And Amoxicillin

Uses

Amoxicillin is used for the treatment of the following bacterial infections when caused by susceptible organisms:

• Respiratory tract, ENT infections: Acute and chronic bronchitis, pneumonia, otitis media, sinusitis, tonsillitis, pharyngitis & laryngitis, lobar & bronchopneumonia, chronic bronchial sepsis.
• Urinary tract infections: Pyelonephritis, cystitis and urethritis.
• Obstetric & gynaecological infections: Bacteriuria in pregnancy, septic abortion, intra-abdominal sepsis and puerperal sepsis.
• Gastro-intestinal infections: Typhoid and paratyphoid.
• Skin & soft tissue infections: Cellulitis, infected wounds and abscesses.
• Generalized infections: Septicemia, bacterial endocarditis, meningitis, peritonitis and osteomyelitis.
• Venereal infections: Gonorrhea and syphilis. Amoxicillin may also be used as prophylactic cover for patients at risk of developing endocarditis when undergoing dental surgery.

• LRTIs for example, acute and chronic bronchitis and pneumonia.
• URTIs for example, sinusitis and pharyngitis.
• Community-acquired pneumonia, atypical pneumonia
• Skin and soft tissue infection
• Adjunct in the treatment of duodenal ulcers to eradicate of H. pylori

Each film coated MUPS tablet contains 20 mg Omeprazole enteric coated micro pellets

Omeprazole (Multiple-Unit Pellet System) is indixated in-

• Duodenal and Gastric ulcers
• NSAID-induced gastric and duodenal ulcers
• Reflux Oesophagitis
• GERD (Gastroesophageal Reflux Disease)
• Eradication of H. pylori with appropriate antibiotics
• Zollinger-Ellison Syndrome

MUPS is abbreviation for Multiple-Unit Pellet System. However, from pharmaceutical industry and research perspective, the term in general refers to MUPS compacted into tablets. Thus, the resulting tablets prepared by compaction of modified release coated multiparticulates or pellets are called as MUPS. It is the more recent and challenging technology that combines the advantages of both tablets and pellet filled capsules in one dosage form.

MUPS ensure rapid and uniform gastric emptying and subsequently uniform drug dissolution of pellets in the gastrointestinal tract due to their small size and larger surface, uniform drug absorption is facilitated which results in consistent and controlled pharmacological action.

A further reduction in inter- and intra-subject variability in drug absorption and clinical response is facilitated since the number of pellets per MUPS dosage form is much more than a conventional pellet-filled capsule and possibility of dose dumping(in stomach) and incomplete drug release is further minimized.

And Amoxicillin is also used to associated treatment for these conditions: Acute Bacterial Sinusitis (ABS), Acute Otitis Media, Acute Otitis Media (AOM), Bacterial Infections, Community Acquired Pneumonia (CAP), Duodenal ulcer caused by helicobacter pylori, Genitourinary infections, Helicobacter Pylori Infection, Lower Respiratory Tract Infection (LRTI), Peptic Ulcer With H. Pylori Infection, Sinusitis, Skin and Subcutaneous Tissue Bacterial Infections, Urinary Tract Infection, Acute, uncomplicated Gonorrhea, Ear, nose, and throat infectionsAcute Bacterial Exacerbation of Chronic Bronchitis (ABECB), Acute maxillary sinusitis, Bacterial Infections, Bartonellosis, Community Acquired Pneumonia (CAP), Duodenal ulcer caused by helicobacter pylori, Infective Endocarditis, Lyme Disease, Mycobacterial Infections, Otitis Media (OM), Pertussis, Streptococcal Pharyngitis, Streptococcal tonsillitis, Uncomplicated skin and subcutaneous tissue bacterial infectionsAnkylosing Spondylitis (AS), Duodenal Ulcer, Erosive Esophagitis, Gastric Ulcer, Gastro-esophageal Reflux Disease (GERD), Healing, Heartburn, Helicobacter Pylori Infection, NSAID Associated Gastric Ulcers, Osteoarthritis (OA), Rheumatoid Arthritis, Zollinger-Ellison Syndrome, Hypersecretory conditions, Multiple endocrine adenomas

How And Amoxicillin works

Amoxicillin competitively inhibits penicillin-binding protein 1 and other high molecular weight penicillin binding proteins. Penicillin bind proteins are responsible for glycosyltransferase and transpeptidase reactions that lead to cross-linking of D-alanine and D-aspartic acid in bacterial cell walls. Without the action of penicillin binding proteins, bacteria upregulate autolytic enzymes and are unable to build and repair the cell wall, leading to bacteriocidal action.

Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound. Like other macrolides, it then penetrates bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump.

