Risek Plus capsules are indicated in adults for the:

§   short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

§   short-term treatment (4 to 8 weeks) of active benign gastric ulcer.

§   treatment of heartburn and other symptoms associated with GERD for up to 4 weeks.

§   short-term treatment (4 to 8 weeks) of EE due to acid-mediated GERD which has been diagnosed by endoscopy in adults.

The efficacy of Omeprazole/ Sodium bicarbonate used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8-week courses of Risek Plus may be considered.

§   maintenance of healing of EE due to acid-mediated GERD. Controlled studies do not extend beyond 12 months.

Important Administration Instructions

The sodium content of Risek Plus capsules should be taken into consideration when prescribing this product (See section 4.4).

Due to the sodium bicarbonate content of Risek Plus:

§ Do not substitute two 20mg Risek Plus capsules with one Risek Plus 40mg capsule.

Dosage Regimen

All recommended dosages are based upon omeprazole content.

Recommended Dosage Regimen of Risek Plus capsules in Adults by Indication:

¹ Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy.

² The efficacy of Omeprazole/ Sodium bicarbonate used for longer than 8 weeks in patients with EE has not been established.

If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8-week courses of Risek Plus capsules may be considered.

Method of administration:

§ Swallow capsules intact with water.

Do not open the capsule and do not administer with liquids other than water.

§ Take on an empty stomach at least one hour before a meal (See section 5.2).

Presence of Gastric Malignancy

In adults, symptomatic response to therapy with Omeprazole/Sodium bicarbonate does not preclude the presence of gastric malignancy. 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 proton pump inhibitor (PPI). In older patients, also consider an endoscopy.

Acute Tubulointerstitial Nephritis

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

Discontinue Risek Plus and evaluate patients with suspected acute TIN (See section 4.3) and appropriate treatment should be promptly initiated.

Sodium Bicarbonate Content

Risek Plus capsule contains 1100mg of sodium bicarbonate.

Chronic administration of bicarbonate with calcium or milk can cause milk-alkali syndrome. Chronic use of sodium bicarbonate may lead to systemic alkalosis, and increased sodium intake can produce edema and weight gain.

The sodium content of Risek Plus products should be taken into consideration when administering to patients on a sodium-restricted diet or those at risk for developing congestive heart failure.

Avoid this medicine in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance.

Clostridium difficile-Associated Diarrhoea

Published observational studies suggest that PPI therapy like Omeprazole/Sodium bicarbonate may be associated with an increased risk of Clostridium difficile-associated diarrhoea, especially in hospitalized patients. This diagnosis should be considered for diarrhoea that does not improve. (See section 4.8)

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Bone Fracture

Several published observational studies suggest that proton pump inhibitor (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 for osteoporosis-related fractures should be managed according to the established treatment guidelines. (See sections 4.2 and 4.8)

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see section 4.8]. Discontinue this medicine at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. 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 subacute 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.

Systemic lupus erythematosus (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 in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia 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 Omeprazole/Sodium bicarbonate, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Interaction with Clopidogrel

Avoid concomitant use of Omeprazole/Sodium bicarbonate with clopidogrel.

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Concomitant use of clopidogrel with 80mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using Omeprazole/Sodium bicarbonate, consider alternative antiplatelet therapy. (See sections 4.5 and 5.2)

Cyanocobalamin (Vitamin B₁₂) Deficiency

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 in patients treated with Omeprazole/Sodium bicarbonate.

Hypomagnesemia and Mineral Metabolism

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemiamay lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia 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 hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. (See sections 4.8)

Consider monitoring magnesium and calcium levels prior to initiation of omeprazole and Sodium Bicarbonate and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

Interaction with St. John’s Wort or Rifampin

Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s wort or rifampin) can substantially decrease omeprazole concentrations (See sections 4.5). Avoid concomitant use of Omeprazole/Sodium bicarbonate with St. John’s wort or rifampin.

