For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Generic Name
Pantoprazole Gastro-resistant and Domperidone Prolonged Release Capsules IP

BRAND NAME
PANTOSEC D SR Capsule

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard gelatin capsule contains:
Pantoprazole Sodium IP
Eq. to Pantoprazole........... 40 mg
(As gastro-resistant pellets)
Colour: Indigo Carmine Blue Supra
Domperidone IP...................30mg
(As prolonged release pellets)
Colours: Sunset Yellow FCF Lake and Sunset Yellow FCF Supra
Excipients …..............................…. q.s.
Approved colours used in capsule shell.

DOSAGE FORM AND STRENGTH

Hard gelatin Capsule
Pantoprazole 40 mg and Domperidone 30 mg

CLINICAL PARTICULARS
Therapeutic Indications
For the treatment of gastroesophageal reflux disease (GERD) not responding to
pantoprazole alone.

Posology and Method of Administration

The recommended dose of PANTOSEC D SR Capsule is one capsule daily before
breakfast.

Contraindications
Pantoprazole
Pantoprazole capsules are contraindicated in case of hypersensitivity to the active
substance, substituted benzimidazoles, or to any of the other excipients of the capsule.
Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angio-oedema,
bronchospasm, acute interstitial nephritis, and urticaria. Proton-pump inhibitors (PPIs),
including pantoprazole sodium capsule, are contraindicated with rilpivirine-containing
products.
Domperidone
Domperidone is contraindicated in the following situations:
• In patients with moderate or severe hepatic impairment
• In patients who have known existing prolongation of cardiac conduction intervals,
particularly QTc, patients with significant electrolyte disturbances or underlying cardiac
diseases such as congestive heart failure
• Co-administration with QT-prolonging drugs, with the exception of apomorphine
• Co-administration with potent CY3A4 inhibitors (regardless of their QT-prolonging
effects)
• Known hypersensitivity to domperidone or any of the excipients.
• Prolactin-releasing pituitary tumour (prolactinoma)
• Renal impairment

Domperidone should not be used when stimulation of gastric motility could be harmful:
gastrointestinal haemorrhage, mechanical obstruction or perforation.

Special Warnings and Precautions for Use

Pantoprazole
Presence of Gastric Malignancy
Symptomatic response to therapy with pantoprazole sodium does not preclude the
presence of gastric malignancy. In the presence of any alarm symptom (e.g. significant
unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or
melaena) and when gastric ulcer is suspected or present, malignancy should be
excluded, as treatment with pantoprazole sodium may alleviate symptoms and delay
diagnosis. Consider additional follow-up and diagnostic testing in adult patients who have
a suboptimal response or an early symptomatic relapse after completing treatment with
a PPI. In older patients, also consider an endoscopy.

Acute Tubointerstitial Nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may
occur at any point during PPI therapy. Patients may present with varying signs and
symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of
decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some
patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g.,
fever, rash or arthralgia). Discontinue pantoprazole sodium delayed-release capsule if
acute interstitial nephritis develops.

Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have
been reported in patients taking PPIs, including pantoprazole sodium. These events have
occurred as both new-onset and an exacerbation of existing autoimmune disease. The
majority of PPI-induced lupus erythematosus cases were CLE. The most common form
of CLE reported in patients treated with PPIs was sub-acute CLE (SCLE) and occurred
within weeks to years after continuous drug therapy in patients ranging from infants to the
elderly. Generally, histological findings were observed without organ involvement. SLE is
less commonly reported than CLE in patients receiving PPIs. PPI-associated SLE is
usually milder than non-drug-induced SLE. Onset of SLE typically occurred within days
to years after initiating treatment, primarily in patients ranging from young adults to the
elderly. The majority of patients presented with rash; however, arthralgia and cytopaenia
were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms
consistent with CLE or SLE are noted in patients receiving pantoprazole sodium delayed-
release capsule, discontinue the drug and refer the patient to the appropriate specialist
for evaluation. Most patients improve with discontinuation of the PPI alone in 4–12 weeks.
Serological testing (e.g. ANA) may be positive and elevated serological test results may
take longer to resolve than clinical manifestations.

Cyanocobalamin (Vitamin B12) Deficiency

Generally, daily treatment with any acid-suppressing medications over a long period of
time (e.g. longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin
B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency
occurring with acid-suppressing therapy have been reported in the literature. This
diagnosis should be considered if clinical symptoms consistent with cyanocobalamin
deficiency are observed.

Clostridium difficile-associated Diarrhoea

Published observational studies suggest that PPI therapy such as pantoprazole sodium
may be associated with an increased risk of Clostridium difficile-associated diarrhoea,
especially in hospitalised patients. This diagnosis should be considered for diarrhoea that
does not improve. Patients should use the lowest dose and shortest duration of PPI
therapy appropriate to the condition being treated.

Bone Fracture
Several published observational studies suggest that PPI therapy may be associated with
an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of
fracture was increased in patients who received high-dose, defined as multiple daily
doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose
and shortest duration of PPI therapy appropriate to the condition being treated. Patients
at risk of osteoporosis should receive care according to current clinical guidelines and
they should have an adequate intake of vitamin D and calcium.

Hypomagnesaemia and Mineral Metabolism

Hypomagnesaemia, symptomatic and asymptomatic, has been reported rarely in patients
treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious
adverse events include tetany, arrhythmias and seizures. In most patients, treatment of
hypomagnesaemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications
such as digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare
professionals may consider monitoring magnesium levels prior to initiation of PPI
treatment and periodically.
Consider monitoring magnesium and calcium levels prior to initiation of pantoprazole and
periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g.,
hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If
hypocalcemia is refractory to treatment, consider discontinuing the PPI

Tumourigenicity
Due to the chronic nature of GERD, there may be a potential for prolonged administration
of pantoprazole sodium. In long-term rodent studies, pantoprazole sodium was
carcinogenic and caused rare types of gastrointestinal tumours. The relevance of these
findings to tumour development in humans is unknown.

Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with
long-term use, especially beyond 1 year. Most PPI users who developed fundic gland
polyps were asymptomatic and fundic gland polyps were identified incidentally on
endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being
treated.

Interference with Investigations for Neuroendocrine Tumours

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in
gastric acidity. The increased CgA level may cause false-positive results in diagnostic
investigations for neuroendocrine tumours. Healthcare providers should temporarily stop
pantoprazole sodium delayed-release capsule treatment at least 14 days before
assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial
tests are performed (e.g. for monitoring), the same commercial laboratory should be used
for testing, as reference ranges between tests may vary.

Interference with Urine Screen for THC

There have been reports of false-positive urine screening tests for tetrahydrocannabinol
(THC) in patients receiving PPIs, including pantoprazole sodium delayed-release
capsule.

Concomitant Use of Pantoprazole with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high
dose; see methotrexate prescribing information) may elevate and prolong serum levels
of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-
dose methotrexate administration, a temporary withdrawal of the PPI may be considered
in some patients.

Hepatic Impairment
In patients with severe liver impairment, the liver enzymes should be monitored regularly
during treatment with pantoprazole sodium, particularly on long-term use. In the case of
a rise of the liver enzymes, the treatment should be discontinued.
Co-administration of HIV Protease Inhibtiors
Co-administration of pantoprazole sodium is not recommended with HIV protease
inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir
due to significant reduction in their bioavailability. If the combination of HIV protease
inhibitors with a PPI is judged unavoidable, close clinical monitoring (e.g. virus load) is
recommended. A pantoprazole sodium dose of 20 mg per day should not be exceeded.
Dosage of the HIV protease inhibitors may need to be adjusted.

Gastrointestinal Infections Caused by Bacteria

Pantoprazole sodium, like all PPIs, might be expected to increase the counts of bacteria
normally present in the upper gastrointestinal tract. Treatment with pantoprazole sodium
may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such
as Salmonella and Campylobacter or C. difficile.

Domperidone
Cardiovascular effects
Domperidone has been associated with prolongation of the QT interval on the
electrocardiogram. During postmarketing surveillance, there have been very rare cases
of QT prolongation and torsades de pointes in patients taking domperidone. These
reports included patients with confounding risk factors, electrolyte abnormalities and
concomitant treatment which may have been contributing factors.

Epidemiological studies showed that domperidone was associated with an increased risk
of serious ventricular arrhythmias or sudden cardiac death. A higher risk was observed in
patients older than 60 years, patients taking daily doses greater than 30 mg, and patients
concurrently taking QT-prolonging drugs or CYP3A4 inhibitors.
Domperidone should be used at the lowest effective dose in adults and children.

Domperidone is contraindicated in patients with known existing prolongation of cardiac

conduction intervals, particularly QTc, in patients with significant electrolyte disturbances
(hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in
patients with underlying cardiac diseases such as congestive heart failure due to
increased risk of ventricular arrhythmia.

Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or

bradycardia are known to be conditions increasing the proarrythmic risk. Treatment with
domperidone should be stopped if signs or symptoms occur that may be associated with
cardiac arrhythmia, and the patients should consult their physician. Patients should be
advised to promptly report any cardiac symptoms.