Hydrochloric acid (HCl) secretion into the gastric lumen is a process regulated mainly by the H(+)/K(+)-ATPase of the proton pump , expressed in high quantities by the parietal cells of the stomach. ATPase is an enzyme on the parietal cell membrane that facilitates hydrogen and potassium exchange through the cell, which normally results in the extrusion of potassium and formation of HCl (gastric acid) .

Omeprazole is a member of a class of antisecretory compounds, the substituted benzimidazoles, that stop gastric acid secretion by selective inhibition of the H+/K+ ATPase enzyme system. Proton-pump inhibitors such as omeprazole bind covalently to cysteine residues via disulfide bridges on the alpha subunit of the H+/K+ ATPase pump, inhibiting gastric acid secretion for up to 36 hours . This antisecretory effect is dose-related and leads to the inhibition of both basal and stimulated acid secretion, regardless of the stimulus .

Mechanism of H. pylori eradication

Peptic ulcer disease (PUD) is frequently associated with Helicobacter pylori bacterial infection (NSAIDs) . The treatment of H. pylori infection may include the addition of omeprazole or other proton pump inhibitors as part of the treatment regimen , . H. pylori replicates most effectively at a neutral pH . Acid inhibition in H. pylori eradication therapy, including proton-pump inhibitors such as omeprazole, raises gastric pH, discouraging the growth of H.pylori . It is generally believed that proton pump inhibitors inhibit the urease enzyme, which increases the pathogenesis of H. pylori in gastric-acid related conditions .

Dosage

And Amoxicillin dosage

Ear/Nose/ThroatInfection (Mild to Moderate):

• Adult:500 mg every 12 hours or 250 mg every 8 hours
• Children:25 mg/kg/day in divided doses every 12 hours or 20 mg/kg/day in divided doses every 8 hours

Ear/Nose/ThroatInfection (Severe):

• Adult: 875 mg every 12 hours or 500 mg every 8 hours
• Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours

Lower respiratory tractInfection (Mild/ Moderate/Severe):

• Adult: 875 mg every 12 hours or 500 mg every 8 hours
• Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours

Skin/skin structureInfection (Mild/Moderate):

• Adult: 500 mg every 12 hours or 250 mg every 8 hours
• Children: 25 mg/kg/day in divided doses every 12 hours or 20 mg/kg/day in divided doses every 8 hours

Skin/skin structureInfection (Severe):

• Adult: 875 mg every 12 hours or 500 mg every 8 hours
• Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours

Genitourinary tractInfection (Mild/ Moderate):

• Adult: 500 mg every 12 hours or 250 mg every 8 hours
• Children: 25 mg/kg/day in divided doses every 12 hours or 20 mg/kg/day in divided doses every 8 hours

Genitourinary tractInfection (Severe):

• Adult: 875 mg every 12 hours or 500 mg every 8 hours
• Children: 45 mg/kg/day in divided doses every 12 hours or 40 mg/kg/day in divided doses every 8 hours

Gonorrhea, Acute, uncomplicated ano-genital, and urethral infections in males and females:

• Adult: 3 g as single oral dose
• Prepubertal children: 50 mg/Kg/Amoxycillin, combined with 25 mg/kg Probenecid as a single dose. Since Probenecid is contraindicated in children under 2 years, do not use this regimen in these cases.

Clarithromycin may be given with or without meals.

Adults (12 years or above):

250 mg twice daily for 7 days. Dose may be increased to 500 mg twice daily for up to 14 days in pneumonia or severe infections.

Combination therapy for H. pylori infection:

Clarithromycin 500 mg (two 250 mg tablets or one 500 mg tablet) twice daily in combination with Amoxicillin 1000 mg twice daily and Omeprazole 20 mg twice daily should be continued for 10 days.

Children:

The usual recommended daily dosage is 15 mg/kg in 2 divided doses for 10 days.

Approximate Calculation of dose:

1. For 9kg body weight 2.5ml 12 hourly for 10 days

2. For 17kg body weight 5ml 12 hourly for 10 days

3. For 25kg body weight 7.5ml 12 hourly for 10 days

4. For 33kg body weight 10ml 12 hourly for 10 days

Direction for reconstitution of suspension:

Shake the bottle to loosen granules. Add 35 ml of boiled and cooled water with the help of the supplied cup, to the dry granules of the bottle. For ease of preparation, add water to the bottle in two proportions. Shake well after each addition until all the granules is in suspension.

Note: Shake the suspension well before each use. Keep the bottle tightly closed. The reconstituted suspension should be stored in a cool and dry place, preferably in refrigerator.

