HYMOX is indicated for the treatment of the following infections in adults and children (seesections 4.2, 4.4 and 5.1):

•       Acute bacterial sinusitis.

•       Acute otitis media.

•       Acute streptococcal tonsillitis and pharyngitis.

•       Acute exacerbations of chronic bronchitis.

•       Community acquired pneumonia.

•       Acute cystitis.

•       Asymptomatic bacteriuria in pregnancy.

•       Acute pyelonephritis.

•       Typhoid and paratyphoid fever.

•       Dental abscess with spreading cellulitis.

•       Prosthetic joint infections.

•       Helicobacter pylori eradication.

•       Lyme disease.

HYMOX is also indicated for the prophylaxis of endocarditis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

The dose of HYMOX that is selected to treat an individual infection should take into account:

•       The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4).

•       The severity and the site of the infection.

•       The age, weight and renal function of the patient; as shown below.

The duration of therapy should be determined by the type of infection and the response of the patient, and shouldgenerally be as short as possible. Some infections require longer periods of treatment (see section 4.4 regardingprolonged therapy).

Adults and children ≥40 kg

Children <40 kg

Children may be treated with HYMOX capsules, dispersible tablets suspensions or sachets. HYMOXPaediatric Suspension is recommended for children under six months of age.

Children weighing 40 kg or more should be prescribed the adult dosage.

Recommended doses:

Elderly

No dose adjustment is considered necessary.

Renal impairment

In patients receiving haemodialysis

Amoxicillin may be removed from the circulation by haemodialysis.

In patients receiving peritoneal dialysis

Amoxicillin maximum 500 mg/day.

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals (see sections 4.4 and 4.8).

Method of administration

HYMOX is for oral use.

Absorption of HYMOX is unimpaired by food.

Therapy can be started parenterally according to the dosing recommendations of the intravenous formulation andcontinued with an oral preparation.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity reactions

Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactionsto penicillins, cephalosporins or other betalactamagents (see sections 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillintherapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopicindividuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and appropriate alternative therapyinstituted.

Non-susceptiblemicroorganisms

Amoxicillin is not suitable for the treatment of some types of infection unless the pathogen is already documented andknown to be susceptible or there is a very high likelihood that the pathogen would be suitable for treatment withamoxicillin (see section 5.1). This particularly applies when considering the treatment of patients with urinary tractinfections and severe infections of the ear, nose and throat.

Convulsions

Convulsions may occur in patients with impaired renal function or in those receiving high doses or in patients withpredisposing factors (e.g. history of seizures, treated epilepsy or meningeal disorders (see section 4.8).

Renal impairment

In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).

Skin reactions

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be asymptom of acute generalisedexanthemouspustulosis (AEGP, see section 4.8). This reaction requires amoxicillindiscontinuation and contraindicatesany subsequent administration.

Amoxicillin should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash hasbeen associated with this condition following the use of amoxicillin.

Severe Cutaneous Adverse Reactions

Amoxicillin may cause severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If patients develop a skin rash they should be monitored closely and amoxicillin discontinued if lesions progress.

Jarisch-Herxheimerreaction

The Jarisch-Herxheimerreaction has been seen following amoxicillin treatment of Lyme disease (see section 4.8). Itresults directly from the bactericidal activity of amoxicillin on the causative bacteria of Lyme disease, the spirochaeteBorreliaburgdorferi. Patients should be reassured that this is a common and usually self-limitingconsequence ofantibiotic treatment of Lyme disease.

Overgrowth of non-susceptiblemicroorganisms

Prolonged use may occasionally result in overgrowth of non-susceptibleorganisms.

Antibiotic-associatedcolitis has been reported with nearly all antibacterial agents and may range in severity from mild tolife threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present withdiarrhoea during, or subsequent to, the administration of any antibiotics. Should antibiotic-associatedcolitis occur,amoxicillin should immediately be discontinued, a physician consulted and an appropriate therapy initiated. Anti- peristalticmedicinal products are contraindicated in this situation.

Prolonged therapy

Periodic assessment of organ system functions; including renal, hepatic and haematopoietic function is advisableduring prolonged therapy. Elevated liver enzymes and changes in blood counts have been reported (see section 4.8).

Anticoagulants

Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin. Appropriate monitoringshould be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulantsmay be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8).

Crystalluria

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy.During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary outputin order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, a regular check of patencyshould be maintained (see section 4.8 and 4.9).

Interference with diagnostic tests

Elevated serum and urinary levels of amoxicillin are likely to affect certain laboratory tests. Due to the high urinaryconcentrations of amoxicillin, false positive readings are common with chemical methods.

It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymaticglucose oxidase methods should be used.

The presence of amoxicillin may distort assay results for oestriol in pregnant women. Important information about excipients

This medicinal product contains sodium benzoate which is a mild irritant to the eyes, skin and mucousmembrane. May increase the risk of jaundice in new born babies.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin.Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin.

Allopurinol

Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skinreactions.

Tetracyclines

Tetracyclines and other bacteriostatic drugs may interfere with the bactericidal effects of amoxicillin.

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However,in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol orwarfarin and prescribed a course ofamoxicillin. If co-administrationis necessary, the prothrombin time or internationalnormalised ratio should be 

carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments inthe dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).

