RAB Injection

 Rabeprazole Sodium Injection IP 20 mg/vial

 (Lyophilized Powder)

 COMPOSITION

Each vial contains:

Rabeprazole Sodium                             IP         20 mg

 DESCRIPTION

A sterile lyophilized cake / powder.

 PHARMACODYNAMIC

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.

In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.

PHARMACOKINETICS

The rabeprazole C_max and AUC are linear over an oral dose range of 10 mg to 40 mg. There

is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole are not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.

In a randomized, balanced open-label, two period, two treatment, two way cross over study in 28 health male and female volunteers, the pharmacokinetics (PK) of 20 mg intravenous rabeprazole was compared with 20 mg oral rabeprazole. The PK parameters are listed below:

# Two subjects had no detectable levels of rabeprazole after oral administration

_a p value is 0.0001

_b p value is 0.0122

Statistically significant treatment differences were observed for all PK parameters.

In another study, a total of 63 subjects (33 males and 30 females) were recruited at four research centers and given a 5-day therapeutic course of rabeprazole (10, 20, or 40 mg) administered as single daily doses during a 30-minute period. The PK parameters on Day 1 and Day 5 are listed below:

Pharmacokinetic parameters for the three dose groups following the administration of a single dose on the first day and repeated daily doses on the fifth day of rabeprazole by intravenous infusion over a 30-min period for 5 days.

Values are given as the mean ± SD

AUC, Mean area under the plasma concentration–time curve:

AUC (0-τ): AUC over a dosing interval at steady-state;

AUC (0-∞): AUC for time 0 to infinity;

C_max: peak plasma level; T^½: elimination half-life of drug;

MRT, mean retention time; CL_Total: total clearance; V_d: volume of distribution

a Day 1 and Day 5 denote the first and fifth day of rabeprazole infusion, respectively.

THERAPEUTIC INDICATION

Intravenous rabeprazole is indicated for the treatment of:

• Active duodenal ulcer with bleeding or severe erosions.
• Active / Benign gastric ulcer with bleeding or severe erosions.
• Severe erosive or ulcerative gastro-esophageal reflux diseases (GORD/GERD) or Non-erosive Reflux Diseases [NERD].
• Prevention of Acid-Aspiration during Surgery
• Stress-induced mucosal injury in clinical care, e.g. head-injury, burns, MI, etc.
• Sequential-therapy [Step-Up] therapy from oral Rabeprazole, e.g. a patient previously on Oral Rabeprazole who is temporarily unable to take oral Rx for any reason, e.g. during a surgical procedure.
• Any condition where patient is unable to take oral PPIs.
• Prevention of Pulmonary Acid Aspiration During Surgery.

 DOSAGE AND ADMINISTRATION

Use by the indication of treating physician.

Parenteral rabeprazole is only used when the oral form is not appropriate and it should be

changed to the oral route as soon as possible.

Dosage

No dosage adjustment is necessary for patients with renal or hepatic impairment or old age.

No need to adjust dose in patients with haemodialysis.

Dosage of over 40mg/day has not yet been studied in patients with hepatic impairment. No

need to adjust dose in patients with haemodialysis.

Recommended dose for adults: 20 mg rabeprazole given once daily by intravenous bolus

injection or by intravenous infusion for 7 to 10 days.

It is not recommended for use in children, as there is no experience of its use in this group.

 Method of administration: Intravenous injection.

 OVERDOSE

There has been no experience with large overdoses with rabeprazole. Seven reports of accidental overdosage with rabeprazole have been received. The maximum reported overdose was 80 mg. There were no clinical signs or symptoms associated with any reported overdose. Patients with Zollinger-Ellison syndrome have been treated with up to 120 mg rabeprazole QD. No specific antidote for rabeprazole is known. Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive. Single oral doses of rabeprazole at 786 mg/kg and 1024 mg/kg were lethal to mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal to dogs. The major symptoms of acute toxicity were hypoactivity, labored respiration, lateral or prone position and convulsion in mice and rats and watery diarrhea, tremor, convulsion and coma in dogs.

CONTRAINDICATION

• Patients with known hypersensitivity to rabeprazole sodium substituted benzimidazoles or to any Excipients used in the formulations.
• Pregnancy and lactation.

 WARNING AND PRECAUTIONS

Symptomatic responses to therapy with rabeprazole sodium does not preclude the presence of gastric or oesophageal malignancy, therefore the possibility of malignancy should be excluded prior to commencing treatment with rabeprazole.

