Rabeprazole Injection IP

Each vial contains:

Rabiprazole Sodium IP 20 mg

Each ampoule contains

Sterile Water for Injections IP q.s

A sterile freeze dried powder for reconstitution.

Powder for solution for infusion.

20 mg

4.1 Therapeutic indication

For the treatment of gastritic & deodenal ulcer, gastroesophagal reflux disease (GERD) as an alternative to oral therapy in patients who are unable to take oral proton pump inhibitor.

4.2 Posology and method of administration

The intravenous administration is recommended only in cases where the oral administration is not indicated. As soon as an oral therapy is possible, the intravenous therapy should be discontinued.

Recommended dose is intravenous administration of the content of one vial (20 mg Rabeprazole) once daily.

Parenteral routes of administration other than intravenous are not recommended.

Injection: The content of the vial needs to be reconstituted with 5 ml Sterile Water for Injections IP, which should be given slowly over 5 - 15 min.

Infusion: For intravenous infusion the reconstituted solution should be further diluted and administered as short-term infusion over 15 - 30 min.

Compatibility with various I.V. fluids: Rabeprazole I.V. is compatible with Sterile Water for Injections IP and 0.9% Sodium Chloride Injection IP. No other solvent or infusion fluid must be used for administration of Rabeprazole I.V. injection.

Reconstitution: To reconstitute add 5 ml of Sterile Water for Injections IP to make a solution. After preparation, the reconstituted solution must be used within 4 hours and the unused portion discarded. As with all parenteral admixtures, the reconstituted or further diluted solution should be examined for change in colour, precipitation, haziness or leakage. The unused portion should be discarded. pH of the reconstituted solution: Between 11.2-12.5.

4.3 Contraindications

Rabeprazole is contraindicated in patients with known hypersensitivity to Rabeprazole, substituted benzimidazoles or to any component of the formulation

4.4 Special warnings and precautions for use

• Presence of gastric malignancy: Symptomatic response to therapy with Rabeprazole does not preclude the presence of gastric malignancy.
• Renal impairment: No dose adjustment is necessary in patients with renal impairment.
• Hepatic impairment: No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Due to the lack of clinical data on Rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients.

4.5 Drug interactions

Drugs metabolized by CPY450: Studies in healthy subjects have shown that Rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing).

Warfarin: There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including Rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Cyclosporine: In vitro incubations employing human liver microsomes indicated that Rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 μM, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of Rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

Compounds dependent on gastric pH for absorption: Co-administration of Rabeprazole 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with Rabeprazole. Concomitant use of atazanavir and proton pump inhibitors is not recommended. Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.

4.6 Use in special populations

Pregnancy

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.

Breast-feeding

Since many drugs are excreted in milk, caution should be exercised when Rabeprazole is administered to a nursing mother.

Pediatric use

The safety and effectiveness of Rabeprazole in pediatric patients has not been established.

Geriatric use

No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

4.7 Effects on the ability to drive and use machines

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

4.8 Undesirable effects

Worldwide, over 2900 patients have been treated with oral Rabeprazole in Phase II-III clinical trials involving various dosages and durations of treatment.

The most commonly reported adverse reactions observed in patients included pain, pharyngitis, flatulence, infection, and constipation. Other adverse reactions observed include headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia. Proton Pump Inhibitors associated with acute kidney injury.

Reporting of side effects

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: www.zuventus.co.in and click the tab “Safety Reporting” located on the top end of the home page.

Website link: https://www.zuventus.co.in/drug-safety-reporting

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

4.9 Overdose

There has been no experience with large overdoses of Rabeprazole.

No specific antidote for Rabeprazole is known. Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

5.1 Mechanism of Action

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine-2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+/K+-ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, Rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.

5.2 Pharmacodynamic properties

In gastric parietal cells, Rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, Rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds.

The anti-secretory effect begins within one hour after oral administration of 20 mg Rabeprazole. The median inhibitory effect of Rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose.

5.3 Pharmacokinetic properties

The plasma concentration time profile of Rabeprazole after intravenous administration of a single 20 mg dose is biphasic, with a terminal half-life of 1.02 ± 0.63 hrs. Peak plasma concentration of 1646.07 ± 461.27 ng/mL is obtained within 0.14 ± 0.08 hrs of administration. Intravenous infusion of 20 mg Rabeprazole over five minutes results in a four-fold increase in peak concentration and a more rapid elimination as compared to the same oral dose. The AUC0-t and AUC0-∞ are 1297.70 ± 357.07 and 1289.83 ± 356.52 ng*h/mL, respectively. The total body clearance of Rabeprazole is 282.93 ± 98.01 mL/min.