Use with Apomorphine

Domperidone is contraindicated with QT prolonging drugs, including apomorphine, unless
the benefit of the co-administration with apomorphine outweighs the risks, and only if the
recommended precautions for co-administration mentioned in the apomorphine SmPC
are strictly fulfilled.
Use in Infants
Although neurological side effects are rare, the risk of neurological side effects is higher
in young children since metabolic functions and the blood-brain barrier are not fully
developed in the first months of life. Overdosing may cause extrapyramidal symptoms in
children, but other causes should be taken into consideration.
Renal Impairment
The elimination half-life of domperidone is prolonged in severe renal impairment. For
repeated administration, the dosing frequency of domperidone should be reduced to once
or twice daily depending on the severity of the impairment. The dose may also need to
be reduced.

Drug Interactions
Pantoprazole

Antiretrovirals
Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical
importance and the mechanisms behind these interactions are not
always known.
• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine,
atazanavir, and nelfinavir) when used concomitantly with
pantoprazole
may reduce antiviral effect and promote the development of drug
resistance.
• Increased exposure of other antiretroviral drugs (e.g., saquinavir)
when used concomitantly with pantoprazole may increase toxicity
of the antiretroviral drugs.
• There are other antiretroviral drugs which do not result in
clinically relevant interactions with pantoprazole.
Intervention: Rilpivirine-containing products: Concomitant use with
pantoprazole is contraindicated. See prescribing information.
Atazanavir: See prescribing information for atazanavir for dosing
information.
Nelfinavir: Avoid concomitant use with pantoprazole. See
prescribing information for nelfinavir.
Saquinavir: See the prescribing information for saquinavir and
monitor for potential saquinavir toxicities.
Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs,
including
pantoprazole, and warfarin concomitantly. Increases in INR and
prothrombin
time may lead to abnormal bleeding and even death.
Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin
may be needed to maintain target INR range. See prescribing
information for warfarin.
Clopidogrel
Clinical Impact: Concomitant administration of pantoprazole and clopidogrel in
healthy subjects had no clinically important effect on exposure to
the active metabolite of clopidogrel or clopidogrel-induced platelet
inhibition.
Intervention: No dose adjustment of clopidogrel is necessary when
administered with an approved dose of pantoprazole.
Methotrexate
Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high
dose) may elevate and prolong serum concentrations of
methotrexate and/or its metabolite hydroxymethotrexate, possibly
leading to methotrexate toxicities. No formal
drug interaction studies of high-dose methotrexate with PPIs have
been conducted [see Warnings and Precautions].
Intervention: A temporary withdrawal of pantoprazole may be considered in
some patients receiving high-dose methotrexate.
Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its
effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of pantoprazole
sodium in healthy subjects and in transplant patients receiving
MMF has been reported to reduce the exposure to the active
metabolite, mycophenolic acid (MPA), possibly due to a decrease
in MMF solubility at an increased gastric pH. The clinical
relevance of reduced MPA exposure on organ rejection has not
been established in transplant patients receiving
PANTOPRAZOLE and MMF. Use PANTOPRAZOLE with caution
in transplant patients receiving MMF.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: CgA levels increase secondary to PPI-induced decreases in
gastric acidity. The
increased CgA level may cause false positive results in diagnostic
investigations for neuroendocrine tumors.
Intervention: Temporarily stop PANTOPRAZOLE treatment at least 14 days
before assessing CgA levels and consider repeating the test if
initial CgA levels are high. If serial tests are performed (e.g., for
monitoring), the same commercial laboratory should be used for
testing, as reference ranges between tests may vary.
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for
tetrahydrocannabinol (THC) in patients receiving PPIs [see
Warnings and Precautions ].
Intervention: An alternative confirmatory method should be considered to verify
positive results.
Domperidone
The main metabolic pathway of domperidone is through CYP3A4.In vitro data suggest
that the concomitant use of drugs that significantly inhibit this enzyme may result in
increased plasma levels of domperidone.
There is increased risk of occurrence of QT-interval prolongation due to
pharmacodynamic and/or pharmacokinetic interactions.
Concomitant use of the following substances is contraindicated:
QTc-prolonging medicinal products
• anti-arrhythmics class IA (e.g. disopyramide, hydroquinidine, quinidine)
• anti-arrhythmics class III (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
• certain antipsychotics (e.g. haloperidol, pimozide, sertindole)
• certain antidepressants (e.g. citalopram, escitalopram)
• certain antibiotics (e.g. erythromycin, levofloxacin, moxifloxacin, spiramycin)
• certain antifungal agents (e.g. pentamidine)
• certain antimalarial agents (in particular, halofantrine, lumefantrine)
• certain gastro-intestinal medicines (e.g. cisapride, dolasetron, prucalopride)
• certain antihistaminics (e.g. mequitazine, mizolastine)
• certain medicines used in cancer (e.g. toremifene, vandetanib, vincamine)
• certain other medicines (e.g. bepridil, diphemanil, methadone)
• apomorphine, unless the benefit of the co-administration outweighs the risks, and only
if the recommended precautions for co-administration are strictly fulfilled.
Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e.
• protease inhibitors
• systemic azole antifungals
• some macrolides (erythromycin, clarithromycin and telithromycin)
Concomitant use of the following substances is not recommended:
Moderate CYP3A4 inhibitors, i.e. diltiazem, verapamil and some macrolides.
Concomitant use of the following substances requires caution in use:
Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following
macrolides involved in QT-interval prolongation: azithromycin and roxithromycin
(clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).
The above list of substances is representative and not exhaustive.
Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral
ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of
domperidone's CYP3A4 mediated first-pass metabolism by these drugs.
With the combination of oral domperidone 10 mg four times daily and ketoconazole
200mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation
period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the
combination of domperidone 10 mg four times daily and oral erythromycin 500 mg three
times daily, mean QTc over the observation period was prolonged by 9.9 msec, with
changes at individual time points ranging from 1.6 to 14.3 msec. Both the C max and AUC
of domperidone at steady state were increased approximately three-fold in each of these
interaction studies. In these studies, domperidone monotherapy at 10 mg given orally four
times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5
msec (erythromycin study), while ketoconazole monotherapy (200 mg twice daily) led to
increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Use in Special Populations

Pantoprazole
Patients with Renal Impairment
No dosage adjustment is required in patients with impaired renal function (including
dialysis patients).
Patients with Hepatic Impairment
No dosage adjustment is needed in patients with mild-to-severe hepatic impairment. In
patients with severe liver impairment, the liver enzymes should be monitored during
therapy. Doses higher than 40 mg/day have not been studied in patients with hepatic
impairment
Pregnant Women
There are no adequate and well-controlled studies in pregnant women. Advise pregnant
women of the potential risk of foetal harm. Because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy only if
the potential benefit justifies the potential risk to the foetus.
Lactating Women
Pantoprazole sodium and its metabolites are excreted in the milk of rats. Pantoprazole
sodium excretion in human milk has been detected in a study of a single nursing mother
after a single 40 mg oral dose. The clinical relevance of this finding is not known. Based
on the potential for tumourigenicity shown for pantoprazole sodium in rodent
carcinogenicity studies, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the benefit of the drug to the mother.

Risk Summary

Available data from published observational studies did not demonstrate an association
of major malformations or other adverse pregnancy outcomes with pantoprazole.
In animal reproduction studies, no evidence of adverse development outcomes was
observed with pantoprazole. Reproduction studies have been performed in rats at oral
doses up to 450 mg/kg/day (about 88 times the recommended human dose) and rabbits
at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose) with
administration of pantoprazole during organogenesis in pregnant animals and have
revealed no evidence of harm to the fetus due to pantoprazole in this study (see Data).

A pre-and postnatal development toxicity study in rats with additional endpoints to

evaluate the effect on bone development was performed with pantoprazole sodium. Oral
pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the
human dose of 40 mg/day) were administered to pregnant females from gestation day
(GD) 6 through lactation day (LD) 21. Changes in bone morphology were observed in
pups exposed to pantoprazole in utero and through milk during the period of lactation as
well as by oral dosing from postnatal day (PND) 4 through PND 21 [see Use in Specific
Populations (8.4)]. There were no drug-related findings in maternal animals. Advise
pregnant women of the potential risk of fetal harm.

The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss or
other adverse outcomes. In the U.S. general population, the estimated background risk
of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4%
and 15 to 20%, respectively.