Methotrexate

Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Limited data on theuse of amoxicillin during pregnancy in humans do not indicate an increased risk of congenital malformations. Amoxicillinmay be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

Breastfeeding

Amoxicillin is excreted into breast milk in small quantities with the possible risk of sensitisation. Consequently,diarrhoea and fungus infection of the mucous membranes are possible in the breastfedinfant, so that breastfeedingmight have to be discontinued. Amoxicillin should only be used during breastfeedingafter benefit/risk assessment bythe physician in charge.

Fertility

There are no data on the effects of amoxicillin on fertility in humans. Reproductive studies in animals have shown noeffects on fertility

No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines(see section 4.8).

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and skinrash.

The ADRs derived from clinical studies and post-marketingsurveillance with amoxicillin, presented by MedDRA SystemOrgan Class are listed below.

The following terminologies have been used in order to classify the occurrence of undesirable effects.

Very common (≥1/10) Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuedmonitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report anysuspected adverse reactions via:

To report any side effect(s):

The National Pharmacovigilance Centre (NPC): Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa Website: https://ade.sfda.gov.sa

Symptoms and signs of overdose

Gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) and disturbance of the fluid and electrolytebalances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed.Convulsions may occur in patients with impaired renal function or in those receiving high doses (see sections 4.4 and4.8).

Treatment of intoxication

Gastrointestinal symptoms may be treated symptomatically, with attention to thewater/electrolyte balance.

Amoxicillin can be removed from the circulation by haemodialysis.

Pharmacotherapeutic group: penicillins with extended spectrum; ATC code: J01CA04. Mechanism of action

Amoxicillin is a semisynthetic penicillin (betalactamantibiotic) that inhibits one or more enzymes (often referred to aspenicillin-bindingproteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structuralcomponent of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which isusually followed by cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamasesproduced by resistant bacteria and therefore the spectrumof activity of amoxicillin alone does not include organisms which produce these enzymes.

Pharmacokinetic/pharmacodynamic relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy foramoxicillin.

Mechanisms of resistance

The main mechanisms of resistance to amoxicillin are:

•       Inactivation by bacterial beta-lactamases.

•       Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly inGram-negativebacteria.

Breakpoints

MIC breakpoints for amoxicillin are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST)version 5.0.

The prevalence of resistance may vary geographically and with time for selected species, and local information onresistance is desirable, particularly when treating severe infections. As necessary, expert advice should be soughtwhen the local prevalence of resistance is such that the utility of the agent in at least some types of infections isquestionable.

Absorption

Amoxicillin fully dissociates in aqueous solution at physiological pH. It is rapidly and well absorbed by the oral route ofadministration. Following oral administration, amoxicillin is approximately 70% bioavailable. The time to peak plasmaconcentration (Tmax) isapproximately one hour.

The pharmacokinetic results for a study, in which an amoxicillin dose of 250 mg three times daily was administered inthe fasting state to groups of healthy volunteers are presented below.

In the range 250 to 3000 mg the bioavailability is linear in proportion to dose (measured as Cmax and AUC). Theabsorption is not influenced by simultaneous food intake.

Haemodialysis can be used for elimination of amoxicillin. Distribution

About 18% of total plasma amoxicillin is bound to protein and the apparent volume of

distribution is around 0.3 to 0.4l/kg.

Following intravenous administration, amoxicillin has been found in gall bladder, abdominal tissue, skin, fat, muscletissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinalfluid.

From animal studies there is no evidence for significant tissue retention of drugderived material. Amoxicillin, like mostpenicillins, can be detected in breast milk (see section 4.6).

Amoxicillin has been shown to cross the placental barrier (see section 4.6). Biotransformation

Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% ofthe initial dose.

Elimination

The major route of elimination for amoxicillin is via the kidney.

Amoxicillin has a mean elimination half-lifeof approximately one hour and a mean total clearance of approximately 25l/hour in healthy subjects. Approximately 60 to 70% of the amoxicillin is excreted unchanged in urine during the first 6hours after administration of a single 250 mg or 500 mg dose of amoxicillin. Various studies have found the urinaryexcretion to be 50- 85%for amoxicillin over a 24 hour period.

Concomitant use of probenecid delays amoxicillin excretion (see section 4.5).

Age

The elimination half-lifeof amoxicillin is similar for children aged around 3 months to 2 years and older children andadults. For very young children (including preterm newborns) in the first week of life the interval of administration shouldnot exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients aremore likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Gender

Following oral administration of amoxicillin/ to healthy males and female subjects, gender has no significant impact onthe pharmacokinetics of amoxicillin.

Renal impairment

The total serum clearance of amoxicillin decreases proportionately with decreasing renal function (see sections 4.2 and4.4).

Hepatic impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

Nonclinicaldata reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity,genotoxicity and toxicity to reproduction and development.

Carcinogenicity studies have not been conducted with amoxicillin

Sodium Benzoate, Sodium Citrate Anhydrous, Disodium Edetate, Quinoline Yellow, Citric Acid Anhydrous, Peach Dry Flavour, Strawberry Dry Flavour, Lemon Dry Flavour, Sucrose (Milled), Kletrol (Xanthan Gum), Bubble Gum Flavour Powder, Sicovit Azofubine 85 E122 and Silicon Dioxide NF 18 (Silica Gel)

Not applicable.

Do not store above 25°C.

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

150ml/pack (125mg/250mg) Clear bottle with child resistant cap and tamper evident ring.

Check cap seal is intact before use. Invert and shake bottle to loosen powder.

Fill the bottle with water to just below the mark on the bottle label.

Invert and shake well, then top up with water to the mark. Invert and shake again. Shake well before taking each dose.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.