·     Indicated in gastroesophageal reflux disease.

·     Gastric and duodenal ulcer.

·     Zollinger-Ellison Syndrome and to be used in other pathological hypersecretory conditions.

Posology/duration and frequency of administration

This medicine should be administered by a healthcare professional and under appropriate medical supervision.

 

Intravenous administration is recommended only if oral administration is not appropriate. Data are available on intravenous use for up to 7 days. Therefore, as soon as oral therapy is possible, treatment with PANTOXEROL IV injection should be discontinued and oral 40 mg pantoprazole should be administered instead.

 

Gastric and duodenal ulcer, moderate and severe gastroesophageal reflux treatment:

The recommended intravenous dose is one vial (40 mg pantoprazole) per day.

 

Zollinger-Ellison-Syndrome and long-term treatment of other pathological hypersecretory conditions:

Treatment should be initiated with 80 mg daily dose. Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dose above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.

 

In case a rapid acid control is required, a starting 2×80 mg IV dose is sufficient to manage a decrease of acid output into the target range (<10 mEq/h) within one hour in the majority of patients.

 

When verified clinically it should be switched to oral treatment.

 

Method of administration:

PANTOXEROL is administrated by intravenous injection.

 

The solution is prepared by adding 10 ml sodium chloride 9 mg/ml (0.9%) solution for injection to the vial containing powder for injection. The prepared solution may be administered directly or may be administered after mixing it with 100 ml sodium chloride 9 mg/ml (0.9%) solution for injection or 5% (55 mg/ml) or 10% (110 mg/ml) glucose solution.

 

PANTOXEROL should not be mixed with other agents except the specified solvents.

 

Intravenous injection should be administered over 2-15 minutes.

 

After preparation the solution must be used within 12 hours.

 

Additional information regarding special populations:

 

Renal impairment

No dose adjustment is necessary in patients with impaired renal function.

 

Hepatic impairment

A daily dose of 20 mg pantoprazole (half a vial of 40 mg pantoprazole) should not be exceeded in patients with severe liver impairment. In addition, liver enzymes should be monitored during PANTOXEROL treatment. When elevation of liver enzymes was observed PANTOXEROL therapy should be discontinued.

 

Pediatric population

Adequate clinical experience with treatment in children is not available. Therefore, PANTOXEROL Powder for solution for Injection should not be used for children below 18 years of age until further data become available.

 

Geriatric population

No dose adjustment is necessary in elderly patients.

PANTOXEROL should not be used in patients with hypersensitivity to the active substance substituted benzimidazoles, or to any of the excipients in the composition.

Hepatic Impairment:

In patients with severe liver impairment, the liver enzymes should be monitored regularly during therapy especially in long-term use. In the case of a rise of the liver enzymes, PANTOXEROL treatment should be discontinued.

 

In presence of alarm symptoms:

In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia or melena) and when gastric ulcer is suspected or present, malignancy should be excluded. As treatment with pantoprazole may alleviate symptoms and delay diagnosis.

 

Further investigation is to be considered if symptoms persist despite adequate treatment.

 

Sodium:

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. is essentially 'sodium free'. At this dose, it is not expected to cause any side effects related to sodium.

 

 

Co-administration with atazanavir:

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir. A pantoprazole dose of 20 mg per day should not be exceeded.

 

Bone fractures:

Published several observational studies suggests that, proton pump inhibitors (PPI) may modestly increase fracture risk of hip, wrist or spine associated with osteoporosis. Fracture risk may increase in patients receiving high doses defined as multi daily doses and long-term PPI treatment (one year or more). Patients should use lowest dose and the shortest duration of PPI therapy appropriate to the condition being treated.