Data

Human Data

Available data from published observational studies failed to demonstrate an association

of adverse pregnancy-related outcomes and pantoprazole use. Methodological limitations
of these observational studies cannot definitely establish or exclude any drug-associated
risk during pregnancy. In a prospective study by the European Network of Teratology
Information Services, outcomes from a group of 53 pregnant women administered median
daily doses of 40 mg pantoprazole were compared to a control group of 868 pregnant
women who did not take any proton pump inhibitors (PPIs). There was no difference in
the rate of major malformations between women exposed to PPIs and the control group,
corresponding to a Relative Risk (RR)=0.55, [95% Confidence Interval (CI) 0.08-3.95]. In
a population-based retrospective cohort study covering all live births in Denmark from
1996 to 2008, there was no significant increase in major birth defects during analysis of
first trimester exposure to pantoprazole in 549 live births. A meta-analysis that compared
1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410
unexposed pregnant women showed no significant increases in risk for congenital
malformations or spontaneous abortion with exposure to PPIs (for major malformations
OR=1.12 ([95% CI 0.86-1.45] and for spontaneous abortions OR=1.29 [95% CI 0.84-
1.97]).
Animal Data

Reproduction studies have been performed in rats at oral pantoprazole doses up to 450
mg/kg/day (about 88 times the recommended human dose based on body surface area)
and in rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended
human dose based on body surface area) with administration of pantoprazole sodium
during organogenesis in pregnant animals. The studies have revealed no evidence of
impaired fertility or harm to the fetus due to pantoprazole.

A pre-and postnatal development toxicity study in rats with additional endpoints to

evaluate the effect on bone development was performed with pantoprazole sodium. Oral
pantoprazole doses of 5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the
human dose of 40 mg/day on a body surface area basis) were administered to pregnant
females from gestation day (GD) 6 through lactation day (LD) 21. On postnatal day (PND
4) through PND 21, the pups were administered oral doses at 5, 15, and 30 mg/kg/day
(approximately 1, 2.3, and 3.2 times the exposure (AUC) in humans at a dose of 40 mg).
There were no drug-related findings in maternal animals. During the preweaning dosing
phase (PND 4 to 21) of the pups, there were increased mortality and/or moribundity and
decreased body weight and body weight gain at 5 mg/kg/day (approximately equal
exposures (AUC) in humans receiving the 40 mg dose) and higher doses. On PND 21,
decreased mean femur length and weight and changes in femur bone mass and geometry
were observed in the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in
humans at the 40 mg dose) and higher doses. The femur findings included lower total
area, bone mineral content and density, periosteal and endosteal circumference, and
cross-sectional moment of inertia. There were no microscopic changes in the distal femur,
proximal tibia, or stifle joints. Changes in bone parameters were partially reversible
following a recovery period, with findings on PND 70 limited to lower femur metaphysis
cortical/subcortical bone mineral density in female pups at 5 mg/kg/day (approximately
equal exposures (AUC) in humans at the 40 mg dose) and higher doses.

Lactating Women
Risk Summary

Pantoprazole has been detected in breast milk of a nursing mother after a single 40 mg
oral dose of pantoprazole. There were no effects on the breastfed infant (see Data). There
are no data on pantoprazole effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with
the mother’s clinical need for pantoprazole and any potential adverse effects on the
breastfed child from pantoprazole or from the underlying maternal condition.

Data

The breast milk of a 42-year-old woman receiving 40 mg of oral pantoprazole, at 10

months postpartum, was studied for 24 hours, to demonstrate low levels of pantoprazole
present in the breast milk. Pantoprazole was detectable in milk only 2 and 4 hours after
the dose with milk levels of approximately 36 mcg/L and 24 mcg/L, respectively. A milk-
to-plasma ratio of 0.022 was observed at 2 hours after drug administration. Pantoprazole
was not detectable (<10 mcg/L) in milk at 6, 8 and 24 hours after the dose. The relative
dose to the infant was estimated to be 7.3 mcg of pantoprazole, which is equivalent to
0.14% of the weight-adjusted maternal dose. No adverse events in the infant were
reported by the mother.

Paediatric Patients
The safety and effectiveness of pantoprazole sodium for short-term treatment (up to 8
weeks) of EE associated with GERD have been established in paediatric patients, 1 year
through 16 years of age. Effectiveness for EE has not been demonstrated in patients less
than 1 year of age. In addition, for patients less than 5 years of age, there is no appropriate
dosage strength in an age-appropriate formulation available. Therefore, pantoprazole
sodium is indicated for the short-term treatment of EE associated with GERD for patients
5 years and older. The safety and effectiveness of pantoprazole sodium for paediatric
uses other than EE have not been established.

1-year through16 years of age

Use of pantoprazole sodium in paediatric patients, 1 year through 16 years of age, for
short-term treatment (up to 8 weeks) of EE associated with GERD is supported by a)
extrapolation of results from adequate and well-controlled studies that supported the
approval of pantoprazole sodium for treatment of EE associated with GERD in adults;
and, b) safety, effectiveness, and pharmacokinetic studies performed in paediatric
patients.

Safety of pantoprazole sodium in the treatment of EE associated with GERD in paediatric

patients, 1 through 16 years of age, was evaluated in three multicentre, randomised,
double-blind, parallel-treatment studies, involving 249 paediatric patients, including 8 with
EE (4 patients aged 1 year to 5 years; and 4 patients aged 5 years to 11 years). The
children aged 1 year to 5 years with endoscopically diagnosed EE (defined as an
endoscopic Hetzel-Dent score ≥2) were treated once daily for 8 weeks with one of two
dose levels of pantoprazole sodium (approximating 0.6 mg/kg or 1.2 mg/kg). All 4 of these
patients with EE were healed (Hetzel-Dent score of 0 or 1) at 8 weeks. Because EE is
uncommon in the paediatric population, predominantly paediatric patients with
endoscopically-proven or symptomatic GERD were also included in these studies.
Patients were treated with a range of doses of pantoprazole sodium once daily for 8
weeks. Because these paediatric trials had no placebo, active comparator or evidence of
a dose response, the trials were inconclusive regarding the clinical benefit of pantoprazole
sodium for symptomatic GERD in the paediatric population. The effectiveness of
pantoprazole sodium for treating symptomatic GERD in paediatric patients has not been
established.

Although the data from the clinical trials support use of pantoprazole sodium for the short-
term treatment of EE associated with GERD in paediatric patients, 1 year through 5 years
of age, there is no commercially available dosage formulation appropriate for patients
less than 5 years of age.
In a population pharmacokinetic analysis, clearance values in the children aged 1 to 5
years old with endoscopically proven GERD had a median value of 2.4 L/h. Following a
1.2 mg/kg equivalent dose (15 mg for ≤12.5 kg and 20 mg for >12.5 to <25 kg), the plasma
concentrations of pantoprazole sodium were highly variable and the median time to peak
plasma concentration was 3–6 hours. The estimated AUC for patients, 1 to 5 years old,
was 37% higher than for adults receiving a single 40 mg tablet, with a geometric mean
AUC value of 6.8 mcg•hr/mL.

Neonates to <1year of age

Pantoprazole sodium was not found to be effective in a multicentre, randomised, double-
blind, placebo-controlled, treatment-withdrawal study of 129 paediatric patients,1 through
11 months of age. Patients were enrolled if they had symptomatic GERD based on
medical history and had not responded to non-pharmacologic interventions for GERD for
2 weeks. Patients received pantoprazole sodium daily for 4 weeks in an open-label phase;
then, patients were randomised in equal proportion to receive pantoprazole sodium
treatment or placebo for the subsequent 4 weeks in a double-blind manner. Efficacy was
assessed by observing the time from randomisation to study discontinuation due to
symptom worsening during the 4-week treatment-withdrawal phase. There was no
statistically significant difference between pantoprazole sodium and placebo in the rate
of discontinuation.

In this trial, the adverse reactions that were reported more commonly (difference of ≥4%)
in the treated population compared with the placebo population were elevated creatine
kinase, otitis media, rhinitis and laryngitis.

In a population pharmacokinetic analysis, the systemic exposure was higher in patients

less than 1 year of age with GERD compared with adults who received a single 40 mg
dose (geometric mean AUC was 103% higher in pre-term infants and neonates receiving
a single dose of 2.5 mg of pantoprazole sodium, and 23% higher in infants, 1 through 11
months of age, receiving a single dose of approximately 1.2 mg/kg). In these patients, the
apparent clearance (CL/F) increased with age (median clearance: 0.6 L/hr, range: 0.03–
3.2 L/hr).

These doses resulted in pharmacodynamic effects on gastric but not oesophageal pH.
Following once-daily dosing of 2.5 mg of pantoprazole sodium in pre-term infants and
neonates, there was an increase in the mean gastric pH (from 4.3 at baseline to 5.2 at
the steady state) and in the mean percent time that gastric pH was >4 (from 60% at
baseline to 80% at the steady state). Following once-daily dosing of approximately 1.2
mg/kg of pantoprazole sodium in infants 1 through 11 months of age, there was an
increase in the mean gastric pH (from 3.1 at baseline to 4.2 at the steady state) and in
the mean % time that gastric pH was >4 (from 32% at baseline to 60% at the steady
state). However, no significant changes were observed in mean intra-oesophageal pH or
% time that oesophageal pH was <4 in either age group.
Because pantoprazole sodium was not shown to be effective in the randomised, placebo-
controlled study in this age group, the use of pantoprazole sodium for treatment of
symptomatic GERD in infants less than 1 year of age is not indicated.

