Download Protonix (pantoprazole sodium) Tablets: Mechanism, Pharmacology, Interactions and more Study notes Pharmacokinetics in PDF only on Docsity!
(pantoprazole sodium) Delayed-Release Tablets
DESCRIPTION The active ingredient in PROTONIX^ (pantoprazole sodium) Delayed-Release Tablets is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1 H -benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C 16 H 14 F 2 N 3 NaO 4 S x 1.5 H 2 O, with a molecular weight of 432.4. The structural formula is:
N
N
S N O
OCH 3 H 3 CO
OCF 2 H
Na+
• 1.5 H 2 O
_
Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane.
The stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5.0 and approximately 220 hours at pH 7.8.
PROTONIX is supplied as a delayed-release tablet for oral administration. Each delayed-release tablet contains 45.1 mg of pantoprazole sodium sesquihydrate (equivalent to 40 mg pantoprazole) with the following inactive ingredients: anhydrous sodium carbonate NF, mannitol USP, crospovidone NF, povidone USP, calcium stearate NF, hydroxypropyl methylcellulose USP, titanium dioxide USP, yellow iron oxide NF, propylene glycol USP, methacrylic acid copolymer NF, polysorbate 80 NF, sodium lauryl sulfate NF, and triethyl citrate NF.
(pantoprazole sodium) Delayed-Release Tablets
CLINICAL PHARMACOLOGY Pharmacokinetics PROTONIX is prepared as an enteric-coated tablet so that absorption of pantoprazole 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 does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers (see Metabolism section) with normal liver function receiving an oral dose of the enteric- coated 40 mg pantoprazole tablet, the peak concentration (Cmax) is 2.4 :g/mL, the time to reach the peak concentration (tmax) is 2.4 h and the total area under the plasma concentration versus time curve (AUC) is 4.8 μg·hr/mL. When pantoprazole is given with food, its tmax is highly variable and may increase significantly. Following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6-14.0 L/h and its apparent volume of distribution is 11.0-23.6L.
Absorption The absorption of pantoprazole is rapid, with a Cmax of 2.5 :g/mL that occurs approximately 2.5 hours after single or multiple oral 40-mg doses. Pantoprazole is well absorbed; it undergoes little first-pass metabolism resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of pantoprazole with food may delay its absorption up to 2 hours or longer; however, the Cmax and the extent of pantoprazole absorption (AUC) are not altered. Thus, pantoprazole may be taken without regard to timing of meals.
Distribution The apparent volume of distribution of pantoprazole is approximately 11.0-23.6L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.
Metabolism 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 sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a
(pantoprazole sodium) Delayed-Release Tablets
needed in patients with mild or moderate hepatic impairment. The pharmacokinetics of pantoprazole have not yet been well characterized in patients with severe hepatic impairment. Therefore, the potential for modest drug accumulation (≤ 21%) when dosed once daily needs to be weighed against the potential for reduced acid control when dosed every other day in these patients.
Drug-Drug Interactions Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6 and 2C9. In in vivo drug- drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4 substrate] and phenytoin [also a CYP3A inducer]), nifedipine (a CYP3A4 substrate), metoprolol (a CYP2D6 substrate), diclofenac (a CYP2C9 substrate) and theophylline (a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered. It is, therefore, expected that other drugs metabolized by CYPs 2C19, 3A4, 2D6, 2C9 and 1A2 would not significantly affect the pharmacokinetics of pantoprazole. In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of other drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine and oral contraceptives) metabolized by CYPs 2C19, 3A4, 2C9, 2D6 and 1A2. Therefore, it is expected that pantoprazole would not significantly affect the pharmacokinetics of other drugs metabolized by these isozymes. Dosage adjustment of such drugs is not necessary when they are co-administered with pantoprazole. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, and caffeine had no clinically relevant interactions with pantoprazole.
Pharmacodynamics Mechanism of Action Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by forming a covalent bond to two sites of the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect is dose-related and 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 antisecretory effect that persists longer than 24 hours.
