mg/kg/day and cisapride

(Cucchiara et al, 1993). Both drugs produced comparable oesophagitis healing and

symptom relief.

I.2.3 Prophylaxis of stress ulceration

For prophylaxis of stress ulceration in critically ill children ranitidine is administered either

as an intermittent intravenous infusion (2-6mg/kg/day in divided doses) (Harrison et al,

1998; Kuusela et al, 1997; Kuusela, 1998; Lopez-Herce et al 1988; Osteyee et al

1994; Rylance 1987; Santucci et al, 1991) or as a continuous infusion (0.1-

0.2mg/kg/hr) (Osteyee et al, 1994; Santucci et al, 1991; Dimand et al 1989;

Eddleston et al, 1989) has been successfully used to maintain gastric pH levels above

4.0. Both dosing regimens were effective in increasing and maintaining gastric pH above

4, however the pH values fluctuate more with the intermittent regimens (Osteyee et al,

1994; Santucci et al, 1991).

Oral (via naso-gastric tube) vs intravenous administration of ranitidine in prevention of

stress ulceration has been studied. (Lopez-Herce et al, 1988; Hartemann et al 1987)

The median time pH was above 4 was less in the oral group. The authors suggest that

oral ranitidine may not be as effective due to decreased oral absorption in critically ill

children (Lopez-Herce et al, 1988).

II. SCIENTIFIC DISCUSSION II.1 Quality aspects

N/A II.2 Non-Clinical aspects

See for Non-Clinical aspects section 4.2 of the SmPC for Zantac Syrup 150 mg/10 ml.

II.3 Clinical aspects Several studies have previously been submitted to the MHRA, and the rapporteur took

the liberty to copy the MHRA report as an annex to this report (see Annex I). Therefore

only Study RC1 998/00023/00, which was not included in the submission to the MHRA,

will be discussed in detail in this report, see below. Also an overview of the safety data is

summarized in this report (see Annex II).

II.3.1 Study RC1 998/00023/00

A randomized, double-blind, parallel, single-dose, placebo-controlled study design was

used to investigate the pharmacokinetics and pharmacodynamics of ranitidine 75 mg

administered as Zantac 75 tablets. Seven centers were to enroll children ages 4-11 with

suspected abnormal acid reflux. Approximately 24 evaluable subjects with a

7

randomization schedule of 2:l active to placebo were to be enrolled. All subjects were to

undergo a Screening Visit (Visit l), and those who qualified were to be scheduled to

attend a pharmacokinetic and pharmacodynamic evaluation visit (Visit 2, Treatment

Visit) within 14 days of Visit 1. At Visit 2, an intravenous catheter for blood sampling and

for potential fluid administration was to be inserted, and a gastric pH probe was to be

placed. After an approximate l-hour baseline period of gastric pH monitoring, subjects

were to receive a double-blind, randomized, single-dose administration of study drug.

Subjects were to undergo 6-hours of gastric pH sampling for pharmacodynamic

information and provide ten 2.5 mL samples of blood at scheduled intervals for

pharmacokinetic information. Safety was to be assessed by adverse event monitoring for

the duration of Visit 2.

II.3.1.1 Study objectives

Primary:

Characterize the pharmacokinetics of ranitidine 75 mg in a pediatric population

following a single-dose.

Determine the effect on intragastric pH in a pediatric population of single dose

ranitidine 75mg as compared to placebo.

Secondary:

Obtain adverse experience data in a pediatric population following single doses of

ranitidine 75mg.

II.3.1.2 Pharmacodynamic measures

At Visit 2, each subject had a gastric pH probe inserted through the nose while in the

sitting position. The probe's presence in the stomach was confirmed by the distance of

the tip from the nostril and the recording of a consistent baseline gastric pH (I 3.0) on Qe

pH monitor. For some subjects, x-ray was used to confirm positioning. Only water (not

exceeding 200 mL) was provided to the subject as an aid to swallowing the tube. pH

values were determined prior to dosing and at 4 second intervals for six hours after study

drug administration. In the event that an appropriate and consistent baseline pH could

not be obtained, the subject was to be removed from the study.

From the pH data, the following parameters were calculated for each subject for both the

last 30 minutes of the pre-treatment period and for study hours 0-6 (post-treatment):

AUC of H+ ion concentration,

median gastric pH over the total duration, and

percentage of time gastric pH 3 and gastric pH 4

II.3.1.3 Results

Seventy-one subjects were screened and not enrolled. The reasons these screened

subjects were not enrolled are presented in the following table.

Reason a Screened Subject Was Not Enrolled Number of subjects

Family or subject unwilling/unable to participate (exact reason not specified) 16

Unable to swallow pills 12

Insufficient signs or symptoms of reflux 12

Unwilling/unable to have pH probe 9

Unwilling/unable to fit study into schedule 8

Family unwilling for child to undergo study procedures 6

Prohibitive medical condition 5

Prohibited concomitant medication(s) 2

Subject responding to other medication(s) 1

Total number of subjects 17

A total of 31 subjects were enrolled from the six investigational sites. (One of the 7

investigational sites did not enrol1 any subjects.) Two enrolled subjects were intubated

8

but not randomized due to withdrawn consent. Twenty-nine subjects were randomized to

study drug.

The mean age of the randomized subjects was 8.3 years (range: 4 to 11 years).

Seventeen (59%) of the subjects were male and 12 (41%) were female. All 29 subjects

were white.

The mean height was 133.3 cm (range: 105 - 193 cm) and the mean weight was 31.97

kg (range: 14.4 - 56.2 kg).

On average, the subjects in the placebo group appeared to be slightly older (8.7 years

versus 8.2 years), taller (138.3 cm versus 130.7 cm), and heavier (33.77 kg versus

31.02 kg) than those in the Zantac 75 group.

Among the randomized subjects, the mean number of months with acid reflux symptoms

prior to screening was 35.0 (range: 2-1 12 months), however, there was a notable

difference between the treatment groups. The duration was shorter for the Zantac 75

subjects (mean 30.8, median 14.0) as compared to the placebo subjects (mean 43.0,

median 46.0).

All randomized subjects had at least two acid reflux symptoms at the screening visit, with

no particular symptom being reported more or less often than the others were.

II.3.1.4 Pharmacodynamic Response Data

All 29 randomized subjects had sufficient pH data (at least 5.5 hours) to be included in

the analysis of the pharmacodynamic parameters.

The pharmacodynamic parameters were calculated based on gastric pH values taken

every four-seconds. All pH values outside the physiological range (i.e., <0.7 or 8.5)

were excluded from all statistical analyses. These pH values are referred to as 'invalid pH

values'.

Figure 5 presents the mean gastric pH during the 6.5 hours of measurement for the

Zantac 75 and placebo groups. Gastric pH values are similar for both groups during the

pretreatment period but begin to diverge approximately one half hour after drug

administration. Values in the Zantac 75 group show the greatest rate of increase

between 0.5 to 1 hour after dosing, reaching their highest level approximately 4 hours

after dosing, then slowly decreasing but remaining higher than the placebo group

throughout the balance of the measurements. Gastric pH in the placebo group shows

little change over the period of observation.

9

The following table summarizes the mean value for the pharmacodynamic parameters by

treatment group for both the pre-treatment and post-treatment phases.

Pharmacodynamic Parameter

Phase (hours)

Zantac 75 (N=19)

Placebo (N=10)

AUC for H+ Pre (-0.5 to 0) 39.11 41.99

Post (0 to 6) 227.42 555.11

Median gastric pH Pre (-0.5 to 0) 1.27 6 1.161

Post (0 to 6) 2.861 1.247

% of time gastric pH>4 - Pre (-0.5 to 0) l.2% 1.4%

Post (0 to 6) 31.3% 4.4%

% of time gastric pH>3 - Pre (-0.5 to 0) 1.7% 2.4%

Post (0 to 6) 37.6% 5.3%

No statistically significant treatment group differences were observed for any of the

pharmacodynamic parameters during the pretreatment period. The Zantac 75 treatment

group had numerically lower values than the placebo group for the pretreatment

pharmacodynamic parameters area under the H+ time curve from -0.5 to 0 hours,

percentage of pretreatment time pH>4, and percentage of pretreatment time pH>3. The

Zantac 75 group had a numerically higher value of pretreatment median pH than the

placebo group.

Statistically significant differences between the Zantac75 and placebo treatment groups

were observed for all of the pharmacodynamic parameters from 0-6 hours. The mean

area under the curve for H+ was significantly lower for Zantac 75 subjects (227.42 vs.

555.11, p<0.001); the median pH was significantly greater for Zantac 75 subjects (2.861

vs. 1.247, p=0.014). The Zantac 75 treatment group had larger mean values for the

following post-treatment pharmacodynamic parameters: median pH, percentage of time

pH>4, and percentage of time pH>3. The p-values for the hypothesis tests of equality of

10

means with respect to each post-treatment pharmacodynamic parameter were all less

than 0.015.

In the planned analysis of the pharmacodynamic parameters, the two treatment groups

were compared using- a two-sample t-test. This methodology assumes the distribution

was normal and the variance was the same in both treatment groups. However, the

results of the planned analysis indicated that these assumptions may not have been

valid. Therefore a post-hoc analysis of each pharmacodynamic parameter using a non-

parametric test was performed. For all pharmacodynamic parameters, the analysis

results and conclusions of the planned two-sample t-test are confirmed using a non-

parametric test.

Extent of Exposure

Each subject received a single dose of either Zantac 75 (N=19) or placebo (N=10).

Adverse Events

As summarized in Table 12, 12 (63%) subjects randomized to Zantac 75 experienced at

least one treatment emergent adverse event during this study. No treatment emergent

adverse events were reported by subjects randomized to placebo.

Among the Zantac 75 treated subjects, 10 reported a gastrointestinal event: 5 (26%)

experienced vomiting, 4 (21%) reported nausea, and 3 (16%) noted gastric pain. Three

(16%) Zantac 75 subjects reported a neurological adverse event (2 headaches, 1 report

of dizziness, 1 intermittent headache, and 1 lightheaded experience). In the remaining

body systems, 1 subject reported a sore throat (ear, nose, and throat system), and 1

subject (who previously experienced intermittent episodes of emesis) reported

dehydration (endocrine and metabolic system). No subjects were withdrawn due to

adverse events. All adverse events were either mild or moderate in intensity.

Zantac 75

(N=19)

Placebo

(N=10)

Any event 12 63% 0 0

Gastrointestinal

Any event 10 53% 0 0

Vomiting 5 26% 0 0

Nausea 4 16% 0 0

Gastric pain 3 16% 0 0

Neurology

Any event 3 16% 0 0

Headache 2 11% 0 0

Dizziness 1 5% 0 0

Intermittent headache 1 5% 0 0

Lightheaded 1 5% 0 0

Ear Nose & Troath

Any event 1 5% 0 0

11

Nasal discomfort 1 5% 0 0

Endocrine & metabolic

Any event 1 5% 0 0

Dehydration 1 5% 0 0

Deaths, Serious Adverse Events, and Other Significant Adverse Events

There were no deaths, serious adverse events, or pregnancies reported in this study.

Rapporteur’s comments

No serious adverse events or deaths were reported during the conduct of this study.

Twelve (63%) subjects randomized to Zantac 75 experienced at least one treatment

emergent adverse event during this study. No treatment emergent adverse events were

reported by subjects randomized to placebo. The frequency of these events is

comparable to those seen in prescription ranitidine clinical trails, with the exception of

vomiting which is increased. No new adverse events were noted that were not already

high lighted the prescription and non-prescription adult clinical trails and spontaneous

reporting with ranitidine over the last 15 years. Therefore, these results do not raise any

safety concerns about the use of Zantac 75 in this population.

II.3.1 Pharmacokinetics

For pharmacokinetics of ranitidine in paediatric patients reference has been made to

published data and four studies investigating the pharmacokinetics of ranitidine in

paediatric patients were included in Module 5 of this submission:

Pharmacokinetics of ranitidine syrup in children. Report No GGL/91/005. Protocol

No 69-RAN-1149.

The pharmacokinetics and pharmacodynamics of intravenous ranitidine (1mg/kg)

in children in intensive care. Report No GGA/87/002. Protocol No. RAN-69-1149

(Rylance et al. 1987).

A pharmacokinetic and pharmacodynamic study of intravenous ranitidine in

neonates. Report No RC1998/00030/00. Published as Wells et al. Br J Clin

Pharmacol 1998; 38: 402-407.

A double-blind, placebo-controlled, pharmacokinetic, pharmacodynamic evaluation

of ranitidine 75 mg tablets in four through eleven year old subjects with suspected

abnormal acid reflux. Report No RC1998/00023/00. Protocol No RAN20006.

Published information regarding average pharmacokinetic values for ranitidine in children

with peptic ulcer disease are similar to those for adults when corrections for body weight

are made (Blumer et al, 1985; Leeder et al, 1986). Pharmacokinetic values for

ranitidine following either oral or intravenous administration are similar for an individual

child (Blumer et al, 1985). The bioavailability of ranitidine given orally averaged 48%

(Blumer et al, 1985). The pharmacokinetic parameters following intravenous and oral

administration are summarised in Table 1.

Table 1: Pharmacokinetic parameters following administration of Zantac in paediatric Patients.