Animal Toxicity Data

In a pre-and post-natal development study in rats, the pups were administered oral doses
of pantoprazole at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the
exposure (AUC) in children aged 6 to 11 years at a dose of 40 mg) on postnatal day (PND
4) through PND 21, in addition to lactational exposure through milk. On PND 21,
decreased mean femur length and weight and changes in femur bone mass and geometry
were observed in the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in
children aged 6 to 11 years at the 40 mg dose) and higher doses. Changes in bone
parameters were partially reversible following a recovery period.

In neonatal/juvenile animals (rats and dogs) toxicities were similar to those observed in
adult animals, including gastric alterations, decreases in red cell mass, increases in lipids,
enzyme induction and hepatocellular hypertrophy. An increased incidence of eosinophilic
chief cells in adult and neonatal/juvenile rats, and atrophy of chief cells in adult rats and
in neonatal/juvenile dogs, was observed in the fundic mucosa of stomachs in repeated-
dose studies. Full to partial recovery of these effects were noted in animals of both age
groups following a recovery period.

Domperidone
Pregnant Women
There are limited postmarketing data on the use of domperidone in pregnant women.
Studies in animals have shown reproductive toxicity at maternally toxic doses.
Domperidone should only be used during pregnancy when justified by the anticipated
therapeutic benefit.

Lactating Women
Domperidone is excreted in human milk and breastfed infants receive less than 0.1% of
the maternal weight-adjusted dose.

Occurrence of adverse effects, in particular cardiac effects cannot be excluded after

exposure via breast milk. A decision should be made whether to discontinue
breastfeeding or to discontinue/abstain from domperidone therapy, taking into account
the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Caution should be exercised in case of QTc prolongation risk factors in breastfed infants.
Paediatric Patients
Domperidone is not recommended in cases other than that of nausea and vomiting during
cancer therapy. There may be an increased risk for extra-pyramidal reactions in young
children because of an incompletely developed blood-brain barrier. Hence, PANTOSEC
D SR Capsule are not recommended in paediatric patients.
Geriatric Patients
No special precautions are necessary while recommending PANTOSEC D SR Capsule
to older patients.

Effects on Ability to Drive and Use Machines

Pantoprazole
Pantoprazole sodium has no or negligible influence on the ability to drive and use
machines. Adverse drug reactions, such as dizziness and visual disturbances, may occur.
If affected, patients should not drive or operate machines.

Domperidone
Domperidone has no or negligible influence on the ability to drive and use machines.

Undesirable Effects
Pantoprazole
The following serious adverse reactions are described below and elsewhere in the
labelling:
• Acute Interstitial Nephritis
• Clostridium difficile-associated Diarrhoea
• Bone Fracture Severe Cutaneous Adverse Reactions
• Cutaneous and Systemic Lupus Erythematosus
• Cyanocobalamin (Vitamin B12) Deficiency
• Hypomagnesaemia
• Fundic Gland Polyps
• Acute Kidney Failure
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adults
Safety in nine randomised comparative US clinical trials in patients with GERD included
1,473 patients on oral pantoprazole sodium (20 mg or 40 mg), 299 patients on an H2-
receptor antagonist, 46 patients on another PPI, and 82 patients on placebo. The most
frequently occurring adverse reactions are listed in Table 2.

Table 1: Adverse Reactions Reported in Clinical Trials of Adult Patients with

GERD at a Frequency of >2%
Pantoprazole Comparators Placebo
(n=1,473) (n=345) (n=82)
% % %
Headache 12.2 12.8 8.5
Diarrhoea 8.8 9.6 4.9
Nausea 7.0 5.2 9.8
Abdominal pain 6.2 4.1 6.1
 Vomiting 4.3 3.5 2.4
Flatulence 3.9 2.9 3.7
Dizziness 3.0 2.9 1.2
Arthralgia 2.8 1.4 1.2

Additional adverse reactions that were reported for pantoprazole sodium in clinical trials
with a frequency of ≤2% are listed below by body system:
BODY AS A WHOLE: allergic reaction, pyrexia, photosensitivity reaction, facial oedema
GENERAL DISORDERS AT SITE OF ADMINISTRATION: asthenia, fatigue and malaise,
body temperature increased; oedema peripheral
GASTROINTESTINAL: hepatitis.
HAEMATOLOGIC: leucopaenia, thrombocytopaenia,
IMMUNE SYSTEM DISORDERS: hypersensitivity (including anaphylactic reactions and
anaphylactic shock)
METABOLIC/NUTRITIONAL: elevated creatine kinase, generalised oedema, elevated
triglycerides, liver enzymes (transaminases, gamma-GT) and bilirubin elevated
MUSCULOSKELETAL: myalgia
PSYCHIATRIC AND NERVOUS SYSTEM DISORDERS: depression vertigo
SKIN AND APPENDAGES: rash, urticaria, pruritus
SPECIAL SENSES: blurred vision

Adverse reactions whose frequency of occurrence is not known but may occur include
hyponatraemia, hypomagnesaemia, hallucination; confusion (especially in pre-disposed
patients, as well as the aggravation of these symptoms in case of pre-existence),
hepatocellular injury; jaundice; hepatocellular failure, Stevens-Johnson syndrome; Lyell
syndrome; erythema multiforme; photo-sensitivity; and interstitial nephritis.

Paediatric Patients
Safety of pantoprazole sodium in the treatment of EE associated with GERD was
evaluated in paediatric patients aged 1 year through 16 years in three clinical trials. Safety
trials involved paediatric patients with EE; however, as EE is uncommon in the paediatric
population, 249 paediatric patients with endoscopically-proven or symptomatic GERD
were also evaluated. All adult adverse reactions to pantoprazole sodium are considered
relevant to paediatric patients. In patients aged 1 year through 16 years, the most
commonly reported (>4%) adverse reactions include URI, headache, fever, diarrhoea,
vomiting, rash, and abdominal pain.

Additional adverse reactions that were reported for pantoprazole sodium in paediatric
patients in clinical trials with a frequency of ≤4% are listed below by body system:
BODY AS A WHOLE: allergic reaction, facial oedema
GASTROINTESTINAL: constipation, flatulence, nausea
METABOLIC/NUTRITIONAL: elevated triglycerides, elevated liver enzymes, elevated
creatine kinase
MUSCULOSKELETAL: arthralgia, myalgia
NERVOUS: dizziness, vertigo
SKIN AND APPENDAGES: urticaria
The following adverse reactions seen in adults in clinical trials were not reported in
paediatric patients in clinical trials but are considered relevant to paediatric patients:
photosensitivity reaction, dry mouth, hepatitis, thrombocytopaenia, generalised oedema,
depression, pruritus, leucopaenia, and blurred vision.

Zollinger-Ellison Syndrome
In clinical studies of Zollinger-Ellison syndrome, adverse reactions reported in 35 patients
taking pantoprazole sodium 80 mg/day to 240 mg/day for up to 2 years were similar to
those reported in adult patients with GERD

Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
pantoprazole sodium. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.

These adverse reactions are listed below by body system:

GASTROINTESTINAL DISORDERS: fundic gland polyps
GENERAL DISORDERS AND ADMINISTRATION CONDITIONS: asthenia, fatigue,
malaise
HAEMATOLOGIC: pancytopaenia, agranulocytosis
HEPATOBILIARY DISORDERS: hepatocellular damage, leading to jaundice and hepatic
failure
IMMUNE SYSTEM DISORDERS: anaphylaxis (including anaphylactic shock), systemic
lupus erythematosus
INFECTIONS AND INFESTATIONS: Clostridium difficile-associated diarrhoea
INVESTIGATIONS: weight changes
METABOLISM AND NUTRITIONAL DISORDERS: hyponatraemia, hypomagnesaemia,
hypocalcemia, hypokalemia.
MUSCULOSKELETAL DISORDERS: Rhabdomyolysis, bone fracture
NERVOUS: ageusia, dysgeusia
PSYCHIATRIC DISORDERS: hallucination, confusion, insomnia, somnolence
RENAL AND URINARY DISORDERS: acute tubulointerstitial nephritis
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: severe dermatologic reactions
(some fatal), including erythema multiforme, Stevens-Johnson syndrome, and toxic
epidermal necrolysis (TEN, some fatal), drug reaction with eosinophilia and systemic
symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), angio-
oedema (Quincke's oedema) and cutaneous lupus erythematosus

Domperidone
The safety of domperidone was evaluated in 1,275 patients with dyspepsia, GERD,
irritable bowel syndrome (IBS), nausea and vomiting or other related conditions in 31
double-blind, placebo-controlled studies.
Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or
Parkinsonism were excluded. The following terms and frequencies are applied: very
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare
(≥1/10,000 to <1/1,000), and very rare (<1/10,000).

Where frequency cannot be estimated from clinical trials data, it is recorded as ‘Not
known’.

