Cefixime Dispersible Tablets IP 100 mg

Cefixime Tablets IP

C Tax-O 100 DT

Each uncoated dispersible tablet contains:

Cefixime IP (as Trihydrate) equivalent to

Cefixime (Anhydrous)………………………… 100 mg

Excipients………………………………………...q.s.

Colour: Lake of Quinoline Yellow

Flavour added

C Tax-O 200

Each film coated tablet contains:

Cefixime IP (as Trihydrate)

equivalent to Cefixime (Anhydrous) ………………………200 mg

Excipients…………………………………… q.s.

Colour: Titanium Dioxide IP

100mg uncoated dispersible Tablets

200mg Tablets

4.1.Therapeutic indications

Oral cephalosporin- in the treatment of

• Urinary tract infection (UTI)
• Respiratory tract infections: upper respiratory tract infections (URTI) and lower respiratory tract infections
• Biliary tract infections

4.2. Posology and method of administration

The usual course of treatment is 7 days. This may be continued for up to 14 days if required.

Posology

Adults and Children over 10 years or weighing more than 50 kg:

The recommended dose is 200 – 400 mg daily according to the severity of infection, given either as a single dose or in two divided doses.

Elderly: Elderly patients may be given the same dose as recommended for adults. Renal function should be assessed and dosage should be adjusted in severe renal impairment.

Pediatric Patients (6 months or older)

The recommended dose is 8 mg/kg/day of the suspension. This may be administered as a single daily dose or may be given in two divided doses, as 4 mg/kg every 12 hours.

Table 1. Suggested doses for pediatric patients

Safety and effectiveness of cefixime in children aged less than six months old have not been established.

Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose.

In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of cefixime should be administered for at least 10 days.

Renal impairment:

Method for administration:

4.3.Contraindications

Hypersensitivity to cephalosporin antibiotics or to any of the excipients.

4.4. Special warnings and precautions for use

Encephalopathy

Beta-lactams, including cefixime, predispose the patient to encephalopathy risk (which may include convulsions, confusion, impairment of consciousness, movement disorders), particularly in case of overdose or renal impairment.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARS) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS) drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in association with cefixime. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of skin hypersensitivity.

Cefixime should be given with caution to patients who have shown hypersensitivity to other drugs.

Hypersensitivity to penicillins

As with other cephalosporins, cefixime should be given with caution to patients with a history of hypersensitivity to penicillin, as there is some evidence of partial cross-allergenicity between the penicillins and cephalosporins.

Patients have had severe reactions (including anaphylaxis) to both classes of drugs. If an allergic effect occurs with Cefixime, the drug should be discontinued and the patient treated with appropriate agents if necessary.

Haemolytic anaemia

Drug-induced haemolytic anaemia, including severe cases with a fatal outcome, has been described for cephalosporins (as a class). The recurrence of haemolytic anaemia after re-administration of cephalosporins in a patient with a history of cephalosporin (including cefixime) – associated haemolytic anaemia has also been reported.

Acute renal failure

As with other cephalosporins, cefixime may cause acute renal failure including tubulointerstitial nephritis as an underlying pathological condition. When acute renal failure occurs, cefixime should be discontinued and appropriate therapy and/or measures should be taken.

Renal impairment

Cefixime should be administered with caution in patients with markedly impaired renal function.

Paediatric use

Safety of cefixime in premature or new-born infant has not been established.

Antibiotic-associated colitis

Treatment with broad spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated diarrhoea. Pseudomembranous colitis is associated with the use of broad-spectrum antibiotics (including macrolides, semi-synthetic penicillins, lincosamides and cephalosporins); it is therefore important to consider its diagnosis in patients who develop diarrhoea in association with the use of antibiotics. Symptoms of pseudomembranous colitis may occur during or after antibiotic treatment. Management of pseudomembranous colitis should include sigmoidoscopy, appropriate bacteriologic studies, fluids, electrolytes and protein supplementation. If the colitis does not improve after the drug has been discontinued, or if the symptoms are severe, oral vancomycin is the drug of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile. Other causes of colitis should be excluded.

4.5. Interaction with other medicinal products and other forms of interaction

Anticoagulants

In common with other cephalosporins, increases in prothrombin times have been noted in a few patients. Care should therefore be taken in patients receiving anticoagulation therapy.

Cefixime should be administered with caution to patients receiving coumarin-type anticoagulants, e.g. warfarin potassium. Since cefixime may enhance effects of the anticoagulants, prolonged prothrombin time with or without bleeding may occur.

Other forms of interaction

A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions or with copper sulphate test tablets, but not with tests based on enzymatic glucose oxidase reactions.

A false positive direct Coombs test has been reported during treatment with cephalosporin antibiotics, therefore it should be recognised that a positive Coombs test may be due to the drug.

4.6. Fertility, pregnancy and lactation

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of harm to the fetus due to cefixime. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Cefixime has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.

Nursing Mothers

It is not known whether cefixime is excreted in human milk. Consideration should be given to discontinuing nursing temporarily during treatment with this drug.

4.7. Effects on ability to drive and use machines

In the case of side effects such as encephalopathy (which may include convulsion, confusion, impairment of consciousness, movement disorders), the patient should not operate machines or drive a vehicle.

4.8. Undesirable effects

The most commonly seen adverse reactions were gastrointestinal events, which were reported in 30% of adult patients on either the twice-daily or the once-daily regimen. Clinically mild gastrointestinal side effects occurred in 20% of all patients, moderate events occurred in 9% of all patients and severe adverse reactions occurred in 2% of all patients.

Individual adverse reactions included diarrhoea (16%), loose or frequent stools (6%), abdominal pain (3%), nausea (7%), dyspepsia (3%), and flatulence (4%). Diarrhoea has been more commonly associated with higher doses. Other gastrointestinal side effects seen less frequently are vomiting and flatulence. Pseudomembranous colitis has been reported.

Acute generalized exanthematous pustulosis has been reported with Cefixime use in India.

The following adverse reactions have been reported following the post-approval use of cefixime. Incidence rates were less than 1 in 50 (less than 2%).

Gastrointestinal: Diarrhea, loose stools, abdominal pain, dyspepsia, nausea, and vomiting, pseudomembranous colitis

Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions (including shock and fatalities), skin rashes, urticaria, drug fever, pruritus, angioedema, and facial edema. Erythema multiforme, Stevens-Johnson syndrome, and serum sickness-like reactions have been reported;

Hepatic: Transient elevations in SGPT, SGOT, alkaline phosphatase, hepatitis, jaundice; Renal : Transient elevations in BUN or creatinine, acute renal failure; Central Nervous System : Headaches, dizziness, seizures;

Hemic and Lymphatic Systems: Transient thrombocytopenia, leukopenia, neutropenia, and eosinophilia. Prolongation in prothrombin time was seen rarely;

Abnormal Laboratory Tests: Hyperbilirubinemia;

Other: Genital pruritus, vaginitis, candidiasis, toxic epidermal necrolysis. In addition to the adverse reactions listed above which have been observed in patients treated with cefixime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:

Adverse reactions: Allergic reactions, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, haemorrhage and colitis. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Abnormal Laboratory Tests: Positive direct Coombs test, elevated LDH, pancytopenia, agranulocytosis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to:medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9.Overdose

There is a risk of encephalopathy in cases of administration of beta-lactam antibiotics, including cefixime, particularly in case of overdose or renal impairment.

Adverse reactions seen at dose levels up to 2 g cefixime in normal subjects did not differ from the profile seen in patients treated at the recommended doses. Cefixime is not removed from the circulation in significant quantities by dialysis.

No specific antidote exists. General supportive measures are recommended.

5.1 Pharmacodynamic properties

Mechanism of Action

Pharmacotherapeutic group: third generation cephalosporin, ATC code: J01DD08

Cefixime is an oral third generation cephalosporin which has marked in vitro bactericidal activity against a wide variety of Gram-positive and Gram-negative organisms.

Clinical efficacy has been demonstrated in infections caused by commonly occurring pathogens including Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Proteus mirabilis, Klebsiella species, Haemophilus influenzae (beta-lactamase positive and negative), Branhamella catarrhalis (beta-lactamase positive and negative) and Enterobacter species. It is highly stable in the presence of beta-lactamase enzymes.

Most strains of enterococci (Streptococcus faecalis, group D Streptococci) and Staphylococci (including coagulase positive and negative strains and methicillin-resistant strains) are resistant to cefixime. In addition, most strains of Pseudomonas, Bacteroides fragilis, Listeria monocytogenes and Clostridia are resistant to cefixime.

5.2 Pharmacokinetic properties

Absorption

The absolute oral bioavailability of cefixime is in the range of 22 to 54%. Cefixime tablets and suspension, given orally, are about 40 to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. Typically, the peak serum levels following the recommended adult or paediatric doses are between 1.5 and 3 mcg/ml. A single 200 mg tablet of cefixime produces an average peak serum concentration of approximately 2 mcg/mL(range: 1 to 4 mcg/mL). The oral suspension produces average peak concentrations approximately 25 to 50% higher than the tablets, when tested in normal adultvolunteers. Oral suspension 200 mg doses produce average peak concentrations of 3 mcg/mL (range: 1 to 4.5 mcg/mL), when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10 to 25% with the oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Because of the lack of bioequivalence, tablets should not be substituted for oral suspension in the treatment

of otitis media. Crossover studies of tablet versus suspension have not been performed in children.

Absorption is not significantly modified by the presence of food. Cefixime may, therefore, be given without regard to meals. Peak serum concentrations occur between 2 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg tablet, or 400 mg of cefixime suspension. Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of suspension.

From in vitro studies, serum or urine concentrations of 1 mcg/ml or greater were considered to be adequate for most common pathogens against which cefixime is active.

Distribution

Cefixime is almost exclusively bound to the albumin fraction, the mean free fraction being approximately 30%. Serum protein binding is concentration independent, with a bound fraction of approximately 65%. Protein binding of cefixime is only concentration-dependent in human serum at very high concentrations, which are not seen following clinical dosing. In a multiple-dose study conducted with a research formulation, which is less bioavailable than the tablet or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days.

Metabolism and Excretion

There is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3 to 4 hours, but may range up to 9 hours in some normal volunteers.

Special Populations

Geriatrics

Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for 5 days are summarized as follows: Pharmacokinetic Parameters (mean ± SD) for Cefixime in Both Young & Elderly Subjects

Renal Impairment:

In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, a study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

Cefixime is a semisynthetic, cephalosporin antibacterial for oral administration. Chemically, it is (6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 72-(Z)-[O-(carboxy methyl) oxime] trihydrate.

Molecular weight = 507.50 as the Trihydrate.

Chemical Formula is C₁₆H₁₅N₅O₇S₂.3H₂O

The structural formula for cefixime is:

1.Incompatibilities

Not applicable.

2.Shelf-life

Refer on the pack.

3.Packaging information

C Tax-O 100 DT: A Strip of 10 tablets.

C Tax-O 200: A Strip of 10 tablets.

4.Storage and handing instructions

C Tax-O 100 DT: Store protected from moisture at a temperature not

exceeding 25°C. C Tax-O 200: Store in a cool & dry place. Protect from light. Keep out of reach of children.

Counsel patients that antibacterial drugs, including cefixime, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefixime is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefixime tablets or other antibacterial drugs in the future.

Advise patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.

18th Sept. 2024

Cefotaxime Sodium Injection IP 250 mg / 500 mg / 1 gm

C-Tax 250

Each vial contains:

Cefotaxime Sodium IP

equivalent to Cefotaxime 250 mg

This pack contains Sterile Water for Injections IP 5 ml.

C-Tax 500

Each vial contains:

Cefotaxime Sodium IP

equivalent to Cefotaxime 500 mg

This pack contains Sterile Water for Injections IP 5 ml.

C-Tax 1.0 g

Each vial contains:

Cefotaxime Sodium IP

equivalent to Cefotaxime 1.0 g

This pack contains Sterile Water for Injections IP 5 ml.

Powder for solution for injection/infusion

250 mg / 500 mg / 1 gm

4.1.Therapeutic indication

Indicated in the treatment of patients with serious infections.

1. Cefotaxime is indicated in the treatment of serious infections, either before the infecting organism has been identified or when caused by bacteria of established sensitivity, including

• osteomyelitis,
• septicaemia,
• bacterial endocarditis,
• meningitis,
• peritonitis
• and other serious bacterial infections suitable for parenteral antibiotic therapy.

2. Cefotaxime may be used for pre-operative prophylaxis in patients undergoing surgical procedures, that may be classified as contaminated or potentially so.

4.2.Posology and method of administration

Cefotaxime may be administered intravenously by bolus injection or by infusion, or by intramuscular injection. The dosage, route and frequency of administration should be determined by the severity of infection, the sensitivity of causative organisms and condition of the patient. Therapy may be initiated before the results of sensitivity tests are known.

Adults:

The recommended dosage for mild to moderate infections is 1g 12 hourly. However, dosage may be varied according to the severity of the infection, sensitivity of causative organisms and condition of the patient. Therapy may be initiated before the results of sensitivity tests are known.

In severe infections dosage may be increased up to 12g daily given in three or four divided doses. For infections caused by sensitive Pseudomonas species daily doses of greater than 6g will usually be required.

Children:

The usual dosage range is 100-150mg/kg/day in two to four divided doses. However, in very severe infection doses of up to 200mg/kg/day may be required.

Neonates: The recommended dosage is 50mg/kg/day in two to four divided doses. In severe infections 150-200mg/kg/day, in divided doses, have been given.

Dosage in renal impairment: Because of extra-renal elimination, it is only necessary to reduce the dosage of cefotaxime in severe renal failure (GFR <5ml/min = serum creatinine approximately 751 micromol/litre). After an initial loading dose of 1g, daily dose should be halved without change in the frequency of dosing, i.e. 1g twelve hourly becomes 0.5g twelve hourly, 1g eight hourly becomes 0.5g eight hourly, 2g eight hourly becomes 1g eight hourly etc. As in all other patients, dosage may require further adjustment according to the course of the infection and the general condition of the patient.

Dosage in hepatic impairment: No dosage adjustment is required.

Intravenous and Intramuscular Administration

Dissolve the contents in 3 ml (for 250 mg / 500 mg) or 5 ml (for 1 gm) of Sterile Water for Injections IP, provided with this pack. Use immediately after reconstitution. Any unused portion must be discarded. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Intravenous Administration (Injection or Infusion): For intermittent I.V. injections, the solution must be injected over a period of 3 to 5 minutes.

Intravenous Infusion: 1-2 gm cefotaxime are dissolved in 40-100 ml of infusion fluid. After 24 hours any unused solution should be discarded. The prepared infusion may be administered over 20-60 minutes. Cefotaxime and aminoglycosides should not be mixed in the same syringe or perfusion fluid.

Compatible Infusion Solutions:

• Sodium Chloride 0.9%
• Dextrose 5 and 10%
• Ringer-Lactate Solution

Intramuscular Administration: Cefotaxime should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock; aspiration is necessary to avoid inadvertent injection into a blood vessel.

4.3.Contraindications

• Hypersensitivity to cephalosporins.
• In patients with a history of hypersensitivity to Cefotaxime and/or to any of the component listed in the formulation, a penicillin or to any other type of β-lactam drug.
• Allergic cross reactions can exist between penicillins and cephalosporins.

4.4.Special warnings and precautions for use

As with other antibiotics, the use of cefotaxime, especially if prolonged, may result in overgrowth of non-susceptible organisms, such as Enterococcus spp, candida, Pseudomonas aeruginosa. Repeated evaluation of the condition of the patient is essential. If superinfection occurs during treatment with cefotaxime, appropriate measures should be taken and specific anti-microbial therapy should be instituted if considered clinically necessary.

Anaphylactic reactions: Preliminary enquiry about hypersensitivity to penicillin and other β -Lactam antibiotics is necessary before prescribing cephalosporins since cross allergy occurs in 5– 10% of cases. The use of cefotaxime is strictly contra-indicated in subjects with a previous history of immediate-type hypersensitivity to cephalosporins. Since cross allergy exists between penicillins and cephalosporins, use of the latter should be undertaken with extreme caution in penicillin sensitive subjects. Serious, including fatal hypersensitivity reactions have been reported in patients receiving cefotaxime (see sections 4.3 and 4.8). If a hypersensitivity reaction occurs, treatment must be stopped.

Severe skin reactions: Severe cutaneous adverse reactions (SCARs) including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported post-marketing in association with cefotaxime treatment.

At the time of prescription patients should be advised of the signs and symptoms for skin reactions.

If signs and symptoms suggestive of these reactions appear, cefotaxime should be withdrawn immediately. If the patient has developed AGEP, SJS, TEN or DRESS with the use of cefotaxime, treatment with cefotaxime must not be restarted and should be permanently discontinued.

In children, the presentation of a rash can be mistaken for the underlying infection or an alternative infectious process, and physicians should consider the possibility of a reaction to cefotaxime in children that develop symptoms of rash and fever during therapy with cefotaxime.

Patients with renal insufficiency: The dosage should be modified according to the creatinine clearance calculated. Patients with severe renal dysfunction should be placed on the dosage schedule recommended under “Posology and Method of Administration”.

Caution should be exercised if cefotaxime is administered together with aminoglycosides, probenecid or other nephrotoxic drugs (see section 4.5). Renal function must be monitored in these patients, the elderly, and those with pre-existing renal impairment.

Haematological reactions: Leukopenia, neutropenia, and more rarely, agranulocytosis may develop during treatment with cefotaxime, particularly if given over long periods. For treatment courses lasting longer than 7-10 days, the blood white cell count should be monitored and treatment stopped in the event of neutropenia.

Some cases of eosinophilia and thrombocytopenia, rapidly reversible on stopping treatment, have been reported. Cases of haemolytic anaemia have also been reported (see section 4.8).