Adult:

• GERD (Gastroesophageal Reflux Disease):20 mg Once daily for 4 weeks
• Gastric ulcer:20 mg Once daily for 4-8 weeks; in severe cases Twice daily
• Duodenal ulcer:20 mg Once daily for 2-4 weeks; in severe cases Twice daily
• NSAID-induced ulceration:20 mg Once daily for 4-8 weeks
• Reflux esophagitis:20 mg Once daily for 4-8 weeks; in severe cases Twice daily
• H. pylori eradication (Omeprazole MUPS tablet with Amoxicillin and Clarithromycin or Metronidazole):20 mg Twice daily for 1 week
• Zollinger-Ellison Syndrome:60 mg Once daily; Usual maintenance, 20-120mg daily

Children:

• Acid regurgitation in GERD (Gastroesophageal Reflux Disease):20 mg Once daily for 2-4 week
• Reflux esophagitis:20 mg Once daily for 4-8 weeks

Suspension: Shake the bottle well before adding water. Then add 12 tea spoonful (60 ml) of boiled and cooled water to the bottle and shake well to make 100 ml suspension.

Amoxycillin 500 mg Injection:

• Intramuscular : Add 2.5 ml water for injection to Amoxycillin 500 mg injection vial.
• Intravenous : Dissolve Amoxycillin 500 mg injection in 10 ml water for injection.

This may be given with or without meals.

The usual duration of treatment is 6 to 14 days.

Children older than 12 years: As for adults.

Eradication of H. pylori in patients with duodenal ulcers: Adults: The usual duration of treatment is 6 to 14 days.

45 ml of water is to be added to the granules in the bottle and shaken to yield 70 ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 125 mg per 5 ml.

Swallow the tablet whole with a glass of water. The tablet must not be chewed or crushed. OR

If the patients have trouble swallowing the tablets, put the tablet into a glass of water (Do not use other liquids). Stir the preparation until the tablets disintegrate. Then drink the liquid within 30 minutes. Stir the mixture just always before drinking.

Side Effects

Side effects are mild, rare and infrequent. As with other penicillins, it may induce diarrhea, indigestion or skin rashes that usually stop during treatment and rarely calls for discontinuation of therapy.

The most frequently reported events in adults taking Clarithromycin were diarrhoea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), headache (2%) and oral monilia.

Toxicity

Patients experiencing an overdose may present with hematuria, oliguria, abdominal pain, acute renal failure, vomiting, diarrhea, rash, hyperactivity, and drowsiness. Treat overdose with symptomatic and supportive treatment, which may include emesis or hemodialysis.

Symptoms of toxicity include diarrhea, nausea, abnormal taste, dyspepsia, and abdominal discomfort. Transient hearing loss with high doses has been observed. Pseudomembraneous colitis has been reported with clarithromycin use. Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have also occurred. Rare cases of severe hepatic dysfunctions also have been reported. Hepatic failure is usually reversible, but fatalities have been reported. Clarithromycin may also cause tooth decolouration which may be removed by dental cleaning. Fetal abnormalities, such as cardiovascular defects, cleft palate and fetal growth retardation, have been observed in animals. Clarithromycin may cause QT prolongation.

Oral acute (LD50): 4000 mg/kg (mouse), 2210 mg/kg (rat) .

Overdose

Symptoms of overdose include confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, and dry mouth.

Carcinogenesis and mutagenesis

In 24-month studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was seen in male and female animals. Carcinoid tumors have also been found in rats treated with a fundectomy or long-term treatment with other proton pump inhibitors, or high doses of H2-receptor antagonists .

Omeprazole showed positive clastogenic effects in an in vitro human lymphocyte chromosomal aberration study, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration test. Omeprazole tested 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 .

The use in breastfeeding

Limited data indicate that omeprazole may be present in human milk. There is currently no information on the effects of omeprazole on the breastfed infant or production of milk. The benefits of breastfeeding should be considered along with the level of need for omeprazole and any potential adverse effects on the breastfed infant from omeprazole .

Effects on fertility

Effects of omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times an oral human dose) was found to have no impact on fertility and reproductive performance .

Precaution

In renal impairment, the excretion of antibiotic will be delayed and depending on the degree of impairment it may be necessary to reduce the total daily dose.

Caution should be taken in administering this antibiotic to patients with impaired hepatic and renal function. Prolonged or repeated use of Clarithromycin may result in an overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, Clarithromycin should be discontinued.

Pharmaceutical precaution

Clarithromycin tablet should be stored in a cool and dry place and away from sunlight.

Omeprazole tablet should be used carefully if the patient has severe liver dysfunction and severe renal impairment.

Interaction

The simultaneous use of Amoxicillin and an oral contraceptive might cause breakthrough bleeding or pregnancy on rare occasions. Concurrent administration of probenecid delays the excretion of Amoxicillin.