Table 2
System Organ Adverse Drug Reaction
Class Frequency
Common Uncommon Not known
Immune System Anaphylactic reaction (including
Disorder anaphylactic shock)
Psychiatric Loss of libido Agitation
Disorders Anxiety Nervousness
Nervous System Somnolence Convulsion
Disorders Headache Extrapyramidal disorder
Eye Disorder Oculogyric crisis
Cardiac Disorder Ventricular arrhythmias
Sudden cardiac death
QTc prolongation
Torsades de pointes
Gastrointestinal Dry mouth Diarrhoea
Disorders
Skin and Rash Urticaria
Subcutaneous Pruritus Angio-oedema
Tissue Disorder
Renal and urinary Urinary retention
Disorders
Reproductive Galactorrhoea Gynaecomastia
System and Breast Breast pain Amenorrhoea
Disorders Breast
tenderness
General Disorders Asthenia
and Administration
Site Conditions
Investigations Liver function test abnormal
Blood prolactin increased
In 45 studies where domperidone was used at higher dosages, for longer duration and
for additional indications including diabetic gastroparesis, the frequency of adverse
events (apart from dry mouth) was considerably higher. This was particularly evident for
pharmacologically predictable events related to increased prolactin. In addition to the
reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling,
depression, hypersensitivity, lactation disorder, and irregular menstruation were also
noted.

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to
[email protected]. You can also report side effects directly via the National
Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to
Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more
information on the safety of this product.

Overdose
Pantoprazole
Experience in patients taking very high doses of pantoprazole sodium (>240 mg) is
limited. Spontaneous postmarketing reports of overdose are generally within the known
safety profile of pantoprazole sodium.

Pantoprazole sodium is not removed by haemodialysis. In case of overdosage, treatment

should be symptomatic and supportive.

Single oral doses of pantoprazole sodium at 709 mg/kg, 798 mg/kg and 887 mg/kg were
lethal to mice, rats and dogs, respectively. The symptoms of acute toxicity were
hypoactivity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of
ear reflex, and tremor.

Domperidone
Symptoms
Overdose has been reported primarily in infants and children. Symptoms of overdosage
may include agitation, altered consciousness, convulsions, disorientation, somnolence
and extrapyramidal reactions.

Treatment
There is no specific antidote to domperidone, but in the event of overdose, standard
symptomatic treatment should be given immediately. Gastric lavage as well as the
administration of activated charcoal, may be useful. ECG monitoring should be
undertaken, because of the possibility of QT interval prolongation. Close medical
supervision and supportive therapy is recommended.

Anticholinergic, anti-Parkinson drugs may be helpful in controlling the extrapyramidal

reactions.
PHARMACOLOGICAL PROPERTIES
Mechanism of Action
Pantoprazole
Pantoprazole sodium is a PPI that suppresses the final step in gastric acid production by
covalently binding to the (H+, K+)-ATPase enzyme system at the secretory surface of the
gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid
secretion, irrespective of the stimulus. The binding to the (H+, K+)-ATPase results in a
duration of anti-secretory effect that persists longer than 24 hours for all doses tested
(20–120 mg).

Domperidone
Domperidone is a dopamine antagonist with anti-emetic properties. Domperidone does
not readily cross the blood-brain barrier. In domperidone users, especially adults, extra-
pyramidal side effects are very rare, but domperidone promotes the release of prolactin
from the pituitary. Its anti-emetic effect may be due to a combination of peripheral
(gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor
trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal
studies, together with the low concentrations found in the brain, indicate a predominantly
peripheral effect of domperidone on dopamine receptors.

Studies in humans have shown oral domperidone to increase lower oesophageal

pressure, improve antroduodenal motility and accelerate gastric emptying. There is no
effect on gastric secretion.

Pharmacodynamic Properties
Pantoprazole
Anti-Secretory Activity
Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent
decrease in gastric acid output occurs after a single dose of oral (20–80 mg) pantoprazole
sodium in healthy volunteers. Pantoprazole sodium given once daily results in increasing
inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole
sodium, a 51% mean inhibition was achieved by 2.5 hours. With once-a-day dosing for 7
days, the mean inhibition was increased to 85%. Pantoprazole sodium suppressed acid
secretion in excess of 95% in half of the subjects. Acid secretion returned to normal within
a week after the last dose of pantoprazole sodium; there was no evidence of rebound
hypersecretion.
In a series of dose-response studies, pantoprazole sodium, at oral doses ranging from 20
to 120 mg, caused dose-related increases in median basal gastric pH and in the percent
of time gastric pH was >3 and >4. Treatment with 40 mg of pantoprazole sodium produced
significantly greater increases in gastric pH than the 20 mg dose. Doses higher than 40
mg (60, 80, 120 mg) did not result in further significant increases in median gastric pH.
The effects of pantoprazole sodium on median pH from one double-blind crossover study
are shown in Table 3.
 Table 3: Effect of Single Daily Doses of Oral Pantoprazole
Sodium on Intra-Gastric pH
Median pH on day 7
Time Placebo 20 mg 40 mg 80 mg
8 a.m. – 8 a.m. 1.3 2.9* 3.8*† 3.9*†
(24 hours)
8 a.m. – 10 p.m. 1.6 3.2* 4.4*† 4.8*†
(Daytime)
10 p.m. – 8 a.m. 1.2 2.1* 3.0* 2.6*
(Night-time)
*Significantly different from placebo
†Significantly different from 20 mg

Serum Gastrin Effects

Fasting serum gastrin levels were assessed in two double-blind studies of the acute
healing of EE in which 682 patients with GERD received 10, 20, or 40 mg of pantoprazole
sodium for up to 8 weeks. At 4 weeks of treatment, there was an increase in mean gastrin
levels of 7%, 35%, and 72% over pre-treatment values in the 10, 20, and 40 mg treatment
groups, respectively. A similar increase in serum gastrin levels was noted at the 8-week
visit with mean increases of 3%, 26%, and 84% for the three pantoprazole sodium dose
groups.

In long-term international studies involving over 800 patients, a 2- to 3-fold mean increase
from the pre-treatment fasting serum gastrin level was observed in the initial months of
treatment with pantoprazole sodium at doses of 40 mg per day during GERD
maintenance studies and at 40 mg or higher per day in patients with refractory GERD.
Fasting serum gastrin levels generally remained at approximately 2 to 3 times baseline
for up to 4 years of periodic follow-up in clinical trials. Following short-term treatment with
pantoprazole sodium delayed-release tablets, elevated gastrin levels return to normal by
at least 3 months.

Enterochromaffin-Like (ECL) Cell Effects

In 39 patients treated with oral pantoprazole sodium 40–240 mg daily (majority receiving
40–80 mg) for up to 5 years, there was a moderate increase in ECL-cell density, starting
after the first year of use, which appeared to plateau after 4 years.
In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to
pantoprazole sodium at doses of 0.5–200 mg/kg/day resulted in dose-related increases
in gastric ECL cell proliferation and gastric neuroendocrine (NE)-cell tumours. Gastric NE-
cell tumours in rats may result from chronic elevation of serum gastrin concentrations.
The high density of ECL cells in the rat stomach makes this species highly susceptible to
the proliferative effects of elevated gastrin concentrations produced by PPIs. However,
there were no observed elevations in serum gastrin following the administration of
pantoprazole sodium at a dose of 0.5 mg/kg/day.
In a separate study, a gastric NE-cell tumour without concomitant ECL-cell proliferative
changes was observed in 1 female rat following 12 months of dosing with pantoprazole
sodium at 5 mg/kg/day and a 9 month off-dose recovery.

Endocrine Effects

In a clinical pharmacology study, PANTOPRAZOLE 40 mg given once daily for 2 weeks

had no effect on the levels of the following hormones: cortisol, testosterone,
triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), thyronine-
binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-
stimulating hormone, luteinizing hormone, prolactin, and growth hormone.

In a 1-year study of GERD patients treated with PANTOPRAZOLE 40 mg or 20 mg, there

were no changes from baseline in overall levels of T3, T4, and TSH.

Pharmacokinetic Properties
Pantoprazole
Pantoprazole sodium capsule are prepared as enteric-coated capsule so that absorption
of pantoprazole sodium begins only after the capsule leaves the stomach. Peak serum
concentration (Cmax) and area under the serum concentration time curve (AUC) increase
in a manner proportional to oral and intravenous doses from 10 mg to 80 mg.
Pantoprazole sodium does not accumulate, and its pharmacokinetics are unaltered with
multiple daily dosing. Following oral or intravenous administration, the serum
concentration of pantoprazole sodium declines biexponentially, with a terminal elimination
half-life of approximately 1 hour.