Sodium intake: The sodium content of cefotaxime (2.09mmol/g) should be taken into account when prescribing to patients requiring sodium restriction.

Clostridium difficile associated disease (e.g. pseudomembranous colitis): Cefotaxime may predispose patients to pseudomembranous colitis. Although any antibiotic may predispose to pseudomembranous colitis, the risk is higher with broad spectrum drugs, such as cephalosporins. This side effect, which may occur more frequently in patients receiving higher doses for prolonged periods, should be considered as potentially serious.

Diarrhoea, particularly if severe and/or persistent, occurring during treatment or in the initial weeks following treatment, may be symptomatic of Clostridium difficile associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudo-membranous colitis.

The diagnosis of this rare but possibly fatal condition can be confirmed by endoscopy and/or histology.

It is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of cefotaxime.

If a diagnosis of pseudomembranous colitis is suspected, cefotaxime should be stopped immediately and appropriate specific antibody therapy should be started without delay.

Clostridium difficile associated disease can be favoured by faecal stasis.

Medicinal products that inhibit peristalsis should not be given.

Neurotoxicity: High doses of beta-lactam antibiotics, including cefotaxime, particularly in patients with renal insufficiency, may result in encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions).

Patients should be advised to contact their doctor immediately prior to continuing treatment if such reactions occur.

Precautions for administration: During post-marketing surveillance, potentially life-threatening arrhythmia has been reported in a very few patients who received rapid intravenous administration of cefotaxime through a central venous catheter. The recommended time for injection or infusion should be followed.

Effects on Laboratory Tests: As with other cephalosporins a positive Coombs' test has been found in some patients treated with cefotaxime. This phenomenon can interfere with the cross-matching of blood.

Urinary glucose testing with non-specific reducing agents may yield false-positive results. This phenomenon is not seen when a glucose-oxydase specific method is used.

4.5.Interaction with other medicinal products and other forms of interaction

Aminoglycoside antibiotics and diuretics: As with other cephalosporins, cefotaxime may potentiate the nephrotoxic effects of nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. furosemide). Renal function must be monitored.

Uricosurics: Probenecid interferes with renal tubular transfer of cefotaxime, thereby increasing cefotaxime exposure about 2-fold and reducing renal clearance to about half at therapeutic doses. Due to the large therapeutic index of cefotaxime, no dosage adjustment is needed in patients with normal renal function. Dosage adjustment may be needed in patients with renal impairment.

Interference with Laboratory Tests: A false positive Coombs test may be seen during treatment with cephalosporins. This phenomenon may occur during treatment with cefotaxime and can interfere with blood cross-matching.

A false positive reaction to urinary glucose may occur with copper reduction methods (Benedict's, Fehling's or Clinitest) but not with the use of specific glucose oxidase methods.

There is a potential for mezlocillin and azlocillin to reduce the clearance of cefotaxime.

4.6. Fertility, pregnancy and lactation

Pregnancy: Teratogenic Effects: Pregnancy Category B:

Reproduction studies have been performed in pregnant mice given C TAX injection intravenously at doses up to 1200 mg/kg/day (0.4 times the recommended human dose based on mg/m2) or in pregnant rats when administered intravenously at doses up to 1200 mg/kg/day (0.8 times the recommended human dose based on mg/m2). No evidence of embryotoxicity or teratogenicity was seen in these studies. Although cefotaxime has been reported to cross the placental barrier and appear in cord blood, the effect on the human fetus is not known. There are no well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation: Cefotaxime passes into human breast milk in small amounts and is usually compatible with breast feeding, but careful monitoring of the infant is recommended. Effects on the physiological intestinal flora of the breast-fed infant leading to diarrhoea, colonisation by yeast-like fungi, and sensitisation of the infant cannot be excluded.

Therefore, a decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7. Effects on ability to drive and use machines

Cefotaxime has been associated with dizziness, which may affect the ability to drive or operate machinery. There is no evidence that cefotaxime directly impairs the ability to drive or to operate machines. High doses of cefotaxime, particularly in patients with renal insufficiency, may cause encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions). Patients should be advised not to drive or operate machinery if any such symptoms occur.

4.8.Undesirable effects

Jarisch-Herxheimer reaction

For the treatment of borreliosis, a Jarisch-Herxheimer reaction may develop during the first days of treatment.

The occurrence of one or more of the following symptoms has been reported after several week's treatment of borreliosis: skin rash, itching, fever, leucopenia, increase in liver enzymes, difficulty of breathing, joint discomfort.

Hepatobiliary disorders

Increase in liver enzymes (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase) and/or bilirubin have been observed. These laboratory abnormalities may rarely exceed twice the upper limit of the normal range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions

via email to: medico@zuventus.com

Website: Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9.Overdose

Symptoms of overdose may largely correspond to the profile of side effects. There is a risk of reversible encephalopathy in cases of administration of high doses of β – lactam antibiotics including cefotaxime.

In case of overdose, cefotaxime must be discontinued, and supportive treatment initiated, which includes measures to accelerate elimination, and symptomatic treatment of adverse reactions (e.g. convulsions). No specific antidote exists. Serum levels of cefotaxime may be reduced by peritoneal dialysis or haemodialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta-lactam antibiotics, cephalosporins.

ATC Code: J01D A10

Mode of action

Cefotaxime is a third generation broad spectrum bactericidal cephalosporin antibiotic. The bactericidal properties are due to the inhibitory effect of cefotaxime on bacterial cell wall synthesis.

Mechanisms of resistance

Resistance to Cefotaxime may be due to production of extended-spectrum beta-lactamases that can efficiently hydrolyse the drug, to the induction and/or constitutive expression of AmpC enzymes, to impermeability or to efflux pump mechanisms. More than one of these possible mechanisms may co-exist in a single bacterium.

Breakpoints:

Current MIC breakpoints used to interpret cefotaxime susceptibility data are shown below.

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical MIC Breakpoints (V1.1, 31/03/2006)

1. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with -- or IE in the table).

2. The cephalosporin breakpoints for Enterobacteriaceae will detect resistance mediated by most ESBLs and other clinically important beta-lactamases in Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible or intermediate with these breakpoints. Laboratories may want to use a test which specifically screens for the presence of ESBL.

3. Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility (except ceftazidime which should not be used for staphylococcal infections).

4. Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant.-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.

IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.

RD = rationale document listing data used by EUCAST for determining breakpoints.

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an approximate guidance on the probabilities whether micro-organisms will be susceptible to cefotaxime or not.

Methicillin-(oxacillin) resistant staphylococci (MRSA) are resistant to all currently available β -lactam antibiotics including cefotaxime.

Penicillin-resistant Streptococcus pneumoniae show a variable degree of cross-resistance to cephalosporins such as cefotaxime.

5.2 Pharmacokinetic properties

After a 1000mg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 microgram/ml. Doses of 500mg and 2000mg produce plasma concentrations of 38 and 200 micrograms/ml, respectively. There is no accumulation following administration of 1000mg intravenously or 500mg intramuscularly for 10 or 14 days.

The apparent volume of distribution at steady-state of cefotaxime is 21.6 litres/1.73m2 after 1g intravenous 30-minute infusion.

Concentrations of cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 microgram/ml in children with meningitis. Cefotaxime usually passes the blood-brain barrier in levels above the minimum inhibitory concentration of common sensitive pathogens when the meninges are inflamed. Concentrations (0.2-5.4 microgram/ml), inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gall bladder wall, after usual therapeutic doses. High concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile.

Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390ml/minute and renal clearance 145 to 217 ml/minute.

After intravenous administration of cefotaxime to healthy adults, the elimination half-life of the parent compound is 0.9 to 1.14 hours and that of the desacetyl metabolite, about 1.3 hours.

In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight neonates of the same age.

In severe renal dysfunction the elimination half-life of cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with reduction in renal function.

Carcinogenesis, Mutagenesis

Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. C TAX injection was not mutagenic in the mouse micronucleus test or in the Ames test. C TAX injection did not impair fertility to rats when administered subcutaneously at doses up to 250 mg/kg/day (0.2 times the maximum recommended human dose based on mg/m2) or in mice when administered intravenously at doses up to 2000 mg/kg/day (0.7 times the recommended human dose based on mg/m2).

Nonteratogenic Effects

Use of the drug in women of child-bearing potential requires that the anticipated benefit be weighed against the possible risks. In perinatal and postnatal studies with rats, the pups in the group given 1200 mg/kg/day of C TAX injection were significantly lighter in weight at birth and remained smaller than pups in the control group during the 21 days of nursing.

C TAX injection (cefotaxime sodium) is a semisynthetic, broad spectrum cephalosporin antibiotic for parenteral administration.

IUPAC Name:

It is the sodium salt of 7-[2-(2-amino-4-thiazolyl) glyoxylamido]-3- (hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 72 (Z)-(o-methyloxime), acetate (ester).

The molecular formula of cefotaxime is C₁₆H₁₆N₅NaO₇S₂ Molecular weight is 477.442 g/mol.

1.Incompatibilities

Cefotaxime sodium should not be mixed with alkaline solutions such as sodium bicarbonate injection or solutions containing aminophylline.

Cefotaxime should not be admixed with aminoglycosides. If they are used concurrently they should be administered in separate sites.

2.Shelf-life

Refer on the pack.

3. Packaging information

C-Tax 250: A vial of 250 mg with SWFI IP 5 ml.

C-Tax 500: A vial of 500 mg with SWFI IP 5 ml.

C-Tax 1.0 g: A vial of 1 g with SWFI IP 5 ml.

4. Storage and handing instructions

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

Keep out of reach of children.

After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Patients should be counseled that antibacterial drugs including C-Tax injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When C-Tax injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by C-Tax injection or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

17th Sept. 2024

Cefotaxime Sodium Injection IP 250 mg / 500 mg / 1 gm

C-Tax 250

Each vial contains:

Cefotaxime Sodium IP

equivalent to Cefotaxime 250 mg

This pack contains Sterile Water for Injections IP 5 ml.

C-Tax 500

Each vial contains:

Cefotaxime Sodium IP

equivalent to Cefotaxime 500 mg

This pack contains Sterile Water for Injections IP 5 ml.

C-Tax 1.0 g

Each vial contains:

Cefotaxime Sodium IP

equivalent to Cefotaxime 1.0 g

This pack contains Sterile Water for Injections IP 5 ml.

Powder for solution for injection/infusion

250 mg / 500 mg / 1 gm

4.1.Therapeutic indication

Indicated in the treatment of patients with serious infections.

1. Cefotaxime is indicated in the treatment of serious infections, either before the infecting organism has been identified or when caused by bacteria of established sensitivity, including

• osteomyelitis,
• septicaemia,
• bacterial endocarditis,
• meningitis,
• peritonitis
• and other serious bacterial infections suitable for parenteral antibiotic therapy.

2. Cefotaxime may be used for pre-operative prophylaxis in patients undergoing surgical procedures, that may be classified as contaminated or potentially so.

4.2.Posology and method of administration

Cefotaxime may be administered intravenously by bolus injection or by infusion, or by intramuscular injection. The dosage, route and frequency of administration should be determined by the severity of infection, the sensitivity of causative organisms and condition of the patient. Therapy may be initiated before the results of sensitivity tests are known.

Adults:

The recommended dosage for mild to moderate infections is 1g 12 hourly. However, dosage may be varied according to the severity of the infection, sensitivity of causative organisms and condition of the patient. Therapy may be initiated before the results of sensitivity tests are known.

In severe infections dosage may be increased up to 12g daily given in three or four divided doses. For infections caused by sensitive Pseudomonas species daily doses of greater than 6g will usually be required.

Children:

The usual dosage range is 100-150mg/kg/day in two to four divided doses. However, in very severe infection doses of up to 200mg/kg/day may be required.

Neonates: The recommended dosage is 50mg/kg/day in two to four divided doses. In severe infections 150-200mg/kg/day, in divided doses, have been given.

Dosage in renal impairment: Because of extra-renal elimination, it is only necessary to reduce the dosage of cefotaxime in severe renal failure (GFR <5ml/min = serum creatinine approximately 751 micromol/litre). After an initial loading dose of 1g, daily dose should be halved without change in the frequency of dosing, i.e. 1g twelve hourly becomes 0.5g twelve hourly, 1g eight hourly becomes 0.5g eight hourly, 2g eight hourly becomes 1g eight hourly etc. As in all other patients, dosage may require further adjustment according to the course of the infection and the general condition of the patient.

Dosage in hepatic impairment: No dosage adjustment is required.

Intravenous and Intramuscular Administration

Dissolve the contents in 3 ml (for 250 mg / 500 mg) or 5 ml (for 1 gm) of Sterile Water for Injections IP, provided with this pack. Use immediately after reconstitution. Any unused portion must be discarded. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Intravenous Administration (Injection or Infusion): For intermittent I.V. injections, the solution must be injected over a period of 3 to 5 minutes.

Intravenous Infusion: 1-2 gm cefotaxime are dissolved in 40-100 ml of infusion fluid. After 24 hours any unused solution should be discarded. The prepared infusion may be administered over 20-60 minutes. Cefotaxime and aminoglycosides should not be mixed in the same syringe or perfusion fluid.

Compatible Infusion Solutions:

• Sodium Chloride 0.9%
• Dextrose 5 and 10%
• Ringer-Lactate Solution

Intramuscular Administration: Cefotaxime should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock; aspiration is necessary to avoid inadvertent injection into a blood vessel.

4.3.Contraindications

• Hypersensitivity to cephalosporins.
• In patients with a history of hypersensitivity to Cefotaxime and/or to any of the component listed in the formulation, a penicillin or to any other type of β-lactam drug.
• Allergic cross reactions can exist between penicillins and cephalosporins.

4.4.Special warnings and precautions for use

As with other antibiotics, the use of cefotaxime, especially if prolonged, may result in overgrowth of non-susceptible organisms, such as Enterococcus spp, candida, Pseudomonas aeruginosa. Repeated evaluation of the condition of the patient is essential. If superinfection occurs during treatment with cefotaxime, appropriate measures should be taken and specific anti-microbial therapy should be instituted if considered clinically necessary.

Anaphylactic reactions: Preliminary enquiry about hypersensitivity to penicillin and other β -Lactam antibiotics is necessary before prescribing cephalosporins since cross allergy occurs in 5– 10% of cases. The use of cefotaxime is strictly contra-indicated in subjects with a previous history of immediate-type hypersensitivity to cephalosporins. Since cross allergy exists between penicillins and cephalosporins, use of the latter should be undertaken with extreme caution in penicillin sensitive subjects. Serious, including fatal hypersensitivity reactions have been reported in patients receiving cefotaxime (see sections 4.3 and 4.8). If a hypersensitivity reaction occurs, treatment must be stopped.

Severe skin reactions: Severe cutaneous adverse reactions (SCARs) including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported post-marketing in association with cefotaxime treatment.

At the time of prescription patients should be advised of the signs and symptoms for skin reactions.

If signs and symptoms suggestive of these reactions appear, cefotaxime should be withdrawn immediately. If the patient has developed AGEP, SJS, TEN or DRESS with the use of cefotaxime, treatment with cefotaxime must not be restarted and should be permanently discontinued.

In children, the presentation of a rash can be mistaken for the underlying infection or an alternative infectious process, and physicians should consider the possibility of a reaction to cefotaxime in children that develop symptoms of rash and fever during therapy with cefotaxime.

Patients with renal insufficiency: The dosage should be modified according to the creatinine clearance calculated. Patients with severe renal dysfunction should be placed on the dosage schedule recommended under “Posology and Method of Administration”.

Caution should be exercised if cefotaxime is administered together with aminoglycosides, probenecid or other nephrotoxic drugs (see section 4.5). Renal function must be monitored in these patients, the elderly, and those with pre-existing renal impairment.

Haematological reactions: Leukopenia, neutropenia, and more rarely, agranulocytosis may develop during treatment with cefotaxime, particularly if given over long periods. For treatment courses lasting longer than 7-10 days, the blood white cell count should be monitored and treatment stopped in the event of neutropenia.

Some cases of eosinophilia and thrombocytopenia, rapidly reversible on stopping treatment, have been reported. Cases of haemolytic anaemia have also been reported (see section 4.8).

Sodium intake: The sodium content of cefotaxime (2.09mmol/g) should be taken into account when prescribing to patients requiring sodium restriction.

Clostridium difficile associated disease (e.g. pseudomembranous colitis): Cefotaxime may predispose patients to pseudomembranous colitis. Although any antibiotic may predispose to pseudomembranous colitis, the risk is higher with broad spectrum drugs, such as cephalosporins. This side effect, which may occur more frequently in patients receiving higher doses for prolonged periods, should be considered as potentially serious.

Diarrhoea, particularly if severe and/or persistent, occurring during treatment or in the initial weeks following treatment, may be symptomatic of Clostridium difficile associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudo-membranous colitis.

The diagnosis of this rare but possibly fatal condition can be confirmed by endoscopy and/or histology.

It is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of cefotaxime.

If a diagnosis of pseudomembranous colitis is suspected, cefotaxime should be stopped immediately and appropriate specific antibody therapy should be started without delay.

Clostridium difficile associated disease can be favoured by faecal stasis.

Medicinal products that inhibit peristalsis should not be given.

Neurotoxicity: High doses of beta-lactam antibiotics, including cefotaxime, particularly in patients with renal insufficiency, may result in encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions).

Patients should be advised to contact their doctor immediately prior to continuing treatment if such reactions occur.

Precautions for administration: During post-marketing surveillance, potentially life-threatening arrhythmia has been reported in a very few patients who received rapid intravenous administration of cefotaxime through a central venous catheter. The recommended time for injection or infusion should be followed.

