For the use of a Registered Medical Practitioner only

Qualitative and Quantitative Composition

Each enteric-coated tablet contains:

Pantoprazole Sodium sesquihydrates equivalent to Pantoprazole.... 40 mg

Dosage Form and Strength

Tablet (40 mg) for oral administration

Clinical Particulars

Therapeutic Indications

• For the treatment of gastric ulcer
• For the treatment of duodenal ulcer
• For the treatment of moderate and severe reflux oesophagitis.

Posology and Method of Administration

Tablets should not be chewed or crushed and should be swallowed whole 1 hour before a meal with some water.

The recommended dosages of pantoprazole are outlined in Table 1.

Table 1: Recommended Dosing Schedule for Pantoprazole Tablets
Indication	Dose	Frequency
Short-Term Treatment of EE Associated with GERD
Adults	40 mg	Once daily for up to 8 weeks*
Children (5 years and older)
≥15 kg to <40 kg	20 mg	Once daily for up to 8 weeks
≥40 kg	40 mg
Maintenance of Healing of EE
Adults	40 mg	Once daily#

For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole may be considered.

^# Controlled studies did not extend beyond 12 months.

Treatment of Gastric Ulcers

One tablet of pantoprazole per day. In individual cases, the dose may be doubled (increase to two tablets of pantoprazole daily), especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of Duodenal Ulcers

One tablet of pantoprazole per day. In individual cases, the dose may be doubled (increase to two tablets of pantoprazole daily), especially when there has been no response to other treatment. A duodenal ulcer generally heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Contraindications

Pantoprazole tablets are contraindicated in case of hypersensitivity to the active substance, substituted benzimidazoles, or to any of the other excipients of the tablet. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angio-oedema, bronchospasm, acute interstitial nephritis, and urticaria. Proton-pump inhibitors (PPIs), including pantoprazole tablets, are contraindicated with rilpivirine-containing products.

Special Warnings and Precautions for Use

Presence of Gastric Malignancy

Symptomatic response to therapy with pantoprazole 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 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 Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs, including pantoprazole delayed-release tablets. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue pantoprazole delayed-release tablets 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. 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 delayed-release tablets, 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 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

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.

Tumourigenicity

Due to the chronic nature of GERD, there may be a potential for prolonged administration of pantoprazole. In long-term rodent studies, pantoprazole 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 delayed-release tablet 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 delayed-release tablets.

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, particularly on long-term use. In the case of a rise of the liver enzymes, the treatment should be discontinued.

Combination Therapy

In the case of combination therapy, the summaries of product characteristics of the respective medicinal products should be observed.

HIV Protease Inhibtiors

Co-administration of pantoprazole 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 proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended. A pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitors may need to be adjusted.

Long-term Treatment

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Gastrointestinal Infections Caused by Bacteria

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

Drug Interactions

Pantoprazole is extensively metabolised in the liver via the cytochrome (CY) P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4.

Interaction studies with drugs also metabolised with these pathways such as carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyloestradiol did not reveal clinically significant interactions.

An interaction of pantoprazole with other medicinal products or compounds, which are metabolised using the same enzyme system, cannot be excluded. Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with P-glycoprotein related absorption of digoxin.

Antacids

There were no interactions with concomitantly administered antacids.

HIV Protease Inhibitors

Co-administration of pantoprazole 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 dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitors may need to be adjusted.

Coumarin Anticoagulants (Phenprocoumon or Warfarin)

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Clopidogrel

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. No dose adjustment of clopidogrel is necessary when administered with an approved dose of pantoprazole.

Drugs for Which Gastric pH Can Affect Bioavailability

Pantoprazole causes long-lasting inhibition of gastric acid secretion. Therefore, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole, ampicillin esters, iron salts and other medicines such as erlotinib).

False-Positive Urine Tests for THC

There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. An alternative confirmatory method should be considered to verify positive results.

Methotrexate

Case reports, published population pharmacokinetic studies and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high doses; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

Medicinal Products That Inhibit or Induce CYP2C19

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of pantoprazole, or those with hepatic impairment. Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St John´s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems.

Interactions with Investigations of Neuroendocrine Tumours

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 tumours. Temporarily stop pantoprazole delayed-release tablet 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.

Use in Special Populations

Paediatric Patients (Below 12 Years of Age)

Pantoprazole is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group.

Patients with Hepatic Impairment

A daily dose of 20 mg pantoprazole (one tablet of 20 mg pantoprazole) should not be exceeded in patients with severe liver impairment. Pantoprazole must not be used in combination treatment for eradication of H. pylori in patients with moderate-to-severe hepatic dysfunction since currently no data are available on the efficacy and safety of pantoprazole in combination treatment of these patients.