 

Subacute cutaneous lupus erythematosus (SCLE):

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping PANTOXEROL. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

 

Hypomagnesemia:

Rarely symptomatic and asymptomatic hypomagnesemia has been reported in patients treated with PPIs for at least three months, and in most cases for a year. Serious adverse events include tetany, arrhythmia and seizure. In most affected patients, hypomagnesemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

 

The investigation in the interactions for neuroendocrine tumors:

Secondary to drug-induced reduction in gastric acid levels, serum chromogranin A (CgA) levels are increasing. Increased CgA level may lead to false-positive results in the diagnosis of neuroendocrine examination for tumors. Practitioners should give a temporarily pause to PPI therapy before evaluating CgA levels and if initial CgA levels are high, the test should be repeated. If a series of tests performed (i.e. for motorization), tests should be performed in the same laboratory due to reference ranges may vary between tests.

 

Gastrointestinal infections caused by bacteria:

Pantoprazole, like all proton pump inhibitors, might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with PANTOXEROL may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter and Clostridium difficile (see section 5.1).

Effect of pantoprazole on the absorption of other medicinal products:

Because of profound and long lasting inhibition of gastric acid secretion, PANTOXEROL may reduce the absorption of drugs with a gastric pH dependent bioavailability, e.g some antifungals such as ketoconazole, itraconazole, posaconazole, and other medicine as erlotinib).

 

HIV medications (atazanavir):

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir is not recommended (see section 4.4).

 

Coumarin anticoagulants (phenprocoumon or warfarin):

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in International Normalised Ratio (INR) have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants (e.g. phenprocoumon or warfarin), monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

 

Methotrexate:

Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered.

 

Other interactions studies:

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4. Interaction studies with drugs also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.

 

Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolized 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.

 

Interaction studies have also been performed administering pantoprazole concomitantly with antibiotics such as clarithromycin, metronidazole, amoxicillin. No clinically relevant interactions were found.

 

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.

 

Additional information regarding special populations:

There is no interaction studies have been performed regarding special populations.

General advice

Pregnancy Category: B

 

 

Women of childbearing potential/Birth control (Contraception)

In specific tests with an oral contraceptive containing levonorgestrel and ethinyl oestradiol, no clinically relevant interactions were observed (see section 4.5).

 

Pregnancy

There are limited data from the use of pantoprazole in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. PANTOXEROL should not be used during pregnancy unless clearly necessary.

In animal reproduction studies, mild fetotoxicity symptoms were observed at doses above 5 mg/kg. Caution must be exercised when used in pregnant women.

 

Lactation

Animal studies have shown excretion of pantoprazole in breast milk. Excretion of pantoprazole in human milk has been reported. Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue PANTOXEROL therapy should be made taking into account the benefit of breast-feeding to the child and the benefit of PANTOXEROL therapy for the women.

In nursing mothers pantoprazole should only be used if the benefit to mother outweighs the potential risk to the baby.

 

Fertility

No evidence has been found for deterioration of fertility or teratogen effects in humans.

In animal reproduction studies there is no finding that is related to loss of fertility or teratogenicity (see section 5.3).

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). In case of occurrence of adverse events, patients should not drive or operate machines.

a. Summary of the safety profile

Approximately 5% of patients can be expected to experience adverse drug reactions. The most commonly reported adverse reactions are diarrhea and headache, both occurring in approximately 1% of patients.

 

b. Tabulated summary of adverse reactions

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

 

The following adverse reactions were reported:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

 