Effects on Laboratory Tests: As with other cephalosporins a positive Coombs' test has been found in some patients treated with cefotaxime. This phenomenon can interfere with the cross-matching of blood.

Urinary glucose testing with non-specific reducing agents may yield false-positive results. This phenomenon is not seen when a glucose-oxydase specific method is used.

4.5.Interaction with other medicinal products and other forms of interaction

Aminoglycoside antibiotics and diuretics: As with other cephalosporins, cefotaxime may potentiate the nephrotoxic effects of nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. furosemide). Renal function must be monitored.

Uricosurics: Probenecid interferes with renal tubular transfer of cefotaxime, thereby increasing cefotaxime exposure about 2-fold and reducing renal clearance to about half at therapeutic doses. Due to the large therapeutic index of cefotaxime, no dosage adjustment is needed in patients with normal renal function. Dosage adjustment may be needed in patients with renal impairment.

Interference with Laboratory Tests: A false positive Coombs test may be seen during treatment with cephalosporins. This phenomenon may occur during treatment with cefotaxime and can interfere with blood cross-matching.

A false positive reaction to urinary glucose may occur with copper reduction methods (Benedict's, Fehling's or Clinitest) but not with the use of specific glucose oxidase methods.

There is a potential for mezlocillin and azlocillin to reduce the clearance of cefotaxime.

4.6. Fertility, pregnancy and lactation

Pregnancy: Teratogenic Effects: Pregnancy Category B:

Reproduction studies have been performed in pregnant mice given C TAX injection intravenously at doses up to 1200 mg/kg/day (0.4 times the recommended human dose based on mg/m2) or in pregnant rats when administered intravenously at doses up to 1200 mg/kg/day (0.8 times the recommended human dose based on mg/m2). No evidence of embryotoxicity or teratogenicity was seen in these studies. Although cefotaxime has been reported to cross the placental barrier and appear in cord blood, the effect on the human fetus is not known. There are no well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation: Cefotaxime passes into human breast milk in small amounts and is usually compatible with breast feeding, but careful monitoring of the infant is recommended. Effects on the physiological intestinal flora of the breast-fed infant leading to diarrhoea, colonisation by yeast-like fungi, and sensitisation of the infant cannot be excluded.

Therefore, a decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7. Effects on ability to drive and use machines

Cefotaxime has been associated with dizziness, which may affect the ability to drive or operate machinery. There is no evidence that cefotaxime directly impairs the ability to drive or to operate machines. High doses of cefotaxime, particularly in patients with renal insufficiency, may cause encephalopathy (e.g. impairment of consciousness, abnormal movements and convulsions). Patients should be advised not to drive or operate machinery if any such symptoms occur.

4.8.Undesirable effects

Jarisch-Herxheimer reaction

For the treatment of borreliosis, a Jarisch-Herxheimer reaction may develop during the first days of treatment.

The occurrence of one or more of the following symptoms has been reported after several week's treatment of borreliosis: skin rash, itching, fever, leucopenia, increase in liver enzymes, difficulty of breathing, joint discomfort.

Hepatobiliary disorders

Increase in liver enzymes (ALAT, ASAT, LDH, gamma-GT and/or alkaline phosphatase) and/or bilirubin have been observed. These laboratory abnormalities may rarely exceed twice the upper limit of the normal range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions

via email to: medico@zuventus.com

Website: Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9.Overdose

Symptoms of overdose may largely correspond to the profile of side effects. There is a risk of reversible encephalopathy in cases of administration of high doses of β – lactam antibiotics including cefotaxime.

In case of overdose, cefotaxime must be discontinued, and supportive treatment initiated, which includes measures to accelerate elimination, and symptomatic treatment of adverse reactions (e.g. convulsions). No specific antidote exists. Serum levels of cefotaxime may be reduced by peritoneal dialysis or haemodialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta-lactam antibiotics, cephalosporins.

ATC Code: J01D A10

Mode of action

Cefotaxime is a third generation broad spectrum bactericidal cephalosporin antibiotic. The bactericidal properties are due to the inhibitory effect of cefotaxime on bacterial cell wall synthesis.

Mechanisms of resistance

Resistance to Cefotaxime may be due to production of extended-spectrum beta-lactamases that can efficiently hydrolyse the drug, to the induction and/or constitutive expression of AmpC enzymes, to impermeability or to efflux pump mechanisms. More than one of these possible mechanisms may co-exist in a single bacterium.

Breakpoints:

Current MIC breakpoints used to interpret cefotaxime susceptibility data are shown below.

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical MIC Breakpoints (V1.1, 31/03/2006)

1. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with -- or IE in the table).

2. The cephalosporin breakpoints for Enterobacteriaceae will detect resistance mediated by most ESBLs and other clinically important beta-lactamases in Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible or intermediate with these breakpoints. Laboratories may want to use a test which specifically screens for the presence of ESBL.

3. Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility (except ceftazidime which should not be used for staphylococcal infections).

4. Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant.-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.

IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.

RD = rationale document listing data used by EUCAST for determining breakpoints.

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an approximate guidance on the probabilities whether micro-organisms will be susceptible to cefotaxime or not.

Methicillin-(oxacillin) resistant staphylococci (MRSA) are resistant to all currently available β -lactam antibiotics including cefotaxime.

Penicillin-resistant Streptococcus pneumoniae show a variable degree of cross-resistance to cephalosporins such as cefotaxime.

5.2 Pharmacokinetic properties

After a 1000mg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 microgram/ml. Doses of 500mg and 2000mg produce plasma concentrations of 38 and 200 micrograms/ml, respectively. There is no accumulation following administration of 1000mg intravenously or 500mg intramuscularly for 10 or 14 days.

The apparent volume of distribution at steady-state of cefotaxime is 21.6 litres/1.73m2 after 1g intravenous 30-minute infusion.

Concentrations of cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 microgram/ml in children with meningitis. Cefotaxime usually passes the blood-brain barrier in levels above the minimum inhibitory concentration of common sensitive pathogens when the meninges are inflamed. Concentrations (0.2-5.4 microgram/ml), inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gall bladder wall, after usual therapeutic doses. High concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile.

Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390ml/minute and renal clearance 145 to 217 ml/minute.

After intravenous administration of cefotaxime to healthy adults, the elimination half-life of the parent compound is 0.9 to 1.14 hours and that of the desacetyl metabolite, about 1.3 hours.

In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight neonates of the same age.

In severe renal dysfunction the elimination half-life of cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with reduction in renal function.

Carcinogenesis, Mutagenesis

Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. C TAX injection was not mutagenic in the mouse micronucleus test or in the Ames test. C TAX injection did not impair fertility to rats when administered subcutaneously at doses up to 250 mg/kg/day (0.2 times the maximum recommended human dose based on mg/m2) or in mice when administered intravenously at doses up to 2000 mg/kg/day (0.7 times the recommended human dose based on mg/m2).

Nonteratogenic Effects

Use of the drug in women of child-bearing potential requires that the anticipated benefit be weighed against the possible risks. In perinatal and postnatal studies with rats, the pups in the group given 1200 mg/kg/day of C TAX injection were significantly lighter in weight at birth and remained smaller than pups in the control group during the 21 days of nursing.

C TAX injection (cefotaxime sodium) is a semisynthetic, broad spectrum cephalosporin antibiotic for parenteral administration.

IUPAC Name:

It is the sodium salt of 7-[2-(2-amino-4-thiazolyl) glyoxylamido]-3- (hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 72 (Z)-(o-methyloxime), acetate (ester).

The molecular formula of cefotaxime is C₁₆H₁₆N₅NaO₇S₂ Molecular weight is 477.442 g/mol.

1.Incompatibilities

Cefotaxime sodium should not be mixed with alkaline solutions such as sodium bicarbonate injection or solutions containing aminophylline.

Cefotaxime should not be admixed with aminoglycosides. If they are used concurrently they should be administered in separate sites.

2.Shelf-life

Refer on the pack.

3. Packaging information

C-Tax 250: A vial of 250 mg with SWFI IP 5 ml.

C-Tax 500: A vial of 500 mg with SWFI IP 5 ml.

C-Tax 1.0 g: A vial of 1 g with SWFI IP 5 ml.

4. Storage and handing instructions

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

Keep out of reach of children.

After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Patients should be counseled that antibacterial drugs including C-Tax injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When C-Tax injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by C-Tax injection or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

17th Sept. 2024

Buprenorphine Transdermal Patch

BuprePLAST 5 mcg/hr

Each 6.25 cm2 transdermal patch contains :

Buprenorphine Ph.     Eur. 5 mg

Excipients     q.s.

Each patch delivers 5 mcg/hr Buprenorphine

BuprePLAST 10 mcg/hr

Each 12.5 cm2 transdermal patch contains :

Buprenorphine Ph. Eur.    10 mg

Excipients    q.s.

Each patch delivers 10 mcg/hr Buprenorphine

Transdermal Patch

4.1 Therapeutic indication

For the treatment of severe opioid responsive pain conditions which are not adequately responding to nonopioid analgesics.

4.2 Posology and method of administration

Bupreplast patch should be administered every 7th day. Bupreplast patch is not suitable for the treatment of acute pain.

Patients aged 18 years and over

The lowest Bupreplast patch dose (Bupreplast 5 mcg/hr transdermal patch) should be used as the initial dose. Consideration should be given to the previous opioid history of the patient as well as to the current general condition and medical status of the patient.

Titration

During initiation and titration with Bupreplast, patients should use the usual recommended doses of short acting supplemental analgesics as needed until analgesic efficacy with Bupreplast patch is attained. The dose should not be increased before 3 days, when the maximum effect of a given dose is established. Subsequent dosage increases may then be titrated based on the need for supplemental pain relief and the patient's analgesic response to the patch.

To increase the dose, a larger patch should replace the patch that is currently being worn, or a combination of patches should be applied in different places to achieve the desired dose. It is recommended that no more than two patches are applied at the same time, regardless of the patch strength. A new patch should not be applied to the same skin site for the subsequent 3-4 weeks. Patients should be carefully and regularly monitored to assess the optimum dose and duration of treatment.

Conversion from opioids

Patch can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (Bupreplast 5 mcg/hr transdermal patch) and continue taking short-acting supplemental analgesics during titration as required.

Patients under 18 years of age

As buprenorphine patch has not been studied in patients under 18 years of age,the use of Bupreplast patch in patients below this age is not recommended.

Elderly

No dosage adjustment of Bupreplast patch is required in elderly patients.

Renal impairment

No special dose adjustment of Bupreplast patch is necessary in patients with renal impairment.

Hepatic impairment

Buprenorphine is metabolised in the liver. The intensity and duration of its action may be affected in patients with impaired liver function. Therefore patients with hepatic insufficiency should be carefully monitored during treatment with Bupreplast patch. Patients with severe hepatic impairment may accumulate buprenorphine during Bupreplast patch treatment. Consideration of alternate therapy should be considered, and Bupreplast should be used with caution, if at all, in such patients.

Patch application

Bupreplast should be applied to non-lrritated, Intact skin of the upper outer arm, upper chest, upper back or side of the chest, but not to any parts of the skin with large scars. Bupreplast patch should be applied to a relatively hairless or nearly hairless skin site. If none are available, the hair at the site should be cut with scissors, not shaven.

If the application site must be cleaned, It should be done with clean water only. Soaps, alcohol, oil, lotions of abrasive devices must not be used. The skin must be dry before the patch is applied. Bupreplast should be applied immediately after removal from the sealed sachet. Following removal of the protective layer, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges. If the edges of the patch begin to peel off, the edges may be taped down with suitable skin tape.

The patch should be worn continuously for 7 days.

Bathing, showering, or swimming should not affect the patch. If a patch falls off, a new one should be applied.

Duration of administration

Bupreplast should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Bupreplast is necessary in view of the nature and severity to the illness, then careful and regular monitoring should be carried out (If necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.

Discontinuation

After removal of the patch, buprenorphine serum concentrations decrease gradually and thus the analgesic effect is maintained for a certain amount of time. This should be considered when therapy with Bupreplast is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of the patch. At present, only limited information is available on the starting dose of other opioids administered after discontinuation of the transdermal patch.

Patients with fever or exposed to external heat

While wearing the patch, patients should be advised to avoid exposing the application site to external heat sources, such as heating pads, electric blankets, heat lamps, sauna, hot tubs, and heated water beds, etc., as an increase in absorption of buprenorphine may occur. When treating febrile patients, one should be aware that fever may also increase absorption resulting in increased plasma concentrations of buprenorphine and thereby increased risk of opioid reactions.

4.3 Contraindications

Buprenorphine patch is contraindicated in :

• Patients with known hypersensitivity to the active substance buprenorphine or to any of the excipients.
• The treatment of opioid dependence and narcotic withdrawal.
• Conditions in which the respiratory centre and function are severely impaired or may become so.
• Patients who are receiving MAO inhibitors or have taken them within the last two weeks.
• Patients suffering from myasthenia gravis
• Patients suffering from delirium tremens
• Pregnancy (see "Warnings & Precautions").

4.4 Special warnings and precautions for use

• Buprenorphine should be used with particular caution in patients with acute alcohol intoxication, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure, or in patients with severe hepatic impairment.
• Buprenorphine may lower the seizure threshold in patients with a history of seizure disorder.
• Significant respiratory depression has been associated with buprenorphine, particularly by the intravenous route. A number of overdose deaths have occurred when addicts have intravenously abused buprenorphine, usually with benzodiazepines concomitantly. Additional overdose deaths due to ethanol and benzodiazepines in combination with buprenorphine have been reported.
• Since CYP3A4 inhibitors may increase concentrations of buprenorphine, patients already treated with CYP3A4 inhibitors should have their dose of Buprenorphine carefully titrated since a reduced dosage might be sufficient in these patients.
• Buprenorphine is not recommended for analgesia in the immediate post-operative period or in other situations characterised by a narrow therapeutic index or a rapidly varying analgesic requirement.
• Controlled human and animal studies indicate that buprenorphine has a lower dependence liability than pure agonist analgesics. In humans limited euphorigenic effects have been observed with buprenorphine. This may result in some abuse of the medicinal product and caution should be exercised when prescribing to patients known to have, or suspected of having, a history of drug abuse or alcohol abuse or serious mental illness.
• As with all opioids chronic use of buprenorphine can result in the development of physical dependence. Withdrawal (abstinence syndrome), when it occurs, is generally mild, begins after 2 days and may last up to 2 weeks. Withdrawal symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disorders.
• Athletes should be aware that this medicine may cause a positive reaction to sports doping control tests.
• Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs : Concomitant use of Buprenorphine and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Buprenorphine concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
• The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms.

Serotonin syndrome

Concomitant administration of Buprenorphine and other serotonergic agents, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition.

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

4.5 Drugs interactions

Buprenorphine must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous two weeks. Effect of other active substances on the pharmacokinetics of buprenorphine :

• Buprenorphine is primarily metabolised by glucuronidation and to a lesser extent (about 30%) by CYP3A4.
• Concomitant treatment with CYP3A4 inhibitors may lead to elevated plasma concentrations with intensified efficacy of buprenorphine.
• Studies with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following buprenorphine with ketoconazole as compared to buprenorphine alone.
• The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied.
• Co-administration of buprenorphine and enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin and rifampicin) could lead to increased clearance which might result in reduced efficacy.
• Reductions in hepatic blood flow induced by some general anaesthetics (e.g. halothane) and other medicinal products may result in a decreased rate of hepatic elimination of buprenorphine.

Pharmacodynamic interactions

Buprenorphine should be used cautiously with :

• Other central nervous system depressants : other opioid derivatives (analgesics and antitussives containing e.g. morphine, dextropro-poxyphene, codeine, dextromethorphan or noscapine). Certain anti-depressants, sedative H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances. These combinations increase the CNS depressant activity. Benzodiazepines : This combination can potentiate respiratory depression of central origin.
• At typical analgesic doses buprenorphine is described to function as a pure mu receptor agonist. In buprenorphine clinical studies subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to buprenorphine. There were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to buprenorphine.
• Sedative medicines such as benzodiazepines or related drugs The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited Co-administration of Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased.

4.6 Use in special populations

Pregnancy

There are no or limited amount of data from the use of buprenorphine in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Prolonged use of buprenorphine during pregnancy can result in neonatal opioid withdrawal. Therefore, buprenorphine should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.

Nursing Mothers

Buprenorphine is excreted in human milk. Studies in rats have shown that buprenorphine may inhibit lactation. Available pharmacodynamic / toxicological data in animals has shown excretion of buprenorphine in milk. Therefore, the use of buprenorphine during lactation should be avoided.

Fertility

No human data on the effect of buprenorphine on fertility are available. In a fertility and early embryonic development study, no effects on reproductive parameters were observed in male or female rats

4.7 Effects on ability to drive and use machines

Buprenorphine has major influence on the ability to drive and use machines. Even when used according to instructions, buprenorphine patch may affect the patient's reactions to such an extent that road safety and the ability to operate machinery may be impaired. This applies particularly in the beginning of treatment and in conjunction with other centrally acting substances including alcohol, tranquillisers, sedatives and hypnotics. An individual recommendation should be given by the physician. A general restriction is not necessary in cases where a stable

dose is used.

In patients who are affected, such as during treatment initiation or titration to a higher dose, these patients should not drive or use machines, nor for at least 24 hours after the patch has been removed.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. When prescribing this medicine, patients should be told :

• The medicine is likely to affect your ability to drive.
• Do not drive until you know how the medicine affects you.

4.8 Undesirable effects

Serious adverse reactions that may be associated with buprenorphine patch therapy in clinical use are similar to those observed with other opioid analgesics, including respiratory depression (especially when used with other CNS depressants) and hypotension. The following undesirable effects have occurred :

Very common (> 1/10, common (> 1/100, <1/10, uncommon (>/1000, < 1/100), rare (> 1/10,000 < 1/1000), very rare (< 1/10,000 including isolated reports).