Rabeprazole is extensively metabolized. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites are not observed to have significant antisecretory activity. In vitro studies have demonstrated that Rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl Rabeprazole. The thioether metabolite is formed non-enzymatically by reduction of Rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations; therefore, they are referred to as poor metabolizers of the drug.

6.1 Animal Toxicology or Pharmacology

Non-clinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that make concerns for human safety negligible in respect of animal data.

Studies on mutagenicity gave equivocal results. Tests in mouse lymphoma cell line were positive, but in vivo micronucleus and in vivo and in vitro DNA repair tests were negative. Carcinogenicity studies revealed no special hazard for humans.

RABIFAST-IV contains Rabeprazole, a substituted benzimidazole that inhibits gastric acid secretion.

IUPAC Name: Sodium;2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]-benzimidazol-1-ide

Molecular Formula: C₁₈H₂₀N₃NaO₃S

Molecular Weight: 381.4 g/mol

Structure:

Adverse Reactions

Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:

• Injection Site Reactions
• Potential for Exacerbation of Zinc Deficiency
• Acute Tubulointerstitial Nephritis
• Clostridium difficile-Associated Diarrhea
• Bone Fracture
• Severe Cutaneous Adverse Reactions
• Cutaneous and Systemic Lupus Erythematosus
• Hepatic Effects
• Hypomagnesemia and Mineral Metabolism

Drug Interactions

• Instruct patients to inform their healthcare provider of any other medications they are currently taking, including rilpivirine-containing products and high dose methotrexate.

Pregnancy

• Advise a pregnant woman of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

If you have any further questions, ask your doctor or pharmacist.

This leaflet was last revised in July 2024.

Bacillus subtilis (HU58*) 2 Billion CFU / 5 ml & Bacillus coagulans (SC208Ψ) 1 Billion CFU / 5 ml

Per 5 ml mini bottle contains:

Bacillus subtilis (HU58*) 2 Billion CFU

Bacillus coagulans (SC208Ψ) 1 Billion CFU

HU58* is a trademark of Synergia Life Sciences Pvt. Ltd.

Original Research of Royal Holloway, University of London.

ΨSC208 is a trademark of Synergia Life Sciences Pvt. Ltd

Oral suspension

Bacillus subtilis (HU58*) 2 Billion CFU / 5 ml & Bacillus coagulans (SC208Ψ) 1 Billion CFU / 5 ml

4.1 Therapeutic Indication

Helps in the restoration of intestinal flora altered during diarrhoea, constipation and course of antibiotic therapy.

4.2 Posology and method of administration

One - Two serving sizes daily

4.3 Contraindications

Ascertained hypersensitivity towards the components of the product

4.4 Special warnings and precautions for use

• Shake well before use.
• Not to exceed the recommended daily usage.
• To be given under medical advice by a recognized medical doctor or dietician or nutritionist for children 2 to 5 year.
• This product is not intended to mitigate, treat, cure or prevent any disease.
• This product is not to be used as a substitute for a varied diet.
• This medicine is for oral use only. Do not inject or administer in any other way

4.5 Drugs interactions

There are no known medicinal interactions subsequent to the concomitant administration of other drugs

4.6 Use in special populations

Pregnancy and lactation

Pregnant or lactating women or anyone with a medical condition should consult with a healthcare professional before consuming this product

4.7 Effects on ability to drive and use machines

The drug does not interfere with the ability to drive or use machinery.

4.8 Undesirable effects

During post marketing experience, hypersensitivity reactions, including rash urticaria and angioedema have been reported. Bacteremia, septicemia or sepsis in immunocompromised patients or those hospitalized due to a serious illness.

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.co.in/drug-safety-reporting

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

4.9 Overdose

Up to the present time no clinical manifestations of overdose have been reported. However, in case of accidental overdose, contact a healthcare professional.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data

The preparation consists of spores of Bacillus subtilis & Bacillus coagulans which are normal non-pathogenic inhabitants of the intestine.

8.1 Incompatibilities

None

8.2 Shelf-life

Refer the pack

Viability at the end of shelf life: 3 billion CFU per 5 ml.

8.3 Packaging information

Net quantity: 30ml

6 mini bottles of 5 ml each

8.4 Storage and handing instructions

Store at a temperature below 30°C, protect from direct sunlight

Product is required to be stored out of reach of children.

Consume immediately after opening.

Do not use if cap / seal broken of the bottle.