Antisecretory Activity Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent decrease in gastric acid output occurs after a single dose of oral (20-80 mg) or a single dose of intravenous (20-120 mg) pantoprazole in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once a day dosing for 7 days the mean inhibition was increased to 85%. Pantoprazole suppressed acid secretion in excess of 95% in half of the
(pantoprazole sodium) Delayed-Release Tablets
subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole; there was no evidence of rebound hypersecretion.
In a series of dose-response studies pantoprazole, at oral doses ranging from 20 to 120 mg, caused dose-related increases in median basal gastric pH and in the percent of time gastric pH was > 3 and > 4. Treatment with 40 mg of pantoprazole produced optimal increases in gastric pH which were significantly greater than the 20-mg dose. Doses higher than 40 mg (60, 80, 120 mg) did not result in further significant increases in median gastric pH. The effects of pantoprazole on median pH from one double-blind crossover study are shown below.
Effect of Single Doses of Oral Pantoprazole on Intragastric pH -----------------Median pH---------------- Time Placebo 20 mg 40 mg 80 mg 8 a.m. - 8 a.m. (24 hours)
1.3 2.9* 3.8# 3.9# 8 a.m. - 10 p.m. (Daytime)
1.6 3.2* 4.4# 4.8# 10 p.m. - 8 a.m. (Nighttime)
1.2 2.1* 3.0* 2.6*
- Significantly different from placebo
Significantly different from 20 mg
A double-blind crossover study compared pantoprazole 40 mg with omeprazole 20 mg once daily for 7 days. For both one day and one week treatment periods, pantoprazole administered in the morning produced significantly greater increases in median pH during 24 hours than did omeprazole.
(pantoprazole sodium) Delayed-Release Tablets
Other Effects No clinically relevant effects of pantoprazole on cardiovascular, respiratory, ophthalmic, or central nervous system function have been detected. In a clinical pharmacology study, pantoprazole 40 mg given once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T3), thyroxine (T4), thyroid- stimulating hormone, thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle- stimulating hormone, luteinizing hormone, prolactin and growth hormone.
Clinical Studies PROTONIX Delayed-Release Tablets were used in all clinical trials.
Erosive Esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD) A US multicenter double-blind, placebo-controlled study of PROTONIX 10 mg, 20 mg or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE of grade 3 and 10% had grade 4. The percentages of patients healed (per protocol, n=541) in this study were as follows:
Erosive Esophagitis Healing Rates (per protocol) ------------- PROTONIX ------------ Placebo
Week
10 mg QD (n = 153)
20 mg QD (n = 158)
40 mg QD (n = 162) (n =68 ) 4 45.6%+^ 58.4%+#^ 75.0%+^ 14.3% 8 66.0%+^ 83.5 %+#^ 92.6%+^ 39.7% +(p < 0.001) PROTONIX versus placebo. *(p <0.05) versus 10 mg, or 20 mg PROTONIX
(p<0.05) versus 10 mg PROTONIX
In this study, all PROTONIX treatment groups had significantly greater healing rates than the placebo group. This was true regardless of H. pylori status for the 20-mg and 40-mg PROTONIX treatment groups. The 40-mg dose of PROTONIX resulted in healing rates significantly greater than those found with either the 20- or 10-mg dose.
(pantoprazole sodium) Delayed-Release Tablets
A significantly greater proportion of patients taking PROTONIX 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation starting from the first day of treatment compared with placebo. Patients taking PROTONIX consumed significantly fewer antacid tablets per day than those taking placebo.
PROTONIX 20 mg and 40 mg once daily was also compared with nizatidine 150 mg twice daily in a US multicenter, double-blind study of 243 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above. The percentages of patients healed (per protocol, n=212) were as follows:
Erosive Esophagitis Healing Rates (per protocol) ------------- PROTONIX ------------- Nizatidine
Week
20 mg QD (n = 72)
40 mg QD (n = 70)
150 mg BID (n = 70) 4 61.4%+^ 64.0%+^ 22.2% 8 79.2%+^ 82.9%+^ 41.4% +(p < 0.001) PROTONIX versus nizatidine.
Once daily treatment with PROTONIX 20 or 40 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori status.
A significantly greater proportion of the patients in the PROTONIX treatment groups experienced complete relief of nighttime heartburn and regurgitation starting on the first day and of daytime heartburn on the second day compared with those taking nizatidine 150 mg twice daily. Patients taking PROTONIX consumed significantly fewer antacid tablets per day than those taking nizatidine.