Author / protocol

Population Age

N

Dose (mg/kg

body weight)

Admin (IV or O)

T1/2 (h)

Mean

±SD

Vd (L/kg) Mean

±SD

Cl /F (ml/(min*kg))

Mean ±SD

Blumer et al

3.5-16y 11 iv: 0.13-

0.80 1.8±0.3 2.3±0.9 22 ± 8#

1985 3.5-16y 12 po (tablet): dose ≥ 90%

2.0±0.5 2.5±1.0 22 ± 8#

12

inh gastric

output

Leeder et al

<6y 6 iv: 1.25 or

2.5 2.2±2.1 1.3±0.8 11 ±7

1986 6-11.9 y >12 y

11 6

iv: 1.25 or 2.5

iv: 1.25 or 2.5

2.1±1.0 1.7±0.5

1.1±0.5 1.0±0.3

9 ± 3 10 ± 3

Adults 6 iv: 2.5 1.9±0.3 1.0±0.1 8.8 ± 0.7

Fontana et al. 1993

Neonate 1d 27 iv: 2.4 3.5 1.5 ± 0.9

5.0 ± 0.5

RAN-69-1149

1 day- 1 m 1.5 m- 12 y

2 15

iv: 1

4.2 ±

0.7 2.1 ± 0.6

1.0 ±

0.1 2.4 ± 1.2

2.7 ± 0.6 13 ± 5

69-RAN-

1149 0.5-14y 10

po (syrup):

2

2.7 ±

0.5 27 ± 10

Wells et al,

Term neonates

13 iv: 2 6.6 ± 2.8

1.8 ± 0.6

4.1 ± 2.4

1998 1-29 d ECMO

RAN20006 4-11y 19 po 75 mg

(median 2.5

mg/kg)

2.1 ± 0.7

4.9 ± 3.7

25 ± 10

Key: T½ = half life, Vd=volume of distribution, CL= plasma clearance of ranitidine, ECMO= extracorporeal membrane oxygenation. # Cl in ml/min/kg were estimated by assessor from 794 and 788 ml/min/1.73m2 (Blumer et al. 1985) using the individual body weight of the children.

The pharmacokinetics of ranitidine in the four studies included in this submission are

comparable to the previous published data. Following oral administrion as syrup or

tablets only limited data (N=4) are available in children <3 years of age but

pharmacokinetics were in line with that of the older children. In comparison with infants

and children, the neonate may have substantially reduced renal and plasma clearance of

ranitidine (Fontana et al, 1993, Wells et al, 1998, Rylance et al. 1987). In neonates

undergoing ECMO, total clearance was related to estimated glomerular filtration rate (see

Figure below).

0

1

2

3

4

5

6

7

8

9

0 10 20 30 40 50 60 70

estimated GFR (ml/min/1.7m2)

Cl (m

l/(m

in*k

g))

Figure 1. Ranitidine clearance as function of glomerular filtration rate

(calculated according to Schwarz) in neonates undergoing ECMO (Wells et al,

1998).

13

In conclusion, pharmacokinetics of ranitidine following either oral or intravenous

administration are similar for an individual child and pharmacokinetics are comparable in

paediatric and adult patients when corrections for body weight are made. In neonates the

clearance is substantially lower and due to the lower GFR in neonates the dose interval

may need to be lengthened.

II.3.3 Pharmacodynamics and Efficacy

Six controlled pharmacodynamic and/or clinical studies of use of ranitidine oral and

intravenous formulation in children are included in Module 5 of this submission:

An investigation to compare the safety and efficacy of ranitidine 150mg nocte with

placebo in the prevention of symptomatic duodenal ulcer relapse in paediatric

patients. Report No GGL/95/006. Protocol No RAN M15.

Evaluation of the efficacy and pharmacokinetics of ranitidine in paediatric ulcer

disease. Protocol No RAN I-145. No study report - published as Blumer et al 1985

Evaluation of the efficacy and pharmacokinetics of ranitidine in paediatric ulcer

disease. Protocol No RAN I-145A. Study stopped prematurely.

A double-blind, randomized trial of ranitidine therapy in patients with cystic

fibrosis and pancreatic insufficiency. Report No UCD/95/013. Protocol No RAN-

147.

A comparison of continuous intravenous infusion and bolus injections of ranitidine

in critically ill paediatric patients for inhibition of gastric acid production. Report

No UCD/95/019. Protocol No RAN-7001.

A double-blind, placebo-controlled, pharmacokinetic, pharmacodynamic evaluation

of ranitidine in four through eleven year old subjects with suspected abnormal

acid reflux. Report No RC1998/00023/00. Protocol No RAN20006

In addition to the studies conducted by the MAH, published literature on therapeutic use

of ranitidine in the clinical management of paediatric patients, ranging from neonates to

adolescents is submitted. These publications are referred to in the supplementary

paragraph.

II.3.4 Efficacy data

There were no company- sponsored clinical efficacy studies for the following proposed

indications: ‘the treatment of gastro-oesophageal reflux, (including reflux oesophagitis

and the symptom relief of gastro-oesophageal reflux disease) and the prophylaxis of

stress ulceration in seriously ill patients for the injection formulation’.

For the proposed indication of short and long term treatment of peptic ulcer, the

following trials were undertaken:

II.3.4.1 Study 145 and 145A

Both of these open label trials provided supportive data for the use of ranitidine for the

short term treatment of peptic ulcer, which is already indicated for the oral formulations.

Study 145 was an open-label single centre study (conducted in the US) of 12 patients,

aged 3.5-16 years, with endoscopically diagnosed duodenal and/or gastric ulcers

associated with epigastric pain and/or vomiting and melaena. After an initial treatment

with intravenous therapy, patients received oral therapy 12 hourly for 6 weeks. Ulcers

were healed in all cases at 6 weeks. In study 145A, 3 children received oral therapy for 6

weeks with ranitidine syrup, after a similar initial phase to study 145. Ulcers healed in 2

out of 3 cases.

Studies RAN 147 and 701 were also small studies that did not provide any useful data for

the proposed indications.

II.3.4.2 Study RAN M15.

This double-blind, placebo controlled trial, undertaken in 194 children aged 8 to 16

(mean 13 years) with duodenal ulcer compared the efficacy of ranitidine 150mg at night

with placebo, in the prevention of duodenal ulcer over a 12 month treatment period. The

cumulative ulcer relapse at 12 months was only 30 % in those receiving placebo

14

compared to 9% for ranitidine (p<0.001). Relapse rates of 70 to 80% have been

reported for adult populations, suggesting that the natural history of duodenal ulcer

disease in this population differed from that in the adult population. It is also of note that

few patients suffered a symptomatic relapse – six in the placebo group and two in the

ranitidine group.

Although the risk of relapse was reduced with maintenance ranitidine therapy, the

incidence of symptomatic relapse was low in both groups. In addition, H.pylori status was

not considered; present management of peptic ulceration would include this. In

summary, these data do not provide robust evidence for the indication of ‘long term’

treatment of peptic ulceration in children aged 1 month and above.

Issue raised

With regard to the proposed therapeutic indication ‘prophylaxis of stress ulceration in

seriously ill children’, The MAH was asked to provide further information on whether or

not there is evidence that the prophylaxis of stress ulceration in seriously ill children with

ranitidine:

- is associated with a decrease in gastric bleeding,

- had a better overall outcome,

- did not result in an increase in infections/complications compared to those who did

not undergo prophylaxis with ranitidine.

15

Response of the MAH to the issue

In response the MAH stated that analysis of the literature has revealed no additional

studies conducted with ranitidine for the prophylaxis of stress ulceration further to those

submitted previously. The MHRA, in their review of the data package in consultation with

expert advice from the Commission on Human Medicines, found that the use of ranitidine

was well established in this indication (the scientific justification for this position is not

available for assessment). Additional confirmation regarding the use of ranitidine in this

indication was provided in a clinical expert statement which discusses current clinical

practice for the treatment of the prophylaxis of stress ulceration in a paediatric intensive

care unit at Addenbrooke’s hospital in the UK. GSK believe that the available studies and

literature show that ranitidine is used for the prophylaxis of stress ulceration in the

paediatric population and thus the SPC should reflect this with appropriate information

for the prescriber. As discussed the dosing recommendation proposed in the SPC are in

line with the guidance in the British National Formulary for Children (BNFc) and is

supported by the literature, where doses of up to 6 mg/kg/day have been used.

Previously the MAH submitted literature discussing the prophylaxis of stress ulceration in

critically ill children. Ranitidine administered either as an intermittent intravenous infusion

(2-6mg/kg/day in divided doses) (Harrison et al, 1998; Kuusela et al, 1997; Kuusela,

1998; Lopez-Herce et al 1988; Osteyee et al 1994; Rylance 1987; Santucci et al,

1991) or as a continuous infusion (0.1-0.2mg/kg/hr) (Osteyee et al, 1994; Santucci et

al, 1991; Dimand et al 1989; Eddleston et al, 1989) has been successfully used to

maintain gastric pH levels above 4.0. Both dosing regimens were effective in increasing

and maintaining gastric pH above 4, however the pH values fluctuate more with the

intermittent regimens (Osteyee et al, 1994; Santucci et al, 1991).

In general this surrogate endpoint (pH >4) is accepted and has shown a reasonable

relation with the clinical outcome of the prevention of gastric and duodenal ulcera. The

relation to the prevention of bleedings (and their complications) remains to be

established. Therefore, it can not be assumed that the depicted effects from literature are

clinical meaningful for the applied ‘prophylaxis of stress ulceration in seriously ill

children’. The MAH was not able to convincingly show that ranitidine is associated with a

decrease in gastric bleeding, had a better overall outcome or did not result in an increase

in infections/complications compared to those who did not undergo prophylaxis with

ranitidine.

II.3.5 Safety

A cumulative review of all serious and non-serious clinical trial and spontaneous adverse

events in children and adolescents aged less than 18 years associated with ranitidine

administration has been provided. A search of the safety database revealed a total of 971

adverse event reports associated with ranitidine administration in patients aged less than

18 years that have been received worldwide by the GSK global safety group since first

launch in 1981 up to 02 August 2004. Review of the most commonly reported events in

cases received up to 02 August 2004 did not highlight any safety issues for paediatric

patients. In addition PSURs covering the time period from June 2001 – May 2006 are also

included.

Isue raised

It was noted that it is difficult to compare severity and frequency of undesirable effects

between adults and children. The MAH was asked to provide comparative data on this

point.

Resolving the issue

The MAH responded by providing a tabular comparison of the non-serious and serious

AEs in both the adult (greater than 18 years) and the paediatric population (less than 18

years) by system organ class, as well as a comparison of events from a cumulative

summary of events reported for ranitidine. See tables 2-5 below.

Table 2 - Body System Distribution: Comparison Between Adults (age >18 Years) and Children (< 18 Years)Non-serious Cases: System Organ Class (SOC) Comparison Based on the Primary AE.

System Organ Class Adults: Number of

Cases System Organ Class

Children: Number of

Cases

Skin and subcutaneous tissue disorders 1723 Gastrointestinal disorders 270

Gastrointestinal disorders 1551 Injury, poisoning and procedural complications 136

General disorders and administration site conditions 1136 General disorders and administration site conditions 104

Nervous system disorders 1030 Nervous system disorders 101

Psychiatric disorders 781 Skin and subcutaneous tissue disorders 95

Reproductive system and breast disorders 696 Psychiatric disorders 75

Investigations 535 Investigations 50

Blood and lymphatic system disorders 396 Respiratory, thoracic and mediastinal disorders 30

Musculoskeletal and connective tissue disorders 372 Reproductive system and breast disorders 25

Hepatobiliary disorders 256 Eye disorders 18

Respiratory, thoracic and mediastinal disorders 244 Blood and lymphatic system disorders 14

Eye disorders 228 Immune system disorders 14

Immune system disorders 213 Renal and urinary disorders 12

Cardiac disorders 201 Musculoskeletal and connective tissue disorders 12

Renal and urinary disorders 171 Hepatobiliary disorders 10

Vascular disorders 132 Cardiac disorders 8

Metabolism and nutrition disorders 84 Infections and infestations 8

Ear and labyrinth disorders 82 Surgical and medical procedures 5

Pregnancy, puerperium and perinatal conditions 70 Metabolism and nutrition disorders 5

Injury, poisoning and procedural complications 60 Endocrine disorders 2

Infections and infestations 53 Ear and labyrinth disorders 2

Endocrine disorders 12 Vascular disorders 2

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

11 Social circumstances 1

Surgical and medical procedures 2 Pregnancy, puerperium and perinatal conditions 1

Congenital, familial and genetic disorders 2

Social circumstances 2

Total Cases 10043 Total Cases 1000

17

Table 3 - Non-Serious: Comparison of Number of Cases within each System Organ Class (SOC).



Children: Number of

Cases

Skin and subcutaneous tissue disorders 1723 Skin and subcutaneous tissue disorders 95

Gastrointestinal disorders 1551 Gastrointestinal disorders 270



Psychiatric disorders 781 Psychiatric disorders 75

Reproductive system and breast disorders 696 Reproductive system and breast disorders 25


Blood and lymphatic system disorders 396 Blood and lymphatic system disorders 14

Musculoskeletal and connective tissue disorders 372 Musculoskeletal and connective tissue disorders 12

Hepatobiliary disorders 256 Hepatobiliary disorders 10

Respiratory, thoracic and mediastinal disorders 244 Respiratory, thoracic and mediastinal disorders 30

Eye disorders 228 Eye disorders 18

Immune system disorders 213 Immune system disorders 14

Cardiac disorders 201 Cardiac disorders 8

Renal and urinary disorders 171 Renal and urinary disorders 12

Vascular disorders 132 Vascular disorders 2

Metabolism and nutrition disorders 84 Metabolism and nutrition disorders 5

Ear and labyrinth disorders 82 Ear and labyrinth disorders 2

Pregnancy, puerperium and perinatal conditions 70 Pregnancy, puerperium and perinatal conditions 1

Injury, poisoning and procedural complications 60 Injury, poisoning and procedural complications 136

Infections and infestations 53 Infections and infestations 8

Endocrine disorders 12 Endocrine disorders 2


11 Neoplasms benign, malignant and unspecified (incl cysts and polyps)

0

Surgical and medical procedures 2 Surgical and medical procedures 5

Congenital, familial and genetic disorders 2 Congenital, familial and genetic disorders 0

Social circumstances 2 Social circumstances 1


18

Table 4 - Serious Cases: System Organ Class (SOC) Comparison Based on the Primary AE.