In extensive metabolisers with normal liver function receiving an oral dose of the enteric-
coated 40 mg pantoprazole sodium tablet, the peak concentration (Cmax) is 2.5 mcg/mL;
the time to reach the peak concentration (tmax) is 2.5 hours, and the mean total area under
the plasma concentration versus time curve (AUC) is 4.8 mcg•h/mL (range: 1.4–13.3
mcg•h/mL). Following intravenous administration of pantoprazole sodium to extensive
metabolisers, its total clearance is 7.6–14.0 L/hour, and its apparent volume of distribution
is 11.0–23.6 L.
Absorption
Pantoprazole sodium is rapidly absorbed and the maximal plasma concentration is
achieved even after one single 40 mg oral dose. On average at about 2.5 hours p.a., the
maximum serum concentrations of about 2–3 mcg/ml are achieved and these values
remain constant after multiple administration.

Pharmacokinetics does not vary after single or repeated administration. In the dose range
of 10–80 mg, the plasma kinetics of pantoprazole sodium is linear after both oral and
intravenous administration.

The absolute bioavailability from the capsule was found to be about 77%. Concomitant
intake of food had no influence on the AUC, maximum serum concentrations and, thus,
bioavailability. Only the variability of the lag-time will be increased by concomitant food
intake.

Distribution
Pantoprazole's serum protein-binding is about 98%. Volume of distribution is about 0.15
l/kg.

Elimination
Pantoprazole sodium is almost exclusively metabolised in the liver. The main metabolic
pathway is demethylation by CYP2C19, with subsequent sulphate conjugation; other
metabolic pathways include oxidation by CYP3A4. Terminal half-life is about 1 hour and
clearance is about 0.1 l/hour/kg. There were a few cases of subjects with delayed
elimination. Because of the specific binding of pantoprazole sodium to the proton pumps
of the parietal cell, the elimination half-life does not correlate with the much longer
duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80%) for the metabolites
of pantoprazole sodium; the rest is excreted with the faeces. The main metabolite in both
the serum and urine is desmethylpantoprazole, which is conjugated with sulphate. The
half-life of the main metabolite (about 1.5 hours) is not much longer than that of
pantoprazole sodium.

Special Populations
POOR METABOLISERS
Approximately 3% of the European population lack a functional CYP2C19 enzyme and
are called poor metabolisers. In these individuals the metabolism of pantoprazole sodium
is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg
pantoprazole sodium, the mean area under the plasma concentration-time curve was
approximately 6 times higher in poor metabolisers than in subjects having a functional
CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were
increased by about 60%. These findings have no implications for the posology of
pantoprazole sodium.

PATIENTS WITH RENAL IMPAIRMENT

In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole
were similar to those of healthy subjects..

PATIENTS WITH HEPATIC IMPAIRMENT

In patients with mild to severe hepatic impairment (Child-Pugh A to C cirrhosis), maximum
pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects.
Although serum half-life values increased to 7-9 hours and AUC values increased by 5-
to 7-fold in hepatic-impaired patients, these increases were no greater than those
observed in CYP2C19 poor metabolizers, where no dosage adjustment is warranted.
These pharmacokinetic changes in hepatic-impaired patients result in minimal drug
accumulation following once-daily, multiple-dose administration. Doses higher than 40
mg/day have not been studied in hepatically impaired patients.
Male and Female Patients

There is a modest increase in pantoprazole AUC and Cmax in women compared to men.
However, weight-normalized clearance values are similar in women and men.

In pediatric patients ages 1 through 16 years there were no clinically relevant effects of
gender on clearance of pantoprazole, as shown by population pharmacokinetic analysis.

GERIATRIC PATIENTS
A slight increase in the AUC and Cmax in elderly volunteers, compared with younger
counterparts, is also not clinically relevant.

PAEDIATRIC PATIENTS
Following administration of single oral doses of 20 mg or 40 mg pantoprazole sodium to
children aged 5 to 16 years, the AUC and Cmax were in the range of corresponding values
in adults.

Following administration of single intravenous doses of 0.8 mg or 1.6 mg/kg pantoprazole

sodium to children aged 2 to 16 years, there was no significant association between
pantoprazole sodium clearance and age or weight. The AUC and volume of distribution
were in accordance with data from adults.

Domperidone
Absorption
In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak
plasma concentrations at 30 to 60 minutes. The low absolute bioavailability of oral
domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut
wall and liver. Although domperidone's bioavailability is enhanced in normal subjects
when taken after a meal, patients with gastrointestinal complaints should take
domperidone 15–30 minutes before a meal. Reduced gastric acidity impairs the
absorption of domperidone. Oral bioavailability is decreased by prior concomitant
administration of cimetidine and sodium bicarbonate. The time of peak absorption is
slightly delayed and the AUC somewhat increased when domperidone is taken after a
meal.

Distribution
Oral domperidone does not appear to accumulate or to induce its own metabolism; a peak
plasma level of 21 ng/mL after 90 minutes (after 2 weeks of oral administration of 30 mg
per day) was almost the same as that of 18 ng/mL after the first dose. Domperidone is
91–93% bound to plasma proteins. Distribution studies with radiolabelled drug in animals
have shown wide tissue distribution, but low brain concentration. Small amounts of drug
cross the placenta in rats
Metabolism
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and
N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that
CYP3A4 is a major form of CYP450 involved in the N-dealkylation of domperidone,
whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic
hydroxylation.

Excretion
Urinary and faecal excretions amount to 31% and 66% of the oral dose, respectively. The
proportion of the drug excreted unchanged is small (10% of faecal excretion and
approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7–
9 hours in healthy subjects, but is prolonged in patients with severe renal impairment.

Special Populations
Hepatic Impairment
In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B),
the AUC and Cmax of domperidone is 2.9- and 1.5-fold higher, respectively, than in healthy
subjects. The unbound fraction is increased by 25%, and the terminal elimination half-life
is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat
lower systemic exposure than healthy subjects based on Cmax and AUC, with no change
in protein-binding or terminal half-life. Subjects with severe hepatic impairment were not
studied. Domperidone is contraindicated in patients with moderate or severe hepatic
impairment

Renal Impairment
In subjects with severe renal insufficiency (creatinine clearance <30 mL/min/1.73 m2) the
elimination half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug
levels are lower than in healthy volunteers. Since very little unchanged drug
(approximately 1%) is excreted via the kidneys, it is unlikely that the dose of a single
administration needs to be adjusted in patients with renal insufficiency.

However, on repeated administration, the dosing frequency should be reduced to once

or twice daily, depending on the severity of the impairment, and the dose may need to be
reduced.

Paediatric Patients
No pharmacokinetic data are available in the paediatric population.

NON-CLINICAL PROPERTIES
Animal Toxicology or Pharmacology
Pantoprazole
Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with

pantoprazole doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a
body surface area basis of a 50 kg person dosed with 40 mg/day. In the gastric fundus,
treatment with 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell
hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related
manner. In the forestomach, treatment with 50 and 200 mg/kg/day (about 10 and 40 times
the recommended human dose on a body surface area basis) produced benign
squamous cell papillomas and malignant squamous cell carcinomas. Rare
gastrointestinal tumors associated with pantoprazole treatment included an
adenocarcinoma of the duodenum with 50 mg/kg/day and benign polyps and
adenocarcinomas of the gastric fundus with 200 mg/kg/day. In the liver, treatment with
0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular
adenomas and carcinomas. In the thyroid gland, treatment with 200 mg/kg/day produced
increased incidences of follicular cell adenomas and carcinomas for both male and female
rats.

In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5
to 50 mg/kg/day of pantoprazole, approximately 1 to 10 times the recommended human
dose based on body surface area. In the gastric fundus, treatment with 5 to 50 mg/kg/day
produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant
neuroendocrine cell tumors. Dose selection for this study may not have been adequate
to comprehensively evaluate the carcinogenic potential of pantoprazole.

In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to
150 mg/kg/day of pantoprazole, 0.5 to 15 times the recommended human dose based on
body surface area. In the liver, treatment with 150 mg/kg/day produced increased
incidences of hepatocellular adenomas and carcinomas in female mice. Treatment with
5 to 150 mg/kg/day also produced gastric-fundic ECL cell hyperplasia.

A 26-week p53 +/-transgenic mouse carcinogenicity study was not positive.

Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration

assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro
Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects.
Equivocal results were observed in the in vivo rat liver DNA covalent binding assay.
Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled
DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-
forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse
lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration
assay.

There were no effects on fertility or reproductive performance when pantoprazole was

given at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human
dose based on body surface area) and 450 mg/kg/day in female rats (88 times the
recommended human dose based on body surface area).