Immune system disorders

Uncommon : hypersensitivity

Very rare : anaphylactic reaction, anaphylactoid reaction

Metabolism and nutrition disorders

Common : anorexia

Uncommon : dehydration

Psychiatric disorders

Common : confusion, depression, insomnia, nervousness

Uncommon : sleep disorder, restlessness, agitation, depersonalization, euphoric mood, affect lability, anxiety, hallucinations, nightmares

Rare : psychotic disorder, decreased libido

Very rare : drug dependence, mood swings

Nervous system disorders

Very common : headache, dizziness, somnolence Common: paresthesia Uncommon : sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, tremor, abnormal coordination, disturbance in attention

Rare : balance disorder, speech disorder Very rare: involuntary muscle contractions

Eye disorders

Uncommon : dry eye, blurred vision

Rare : visual disturbance, eyelid oedema, miosis

Ear and labyrinth disorders

Uncommon : tinnitus, vertigo

Very rare : ear pain

Cardiac disorders

Uncommon : angina pectoris, palpitations, tachycardia

Vascular disorders

Common : vasodilation

Uncommon : hypotension, circulatory collapse, hypertension, flushing

Respiratory, thoracic and mediastinal disorders

Common : dyspnoea

Uncommon : asthma aggravated, cough, hypoxia, rhinitis, wheezing, hyperventilation, hiccups Rare: respirator y depression, respirator y failure

Gastrointestinal disorders

Very common : constipation, dry mouth, nausea, vomiting

Common : abdominal pain, diarrhoea, dyspepsia

Uncommon : flatulence

Rare : diverticulitis, dysphagia, ileus

Hepatobiliary disorders

Rare : Biliary colic

Skin and subcutaneous tissue disorders

Very common : pruritus, erythema

Common : rash, sweating, exanthema

Uncommon : dry skin, face oedema, urticaria Very rare : pustules, vesicles

Musculoskeletal and connective tissue disorders

Uncommon : Muscle cramp, myalgia, muscular weakness, muscle spasms

Renal and urinary disorders

Uncommon : urinary retention, micturition disorders

Reproductive system and breast disorders

Rare : erectile dysfunction, sexual dysfunction

General disorders and administration site conditions

Very common : application site pruritus, application site reaction

Common : tiredness, asthenia pain, peripheral oedema, application site reaction, erythema at site, rash at site, oedema, chest pain

Uncommon : fatigue, influenza like illness, pyrexia, rigors, malaise, oedema, drug withdrawal syndrome

Rare : application site inflammation

Investigations

Uncommon : alanine aminotransferase increased, weight decreased

Injury, poisoning and procedural complications

Uncommon : Accidental injury fall

* In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases treatment with buprenorphine patch should be terminated.

Buprenorphine has a low risk of physical dependence. After discontinuation of buprenorphine patch, withdrawal symptoms are unlikely. This may be due to the very slow dissociation of buprenorphine from the opioid receptors and to the gradual decrease of buprenorphine plasma concentrations (usually over a period of 30 hours after removal of the last patch). However, after long-term use of buprenorphine patch, withdrawal symptoms similar to those occurring during opioid withdrawal, cannot be entirely excluded. These symptoms include agitation, anxiety, nervousness, insomnia, hyperkinesia tremor and gastrointestinal disorders.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to :medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

Very common : headache, dizziness, somnolence Common: paresthesia Uncommon : sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, tremor, abnormal coordination, disturbance in attention Rare : balance disorder, speech disorder Very rare: involuntary muscle contractions

4.9 Overdose

Symptoms : Symptoms similar to those of other centrally acting analgesics are to be expected. These include respiratory depression, sedation, drowsiness, nausea, vomiting, cardiovascular collapse and marked miosis.

Treatment : Remove any patches from the patient's skin. Establish and maintain a patent airway, assist or control respiration as indicated and maintain adequate body temperature and fluid balance. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

A specific opioid antagonist such as naloxone may reverse the effects of buprenorphine. The dose of naloxone may be in the range 5 to 12 mg intravenously.

5.1 Mechanism of action

Buprenorphine is a partial agonist opioid, acting at the mu opioid receptor. It also has antagonistic activity at the kappa opioid receptor.

5.2 Pharmacodynamic properties

Buprenorphine can displace or block morphine binding to µ-receptor thus contributes to reduced opioid dependence. Buprenorphine agonist activity on µ receptor is the primary contributing factor to its analgesic signaling events. Buprenorphine interacts with nociceptin / ORL1 with much lower affinity and thus is unlikely to contribute to analgesic effects at therapeutic doses. Buprenorphine is a potent antagonist of κ-opioid receptor and this interaction could contribute to reduced tolerance and antidepressant like activity.

5.3 Pharmacokinetic properties

There is evidence of enterohepatic recirculation.

Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers. Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration. After intramuscular or oral administration buprenorphine apparently accumulates in the foetal gastrointestinal lumen - presumably due to biliary excretion, as enterohepatic circulation has not fully developed. Each patch provides a steady delivery of buprenorphine for up to seven days. Steady state is achieved during the first application. After removal of buprenorphine, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10 - 24 h).

Absorption

Following buprenorphine application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for “buprenorphine 10 microgram/hour” to deliver detectable buprenorphine concentrations (25 picograms/ml) was approximately 17 hours. Analysis of residual buprenorphine in patches after 7-day use shows 15% of the original load delivered. A study of bioavailability, relative to intravenous administration, confirms that this amount is systemically absorbed. Buprenorphine concentrations remain relatively constant during the 7-day patch application.

Application site

A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by buprenorphine is similar when applied to upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). The absorption varies to some extent depending on the application site and the exposure is at the most approximately 26 % higher when applied to the upper back compared to the side of the chest.

In a study of healthy subjects receiving buprenorphine repeatedly to the same site, an almost doubled exposure was seen with a 14-day rest period. For this reason, rotation of application sites is recommended, and a new patch should not be applied to the same skin site for 3-4 weeks. In a study of healthy subjects, application of a heating pad directly on the transdermal patch caused a transient 26 - 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hours after the heat was removed. For this reason, applying direct heat sources such as hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a buprenorphine site immediately after patch removal did not alter absorption from the skin depot.

Distribution

Buprenorphine is approximately 96% bound to plasma proteins. Studies of intravenous buprenorphine have shown a large volume of distribution, implying extensive distribution of buprenorphine. In a study of intravenous buprenorphine in healthy subjects, the volume of distribution at steady state was 430 l, reflecting the large volume of distribution and lipophilicity of the active substance.

Following intravenous administration, buprenorphine and its metabolites are secreted into bile, and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be approximately 15% to 25% of concurrent plasma concentrations.

Biotransformation and elimination

Buprenorphine metabolism in the skin following buprenorphine application is negligible. Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes, results in two primary metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before elimination. Buprenorphine is also eliminated in the faeces. In a study in post-operative patients, the total elimination of buprenorphine was shown to be approximately 551/h. Norbuprenorphine is the only known active metabolite of buprenorphine.

Effect of buprenorphine on the pharmacokinetics of other active substances

Based on in vitro studies in human microsomes and hepatocytes, buprenorphine does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of buprenorphine 20μg/h transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.

6.1 Animal toxicology or pharmacology

Systemic toxicity and dermal toxicity

In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, buprenorphine caused minimal or no adverse systemic events, whereas skin irritation was observed in all species examined. Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.

Reproductive and developmental toxicity

No effect on fertility or general reproductive performance was observed in rats treated with buprenorphine. In embryofoetal developmental toxicity studies conducted in rats and rabbits using buprenorphine, no embryofoetal toxicity effects were observed. In a rat pre- and post-natal developmental toxicity study with buprenorphine there was pup mortality, decreased pup body weight and concomitant maternal reduced food consumption and clinical signs.

Genotoxicity

A standard battery of genotoxicity tests indicated that buprenorphine is non-genotoxic.

Carcinogenicity

In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.

Buprenorphine is a semi synthetic derivative of an opiate alkaloid thebaine that is isolated from the poppy Papaver somniferum. Buprenorphine is a hydrophobic molecule and carries a complex chemical structure with multiple chiral centers.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A pouch of 1 patch.

8.4 Storage and handling instructions

Store in a cool & dry place. Protect from light & moisture.

Keep out of reach of children.

• These patches contain a strong pain killer.
• Ensure that old patches are removed before applying a new one.
• Patches must not be cut.
• Do not expose the patches to a heat source (such as a hot water bottle).
• Do not soak in a hot bath or take a hot shower whilst wearing a patch.
• If you develop a fever tell your doctor immediately.
• Follow the dosage instructions carefully and only change your patch on the same day and at the same time 7 days later.
• If your breathing becomes shallow and weak take the patch off and seek medical help.

21 August 2024

Sultamicillin Tablets

Bactomin 375

Each film coated tablet contains:

Sultamicillin Tosilate Dihydrate BP

equivalent to Sultamicillin………………………………………. 375 mg

Bactomin 750

Each film coated tablet contains:

Sultamicillin Tosilate Dihydrate BP

equivalent to Sultamicillin………………………………………. 750 mg

Tablet 375 mg/750 mg

4.1 Therapeutic indication

• Intra-abdominal infections
• Obstetrics and gynaecological infections
• Skin and soft tissue infections
• Bone and joint infections
• Upper and lower respiratory tract infections
• ENT infections
• Urinary tract infections
• Gonorrhoea

4.2 Posology and method of administration

The recommended dose of sultamicillin in adults (including elderly patients) is 375-750 mg orally twice daily.

In both adults and children, treatment is usually continued until 48 hours after pyrexia and other abnormal signs have resolved. Treatment is normally given for 5-14 days but the treatment period may be extended if necessary.

In the treatment of uncomplicated gonorrhea, sultamicillin can be given as a single oral dose of 2.25 g (six 375 mg tablets or three 750 mg tablets). Concomitant probenecid 1.0 g should be administered in order to prolong plasma concentrations of sulbactam and ampicillin.

Cases of gonorrhea with a suspected lesion of syphilis should have dark field examinations before receiving sultamicillin and monthly serological tests for a minimum of four months.

It is recommended that there be at least 10 days’ treatment for any infection caused by hemolytic streptococci to prevent the occurrence of acute rheumatic fever or glomerulonephritis.

Use in Children and Infants

The dosage for most infections in children weighing less than 30 kg is sultamicillin 25-50 mg/kg/day orally in two divided doses, depending on the severity of the infection and the physician's judgment. For children weighing 30 kg or more, the usual adult dose should be given.

Use in Patients with Renal Impairment

In patients with severe impairment of renal function (creatinine clearance ≤30 mL/min), the elimination kinetics of sulbactam and ampicillin are similarly affected and hence the plasma ratio of one to the other will remain constant. The dose of sultamicillin in such patients should be administered less frequently in accordance with usual practice for ampicillin.

4.3 Contraindications

Individuals with a history of an allergic reaction to any of the penicillins.

4.4 Special warnings and precautions for use

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy including sultamicillin. These reactions are more apt to occur in individuals with a history of penicillin hypersensitivity and/or hypersensitivity reactions to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction occurs, the drug should be discontinued and the appropriate therapy instituted.

Serious anaphylactic reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

Severe skin reactions, such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), dermatitis exfoliative, and erythema multiforme have been reported in patients on ampicillin/sulbactam therapy. If a severe skin reaction occurs, use of the product should be discontinued and appropriate therapy should be initiated. As with any antibiotic preparation, constant observation for signs of overgrowth of non-susceptible organisms, including fungi, is essential. Should super-infection occur, the drug should be discontinued and/or appropriate therapy instituted.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sultamicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Drug induced liver injury such as cholestatic hepatitis and jaundice have been associated with the use of ampicillin/sulbactam. Patients should be advised to contact their doctor if signs and symptoms of hepatic disease develop.

Since infectious mononucleosis is viral in origin, ampicillin should not be used in the treatment. A high percentage of patients with mononucleosis who receive ampicillin develop a skin rash. It is advisable to check periodically for organ system dysfunction during prolonged therapy; this includes renal, hepatic and hematopoietic systems. The principal route of excretion of sulbactam and ampicillin following oral administration of sultamicillin is via the urine. Because renal function is not fully developed in neonates, this should be considered when using sultamicillin in neonates.

4.5 Drugs interactions

Allopurinol

The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone.

Anticoagulants

Penicillins can produce alterations in platelet aggregation and coagulation tests. These effects may be additive with anticoagulants.

Bacteriostatic drugs (chloramphenicol, erythromycin, sulfonamides and tetracyclines)

Bacteriostatic drugs may interfere with the bactericidal effect of penicillins; it is best to avoid concurrent therapy.

Estrogen-containing oral contraceptives

There have been case reports of reduced oral contraceptive effectiveness in women taking ampicillin, resulting in unplanned pregnancy. Although the association is weak, patients should be given the option to use an alternate or additional method of contraception while taking ampicillin.

Methotrexate

Concurrent use with penicillins has resulted in decreased clearance of methotrexate and a corresponding increase in methotrexate toxicity. Patients should be closely monitored. Leucovorin dosages may need to be increased and administered for longer periods of time.

Probenecid

Probenecid decreases renal tubular secretion of ampicillin and sulbactam when used concurrently; this effect results in increased and prolonged serum concentrations, prolonged elimination half-life, and increased risk of toxicity.

4.6 Use in special populations

Pregnancy

Animal reproduction studies have revealed no evidence of impaired fertility or harm to the fetus due to sultamicillin. Sulbactam and ampicillin cross the placental barrier. However, safety for use in human pregnancy has not been established. Therefore, sultamicillin should be used during pregnancy only if the potential benefits outweigh the potential risk.

Lactation

The use of sultamicillin during lactation is not recommended. Low concentrations of ampicillin and sulbactam are excreted in the milk. This should be considered as the neonate may be exposed, particularly since renal function is not fully developed in neonates.

4.7 Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Sultamicillin is generally well tolerated. The majority of side effects observed were of mild or moderate severity and were normally tolerated with continued treatment.

Infections and Infestations: Pseudomembranous colitis, Candida infection.

Blood and Lymphatic System Disorders: Thrombocytopenia.

Immune System Disorders: Anaphylactic shock, Anaphylactic reaction, Kounis syndrome, Hypersensitivity.

Nervous System Disorders: Dizziness, Somnolence, Sedation, Headache.

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea.

Gastrointestinal Disorders: Enterocolitis, Melena, Diarrhea, Vomiting, Abdominal pain, Dyspepsia, Nausea, Stomatitis, Dysgeusia, Tongue discoloration.

Hepatobiliary Disorders: Jaundice, Hepatic function abnormal

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Erythema multiforme, Angioedema, Urticaria, Dermatitis, Rash, Pruritus.

Musculoskeletal and Connective Tissue Disorders: Arthralgia.

General Disorders and Administration Site Conditions: Fatigue, Malaise.

Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Limited information is available on the acute toxicity of ampicillin sodium and sulbactam sodium in humans. Overdosage of the drug would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug. The fact that high cerebrospinal fluid (CSF) concentrations of beta-lactam antibiotics may cause neurologic effects, including seizures, should be considered. Because ampicillin and sulbactam are both removed from the circulation by hemodialysis, these procedures may enhance elimination of the drug from the body if overdosage occurs in patients with impaired renal function.

5.1 Mechanism of Action / Pharmacodynamic Properties

Biochemical studies with cell-free bacterial systems have shown sulbactam to be an irreversible inhibitor of most important beta-lactamases that occur in penicillin-resistant organisms. While sulbactam antibacterial activity is mainly limited to Neisseriaceae, the potential for sulbactam sodium in preventing the destruction of penicillins and cephalosporins by resistant organisms was confirmed in whole-organism studies using resistant strains, in which sulbactam sodium exhibited marked synergistic effects with penicillins and cephalosporins. Since sulbactam also binds to some penicillin-binding proteins, some sensitive strains are rendered more susceptible to the combination than to the beta-lactam antibiotic alone. The bactericidal component of this product is ampicillin, which, like benzyl penicillin, acts against sensitive organisms during the stage of active multiplication by the inhibition of biosynthesis of cell wall mucopeptide.

Sultamicillin is effective against a wide range of gram-positive and gram-negative bacteria including: Staphylococcus aureus and Staphylococcus epidermidis (including penicillin-resistant and some methicillin-resistant strains); Streptococcus pneumoniae, Streptococcus faecalis and other Streptococcus species; Haemophilus influenzae and Haemophilus parainfluenzae (both beta-lactamase-positive and -negative strains); Moraxella catarrhalis; anaerobes including Bacteroides fragilis and related species; Escherichia coli; Klebsiella species; Proteus species (both indole-positive and indole-negative); Enterobacter species; Morganella morganii; Citrobacter species; Neisseria meningitidis and Neisseria gonorrhoeae.

5.2 Pharmacokinetic properties

Following oral administration in humans, sultamicillin is hydrolyzed during absorption to provide sulbactam and ampicillin in a 1:1 molar ratio in the systemic circulation. The bioavailability of an oral dose is 80% of an equal intravenous dose of sulbactam and ampicillin. Administration following food does not affect the systemic bioavailability of sultamicillin. Peak serum levels of ampicillin, following administration of sultamicillin, are approximately twice those of an equal dose of oral ampicillin. Elimination half-lives are approximately 0.75 and 1 hour for sulbactam and ampicillin, respectively, in healthy volunteers, with 50%-75% of each agent being excreted unchanged in the urine. Elimination half-lives are increased in the elderly and in patients with renal dysfunction. Probenecid decreases the renal tubular secretion of both ampicillin and sulbactam. Concurrent use of probenecid with sultamicillin results in increased and prolonged blood levels of ampicillin and sulbactam.