Blood and lymphatic system disorders
Rare:	Agranulocytosis
Very rare:	Thrombocytopenia, leukopenia, pancytopenia
Immune system disorders
Rare:	Hypersensitivity (including anaphylactic reactions and anaphylactic shock)
Metabolism and nutrition disorders
Rare:	Hyperlipidemia and lipid increases (triglycerides, cholesterol), weight changes
Not known:	Hypernatremia, hypomagnesemia (see section 4.4), hypocalcaemia (1), hypokalaemia
Psychiatric disorders
Uncommon:	Sleep disorders
Rare:	Depression (and all aggravations)
Very rare:	Disorientation (and all aggravations)
Not known:	Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)
Nervous system disorders
Uncommon:	Headache, dizziness
Rare:	Taste disorders
Not known:	Parasthesia
Eye disorders
Rare:	Disturbances in vision (blurred vision)
Gastrointestinal disorders
Common:	Fundic gland polyps (benign)
Uncommon:	Nausea/vomiting, abdominal distension and bloating, constipation, dry mouth, abdominal pain and discomfort, diarrhea
Hepatobiliary disorders
Uncommon:	Liver enzymes increased (transaminases, γ-GT)
Rare:	Bilirubin increased
Not known:	Hepatocellular injury, jaundice, hepatocellular failure
Skin and subcutaneous tissue disorders
Uncommon:	Itching, allergic reactions like rash/exanthema, eruption, pruritus
Rare:	Urticaria, angioedema
Not known:	Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme, photosensitivity; Subacute cutaneous lupus erythematosus (see section 4.4)
Musculoskeletal and connective tissue
Uncommon:	Hip, wrist and spine fracture (see section 4.4.)
Rare:	Arthralgia, myalgia
Not known:	Muscle spasm(2)
Renal and urinary disorders
Not known:	Interstitial nephritis (with possible progression to renal failure)
Reproductive system and breast disorders
Rare:	Gynaecomastia
General disorders and administration site conditions
Common:	Injection site thrombo-phlebitis
Uncommon:	Asthenia, fatigue and malaise
Rare:	Body temperature increased, edema peripheral

⁽¹⁾Hypomagnesemia associated hypocalcemia

⁽²⁾Muscle spasm due to electrolyte disturbance

 

c. Description of selected adverse reactions

Gastroesophageal Reflux Disease ﴾GERD﴿

Safety in nine randomized comparative U.S. 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 proton pump inhibitor, and 82 patients on placebo. The most frequently occurring adverse reactions are listed in Table 1.

 

The number of patients treated in comparative studies with I.V. pantoprazole is limited; however, the adverse reactions seen were similar to those seen in the oral studies. Thrombophlebitis was the only new adverse reaction identified with I.V. pantoprazole.

 

Table 1: Adverse Reactions Reported in Clinical Trials of Adult Patients with GERD at a Frequency of > 2%
	Pantoprazole Sodium ﴾n=1473﴿ %	Comparators ﴾n=345﴿ %	Placebo ﴾n=82﴿ %
Headache	12.2	12.8	8.5
Diarrhea	8.8	9.6	4.9
Nausea	7	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	2.9	1.2
Arthralgia	2.8	1.4	1.2

 

Additional adverse reactions that were reported for pantoprazole sodium in U.S. clinical trials with a frequency of ≤ 2% are listed below by body system:

 

Body as a Whole: allergic reaction, fever, photosensitivity reaction, facial edema, thrombophlebitis ﴾I.V. only﴿

Gastrointestinal: constipation, dry mouth, hepatitis

Hematologic: leukopenia ﴾reported in ex‐U.S. clinical trials only﴿, thrombocytopenia

Metabolic/Nutritional: elevated CPK ﴾creatine phosphokinase﴿, generalized edema, elevated triglycerides, liver function tests abnormal

Musculoskeletal: myalgia

Nervous: depression, vertigo

Skin and Appendages: urticaria, rash, pruritus

Special Senses: blurred vision

 

Zollinger‐Ellison Syndrome

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

 

d. Pediatric population

Safety and effectiveness of pantoprazole sodium for injection in pediatric patients have not been established.

 

e. Other special populations

 

Geriatric Patients:

No age‐related differences in the safety profile of intravenous pantoprazole were seen in international trials involving 86 elderly ﴾≥ 65 years old﴿ and 200 younger ﴾< 65 years old﴿ patients with erosive esophagitis associated with GERD. Erosive esophagitis healing rates in the 107 elderly patients ﴾≥ 65 years old﴿ treated with oral pantoprazole in U.S. clinical trials were similar to those found in patients under the age of 65. The incidence rates of adverse events and laboratory abnormalities in patients aged 65 years and older were similar to those associated with patients younger than 65 years of age.

 

Gender:

No gender‐related differences in the safety profile of intravenous pantoprazole were seen in international trials involving 166 men and 120 women with erosive esophagitis associated with GERD. Erosive esophagitis healing rates in the 221 women treated with oral pantoprazole in U.S. clinical trials were similar to those found in men. The incidence rates of adverse reactions were also similar for men and women.