Domperidone
Electrophysiological in vitro and in vivo studies indicate an overall moderate risk of
domperidone to prolong the QT interval in humans. In in vitro experiments on isolated
cells transfected with hERG and on isolated guinea pig myocytes, exposure ratios ranged
between 26- to 47-fold, based on IC50 values inhibiting currents through IKr ion channels
in comparison with the free plasma concentrations in humans after administration of the
maximum daily dose of 10 mg administered three times a day. Safety margins for
prolongation of action potential duration in in vitro experiments on isolated cardiac tissues
exceeded the free plasma concentrations in humans at maximum daily dose (10 mg
administered three times a day) by 45-fold. Safety margins in in vitro pro-arrhythmic
models (isolated Langendorff perfused heart) exceeded the free plasma concentrations
in humans at maximum daily dose (10 mg administered three times a day) by 9-fold up
to 45-fold. In in vivo models the no effect levels for QTc prolongation in dogs and induction
of arrhythmias in a rabbit model sensitized for torsades de pointes exceeded the free
plasma concentrations in humans at maximum daily dose (10 mg administered three
times a day) by more than 22-fold and 435-fold, respectively. In the anaesthetized guinea
pig model following slow intravenous infusions, there were no effects on QTc at total
plasma concentrations of 45.4 ng/mL, which are 3-fold higher than the total plasma levels
in humans at maximum daily dose (10 mg administered three times a day). The relevance
of the latter study for humans following exposure to orally administered domperidone is
uncertain.

In the presence of inhibition of the metabolism via CYP3A4 free plasma concentrations
of domperidone can rise up to 3-fold. At a high, maternally toxic dose (more than 40 times
the recommended human dose), teratogenic effects were seen in the rat.
No teratogenicity was observed in mice and rabbits.

DESCRIPTION
The active ingredients in PANTOSEC D SR Capsule are pantoprazole sodium and
domperidone.

Pantoprazole
Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is
racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium
sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH
7.4, and practically insoluble in n-hexane.

Molecular Formula: C16H14F2N3NaO4S x 1.5 H2O

Molecular Weight: 432.4 g/mol
Chemical name: sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]
sulfinyl]-1H-benzimidazole sesquihydrate
Domperidone
Domperidone belongs to a group of medicines called ‘dopamine antagonists’. It is used
in adults and in children to treat nausea (feeling sick) and vomiting (being sick).

Molecular Formula: C22H24ClN5O2

Molecular Weight: 425.9 g/mol
Chemical name: 1-[3-(Piperidin-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one

PHARMACEUTICAL PARTICULARS
Incompatibilities
NA

Shelf-Life
See on the pack
Packaging information
PANTOSEC D SR ……20 x 10 Alu-Alu Blister pack

Storage and Handling Instructions

Store at a temperature not exceeding 25°C. Protect from moisture.

PATIENT COUNSELLING INFORMATION

● What is PANTOSEC D SR Capsule?

PANTOSEC D SR capsule contain the active substances, pantoprazole sodium and
domperidone. Pantoprazole sodium is a selective proton-pump inhibitor (PPI), a medicine
that reduces the amount of acid produced in your stomach. It is used for treating acid-
related diseases of the stomach and intestine.

Pantoprazole sodium is used to treat adults and adolescents, 12 years of age and above,
for the following:
- Reflux oesophagitis, which is an inflammation of your oesophagus (the tube that
connects your throat to your stomach) accompanied by the regurgitation of
stomach acid.
Pantoprazole sodium is used to treat adults with stomach and duodenal ulcers.

Domperidone belongs to a group of medicines called ‘dopamine antagonists’ having anti

emetic properties. It used in adults and in children to treat nausea (feeling sick) and
vomiting (being sick).

Do not take if you have an allergy to this drug

This product should not be used by patients who are hypersensitive to any of the
ingredients.

● Before you take PANTOSEC D SR Capsule, tell your HCP about other conditions
you have and medications you may be taking;
- If you have severe liver problems. Please tell your doctor if you ever had
problems with your liver in the past because your liver enzymes need to be
checked more frequently, especially when you are taking pantoprazole sodium as
a long-term treatment. In the case of an increase in liver enzymes, the treatment
should be stopped.
- If you have reduced body stores or risk factors for reduced vitamin B 12 and
receive long-term treatment with pantoprazole sodium. As with all acid-
reducing agents, pantoprazole sodium may lead to a reduced absorption of vitamin
B12.
- If you are taking HIV protease inhibitors such as atazanavir (for the treatment
of HIV-infection) at the same time as pantoprazole sodium, ask your doctor for
specific advice.
- Taking a PPI such as pantoprazole sodium, especially over a period of more
than 1 year, may slightly increase your risk of fracture in the hip, wrist or
spine. Tell your doctor if you have osteoporosis or if you are taking corticosteroids
(which can increase the risk of osteoporosis).
- If you are on pantoprazole sodium for more than 3 months it is possible that
the levels of magnesium in your blood may fall. Low levels of magnesium can
be seen as fatigue, involuntary muscle contractions, disorientation, convulsions,
dizziness, and increased heart rate. If you get any of these symptoms, please tell
your doctor promptly. Low levels of magnesium can also lead to a reduction in
potassium or calcium levels in the blood. Your doctor may decide to perform
regular blood tests to monitor your levels of magnesium.
- If you have ever had a skin reaction after treatment with a medicine similar to
pantoprazole sodium that reduces stomach acid.
 - If you get a rash on your skin, especially in areas exposed to the sun, tell your
doctor as soon as you can, as you may need to stop your treatment with
pantoprazole sodium. Remember to also mention any other ill-effects such as
pain in your joints.
- If you are due to have a specific blood test (chromogranin A).
Tell your doctor immediately, before or after taking this medicine, if you notice any of
the following symptoms, which could be a sign of another, more serious, disease:
- An unintentional loss of weight
- Vomiting, particularly if repeated
- Vomiting blood; this may appear as dark coffee grounds in your vomit
- You notice blood in your stools, which may be black or tarry in appearance
- Difficulty in swallowing or pain when swallowing
- You look pale and feel weak (anaemia)
- Chest pain
- Stomach pain
- - Severe and/or persistent diarrhoea, because this medicine has been associated with
a small increase in infectious diarrhoea You have a tumour of the pituitary gland
(prolactinoma)
- You have a blockage or tear in your intestines
- You have black, tarry bowel motions (stools) or notice blood in your bowel motions. This
could be a sign of bleeding in the stomach or intestines.
- You have a moderate or severe liver disease.
- Your ECG (electrocardiogram) shows a heart problem called ‘prolonged QT corrected
interval’.
- You have or had a problem where your heart cannot pump the blood round your body
as well as it should (condition called heart failure)
- You suffer from kidney problems (kidney function impairment or failure).
- You have a problem that gives you a low level of potassium or magnesium, or a high
level of potassium in your blood.
- You are taking certain medicines
If you are not sure, talk to your doctor or pharmacist before taking domperidone.

Your doctor may decide that you need some tests to rule out malignant disease because
pantoprazole sodium also alleviates the symptoms of cancer and could cause delay in
diagnosing it. If your symptoms continue in spite of your treatment, further investigations
will be considered.

If you take pantoprazole sodium on a long-term basis (longer than 1 year), your doctor
will probably keep you under regular surveillance. You should report any new and
exceptional symptoms and circumstances whenever you see your doctor.

Children and adolescents

Pantoprazole sodium is not recommended for use in children as it has not been proven
to work in children below 12 years of age.
Other medicines and pantoprazole sodium
Tell your doctor or pharmacist if you are taking, have recently taken or might take any
other medicines, including medicines obtained without a prescription. This is because
pantoprazole sodium may influence the effectiveness of other medicines, so tell your
doctor if you are taking the following:
- Medicines such as ketoconazole, itraconazole and posaconazole (used to treat fungal
infections) or erlotinib (used for certain types of cancer) because pantoprazole aosium
may stop these and other medicines from working properly.
- Warfarin and phenprocoumon, which affect the thickening, or thinning of the blood. You
may need further checks.
- Medicines used to treat HIV-infection, such as atazanavir.
- Methotrexate (used to treat rheumatoid arthritis, psoriasis, and cancer) – if you are taking
methotrexate, your doctor may temporarily stop your pantoprazole sodium treatment
because pantoprazole sodium can increase levels of methotrexate in the blood.
- Fluvoxamine (used to treat depression and other psychiatric diseases) – if you are taking
fluvoxamine your doctor may reduce the dose.
- Rifampicin (used to treat infections).
- St John’s wort (Hypericum perforatum) (used to treat mild depression).

Pregnancy and breastfeeding

There are no adequate data from the use of pantoprazole sodium in pregnant women.
Excretion into human milk has been reported.

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have
a baby, ask your doctor or pharmacist for advice before taking this medicine.
You should use this medicine only if your doctor considers the benefit for you greater than
the potential risk for your unborn child or baby.

Driving and using machines

Pantoprazole sodium has no or negligible influence on the ability to drive and use
machines. If you experience side effects like dizziness or disturbed vision, you should not
drive or operate machines

Other medicines and domperidone

Please tell your doctor or pharmacist if you are taking or have recently taken any other
medicines. This includes medicines you can buy without a prescription, including herbal
medicines. This is because domperidone can affect the way some other medicines work.
Also, some medicines can affect the way domperidone works.