• ProDiof help to maintain a healthy intestinal microflora and supports healthy digestion.
• They help to restore the equilibrium of the intestinal flora altered during diarrhea, constipation and during the course of antibiotic therapy.
• Tell patients that after the mini bottle has been opened, the preparation should be consumed within a very short period of time to avoid deterioration of the suspension.
• Tell the patients if they get any side effects, talk to the doctor. This includes any possible side effects not listed in this leaflet. Advice patients if they have any further questions, ask the doctor or pharmacist.

04-07-2024

Pantoprazole Gastro-resistant and Domperidone Prolonged-release Capsules IP [40 mg + 30 mg]

Each hard gelatin capsule contains :

Pantoprazole Sodium IP

equivalent to Pantoprazole 40 mg

(As Gastro-resistant pellets)

Colour : Indigo Carmine

Domperidone IP 30 mg

(As Prolonged-release pellets)

Colour : Lake of Sunset Yellow

Approved colours used in the capsule shell.

Capsule, Pantoprazole (40 mg) and Domperidone (30 mg).

4.1 Therapeutic indications

For the treatment gastro-esophageal reflux disease (GERD) not responding adequately to Pantoprazole alone.

4.2 Posology and method of administration

1 Capsule to be administered once daily.

Pansa DSR 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.

Pediatric patients

Pansa DSR Capsules are not recommended for use in children.

4.3 Contraindications

• Patients with known hypersensitivity to Pantoprazole or to any substituted Benzimidazole derivative or to Domperidone or to any component of the formulation.
• In patients receiving Rilpivirine-containing products.
• Prolactin-releasing pituitary tumor (prolactinoma).
• In patients with gastrointestinal hemorrhage, mechanical obstruction or perforation (i.e. when stimulation of the gastric motility could be harmful).
• In patients with moderate or severe hepatic impairment.
• In patients who have known existing prolongation of cardiac conduction intervals, particularly QTc.
• Patients with significant electrolyte disturbances (hypokalemia, hyperkalemia, hypomagnesemia) or underlying cardiac disease such as congestive heart failure (CHF).
• Co-administration with QT-prolonging drugs.
• Co-administration with potent CYP3A4 inhibitors.

4.4 Special warnings and precautions for use

Pantoprazole

Presence of gastric malignancy

In adults, symptomatic response to therapy with Pantoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a Pantoprazole.

Acute interstitial nephritis

Acute interstitial nephritis has been observed in patients taking Pantoprazole. Acute interstitial nephritis may occur at any point during Pantoprazole therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Pantoprazole if acute interstitial nephritis develops.

Clostridium difficile-associated diarrhea (CDAD)

Published observational studies suggest that Pantoprazole therapy may be associated with an increased risk of CDAD, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.

Risk of bone fractures

Proton pump inhibitors (PPIs), 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 recognized risk factors. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 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.

Cutaneous and systemic lupus erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including Pantoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. The occurrence of CLE with previous PPI treatment may increase the risk of CLE with other PPIs. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. The majority of patients presented with rash. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and Pantoprazole therapy should be stopped immediately. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks.

Cyanocobalamin (Vitamin B12) deficiency

Generally, daily treatment with any acid-suppressing medication over a long period of time (e.g. longer than 3 years) may lead to malabsorption of Vitamin B12 caused by hypo- or achlorhydria. Rare reports of Cyanocobalamin deficiency occurring with acidsuppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with Cyanocobalamin deficiency are observed.

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 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), monitoring of magnesium levels prior to initiation of PPI treatment and periodically thereafter should be considered.

Domperidone

Cardiovascular effects

Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking Domperidone. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors.

Epidemiological studies showed that Domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. A higher risk was observed in patients older than 60 years, patients taking daily doses greater than 30 mg and patients concurrently taking QT-prolongation drugs or CYP3A4 inhibitors.

Domperidone is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with underlying cardiac diseases such as congestive heart failure (CHF) due to increased risk of ventricular arrhythmia. Electrolyte disturbances or bradycardia are known to be conditions increasing the proarrythmic risk. Treatment with Domperidone should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patients should consult their physician. Patients should be advised to promptly report any cardiac symptoms.

Use with Apomorphine

Domperidone is contraindicated with QT prolonging drugs including Apomorphine, unless the benefit of the co-administration with Apomorphine outweighs the risks.

Use in infants and children

Although neurological side effects are rare, the risk of neurological side effects are higher in young children since metabolic

functions and the blood-brain barrier are not fully developed in the first months of life. Overdosing may cause extrapyramidal

symptoms in children, but other causes should be taken into consideration.