 

Reporting of suspected adverse reactions:

The National Pharmacovigilance and Drug Safety Centre (NPC)

• Fax: +966-11-205-7662

• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

• Toll free phone: 8002490000

• E-mail: npc.drug@sfda.gov.sa

• Website: www.sfda.gov.sa/npc

There are no known symptoms of overdose in man.

It was administrated with up to 240 mg IV dose over 2 minutes and well tolerated.

As pantoprazole is extensively protein bound, it is not readily dialyzable. In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

Pharmacotherapeutic Group: Proton pump inhibitors

ATC code: A02BC02

 

Mechanism of action:

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H₂ receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.

 

Pharmacodynamic effects:

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) have not been observed in humans.

 

Decreased gastric acid due to proton pump inhibitors or any other reason, leads to an increase in the counts of bacteria normally present in the gastrointestinal tract. Therapy with proton pump inhibitors may slightly increase gastrointestinal infection risk caused by Salmonella and Camphylobacter and Clostridium difficile possibly also in hospitalized patients.

 

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.

 

Clinical efficacy and safety:

Gastroesophageal Reflux Disease ﴾GERD﴿ Associated with a History of Erosive Esophagitis

A multicenter, double‐blind, two‐period placebo‐controlled study was conducted to assess the ability of pantoprazole sodium for injection to maintain gastric acid suppression in patients switched from the oral dosage form of pantoprazole to the intravenous dosage form. Gastroesophageal reflux disease ﴾GERD﴿ patients ﴾n=65, 26 to 64 years; 35 female; 9 Black, 11 Hispanic, 44 White, 1 other﴿ with a history of erosive esophagitis were randomized to receive either 20 or 40 mg of oral pantoprazole once per day for 10 days ﴾period 1﴿, and then were switched in period 2 to either daily intravenous pantoprazole or placebo for 7 days, matching their respective dose level from period 1. Patients were administered all test medication with a light meal. Maximum acid output ﴾MAO﴿ and basal acid output ﴾BAO﴿ were determined 24 hours following the last day of oral medication ﴾day 10﴿, the first day ﴾day 1﴿ of intravenous administration and the last day of intravenous administration ﴾day 7﴿. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6 mcg/kg of pentagastrin.

 

This study demonstrated that, after 10 days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of pantoprazole sodium 40 mg are similar in their ability to suppress MAO and BAO in patients with GERD and a history of erosive esophagitis ﴾see Table 2﴿. Also, patients on oral pantoprazole sodium who were switched to intravenous placebo experienced a significant increase in acid output within 48 hours of their last oral dose ﴾see Table 2﴿. However, at 48 hours after their last oral dose, patients treated with pantoprazole sodium for injection had a significantly lower mean basal acid output ﴾see Table 2﴿ than those treated with placebo.

 

Table 2: ANTISECRETORY EFFECTS (mEq/h) OF 40 mg PANTOPRAZOLE SODIUM for INJECTION AND 40 mg ORAL PANTOPRAZOLE SODIUM IN GERD PATIENTS WITH A HISTORY OF EROSIVE ESOPHAGITIS
* p<0.0001 Significantly different from pantoprazole sodium for injection.
Parameter	Pantoprazole Sodium Delayed‐Release Tablets	Pantoprazole Sodium for Injection	Placebo I.V.
	DAY 10	DAY 7	DAY 7
Mean maximum acid output	6.49 n=30	6.62 n=23	29.19* n=7
Mean basal acid output	0.8 n=30	0.53 n=23	4.14* n=7

 

 

To evaluate the effectiveness of pantoprazole sodium for injection as an initial treatment to suppress gastric acid secretion, two studies were conducted.