Children: Number of

Cases

Blood and lymphatic system disorders 679 Injury, poisoning and procedural complications 37

Hepatobiliary disorders 374 Nervous system disorders 34

Gastrointestinal disorders 371 Blood and lymphatic system disorders 32

Cardiac disorders 348 Skin and subcutaneous tissue disorders 23

Skin and subcutaneous tissue disorders 322 Gastrointestinal disorders 21

Nervous system disorders 321 General disorders and administration site conditions 20

General disorders and administration site conditions 271 Hepatobiliary disorders 19

Immune system disorders 225 Congenital, familial and genetic disorders 19

Neoplasms benign, malignant and unspecified (incl cysts and polyps) 223 Respiratory, thoracic and mediastinal disorders 18

Psychiatric disorders 220 Investigations 15

Investigations 190 Psychiatric disorders 15

Infections and infestations 178 Cardiac disorders 14

Respiratory, thoracic and mediastinal disorders 159 Immune system disorders 13

Vascular disorders 114 Infections and infestations 12



Injury, poisoning and procedural complications 87 Vascular disorders 4




Surgical and medical procedures 19 Endocrine disorders 1

Ear and labyrinth disorders 17 Pregnancy, puerperium and perinatal conditions 1

Endocrine disorders 12 Ear and labyrinth disorders 1

Pregnancy, puerperium and perinatal conditions 9

Congenital, familial and genetic disorders 5

Social circumstances 2


19

Table 5 - Serious: Comparison of Number of Cases within each System Organ Class (SOC)



Children: Number of

Cases

Blood and lymphatic system disorders 679 Blood and lymphatic system disorders 32

Hepatobiliary disorders 374 Hepatobiliary disorders 19

Gastrointestinal disorders 371 Gastrointestinal disorders 21

Cardiac disorders 348 Cardiac disorders 14

Skin and subcutaneous tissue disorders 322 Skin and subcutaneous tissue disorders 23



Immune system disorders 225 Immune system disorders 13

Neoplasms benign, malignant and unspecified (incl cysts and polyps) 223


0

Psychiatric disorders 220 Psychiatric disorders 15


Infections and infestations 178 Infections and infestations 12

Respiratory, thoracic and mediastinal disorders 159 Respiratory, thoracic and mediastinal disorders 18

Vascular disorders 114 Vascular disorders 4



Injury, poisoning and procedural complications 87 Injury, poisoning and procedural complications 37




Surgical and medical procedures 19 Surgical and medical procedures 0

Ear and labyrinth disorders 17 Ear and labyrinth disorders 1

Endocrine disorders 12 Endocrine disorders 1

Pregnancy, puerperium and perinatal conditions 9 Pregnancy, puerperium and perinatal conditions 1

Congenital, familial and genetic disorders 5 Congenital, familial and genetic disorders 19

Social circumstances 2 Social circumstances 0


A cumulative summary of events for the serious and non-serious cases reported

for adults and children was reviewed. Overall, the events reported were similar

for adults and children.

For the serious cases, irritability was reported more frequently in children than in

adults. However, this would not be unexpected in infants and children with

gastroesophageal reflux disease. Accidental overdose was also reported more

frequently with children; about half of the reports involved an error in the amount

of ranitidine syrup.

For the non-serious cases, retching, tooth discolouration, irritability, crying,

accidental overdose/overdose, and medication errors were reported more

frequently in children compared to adults. Irritability and crying would not be

unexpected in infants and children with gastroesophageal reflux disease. Retching

was reported only with the syrup formulation and many cases reported the event

was due to the taste of the medication.

Ten cases total of tooth discolouration in children were reported to GSK. Three of

these cases involved co-suspect or multiple concurrent medications. One other

case reported the discolouration was removed with cleaning. Three cases did not

provide further details and outcome was unknown. Two other cases reported

events that occurred after a year or more of therapy; outcome was not reported.

The remaining case reported the event occurred after 4 months of therapy; no

action was taken and outcome was unresolved.

The majority of cases reporting overdose/accidental overdose involved a

dispensing error with the syrup. The majority of cases reporting medication

errors involved ranitidine syrup and either an accidental overdose or another

medication dispensed in error instead of ranitidine, mainly cetirizine (Zyrtec).

This issue is considerd resolved. The MAH however could not explain the tooth

discoloration and therefore was asked to add this adverse event to SPC section

4.8.

Patient exposure

Cumulatively, patient exposure to ranitidine tablets is estimated to be

approximately 41.6 billion treatment days.

Adverse events (post-marketing)

Period 1981 up to 02 August 2004

The MAH provided a cumulative review of all serious and non-serious clinical

adverse events in children and adolescents aged less than 18 years associated

with ranitidine administration, since first launch in 1981 up to 02 August 2004.

The cases involving paediatric patients (n=971) represent about 5% of all

ranitidine cases in the MAH’s Safety Database. The majority of the 971 cases were

non-serious spontaneous reports received from medical professionals and

described patients 2 years of age or younger. Appendix 1 shows the most

common MedDRA System Organ Class for the reported adverse events.

Most patients received ranitidine to treat a condition (e.g. gastroesophageal reflux

disease, ulcer) for which some of the reported events (e.g. vomiting, irritability,

abdominal pain, crying, insomnia) could be a symptom. Review of the most

commonly reported events in cases received up to 02 August 2004 did not

highlight any safety issues for paediatric patients.

Period 01 June 2004 to 31 May 2006

Table 6 shows an overview of the adverse reactions in paediatric patients (<18

years) by MedDRA System Organ Class reported in PSURs during period 01 June

2004 to 31 May 2006 for Zantac.

21

Table 6 - Overview of the adverse reactions in paediatric patients (<18 years)

by MedDRA System Organ Class reported in PSURs during period 01 June 2004 to 31 May 2006 for Zantac. System Organ Class Adverse reaction Total

Blood and the lymphatic system disorders

Thrombocytopenia (1) Agranulocytosis (1) Aplastic anaemia (1) Leukopenia (1)

4

Psychiatric disorders Insomnia (2) Suicide attempt (1)

3

Nervous system disorders Psychomotor hyperactivity (1) Tardive dyskinesia (1) Tremor (3) Convulsion (1) Dysgeusia (3) Hyper somnia (1) Somnolence (2)

12

Eye disorders Eye disorder (1) 1

Vascular disorders Flushing (1) 1

Respiratory, thoracic and mediastinal disorders

Choking (1) Apnoea (2)

Epistaxis (1)

4

Gastrointestinal disorders Vomiting (8) Haematochezia (1) Dysphagia (1) Consipation (1)

Abdominal pain (1) Colitis ulcerative (1) Faeces discoloured (2) Oral discomfort (1) Stomach discomfort (1)

17

Hepato-biliary disorders Hepatitis (1) 1

Skin and subcutaneous tissue disorders Rash (3) Alopecia (2) Photosensitivity reaction (1)

6

Renal and urinary disorders Urine odour abnormal (2) Tubulointerstitial nephritis (2)

4

Reproductive system and breast disorders

Hypertrophy breast (1) Gynaecomastia (1)

2

Congenital and familial/genetic disorders Epidermolysis bullosa (1) Ventricular septal defect (3) Cleft palate (1) Syndactyly (1) Talipes (1)

7

General disorders and administration site conditions

Drug ineffective (2) Feeling jittery (1) Condition aggravated (1) Chills (1) Irritability (1) Malaise (1) Pyrexia (1)

8

Investigations Increased Blood Amylase (1) 1

Injury and poisoning Overdose (18) Medication error (8) Incorrect dose (2)

26

Total: 97

Several remarks were made:

- The periods covered by the cumulative overview and the PSURs show a time

overlap of several months.

- A complete overview of the adverse reactions, subdivided in serious and

nonserious, in children and adolescents aged less than 18 years associated

with ranitidine administration, since 03 August 2004 to 31 May 2006 is lacking.

- The cases in the PSURs reporting adverse events were not restricted to

paediatric patients only

This seriously hampered assessment of the cumulative reported adverse reactions

in the paediatric population. However, neither the review of the paediatric cases in

the period from 1 June 2004 to 31 May 2006, nor the cumulative review of

22

paediatric case report up to August 2004 did highlighted any safety issues.

Therefore the above mentioned shortcommings were considered acceptable.

Pregnancy

Cumulative, a total of 280 reports (258 spontaneous, 22 clinical trial). Forty-three

of the 280 reports involved patients given ranitidine for labour or caesarean

section. Outcomes of pregnancies in the remaining 237 cases in which ranitidine

was administered during pregnancy for other indications are summarised below.

Outcome Total Number

Normal infant 76

Spontaneous abortion/miscarriage 6

Elective termination 6

Stillbirth 2

Abnormal infant 23

Pregnancy ongoing/unknown 124

Total 237

Issue raised

The MAH was requested to specify the category ‘Pregnancy ongoing/unknown’ in

‘Pregnancy ongoing’ and ‘Pregnancy unknown’. In addition, an explanation was

asked as to why no follow-up has been received for pregnancy cases in category

‘unknown’.

Resolving the issue

The MAH responded by stating that ‘Pregnancy Ongoing’ and ‘Pregnancy

Unknown’, which are coded in the safety database at the time of the initial report,

are assumed to be both unknown since GSK have not received any follow-up

information on the outcome. Therefore they are placed in the same category.

GSK is diligent in following up on all case reports of pregnancy, however, due to

the nature of spontaneous reporting receipt of follow-up information cannot be

guaranteed.

The issue is considered resolved.

Long-term safety data; effect on development (growth, motor, mentally, sexually)

and cognition

In study RAN M15 (duration of 12 months), there were minor haematological

abnormalities detected in 89% of patients treated with ranitidine. In addition,

15% of patients had minor elevations of serum alkaline phosphatase levels. No

other long-term data (in particular, longitudinal growth measurements) were

available from this study.

III OVERALL CONCLUSION There is some clinical evidence in the published literature to support the use of

Zantac in paediatric practice. Limited data exist concerning the use of ranitidine in

children for indications other than peptic ulcer. This includes studies in

gastroesophageal reflux disease and prophylaxis of stress ulceration and upper

gastrointestinal bleeding.

Literature strongly suggests that oral ranitidine therapy is effective in the

treatment of gastro-oesophageal reflux disease and peptic ulceration in children.

Submitted peadiatric data considering the intravenous ranitidine therapy showed

conflicting results in the prevention of bleeding from stress ulcers in children,

therefore no firm conclusions can be drawn. Efficacy in the prevention of bleeding

remains to be demonstrated.

23

Studies have confirmed the pharmacokinetics and pharmacodynamics of ranitidine

in both oral and intravenous regimens. Pharmacokinetics of ranitidine following

either oral or intravenous administration are similar for an individual child and

pharmacokinetics are comparable in paediatric and adult patients when

corrections for body weight are made. In neonates the clearance is substantially

lower and was related to the lower glomerular filtration rate encountered in these

patients.

From the clinical trial data and spontaneous reports, ranitidine appears to be well

tolerated in the short term treatment, with an adverse effect profile similar to that

in adults. The limited long term safety data from study RAN M15 (duration of 12

months) did not reveal unexpected safety issues.

The ethanol content of ranitidine syrup is high (7.5%). The clinical implications of

this are not known but the use of ethanol in formulations for paediatric patients is

not recommendable. Further the fixed oral dose of 150 mg limits the

administration to children above 30 kg. This is reflected in the SmPC.

The limited literature suggests some efficacy concerning the use of ranitidine in

children for indications peptic ulcer, gastroesophageal reflux disease and upper

gastrointestinal bleeding. While no unexpected safety issues were seen, the

proposed indications have been approved.

24

IV. FINAL AGREED CHANGES IN THE SMPC’S

See below for the amended sections of the SmPC’s for the

tablets/syrup/solution for injection.

Zantac solution for injection 50 mg/2 ml:

Section 4.1

Children (6 months to 18 years)

Short term treatment of peptic ulcer

Treatment of gastro-oesophageal reflux, including reflux oesophagitis and

symptomatic relief of gastro-oesophageal reflux disease.

Section 4.2

Children / Infants (6 months to 11 years)

See section 5.2 Pharmacokinetic properties – Special Patient Populations.

Zantac injection may be given as a slow (over 2 minutes) i.v. injection up to a

maximum of 50 mg every 6 to 8 hours.

Peptic Ulcer Acute Treatment and Gastro-Oesophageal Reflux

Intravenous therapy in children with peptic ulcer disease is indicated only

when oral therapy is not possible.

For acute treatment of peptic ulcer disease and gastro-oesophageal reflux in

paediatric patients, Zantac injection may be administered at doses that have

been shown to be effective for these diseases in adults and effective for acid

suppression in critically ill children. The initial dose (2.0 mg/kg or 2.5 mg/kg,

maximum 50 mg) may be administered as a slow intravenous infusion over

10 minutes, either with a syringe pump followed by a 3 mL flush with normal

saline over 5 min, or following dilution with normal saline to 20 mL.

Maintenance of pH > 4.0 can be achieved by intermittent infusion of 1.5

mg/kg every 6 h to 8 h. Alternatively treatment can be continuous,

administering a loading dose of 0.45 mg/kg followed by a continuous infusion

of 0.15 mg/kg/hr.

Neonates (under 1 month)

See Section 5.2 Pharmacokinetic Properties – Special Patient Populations.

Section 4.8

The safety of ranitidine has been assessed in children aged 0 to 16 years with

acid-related disease and was generally well tolerated with an adverse event

profile resembling that in adults. There are limited long term safety data

available, in particular regarding growth and development.

Section 5.1

The clinical data available mentions the use of ranitidine in children to prevent

stress ulcers. No direct evidence for prevention of stress ulcers is available.

Treatment for these patients is based on the observation that pH is below 4

after administration of ranitidine. The value of this surrogate parameter in

children with stress ulcers remains to be established.

25

Section 5.2

Special Patient Populations

Children/infants (6 months and above)

Limited pharmacokinetic data show that there were no significant differences

in half-life (range for children 3 years and above: 1.7 - 2.2 h) and plasma

clearance (range for children 3 years and above: 9 - 22 ml/min/kg) between

children and healthy adults receiving intravenous ranitidine when correction is

made for body weight. Pharmacokinetic data in infants is extremely limited

but appears to be in line with that for older children.

Neonates (under 1 month)

Limited pharmacokinetic data from term babies undergoing treatment with

Extracorporeal Membrane Oxygenation (EMCO) suggests that plasma

clearance following iv administration may be reduced (1.5-8.2 ml/min/kg) and

the half-life increased in the new-born. Clearance of ranitidine appeared to be

related to the estimated glomerular filtration rate in the neonates.

Zantac Tablets 150 & 300mg; Effervescent tablets 150 & 300mg:

Section 4.1

Children (3 to 18 years)

Short term treatment of peptic ulcer.



Section 4.2

Children 12 years and over For children 12 years and over the adult dosage is given.