While reversible glycogenosis was observed in laboratory animals, this phenomenon was dose- and time-dependent and is not expected to develop at the therapeutic doses and corresponding plasma levels attained during the relatively short periods of combined ampicillin/sulbactam therapy in humans. Long-term studies in animals have not been performed to evaluate the carcinogenic potential. The individual components of sultamicillin (ampicillin/sulbactam) tested negative for mutagenicity. Reproduction studies have been performed in mice and rats at doses in excess of the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to sultamicillin.

Sultamicillin is a double ester in which Ampicillin and the beta-lactamase inhibitor sulbactam are linked via a methylene group.

Chemical name: Oxymethylpenicillinate Sulphone ester of Ampicillin

Molecular weight: 594.7

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

8.3 Packaging information

8.4 Storage and handing instructions

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

Keep out of reach of children.

• Your doctor has prescribed Bactomin Tablet to cure your infection and improve your symptoms.
• Do not skip any doses and finish the full course of treatment even if you feel better. Stopping it early may make the infection to come back and harder to treat.
• It can be taken with or without food or as directed by your doctor.
• Diarrhea may occur as a side effect but should stop when your course is complete. Inform your doctor if it doesn't stop or if you find blood in your stools.
• Discontinue Bactomin Tablet and inform your doctor immediately if you get a rash, itchy skin, swelling of face and mouth, or have difficulty in breathing.

16.09.2022

Esomeprazole (GR) & Levosulpiride (PR) Capsules

Each Hard Gelatin Capsule Contains:

Esomeprazole Magnesium USP (Trihydrate)

equivalent to Esomeprazole ……. ….. 40 mg

(as gastro-resistant pellets)

Levosulpiride ………………………… 75 mg

(as prolonged release pellets)

Capsule Esomeprazole (40 mg) & Levosulpiride (75 mg)

4.1 Therapeutic indications

For the treatment of gastro-esophageal reflux disease (GERD) in patients who do not respond to PPI (proton-pump inhibitor) alone.

4.2 Posology and method of administration

1 capsule to be administered once daily. Zosa L Capsules should be administered on empty stomach, preferably in the morning or at least 1 hour prior to meal. The capsules should be swallowed whole with water and not to be opened, chewed or crushed. Or, as prescribed by the physician

Pediatric Patients

Safety and efficacy of esomeprazole with levosulpiride combination therapy has not been established in paediatric patients. Thus, Zosa L Capsules are not recommended for use in children and adolescents below 18 years of age.

Geriatric Patients

No dosage adjustment is generally necessary in the elderly patients with normal renal function, but dose should be reduced if there is evidence of renal impairment. Elderly patients are more susceptible to postural hypotension, sedation, and extrapyramidal side effects. Thus, caution should be exercised in the elderly population while on Zosa L therapy.

Renal Impairment Patients

Zosa L Capsules should be used with caution and dose/dosage frequency may need to be reduced depending on the severity of the renal dysfunction. Zosa L Capsules are contraindicated in patients with severe renal impairment.

Hepatic Impairment Patients

With esomeprazole, dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg esomeprazole should not be exceeded. There is no information available on use of levosulpiride in patients with hepatic dysfunction. Thus, as a precautionary measure, Zosa L Capsules should be avoided in patients with hepatic impairment.

4.3 Contraindications

• Patients with known hypersensitivity to esomeprazole or to any substituted benzimidazole derivative or to levosulpiride or to any component of the formulation.
• In patients receiving rilpivirine-containing products.
• Gastrointestinal bleeding and intestinal obstruction.
• Severe renal or hepatic insufficiency.
• Porphyrias.
• Alcohol intoxication.
• Certain tumors like phaeochromocytoma and pituitary prolactinoma.
• Concurrent use with levodopa or other antiparkinson drugs (including ropinirole).

4.4 Special warnings and precautions for use

Esomeprazole

Gastric Malignancy: In the presence of any alarm symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with esomeprazole may alleviate symptoms and delay diagnosis.

Helicobacter Pylori Eradication: When prescribing esomeprazole for eradication of Helicobacter pylori, possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4, such as cisapride.

Gastrointestinal Infections/Gastritis: Treatment with proton pump inhibitors (PPIs) may lead to a slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer.

Clostridium Difficile-Associated Diarrhea (CDAD): Published observational studies suggest that PPI therapy like esomeprazole may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Absorption of Vitamin B12: Esomeprazole, like all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy.

Risk of Bone Fracture: Several published observational studies suggest that 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 established treatment guidelines and they should have an adequate intake of vitamin D and calcium.

Subacute Cutaneous Lupus Erythematosus (SCLE): PPIs have been associated with cases of SCLE, although very infrequently. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and esomeprazole therapy should be stopped immediately. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs.

Hypomagnesemia: Hypomagnesemia (symptomatic/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. 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), it is recommended to monitor magnesium levels prior to initiation of PPI treatment, and periodically thereafter.

Levosulpiride

History of Breast Cancer: Levosulpiride may increase prolactin levels. Therefore, caution should be exercised and patients with a history or a family history of breast cancer should be closely monitored during levosulpiride therapy.

Prolongation of the QT Interval: Levosulpiride induces a prolongation of the QT interval. This effect is known to potentiate the risk of serious ventricular arrhythmias such as torsade de pointes. Levosulpiride should be used with caution in patients with cardiovascular disease or with a family history of QT prolongation.

Gastrointestinal Disorders: Levosulpiride should not be used when gastrointestinal stimulation of motility can be harmful e.g., in presence of gastrointestinal hemorrhage, mechanical obstructions or perforations.

Drugs Acting on CNS: Caution is advised when levosulpiride is administered concomitantly with other centrally acting drugs.

Alcohol: Concomitant intake of alcohol should be avoided during levosulpiride therapy as there is an increased chance of sedation.

Smoking: Smoking increases metabolism of the drug and thus, require higher dose of levosulpiride.

Parkinson’s Disease: In patient with Parkinson's disease, levosulpiride use should be avoided and an alternative drug therapy should be considered.

Convulsions: Cases of convulsions, sometimes in patients with no previous history, have been reported. In patients requiring levosulpiride who are receiving anticonvulsant therapy, the dose of the anticonvulsant should not be changed.

Anticholinergic Effects: Levosulpiride has an anticholinergic effect and, therefore, should be used with caution in patients with a history of glaucoma, ileus, congenital digestive stenosis, urine retention or hyperplasia of the prostate.

Hypertensive Patients: Levosulpiride should be used with caution in hypertensive patients, especially in the elderly population, due to the risk of hypertensive crisis. Patients should be adequately monitored.

4.5 Interaction with other medicinal products and other forms of interaction Esomeprazole

1) Interference with Antiretroviral Therapy Reduced Concentrations of Atazanavir and Nelfinavir: Concomitant use of atazanavir and nelfinavir with PPIs is not recommended. Co-administration of atazanavir with PPIs is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. If the combination of atazanavir with a PPI is unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded.

Increased Concentrations of Saquinavir: Co-administration of saquinavir with PPIs is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with other antiretroviral drugs, too. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19.

2) Drugs for Which Gastric PH Can Affect Bioavailability (ketoconazole, atazanavir, iron salts, erlotinib, mycophenolate mofetil, digoxin) Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability. Like with other drugs that decrease intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Digoxin: Concomitant treatment with omeprazole (20 mg daily), of which esomeprazole is an enantiomer, and digoxin in healthy subjects increased the bioavailability of digoxin by 10%. Co-administration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole.

Mycophenolate Mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole and MMF. Use esomeprazole with caution in transplant patients receiving MMF.

3) Effects on Hepatic Metabolism/Cytochrome P-450 Pathways Esomeprazole is extensively metabolized in the liver by CYP 2C19 and CYP 3A4. In-vitro and in-vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with quinidine, clarithromycin, or amoxicillin.

Warfarin: Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR (International Normalized Ratio) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding.

Clopidogrel: Avoid concomitant use of esomeprazole 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 of concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with esomeprazole 40 mg reduces the pharmacological activity of clopidogrel. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged or when using esomeprazole consider alternative anti-platelet therapy.

Diazepam: Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Co-administration of esomeprazole and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Phenytoin: Concomitant administration of esomeprazole 40 mg resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

Cilostazol: Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, of which esomeprazole is an enantiomer, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69%, respectively. Cisapride: In healthy volunteers, concomitant administration of esomeprazole 40 mg resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t½), but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole. Voriconazole: Concomitant administration of esomeprazole and a combined inhibitor of CYP 2C19 and CYP3A4, such as voriconazole, may result in a more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. However, in patients with Zollinger-Ellison's Syndrome, who may require higher doses (up to 240 mg/day), dose adjustment may be considered. Rifampicin: Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampin) may lead to decreased esomeprazole serum levels. Avoid concomitant use of rifampin with esomeprazole. St. John's Wort: Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. John's wort, an inducer of CYP3A4. Avoid concomitant use of St. John's wort with esomeprazole.

4) Concomitant Administration with Other Drugs

Tacrolimus: Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.

Combination Therapy with Clarithromycin: Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in an increase in plasma levels of esomeprazole and 14-hydroxyclarithromycin.

Methotrexate: Concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, leading to a risk of methotrexate toxicity. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.

5) Drug / Laboratory Tests Interactions

Interactions with Investigations of 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. To avoid this interference, esomeprazole treatment should be stopped for at least 5 days before CgA measurements; consider repeating the test if initial CgA levels are high. Levosulpiride

Antacids and Sucralfate: Bioavailability of levosulpiride is reduced if it is taken concomitantly with sucralfate and aluminum/magnesium-containing antacids. So, these medicines should not be taken along with levosulpiride. There should be a minimum 2 hour time lag between the two medicines. Anticholinergic Drugs, Narcotics and

Analgesic Drugs: The effect of levosulpiride on gastrointestinal motility can be antagonized by these drugs. Antihypertensive Drugs: Concomitant use of levosulpiride may enhance the hypotensive effects of these drugs.

Anticholinergic Drugs: Concomitant administration may cause increase in incidence of anticholinergic side effects.

Levodopa/Antiparkinson Drugs (including ropinirole): There is reciprocal antagonism of effects between levodopa or antiparkinson drugs (including ropinirole) and levosulpiride. Levodopa reduces effects of levosulpiride; conversely, levosulpiride may decrease the efficacy of levodopa in the management of Parkinson’s disease. Thus, concomitant use of these drugs are contraindicated.

Atomoxetine, Antiarrhythmics, Terfenadine, Chloroquine, Quinine, Cisapride, and Drugs Causing Hypokalemia (corticosteroids, laxatives, and diuretics like furosemide): Concurrent use of levosulpiride with these drugs may cause arrhythmia, especially prolonged QT interval.

Alcohol: Levosulpiride can potentiate the cognitive and motor effects of alcohol. Thus, concurrent use should be avoided.

Lithium: Increased risk of extrapyramidal effects. Discontinuation of both drugs is recommended at first signs of neurotoxicity.

4.6 Use in special populations

Pregnancy Zosa L capsules are not recommended for use in pregnant women. Breast-feeding Zosa L capsules should not be used during breast feeding. Accordingly, a decision should be made whether to discontinue nursing or to discontinue/abstain from drug therapy, taking into account the benefit of the drug to the mother.

4.7 Effects on ability to drive and use machines

Patients should avoid driving or operating machinery or not to engage in activities that require full mental alertness.

4.8 Undesirable effects

Esomeprazole

Acute kidney injury as an adverse drug reaction reported with the use of proton pump inhibitors.

The most frequently reported (≥ 1%) adverse reactions with esomeprazole were headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. Additional adverse reactions that were reported as possibly or probably related to esomeprazole with an incidence < 1% are as follows:

Body as a Whole: Enlarged abdomen, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like symptoms, generalized edema, leg edema, malaise, pain, rigors.

Cardiovascular: Flushing, hypertension, tachycardia.

Endocrine: Goiter.

Gastrointestinal (GI): Bowel irregularity, constipation aggravated, dyspepsia, dysphagia, GI dysplasia, epigastric pain, eructation, esophageal disorders, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorders, pharyngeal disorders, rectal disorders, increase in serum gastrin, tongue disorders, tongue edema, ulcerative stomatitis, vomiting.

Hearing: Earache, tinnitus.

Hematologic: Anemia, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia.

Hepatic: Abnormalities in hepatic function, including bilirubinemia, increase in AST (aspartate aminotransferase) and ALT (alanine aminotransferase).

Metabolic/Nutritional: Glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase/decrease.

Musculoskeletal: Arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica.

Nervous System/Psychiatric: Anorexia, apathy, increased appetite, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect.

Reproductive: Dysmenorrhea, menstrual disorders, vaginitis.

Respiratory: Aggravated asthma, coughing, dyspnea, laryngeal edema, pharyngitis, rhinitis, sinusitis.

Skin and Appendages: Acne, angioedema, dermatitis, pruritus, rash, urticaria, sweating.

Special Senses: Otitis media, parosmia, taste loss, taste perversion.

Urogenital: Albuminuria, cystitis, dysuria, fungal infection, hematuria, frequent micturition, moniliasis, polyuria.

Visual: Conjunctivitis, abnormal vision.

Laboratory Abnormalities

The following clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole, were reported in ≤ 1% of patients: Increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone. Decreased levels of hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Post-Marketing Experience The following adverse reactions have been identified during post-marketing use of esomeprazole. 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.

Blood and Lymphatic: Agranulocytosis, pancytopenia.

Eye: Blurred vision.

Gastrointestinal: Pancreatitis, stomatitis, microscopic colitis.

Hepatobiliary: Hepatitis with or without jaundice, hepatic failure.

Immune System: Anaphylactic reaction/shock.

Infections and Infestations: GI candidiasis, Clostridium difficile-associated diarrhea.

Metabolism and Nutritional Disorders: Hypomagnesemia.

Musculoskeletal and Connective Tissue: Muscular weakness, myalgia, fractures.

Nervous System: Hepatic encephalopathy, taste disturbance.

Psychiatric: Aggression, agitation, depression, hallucination.

Renal and Urinary: Interstitial nephritis.

Reproductive System and Breast: Gynecomastia.

Respiratory, Thoracic, and Mediastinal: Bronchospasm.

Skin and Subcutaneous Tissue: Alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (sometime fatal), cutaneous lupus erythematosus.

Levosulpiride

The following side effects may occur with the use of levosulpiride: Acute muscular dystonia characterized by abnormal movements (twitching, tremor, etc.) of the hands, leg, tongue and facial muscles.

Sedation or drowsiness (because of decrease in sensory inputs to reticular activating system).

Increase in plasma prolactin levels manifested by breast enlargement (gynecomastia), production of milk (galactorrhea) and stopping of menstrual periods (amenorrhea).

Neuroleptic malignant syndrome (characterized by hyperpyrexia, muscle rigidity, increased myoglobin and creatine kinase).

Akathisia (uncontrollable desire to move about without any anxiety).

Tardive dyskinesia, it occurs late in the therapy and its features include involuntary rhythmical movements of face, mouth and jaw. The reason for tardive dyskinesia is synthesis of newer dopamine receptors which are supersensitive to even a small amount of dopamine. This causes a decrease in cholinergic activity in the striatum followed by decrease in gamma-amino butyric acid (GABA) release. This decreased in inhibitory GABA is responsible for increased involuntary motor activity.

Postural hypotension (because of autonomic blockade), tolerance develops to this effect after some time.

Weight gain. Elevated liver transaminases.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via

email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Experience with overdose is limited. There is no specific antidote. Treatment is only symptomatic. Appropriate supportive measures should therefore be instituted, close supervision of vital functions and cardiac monitoring (risk of QT interval prolongation and subsequent ventricular arrhythmias) is recommended until the patient recovers. If severe extrapyramidal symptoms occur anticholinergic drugs should be administrated. Overdose may be treated with alkaline osmotic diuresis and, if necessary, anti-parkinson drugs. Coma needs appropriate nursing, and cardiac monitoring is recommended until the patient recovers.

5.1 Mechanism of action

Esomeprazole

Esomeprazole is a proton pump inhibitor (PPI) that suppresses gastric acid (hydrochloric acid - HCl) secretion by specific inhibition of the H+/K+-ATPase enzyme system at the secretory surface of the gastric parietal cell. Esomeprazole is a weak base and is concentrated and converted to the active form (i.e., the achiral sulphenamide) in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase (the acid/proton pump), and inhibits both basal and stimulated acid secretion. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thereby reducing gastric acidity.

Levosulpiride

Prokinetic Effect: Levosulpiride is principally a dopamine D2 antagonist. Dopamine has a direct relaxant effect on the gut by activating muscular D2 receptors. Levosulpiride stimulates gut motility by blocking D2 receptors in lower esophageal sphincter (LES) and stomach. Levosulpiride also acts as an agonist on serotonin 5-HT4 receptors and thus, increases acetylcholine level which leads to increase in GI motility. Antiemetic Effect: Levosulpiride exerts a selective antagonist activity on the D2 receptors on neurons in the CNS (postrema area of 4th ventricle) and thus, produces antiemetic effect. Levosulpiride is also a weak inhibitor of 5-HT3 receptors. Levosulpiride also acts as a moderate agonist at the serotonergic (5-HT4) receptor. This enhances its therapeutic efficacy in gastrointestinal disorders (reduction of nausea and vomiting).

5.2 Pharmacodynamic properties

Esomeprazole

Esomeprazole is the S-isomer of omeprazole. Esomeprazole reduces gastric acid secretion through a specific targeted mechanism of action i.e., inhibition of the acid pump in the gastric parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.

After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for 5 days, mean peak acid output decreases by 90% when measured 6 to 7 hours after dosing on day five.

After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were 76%, 54% and 24% for esomeprazole 20 mg. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.

Esomeprazole increases the mean fasting gastrin level in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.

