For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only
Each hard gelatin capsule contains:
Pantoprazole Sodium IP,
equivalent to Pantoprazole, IP…..40 mg
(As enteric-coated pellets)
(As sustained-release pellets)
Capsule for oral administration
Pantoprazole Sodium, IP 40 mg and Levosulpiride 75 mg
PANSEC L Capsules are indicated for the short-term treatment of gastro-oesophageal reflux disease (GERD) in patients who do not respond to proton-pump inhibitors (PPIs) alone
Posology and Method of Administration
The recommended dosage of PANSEC L Capsules is one capsule once daily before meals. Capsules should be swallowed whole and are not to be chewed.
- Hypersensitivity to pantoprazole, levosulpiride or any other components in the formulation
- Pheochromocytoma – as it can cause a hypertensive attack, probably due to release of catecholamine from a tumour; such attacks can be controlled with phentolamine
- Epilepsy, manic states such as in the manic phase of manic-depressive psychosis.
- Concomitant prolactin-dependent tumours such as pituitary gland prolactinomas and breast cancer
- Pregnancy and lactation
- Severe renal and hepatic insufficiency
- Levosulpiride is contraindicated in gastrointestinal bleeding and intestinal obstruction
Special Warnings and Precautions for Use
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 Interstitial Nephritis
Acute interstitial nephritis has been observed in patients taking PPIs, including pantoprazole sodium 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 sodium 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 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 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 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.
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, 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.
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 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 sodium 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.
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.
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 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.
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 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.
Patients may experience drowsiness, dizziness and dyskinesia with the use of levosulpiride and, hence, patients under treatment should be advised to avoid driving vehicles or operating machinery.
Levosulpiride should not be used when stimulation of gastrointestinal motility could be harmful, e.g. in the presence of gastrointestinal bleeding, mechanical obstruction or perforation.
Cautious use is advised in patients with cardiovascular disease or a family history of QT prolongation and in patients with risk factors for stroke.
During treatment with antipsychotic drugs, potentially fatal complex symptoms called neuroleptic malignant syndrome (NMS) have been reported. Avoid concomitant therapy with other neuroleptics.
Pantoprazole sodium 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 sodium 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 sodium 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.
There were no interactions with concomitantly administered antacids.
HIV Protease Inhibitors
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.
Coumarin Anticoagulants (Phenprocoumon or Warfarin)
Co-administration of pantoprazole sodium 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 sodium and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.
Concomitant administration of pantoprazole sodium 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 sodium.
Drugs for Which Gastric pH Can Affect Bioavailability
Pantoprazole sodium causes long-lasting inhibition of gastric acid secretion. Therefore, pantoprazole sodium 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.
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 sodium. A dose reduction may be considered for patients treated long-term with high doses of pantoprazole sodium, 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 sodium 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.
- Reduced bioavailability is seen with sucralfate, aluminium- and magnesium-containing antacids. Effect on gastrointestinal motility may be antagonised by anticholinergic agents, narcotics and analgesics.
- Additive sedative effects can occur when levosulpiride is given with alcohol, sedatives, hypnotics, narcotics or tranquilisers.
- Levosulpiride releases catecholamines in patients with essential hypertension. So it should be used cautiously, if at all, in patients receiving monoamine oxidase inhibitors.
- The risk of cardiac arrhythmias increases on combined use with other drugs that prolong the QT interval including certain anti-arrhythmics, other antipsychotics, some non-sedating anti-histamines, antimalarials and cisapride.
- Levosulpiride should be avoided with drugs that cause electrolyte abnormalities such as diuretics
Use in Special Populations
Patients with Hepatic Impairment
A daily dose of 20 mg pantoprazole should not be exceeded in patients with mild to moderate severe hepatic cirrhosis. The liver enzymes should be monitored during therapy. However, there is no data on pharmacokinetics of PANSEC L Capsules in patients with impaired liver function.
Patients with Renal Impairment
Dosage reductions for pantoprazole are not necessary for patients with renal insufficiency or on haemodialysis. However, there is no data on pharmacokinetics of PANSEC L Capsules in patients with impaired kidney function.
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.
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.
The safety and effectiveness of pantoprazole sodium for short‑term treatment (up to 8 weeks) of erosive oesophagitis (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.
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
Pregnancy Category B
Sustained-release levosulpiride capsules are contraindicated during pregnancy.
Sustained-release levosulpiride capsules are contraindicated during lactation.
Safety and efficacy of levosulpride has not been established in paediatric patients.
No dosage adjustment is necessary in geriatric/elderly patients.
Effects on Ability to Drive and Use Machines
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
Levosulpiride may have an influence on the ability to drive and use machines.
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
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.
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 1.
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: 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.
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.
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.
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.
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
Adverse effects reported with levosulpiride include drowsiness, amenorrhoea, gynaecomastia, galactorrhoea, and change in libido.
Serious side effects include neuroleptic malignant syndrome and drug-induced movement disorders.
Reporting of Side Effects
If you experience any side effects, talk to your doctor or pharmacist or write to firstname.lastname@example.org. 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.