Children from 3 to 11 years and over 30 kg of weight


Peptic Ulcer Acute Treatment

The recommended oral dose for the treatment of peptic ulcer in children is 4

mg/kg/day to 8 mg/kg/day administered as two divided doses to a maximum

of 300mg ranitidine per day for a duration of 4 weeks. For those patients with

incomplete healing, another 4 weeks of therapy is indicated, as healing

usually occurs after eight weeks of treatment.

Gastro-Oesophageal Reflux

The recommended oral dose for the treatment of gastro-oesophageal reflux in

children is 5 mg/kg/day to 10 mg/kg/day administered as two divided doses

in a maximum dose of 600mg (the maximum dose is likely to apply to heavier

children or adolescents with severe symptoms).

Neonates

Safety and efficacy in new-born patients has not been established.

Section 4.8



26



Section 5.2


Children (3 years and above)

Limited pharmacokinetic data have shown that there are no significant

differences in half-life (range for children 3 years and above: 1.7 - 2.2 h) and

plasma clearance (range for children 3 years and above: 9 - 22 ml/min/kg)

between children and healthy adults receiving oral ranitidine when correction

is made for body weight.

Zantac syrup:

Section 4.1


Short term treatment of peptic ulcer



See section 4.4 Special warnings and precautions for use.

Section 4.2

Children 12 years and over

For children 12 years and over the adult dosage is given.



Zantac syrup contains approximately 7.5%w/v ethanol. Therefore an

alternative formulation of ranitidine may be considered necessary for at-risk

groups, including children (see section 4.4 Special warnings and precautions

for use).

Peptic Ulcer Acute Treatment

The recommended oral dose for the treatment of peptic ulcer in children is 4

mg/kg/day to 8 mg/kg/day administered as two divided doses to a maximum

of 300mg ranitidine per day for a duration of 4 weeks. For those patients with

incomplete healing, another 4 weeks of therapy is indicated, as healing

usually occurs after eight weeks of treatment.

Gastro-Oesophageal Reflux

The recommended oral dose for the treatment of gastro-oesophageal reflux in

children is 5 mg/kg/day to 10 mg/kg/day administered as two divided doses

in a maximum dose of 600mg (the maximum dose is likely to apply to heavier

children or adolescents with severe symptoms).

Neonates

Safety and efficacy in new-born patients has not been established.

Section 4.4

Zantac syrup contains approximately 7.5%w/v ethanol (alcohol), i.e. up to

405 mg per 5ml spoonful which is equivalent to about 11ml of beer or 5ml of

27

wine. It is harmful for those suffering from alcoholism. It should be taken

into account in pregnant or lactating women, high risk groups (those suffering

from alcoholism, liver disease, epilepsy, brain injury or disease) and children

(see section 4.2). It may modify or increase the effect of other medicines.

Section 4.8





Section 5.2


Children (3 years and above)

Limited pharmacokinetic data have shown that there are no significant

differences in half-life (range for children 3 years and above: 1.7 - 2.2 h) and

plasma clearance (range for children 3 years and above: 9 - 22 ml/min/kg)

between children and healthy adults receiving oral ranitidine when correction

is made for body weight.

28

ANNEX I: THE MHRA REPORT ON ZANTAC TABLETS,

ZANTAC EFFERVESCENT TABLETS, 300MG, 150MG,

ZANTAC INJECTION 50MG/2ML, ZANTAC SYRUP 75MG/5ML

ASSESSMENT REPORT MA NUMBER: PLs 10949/0042, 10949/0137-8, 10949/0108-9

PRODUCT NAME: Zantac tablets, Zantac effervescent tablets 300mg,150mg Zantac injection 50mg/2ml Zantac syrup 75mg/5ml

LICENCE HOLDER: Glaxo SmithKline UK Ltd

THERAPEUTIC CLASSIFICATION: Histamine 2 –receptor antagonist

MEETING: COMMISSION ON HUMAN

MEDICINES- 14 December 2005

ACTIVE INGREDIENT Ranitidine

LEGAL STATUS: POM

A national variation application to include paediatric indications for the long

term management of peptic ulcer and the treatment of gastro-oesophageal

reflux (including reflux oesophagitis and gastro-oesophageal reflux disease)

from 1 month of age and above. In addition, for the injection formulation the

MAH has applied for the following indications from 1 month onwards: the

short term treatment of peptic ulcer and the prevention of stress ulcers in

seriously ill children.

EXECUTIVE SUMMARY This is a national variation application for ranitidine tablets, injection and

syrup. Discussion and CHM Advice (page 29)

The Commission considered that the use of ranitidine was well

established, particularly for the treatment of gastro-oesophageal reflux

and the prevention of stress ulcers in seriously ill children and that there

were no safety issues associated with its use in children. However, the

Commission noted that there were insufficient data regarding dosage to

warrant extrapolation from adults for prevention of stress ulcers. The

Commission considered that there were sufficient published data to grant

the indication for the treatment of gastro-oesophageal reflux.

The submitted data for the indication for the long term treatment of peptic

ulcer were considered to be poor and this condition is uncommon in

children. In addition, current practice for the treatment of peptic ulceration

does not generally include the use of H2 antagonists for long periods. The

Commission therefore advised that this indication should be refused.

The Commission advised that the MAH should be not use ethanol in

paediatric formulations unless this was necessary.

1. INTRODUCTION This is a national variation application for ranitidine (tablets, injection and

syrup) that includes several changes to the current licence with respect to its

use in children. These data were requested by the MHRA following changes to

the US licence as a result of the paediatric exclusivity provision. The MHRA

contacted companies whose products appear on the FDA Paediatric exclusivity

granted list1. This is a list of active substances (with relevant sponsors) for

which the FDA has granted data exclusivity in return for the submission of

paediatric studies carried out in compliance with an FDA written request. The

29

MAH have submitted these data to support an application for a licence

variation.

The current granted US paediatric indications for ranitidine are: the treatment

of duodenal and gastric ulcers, gastro-oesophageal reflux disease and erosive

oesophagitis, and the maintenance of healed duodenal and gastric ulcers. The

US labelling also includes details regarding the pharmacokinetic studies.

The applicant proposes to broaden the present paediatric indication of the oral

formulations for the treatment of peptic ulcer (age unspecified), to include

indications for the long term management of peptic ulcer and the treatment of

gastro-oesophageal reflux (including reflux oesophagitis and gastro-

oesophageal reflux disease) in children aged 1 month and above. In addition

to the above, there is a further indication for the injection formulation that is

not included in the US label: the prevention of stress ulcers in seriously ill

children, from 1 month of age and above.

2. LICENSING HISTORY Ranitidine, an H2 receptor antagonist, which was first authorised in 1981, is

an established drug substance in 98 markets worldwide including the USA,

Japan and all Member States (MS) of the EU. In the UK, prescription only

licences (POM) include tablets, effervescent tablets and syrup formulations. In

addition, there are Pharmacy (P) and General Sales (GSL) licences for the

75mg tablet for the short-term symptomatic relief of heartburn, dyspepsia

and hyperacidity and for the prevention of these symptoms in adults. The

current variations apply to the POM licences only.

Ranitidine is licensed in the UK for use in adults for gastro-oesophageal reflux

disease (GORD), the treatment of duodenal ulcer, gastric ulcer, NSAID

associated ulcer, post-operative ulcer, duodenal ulcer associated with

Helicobacter pylori (in combination with appropriate antibiotics), relief of

chronic-episodic dyspepsia, and the long term management of Zollinger-

Ellison syndrome. Ranitidine is also authorised in the UK in adults for the

prophylaxis of gastro-intestinal haemorrhage from stress ulcer, recurrent

haemorrhage in patients with bleeding peptic ulcer and Mendelson’s

syndrome.

In children (age limits unspecified), ranitidine oral formulations are currently

licensed for the treatment of peptic ulcer at a dose of 2mg/kg to 4 mg/kg

twice daily to a maximum of 300mg/day. The injection formulation is

currently not licensed in children for any indication.

1 http://www.fda.gov./cder/pediatric/exgrant.htm

Ranitidine underwent an Article 30 referral procedure in 2002, the purpose of

which was to harmonise the SmPC throughout Member States. However, the

referral was withdrawn in 2003, due to procedural difficulties. However, one

of the outstanding issues was the extremely high alcohol content of the syrup

formulation. At this time, GSK agreed to the proposal to add a precautionary

statement in the SmPC regarding this.

3. BACKGROUND

Gastro-oesophageal Reflux Disease Gastro-oesophageal Reflux (GOR) is an extremely common and usually self-

limiting condition, affecting 20 – 67% of infants. GOR is the passage of gastric

contents into the oesophagus. It occurs as the result of transient,

inappropriate relaxation of the lower oesophageal sphincter, permitting the

stomach contents to pass into the oesophagus. In most infants with GOR the

outcome is benign and self- limiting. The peak incidence of GOR is around 4

months and it resolves spontaneously by 1 to 2 years of age in most patients.

There may be parental anxiety or intolerance of symptoms which lead to

medical advice being sought. This form of GOR is best managed with

reassurance and on-going clinical monitoring.

30

In a minority of cases gastro-oesophageal reflux is complicated by

oesophagitis, respiratory symptoms, neuro-behavioural symptoms or failure

to thrive and is then referred to as gastro-oesophageal reflux disease

(GORD). Many of these children have underlying conditions, such as cerebral

palsy, cystic fibrosis and congenital abnormalities. Treatment is medically

indicated in such cases, which represent a small percentage of cases with

GOR.

Omeprazole is currently the only authorised treatment for GORD and is

currently restricted to the indication of severe ulcerating oesophagitis, in

children aged 1 year and above. Other drug options include the use of

domperidone and metoclopramide, which are used in less severe cases of

GORD, and ranitidine. None of these drugs are authorised for use in GOR and

GORD.

In 2004, the US data for omeprazole was assessed; the CSM advised against

an indication for ‘acid- related disorders (including non-ulcerating GORD) and

the treatment of Helicobacter pylori. (See assessment report at mhra.gov.uk.)

Peptic Ulcer Disease

The term “peptic ulcer disease” (PUD) refers to a defect in the gastrointestinal

mucosa which has been exposed to acid and pepsin. The defect penetrates

through the mucosa and muscularis mucosa into the sub-mucosa or muscular

layer. Primary peptic ulcers are usually duodenal, whereas secondary peptic

ulcers can be duodenal or gastric. In infancy, 80% of ulcers are secondary.

After the age of 6, 70% of ulcers are primary.

The pathogenesis of PUD in children, as in adults, is multifactorial with the

final common pathway being a breakdown in the normal mucosal defence

which permits acid peptic digestion of the mucosa. In their summary of

current clinical practice that was submitted in the dossier, the MAH quoted

rates of infection of H.pylori in primary PUD in children that varied between

39% and 91%, although the original articles were not referenced.

The clinical manifestations of PUD vary according to the age of the patient. In

neonates, the two major presentations are gastro-intestinal haemorrhage

and/or perforation. Most ulcers in this age group are acute and are secondary

to stress, with other medical disorders usually present. Neonates may also

present with vomiting, feeding difficulties, or failure to thrive.

Chronic peptic ulceration (primary PUD) occurs most commonly in children

over the age of 5 years. Older children and adolescents have clinical

manifestations similar to adults; i.e., epigastric pain which is relieved by food

or antacids; nocturnal pain; nausea; vomiting; anaemia; perforation; and

occult or gross bleeding. However, younger children may present with vague

symptoms such as abdominal pain, nausea and vomiting. Suspected peptic

ulcer should be diagnosed by endoscopy, by which in addition to visualisation

of the ulcer, the presence of H.pylori can be established.

The treatment of peptic ulcer disease in children has largely been

extrapolated from adult experience, due to lack of data. Treatment usually

includes agents that block acid secretion (H2 antagonists or proton pump

inhibitors (PPIs) and eradication of H.pylori, if present (with amoxicillin,

metronidazole or clarithromycin and a PPI).

Prior to the current understanding of the role H.pylori in the pathogenesis of

chronic peptic ulcer, H2-receptor antagonists were the mainstay of ulcer

therapy for adults and children. Ranitidine has a higher affinity for the H2

receptor and is considered to be 2-4 times more potent than cimetidine. It is

longer acting and has few adverse effects, mainly nausea, vomiting and

headache. It also has significantly less effect on the cytochrome P450 system

than cimetidine. The use of two other H2 receptor antagonists, famotidine and

nizatidine, is limited in children. Surgery is reserved for children with

perforation, haemorrhage, obstruction and, rarely, intractable pain.

Stress ulceration

31

Peptic ulcers may arise as a complication of physiological stress in severely ill

children. Stress is believed to compromise the gastric mucosal defence

mechanisms and allow normal amounts of gastric acid to cause ulceration,

which is frequently associated with acute haemorrhage. The therapeutic

strategy for prevention or treatment of stress ulcers or haemorrhage is to

maintain intragastric pH above 4.0 (Kelly, 1994). For the prophylaxis of stress

ulceration and subsequent gastrointestinal bleeding in critically ill children,

ranitidine administered as an intermittent infusion (2 to 6 mg/kg/day given in

divided doses), or as a continuous infusion (0.1 to 0.2mg/kg/hr), has been

used to maintain intragastric pH levels above 4.0.

4. RANITIDINE AND FDA PAEDIATRIC EXCLUSIVITY The data submitted to the FDA resulted in the labelling change as summarised

below (full details available on the FDA web-site).

In the FDA’s Medical Review, the assessor concluded that: ‘current medical

practice and response to H2 antagonists suggests that adult efficacy data with

H2 antagonists may be extrapolated to children, except for critically- ill

children where the pathophysiology seems to be different to other children’.

4.1 US label changes

These are extensive and include (in the clinical pharmacology section), the

following indications in children aged 1 month and above: the treatment of

duodenal and gastric ulcers, gastro-oesophageal reflux disease and erosive

oesophagitis, and the maintenance of healed duodenal and gastric ulcers. For

Zantac injection only there is a statement suggesting that: ‘Limited data in

neonatal patients (less than one month of age) receiving ECMO suggest that

ZANTAC may be useful and safe for increasing gastric pH for patients at risk

of gastrointestinal haemorrhage’. In addition, there are pharmacokinetic

statements added for both oral and injection formulations.

5. PROPOSED VARIATION- SPC CHANGES Proposed SPC changes for Zantac tablets, effervescent tablets and syrup

include: additional indications for the long term management of peptic ulcer

and the treatment of gastro-oesophageal reflux, including reflux oesophagitis

and the symptomatic relief of gastro-oesophageal reflux disease. A

pharmacokinetic statement is also included.

