Clavam

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLAVAM (CLAVAM)

Composition:

Active substances: 5 ml of suspension contains amoxicillin trihydrate equivalent to amoxicillin 200 mg, potassium clavulanate with silicified (1:1) equivalent to clavulanic acid 28.5 mg;

Excipients: mannite (E 421), sodium citrate, citric acid monohydrate, sodium benzoate (E 211), xanthan gum, colloidal anhydrous silicon dioxide, peppermint flavor DC-117, aspartame (E 951).

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white granular powder, which forms a white homogeneous suspension with peppermint odor upon reconstitution with water.

Pharmacotherapeutic group.

Antibacterials for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATC code J01CR02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Amoxicillin is a semisynthetic penicillin (β-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, resulting in cell lysis and death.

Amoxicillin is susceptible to degradation by β-lactamases produced by resistant bacteria; therefore, the antimicrobial spectrum of amoxicillin as monotherapy does not include organisms producing these enzymes.

Clavulanic acid is a β-lactam compound structurally related to penicillins. It inactivates certain β-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid has no clinically useful antibacterial activity when used alone.

PK/PD relationship

Time above the minimum inhibitory concentration (T>MIC) is considered the primary pharmacodynamic determinant of efficacy for amoxicillin.

Resistance mechanisms

There are two main resistance mechanisms to amoxicillin/clavulanic acid:

• inactivation by bacterial β-lactamases that are not themselves inhibited by clavulanic acid, including class B, C, and D enzymes;
• modification of PBPs, leading to reduced affinity of the antimicrobial agent for its target.

Reduced bacterial permeability or efflux pump mechanisms may contribute to or cause bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

The minimum inhibitory concentration (MIC) breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Microorganisms	Breakpoints of susceptibility (μg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae 1	≤1	-	> 1
Moraxella catarrhalis 1	≤1	-	> 1
Staphylococcus aureus 2	≤2	-	>2
Coagulase-negative staphylococci 2	≤ 0.25		> 0.25
Enterococcus 1	≤4	8	> 8
Streptococcus A, B, C, G 5	≤ 0.25	-	> 0.25
Streptococcus pneumoniae 3	≤ 0.5	1–2	>2
Enterobacteriaceae 1, 4	-	-	> 8
Gram-negative anaerobic bacteria 1	≤4	8	> 8
Gram-positive anaerobic bacteria 1	≤4	8	> 8
Breakpoints not specific to individual species 1	≤2	4–8	> 8
1 The reported values are for amoxicillin concentrations. For susceptibility testing, the concentration of clavulanic acid is set at 2 mg/l. 2 The reported values are for oxacillin concentrations. 3 The breakpoints listed in the table are derived from breakpoints for ampicillin. 4 The resistance breakpoint R > 8 mg/l indicates that all strains with resistance mechanisms are classified as resistant. 5 The breakpoints listed in the table are derived from breakpoints for benzylpenicillin.

The prevalence of resistance may vary geographically and over time for individual species, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice should be sought when local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Commonly susceptible species

Gram-positive aerobes: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible)£, Coagulase-negative staphylococci (methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae1, Streptococcus pyogenes and other beta-haemolytic streptococci, Streptococcus viridans group. Gram-negative aerobes: Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae2, Moraxella catarrhalis, Pasteurella multocida. Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp.

Species for which acquired resistance may be a problem

Gram-positive aerobes: Enterococcus faecium$. Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris.

Naturally resistant microorganisms

Gram-negative aerobes: Acinetobacter sp., Citrobacter freundii, Enterobacter sp., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas sp., Serratia sp., Stenotrophomonas maltophilia. Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae

$ Natural moderate susceptibility in the absence of acquired resistance mechanisms. £ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 Streptococcus pneumoniae resistant to penicillin should not be treated with this formulation of amoxicillin/clavulanic acid (see sections "Posology and method of administration" and "Special warnings and precautions for use"). 2 Strains with reduced susceptibility have been reported in certain EU countries with frequencies exceeding 10%.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid are completely dissociated in aqueous solutions at physiological pH levels. Both components are rapidly and well absorbed following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% following oral administration. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (Tmax) for each component is approximately one hour.

Serum concentrations of amoxicillin and clavulanic acid achieved after administration of amoxicillin/clavulanic acid are identical to those achieved following oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

Distribution. Approximately 25% of total clavulanic acid in plasma and 18% of total amoxicillin in plasma are protein-bound. The apparent volume of distribution is approximately 0.3–0.4 L/kg for amoxicillin and approximately 0.2 L/kg for clavulanic acid.