INDICATIONS AND USAGE
Short-Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux Disease (GERD)
(pantoprazole sodium) Delayed-Release Tablets
Information for Patients Patients should be cautioned that PROTONIX Delayed-Release Tablets should not be split, crushed or chewed. The tablets should be swallowed whole, with or without food in the stomach. Concomitant administration of antacids does not affect the absorption of pantoprazole.
Drug Interactions Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs metabolized by the cytochrome P450 system, no dosage adjustment is needed with concomitant use of the following drugs: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, or warfarin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when co-administered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids.
Because of profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g., ketoconazole, ampicillin esters, and iron salts).
Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface basis, of a 50-kg person dosed at 40 mg/day. In the gastric fundus, treatment at 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment at 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adenocarcinoma of the duodenum at 50 mg/kg/day, and benign polyps and adenocarcinomas of the gastric fundus at 200 mg/kg/day.. In the liver, treatment at 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats.
(pantoprazole sodium) Delayed-Release Tablets
Sporadic occurrences of hepatocellular adenomas and a hepatocellular carcinoma were observed in Sprague-Dawley rats exposed to pantoprazole in 6-month and 12-month toxicity studies. In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area. In the gastric fundus, treatment at 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole.
In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/kg/day produced increased incidences of combined hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/kg/day also produced gastric fundic ECL cell hyperplasia.
Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects, and in the in vitro Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, , the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay.
Pantoprazole at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.
Pregnancy Teratogenic Effects Pregnancy Category B Teratology studies have been performed in rats at oral doses up to 450 mg/kg/day (88 times the recommended human dose based on body surface area) and rabbits at oral doses up to 40 mg/kg/day (16 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to pantoprazole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
(pantoprazole sodium) Delayed-Release Tablets
Most Frequent Adverse Events Reported as Drug Related in Short-term Domestic Trials ---------------------------------- % Incidence ----------------------------------
Study 300-US Study 301-US
Study Event
PROTONIX (n = 521)
Placebo (n = 82)
PROTONIX (n = 161)
Nizatidine (n = 82) Headache 6 6 9 13 Diarrhea 4 1 6 6 Flatulence 2 2 4 0 Abdominal pain 1 2 4 4 Rash <1 0 2 0 Eructation 1 1 0 0 Insomnia <1 2 1 1 Hyperglycemia 1 0 <1 0 Note: Only adverse events with an incidence greater than or equal to the comparators are shown.
In addition, in these short-term domestic trials, the following treatment-emergent events, regardless of causality, occurred at a rate of $ 1% in PROTONIX-treated patients: asthenia, back pain, chest pain, neck pain, flu syndrome, infection, pain, migraine, constipation, dyspepsia, gastroenteritis, gastrointestinal disorder, nausea, rectal disorder, vomiting, hyperlipemia, liver function tests abnormal, SGPT increased, arthralgia, anxiety, dizziness, hypertonia, bronchitis, cough increased, dyspnea, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, urinary frequency, and urinary tract infection.
In international short-term double-blind or open-label, clinical trials involving 20- to 80 mg per day, the following adverse events were reported to occur in 1% or more of 2805 GERD patients receiving pantoprazole for up to 8 weeks.
(pantoprazole sodium) Delayed-Release Tablets
Adverse Events in GERD Patients in Short-term International Trials ---------------------% Incidence--------------------- Pantoprazole Ranitidine Omeprazole Famotidine Total 300 mg 20 mg 40 mg Study Event (N=2805) (N=594) (N=474) (N=239) Headache 2 3 2 1 Diarrhea 2 2 2 < Abdominal Pain 1 1 <1 <
Additional adverse experiences occurring in <1% of GERD patients based on pooled results from either short-term domestic or international trials are shown below within each body system. In most instances the relationship to pantoprazole was unclear.
BODY AS A WHOLE: abscess, allergic reaction, chills, cyst, face edema, fever, generalized edema, heat stroke, hernia, laboratory test abnormal, malaise, moniliasis, neoplasm, non-specified drug reaction.