Levosulpiride

Levosulpiride, levo-enantiomer (biologically active form) of sulpiride, is a benzamide derivative. The levo-enantiomer shows better/similar pharmacological actions and lower incidence of toxic effects than both dextro as well as the racemic forms of the drug. Due to its peripheral anti-dopaminergic action, levosulpiride exhibits gastrokinetic/prokinetic, antiemetic, and anti-dyspeptic effects. Levosulpiride act as a modulator of the motor activity of the upper digestive tract. Levosulpiride accelerates gastric emptying and improves gastrointestinal (GI) symptoms such as heart burn, regurgitation, etc. by selectively inhibitingdopaminergic receptors (D2) in the submucosal and myoenteric plexus of the gastrointestinal tract (GIT) and chemoreceptor trigger zone (CTZ) of the central nervous system (CNS).

5.3 Pharmacokinetic Properties

Esomeprazole

Absorption: Zosa L Capsules contains esomeprazole as a gastro-resistant tablet. This is necessary because, like other PPIs, esomeprazole is acid-labile drug. Absorption of esomeprazole therefore, begins only after the tablet leaves the stomach. Esomeprazole is rapidly absorbed after oral administration. Onset of effect occurs within one hour after oral dosing with esomeprazole 20 mg and 40 mg. Peak plasma levels (Cmax) occur approximately 1 to 2 hours (Tmax) after oral dose. The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. Effect of Food: Food intake both delays and decreases the absorption of esomeprazole. Thus, esomeprazole should be administered at least one hour before meal. Distribution: Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 μmol/l. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 liters. Metabolism: Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole's metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. Excretion: Total plasma clearance is about 17 l/h after a single dose and about 9 l/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once daily dosing. Esomeprazole is completely eliminated from plasma with no tendency for accumulation during once-daily administration. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces. Less than 1% of parent drug is excreted in the urine.

Levosulpiride

Pharmacokinetics of levosulpiride in sustained release formulation is not available. Conventional formulation of levosulpiride (i.e., immediate release) has following pharmacokinetic properties: Levosulpiride when administered orally exhibited linear pharmacokinetic properties over the dose range of 25 to 100 mg. The bioavailability of levosulpiride when given orally is about 30%. Sulpiride is slowly absorbed from the gastrointestinal tract with peak plasma concentrations are attained 3 to 6 hours after oral dose. After repeated administration, steady state was reached on day 4 of multiple dosing. Sulpiride is about 40% bound to plasma proteins and is reported to have a plasma half-life of about 8 to 9 hours. Levosulpiride is mainly excreted through the renal route.

6.1 Animal Toxicology or Pharmacology

Esomeprazole

Carcinogenicity: The carcinogenic potential of esomeprazole magnesium was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7 mg/kg/day, 3.4 mg/kg/day, 13.8 mg/kg/day, 44 mg/kg/day, and 140.8 mg/kg/day (about 0.4 to 34 times the human dose of 40 mg/day expressed 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. 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 (about 3.4 times the human dose of 40 mg/day on a body surface area basis) for 1 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 1 year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Mutagenesis: Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Impairment of Fertility: The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals. Reproduction Studies: Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole.

Levosulpiride

The values expressed as LD50 acute toxicity after oral administration in mice, rats and rabbits were 2450 mg / kg, 2600 mg / kg and greater than 1500 mg / kg. Subacute toxicity tests were conducted by administering the active ingredient in rat, rabbit and dog, daily, for 12-13 weeks. The appearance of any toxic symptoms was not observed at doses of: 25 mg / kg s.c. and 300 mg / kg p.o. in the rat; 250 mg / kg p.o. and 12.5 mg / kg i.m. in rabbits; and 50 and 100 mg / kg p.o. in the dog. To evidentiate the chronic toxicity after administration of the drug for 180-190 days, the following doses were well tolerated: 100 mg / kg p.o. and 20 mg / kg s.c. in the rat; 10 mg / kg i.m. in rabbits; and 20 mg / kg p.o. in the dog. Studies performed in rats and mice, administering the medicine at a dose higher than that expected for man, have shown that levosulpiride do not possess carcinogenic properties. Studies carried out in rats and rabbits have shown that the medicine is not teratogenic. In vitro tests have ruled out that levosulpiride possesses mutagenic properties.

Each capsule of Zosa L contains 40 mg of esomeprazole (in a gastro-resistant form) and 75 mg of levosulpiride (in a prolonged release form) for oral administration in adults.

Esomeprazole Magnesium

Esomeprazole magnesium is the magnesium salt of esomeprazole, the S-isomer of omeprazole, with gastric proton pump inhibitor activity. Esomeprazole magnesium salt is off-white to pale cream colored powder. It is slightly soluble in water.

Molecular Weight: 713.12 g/mol.

Molecular Formula: C₃₄H₃₆MgN₆O₆S₂.

Chemical Name: 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] sulfinyl]benzimidazole, magnesium salt (2:1).

Levosulpiride

Levosulpiride is the active levorotatory enantiomer of the racemic drug sulpiride, a substituted benzamide. Levosulpiride is a dopaminergic antagonist with prokinetic, antiemetic, antidepressant, and antipsychotic properties. Molecular Weight: 341.4 g/mol.
Molecular Formula: C₁₅H₂₃N3O₄S.

Chemical Name: N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2-methoxy-5-

sulfamoylbenzamide.

8.1 Incompatibilities

Not applicable

8.2 Shelf Life

Refer on pack

8.3 Packaging Information

1 Blister strip of 15 capsules

8.4 Storage and handing Instructions

Store protected from light & moisture at a temperature not exceeding 30°.

Keep out of reach of children.

• Instruct patients to take Zosa L Capsules exactly as prescribed by your doctor. Do not change the dose or stop therapy without consulting to your doctor.
• Instruct patients to take Zosa L capsules on empty stomach, preferably in the morning or at least 1 hour prior to meal. The capsules should be swallowed whole with water and not to be opened, chewed or crushed.
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take 2 doses/capsules at the same time to make up for the missed dose.
• Instruct patients not to use this medicine during pregnancy.
• Advise nursing mothers to avoid use of this medicine during lactation or not to breastfeed their infants while on drug therapy.
• This medicine is not recommended for use in children.
• Instruct patients not to share this medication with other people even though symptoms are similar. It may harm them.
• Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Zosa L Capsules and certain other medicines can interact with each other causing serious side effects.

28.08.2024

Esomeprazole Tablets 40 mg (with Sodium Bicarbonate as buffer)

Each fllm coated tablet contains :

Esomeprazole Magnesium Trihydrate IP

equivalent to Esomeprazole 40 mg

Excipients q.s.

Colour : Titanium Dioxide IP

Tablet 40 mg

4.1 Therapeutic indication

Gastroesophageal Reflux Disease (GERD), erosive reux esophagitis, prevention of relapse of esophagitis and helps in eradication of H.Pylori associated peptic ulcer. It is also indicated for pathological hypersecretory conditions including Zollinger-Ellison syndrome ulcer, risk reduction of NSAID-associated gastric ulcer, and prolonged treatment after I.V. induced prevention of rebleeding of peptic ulcer.

4.2 Posology and method of administration

Adults

Gastroesophageal reflux disease (GERD)

Treatment of erosive reflux esophagitis

40 mg once daily for 4 weeks.

An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.

Long-term management of patients with healed esophagitis to prevent relapse

20 mg once daily

Symptomatic treatment of gastro-oesophageal reux disease (GERD)

20 mg once daily in patients without esophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily. An on demand regimen taking 20 mg once daily, when needed, can be used. In NSAID treated patients at risk of developing gastric and duodenal ulcers, subsequent symptom control using an on demand regimen is not recommended.

In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori

Healing of Helicobacter pylori associated duodenal ulcer. Prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers. 20 mg Esomeprazole tablet with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.

Patients requiring continued NSAID therapy

Healing of gastric ulcers associated with NSAID therapy : The usual dose is 20 mg once daily. The treatment duration is 4 - 8 weeks. Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk : 20 mg once daily.

Prolonged treatment after I.V. induced prevention of rebleeding of peptic ulcers

40 mg once daily for 4 weeks after I.V. induced prevention of rebleeding of peptic ulcers.

Treatment of Zollinger Ellison syndrome

The recommended initial dosage is Esomeprazole 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. Based on the clinical data available, the majority of patients can be controlled on doses between 80 to 160 mg Esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice daily.

Special populations

Renal impairment

Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution.

Hepatic impairment

Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg Esomeprazole tablet should not be exceeded.

Elderly

Dose adjustment is not required in the elderly.

Paediatric population

Adolescents from the age of 12 years

Gastroesophageal reflux disease (GERD)

Treatment of erosive reflux esophagitis

40 mg once daily for 4 weeks.

An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.

Long-term management of patients with healed esophagitis to prevent relapse

20 mg once daily.

Symptomatic treatment of gastroesophageal reflux disease (GERD)

20 mg once daily in patients without esophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily

Treatment of duodenal ulcer caused by Helicobacter pylori

When selecting appropriate combination therapy, consideration should be given to ofcial national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents. The treatment should be supervised by a specialist.

The posology recommendation is :

Children below the age of 12 years

For posology in patients aged 1 to 11 other pharmaceutical forms e.g. sachet should be used.

Method of administration

The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed. For patients who have difficulty in swallowing the tablets can also be dispersed in half a glass of non-carbonated water. No other liquids should be used as the enteric coating may be dissolved. Stir until the tablets disintegrate and drink the liquid with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.

For patients who cannot swallow, the tablets can be dispersed in non-carbonated water and administered through a gastric tube.

4.3 Contraindications

Zosa FAST must not be used in the following conditions :

Hypersensitivity to the active substance, to substituted Benzimidazole or to any of the excipients.

Esomeprazole should not be used concomitantly with Nelfinavir.

4.4 Special warnings and precautions for use

In the presence of any alarm symptom (e.g. signicant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with Esomeprazole may alleviate symptoms and delay diagnosis.

Long term use

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

On demand treatment

Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character.

Helicobacter pylori eradication

When prescribing Esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for Clarithromycin should be considered when the triple therapy is used in patients concurrently taking other medicinal products metabolised via CYP3A4 such as Cisapride.

Gastrointestinal infections

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

Absorption of Vitamin B12

Esomeprazole, as all acid-blocking medicines, may reduce the absorption of Vitamin B12 (Cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced Vitamin B12 absorption on long-term therapy.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like Esomeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after Magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with Digoxin or medicinal products that may cause hypomagnesaemia (e.g. diuretics), health care professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Risk of fracture

Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10 - 40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of Vitamin D and Calcium.

Subacute cutaneous lupus erythematosus (SCLE)

Proton pump inhibitors are associated with very infrequent cases of SCLE. If lesions occur, especially in sunexposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping Esomeprazole. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Combination with other medicinal products

Co-administration of Esomeprazole with Atazanavir is not recommended. If the combination of Atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of Atazanavir to 400 mg with 100 mg of Ritonavir; Esomeprazole 20 mg should not be exceeded. Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with Esomeprazole, the potential for interactions with medicinal products metabolised through CYP2C19 should be considered. An interaction is observed between Clopidogrel and Esomeprazole. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of Esomeprazole and Clopidogrel should be discouraged.

When prescribing Esomeprazole for on demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of Esomeprazole should be considered.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, Esomeprazole treatment should be stopped for at least 5 days before CgA measurements. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

4.6 Drugs interactions

Effects of Esomeprazole on the pharmacokinetics of other medicinal products

Medicinal products with pH dependent absorption

Gastric acid suppression during treatment with Esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intra-gastric acidity, the absorption of medicinal products such as Ketoconazole, Itraconazole and Erlotinib can decrease and the absorption of Digoxin can increase during treatment with Esomeprazole. Concomitant treatment with Omeprazole (20 mg daily) and Digoxin in healthy subjects increased the bioavailability of Digoxin by 10% (up to 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when Esomeprazole is given at high doses in elderly patients. Therapeutic drug monitoring of Digoxin should then be reinforced.

Protease inhibitors

Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during Omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP 2C19.

For Atazanavir and Nelfinavir, decreased serum levels have been reported when given together with Omeprazole and concomitant administration is not recommended. Co-administration of Omeprazole (40 mg once daily) with Atazanavir 300 mg / Ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in Atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the Atazanavir dose to 400 mg did not compensate for the impact of Omeprazole on Atazanavir exposure. The co-administration of Omeprazole (20 mg qd) with Atazanavir 400 mg / Ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the Atazanavir exposure as compared with the exposure observed with Atazanavir 300 mg / Ritonavir 100 mg qd without Omeprazole 20 mg qd. Co-administration of Omeprazole (40 mg qd) reduced mean Nelnavir AUC, Cmax and Cmin by 36 - 39% and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75 - 92%. Due to the similar pharmacodynamic effects and pharmacokinetic properties of Omeprazole and Esomeprazole, concomitant administration with Esomeprazole and Atazanavir is not recommended and concomitant administration with Esomeprazole and Nelnavir is contraindicated.

For Saquinavir (with concomitant Ritonavir), increased serum levels (80 - 100%) have been reported during concomitant Omeprazole treatment (40 mg qd). Treatment with Omeprazole 20 mg qd had no effect on the exposure of Darunavir (with concomitant Ritonavir) and Amprenavir (with concomitant Ritonavir). Treatment with Esomeprazole 20 mg qd had no effect on the exposure of Amprenavir (with and without concomitant Ritonavir). Treatment with Omeprazole 40 mg qd had no effect on the exposure of Lopinavir (with concomitant Ritonavir).

Methotrexate

When given together with PPIs, Methotrexate levels have been reported to increase in some patients. In high-dose Methotrexate administration, a temporary withdrawal of Esomeprazole may need to be considered.

Tacrolimus

Concomitant administration of Esomeprazole has been reported to increase the serum levels of Tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted, if needed.

Medicinal products metabolised by CYP2C19

Esomeprazole inhibits CYP2C19, the major Esomeprazole-metabolising enzyme. Thus, when Esomeprazole is combined with medicinal products metabolised by CYP2C19, such as Diazepam, Citalopram, Imipramine, Clomipramine, Phenytoin, etc., the plasma concentrations of these medicinal products may be increased and a dose reduction could be needed. This should be considered especially when prescribing Esomeprazole for on-demand therapy.

Diazepam

Concomitant administration of 30 mg Esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate Diazepam.

Phenytoin

Concomitant administration of 40 mg Esomeprazole resulted in a 13% increase in trough plasma levels of Phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with Esomeprazole is introduced or withdrawn.

Voriconazole

Omeprazole (40 mg once daily) increased Voriconazole (a CYP2C19 substrate) Cmax and AUC by 15% and 41% respectively.

Warfarin

Concomitant administration of 40 mg Esomeprazole to Warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant Esomeprazole treatment during treatment with warfarin or other Coumarine derivatives.

Cilostazol

Omeprazole as well as Esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for Cilostazol by 18% and 26% respectively and one of its active metabolites by 29% and 69% respectively.

Cisapride

In healthy volunteers, concomitant administration of 40 mg Esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t½) but no significant increase in peak plasma levels of Cisapride. The slightly prolonged QTc interval observed after administration of Cisapride alone, was not further prolonged when Cisapride was given in combination with Esomeprazole.

Clopidogrel

Results from studies in healthy subjects have shown a pharmacokinetic (PK) / pharmacodynamic (PD) interaction between Clopidogrel (300 mg loading dose / 75 mg daily maintenance dose) and Esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of Clopidogrel by an average of 40% and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%.

Investigated medicinal products with no clinically relevant interaction

Amoxicillin and Quinidine

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or Quinidine.

Naproxen or Rofecoxib

Studies evaluating concomitant administration of Esomeprazole and either naproxen or Rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Effects of other medicinal products on the pharmacokinetics of Esomeprazole

Medicinal products which inhibit CYP2C19 and/or CYP3A4

Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of Esomeprazole and a CYP3A4 inhibitor, Clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to Esomeprazole. Concomitant administration of Esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may result in more than doubling of the Esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor Voriconazole increased

Omeprazole AUC by 280 %. A dose adjustment of Esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

Medicinal products which induce CYP2C19 and/or CYP3A4

Medicinal products known to induce CYP2C19 or CYP3A4 or both (such as Rifampicin and St John's wort) may lead to decreased Esomeprazole serum levels by increasing the Esomeprazole metabolism.

Paediatric population

Interaction studies have only been performed in adults.

4.7 Fertility, pregnancy and lactation

Fertility

Animal studies with the racemic mixture Omeprazole, given by oral administration do not indicate effects with respect to fertility.

Pregnancy

Clinical data on exposed pregnancies with Esomeprazole are insufficient. With the racemic mixture, Omeprazole, data on a larger number of exposed pregnancies stemmed from epidemiological studies indicate no malformative nor foeto-toxic effects. Animal studies with Esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal / foetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

A moderate amount of data on pregnant women (between 300 - 1000 pregnancy outcomes) indicates no malformative or foeto/neonatal toxicity of Esomeprazole.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Breast-feeding

It is not known whether Esomeprazole is excreted in human breast milk. There is insufficient information on the effects of Esomeprazole in new-borns / infants. Esomeprazole should not be used during breast-feeding.

4.7 Effects on ability to drive and use machines

(uncommon) and blurred vision (rare) has been reported. If affected patients should not drive or use machines. Undesirable effects

Summary of the safety profile

Headache, abdominal pain, diarrhoea and nausea are among those adverse reactions that have been most commonly reported in clinical trials (and also from post-marketing use). In addition, the safety profile is similar for different formulations, treatment indications, age groups and patient populations. No dose-related adverse reactions have been identified.

Tabulated list of adverse reactions

The following adverse drug reactions have been identified or suspected in the clinical trials programme for Esomeprazole and post-marketing. None was found to be dose-related. The reactions are classified according to frequency 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 authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to :medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is very limited experience to date with deliberate overdose.