Interactions with Investigations for Neuroendocrine Tumors

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 tumors. Providers should temporarily stop Omeprazole/Sodium bicarbonate treatment for 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. (See sections 4.5)

Interaction with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) 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. (See sections 4.5).

Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPIs 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.

Special Population

Paediatric Use

Safety and effectiveness of Omeprazole/Sodium bicarbonate have not been established in paediatric patients.

Geriatric Use

Clinical trials have shown there were no differences in safety and effectiveness between the elderly and younger subjects.  Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Pharmacokinetic studies with buffered omeprazole have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects). The plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking Omeprazole/Sodium bicarbonate. However, no dosage adjustment is necessary in the elderly. (See section 5.2)

Hepatic Impairment

In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole substantially increased compared to healthy subjects. Avoid use of Omeprazole/Sodium bicarbonate in patients with hepatic impairment for maintenance of healing of erosive esophagitis (See section 5.2)

Asian Population

In studies of healthy subjects, Asians had approximately a four-fold higher exposure than Caucasians. Avoid use of Omeprazole/Sodium bicarbonate in Asian patients for maintenance of healing of erosive esophagitis. (See section 5.2)

The below information include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with omeprazole and instructions for preventing or managing them.

Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics

Antiretrovirals

The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.

§ Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance (see section 5.2).

§ Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity) (see section 5.2).

§ There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.

Warfarin

Increased INR and prothrombin time in patients receiving PPIs including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Methotrexate

Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted (See section 4.4).

CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)

Clopidogrel: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition (See section 5.2).

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.

Citalopram: Increased exposure of citalopram leading to an increased risk of QT prolongation.

Cilostazol: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) (See section 5.2).

Phenytoin: Potential for increased exposure of phenytoin.

Diazepam: Increased exposure of diazepam.

Digoxin

Potential for increased exposure of digoxin.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)

Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Tacrolimus

Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19

Interactions with Investigations of Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors (See sections 4.4 and 5.1).

Interaction with Secretin Stimulation Test

Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.

False Positive Urine Tests for THC

There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.

Other

There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).

Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs

CYP2C19 or CYP3A4 Inducers

Decreased exposure of omeprazole when used concomitantly with strong inducers. (See section 4.4)

CYP2C19 or CYP3A4 Inhibitors

Increased exposure of omeprazole.

Pregnancy

Risk Summary

There are no adequate and well-controlled studies with Omeprazole/Sodium bicarbonate in pregnant women. Risek Plus capsules contain omeprazole and sodium bicarbonate.

Omeprazole                                   

There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person).

Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68 times and 42 times, respectively, an oral human dose of 40mg esomeprazole or 40mg omeprazole (based on body surface area for a 60 kg person). Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40mg esomeprazole or 40mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

Sodium Bicarbonate

Available data with sodium bicarbonate use in pregnant women are insufficient to identify a drug associated risk of major birth defects or miscarriage. Published animal studies report that sodium bicarbonate administered to rats, mice or rabbits during pregnancy did not cause adverse developmental effects in offspring.

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

Lactation

Risk Summary

Available data from the published literature suggest both components of the capsules, omeprazole and sodium bicarbonate, are present in human milk. There are no clinical data on the effects of omeprazole or sodium bicarbonate on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for the capsules and any potential adverse effects on the breastfed infant from the capsules or from the underlying maternal condition.

None known

The following serious adverse reactions are described above in section 4.4 (Special warnings and precautions for use)

§  Acute Tubulointerstitial Nephritis 

§  Clostridium difficile-Associated Diarrhoea 

§  Bone Fracture 

§  Cutaneous and Systemic Lupus Erythematosus 

§  Cyanocobalamin (Vitamin B₁₂) Deficiency 

§  Hypomagnesemia and mineral metabolism

§  Fundic Gland Polyps 

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of omeprazole and sodium bicarbonate. 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.

Omeprazole

Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, urticaria (see also Skin below), fever, pain, fatigue, malaise, and systemic lupus erythematosus.

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema.

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis, abdominal swelling and fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), ᵞ-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy.

Infections and Infestations: Clostridium difficile-associated diarrhoea.