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.
In the normal therapeutic dose range, the possibility of side effects is less. But extrapyramidal disturbances and sleep disorders may occur with higher doses and in patients who are sensitive to dopamine antagonists.
In such cases, therapy should be stopped, or the dose should be reduced as dictated by the clinical condition of the patient.
Mechanism of Action
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).
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 2 .
Median pH on day 7
8 a.m. – 8 a.m.
8 a.m. – 10 p.m.
10 p.m. – 8 a.m.
*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.
Levosulpiride is the (-)-enantiomer of sulpiride. It is a selective dopamine D2-receptor antagonist with pro-kinetic activity, is therapeutic option in the management of functional dyspepsia. It has shown greater central antidopaminergic activity, anti-emetic and anti-dyspeptic effects and lower acute toxicity than both the racemic and dextro forms. The main mechanism of action of levosulpiride consists of blocking the D2 dopaminergic receptors, preferentially located on the presynaptic membranes in the dopaminergic pathways of the brain, which means that sulpiride is a selective autoreceptor blocker. On the other hand, the serotonergic (5HT-4) component of levosulpiride may enhance its therapeutic efficacy in functional dyspepsia
Pantoprazole sodium tablets are prepared as enteric-coated tablets so that absorption of pantoprazole sodium begins only after the tablet 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.
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 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.
Pantoprazole's serum protein-binding is about 98%. Volume of distribution is about 0.15 l/kg.
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.
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
No dose reduction is recommended when pantoprazole sodium is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole sodium's half-life is short. Only very small amounts of pantoprazole sodium 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.
Patients with 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.
A slight increase in the AUC and Cmax in elderly volunteers, compared with younger counterparts, is not clinically relevant.
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.
After oral administration the bioavailability of levosulpiride is about 30%. Peak plasma concentration occurs after about 3 hours and it has plasma half-life of about 9.7 hours. It is mostly eliminated by the kidneys in the urine.
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 sodium's 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 sodium-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 sodium in the foetus is increased shortly before birth.
The active ingredients in PANSEC L Capsules are pantoprazole sodium and levosulpiride.
Pantoprazole sodium, a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2- 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. It inhibits specifically and dose-proportionally H+K+ ATPase, the enzyme that is responsible for gastric acid secretion in the parietal cells of the stomach.
Levosulpiride selectively blocks DA2 receptors at the central level and at the submucosal and myenteric plexus peripheral level, which interacts with the cholinergic, adrenergic and peptidergic fibres to regulate the motility of gastrointestinal tract (GIT). Dopamine inhibits the cholinergic neurons of the upper gastrointestinal tract and levosulpiride act as a prokinetic agent blocking the inhibition and hence permitting a sustained cholinergic induced contraction of smooth muscle cell in the myenteric plexus. Via its antagonistic actions on the dopamine receptor in the CTZ, it displays a strong antiemetic effect.
PANSEC L Capsules ……Aluminium pack of 10 capsules
Storage and Handling Instructions
Store below 25⁰C. Protect from light and moisture.
● What is PANSEC L Capsules?
PANSEC L Capsules contain the active substances, pantoprazole sodium and levosulpiride.
Pantoprazole sodium is a selective proton-pump inhibitor (PPI), a medicine that reduces the amount of acid produced in the stomach. It is used for treating acid-related diseases of the stomach and intestine.
Levosulpiride is the (-)-enantiomer of sulpiride. It is a selective dopamine D2-receptor antagonist with pro-kinetic activity, is therapeutic option in the management of functional dyspepsia. It has shown greater central antidopaminergic activity, anti-emetic and anti-dyspeptic effects and lower acute toxicity than both the racemic and dextro forms
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 L Capsules, 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 B12 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).
- If you are taking; certain anti-arrhythmics, other antipsychotics, some non-sedating anti-histamines, antimalarials and cisapride. Since, the risk of cardiac arrhythmias increases on combined use with other drugs that prolong the QT interval
- Levosulpiride should be avoided with drugs that cause electrolyte abnormalities such as diuretics.
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 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. Levosulpiride may have an influence on the ability to drive and use machines.
Pregnancy and Lactation
Enteric-coated pantoprazole sodium and sustained-release levosulpiride capsules are contraindicated during pregnancy and lactation
● How to take PANSEC L 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
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:
One capsule once daily before meals. Capsules should be swallowed whole and are not to be chewed
● 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)
- 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.
- Drowsiness, amenorrhoea, gynaecomastia, galactorrhoea, and change in libido. Serious side effects include neuroleptic malignant syndrome and drug-induced movement disorders.
Reporting of side effects
If you experience any side effects, talk to your doctor or pharmacist or write to email@example.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 L Capsules
- Keep this medicine out of the sight and reach of children.
- Protect from moisture and keep at a temperature not exceeding 25°C.
- 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 PANSEC L Capsules are pantoprazole sodium and levosulpiride. Each hard gelatin capsule contains pantoprazole sodium (equivalent to pantoprazole 40 mg) along with levosulpiride 75 mg.
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