Symptoms

The symptoms described in connection with 280 mg were gastrointestinal symptoms and weakness. Single doses of 80 mg Esomeprazole were uneventful.

Management

No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

5.1 Mechanism of action

Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+/K+-ATPase – the acid pump and inhibits both basal and stimulated acid secretion.

5.2 Pharmacodynamic properties

Esomeprazole is the S-isomer of Omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of Omeprazole have similar pharmacodynamic activity.

Pharmacodynamic effects

After oral dosing with Esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg Esomeprazole once daily for five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6 - 7 hours after dosing on day five. After five days of oral dosing with 20 mg and 40 mg of Esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for Esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for Esomeprazole 40 mg were 97%, 92% and 56%. Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.

Healing of reflux esophagitis with Esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks. One-week treatment with Esomeprazole 20 mg b.i.d. and appropriate antibiotics, results in successful eradication of H. pylori in approximately 90% of patients. After eradication treatment for one week there is no need for subsequent monotherapy with antisecretory medicinal products for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers. During treatment with antisecretory medicinal products serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range. An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in both children and adults during long term treatment with Esomeprazole. The findings are considered to be of no clinical significance.

5.3 Pharmacokinetic properties

Absorption

Esomeprazole is acid labile and is administered orally as gastro-resistant granules. In vivo conversion to the R-isomer is negligible. Absorption of Esomeprazole is rapid, with peak plasma levels occurring approximately 1 - 2 hours after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once daily administration. For 20 mg Esomeprazole, the corresponding values are 50% and 68%, respectively

Food intake both delays and decreases the absorption of Esomeprazole although this has no significant influence on the effect of Esomeprazole on intragastric acidity.

Distribution

The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 l/kg body weight. Esomeprazole is 97% plasma protein bound.

Biotransformation

Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of Esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of Esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of Esomeprazole sulphone, the main metabolite in plasma.

Elimination

The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.

Total plasma clearance is about 17 l/h after a single dose and about 9 l/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once daily dosing. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. The major metabolites of Esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of Esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.

6.1 Animal toxicology or pharmacology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows : No new or unexpected toxicity findings were observed in juvenile rats and dogs, after administration of Esomeprazole for up to 3 months, as compared to adult animals. Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.

No new or unexpected toxicity ndings were observed in juvenile rats and dogs, after administration of Esomeprazole for up to 3 months, as compared to adult animals.

Zosa FAST contains Esomeprazole Magnesium Trihydrate (with Sodium Bicarbonate as buffer). It is a proton pump inhibitor and decreases gastric acid secretion.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage and handing instructions Store protected from moisture, at a temperature not exceeding 30°C.

Keep out of reach of children.

Acute tubulointerstitial nephritis

Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with suspected acute TIN.

Clostridium difficile-associated diarrhea

Advise the patient or caregiver to immediately call the patient’s healthcare provider if they experience diarrhea that does not improve.

Bone fracture

Advise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient’s healthcare provider.

Severe cutaneous adverse reactions

Advise the patient or caregiver to discontinue Zosa FAST and immediately call the patient’s healthcare provider for at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity signs or symptoms associated with Severe Cutaneous Adverse Reactions.

Cutaneous and systemic lupus erythematosus

Advise the patient or caregiver to immediately call the patient’s healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus.

Cyanocobalamin (Vitamin B12) deficiency

Advise the patient or caregiver to report any clinical symptoms that may be associated with Cyanocobalamin deficiency to the patient’s healthcare provider if they have been receiving Zosa FAST for longer than 3 years.

Hypomagnesemia and mineral metabolism

Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to the patient’s healthcare provider, if they have been receiving Zosa FAST for at least 3 months.

Drug interactions

Advise the patient or caregiver to report to their healthcare provider if starting treatment with Rilpivirine-containing products, Clopidogrel, St. John’s Wort or Rifampin or if they take high-dose Methotrexate.

Administration

• Take Zosa FAST tablet at least one hour before meals.
• Antacids may be used concomitantly with Zosa FAST.
• Swallow Zosa FAST tablet whole; do not chew or crush the tablet.

16 November 2023

Ursodeoxycholic acid

Ursomax 150

Each uncoated tablet contains

Ursodeoxycholic acid IP.…………………………150 mg

Excipients……………………………………………...…...q.s.

Ursomax 300

Each uncoated tablet contains

Ursodeoxycholic acid IP.……………………………300 mg

Excipients……………………………………………...…...q.s.

Ursomax 450 SR

Each prolonged-release uncoated tablet contains

Ursodeoxycholic acid IP.……………………………450 mg

Excipients……………………………………………......q.s.

Tablet 150 mg/300 mg/450 mg

4.1 Therapeutic Indication

For the dissolution of radiolucent cholesterol gallstone, chronic cholestatic liver diseases in particular primary biliary cirrhosis, primary sclerosing cholangitis & cholestasis associated with cystic fibrosis.

4.2 Posology and method of administration

The dosage should be calculated based on the patient's body weight. The calculated dosage should be rounded to the nearest number of tablets.

Dissolving of cholesterol stones

Usual dosage: 8 to 10 mg/kg/day, corresponding to, for example, four to six 150 mg tablets, or two to three tablets of 300 mg, or two tablets of 450 mg. The daily dose can be administered two or three times after the meals: two tablets should always be taken after the evening meal.

Also a single evening dose can be selected (e.g., a patient of 60 kg, in the evening two tablets of 300 mg). Preferably, this single dose should be taken one hour before bedtime and ± two hours after the evening meal with a glass of milk or a small snack.

The duration of the treatment in order to obtain lysis of the gallstones depends on their size, but is usually not shorter than three to four months. To assess the result of the therapy properly, it is necessary to determine the size of the stones accurately at the start of the treatment and to check this further regularly, for example every six months, by means of a new contrast X-ray recording and/or sonographic recording.

In patients in whom, after six months of treatment with the indicated dosage, the stones are not reduced in size, it is recommended to determine the lithogenic index in the bile by means of a duodenum drainage. When the bile has an index of > 1.0, it is unlikely that a favourable result can be obtained, and it is better to consider a different form of treatment for the gallstones.

Treatment should be continued for three to four months after it is established by means of ultrasound check that the gallstones are completely dissolved. An interruption of the treatment for three to four weeks results in a return to over-saturation of the bile and prolongs the overall duration of the therapy. The interruption of the treatment after the dissolving of the gallstones can be followed by a recurrence.

Primary Biliary Cholangitis (Primary biliary cirrhosis)

The dosage of Ursodeoxycholic acid in primary biliary cholangitis (stages I-III), amounts to 12-15 mg/kg/day, which is equivalent to four to eight tablets of 150 mg, two to four tablets of 300 mg, to be taken in two to three portions during the day, or with two tablets of 450 mg, to be taken in two portions during the day.

The dosage of ursodeoxycholic acid in primary biliary cholangitis stage IV and an increase of the serum bilirubin contents (> 40 μg/l), should be in the first instance, only a half of the normal dose (6 to 8 mg/kg/day). Thereafter, the liver function should be closely monitored for several weeks (once every two weeks for six weeks). If there is no deterioration of the liver function (AF, ALT (SGPT), AST (SGOT), γ-GT, bilirubin) and no increase in itching occurs, the dose may be further increased to the usual level. Moreover, the liver function must then again be closely monitored for several weeks. If again no deterioration of the liver function takes place, the patient may be held at the normal dosage for a long time.

In patients with primary biliary cholangitis stage IV without elevated serum bilirubin, the usual starting dose is allowed to be administered directly. Anyway, here too an accurate control of the liver function should be executed.

The treatment of the primary biliary cholangitis should be regularly assessed on the basis of liver values (laboratory) and clinical findings.

Paediatric population

Children with cystic fibrosis aged 6 years to 18 years

Treatment of hepatobiliary diseases as a result of cystic fibrosis 20 mg/kg/day divided in two to three divided doses. If necessary, increase to 30 mg/kg/day. This corresponds with four to ten tablets of 150mg, two to five tablets of 300 mg, or with two to three tablets of 450 mg, to be taken in one or two portions during the day

Method of administration

If the patient has difficulty in swallowing because of the size of the tablet, the tablet can be halved if necessary on the dividing score, so that one half tablet can be taken twice directly in sequence.

4.3 Contraindications

Ursodeoxycholic acid tablets should not be used in patients with:

• Acute inflammation of the gall bladder or bile ducts
• Occlusion of the biliary tract (occlusion of the common bile duct or a cystic duct)
• Frequent episodes of biliary colic
• X-ray radiolucent calcified gallstones
• Impaired contractility of the gallbladder
• Hypersensitivity to bile acids or to any of the excipient
• Active gastric and duodenal ulcers

Paediatric population

• Unsuccessful portoenterostomy or without recovery of good bile flow in children with biliary atresia.

4.4 Special warnings and precautions for use

Ursodeoxycholic acid tablets should be taken under medical supervision.

During the first three months of the treatment liver function parameters AST (SGOT), ALT (SGPT) and γ-GT should be monitored by the physician every 4 weeks, thereafter every 3 months. Apart from allowing for identification of responders and non-responders in patients being treated for primary biliary cholangitis, this monitoring would also enable an early detection of potential hepatic deterioration, particularly in patients with advanced primary biliary cholangitis.

When used for dissolving gallstones:

In order to be able to assess the therapeutic progression of the dissolution of gallstones and to timely identify a possible calcification of the stones, the gall bladder, depending on the size of the stones, should be visualized 6 to 10 months after the start of the treatment (oral cholecystography) with total image and occlusions and in the standing and lying position (ultrasound investigation).

If the gallbladder cannot be visualized on X-rays, or in cases of calcified gallstones, impaired contractility of the gall bladder or frequent episodes of biliary colic, the treatment with Ursodeoxycholic acid should be discontinued.

When used for the treatment of advanced primary biliary cholangitis:

In very rare cases decompensation of liver cirrhosis is observed which partially decreased after treatment discontinuation.

In patients with PBC, the clinical symptoms may worsen in rare cases at the start of treatment, e.g. pruritus may increase. In this case, the therapy is to be continued with a dose reduction and subsequently should be gradually increased to the recommended dose as described in section 4.2.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea.

Female patients who use Ursodeoxycholic acid for dissolving gall stones must use an effective non-hormonal method of contraception, since hormonal contraception may increase biliary lithiasis

4.5 Drugs interactions

• Ursodeoxycholic acid tablets should not be used concurrently with colestyramine, colestipol, or an antacid, on the basis of aluminium hydroxide and/or smectite (aluminium oxide), because these preparations bind ursodeoxycholic acid in the intestine and thereby inhibits its absorption and efficacy. If the use of such a medicine is necessary, must it be taken at least 2 hours before or after ursomax.
• Ursodeoxycholic acid may affect the absorption of ciclosporin from the intestine. In patients treated with ciclosporin the blood level of ciclosporin should be monitored and the ciclosporin dose should be adjusted, if necessary.
• In isolated cases Ursodeoxycholic acid can reduce the absorption of ciprofloxacin.
• In a clinical study in healthy volunteers, the concomitant use of UDCA (500 mg/day) and rosuvastatin (20 mg/day) resulted in slightly elevated plasma levels of rosuvastatin.The clinical relevance of this interaction, also with other statins, is not known.
• Ursodeoxycholic acid has been shown to reduce the peak plasma concentration (Cmax) and the AUC of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring of the outcome of concurrent use of nitrendipine and ursodeoxycholic acid is recommended. An increase of the dose of nitrendipine may be necessary. An interaction with a reduction of the therapeutic effect of dapsone was also reported. These observations, together with in vitro findings could be an indication that ursodeoxycholic acid can induce cytochrome P450 3A enzymes. Induction has, however not been observed in a well-designed interaction study with budesonide, which is a known cytochrome P450 3A substrate.
• Oestrogens and blood cholesterol lowering agents such as clofibrate increase hepatic cholesterol secretion and may therefore encourage biliary lithiasis; which is a counter-effect to ursodeoxycholic acid used for dissolution of gallstones.

4.6 Use in special populations

Pregnancy

• There are no or limited amount of data from the use of ursodeoxycholic acid in pregnant women. Studies in animals have shown reproductive toxicity during the early gestation phase.
• Ursodeoxycholic acid must not be used during pregnancy, unless clearly necessary.

Women of childbearing potentialc

• Women of childbearing potential should be treated with ursodeoxycholic acid, only if they practice reliable contraception: non-hormonal contraceptives or oral contraceptives with low oestrogen dose are recommended. However, in patients taking Ursodeoxycholic acid for dissolving gallstones an effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis.
• The possibility of a pregnancy must be excluded before beginning treatment.

Nursing Mothers

• According to few documented cases of breastfeeding women milk levels of ursodeoxycholic acid levels in milk are very low and probably no adverse reactions are to be expected in breastfed infants.

Fertility

Animal studies did not show an influence of ursodeoxycholic acid on fertility. Human data on fertility treatment with ursodeoxycholic acid are not available.

4.7 Effects on ability to drive and use machines

Ursodeoxycholic acid has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The following adverse reactions have been reported during clinical trials and are ranked using the following frequency:

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).

Gastrointestinal disorders:

In clinical studies, reports of pasty stools or diarrhoea during treatment with ursodeoxycholic acid were common.

In very rare cases, severe right upper abdominal pain has occurred during the treatment of primary biliary cholangitis.

Hepatobiliary disorders:

During treatment with ursodeoxycholic acid calcification of gallstones can occur in very rare cases.

During the treatment of advanced stages of primary biliary cholangitis decompensation of cirrhosis has been observed in very rare cases, which partially regressed after treatment discontinuation.

Hypersensitivity reactions:

Very rarely urticaria may occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

In the case of overdose diarrhoea may occur. In general, other symptoms of overdose are unlikely, because the absorption of the ursodeoxycholic acid decreases with increasing dose and therefore more is excreted in the faeces.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea. No specific measures are needed and the consequences of diarrhoea should be treated symptomatically with restoration of fluid and electrolyte balance.

Additional information or special populations: Long-term, high-dose UDCA therapy (28-30 mg/kg/day) by patients with primary sclerosing cholangitis (off-label use) was associated with a higher frequency of serious adverse events.

5.1 Mechanism of Action

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

5.2 Pharmacodynamic properties

Bile acids are among the most important components of the bile and play a role in the stimulation of bile secretion. Bile acids are also important to keep the cholesterol in bile in solution. In a healthy person, the ratio between the concentration of cholesterol and bile acids in the bile is such that the cholesterol will remain in solution for most of the day. In this case, no gallstones can form (the bile is non-lithogenic). In patients with cholesterol stones in the bile, this ratio is changed and the bile is supersaturated with cholesterol (bile is lithogenic). This may cause a precipitation of cholesterol crystals and the formation of gallstones after some time.

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

Investigations of the effect of ursodeoxycholic acid on the cholestasis in patients with impaired biliary drainage and on the clinical symptoms in patients with primary biliary cholangitis and cystic fibrosis have shown that cholestatic symptoms in the blood (to be measured by the increased value of alkaline phosphatase (AF), gamma-GT and bilirubin) and the itch declined rapidly, while also the fatigue decreased in the majority of patients. Moreover, studies seem to indicate a positive benefit-risk ratio of the ursodeoxycholic acid in children and young adult cystic fibrosis patients with mild to moderate hepatobiliary disorders.

Paediatric population

Cystic fibrosis

From clinical reports long-term experience of 10 years and more has been gained with UDCA therapy in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can inhibit bile duct proliferation, can halt progression of histological damage and even reverse hepato-biliary changes, if it happens at an early stage of CFAHD. The treatment with UDCA should be started as soon as the CFAHD diagnosis is made, in order to optimize the effectiveness of the treatment.

5.3 Pharmacokinetic properties

About 90% of the therapeutic dose of the ursodeoxycholic acid is rapidly absorbed in the small intestine after oral administration.

After the absorption, ursodeoxycholic acid is absorbed in the liver (there is a substantial "first-passeffect"), where it is conjugated with glycine or taurine and then secreted into the bile ducts. Only a small portion of ursodeoxycholic acid is found in the systemic circulation. This is excreted renally. With the exception of conjugation, ursodeoxycholic acid is not metabolised. However, a small fraction of orally administered ursodeoxycholic acid undergoes bacterial conversion to 7-keto-lithocholic acid resp. lithocholic acid after each enterohepatic circulation, while bacterial deconjugation also takes place in the duodenum. Ursodeoxycholic acid, 7-keto-lithocholic acid and lithocholic acid are relatively poorly soluble in water, so a large part of it is excreted via the bile into the faeces. Resorbed ursodeoxycholic acid is conjugated again by the liver; 80% of the lithocholic acid formed in the duodenum is excreted in the faeces, but the remaining 20% of it are sulphated by the liver to insoluble lithocholylconjugates after absorption, which in turn are excreted via the bile and faeces. Resorbed 7- keto-lithocholic acid is reduced to chenodeoxycholic acid in the liver. Lithocholic acid can cause cholestatic liver damage, when the liver is unable to sulphate the lithocholic acid. Although a reduced capacity to sulphate the lithocholic acid in the liver is found in some patients, there is for the time being no clinical evidence that cholestatic liver damage can be associated with the therapy using ursodeoxycholic acid.

After repeated dosage, the ursodeoxycholic acid concentration in the bile reaches a "steady state" after approximately 3 weeks: the total concentration of the ursodeoxycholic acid, however, is never higher than about 60% of the total concentration of the bile acid in the bile: also at high doses.

After therapy with ursodeoxycholic acid is stopped, the concentration of ursodeoxycholic acid in bile decreases quickly after 1 week to 5-10% of the "steady-state" concentration.

The biological half-life of ursodeoxycholic acid is approximately 3.5 to 5.8 days.