Although no evidence of significant drug related safety problems was seen in a study of patients with mild to moderate hepatic imperilments versus normal age and sex matched controls, the prescribers are advised to excursive caution when treatment with rabeprazole is fist initiated in patients with severe hepatic dysfunctions.

The extent of rabeprazole concentrations increases by old age, poor metabolizer’s status for CYP2C19 and impairment of liver function is not greater than two-fold, impairment renal function doses not affect the elimination. Even in patients with delayed elimination, no relevant accumulation of rabeprazole was observed upon long-term administration. In in-vivo studies, rabeprazole had no noteworthy effect on the metabolism of other drugs.

Renal and hepatic impairment: No dosage adjustment is necessarily for patients with renal

or hepatic impairment.

Children: It is not recommended for use in children, as there is little experience of its use in this group.

 PREGNANCY, LACTATION AND ABILITY TO DRIVE

Pregnancy:

There are no data on the safety of rabeprazole in human pregnancy.

Lactation:

Since many drugs are excreted in milk, and because of the potential for adverse reactions to nursing infants from Rabeprazole, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Effects on ability to drive and use machines:

Based on the pharmacodynamic properties and the adverse events profile, it is unlikely that Rabeprazole Sodium would cause an impairment of driving performance or compromise the ability to use machinery. If, however, alertness is impaired due to somnolence, it is recommended that driving and operating complex machinery be avoided.

DRUG INTERACTION

Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporin metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with rabeprazole. For example, in normal subjects, co-administration of rabeprazole 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

ADVERSE EFFECTS

Intravenous Rabeprazole has been studied in clinical trials in several populations including patients having GERD with a history of erosive esophagitis, patients with Zollinger-Ellison Syndrome and healthy subjects.

Adverse experiences occurring in of patients treated with intravenous Rabeprazole in clinical trials are shown below by body system. In most instances, the relationship to Rabeprazole was unclear.

Body as a whole: Headache, injection site reaction.

Digestive system: Constipation, Diarrhea.

Nervous system: Insomnia.

Respiratory system: Rhinitis.

The following is a list of possible side-effects that may occur from all constituting ingredients of Rabeprazole IV Injection. This is not a comprehensive list. These side-effects are possible, but do not always occur. Some of the side-effects may be rare but serious. Consult your doctor if you observe any of the following side-effects, especially if they do not go away.

The following undesired events, listed by body system, have been reported with the following frequencies: 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) including isolated reports, not known (cannot be estimated from the available data).

Nervous system disorder

Common: Insomnia, Dizziness, Headache

Rare: Sleepiness

Respiratory, thoracic and mediastinal disorder

Common: Cough, Pharyngitis, Rhinitis

Rare: Bronchitis and Sinusitis

Gastrointestinal Disorder

Common: Abdominal pain, Constipation, Flatulence, Diarrhoea, Vomiting, Nausea

Rare: Dyspepsia, Gastritis

General disorder and administration site condition

Common: Asthenia, Influenza like illness

Uncommon: Chest pain, Fever, Chills

Skin and subcutaneous tissue disorder

Uncommon: Rash, Erythema

Rare: Pruritus, sweating, Bullous reaction

Oropharyngeal Disorder

Rare: Pharyngitis

Mucoskeletal and connective tissue disorder

Common: Back pain, Nonspecific pain

Uncommon: Myalgia, Leg cramps, arthralgia

Infections and infestations

Rare: Flu syndrome, Infection, Bronchitis, Urinary tract infection

Cardiac Disorders

Rare: Chest pain

Psychiatric Disorders

Very Rare: Stress, Depression, Sadness

Eye Disorder

Very Rare: Visual disturbances,

Blood and lymphatic system disorder

Rare: Leucopoenia, Thrombocytopenia, Neutropenia, Leukocytosis

Investigation

Uncommon: Weight gain, Elevated liver enzymes

Rare: weight increased

Head-to-head comparative studies between Rabeprazole I.V. for Injection and oral Rabeprazole other proton pump inhibitors (oral or I.V.), or H2 receptor antagonists (oral or I.V.) have been limited. The available information does not provide sufficient evidence to distinguish the safety profile of these regimens.

PRESENTATION

RAB Injections are supplied in 5 ml Flint, Type I USP, Tubular vial.

STORAGE AND OTHER INFORMATION

Store in a cool and dry place. Protect from light.

Store at below 30°C temperature.

Caution: Not to be used if container is found leaking or solution is hazy or contain any visible solid particles. Keep this medicine out of the sight and reach of children.