Metabolism and Nutritional Disorders: Hypomagnesemia, hypocalcemia, hypokalemia (see

section 4.4), hyponatremia, hypoglycemia, and weight gain.

Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain.

Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.

Respiratory: Epistaxis, pharyngeal pain.

Skin: Severe generalized skin reactions including toxic epidermal necrolysis TEN (some fatal), SJS, DRESS, AGEP. cutaneous lupus erythematosus and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.

Special Senses: Tinnitus, taste perversion.

Ocular: Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis, and double vision.

Urogenital: Rarely, tubulointerstitial nephritis (with possible progression to renal failure), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, gynecomastia and erectile dysfunction.

Hematologic: Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leukocytosis, and hemolytic anemia have been reported.

Sodium Bicarbonate

Metabolic alkalosis, seizures, and tetany.

To report any side effect(s):

§ Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

-        SFDA Call Centre: 19999

-        E-mail: npc.drug@sfda.gov.sa

-        Website: https://ade.sfda.gov.sa/

§ Other GCC States:

-        Please contact the relevant competent authority.

Omeprazole

Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in clinical experience with the recommended dosage (See section 4.8). Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

Sodium Bicarbonate

Overdosage of sodium bicarbonate can cause electrolyte abnormalities (hypocalcemia, hypokalemia, hypernatremia), metabolic alkalosis, and seizures. Institute supportive care and correct electrolyte abnormalities.

Risek Plus (omeprazole and sodium bicarbonate) is a combination of omeprazole, a proton-pump inhibitor, and sodium bicarbonate, an antacid.

Mechanism of Action

Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.

Antisecretory Activity

Results from a separate pharmacokinetic/pharmacodynamics (PK/PD) study of antisecretory effect on repeated once-daily dosing of 40mg/1100mg and 20mg/1100mg of Omeprazole/Sodium bicarbonate capsules in healthy subjects show similar effects in general PD parameters as those for Omeprazole/Sodium bicarbonate for oral suspension 40mg/1680mg and 20mg/1680 mg, respectively.  

The antisecretory effect lasts longer than would be expected from the very short (1 hour) plasma half-life, apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme.

Enterochromaffin-like (ECL) Cell Effects

Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. These studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions.

Serum Gastrin Effects

In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H₂-receptor antagonists, the median increases produced by 20mg doses of omeprazole were higher (1.3 to 3.6-fold vs. 1.1- to 1.8-fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors (see section 4.4).

Other Effects

Systemic effects of omeprazole in the central nervous system (CNS), cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.

No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90mg. In healthy subjects, a single intravenous dose of omeprazole (0.35mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased.

As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment.

Absorption

The table below show the systemic exposures and the time reach peak concentration (T_max) of omeprazole in healthy subjects following administration of Omeprazole/Sodium bicarbonate capsules, on an empty stomach one hour prior to a meal.

Arithmetic Mean (CV%) of the Systemic Exposures (C_max, AUC) and T_max of Omeprazole after a Single Oral Dose and Multiple Once-Daily Doses of Omeprazole/Sodium bicarbonate Capsules

n.a.: not applicable

* AUC_0-24h was used on Day 7

Following single or repeated once-daily dosing, peak plasma concentrations (C_max) of omeprazole from Omeprazole/Sodium bicarbonate capsules were approximately proportional from 20 to 40mg doses. A greater than dose proportional increase in mean steady-state AUC (more than three-fold increase on Day 7) was observed when doubling the dose to 40mg. The bioavailability of omeprazole from Omeprazole/Sodium bicarbonate increases upon repeated administration. The percent changes in C_max and AUC between steady-state (Day 7) and single dose (Day 1) indicate omeprazole is a time-dependent autoinhibitor of CYP2C19. 

When Omeprazole/Sodium bicarbonate capsule 40mg is administered one hour after a meal, the omeprazole AUC is reduced by approximately 27% and 22%, respectively, relative to administration one hour prior to a meal (See section 4.2).

Distribution

Omeprazole is bound to plasma proteins. Protein binding is approximately 95%.