Concomitant use of Clarithromycin who are receiving Theophylline may be associated with an increase in serum Theophylline concentrations. Clarithromycin may alter the metabolism of Terfenadine. The effects of digoxin may be potentiated with concomitant administration of Clarithromycin. Clarithromycin resulted in decrease in serum levels of Rifabutin, followed by an increased risk of uveitis.

Omeprazole is metabolized through CYP2C19 . When starting or stopping treatment with Omeprazole should be taken into account potential interactions with medicines which are CYP2C19 metabolized.

Volume of Distribution

The central volume of distribution of amoxicillin is 27.7L.

Approximately 0.3 L/kg, corresponding to the volume of extracellular water .

Elimination Route

Amoxicillin is approximately 60% bioavailable. A 250mg dose of oral amoxicillin reaches a C_max 3.93±1.13mg/L with a T_max 1.31±0.33h and an AUC of 27.29±4.72mg*h/L. A 875mg dose of oral amoxicillin reaches a C_max 11.21±3.42mg/L with a T_max 1.52±0.40h and an AUC of 55.04±12.68mg*h/L.

Clarithromycin is well-absorbed, acid stable and may be taken with food.

Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules exit the stomach .

Absorption of omeprazole occurs rapidly, with peak plasma concentrations of omeprazole achieved within 0.5-3.5 hours .

Absolute bioavailability (compared with intravenous administration) is approximately 30-40% at doses of 20-40 mg, largely due to pre-systemic metabolism. The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules .

Half Life

The half life of amoxicillin is 61.3 minutes.

3-4 hours

0.5-1 hour (healthy subjects, delayed-release capsule)
Approximately 3 hours (hepatic impairment)

Clearance

The mean clearance of amoxicillin is 21.3L/h.

Healthy subject (delayed release capsule), total body clearance 500 - 600 mL/min

Geriatric plasma clearance: 250 mL/min

Hepatic impairment plasma clearance: 70 mL/min

Elimination Route

125mg to 1g doses of amoxicillin are 70-78% eliminated in the urine after 6 hours.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%.

After a single dose oral dose of a buffered solution of omeprazole, negligible (if any) amounts of unchanged drug were excreted in urine. Most of the dose (about 77%) was eliminated in urine as at least six different metabolites. Two metabolites were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was found in the feces. This suggests significant biliary excretion of omeprazole metabolites. Three metabolites have been identified in the plasma, the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites possess minimal or no antisecretory activity .

Pregnancy & Breastfeeding use

Because of its lack of teratogenicity, Amoxicillin can beused safely throughout pregnancy at the normal adult dose. The small amount of Amoxicillin secreted in maternal milk rarely causes problem in the infant. It can therefore be used safely during lactation in most instances.

Clarithromycin is not recommended for pregnant women. Breast milk from mothers receiving Clarithromycin should not be given to infants until treatment is completed. Clarithromycin may be used in neonates and children in appropriate doses.

Not known to be harmful. Omeprazole can be used during pregnancy. Omeprazole is excreted in breast milk but is not likely to influence the child when therapeutic doses are used.

Contraindication

Amoxicillin is contraindicated for patients hypersensitive to penicillin, infectious mononucleosis, neonatal period or babies born of mothers hypersensitive to penicillin

Hypersensitive to Clarithromycin, Erythromycin or any of the macrolide antibiotics. Patients receiving terfenadine who have pre-existing cardiac abnormalities or electrolyte disturbances.

Omeprazole is contraindicated in those patients who have known hypersensitivity to any other components of the formulation.

Special Warning

Clarithromycin may be used in neonates and children in appropriate doses.

Acute Overdose

If encountered, gastro-intestinal symptoms and disturbance of the fluid and electrolyte balance may be evident. They may be treated symptomatically and supportive with attention to the water/ electrolyte balance. In the absence of an adequate fluid intake and urinary output, crystalluria is a possibility and the antibiotic may be removed from the circulation by haemodialysis. Oral administration can cause gastro intestinal symptoms such as transient diarrhoea, nausea and colic which are dose related and a result of local irritation not toxicity.

Signs & Symptoms : Ingestion of large amounts of Clarithromycin can be expected to produce gastrointestinal symptoms. Symptoms of overdose may largely correspond to the profile of side effects.

Management: There is no specific antidote on overdose. Serum levels of Clarithromycin can not be reduced by haemodialysis or peritoneal dialysis.

Storage Condition

Store in a cool & dry place protected from light. Amoxicillin suspension and drops should be freshly prepared, stored in a cool dry place preferably in a refrigerator. Reconstituted suspension and drops should be used within 5 days if kept at room temperature or within 7 days if kept in a refrigerator.

Store in a cool and dry place, protected from light.

Store in a cool (below 30° C) and dry place, protected from light and moisture.

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