Following intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, abdominal tissue, skin, adipose tissue, muscle tissue, synovial and peritoneal fluid, bile, and pus. Amoxicillin does not adequately distribute into cerebrospinal fluid.

Animal studies have not revealed any evidence of significant accumulation of substances derived from either component of the drug in body tissues. Amoxicillin, like most penicillins, may be detected in breast milk. A small amount of clavulanic acid may also be detected in breast milk (see section "Use in pregnancy or lactation").

Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section "Use in pregnancy or lactation").

Metabolism. Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in the human body and is excreted in urine and feces, as well as in the form of carbon dioxide in expired air.

Elimination. The primary route of elimination for amoxicillin is renal, whereas clavulanic acid is eliminated both by the kidneys and via extrarenal mechanisms.

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately one hour, and the mean total clearance is approximately 25 L/h. Various studies have shown that urinary excretion amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. In the case of clavulanic acid, the greatest amount of the substance is excreted within the first 2 hours after administration.

Concomitant administration of probenecid slows the elimination of amoxicillin but does not affect the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other forms of interaction").

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children, and adults. For neonates (including premature infants) during the first week of life, the dosing frequency should not exceed twice daily due to immaturity of the renal elimination pathway. Since elderly patients are more likely to have decreased renal function, dosage selection should be cautious, and monitoring of renal function is recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a larger fraction of amoxicillin is eliminated by the kidneys. In renal insufficiency, dosing should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Dosage and administration").

Hepatic impairment. Caution is recommended when administering the drug to patients with hepatic impairment, and regular monitoring of liver function is advised.

Clinical characteristics.

Indications.

Treatment in children of bacterial infections caused by microorganisms sensitive to Clavam, such as:

• acute bacterial sinusitis (confirmed);
• acute otitis media;
• confirmed exacerbation of chronic bronchitis;
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including cellulitis, animal bites, severe dent alveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

When prescribing antibacterial agents, the principles of their appropriate use should be followed.

Contraindications.

Hypersensitivity to any component of the drug, to any antibacterial agents of the penicillin group.

History of severe hypersensitivity reactions (including anaphylaxis) associated with the use of other β-lactam agents (including cephalosporins, carbapenems or monobactams).

History of jaundice or liver dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other types of interactions.

Oral anticoagulants

Oral anticoagulants and penicillin-type antibiotics are widely used in clinical practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant use of these drugs is necessary, prothrombin time or INR should be carefully monitored when starting or stopping amoxicillin. In addition, dose adjustment of oral anticoagulants may be required (see sections "Special precautions" and "Adverse reactions").

Methotrexate

Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concurrent administration of probenecid may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients treated with mycophenolate mofetil, initiation of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite, mycophenolic acid, by approximately 50%. This change in pre-dose level may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of transplant dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use.

Prior to initiating therapy with amoxicillin/clavulanic acid, a careful history of previous hypersensitivity reactions to penicillins, cephalosporins, or other β-lactam agents should be obtained (see sections "Contraindications" and "Side effects").

Severe, and in some cases fatal, hypersensitivity reactions (including anaphylactic reactions and severe skin adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)—a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). Such reactions are more likely to occur in patients with a history of penicillin hypersensitivity and in those with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued and appropriate alternative therapy initiated.

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin/clavulanic acid (see section "Side effects"). Drug-induced enterocolitis syndrome is an allergic reaction characterized primarily by persistent vomiting (1–4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases have been reported, including progression to shock.

If the infection is proven to be caused by microorganisms susceptible to amoxicillin alone, switching from amoxicillin/clavulanic acid to amoxicillin should be considered in accordance with established guidelines.

This dosage form of Clavam is not suitable for use when there is a high likelihood that the causative pathogens are resistant to β-lactam agents through mechanisms not mediated by β-lactamases that are sensitive to inhibition by clavulanic acid. This dosage form should not be used for the treatment of penicillin-resistant S. pneumoniae.

Seizures may occur in patients with impaired renal function and in those receiving high doses of the drug (see section "Side effects").

Amoxicillin/clavulanic acid should be avoided in suspected infectious mononucleosis, as administration of amoxicillin has been associated with the development of a maculopapular rash.

Concomitant administration of allopurinol during amoxicillin therapy may increase the likelihood of allergic skin reactions.

Prolonged use may occasionally lead to overgrowth of organisms not susceptible to the drug.

The onset of fever-associated generalized erythema with pustule formation at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Side effects"). This reaction requires discontinuation of Clavam and constitutes a contraindication for further use of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with signs of hepatic dysfunction (see sections "Contraindications", "Dosage and administration", and "Side effects").