4.5 Interaction with other medicinal products and other forms of interaction

Pantoprazole

Antiretroviral drugs

The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.

• Decreased exposure of some antiretroviral drugs (e.g. Rilpivirine, Atazanavir and Nelfinavir) when used concomitantly with Pantoprazole may reduce antiviral effect and promote the development of drug resistance. Concomitant use of Rilpivirine containing products with Pantoprazole is contraindicated. Also, concomitant use of nelfinavir with Pantoprazole should be avoided.
• Increased exposure of other antiretroviral drugs (e.g. Saquinavir) when used concomitantly with Pantoprazole may increase toxicity
• There are other antiretroviral drugs which do not result in clinically relevant interactions with Pantoprazole.

Coumarin anticoagulants / Warfarin

There has been post-marketing reports of increased international normalized ratio (INR) and prothrombin time in patients receiving PPIs, including Pantoprazole and Warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Monitor INR and prothrombin time and adjust the dose of Warfarin if needed, to maintain the target INR range.

Clopidogrel

Concomitant administration of Pantoprazole and Clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of Clopidogrel or Clopidogrel-induced platelet inhibition. No dose adjustment of Clopidogrel is necessary when administered with an approved dose of Pantoprazole.

Methotrexate

Literature suggests that concomitant use of PPIs with Methotrexate (primarily at high dose) may elevate and prolong serum levels of Methotrexate and/or its metabolite, possibly leading to Methotrexate toxicities. A temporary withdrawal of Pantoprazole therapy may be considered in some patients receiving high-dose of Methotrexate.

Drugs for which gastric pH can affect bioavailability (iron salts, Erlotinib, Dasatinib, Nilotinib, Mycophenolate Mofetil, and Ketoconazole)

Pantoprazole causes long-lasting inhibition of gastric acid secretion. Therefore, Pantoprazole may reduce absorption of other drugs where gastric pH is an important determinant of their bioavailability.

Mycophenolate Mofetil (MMF)

Co-administration of Pantoprazole Sodium 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 Pantoprazole therapy and MMF. Use Pantoprazole with caution in transplant patients receiving MMF.

Drug / laboratory tests interactions

False positive urine tests for THC

There have been reports of false positive urine screening tests for Tetrahydrocannabinol (THC) in patients receiving PPIs, including Pantoprazole. An alternative confirmatory method should be considered to verify positive results.

Increased Chromogranin A (CgA) level

Increase in CgA may interfere with investigations for neuroendocrine tumours. To avoid this interference, Pantoprazole 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 Pantoprazole treatment.

Domperidone

The main metabolic pathway of Domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of Domperidone. There is increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.

Concomitant use of the following drugs is contraindicated.

A. QTc-prolonging medicinal products

• Anti-arrhythmic class IA (e.g. Disopyramide, Hydroquinidine, Quinidine).
• Anti-arrhythmic class III (e.g. Amiodarone, Dofetilide, Dronedarone, Ibutilide, Sotalol).
• Certain antipsychotics (e.g. Haloperidol, Pimozide, Sertindole). • Certain antidepressants (e.g. Citalopram, Escitalopram).
• Certain antibiotics (e.g. Erythromycin, Levofloxacin, Moxifloxacin, Spiramycin).
• Certain antifungal agents (e.g. Pentamidine).
• Certain antimalarial agents (e.g. Halofantrine, Lumefantrine).
• Certain gastrointestinal medicines (e.g. Cisapride, Dolasetron, Prucalopride).
• Certain antihistaminic (e.g. Mequitazine, Mizolastine).
• Certain medicines used in cancer (e.g. Toremifene, Vandetanib, Vincamine).
• Other medicines (e.g. Bepridil, Diphemanil, Methadone).

B. Potent CYP3A4 inhibitors (regardless of their QT prolonging effects)

• Protease inhibitors.
• Systemic azole antifungals.
• Some macrolides (e.g. Erythromycin, Clarithromycin and Telithromycin).

Concomitant use of the following drugs is not recommended.

• Moderate CYP3A4 inhibitors (e.g. Diltiazem, Verapamil and some macrolides).

Concomitant use of the following drugs requires caution.

• Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation : Azithromycin and Roxithromycin.