 

Study 1 was a multicenter, double‐blind, placebo‐controlled, study of the pharmacodynamic effects of pantoprazole sodium for injection and oral pantoprazole sodium. Patients with GERD and a history of erosive esophagitis ﴾n=78, 20 to 67 years; 39 females; 7 Black, 19 Hispanic, 52 White﴿ were randomized to receive either 40 mg intravenous pantoprazole, 40 mg oral pantoprazole, or placebo once daily for 7 days. Following an overnight fast, test medication was administered and patients were given a light meal within 15 minutes. MAO and BAO were determined 24 hours following the last day of study medication. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6 mcg/kg of pentagastrin to stimulate acid secretion. This study demonstrated that, after treatment for 7 days, patients treated with pantoprazole sodium for injection had a significantly lower MAO and BAO than those treated with placebo ﴾p<0.001﴿, and results were comparable to those of patients treated with oral pantoprazole sodium ﴾see Table 3﴿.

 

Table 3: ANTISECRETORY EFFECTS (mEq/h) OF INITIAL TREATMENT WITH 40 mg PANTOPRAZOLE SODIUM for INJECTION AND 40 mg ORAL PANTOPRAZOLE SODIUM IN GERD PATIENTS WITH A HISTORY OF EROSIVE ESOPHAGITIS
* p<0.0001 Significantly different from pantoprazole sodium for injection.
Parameter	Pantoprazole Sodium for Injection DAY 7	Pantoprazole Sodium Delayed‐Release Tablets DAY 7	Placebo DAY 7
Maximum acid output ﴾mean ± SD﴿	8.4 ± 5.9 n=25	6.3 ± 6.6 n=22	20.9 ± 14.5* n=24
Basal acid output ﴾mean ± SD﴿	0.4 ± 0.5 n=25	0.6 ± 0.8 n=22	2.8 ± 3* n=23

 

Study 2 was a single‐center, double‐blind, parallel‐group study to compare the clinical effects of pantoprazole sodium for injection and oral pantoprazole sodium. Patients ﴾n=45, median age 56 years, 21 males and 24 females﴿ with acute endoscopically proven reflux esophagitis ﴾Savary/Miller Stage II or III﴿ with at least 1 of 3 symptoms typical for reflux esophagitis ﴾acid eructation, heartburn, or pain on swallowing﴿ were randomized to receive either 40 mg intravenous pantoprazole or 40 mg oral pantoprazole daily for 5 days. After the initial 5 days, all patients were treated with 40 mg oral pantoprazole daily to complete a total of 8 weeks of treatment. Symptom relief was assessed by calculating the daily mean of the sums of the average scores for these 3 symptoms and the daily mean of the average score for each of the symptoms separately. There was no significant difference in symptom relief between pantoprazole sodium for injection and oral pantoprazole sodium therapy within the first 5 days. A repeat endoscopy after 8 weeks of treatment revealed that 20 out of 23 ﴾87%﴿ of the pantoprazole sodium for injection plus oral pantoprazole sodium patients and 19 out of 22 ﴾86%﴿ of the oral pantoprazole sodium patients had endoscopically proven healing of their esophageal lesions.

 

Data comparing pantoprazole sodium for injection to other proton pump inhibitors ﴾oral or I.V.﴿ or H₂‐receptor antagonists ﴾oral or I.V.﴿ are limited, and therefore, are inadequate to support any conclusions regarding comparative efficacy.

 

Pathological Hypersecretion Associated with Zollinger‐Ellison Syndrome

 

Two studies measured the pharmacodynamic effects of 6 day treatment with pantoprazole sodium for injection in patients with Zollinger‐Ellison Syndrome ﴾with and without multiple endocrine neoplasia type I﴿. In one of these studies, an initial treatment with pantoprazole sodium for injection in 21 patients ﴾29 to 75 years; 8 female; 4 Black, 1 Hispanic, 16 White﴿ reduced acid output to the target level ﴾≤ 10 mEq/h﴿ and significantly reduced H⁺ concentration and the volume of gastric secretions; target levels were achieved within 45 minutes of drug administration.

 

In the other study of 14 patients ﴾38 to 67 years; 5 female; 2 Black, 12 White﴿ with Zollinger‐Ellison Syndrome, treatment was switched from an oral proton pump inhibitor to pantoprazole sodium for injection. Pantoprazole sodium for injection maintained or improved control of gastric acid secretion.