Hepatic complications have been reported, primarily in males, including elderly patients, which may be associated with prolonged treatment. Reports in children are very rare. In all patient groups, symptoms usually occur during or shortly after treatment, although in some cases they may appear several weeks after completion of therapy. These events are usually reversible. Hepatic complications may be severe, and in extremely rare cases, fatal outcomes have been reported. Such events have almost always occurred in patients with severe underlying disease or in those receiving concomitant medications with known potential hepatotoxic effects (see section "Side effects").

Antibiotic-associated colitis, with severity ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Side effects"). Therefore, this diagnosis should be considered in patients presenting with diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, Clavam should be discontinued immediately, medical advice should be sought, and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

During prolonged therapy, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is recommended.

Rarely, prolonged prothrombin time has been reported in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring is required when anticoagulants are used concomitantly. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Dosage adjustment is required in patients with impaired renal function depending on the degree of impairment (see section "Dosage and administration").

Crystalluria, predominantly during parenteral therapy, has been very rarely observed in patients with reduced urine output. Adequate fluid intake and diuresis should be maintained during high-dose amoxicillin therapy to reduce the risk of amoxicillin-related crystalluria. In patients with indwelling urinary catheters, catheter patency should be checked regularly (see section "Overdose").

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used for urine glucose testing, as non-enzymatic methods may yield false-positive results.

The presence of clavulanic acid in Clavam may lead to nonspecific binding of IgG and albumin to erythrocyte membranes, potentially resulting in false-positive Coombs' test results.

Positive results in the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have been reported during the Platelia Aspergillus immunoassay (Bio-Rad Laboratories). Therefore, positive results in patients treated with amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Clavam suspension contains aspartame, a source of phenylalanine, and should therefore be used with caution in patients with phenylketonuria.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive studies in animals with oral and parenteral forms of amoxicillin/clavulanic acid revealed no teratogenic effects. In a study involving women with premature rupture of membranes, prophylactic use of Clavam has been associated with an increased risk of necrotizing enterocolitis in newborns. As with other medicinal products, Clavam should be avoided during pregnancy, especially in the first trimester, unless considered necessary by the physician.

Breastfeeding period. Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on the breastfed infant). Diarrhea and fungal infections of mucous membranes may therefore occur in the breastfed infant, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered.

Clavam may be used during breastfeeding only if, in the physician’s opinion, the benefit outweighs the risk.

Ability to affect the speed of reactions when driving or operating machinery.

Studies on the ability of the drug to affect reaction speed during driving or operating machinery have not been conducted. However, undesirable effects (such as allergic reactions, dizziness, seizures) may occur, which could impair the ability to drive or operate machinery (see section "Side effects").

Method of Administration and Dosage

The medication should be used in accordance with official recommendations on antibiotic therapy and local antibiotic susceptibility data, where available. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. When necessary, microbial susceptibility testing to the antibiotic should be performed.

The dosage of the medication should be determined by a physician based on the likely microorganisms involved and their susceptibility to antibacterial agents, the severity and site of infection, as well as the patient’s age, body weight, and renal function.

When necessary, consideration should be given to using alternative dosage forms of the medication (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

For children weighing <40 kg, this dosage form provides a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when administered as recommended below. If a higher dose of amoxicillin is considered necessary, an alternative dosage form of Clavam should be selected to avoid excessively high daily doses of clavulanic acid (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

The duration of treatment should be determined based on the patient’s clinical response. Some infections (e.g., osteomyelitis) require prolonged treatment. Treatment should not exceed 14 days without re-evaluation (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg: other dosage forms of Clavam should be used.

Children with body weight < 40 kg

Recommended daily dosage: 25/3.6 mg/kg to 45/6.4 mg/kg body weight, divided into two doses.

For children with body weight <40 kg, the medication is prescribed at a daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid when administered as described below.

Approximate calculation of Clavam suspension volume (mL) per day (based on amoxicillin)

Child's body weight, kg	Dose 25 mg/kg/day	Dose 45 mg/kg/day
5	2.5 ml	5 ml
7	5 ml	7.5 ml
10	7.5 ml	10 ml
12	7.5 ml	12.5 ml
15	10 ml	15 ml
17	10 ml	20 ml
20	12.5 ml	22.5 ml
22	15 ml	25 ml
25	15 ml	27.5 ml
27	17.5 ml	30 ml
30	20 ml	32.5 ml

For the treatment of certain infections, such as otitis media and sinusitis, lower respiratory tract infections, children aged 2 years and older may be administered daily doses up to 70/10 mg/kg body weight, divided into two doses.

If higher doses of amoxicillin are required for treatment, other formulations of Clavam should be used to avoid administration of unnecessarily high doses of clavulanic acid.