Elimination
Metabolism

Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone.

The mean plasma omeprazole half-life following administration of the capsule in healthy subjects is approximately 1 hour (range 0.4 to 4.2 hours), and the total body clearance is 500 to 600 mL/min.

Excretion

Following single-dose oral administration of a buffered solution of omeprazole, the majority of the dose (about 77%) is eliminated in urine as at least six metabolites. Two metabolites have been identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma – the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.

Specific Populations

Geriatric Patients

The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40mg oral dose of omeprazole (buffered solution) was administered to healthy elderly subjects versus 58% in young subjects given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole, and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects), and its plasma half-life averaged one hour, similar to that of young healthy subjects.

Male and Female Patients

There are no known differences in the absorption or excretion of omeprazole between males and females.

Patients with Renal Impairment

In patients with chronic renal impairment (creatinine clearance between 10 and 62 mL/min/1.73 m²), the disposition of omeprazole was very similar to that in healthy subjects, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. This increase in bioavailability is not considered to be clinically meaningful.

Patients with Hepatic Impairment

In patients with chronic hepatic disease classified as Child-Pugh Class A (n=3), B (n=4) and C (n=1), the bioavailability of omeprazole increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared to the in healthy subjects of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared to a value of 500 to 600 mL/min in healthy subjects (See section 4.4 – Special population).

Drug Interactions Studies

Effect of Omeprazole on Other Drugs

Omeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility (see section 4.5).

Antiretrovirals:

For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been reported when given together with omeprazole (see section 4.5).

Rilpivirine:

Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased by 40%, C_max by 40%, and C_min by 33% for rilpivirine.

Nelfinavir:

Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C_max by 37% and 89% and C_min by 39% and 75% respectively for nelfinavir and M8.

Atazanavir:

Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, C_max by 96%, and C_min by 95%.

Saquinavir:

Following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15.

AUC was increased by 82%, C_max by 75%, and C_min by 106%. The mechanism behind this interaction is not fully elucidated. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole.

Clopidogrel

In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together.

Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days.

Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period.

In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole, but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction (see sections 4.4 and 4.5).

Mycophenolate Mofetil

Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a crossover study resulted in a 52% reduction in the C and 23% reduction in the AUC of MPA (see section 4.5).

Cilostazol

Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased C_max and AUC of cilostazol by 18% and 26% respectively. The C_max and AUC of one of the active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and the above mentioned active metabolite (see section 4.5).

Diazepam

Concomitant administration of omeprazole 20 mg once daily and diazepam 0.1 mg/kg given intravenously resulted in 27% decrease in clearance and 36% increase in diazepam half-life (see section 4.5).

Digoxin

Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) (see section 4.5).

Effect of Other Drugs on Omeprazole

Voriconazole

Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure.

When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_max and AUC0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole  (see section 4.5).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44 and 140.8 mg/kg/day (approximately 0.4 to 34.2 times the human dose of 40 mg/day on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (approximately 3.36 times the human dose of 40 mg/day on a body surface area basis) for one year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated versus 10% controls). By the second year the difference between treated and control rats was much smaller (46% versus 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague Dawley rats, no astrocytomas were found in males and females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.

In a 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other PPIs or high doses of H₂-receptor antagonists.

Omeprazole at oral doses up to 138 mg/kg/day (about 33.6 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on the fertility and general reproductive performance in rats.

Notes:

* Evaporates during manufacturing process and does not appear in the final product.

** Composition of Capsule shell contains: Gelatin & Titanium dioxide.

Not applicable

Store below 30ºC, protected from light and moisture.

§ Pack of 14 Capsules: 14 Capsules in a HDPE plastic bottle with cotton and closed with a plastic cap 3G silica gel CRC packed in a carton, along with a leaflet.

§ Pack of 30 Capsules: 30 in a HDPE plastic bottle with cotton and closed with a plastic cap 3G silica gel CRC packed in a carton, along with a leaflet.

Keep container tightly closed.