Proposed SPC changes for Zantac injection include: the ‘acute’ treatment of

peptic ulcer, gastro-oesophageal reflux, including reflux oesophagitis and the

symptomatic relief of gastro-oesophageal reflux disease. The prophylaxis of

stress ulceration in seriously ill patients is also a proposed new indication in

children.

6. SUBMITTED DOCUMENTATION The MAH submitted the following sponsored studies, in addition to published

studies: Pharmacokinetic (PK)/Pharmacodynamic(PD) Studies- Oral PK study-

Study RAN 2006

Intravenous studies -Protocol RAN-1149, Wells et al (neonates) and RAN 701

Efficacy studies-Study RAN M15 was the pivotal trial for the indication for the

long term treatment of peptic ulcers in children. Additional studies included

open label trials Study 145,145A, studies RAN 147 and 701. 6.1 Clinical expert report

The clinical expert was insufficiently critical regarding the limitations of the

data submitted for the proposed indications.

6.2 Pharmacokinetic (PK)/Pharmacodynamic(PD) Studies

32

A detailed review of the pharmacokinetic (PK) and pharmacodynamic(PD)

data submitted has been summarised in Annex 7.

6.2.1 Oral formulations

Four studies were submitted (see table 1); one company –sponsored trial and

three published studies.8

Table 1: Oral Paediatric Pharmacokinetic Studies Reviewed

Study No Source

1 Blumer J, et al. J Paediatrics,

1985;107: 301

2 Supplemental NDA for Paediatric

Labelling, NDA 18 -703 Zantac Tablets

3 Mallet E, et al. Eur J Clin Pharmac,

1989;36: 641

4 Study RAN 2006

6.2.1.1 Overall conclusions: pharmacokinetic studies of oral ranitidine

Table 2 provides a summary of the submitted oral paediatric pharmacokinetic

studies:

Table 2: Cross-study comparison of oral paediatric pharmacokinetic

data (mean values)

Study

No, age,

no

Dose

T0.5

(hr)

CL

(ml/min/m2)

Vd

(L/kg)

Tmax

(hr)

Cmax

(ng/ml)

AUC12hr

(hr*ng/ml)

1. 3-

6yrs

(12)

150 mg

(tablet)

2.0

(0.5)

455s

(192)

2.5

(1.0)

NA NA NA

2. 7m-

14yrs(8)

2 mg/kg

Single

dose

(syrup)

2.4

(0.5)

NA NA 1.61

(0.50)

244

(109)

1045

(324)

2 mg/kg

Steady

state

2.7

(0.5)

NA NA 1.66

(0.82)

320

(199)

1428

(578)

3. 6w-

6m (11)

5 mg/kg

(iv soln)

2.8

(0.8)

664

(NA)

NA 1.2

(0.4)

476

(164)

NA

4 4-11

yrs (24)

2.7mg/kg 2.1 25.5

(ml/min/kg)

4.94 2.7 476.6

(median)

The submitted data are limited, mainly due to poor methodology and due

to limited numbers, particularly in children under 3 years old. However,

from studies 1 and 4, which were the most robust in design, the

parameters in children were similar to that in adults when adjusted for

body weight.

These data support the inclusion of a statement in Section 5.2 of the Sm

PC and also the proposed dosage regimen for short term treatment of

ulcers.

6.2.2 Intravenous administration

Two company- sponsored trials were submitted, in addition to five published

studies. Study RAN 701 provided no useful information; in addition, 3 of the

publications were abstracts. The company- sponsored study by Wells et al

was undertaken in neonates receiving Extracorporeal Membrane Oxygenation

(EMCO) and is summarised below.

33

Table 3: Intravenous Paediatric Pharmacokinetic Studies Reviewed

Study No Source

1 Blumer J, et al. J Paediatrics,

1985;107: 301

5 Leeder JS, et. Acta Pharm Tox,

1986;59: 79

6 Leeder JL, et al. Clin Pharmac Ther,

1989;12: 7

7 Wiest, DB et al. Dev Pharmac Ther,

1989;12: 7

8 Rylance G. In: Perspective on

therapeutics in Northern Europe:

Hyperacidity states, London 1987;52

9 Protocol RAN-1149

10 Wells et al

RAN 701

6.2.2.1 A Pharmacokinetic and Pharmacodynamic Study of Ranitidine in

Neonates. Report No RC1998/00030/00. Published as Wells et al. Br J Clin

Pharmacol 1998; 38: 402-407 (study no 10.)

Objectives:

To characterise the pharmacokinetics of ranitidine administered as a single

intravenous dose in neonates

To characterize the pharmacokinetics of ranitidine administered as a

continuous intravenous infusion, using a dosing regimen which provides

therapeutically meaningful gastric acid suppression based on the data

from the single dose pharmacokinetic/pharmacodynamic evaluation in the

same subjects.

To collect information on the safety of single and multiple doses of

ranitidine in neonates.

Methodology

This was an open-label single intravenous dose study followed by a constant-

rate intravenous infusion of ranitidine conducted in 12 term neonates

(younger than 1 month of age) presenting to the intensive care unit with a

medically established need for H2-blocker therapy. All subjects had potentially

reversible cardiac or pulmonary failure requiring treatment with

Extracorporeal Membrane Oxygenation (EMCO). Primary diagnoses included:

meconium aspiration (N=6), sepsis (N=1), hypoplastic lungs (N=1), and

persistent pulmonary hypertension (N=1)

Ranitidine (2.0mg/kg) was administered over 10 minutes into the

postmembrane side of the ECMO circuit. Blood samples (1.5mL each) were

collected at baseline and 0.08, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 12, 18

and 24 hours. Twenty-four hours after the initial dose, a continuous

intravenous infusion of ranitidine (0.083mg/kg/hr) was started and continued

for 72 hours or until ECMO was discontinued. Gastric pH measurements were

conducted at specified times throughout the study. If the stomach pH fell to

<4, the rate of the infusion was increased in increments of 0.042mg/kg/hr

(1mg/kg/24hours).

Results

Pharmacokinetic parameters are provided below in table 4. As expected, in

this study ranitidine had a much longer half-life and lower clearance in

neonates than in older children and adults.

After a single 2mg/kg dose of ranitidine, mean intragastric pH increased to >5

within 90 minutes and remained >5 for 16 hours in subjects with an initial pH

of ≤ 4. The investigators therefore suggested that if intermittent intravenous

34

administration is used, a dose interval of ≥ 12 hours might be appropriate in

this population. Total clearance was related to estimated glomerular filtration

rate. Consequently, the dose interval may need to be lengthened in neonates

with severely compromised renal function.

The plasma concentration and pharmacodynamic data suggested that a

continuous infusion of 2mg/kg/24 hours is adequate to maintain intragastric

pH above 4 in greater than 90% of term neonates undergoing ECMO. Of the

13 subjects enrolled, five had an initial gastric pH of ≤ 4. In five subjects,

gastric pH increased to > 4 within 90 minutes after ranitidine was

administered and remained above 4 for a minimum of 15 hours.

Conclusions

This study provided useful data to inform dosing recommendations in

neonates. Although ECMO significantly increases the vascular volume and

may impact the pharmacokinetics of drugs with small volumes of distribution,

the impact of ECMO is minimal for drugs such as ranitidine with a large

volume of distribution. Therefore, it would be possible to extrapolate the

pharmacokinetics data from this study to neonates with normal renal function.

In addition, these data suggest that a dose of 2mg/kg should be sufficient to

increase gastric pH to >4 for at least 16 hours.

6.2.2.2 Overall conclusions: pharmacokinetic studies- intravenous ranitidine

Results are compared in Table 4:

Table 4: Pharmacokinetic parameters following administration of Zantac in

Paediatric patients

Values for half-life and clearance were consistent amongst all ages, with

the exception of the neonates, in whom ranitidine had a much longer half-

life and lower clearance. This was not surprising, in view of the

underdeveloped hepatic and renal capacities in neonates.

There was a lot of variability of kinetic parameters for all age groups (this

is also the case in adults).

The submitted data are limited, mainly due to poor methodology.

However, the parameters in children (excluding neonates) were similar to

those in adults.

These data support the inclusion of a statement in Section 5.2 of the Sm

PC and also the proposed dosage regimen for short term treatment of

ulcers.

35

6.2.3 Pharmacodynamic studies

6.2.3.1 Results of pharmaocodynamic studies are presented in Table 5.

Table 5: Pharmacodynamic data in children

Dose Result

Study 1 0.13 to 0.8 mg/kg IV C90%* to 60ng/ml

Study 3 5 mg/kg po (iv form.) <100 ng /ml results in

pH<4.0, which occurs 9

hrs after the dose

Study 4 2 mg/kg po (syrup) Gastric pH<2.5 in 33%

of patients with serum

drug levels ranging from

18-331 ng/ml. No drug

levels reported for

patients with gastric

pH>2.5

Study 8 1 mg/kg IV 2/20 subjects failed to

produce gastric ph>3.5

with ranitidine conc>60

ng/ml over 6 hr

Study 9

Study 9 1 mg/kg IV Of 10 patients with

gastric pH≤2.0 prior to

drug therapy, had no

acid suppression and the

remaining 8 had variable

response

RAN 20006 75mg oral tablet or

placebo

Rapid decrease in acidity

at 30 min (H+ ,pH

measurements).

Greatest effect (% time

at pH >3) at 1-5hrs.

Report No

RC1998/00030/00

2mg/kg/24 hrs in

neonates

In 5/12 subjects, gastric

pH increased to > 4

within 90 minutes after

ranitidine was

administered and

remained above 4 for a

minimum of 15 hours.

* Serum ranitidine concentration needed to inhibit baseline gastric acid

secretion by ≥90%

In all studies, the pharmacodynamic response was quite variable among

individuals across studies, with many subjects exhibiting complete lack of

response, even after achieving serum ranitidine concentrations shown to

suppress 90% of gastric acid secretion in subjects from Study 1 (see 6.2.1.1.

The large inter-subject variability in gastric acid suppression among the

studies is likely to be due to the different patient diagnoses and the

pharmacodynamic endpoints implemented.

Study 1, RAN 20006 and RC1998/00030/00 (which was undertaken in

neonates receiving ECMO), were the best designed of the 5 studies and

provided the most useful information, as all provided baseline data. In

addition, study 2006 was placebo controlled. In study 1, the subjects had

confirmed active PUD, which is the proposed indication for IV ranitidine.

In adult studies, the ED 50 (dose required to produce 50% of the maximum

effect) is usually measured, whereas this was not measured in the paediatric

36

studies. It is therefore difficult to compare paediatric values with those from

adult studies. However, inter-subject variability is also evident in such

studies. In addition, in one study (Wyeth, 1998), the duration with pH above

4 was similar to that in study RAN 20006.

6.3.2.2 Overall conclusions regarding pharmacodynamic studies

From the available data, the pharmacodynamic response appears to be similar

in children to that in adults. 6.3 Efficacy data

There were no company- sponsored clinical efficacy studies for the following

proposed indications: the treatment of gastro-oesophageal reflux, (including

reflux oesophagitis and the symptom relief of gastro-oesophageal reflux

disease) and, for injection formulations, the prophylaxis of stress ulceration in

seriously ill patients.

6.3.1 Study RAN M15

The objective of this single centre double-blind, placebo controlled trial that

was undertaken in Moscow in 1992-4 was to establish the safety and efficacy

of ranitidine 150mg at night compared to placebo in the prevention of

duodenal ulcer over a 12 month treatment period.

Study Design

195 children aged 8 to 16 (mean 13 yrs), with a male to female ratio of 2:1,

who had endoscopically confirmed ulcers (≥ 5mm in diameter), received open

therapy with ranitidine 150mg bd, for 4 to 8 weeks. On endoscopic

confirmation of healing, children were randomly assigned to either ranitidine

150mg at night or placebo in a double-blind, parallel group study. Symptom

assessment was repeated at 2 monthly intervals with endoscopy every 4

months for up to 12 months.

Inclusion criteria

- endoscopically confirmed duodenal ulcer ≥5mm diameter

- aged between 8 – 16 years

- requirement for an H2-receptor as part of normal clinical management

- able to start treatment within 3 days of the pre-study endoscopy

- written consent provided by child and/or legal guardian

- endoscopic confirmation of ulcer healing after 4 or 8 weeks for entry into

long-term phase

Exclusion criteria

- endoscopic confirmation of gastric ulcer or erosive oesophagitis

- concomitant use of potentially ulcerogenic drugs

- other serious condition

- previous gastric surgery

- treatment with therapeutic doses of anti-ulcer drugs immediately prior to

entry to the study

The primary efficacy analysis in the maintenance phase was based on the

number of patients who had relapsed (symptomatically and endoscopically)

on each treatment at each visit. Patients who reported moderate or severe

symptoms were regarded as symptomatically relapsed. Patients with

endoscopically proven duodenal ulcer, regardless of severity of symptoms,

were regarded as endoscopically relapsed. Patients who reported moderate or

severe symptoms and had an endscopically confirmed duodenal ulcer were

regarded as endoscopically and symptomatically relapsed. The following two

relapse rates were calculated:

Modified Crude Relapse Rate

37

Symptomatic and endoscopic relapse: patients who withdrew from the study

without a relapse before the nth month assessment (n=2, 4, 6, 8, 10, 12)

were excluded from the calculation of modified crude relapse rate from that

visit onwards. Endoscopic relapse also excluded those patients who withdrew

from the study with symptomatic relapse not proven by endoscopy.

At each visit (cumulatively including unscheduled visits), the proportion of

patients relapsed on each treatment was compared using the Mantel-Haenszel

chi-square test without continuity correction. If the sample size assumption

required for the Mantel-Haenszel test was not satisfied then Fisher’s exact

test was used.

Crude Relapse Rate

Symptomatic and endoscopic relapse: patients who withdrew from the study

without a relapse before the nth month assessment (n=2, 4, 6, 8, 10, 12)

were treated as relapsed in the calculation of crude relapse rate from that

visit onwards. Endoscopic relapse excluded those patients who withdrew from

the study with symptomatic relapse not proven by endoscopy. Treatments

were compared by means of the Mantel-Haenszel or Fisher’s exact test as

described above.