Renal impairment.

Dose adjustment is not required in children with creatinine clearance (CrCl) greater than 30 mL/min. The use of Clavam 228.5 mg/5 mL suspension is not recommended in children with creatinine clearance (CrCl) less than 30 mL/min.

Hepatic impairment. Use with caution and monitor liver function regularly. Insufficient data are available to make dosage recommendations.

Method of administration

The medication is intended for oral use and should be taken with food to minimize potential gastrointestinal intolerance.

Treatment may be initiated with parenteral administration of the drug and continued with an oral formulation.

Instructions for preparation of the suspension.

The powder contained in the vial should be reconstituted to form a suspension, as described below.

1. Check the vial for integrity.
2. Invert and shake the vial to loosen the powder.
3. Add boiled water to the vial containing the powder up to the lower level marked by the red line with an arrow.
4. Close the vial with the cap and shake until a suspension is formed.
5. Then add the remaining water up to the upper level marked by the black line with an arrow, and shake again.
6. Allow the suspension to stand for 5 minutes to ensure complete dispersion of the powder.
7. Shake the suspension well before each use.

An oral dosing syringe should be used for accurate measurement of the dose and should be rinsed with water after each use.

Children.

The drug is indicated for children aged 2 months and older. Children with body weight above 40 kg should receive the drug in another pharmaceutical form.

Overdose.

Symptoms

Symptoms of gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Crystalluria associated with amoxicillin intake has been observed, which in some cases led to renal failure (see section "Special precautions").

Seizures may occur in patients with impaired renal function and in patients receiving high doses of the drug.

Amoxicillin precipitation in urinary catheters has been reported, primarily after high-dose intravenous administration. The patency of catheters should be monitored regularly (see section "Special precautions").

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid and electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Side effects.

Adverse effects have been classified according to their frequency of occurrence.

The most commonly reported adverse reactions (ARs) were diarrhea, nausea, and vomiting.

The following classification of adverse effect frequency is used:

very common ≥ 1/10;

common ≥ 1/100 and < 1/10;

uncommon ≥ 1/1000 and < 1/100;

rare ≥ 1/10000 and < 1/1000;

very rare < 1/10000;

not known (frequency cannot be estimated from available data).

Infections and infestations.

Common: candidiasis of skin and mucous membranes.

Not known: overgrowth of microorganisms not sensitive to the drug.

Disorders of the blood and lymphatic system.

Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.

Not known: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin index(^1).

Cardiac disorders.

Not known: Koerner’s syndrome.

Immune system disorders(^10).

Not known: angioneurotic edema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Disorders of the nervous system.

Uncommon: dizziness, headache.

Not known: reversible hyperactivity and convulsions(^2), aseptic meningitis.

Gastrointestinal disorders.

Common: diarrhea, nausea(^3), vomiting.

Uncommon: gastric disturbances.

Not known: antibiotic-associated colitis(^4), "black hairy tongue", discoloration of tooth enamel(^{11}), drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders.

Uncommon: increased levels of AST and/or ALT(^5).

Not known: hepatitis(^6) and cholestatic jaundice(^6).

Skin and subcutaneous tissue disorders(^7).

Uncommon: skin rashes, pruritus, urticaria.

Rare: erythema multiforme.

Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis(^9), drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders.

Very rare: interstitial nephritis, crystalluria(^8) (including acute kidney injury).

1 See section "Special precautions for use".

2 See section "Special precautions for use".

3 Nausea is more frequently associated with higher oral doses of the drug. Gastrointestinal reactions may be reduced in severity by taking the drug with food.

4 Including pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions for use").

5 Mild elevations in AST and/or ALT levels have been more frequently observed in patients receiving β-lactam antibiotics; however, the clinical significance of these findings is unknown.

6 These events have been reported with other penicillins and cephalosporins (see section "Special precautions for use").

7 In case of hypersensitivity reactions (dermatitis), the drug should be discontinued (see section "Special precautions for use").

8 See section "Overdose".

9 See section "Special precautions for use".

10 See section "Contraindications" and "Special precautions for use".

11 Very rarely, superficial tooth discoloration has been observed in children. Proper oral hygiene may prevent this effect. Discoloration can be removed by tooth brushing.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C, in a place inaccessible to children.

After reconstitution, store the suspension for up to 7 days at 2–8 °C.

Packaging.

One vial containing powder for oral suspension (100 ml) with a measuring cap, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Alkem Laboratories Ltd.

Manufacturer's address and place of business.

167 Mahatma Gandhi, Udio Nagar, Dabhel, Daman, 396210, India.