 

In both studies, pantoprazole sodium for injection 160 or 240 mg per day in divided doses maintained basal acid secretion below target levels in all patients. Target levels were 10 mEq/h in patients without prior gastric surgery, and 5 mEq/h in all patients with prior gastric acid‐reducing surgery. Once gastric acid secretion was controlled, there was no evidence of tolerance during this 7 day study. Basal acid secretion was maintained below target levels for at least 24 hours in all patients and through the end of treatment in these studies ﴾3 to 7 days﴿ in all but 1 patient who required a dose adjustment guided by acid output measurements until acid control was achieved. In both studies, doses were adjusted to the individual patient need, but gastric acid secretion was controlled in greater than 80% of patients by a starting regimen of 80 mg q12h. 

 

General characteristics

Pharmacokinetics does not vary after single or repeated administration. Concomitant food intake does not affect AUC, maximum concentration or bioavailability.

 

Absorption:

It is given directly into the bloodstream therefore absorption information not applicable.

 

Distribution:

Volume of distribution is approximately 0.15 L/kg, distributing mainly in extracellular fluid. The serum protein binding is about 98%, primarily to albumin. Total serum clearance is about 0.1 L/hour/kg. Terminal half-life is approximately 1 hour.

 

Biotransformation:

Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulphate conjugation. Other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity.

 

Elimination:

Renal elimination represents the major route of excretion (about 80%) for the metabolites of pantoprazole; the rest is excreted with the feces. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

 

After a single oral or intravenous dose of ¹⁴C-labeled pantoprazole to healthy, normal metabolizer volunteers, approximately 71% of the dose was excreted in the urine, with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole. Clearance is about 0.1 l/h/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).

 

Linearity/non-linearity:

Pharmacokinetics of pantoprazole is linear in 10-80 mg dose range after both oral and intravenous administration.

 

a. Characteristics in patients:

 

Polymorphic metabolism:

Approximately 3% of the European population lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of pantoprazole is probably mainly catalyzed 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 metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). 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 in patients with impaired renal function (incl. dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately delayed half-life (2-3 h), excretion is still rapid and thus accumulation does not occur.

 

Hepatic Impairment:

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

 

Pediatric Population:

Following administration of single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2-16 years there was no significant association between pantoprazole clearance and age or weight. AUC and volume of distribution were in accordance with data from adults.

 

Older people:

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

 

b. Pharmacokinetic/pharmacodynamic relationship:

Pantoprazole’s favorable side effect profile and low incidence of drug-drug interactions make it ideal for using in all patient groups, including special populations.

 

Several reports confirm that pantoprazole is a well-tolerated treatment even for long-term therapy with optimal tolerability. It is perfectly suited for use in patients taking concomitant therapies.

 

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

 

In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the fore stomach 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 two-year rodent studies an increased number of liver tumors was observed in rats and in female mice and was interpreted as being due to pantoprazole'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-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 fetotoxicity 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 fetus is increased shortly before birth.

 

None.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.    

Shelf life is 24 months. After reconstitution, or reconstitution and dilution, chemical and physical in use stability has been demonstrated for 12 hours at 30°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Stored at room temperature below 30°C and in its package.

Keep container in the outer carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

 

Colorless type I glass vial, closed with gray bromobutyl rubber stopper and sealed by aluminum cap. Pack of 1 vial.

Any unused material should be disposed according to local disposal regulations.

 

A ready-to-use solution is prepared by injecting 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into the vial containing the powder. This solution may be administered directly or may be administered after mixing it with 100 ml sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 55 mg/ml (5%) or 110 mg/ml (10%) solution for injection. Glass containers should be used for dilution.

 

After reconstitution, or reconstitution and dilution, chemical and physical in use stability has been demonstrated for 12 hours at 30°C.

 

From a microbiological point of view, the product should be used immediately.

 

PANTOXEROL should not be mixed with solvents other than those stated.

The medicinal product should be administered intravenously over 2-15 minutes.

 

The contents of the vial are for single use only. Any product that has remained in the container or the visual appearance of which has changed (e.g. if cloudiness or precipitation is observed) should be disposed of in accordance with local requirements.