6.1 Animal Toxicology or Pharmacology

Acute toxicity

Acute toxicity studies in animals have not revealed any toxic damage.

b) Chronic toxicity

Subchronic toxicity studies in monkeys showed hepatotoxic effects in the groups given high doses, including functional changes (e.g. liver enzyme changes) and morphological changes such as bile duct proliferation, portal inflammatory foci and hepatocellular necrosis. These toxic effects are most likely attributable to lithocholic acid, a metabolite of ursodeoxycholic acid, which in monkeys – unlike humans – is not detoxified. Clinical experience confirms that the described hepatotoxic effects are of no apparent relevance in humans.

c) Carcinogenic and mutagenic potential

Long-term studies in mice and rats revealed no evidence of ursodeoxycholic acid having carcinogenic potential. In vitro and in vivo genetic toxicology tests with ursodeoxycholic acid were negative. The tests with ursodeoxycholic acid revealed no relevant evidence of a mutagenic effect.

d) Toxicity to reproduction

In studies in rats, tail malformations occurred after a dose of 2000 mg per kg of body weight. In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mg per kg of body weight). ursodeoxycholic acid had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.

Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. The chemical name of ursodiol is 3α,7ß-dihydroxy-5ß-cholan-24-oic (C₂₄H₄₀O₄)

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 Blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store in a cool, dry & dark place.
• Keep out of reach of children.
• Tablet should be swallowed whole & not to be broken, chewed or crushed.

• Ursomax tablet should be taken after a meal with a glass of milk or water.
• Eat a healthy diet, exercise regularly, and avoid alcohol intake.
• Diarrhea may occur as a side effect. Drink plenty of fluids and inform your doctor if diarrhea persists or if you find blood in your stools.
• Your doctor may monitor your liver function and bilirubin levels every month for the next 3 months after the start of therapy, and every 6 months thereafter.
• Do not stop taking the medication without talking to your doctor.

28.08.2024

Ursodeoxycholic acid

Ursomax 150

Each uncoated tablet contains

Ursodeoxycholic acid IP.…………………………150 mg

Excipients……………………………………………...…...q.s.

Ursomax 300

Each uncoated tablet contains

Ursodeoxycholic acid IP.……………………………300 mg

Excipients……………………………………………...…...q.s.

Ursomax 450 SR

Each prolonged-release uncoated tablet contains

Ursodeoxycholic acid IP.……………………………450 mg

Excipients……………………………………………......q.s.

Tablet 150 mg/300 mg/450 mg

4.1 Therapeutic Indication

For the dissolution of radiolucent cholesterol gallstone, chronic cholestatic liver diseases in particular primary biliary cirrhosis, primary sclerosing cholangitis & cholestasis associated with cystic fibrosis.

4.2 Posology and method of administration

The dosage should be calculated based on the patient's body weight. The calculated dosage should be rounded to the nearest number of tablets.

Dissolving of cholesterol stones

Usual dosage: 8 to 10 mg/kg/day, corresponding to, for example, four to six 150 mg tablets, or two to three tablets of 300 mg, or two tablets of 450 mg. The daily dose can be administered two or three times after the meals: two tablets should always be taken after the evening meal.

Also a single evening dose can be selected (e.g., a patient of 60 kg, in the evening two tablets of 300 mg). Preferably, this single dose should be taken one hour before bedtime and ± two hours after the evening meal with a glass of milk or a small snack.

The duration of the treatment in order to obtain lysis of the gallstones depends on their size, but is usually not shorter than three to four months. To assess the result of the therapy properly, it is necessary to determine the size of the stones accurately at the start of the treatment and to check this further regularly, for example every six months, by means of a new contrast X-ray recording and/or sonographic recording.

In patients in whom, after six months of treatment with the indicated dosage, the stones are not reduced in size, it is recommended to determine the lithogenic index in the bile by means of a duodenum drainage. When the bile has an index of > 1.0, it is unlikely that a favourable result can be obtained, and it is better to consider a different form of treatment for the gallstones.

Treatment should be continued for three to four months after it is established by means of ultrasound check that the gallstones are completely dissolved. An interruption of the treatment for three to four weeks results in a return to over-saturation of the bile and prolongs the overall duration of the therapy. The interruption of the treatment after the dissolving of the gallstones can be followed by a recurrence.

Primary Biliary Cholangitis (Primary biliary cirrhosis)

The dosage of Ursodeoxycholic acid in primary biliary cholangitis (stages I-III), amounts to 12-15 mg/kg/day, which is equivalent to four to eight tablets of 150 mg, two to four tablets of 300 mg, to be taken in two to three portions during the day, or with two tablets of 450 mg, to be taken in two portions during the day.

The dosage of ursodeoxycholic acid in primary biliary cholangitis stage IV and an increase of the serum bilirubin contents (> 40 μg/l), should be in the first instance, only a half of the normal dose (6 to 8 mg/kg/day). Thereafter, the liver function should be closely monitored for several weeks (once every two weeks for six weeks). If there is no deterioration of the liver function (AF, ALT (SGPT), AST (SGOT), γ-GT, bilirubin) and no increase in itching occurs, the dose may be further increased to the usual level. Moreover, the liver function must then again be closely monitored for several weeks. If again no deterioration of the liver function takes place, the patient may be held at the normal dosage for a long time.

In patients with primary biliary cholangitis stage IV without elevated serum bilirubin, the usual starting dose is allowed to be administered directly. Anyway, here too an accurate control of the liver function should be executed.

The treatment of the primary biliary cholangitis should be regularly assessed on the basis of liver values (laboratory) and clinical findings.

Paediatric population

Children with cystic fibrosis aged 6 years to 18 years

Treatment of hepatobiliary diseases as a result of cystic fibrosis 20 mg/kg/day divided in two to three divided doses. If necessary, increase to 30 mg/kg/day. This corresponds with four to ten tablets of 150mg, two to five tablets of 300 mg, or with two to three tablets of 450 mg, to be taken in one or two portions during the day

Method of administration

If the patient has difficulty in swallowing because of the size of the tablet, the tablet can be halved if necessary on the dividing score, so that one half tablet can be taken twice directly in sequence.

4.3 Contraindications

Ursodeoxycholic acid tablets should not be used in patients with:

• Acute inflammation of the gall bladder or bile ducts
• Occlusion of the biliary tract (occlusion of the common bile duct or a cystic duct)
• Frequent episodes of biliary colic
• X-ray radiolucent calcified gallstones
• Impaired contractility of the gallbladder
• Hypersensitivity to bile acids or to any of the excipient
• Active gastric and duodenal ulcers

Paediatric population

• Unsuccessful portoenterostomy or without recovery of good bile flow in children with biliary atresia.

4.4 Special warnings and precautions for use

Ursodeoxycholic acid tablets should be taken under medical supervision.

During the first three months of the treatment liver function parameters AST (SGOT), ALT (SGPT) and γ-GT should be monitored by the physician every 4 weeks, thereafter every 3 months. Apart from allowing for identification of responders and non-responders in patients being treated for primary biliary cholangitis, this monitoring would also enable an early detection of potential hepatic deterioration, particularly in patients with advanced primary biliary cholangitis.

When used for dissolving gallstones:

In order to be able to assess the therapeutic progression of the dissolution of gallstones and to timely identify a possible calcification of the stones, the gall bladder, depending on the size of the stones, should be visualized 6 to 10 months after the start of the treatment (oral cholecystography) with total image and occlusions and in the standing and lying position (ultrasound investigation).

If the gallbladder cannot be visualized on X-rays, or in cases of calcified gallstones, impaired contractility of the gall bladder or frequent episodes of biliary colic, the treatment with Ursodeoxycholic acid should be discontinued.

When used for the treatment of advanced primary biliary cholangitis:

In very rare cases decompensation of liver cirrhosis is observed which partially decreased after treatment discontinuation.

In patients with PBC, the clinical symptoms may worsen in rare cases at the start of treatment, e.g. pruritus may increase. In this case, the therapy is to be continued with a dose reduction and subsequently should be gradually increased to the recommended dose as described in section 4.2.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea.

Female patients who use Ursodeoxycholic acid for dissolving gall stones must use an effective non-hormonal method of contraception, since hormonal contraception may increase biliary lithiasis

4.5 Drugs interactions

• Ursodeoxycholic acid tablets should not be used concurrently with colestyramine, colestipol, or an antacid, on the basis of aluminium hydroxide and/or smectite (aluminium oxide), because these preparations bind ursodeoxycholic acid in the intestine and thereby inhibits its absorption and efficacy. If the use of such a medicine is necessary, must it be taken at least 2 hours before or after ursomax.
• Ursodeoxycholic acid may affect the absorption of ciclosporin from the intestine. In patients treated with ciclosporin the blood level of ciclosporin should be monitored and the ciclosporin dose should be adjusted, if necessary.
• In isolated cases Ursodeoxycholic acid can reduce the absorption of ciprofloxacin.
• In a clinical study in healthy volunteers, the concomitant use of UDCA (500 mg/day) and rosuvastatin (20 mg/day) resulted in slightly elevated plasma levels of rosuvastatin.The clinical relevance of this interaction, also with other statins, is not known.
• Ursodeoxycholic acid has been shown to reduce the peak plasma concentration (Cmax) and the AUC of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring of the outcome of concurrent use of nitrendipine and ursodeoxycholic acid is recommended. An increase of the dose of nitrendipine may be necessary. An interaction with a reduction of the therapeutic effect of dapsone was also reported. These observations, together with in vitro findings could be an indication that ursodeoxycholic acid can induce cytochrome P450 3A enzymes. Induction has, however not been observed in a well-designed interaction study with budesonide, which is a known cytochrome P450 3A substrate.
• Oestrogens and blood cholesterol lowering agents such as clofibrate increase hepatic cholesterol secretion and may therefore encourage biliary lithiasis; which is a counter-effect to ursodeoxycholic acid used for dissolution of gallstones.

4.6 Use in special populations

Pregnancy

• There are no or limited amount of data from the use of ursodeoxycholic acid in pregnant women. Studies in animals have shown reproductive toxicity during the early gestation phase.
• Ursodeoxycholic acid must not be used during pregnancy, unless clearly necessary.

Women of childbearing potentialc

• Women of childbearing potential should be treated with ursodeoxycholic acid, only if they practice reliable contraception: non-hormonal contraceptives or oral contraceptives with low oestrogen dose are recommended. However, in patients taking Ursodeoxycholic acid for dissolving gallstones an effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis.
• The possibility of a pregnancy must be excluded before beginning treatment.

Nursing Mothers

• According to few documented cases of breastfeeding women milk levels of ursodeoxycholic acid levels in milk are very low and probably no adverse reactions are to be expected in breastfed infants.

Fertility

Animal studies did not show an influence of ursodeoxycholic acid on fertility. Human data on fertility treatment with ursodeoxycholic acid are not available.

4.7 Effects on ability to drive and use machines

Ursodeoxycholic acid has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The following adverse reactions have been reported during clinical trials and are ranked using the following frequency:

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).

Gastrointestinal disorders:

In clinical studies, reports of pasty stools or diarrhoea during treatment with ursodeoxycholic acid were common.

In very rare cases, severe right upper abdominal pain has occurred during the treatment of primary biliary cholangitis.

Hepatobiliary disorders:

During treatment with ursodeoxycholic acid calcification of gallstones can occur in very rare cases.

During the treatment of advanced stages of primary biliary cholangitis decompensation of cirrhosis has been observed in very rare cases, which partially regressed after treatment discontinuation.

Hypersensitivity reactions:

Very rarely urticaria may occur.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zuventus.com

Website: https://www.zuventus.com/drug-safety-reporting

4.9 Overdose

In the case of overdose diarrhoea may occur. In general, other symptoms of overdose are unlikely, because the absorption of the ursodeoxycholic acid decreases with increasing dose and therefore more is excreted in the faeces.

If diarrhoea occurs, the dosage should be reduced, and treatment should be discontinued in case of persistent diarrhoea. No specific measures are needed and the consequences of diarrhoea should be treated symptomatically with restoration of fluid and electrolyte balance.

Additional information or special populations: Long-term, high-dose UDCA therapy (28-30 mg/kg/day) by patients with primary sclerosing cholangitis (off-label use) was associated with a higher frequency of serious adverse events.

5.1 Mechanism of Action

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

5.2 Pharmacodynamic properties

Bile acids are among the most important components of the bile and play a role in the stimulation of bile secretion. Bile acids are also important to keep the cholesterol in bile in solution. In a healthy person, the ratio between the concentration of cholesterol and bile acids in the bile is such that the cholesterol will remain in solution for most of the day. In this case, no gallstones can form (the bile is non-lithogenic). In patients with cholesterol stones in the bile, this ratio is changed and the bile is supersaturated with cholesterol (bile is lithogenic). This may cause a precipitation of cholesterol crystals and the formation of gallstones after some time.

The ursodeoxycholic acid converts lithogenic bile in non-lithogenic bile and gradually dissolves the cholesterol gallstones.

Investigations of the effect of ursodeoxycholic acid on the cholestasis in patients with impaired biliary drainage and on the clinical symptoms in patients with primary biliary cholangitis and cystic fibrosis have shown that cholestatic symptoms in the blood (to be measured by the increased value of alkaline phosphatase (AF), gamma-GT and bilirubin) and the itch declined rapidly, while also the fatigue decreased in the majority of patients. Moreover, studies seem to indicate a positive benefit-risk ratio of the ursodeoxycholic acid in children and young adult cystic fibrosis patients with mild to moderate hepatobiliary disorders.

Paediatric population

Cystic fibrosis

From clinical reports long-term experience of 10 years and more has been gained with UDCA therapy in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can inhibit bile duct proliferation, can halt progression of histological damage and even reverse hepato-biliary changes, if it happens at an early stage of CFAHD. The treatment with UDCA should be started as soon as the CFAHD diagnosis is made, in order to optimize the effectiveness of the treatment.

5.3 Pharmacokinetic properties

About 90% of the therapeutic dose of the ursodeoxycholic acid is rapidly absorbed in the small intestine after oral administration.

After the absorption, ursodeoxycholic acid is absorbed in the liver (there is a substantial "first-passeffect"), where it is conjugated with glycine or taurine and then secreted into the bile ducts. Only a small portion of ursodeoxycholic acid is found in the systemic circulation. This is excreted renally. With the exception of conjugation, ursodeoxycholic acid is not metabolised. However, a small fraction of orally administered ursodeoxycholic acid undergoes bacterial conversion to 7-keto-lithocholic acid resp. lithocholic acid after each enterohepatic circulation, while bacterial deconjugation also takes place in the duodenum. Ursodeoxycholic acid, 7-keto-lithocholic acid and lithocholic acid are relatively poorly soluble in water, so a large part of it is excreted via the bile into the faeces. Resorbed ursodeoxycholic acid is conjugated again by the liver; 80% of the lithocholic acid formed in the duodenum is excreted in the faeces, but the remaining 20% of it are sulphated by the liver to insoluble lithocholylconjugates after absorption, which in turn are excreted via the bile and faeces. Resorbed 7- keto-lithocholic acid is reduced to chenodeoxycholic acid in the liver. Lithocholic acid can cause cholestatic liver damage, when the liver is unable to sulphate the lithocholic acid. Although a reduced capacity to sulphate the lithocholic acid in the liver is found in some patients, there is for the time being no clinical evidence that cholestatic liver damage can be associated with the therapy using ursodeoxycholic acid.

After repeated dosage, the ursodeoxycholic acid concentration in the bile reaches a "steady state" after approximately 3 weeks: the total concentration of the ursodeoxycholic acid, however, is never higher than about 60% of the total concentration of the bile acid in the bile: also at high doses.

After therapy with ursodeoxycholic acid is stopped, the concentration of ursodeoxycholic acid in bile decreases quickly after 1 week to 5-10% of the "steady-state" concentration.

The biological half-life of ursodeoxycholic acid is approximately 3.5 to 5.8 days.

6.1 Animal Toxicology or Pharmacology

Acute toxicity

Acute toxicity studies in animals have not revealed any toxic damage.

b) Chronic toxicity

Subchronic toxicity studies in monkeys showed hepatotoxic effects in the groups given high doses, including functional changes (e.g. liver enzyme changes) and morphological changes such as bile duct proliferation, portal inflammatory foci and hepatocellular necrosis. These toxic effects are most likely attributable to lithocholic acid, a metabolite of ursodeoxycholic acid, which in monkeys – unlike humans – is not detoxified. Clinical experience confirms that the described hepatotoxic effects are of no apparent relevance in humans.

c) Carcinogenic and mutagenic potential

Long-term studies in mice and rats revealed no evidence of ursodeoxycholic acid having carcinogenic potential. In vitro and in vivo genetic toxicology tests with ursodeoxycholic acid were negative. The tests with ursodeoxycholic acid revealed no relevant evidence of a mutagenic effect.

d) Toxicity to reproduction

In studies in rats, tail malformations occurred after a dose of 2000 mg per kg of body weight. In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mg per kg of body weight). ursodeoxycholic acid had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.

Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. The chemical name of ursodiol is 3α,7ß-dihydroxy-5ß-cholan-24-oic (C₂₄H₄₀O₄)

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 Blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store in a cool, dry & dark place.
• Keep out of reach of children.
• Tablet should be swallowed whole & not to be broken, chewed or crushed.

• Ursomax tablet should be taken after a meal with a glass of milk or water.
• Eat a healthy diet, exercise regularly, and avoid alcohol intake.
• Diarrhea may occur as a side effect. Drink plenty of fluids and inform your doctor if diarrhea persists or if you find blood in your stools.
• Your doctor may monitor your liver function and bilirubin levels every month for the next 3 months after the start of therapy, and every 6 months thereafter.
• Do not stop taking the medication without talking to your doctor.

28.08.2024