Secondary efficacy analysis

Symptomatic Relapse Confirmed by Endoscopy

At each visit (cumulatively including unscheduled visits) the proportion of

patients experiencing a symptomatic relapse, confirmed by endoscopy on

each treatment was compared using the Mantel-Haenszel chi-square test or

Fischer’s exact test.

Secondary efficacy analyses included the proportion of symptomatic relapses

and the time to relapse (symptomatic, endoscopic and symptomatic

confirmed by endoscopy).

Results

Baseline characteristics of participants

The baseline characteristics of the participants were similar in both groups.

Most of the patients were newly diagnosed (68%), whilst the median duration

of peptic ulcer disease in the others was 2 years. A positive family history of

peptic ulcer disease was reported in > 40% of the population. Whilst most

patients presented with mild or moderate epigastric pain, 32% had no pain at

the time of the initial endoscopy. Gastritis was reported at endoscopy for

nearly all patients.

Efficacy analysis

Ulcer healing was observed in 177 of 194 (91%) patients after 4 weeks of

treatment. 16 patients continued treatment to 8 weeks- all patients had

healed ulcers on repeat endoscopy.

191 children entered the long term phase; 189 were included in the Modified

Intention To Treat (MITT) efficacy analysis. Within 4 months, 17 patients

receiving placebo suffered relapse (18%), compared with 5 patients in the

ranitidine group (5%) (p=0.006). The cumulative ulcer relapse rate at 12

months was 30% for placebo and 9% for ranitidine (p<0.001).

However, it is of note that few patients suffered a symptomatic relapse – six

in the placebo group and two in the ranitidine group.

Results of repeat endoscopic examination for the long-term phase are

summarised below in table 6:

38

Table 6: Results of repeat endoscopic examination for the long-term

phase

Month 4 Month 12

Placebo Ranitidine

150mg nocte

Placebo Ranitidine

150mg nocte

Number of

patients in

MITT

population

94 95 94 95

Number of

patients (%)

maintained

(ie. no

evidence of

relapse)

76 (82%) 90 (90%) 65 86

Number of

patients (%)

relapsed

17 (82%) 5 (5%) 28 (30%) 9 (9%)

Number of

patients (%)

withdrawn

1 0 1 0

Odds ratio and

95% CI for

relapsing on

ranitidine

150mg nocte

0.25 (0.09, 0.70) 0.24 (0.11, 0.55)

Significance of

difference

between two

treatments p-

value*

0.006 <0.001

* Fisher’s exact test

Similar results were obtained in a life-table analysis.

Ranitidine was well tolerated; there were few adverse events reported.

Conclusions

The mean age of the participants was 13 yrs. Ranitidine, when given at

the normally recommended adult dose of 150mg bd was effective in the

relief of epigastric pain and the healing of ulcer.

The natural history of duodenal ulcer disease in this population (with a

mean age of 13yrs) differed from that in the adult population: The

cumulative ulcer relapse at 12 months was 30 % in those receiving

placebo compared to 70 to 80% reported for an adult population.

Although the risk of relapse was reduced with maintenance ranitidine

therapy, the incidence of symptomatic relapse was low (6 patients vs 2 for

placebo vs ranitidine); ulcers were either asymptomatic or associated with

mild symptoms only.

H.pylori status was not considered; present long term management of

peptic ulceration would include this. This may have been because this trial

was undertaken in 1994, prior to the understanding of the importance of

this in the pathogenesis of peptic ulceration in children.

Ranitidine was well tolerated.

In summary, the use of ranitidine 150mg given once daily significantly

reduced the incidence of ulcer relapse in older children. However, given

the above findings, these data do not provide robust evidence for the

indication of ‘long term’ treatment of peptic ulceration in children aged 1

month and above.

39

6.3.2 Study 145

Study 145 was an open-label single centre study (conducted in the US) of 12

patients, aged 3.5-16 years, with endoscopically diagnosed duodenal and/or

gastric ulcers. All children had a history of epigastric pain, nine had nausea

and vomiting and one child had melaena.

Phase 1 was designed to support the dosing in Phase 2. During this phase,

each child received an intravenous ranitidine loading dose of 0.6mg/kg over

15 minutes, followed by a continuous intravenous infusion of 0.2mg/kg/hr. At

the end of each hour, a bolus dose equal to 20% of the initial loading dose

was infused and the continuous infusion dose increased by 20%. Doses were

increased in stepwise fashion until gastric acid secretion was inhibited by at

least 90%. Pharmacokinetic sampling was performed both before and after

dosing. The doses administered during this phase ranged from 13.4 to

74.5mg (0.3 to 2.1mg/kg).

Phase 2 was begun on the following day. For this phase, ranitidine was

administered as an intravenous bolus every 6 hours until the patient could

resume enteral feeding. The dose administered was designed to yield the

average serum concentration required to inhibit gastric acid secretion by at

least 90%. Calculations of this dose were based on data from Phase 1. The

doses administered during this phase ranged from 0.13 to 0.80mg/kg/dose.

Phase 3 was designed for the collection of efficacy and safety data. In this

phase, ranitidine was administered orally (as tablets). The dose chosen for

each patient was based on the information obtained in Phases 1 and 2.

Ranitidine was administered every 12 hours for 6 weeks. The doses

administered during this phase were 37.5mg every 12 hours (9 patients) and

75mg every 12 hours (3 patients).

Results

A total of 12 patients, aged 3.5-16 years, with endoscopically diagnosed

duodenal and/or gastric ulcers were enrolled. At the completion of 6 weeks of

treatment, endoscopic examinations revealed that all of the ulcers were

healed. Follow-up evaluations performed at the discretion of the investigator

for up to 12 months after treatment revealed no evidence of recurrence in any

of the children.

Ranitidine was effective at the doses studied in healing duodenal and gastric

ulcers and preventing ulcer recurrence in these patients. The investigator

recommended a paediatric oral dose from 1.25 to 1 .90mg/kg every 12 hours

to treat gastric and duodenal ulcers.

6.3.3 Study 145A

This was an open-label, single centre study to evaluate the efficacy of

ranitidine in the treatment of gastric and/or duodenal ulcers in children. This

study was similar in design to Study 145, except that the patients were

administered ranitidine syrup instead of tablets. Ranitidine was to be

administered every 6 hours as a 15-minute intravenous infusion. When the

patient was able to resume enteral feeding, ranitidine was to be administered

orally (syrup formulation) for 6 weeks. Pharmacokinetic and

pharmacodynamic data were to be collected during the first 2 days of the

study.

A total of three patients aged 5-8 years were enrolled in the study. All

patients responded well to ranitidine therapy over an approximate 6-week

course of treatment. In two of the three patients, the ulcer healed.

6.3.4 Study RAN-701

40

This study compared the use of a continuous infusion with bolus injections of

ranitidine with regard to the inhibition of gastric acid production in critically ill

children. A total of 51 patients aged 4-12 years were enrolled and randomized

to either ranitidine 0.2mg/kg/hr (n=24) or a bolus infusion of ranitidine

1.6mg/kg every 8 hours (n=27).

Twenty (20) patients in the ranitidine 0.2mg/kg/hr treatment group and 19

patients in the ranitidine 1.6mg/kg every 8hr treatment group completed the

study. Efficacy measurements were dependent on intragastric pH

measurements. However, there were inconsistencies in the electronic

intragastric pH data, poor quality blood serum assay data and concern

regarding reliability of the results. Analyses of the data were therefore not

performed.

6.3.5 Study RAN-147

A double-blind, randomized trial of ranitidine therapy in patients with cystic

fibrosis and pancreatic insufficiency.

This study compared the effects of Pancrease and ranitidine 150 mg bd with

Pancrease therapy alone, on pulmonary function, fat and carbohydrate

absorption in 8 children (boys) with cystic fibrosis and pancreatic

insufficiency. The investigators reported that fat and carbohydrate absorption

was improved in 5 patients compared with placebo, but there was no

difference in pulmonary function between the groups.

6.3.6 Efficacy data- published reports

The FDA undertook a comprehensive review of the literature for the proposed

indications (excluding the use of ranitidine for the prophylaxis of stress

ulceration). For all of the proposed indications, these data only included

reviews, open label studies and case reports.

6.3.6.1 .Literature review for the prophylaxis of stress ulceration in seriously

ill children

The Clinical Expert report included a review of the published literature for the

prophylaxis of stress ulceration, which is a proposed indication for the

ranitidine injection formulation. There were no company- sponsored efficacy

trials for this indication.

In this review, there were no published randomised controlled trials with

appropriate end-points such as bleeding. Therefore, no robust evidence was

provided that use in the prophylaxis of stress ulcer provides protection

against bleeding.

In further support for this indication, in their response to a request for

supplementary information (section 7, Q2), the MAH has quoted The

American Society of Health-System Pharmacists guidelines published in 1999

on prophylaxis of stress ulceration. These guidelines specifically reviewed the

literature with regard to stress-induced bleeding associated with trauma,

surgery and acute organ failure, including published meta-analyses that

demonstrated the efficacy of H2 receptor antagonists versus placebo in

adults. They recommend the prophylaxis of stress ulceration in an ICU setting

for adults using medications including H2 receptor antagonists. For children,

although it was noted that there was a distinct lack of published randomised

controlled trials with appropriate end-points such as bleeding, some studies

have suggested that prophylaxis of stress-ulcer might be of use for children.

For example, Kuuseal et al (1997) showed a decreased risk of endoscopically

diagnosed gastric lesions in mechanically ventilated infants treated with

ranitidine. Despite the lack of controlled studies in cases of trauma and

surgery, the guidelines recommended prophylaxis of stress ulcer in the case

of thermal injuries and highlighted that “the risk of stress-induced bleeding is

greater in children with respiratory failure, coagulopathy, a Paediatric Risk of

Mortality Score of ≥ 10, and thermal injuries.”

41

Although there have been no appropriate randomised controlled trials

undertaken in children, there is a large volume of literature discussing the

prophylaxis of stress ulceration in critically ill children. Ranitidine, when

administered either as an intermittent intravenous infusion at a dose of 2-

6mg/kg/day in divided doses; (Harrison et al, 1998; Kuusela et al, 1997;

Kuusela, 1998; Lopez-Herce et al 1988; Osteyee et al 1994; Rylance

1987 and Santucci et al, 1991), or as a continuous infusion at a rate of 0.1-

0.2mg/kg/hr; (Osteyee et al, 1994; Santucci et al, 1991; Dimand et al

1989 and Eddleston et al, 1989), has been successfully used to maintain

gastric pH levels above 4.0. Both dosing regimens were effective in raising

and maintaining gastric pH above 4. However, the pH values fluctuated more

with the intermittent regimens. (Osteyee et al, 1994 and Santucci et al,

1991). Harrison et al recommended that critically ill children with normal renal

and hepatic function should be treated with a minimum of 3mg/kg/day and

the dose be titrated based on gastric pH.

Oral (via naso-gastric tube) vs intravenous administration of ranitidine for the

prevention of stress ulceration has also been studied. (Lopez-Herce et al,

1988; Hartemann et al 1987) The median time pH was above 4 was less in

the oral group. The authors therefore suggested that oral ranitidine may not

be as effective due to decreased absorption in critically ill children. (Lopez-

Herce et al, 1988).

Conclusions

In this review, there were no published randomised controlled trials with

appropriate end-points such as bleeding. Therefore, no robust evidence was

provided that the prophylaxis of stress ulcer provides protection against

bleeding.

Although the ASHP guidelines recommend prophylaxis of stress ulcer in the

case of thermal injuries, this recommendation does not appear to be evidence

based.

6.3.6.2 Literature review for gastro-oesophageal reflux disease

The Clinical Expert report included a review of the published literature for the

proposed indication of the treatment of gastro-oesophageal reflux (GOR),

including reflux oesophagitis and gastro-oesophageal reflux disease. There

were no company- sponsored efficacy trials submitted for this indication. In

the literature review there is an absence of randomised controlled trials to

support the proposed indication; a recent literature review by Cezard in 2004

also found a lack of evidence to support the use of H2 anatagonists for GOR.

In a case series De Angelis and Banchini (1989) reported their experience

of the use of ranitidine in the treatment and prophylaxis of gastro-intestinal

disorders in 391 children aged from 72 hours to 16 years. The children

received oral ranitidine at a dose of 6-8 mg/kg/day initially, followed by

maintenance therapy of 3-4mg/kg/day. Intravenous administration was used

in appropriate cases, such as those with upper gastro-intestinal haemorrhage

or in severe oesophagitis due to the ingestion of caustic substances. Reflux

oesophagitis was treated in 185 children; in 25 severe cases, endoscopy

revealed re-epithelialisation in all cases. In those children with less severe

oesophagitis, 95% had disappeared or showed marked improvement of

lesions, both macroscopically and histologically. In an open label prospective

study, Karjoo and Kane (1995) found visual and/or histological evidence of

oesophagitis in 84% of 153 children aged 6-18 years old (mean 9.9 years)

with chronic abdominal pain lasting more than 3 weeks. The children were

initially treated with 4mg/kg ranitidine twice daily for 2 weeks, increasing to

4mg three times daily for a further 2 weeks. If symptoms persisted patients

were switched to omeprazole. Seventy percent of patients had mild to

moderate symptom improvement with ranitidine. The effect of high dose

ranitidine (10mg/kg twice daily) was compared with omeprazole

42

(40mg/day/1.73m2) in 25 children (aged 6 months to 13.4 years) with

oesophagitis, who had previously not responded to 8 weeks of ranitidine at

8mg/kg/day and cisapride (Cucchiara et al, 1993). Both drugs produced

comparable healing and relief of symptoms. In further support for this

indication (RSI response, section 7, Q2), the MAH has quoted the North

American Society for Paediatric Gastroenterology and Nutrition clinical

practice guidelines (published in 2001) on the diagnosis and treatment of

gastro-oesophageal reflux (GOR). Recommendations were based on a review

of the medical literature for infants and children, (excluding neonates less

than 72 hours old), premature infants and infants and children with

neurological or anatomical impairments or disorders. Despite the lack of

robust evidence, overall recommendations supported the use of H2 receptor

antagonists for the relief of symptoms and mucosal healing in children with

GOR. Specifically, acid suppressants such as H2 receptor antagonists were

recommended for infants with recurrent vomiting, heartburn, oesophagitis

and in patients with asthma and symptoms of GOR. The recommended daily

dose of oral ranitidine in the treatment of gastro-oesophageal reflux in

children was 5-10mg/kg/day administered as two divided doses. The use of

parenteral therapy was recommended only when oral therapy is not

advisable, at a dose of 2-5mg/kg/day administered in divided doses.