CARDIOVASCULAR SYSTEM: angina pectoris, arrhythmia, cardiovascular disorder, chest pain substernal, congestive heart failure, electrocardiogram abnormal, hemorrhage, hypertension, hypotension, myocardial ischemia, palpitation, retinal vascular disorder, syncope, tachycardia, thrombophlebitis, thrombosis, vasodilatation.
DIGESTIVE SYSTEM: anorexia, aphthous stomatitis, cardiospasm, colitis, dry mouth, duodenitis, dysphagia, enteritis, esophageal hemorrhage, esophagitis, gastrointestinal carcinoma, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, glossitis, halitosis, hematemesis, increased appetite, melena, mouth ulceration, oral moniliasis, periodontal abscess, periodontitis, rectal hemorrhage, stomach ulcer, stomatitis, stools abnormal, tongue discoloration, ulcerative colitis.
ENDOCRINE SYSTEM: diabetes mellitus, glycosuria, goiter.
HEPATO-BILIARY SYSTEM: biliary pain, bilirubinemia, cholecystitis, cholelithiasis, cholestatic jaundice, hepatitis, alkaline phosphatase increased, gamma glutamyl transpeptidase increased, SGOT increased.
(pantoprazole sodium) Delayed-Release Tablets
In addition, also observed have been jaundice, confusion, hypokinesia, speech disorder, increased salivation, vertigo, nausea, and tinnitus.
Laboratory Values In two US controlled trials, 0.4 % of the patients on 40 mg pantoprazole experienced SGPT elevations of greater than three times the upper limit of normal at the final treatment visit. Except in those patients where there was a clear alternative explanation for a laboratory value change, such as intercurrent illness, the elevations tended to be mild and sporadic. The following changes in laboratory parameters were reported as adverse events: creatinine increased, hypercholesterolemia, and hyperuricemia.
OVERDOSAGE Some reports of overdosage with pantoprazole have been received. A spontaneous report of a suicide involving an overdosage of pantoprazole (560 mg) has been received; however, the death was more reasonably attributed to the unknown doses of chloroquine and zopiclone which were also taken since two other reported cases of pantoprazole overdosage involved similar amounts of pantoprazole (400 and 600 mg) with no adverse effects observed. One patient in a flexible dosing study of refractory peptic ulcer disease received a dose of 320 mg per day for 3 months; treatment was well tolerated. Doses of up to 240 mg per day, given intravenously for seven days, have been administered to healthy subjects and have been well tolerated.
Pantoprazole is not removed by hemodialysis.
Single oral doses of pantoprazole at 709 mg/kg, 798 mg/kg and 887 mg/kg were lethal to mice, rats and dogs, respectively. The symptoms of acute toxicity were hypoactivity, ataxia, hunched sitting, limb-splay, lateral position, segregation, absence of ear reflex, and tremor.
DOSAGE AND ADMINISTRATION Treatment of Erosive Esophagitis The recommended adult oral dose is 40 mg given once daily for up to 8 weeks. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of PROTONIX may be considered. (See INDICATIONS AND USAGE)
(pantoprazole sodium) Delayed-Release Tablets
No dosage adjustment is necessary in patients with mild, moderate or severe renal insufficiency or in elderly patients. No dosage adjustment is necessary in patients undergoing hemodialysis. No dosage adjustment is needed in patients with mild or moderate hepatic impairment. The pharmacokinetics of pantoprazole have not yet been well characterized in patients with severe hepatic impairment. Therefore, the potential for modest drug accumulation (≤ 21%) when dosed once daily needs to be weighed against the potential for reduced acid control when dosed every other day in these patients.
PROTONIX Delayed-Release Tablets should be swallowed whole, with or without food in the stomach. Concomitant administration of antacids does not affect the absorption of PROTONIX.
Patients should be cautioned that PROTONIX Delayed-Release Tablets should not be split, chewed or crushed.
HOW SUPPLIED
PROTONIX is supplied as 40 mg yellow oval biconvex delayed-release tablets imprinted with PROTONIX (brown ink) on one side.
They are available as follows: NDC 0008-0841-81 bottles of 90
Storage Store PROTONIX Delayed-Release Tablets at 20°–25°C (68°–77°F); excursion permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
Rx only
US Patent No. 4,758,