Patients with Renal Impairment

No dose adjustment is necessary in patients with impaired renal function. Pantoprazole must not be used in combination treatment for eradication of H. pylori in patients with impaired renal function since currently no data are available on the efficacy and safety of pantoprazole in combination treatment for these patients.

Pregnancy Category B

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.

Lactation

Pantoprazole and its metabolites are excreted in the milk of rats. Pantoprazole 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 tumorigenicity shown for pantoprazole 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.

Paediatric Patients

The safety and effectiveness of pantoprazole 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 is indicated for the short-term treatment of EE associated with GERD for patients 5 years and older. The safety and effectiveness of pantoprazole for paediatric uses other than EE have not been established.

1 Year through16 Years of Age

Use of pantoprazole 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 for treatment of EE associated with GERD in adults; and, b) safety, effectiveness, and pharmacokinetic studies performed in paediatric patients.

Safety of pantoprazole 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 (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 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 for symptomatic GERD in the paediatric population. The effectiveness of pantoprazole for treating symptomatic GERD in paediatric patients has not been established.

Although the data from the clinical trials support use of pantoprazole 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 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 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 daily for 4 weeks in an open-label phase; then, patients were randomised in equal proportion to receive pantoprazole 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 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, 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 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 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 was not shown to be effective in the randomised, placebo-controlled study in this age group, the use of pantoprazole for treatment of symptomatic GERD in infants less than 1 year of age is not indicated.

Geriatric Use

The incidence rates of adverse reactions and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age. No dose adjustment is necessary in elderly patients.

Effects on Ability to Drive and Use Machines

Pantoprazole 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

Undesirable Effects

The following serious adverse reactions are described below and elsewhere in the labelling:

• Acute Interstitial Nephritis
• Clostridium difficile-associated Diarrhoea
• Bone Fracture
• Cutaneous and Systemic Lupus Erythematosus
• Cyanocobalamin (Vitamin B₁₂) Deficiency
• Hypomagnesaemia
• Fundic Gland Polyps
• Acute Kidney Injury

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 (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 2: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of >2%
	Pantoprazole (n=1,473) %	Comparators (n=345) %	Placebo (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 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: diarrhoea; nausea/vomiting; abdominal distension and bloating; constipation; dry mouth; abdominal pain and discomfort, hepatitis.

HAEMATOLOGIC: leucopaenia, thrombocytopaenia, pancytopaenia

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, weight changes, hyperlipidaemias and lipid increase (triglycerides, cholesterol), hypocalcaemia and hypokalaemia.

MUSCULOSKELETAL: fracture of the hip, wrist or spine myalgia, arthralgia, muscle spasm.

PSYCHIATRIC AND NERVOUS SYSTEM DISORDERS: depression (and all aggravations), disorientation (and all aggravations), vertigo, taste disorders, paraesthesia, sleep disorders

SKIN AND APPENDAGES: rash/exanthema/eruption, urticaria, pruritus, angio-oedema

SPECIAL SENSES: disturbances in vision/blurred vision

REPRODUCTIVE SYSTEM AND BREAST DISORDERS: gynaecomastia

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 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 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 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pantoprazole. 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.

MUSCULOSKELETAL DISORDERS: Rhabdomyolysis, bone fracture

NERVOUS: ageusia, dysgeusia

PSYCHIATRIC DISORDERS: hallucination, confusion, insomnia, somnolence

RENAL AND URINARY DISORDERS: interstitial nephritis, acute kidney injury

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: severe dermatologic reactions (some fatal), including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN, some fatal), angio-oedema (Quincke's oedema) and cutaneous lupus erythematosus

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. 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

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

Pantoprazole is not removed by haemodialysis. In case of overdosage, treatment should be symptomatic and supportive.

Single oral doses of pantoprazole 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.

Pharmacological Properties

Mechanism of Action

Pantoprazole 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).

Pharmacodynamic Properties

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 in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, 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 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; there was no evidence of rebound hypersecretion.

In a series of dose-response studies, pantoprazole, 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 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 on median pH from one double-blind crossover study are shown in Table 3.

Table 3: Effect of Single Daily Doses of Oral Pantoprazole on Intra-Gastric pH
	Median pH on day 7
Time	Placebo	20 mg	40 mg	80 mg
8 a.m. – 8 a.m.  (24 hours)	1.3	2.9*	3.8*†	3.9*†
8 a.m. – 10 p.m. (Daytime)	1.6	3.2*	4.4*†	4.8*†
10 p.m. – 8 a.m. (Night-time)	1.2	2.1*	3.0*	2.6*
*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 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 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 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 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 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 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 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 at 5 mg/kg/day and a 9 month off-dose recovery.

Pharmacokinetic Properties

Pantoprazole tablets are prepared as enteric-coated tablets so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (C_max) 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 does not accumulate, and its pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration, the serum concentration of pantoprazole 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 tablet, the peak concentration (C_max) is 2.5 mcg/mL; the time to reach the peak concentration (t_max) 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 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 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 is linear after both oral and intravenous administration.