Conclusions

In this review, there were no published randomised controlled trials

submitted. Therefore, no robust evidence was provided to support the

proposed indication of treatment of gastro- oesophageal reflux.

Although the North American Society for Paediatric Gastroenterology and

Nutrition clinical practice guidelines recommend the use of ranitidine for this,

this recommendation did not appear to be evidence based.

6.3.7 Overall conclusions regarding efficacy data for all proposed indications

There were no randomised controlled trials submitted for the following

proposed indications: the treatment of gastro-oesophageal reflux (including

reflux oesophagitis and the symptom relief of gastro-oesophageal reflux

disease) and the prophylaxis of stress ulceration in seriously ill patients for

injection formulations.

The only double blind randomised controlled trial that was submitted for the

prevention of duodenal ulcer was poorly designed as it did not consider the

presence of H.pylori in participants. This may have been because this trial was

undertaken in 1994, prior to the understanding of the importance of H.pylori

in the pathogenesis of peptic ulceration. Even taking this into consideration,

the results of this trial, whilst supportive, did not provide robust evidence that

ranitidine is superior to placebo for the proposed indication.

Overall, the submitted efficacy data were extremely disappointing. In

particular no randomised controlled trial was undertaken in children with

gastro-oesophageal reflux. This should not have been difficult to perform.

6.4 Safety

Adverse effects of ranitidine

Known adverse effects of ranitidine include diarrhoea and other gastro-

intestinal disturbances, altered liver function tests (rarely liver damage),

headache, dizziness, agitation, visual disturbances, rash, alopecia and

tiredness. Rare side-effects include acute pancreatitis, acute interstitial

nephritis, tachycardia, bradycardia, AV block, confusion, depression, and

hallucinations (particularly in the very ill), hypersensitivity reactions (including

fever, arthralgia, myalgia, anaphylaxis), blood disorders (including

agranulocytosis, leucopenia, pancytopenia, thrombocytopenia), and skin

reactions (including erythema multiforme and toxic epidermal necrolysis).

There have been occasional reports of gynaecomastia and impotence

associated with the use of ranitidine.

43

6.4.1 Clinical trial data

The safety data from the submitted clinical trials were detailed in the Medical

Review of the FDA assessment report. In all studies except RAN 701,

ranitidine was well tolerated. There were few reported adverse events, mostly

relating to the gastro-intestinal tract. Routine laboratory data were collected

for all studies.

Study RAN-701

This study assessed inhibition of gastric acid production in 51 critically ill

children. Five (2 1%) patients in the ranitidine 0.2mg/kg/hr group reported

five adverse events and 2 (7%) patients in the 1.6mg/kg Q8hr group reported

two adverse events. The most frequently reported adverse events were death

(3 fatalities) and hypotension. It should be noted that death was not an

unexpected event as this study was conducted in very critically ill patients.

Long term safety data

In study RAN M15 (duration of 12 months), there were minor haematological

abnormalities detected in 89% of patients treated with ranitidine. In addition,

15% of patients had minor elevations of serum alkaline phosphatase levels.

No other long term data (in particular, longitudinal growth measurements)

were available from this study.

6.4.2 Cumulative review of safety- post-marketing reports

A search of the safety database revealed a total of 971 adverse event reports

associated with ranitidine administration in children that had been received

worldwide by GSK from the first launch of Zantac in 1981 until 02 August

2004. The majority of cases were spontaneous, non-serious, and reported by

medical professionals. Twenty-nine percent of all reports were received from

consumers. Cases were received mainly from the US (59%). The majority of

cases involved children aged two years of age or younger. The majority of the

971 cases (74%) were non-serious, spontaneous reports received from

medical professionals and described patients 2 years of age or younger. Most

patients received ranitidine to treat a condition (e.g. GERD, ulcer) for which

some of the reported events (e.g. vomiting, irritability, abdominal pain,

crying, insomnia) could be a symptom. Review of these data did not highlight

any safety issues for children.

Published reports on safety

The FDA undertook a comprehensive review of the literature report. No

significant safety issues were identified in clinical studies involving over 350

and 450 children who received oral and parenteral ranitidine respectively.

7. REQUEST FOR SUPPLEMENTARY INFORMATION (RSI) Following assessment of the data, the following questions were raised by the

MHRA:

7.1. Regarding the proposed changes to section 4.2: please could the

applicant clarify the terms ‘acute’ and ‘long term’ treatment.

Response of the MAH :

‘As the available information reviewed has not been generated as a result of a

specific development programme for the use of Zantac in children, a range of

recommendations on duration of treatment were identified in the literature for

the proposed paediatric indications. Despite this, a number of publications

described treatment duration of paediatric peptic ulcers ranging from four to

eight weeks with oral formulations (Blumer et al 1985; Accadia et al 1986;

de Angelis & Banchini 1989; Scorza et al 1990). Additionally,

44

recommendations for an initial 4 weeks treatment period with an extension to

8 weeks if healing was not resolved was proposed by J Sondheimer (Current

Pediatric Diagnosis and Treatment 1992, Hathway & Hay. Chapter 19.), and

treatment in children with H2 receptor antagonists for 1 to 2 weeks to relieve

symptoms and 6 weeks of treatment required for resolution of chronic peptic

ulcer was recommended by Bisset et al (Forfar and Arneils Textbook of

Pediatrics 2004, Chapter 17.).

Long term maintenance therapy has been shown to reduce the rate of ulcer

reoccurrence in follow-up studies of six months to 1 year duration

(Deganello et al 1990; Scorza et al 1990; Sherman 1994). However,

evidence now indicates that reoccurrence of ulcer after cessation of therapy

could be due to infection with H.pylori and this should be considered in cases

of peptic ulcer with longer time to resolution. Thus GSK propose that this

should be indicated in the proposed text for long-term treatment of peptic

ulcer. Additionally, ranitidine is also used during multi component therapy

regimens of H.pylori infection, with an initial proposed therapy of 2 weeks

(University of Michigan Health System Guidelines for Clinical Care - Peptic

Ulcer, May 2005) and 94.3% healing rate observed in a trial covering 6 weeks

of triple therapy (Scherbakov et al 2001.

Data for the parenteral treatment of peptic ulcer is limited and generally

considered clinically only when oral administration is not possible. Therefore

GSK propose additional wording to indicate this treatment regimen. Taking

into consideration the data available, GlaxoSmithKline feels that dosing of

Zantac for the acute treatment of peptic ulcer in paediatric populations should

be from four weeks to eight weeks for oral administration of Zantac. Further,

the duration of long-term maintenance therapy has been proposed in line with

the literature discussed, however as recent understanding of the aetiology of

peptic ulcers has shown a strong association with infection with H.pylori. GSK

have proposed wording to alert the health care provider to this possibility.

Further GlaxoSmithKline propose that the wording for parenteral

administration should be clarified to indicate that this is not the primary

treatment option’.

7.2. Please could the ‘Clinical Expert’ provide further justification for

the proposed indications of long term management of peptic

ulcer, treatment of gastro-oesophageal reflux, including reflux

oesophagitis and the symptom relief of gastro-oesophageal reflux

disease for oral and injection formulations, and also for the

prophylaxis of stress ulceration in seriously ill patients for

injection formulations.

Response of the MAH:

‘Zantac injection is indicated for the treatment of peptic ulcer, treatment of

gastro –oesophageal reflux, including reflux oesophagitis and symptom relief

of gastro oesophageal reflux disease. It is also indicated for the prophylaxis of

stress ulceration in seriously ill patients.

The American Society of Health-System Pharmacists published guidelines in

1999 on prophylaxis of stress ulceration. These guidelines specifically

reviewed the literature pertaining to stress-induced bleeding associated with

trauma, surgery and acute organ failure, including published meta-analyses

demonstrating the efficacy of prophylaxis with H2 receptor antagonists versus

no prophylaxis in adults (Tryba et al 1991; Cook et al 1991; Cook et al

1996). The ASHP guidelines recommend the prophylaxis of stress ulceration in

an ICU setting for adults using with medications including H2 receptor

antagonists. For the paediatric population it was noted that there was a

distinct lack of published randomised controlled trials with appropriate end-

points such as bleeding and to provide conclusive evidence that prophylaxis of

stress ulcer provides protection against bleeding. However, some studies have

45

suggested that prophylaxis of stress-ulcer may be of use for paediatric

populations, for example Kuuseal et al (1997) showed a decreased risk of

endoscopically diagnosed gastric lesions in mechanically ventilated infants

treated with ranitidine. Despite this lack of controlled studies in cases of

trauma and surgery, the guidelines did recommend prophylaxis of stress ulcer

in the case of thermal injuries and highlighted that “the risk of stress-induced

bleeding is greater in pediatric patients with respiratory failure, coagulopathy,

a Paediatric Risk of Mortality Score of ≥ 10, and thermal injuries”. Taking into

account these guidelines and the most recently reviewed data as provided

(D2004-4586), GSK believes that ranitidine should be indicated for the

prophylaxis of stress ulceration in the paediatric population.

In 2001 the North American Society for Paediatric Gastroenterology and

Nutrition published clinical practise guidelines outlining the diagnosis and

treatment of Gastrooesophageal reflux (GER). Recommendations were based

on a review of the medical literature available pertaining to infants and

children, but excluding neonates less than 72 hours old, premature infants

and infants and children with neurological or anatomic impairments or

disorders. Overall recommendations supported the use of H2 receptor

antagonists for the relief of symptoms and mucosal healing in children with

GER. Specifically acid suppressants such as H2 receptor antagonists were

recommended for infants with recurrent vomiting, heartburn, oesophagitis

and in patients with asthma and symptoms of GER. Therefore, GSK feels that

the extensive body of literature surrounding the use of H2 receptor

antagonists in paediatric populations with GER taken together with these

guidelines support the use of ranitidine for paediatric GER. An extensive body

of literature, including clinical study data, published literature and guidelines

have been reviewed during this submission. A number of clinical care

guidelines were consulted during this review however, as stated in such

guidelines and acknowledged by GSK, there are few prospective randomized

studies specifically in paediatric populations for the proposed indications.

However GSK believe that the comprehensive review as submitted (D2004-

4586) further supports the use of ranitidine in the paediatric populations in

the indications proposed.’

7.3. During the Article 30 procedure, in 2003 one of the outstanding

issues was the high alcohol content of the syrup formulation. At

this time, GSK agreed to the proposal to add a precautionary

statement in the SmPC regarding this. Please could the applicant

comment on this and whether any further steps have been taken

to address this issue.

Response of the MAH:

‘The referral under Article 30 of directive 2001/83/EC to harmonize the SmPC

for Zantac/Ranitidine HCl was halted in 2003. As a consequence GSK are

currently reviewing this issue internally and propose to submit this as a type

II variation at later date’.

8. DISCUSSION

8.1 Do the data support the new indications?

8.1.1 Efficacy considerations

As discussed in the conclusions of the section on efficacy (in section

6.3.7), the submitted data for the proposed indications were

disappointing, even though several studies had been sponsored by the

applicant.

46

For the long term treatment of peptic ulcer, the results of this trial, whilst

supportive, did not provide robust evidence that ranitidine is superior to

placebo for the proposed indication.

With regard to the indications of the treatment of gastro-oesophageal

reflux (including reflux oesophagitis and the symptom relief of gastro-

oesophageal reflux disease) and the prophylaxis of stress ulceration in

seriously ill patients, no randomised controlled trials were submitted and

the published data did not provide sufficient evidence of efficacy. Although

it is recognised that it would be difficult to undertake a randomised

controlled trial in seriously ill children to provide robust evidence for the

prophylaxis of stress ulceration, the submitted studies did not provide

sufficient data regarding dosage to warrant extrapolation from efficacy in

adults.

8.1.2 Safety considerations

From the data submitted, no particular safety concerns were identified.

However, there were only limited long term safety data available from

study RAN M15 (duration of 12 months). It was disappointing that in this

study, no longitudinal growth measurements were undertaken.

The ethanol content of ranitidine syrup is high (approximately 9%). The

clinical significance of this is not known.

Overall conclusion regarding the proposed indications

The efficacy and safety data submitted do not support the proposed

indications of the long term treatment of peptic ulcer, the treatment of

gastro-oesophageal reflux (including reflux oesophagitis and the symptom

relief of gastro-oesophageal reflux disease) and the prophylaxis of stress

ulceration in seriously ill patients

However, as oral ranitidine is already licensed for the treatment of peptic

ulcers in children and given that it established practice in acute treatment

to use the intravenous route in some cases, it seems reasonable to

consider that this indication can be extrapolated to the injection

formulations (see below section 8.2 for discussion about dosage).

8.1.3 Is the proposed age of 1 month onwards supported?

8.1.3.1 For oral formulations:

At present, the oral formulations are licensed for the treatment of peptic

ulceration with no age restriction. The applicant proposes a lower age limit

of one month onwards for all indications.

The pharmacokinetic data submitted were very limited in children aged 1

month to 3 years.

In addition, there were very limited efficacy and pharmacodynamic data in

this age group.

It is therefore proposed that the lower age limit for the short term

treatment of peptic ulcers with oral ranitidine should be 3 years of age.

8.1.3.2 For the intravenous formulation

The submitted pharmacokinetic data, although limited, were consistent in

children aged 6 months and above.

There are no significant safety issues in any age group

It is therefore proposed that the lower age limit for the short term

treatment of peptic ulcers with oral ranitidine should be 6 months of age.

8.1.4 Proposed dosage and method of administration

8.1.4.1Intravenous (IV) ranitidine

The MAH proposes the following regimen for IV ranitidine for children aged 1

month to 16 years:

47

SmPc Section 4.2 Posology and Method of administration (See section 5.2

Pharmacokinetic properties- Special patient Populations)

Zantac injection may be given as slow (over 2 minutes) i.v injection up to a

maximum of 50mg every 6 to 8 hours.