Do not take domperidone if you are taking medicine to treat the following:
- Fungal infections such as azole antifungals, specifically oral ketoconazole,
fluconazole or voriconazole.
- Bacterial infections, specifically erythromycin, clarithromycin, telithromycin,
moxifloxacin, pentamidine (these are antibiotics)
 - Heart problems or high blood pressure (e.g. amiodarone, dronedarone, quinidine,
disopyramide, dofetilide, sotalol, diltiazem, verapamil)
- Psychoses (e.g. haloperidol, pimozide, sertindole)
- Depression (e.g. citalopram, escitalopram)
- Gastro-intestinal disorders (e.g. cisapride, dolasetron, prucalopride)
- Allergy (e.g. mequitazine, mizolastine)
- Malaria (in particular halofantrine)
- AIDS/HIV (protease inhibitors)
- Cancer (e.g. toremifene, vandetanib, vincamine)

Tell your doctor or pharmacist if you are taking drugs to treat infection, heart problems or
AIDS/HIV.

Domperidone and apomorphine

Before you use domperidone and apomorphine, your doctor will ensure that you tolerate
both medicines when used simultaneously. Ask your doctor or specialist for a
personalised advice.

It is important to ask your doctor or pharmacist if domperidone is safe for you when you
are taking any other medicines, including medicines obtained without prescription.

It is recommended to take Domperidone before meals, as when taken after meals the
absorption of the medicine is slightly delayed.

Pregnancy and breastfeeding

Talk to your doctor or pharmacist before taking domperidone if
- You are pregnant, might become pregnant or think you may be pregnant
- You are breastfeeding. It is best not to take domperidone if you are breastfeeding.
Small amounts of domperidone have been detected in breast milk. Domperidone may
cause unwanted side effects affecting the heart in a breastfed baby. Domperidone should
be used during breastfeeding only if your physician considers this clearly necessary. Ask
your doctor for advice before taking this medicine.

Domperidone may be associated with an increased risk of heart rhythm disorder and
cardiac arrest. This risk may be more likely in those over 60 years old or taking doses
higher than 30 mg per day. The risk also increases when domperidone is given together
with some drugs. Tell your doctor or pharmacist if you are taking drugs to treat infection
(fungal infections or bacterial infection) and/or if you have heart problems or AIDS/HIV.

Domperidone should be used at the lowest effective dose in adults and children.

While taking domperidone, contact your doctor if you experience heart rhythm disorders
such as palpitations, trouble breathing, loss of consciousness. Treatment with
domperidone should be stopped.
Driving and using machines
Domperidone does not affect your ability to drive or use machines.
.
● How to take PANTOSEC D SR Capsules
Always take this medicine exactly as your doctor or pharmacist has told you. Check with
your doctor or pharmacist if you are not sure.

Method of administration
The recommended dose of PANTOSEC D SR Capsules is one capsule daily before
breakfast.

● What are the possible side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets
them.

If you get any of the following side effects, stop taking these capsules and tell your
doctor immediately, or contact the casualty department at your nearest hospital:
Pantoprazole
Serious allergic reactions (frequency rare; may affect up to 1 in 1,000 people):
swelling of the tongue and/or throat, difficulty in swallowing, hives (nettle rash), difficulties
in breathing, allergic facial swelling (Quincke’s oedema/angio-oedema), severe dizziness
with very fast heartbeat and heavy sweating.

Serious skin conditions (frequency not known; frequency cannot be estimated from
the available data): blistering of the skin and rapid deterioration of your general condition,
erosion (including slight bleeding) of the eyes, nose, mouth/lips or genitals (Stevens-
Johnson syndrome, Lyell syndrome, erythema multiforme), and sensitivity to light.

Other serious conditions (frequency not known: frequency cannot be estimated from
the available data): acute kidney injury, yellowing of the skin or whites of the eyes (severe
damage to liver cells, jaundice) or fever, rash, and enlarged kidneys sometimes with
painful urination, and lower back pain (serious inflammation of the kidneys), possibly
leading to kidney failure.

Other side effects

Common (may affect up to 1 in 10 people)
Benign polyps in the stomach.

Uncommon (may affect up to 1 in 100 people)

Headache; dizziness; diarrhoea; feeling sick, vomiting; bloating and flatulence (wind);
constipation; dry mouth; abdominal pain and discomfort; skin rash, exanthema, eruption;
itching; feeling weak, exhausted or generally unwell; sleep disorders; fracture of the hip,
wrist or spine.

Rare (may affect up to 1 in 1,000 people)

Distortion or complete lack of the sense of taste; disturbances in vision such as blurred
vision; hives; pain in the joints; muscle pains; weight changes; raised body temperature;
high fever; swelling of the extremities (peripheral oedema); allergic reactions; depression;
breast enlargement in males.

Very rare (may affect up to 1 in 10,000 people)

Disorientation

Not known (frequency cannot be estimated from the available data)

Hallucination, confusion (especially in patients with a history of these symptoms);
decreased sodium level in blood, decreased magnesium level in blood, feeling of tingling,
prickling, pins and needles, burning sensation or numbness, rash, possibly with pain in
the joints; inflammation in the large bowel, that causes persistent watery diarrhoea.

Side effects identified through blood tests

Uncommon (may affect up to 1 in 100 people): an increase in liver enzymes.
Rare (may affect up to 1 in 1,000 people): an increase in bilirubin; increased fat levels in
blood; sharp drop in circulating granular white blood cells, associated with high fever.
Very rare (may affect up to 1 in 10,000 people): a reduction in the number of blood
platelets, which may cause you to bleed or bruise more than normal; a reduction in the
number of white blood cells, which may lead to more frequent infections; coexisting
abnormal reduction in the number of red and white blood cells, as well as platelets.

Domperidone
Stop taking domperidone and see your doctor or go to a hospital straightaway in case of
the following:
- You get swelling of the hands, feet, ankles, face, lips or throat which may cause
difficulty in swallowing or breathing. You could also notice an itchy, lumpy rash
(hives) or nettle rash (urticaria). This may mean you are having an allergic reaction
to domperidone.
- You notice any uncontrolled movements. These include irregular eye movements,
unusual movements of the tongue, and abnormal posture such as a twisted neck,
trembling and muscle stiffness. This is more likely to happen in children. These
symptoms should stop once you stop taking domperidone.
- You have a very fast or unusual heartbeat. This could be a sign of a life-threatening
heart problem.
- You have a fit (seizure)

Other side effects

Common (affects less than 1 in 10 people)
- Dry mouth
Uncommon (affects less than 1 in 1,00 people)
- Lowering of sexual drive (libido) in men
- Feeling anxious
- Feeling drowsy
 - Headaches
- Diarrhoea
- Itchy skin. You may also have a rash
- Unusual production of breast milk in men and women
- Painful or tender breasts
- A general feeling of weakness

Not known (Frequency cannot be estimated from the available data)

- Disorders of the cardiovascular system: heart rhythm disorders (rapid or irregular
heart beat) have been reported; if this happens, you should stop the treatment
immediately. Domperidone may be associated with an increased risk of heart
rhythm disorder and cardiac arrest. This risk may be more likely in those over 60
years old or taking doses higher than 30 mg per day. Domperidone should be used
at the lowest
- effective dose in adults and children.
- Feeling agitated or irritable
- Feeling more nervous than usual
- Abnormal eye movements
- Inability to urinate
- Breast enlargement in men
- In women, menstrual periods may be irregular or stop
- A blood test shows changes in the way your liver is working.

Some patients who have used domperidone for conditions and dosages requiring longer
term medical supervision have experienced the following unwanted effects: restlessness;
swollen or enlarged breasts, unusual discharge from breasts, irregular menstrual periods
in women, difficulty breastfeeding, depression, hypersensitivity. Side effects such as
feeling drowsy, nervous, agitated or irritable or having a fit are more likely to happen in
children.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to
[email protected]. You can also report side effects directly via the National
Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to
Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more
information on the safety of this product.

● How to store PANTOSEC D SR Capsule

- Keep this medicine out of the sight and reach of children.
- Store at a temperature not exceeding 25⁰C.Protect from moisture.
- Do not use this medicine after the expiry date, which is stated on the carton and the
container after EXP. The expiry date refers to the last day of that month.
- This medicine does not require any special storage conditions.
- Do not throw away any medicines via wastewater or household waste. Ask your
pharmacist how to throw away medicines you no longer use. These measures will help
to protect the environment.
● What are the ingredients?
The active substances in PANTOSEC D SR Capsule are pantoprazole sodium and
domperidone. Each capsule contains: Pantoprazole Sodium IP Eq to Pantoprazole 40
mg (as enteric coated pellets) and Domperidone IP 30 mg (as sustained release Pellets)

DETAILS OF THE MANUFACTURER

Manufactured by:
M/S Hetero Labs Ltd. (Unit-II)
Situated at Village Kalyanpur, Chakkan Road,
Baddi (Tehsil), Solan (Distt.),
Himachal Pradesh -173205

Marketed by CIPLA LTD.

Cipla House, Peninsula Business Park,
Ganpatrao Kadam Marg,
Lower Parel,
Mumbai – 400 013, India

DETAILS OF PERMISSION OR LICENCE NUMBER WITH DATE

M.L. MNB/09/780 dated 24/06/2023

DATE OF REVISION
28/06/2023