The absolute bioavailability from the tablet 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 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 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; 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.

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 is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, 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.

Renal Impairment

No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole’s half-life is short. Only very small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately delayed half-life (2–3 hours), excretion is still rapid and, thus, accumulation does not occur.

Hepatic Impairment

Although for patients with liver cirrhosis (Child-Pugh classes A and B), the half-life values increased to between 7 and 9 hours and the AUC values increased by a factor of 5 to 7, the maximum serum concentration only increased slightly by a factor of 1.5, compared with healthy subjects.

Geriatric Patients

A slight increase in the AUC and C_max 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 to children aged 5 to 16 years, the AUC and C_max 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 to children aged 2 to 16 years, there was no significant association between pantoprazole clearance and age or weight. The AUC and volume of distribution were in accordance with data from adults.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Non-clinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In the 2-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment. In the 2-year rodent studies, an increased number of liver tumours was observed in rats and in female mice and was interpreted as being due to pantoprazole high metabolic rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected.

In animal reproduction studies, signs of slight foetotoxicity were observed at doses above 5 mg/kg. Investigations revealed no evidence of impaired fertility or teratogenic effects. Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of pantoprazole in the foetus is increased shortly before birth.

Description

The active ingredient in PANSEC Tablets (pantoprazole sodium) enteric-coated tablet, a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl] sulfinyl]-1H-benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C₁₆H₁₄F₂N₃NaO₄S x 1.5 H₂O, with a molecular weight of 432.4.

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.

Pharmaceutical Particulars

Incompatibilities

NA

Shelf-Life

24 Months

Packaging information

PANSEC Tablets ……Aluminium pack of 15 tablets

Storage and Handling Instructions

Protect from moisture and keep at a temperature not exceeding 30⁰C.

Patient Counselling Information

● What is PANSEC Tablets?

PANSEC Tablets contain the active substance pantoprazole. Pantoprazole 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 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 is used to treat adults with stomach and duodenal ulcers.

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 PANSEC Tablets, 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 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 B₁₂ and receive long-term treatment with pantoprazole. As with all acid-reducing agents, pantoprazole 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, ask your doctor for specific advice.
• Taking a PPI such as pantoprazole, 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 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 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. 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

Your doctor may decide that you need some tests to rule out malignant disease because pantoprazole 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 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 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

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 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 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 treatment because pantoprazole 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 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 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.

● How to take PANSEC Tablets

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

Take the tablets 1 hour before a meal without chewing or breaking them and swallow them whole with some water.

The recommended dose is as follows:

Adults and adolescents, 12 years of age and above

- To treat reflux oesophagitis

The usual dose is one tablet a day. Your doctor may tell you to increase to two tablets daily. The treatment period for reflux oesophagitis is usually between 4 and 8 weeks. Your doctor will tell you how long to take your medicine.

Adults

- For the treatment of stomach and duodenal ulcers.

The usual dose is one tablet a day. After consultation with your doctor, the dose may be doubled.  Your doctor will tell you how long to take your medicine. The treatment period for stomach ulcers is usually between 4 and 8 weeks. The treatment period for duodenal ulcers is usually between 2 and 4 weeks.

Patients with kidney problems

If you have kidney problems, you should not take pantoprazole for the eradication of Helicobacter pylori.

Patients with liver problems

If you suffer from severe liver problems, you should not take more than one tablet 20 mg pantoprazole a day (for this purpose, tablets containing 20 mg pantoprazole are available).  If you suffer from moderate or severe liver problems, you should not take pantoprazole for eradication of Helicobacter pylori.

Use in children and adolescents

These tablets are not recommended for use in children below 12 years of age.

If you take more pantoprazole than you should

Consult your doctor or pharmacist. There are no known symptoms of overdose.

If you forget to take pantoprazole

Do not take a double dose to make up for a forgotten dose. Take your next, normal dose at the usual time.

If you stop taking pantoprazole

Do not stop taking these tablets without first talking to your doctor or pharmacist.

If you have any further questions about the use of this medicine, ask your doctor, pharmacist or nurse.

● 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 tablets and tell your doctor immediately, or contact the casualty department at your nearest hospital:

- 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 level in blood, decreased magnesium level in blood (see section Before you take PANSEC Tablets), 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.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. 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 PANSEC Tablets

- Keep this medicine out of the sight and reach of children.

• Protect from moisture and keep at a temperature not exceeding 30⁰C.
• 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 substance in PANSEC Tablets is pantoprazole. Each enteric-coated tablet contains pantoprazole sodium sesquihydrates equivalent to Pantoprazole 40 mg.

Details of The Manufacturers

Mfd. By Cipla Ltd.

Registered Office :

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

M.L. 27/UA/LL-2006 and 30.04.2016

Date of Revision

19/12/2019