Peptic ulcer-Acute treatment: the recommended dose for the treatment of

peptic ulcer in children is 2 mg/kg/day to 4 mg/kg/day administered as 3 or 4

divided doses.

In section 4.2 for adults and children over 12 years of age only, the SmPC

states the following:

Zantac injection may be given either as slow (over a period of at least 2

minutes) intravenous injection of 50mg, after a dilution to a volume of at

least 20ml per 50mg dosage, which may be repeated every 6- 8 hrs, or as an

intermittent infusion at a rate of 25mg per hour for 2 hours.

The dosage regimen suggested in the BNF for Children ( BNFC, 2005) is as

follows:

By slow intravenous injection

Neonate: 0.5–1mg/kg every 6–8 hours

Child 1 month–18 years: 1mg/kg (max. 50mg) every 6–8 hours (may be

given as an intermittent infusion at a rate of 25mg/hour)

By continuous intravenous infusion

Neonate: 30–60micrograms/kg/hour (max. 3mg/kg daily)

Child 1 month–18 years: 125–250micrograms/kg/hour

Administration

For slow intravenous injection dilute to a concentration of 2.5mg/mL with

sodium chloride 0.9%, glucose 5% or compound sodium lactate intravenous

infusion. Give over at least 3 minutes.

For continuous intravenous infusion, further dilution is required.

Comments:

In the posology for children under 12 years of age, dilution for slow

injection is not recommended;

In addition, there are no details regarding infusion (intermittent or

continuous) in this age group

The proposed dosage (2-4mg/kg for slow injection) is consistent with the

available pharmacokinetic and pharmacodynamic data. The proposed

dosage regimen is similar to that suggested in the BNFC.

The dosage regimen proposed by the MAH is reasonable. However, a

dosage regimen for infusion should be provided, in addition to details

about dilution.

27

8.1.4.2 Oral formulations

The MAH proposes the following dosing regimen for oral ranitidine for the

treatment of acute peptic ulcer:

4-8 mg/kg/day, in 2 divided doses to a maximum of 300 mg/day

The dosage regimen suggested in the BNF for Children ( BNFC, 2005) is as

follows:

By mouth

Neonate: 1–2mg/kg 3 times daily but absorption unreliable (initially 2mg/kg 3

times daily for gastro-oesophageal reflux)

Child 1–6 months: 1 mg/kg 3 times daily (max. 9mg/kg daily in divided

doses)

6 months–12 years: 2–4 mg/kg (max. 150mg) twice daily

12–18 years: 150 mg twice daily

48

Comments

The dosage proposed by the MAH (4-8mg/kg/day) is consistent with the

available pharmacokinetic and pharmacodynamic data. The proposed

dosage regimen is similar to that suggested in the BNFC.

9. OVERALL CONCLUSIONS The submitted data for the proposed indications were extremely

disappointing, even though several studies had been sponsored by the

applicant. In particular, no randomised controlled trial had been

undertaken in children with gastro-oesophageal reflux, which should not

have been difficult to perform. However, in the case of prophylaxis of

stress ulceration in seriously ill children, it is recognised that it would be

difficult to undertake randomised controlled trials.

There were no randomised controlled trials submitted for the following

proposed indications: the treatment of gastro-oesophageal reflux

(including reflux oesophagitis and the symptom relief of gastro-

oesophageal reflux disease) and the prophylaxis of stress ulceration in

seriously ill patients. For these indications, the submitted clinical

guidelines recommend the use of ranitidine. However, these

recommendations do not appear to be evidence based.

The only double blind randomised controlled trial that was submitted for

the prevention of duodenal ulcer was poorly designed, as it did not

consider the presence of H.pylori in participants. This may have been

because this trial was undertaken in 1994, prior to the understanding of

the importance of this in the pathogenesis of peptic ulceration in children.

Even taking this into consideration, robust evidence of efficacy was not

provided because of the low rate of relapse in the placebo group and the

lack of clinical symptoms in either group after treatment. 28

It is therefore considered that there is inadequate evidence of a favourable

risk/benefit profile for the following proposed indications: the long term

management of peptic ulcer and the treatment of gastro-oesophageal

reflux (including reflux oesophagitis and gastro-oesophageal reflux

disease) from 1 month of age and above and the prevention of stress

ulcers in seriously ill children.

However, the CHM may consider that as the oral formulations are already

licensed for the short term treatment of peptic ulceration in children, and

that there is no evidence of any safety concern, that the risk/ benefit

assessment is favourable for this indication for the injection formulation.

In addition, a safer alternative to the oral liquid formulation is required for

young children as it has a high alcohol content (8%). The MAH has agreed

to submit a variation to add a precautionary statement to the SmPC but

this is not considered to be adequate.

The lack robust of efficacy data for GORD has been highlighted particularly

with respect to cisapride, and more recently with domperidone and

lanzoprazole and omeprazole. The quality of submitted data for ranitidine

further emphasises the need for appropriately designed studies to be

undertaken in this common condition.

10. MINUTES OF DISCUSSION BY COMMISSION ON HUMAN

MEDICINES Expert advice was provided by a consultant paediatric gastroenterologist. The

Commission considered that the use of ranitidine was well established,

particularly for the treatment of gastro-oesophageal reflux and the prevention

of stress ulcers in seriously ill children and that there was no safety issues

associated with its use in children. It was also considered that it would be

difficult to persuade the company to undertake clinical trials for these

49

conditions in children. However, the Commission noted that there were

insufficient data regarding dosage to warrant extrapolation from adults for

prevention of stress ulcers. The Commission considered that should further

dosage data be provided, that it would be possible to consider granting this

indication. With regard to the indication for the treatment of gastro-

oesophageal reflux, the Commission considered that there were sufficient

published data of acceptable quality to grant this.

The submitted data for the indication for the long term treatment of peptic

ulcer was considered to be poor and this condition is uncommon in children.

In addition, current practice for the treatment of peptic ulceration does not

generally support the use of H2 antagonists for long periods. The Commission

therefore advised that this indication should be refused.

There was some discussion with regard to the alcohol content of ranitidine

syrup. It was considered that although this concentration should not pose any

serious risk to children, the ethanol should not be used in paediatric

formulations unless this was necessary.

11. FINAL ADVICE OF COMMISSION 1. On the evidence before them, the Commission advised that the variation

application to the Marketing Authorisation for Zantac tablets/

injection/syrup:

2. Should be refused for the indication for the long term treatment of peptic

ulcer.

3. Should be refused for the indication for the prophylaxis of stress ulceration

in seriously ill patients for the injection formulation.

4. Should be granted for the indication for the treatment of gastro-

oesophageal reflux (including reflux oesophagitis and the symptom relief

of gastro-oesophageal reflux disease).

5. Should be granted for the indication for the short term treatment of peptic

ulcers for the injection formulation for children in whom oral therapy is

unsuitable.

6. The Commission considered that:

7. There is inadequate evidence of efficacy for the indication for: the long

term treatment of peptic ulcer and that this condition is uncommon in

children.

8. There is inadequate evidence of efficacy for the indication for gastro-

oesophageal reflux (including reflux oesophagitis and the symptomatic

relief of gastro-oesophageal reflux disease) but the clinical experience of

the use of ranitidine is well established for this condition and there are no

known safety concerns.

9. Although there is inadequate evidence of efficacy for the indication for:

the prophylaxis of stress ulcers, it would be difficult to undertake a clinical

trial in this situation, which is a common and serious problem in children.

However, there are insufficient data regarding dosage to warrant

extrapolation from adult data.

50

Annex II – Safety data overview Clinical safety

This dossier contains copies of paediatric data for ranitidine which have been

previously submitted to the FDA and a safety review covering the period 1981

(first Zantac launch) to 02 August 2004.

The safety review consists of a cumulative review together with line listings of

all reports of serious and non-serious adverse events or suspected adverse

reactions in children and adolescents aged less than 18 years. These include

reports from clinical trials and spontaneous reports arising from both

authorised and off label use.

A comprehensive review of paediatric data included in this dossier, together

with any data relating to paediatric use of ranitidine that have become

available since the submissions to the FDA were completed, is currently being

conducted. Changes to the currently approved UK SmPC's for Ranitidine

(Zantac) across all indications, in line with current guidelines and taking into

consideration the US labelling, will be proposed in a subsequent variation

package.

Cumulative review of paediatric adverse event reports

A search of the safety database revealed a total of 97 1 adverse event reports

associated with ranitidine administration in patients aged less than 18 years

that have been received worldwide by GSK GCSP since first launch in 1981 up

to 02 August 2004. The majority of cases were spontaneous, non-serious, and

reported by medical professionals. Twenty-nine percent of all reports were

received from consumers. Cases were received mainly from the US (59%).

The majority of cases involved children two years of age or younger. Forty-

seven percent of cases involved the syrup formulation. The indication for

ranitidine use was unknown/not reported in 41 % of cases; when reported,

the most common indication for ranitidine use was gastroesophageal reflux

disease (GERD) (26% of cases). See tables 1 and 2 below for summaries of

cases and events.

Table 1 Total cases 971

Non-Serious 74% Serious 26% Case type Spontaneous 99%

Clinical trial 0.9% Age/Age Group Median age 2

years Neonate (less than 1month) 8%

Infant (1 month to 1 year) 34%

Children (1 to 12years) 41%

Adolescent (13 to 17 years) 17%

Indication for Use GERD 26%

Ulcers 6% Oesophagitis 5% Prophylaxis 4%

Other 18%

Unknown 41%

Table 2 System Organ Class Total Number of Cases

Gastrointestinal disorders 197

Injury, poisoning and procedural complications 114

51

Nervous system disorders 104

Skin and subcutaneous tissue disorders 87

Psychiatric disorders 81

General disorders and administration site conditions 77 Investigations 50 Blood and lymphatic system disorders 39

Respiratory, thoracic and mediastinal disorders 35 Hepatobiliary disorders 27 Reproductive system and breast disorders 24

Immune system disorders 23 Cardiac disorders 18 Infections and infestations 17 Renal and urinary disorders 17 Musculoskeletal and connective tissue disorders 16

Eye disorders 15

Metabolism and nutrition disorders 9 Vascular disorders 7

Endocrine disorders 4 Congenital, familial and genetic disorders 4

Surgical and medical procedures 3

Ear and labyrinth disorders 3 Total Number of Cases 971

As shown in Table 2, the most common MedDRA System Organ Classes

(SOCs) for the reported adverse events include Gastrointestinal disorders

(20%), Injury, poisoning and procedural complications (12%), and Nervous

system disorders (1 1%).

Gastrointestinal Disorders

The most commonly reported gastrointestinal events were vomiting (116

reports), diarrhoea (a listed event, 41 reports), and abdominal pain (37

reports). Overall, the majority of such reports were non-serious and resolved

or improved at the time of reporting. A number of cases of vomiting and

abdominal pain were reported in association with an overdose of ranitidine or

confounded by co-suspect medications or underlying medical conditions. In

addition, many cases of vomiting we e reported as associated with the taste

of the medication (mainly the syrup). These cases also may be related to the

disease state being treated.

Injury, Poisoning, and Procedural Complications

The majority of cases in the Injury, poisoning, and procedural complications

SOC described overdose of ranitidine. Most of these cases were non-serious

and involved a medication error. Thirty-three percent of overdose cases did

not report adverse events. Of the cases reporting medication error, 16%

reported that the syrup was administered intravenously. Only two of these

cases reported adverse events (all nonserious); one case reported

hypertension in a patient with a history of blood pressure fluctuations just

prior to ranitidine administration and the other case reported injection site

erythema. Ten cases of medication error reported that cetirizine (Zyrtec) was

given instead of ranitidine and in four cases the patient received ranitidine

instead of cetirizine; all cases were non-serious and the most common events

that occurred were vomiting and somnolence.

Nervous System Disorders

The most commonly reported events in the nervous system disorders SOC

included tremor (21 reports), headache (a listed event, 26 reports), seizure

(25 reports) and somnolence (38 reports). Cases of seizure were either

confounded by CO-suspect or concurrent medications andlor underlying

medical problems (e.g. epilepsy, vomiting, prematurity). Most cases of

somnolence were non-serious and were confounded by either a dispensing

52

error, concurrent medications (e.g. clonazeparn, phenobarbitone), underlying

medical conditions (e.g. apnoea), or symptom of another event (e.g.

anaphylaxis, a cold). Several cases of somnolence were reported in

association with an overdose of ranitidine. The majority of cases of headache

and tremor were nonserious and resolved or improved at the time of

reporting. Most cases of tremor were confounded by CO-suspect or concurrent

medications (e.g. cisapride, metocloprarnide) or significant medical history

(e.g. seizures) or were reported in association with overdose or convulsion.

Reversible involuntary movement disorders is a listed event in the ranitidine

Global Datasheet.

Other events

Forty-five reports of rash were received. The majority of cases were non-

serious and resolved or improved at the time of reporting. Rash is a listed

event in the ranitidine Global Datasheet. Twenty-two cases of pyrexia were

received with 18 cases reported as serious. The majority of cases described

pyrexia as a symptom of another event (e.g. infection, hypersensitivity

reaction) or were confounded by significant medical history (e.g. liver

transplant, leukaemia). Almost half of the cases were reported as resolved or

improved.

Reports of crying (25 reports), irritability (37 reports), and insomnia (26

reports) were also received. The majority of these cases were non-serious and

involved patients less than 2 years in age with gastroesophageal reflux. In

addition, most cases were confounded by CO-suspect or concurrent

medications (e.g. cisapride, hyoscyarnine, steroids, vaccines) or underlying

medical conditions (e.g. nervousness, global developmental delay) and were

resolved or improved at the time of reporting. These events are also

symptoms of infants with GERD and may be related to their underlying

disease.

Conclusion

Cases involving paediatric patients (n=971) represent about 5% of all

ranitidine cases in the GCSP safety database. The majority of the 971 cases

were non-serious, spontaneous reports received from medical professionals

and described patients 2 years of age or younger. Most patients received

ranitidine to treat a condition (e.g. GERD, ulcer) for which some of the

reported events (e.g. vomiting, irritability, abdominal pain, crying, insomnia)

could be a symptom. Review of the most commonly reported events in cases

received up to 02 August 2004 did not highlight any safety issues for

paediatric patients.

53

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