Ketoconazole / Erythromycin and QTc prolongation

Separate in vivo pharmacokinetic / pharmacodynamic interaction studies with oral Ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of Domperidone's CYP3A4 mediated first pass metabolism by these drugs (as both of these drugs significantly inhibit CYP3A4 enzyme). Both the Cmax and AUC of Domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies, concomitant use of Domperidone and Ketoconazole or Erythromycin resulted in increase in QTc, over the observation period.

4.6 Use in special populations

Pregnancy

Pansa DSR capsule should be used during pregnancy only if the potential benefit justifies the possible risk to the fetus.

Breast-feeding

Pansa DSR capsules should not be used during breast feeding. Accordingly, a decision should be made whether to discontinue nursing or to discontinue / abstain from therapy, taking into account the benefit of the drug to the mother.

4.7 Effects on ability to drive and use machines

Both, Pantoprazole and Domperidone have no or negligible influence on the ability to drive and use machines. However, adverse reactions such as dizziness and visual disturbances may occasionally occur in patients on PPIs drug therapy. If affected, patients should not drive or use machines.

4.8 Undesirable effects

Pantoprazole

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in clinical practice. Common adverse reactions reported with Pantoprazole therapy in clinical trials with frequency > 2% include : Headache, diarrhoea, nausea, abdominal pain, vomiting, flatulence, dizziness, and arthralgia. Additional adverse reactions reported in clinical trials with a frequency of ≤ 2% include : Body as a whole :

Allergic reaction, pyrexia, photosensitivity reaction, facial edema

Gastrointestinal : Constipation, dry mouth, hepatitis

Hematologic : Leukopenia, thrombocytopenia

Metabolic / nutritional : Elevated creatine kinase (CK), generalized edema, elevated triglycerides, elevated liver enzymes

Musculoskeletal : Myalgia

Nervous : Depression, vertigo

Skin and appendages : Urticaria, rash, pruritus

Special senses : Blurred vision

Post-marketing experience

Acute kidney injury as an adverse drug reaction reported with the use of proton pump inhibitors. The following adverse reactions have been identified during post-approval use of Pantoprazole. 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.

General disorders and administration conditions : Asthenia, fatigue, malaise

Hematologic : Pancytopenia, agranulocytosis

Hepatobiliary disorders : Hepatocellular damage leading to jaundice and hepatic failure

Immune system disorders : Anaphylaxis (including anaphylactic shock), SLE

Infections and infestations : Clostridium difficile-associated diarrhea

Investigations : Weight changes

Metabolism and nutritional disorders : Hyponatremia, hypomagnesemia

Musculoskeletal disorders : Rhabdomyolysis, bone fracture

Nervous system : Ageusia, dysgeusia

Psychiatric disorders : Hallucination, confusion, insomnia, somnolence

Renal and urinary disorders : Interstitial nephritis

Skin and subcutaneous tissue disorders : Severe dermatologic reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), angioedema (Quincke’s edema) and CLE

Domperidone

Central nervous system : As the pituitary gland is outside the blood-brain barrier, Domperidone may cause an increase in prolactin levels. In rare cases this hyperprolactinaemia may lead to neuro-endocrinological side effects such as galactorrhoea, gynaecomastia and amenorrhoea.

Extrapyramidal side effects are very rare in neonates and infants, and exceptional in adults. These side effects reverse spontaneously and completely as soon as the treatment is stopped. Other central nervous system-related effects of convulsion, agitation and somnolence also are very rare and primarily reported in infants and children.

General disorders

Uncommon : Asthenia.

Immune system disorder

Not known : Anaphylactic reactions including anaphylactic shock and angioedema

Psychiatric disorders

Uncommon : Anxiety, loss of libido;

Not known : Agitation, nervousness

Nervous system disorders

Uncommon : Somnolence, headache;

Not known : Extrapyramidal disorder, convulsions

Eye disorders Not known : Oculogyric crisis Cardiac disorders

Not known : Ventricular arrhythmias, QTc prolongation, Torsade de Pointes, sudden cardiac death. Gastrointestinal disorders

Common : Dry mouth;

Uncommon : Diarrhea Skin and subcutaneous tissue disorders

Uncommon : Rash, pruritus;

Not known : Urticaria, angioedema Reproductive system and breast disorders

Uncommon : Breast pain, breast tenderness, galactorrhoea;

Not known : Gynaecomastia, amenorrhoea

Renal and urinary disorders

Not known : Urinary retention Investigations

Not known : Abnormal liver function test, increased blood prolactin

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.co.in/drug-safety-reporting

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

4.9 Overdose

Symptoms

Symptoms of overdose are agitation, altered consciousness, convulsions, disorientation, somnolence, and extrapyramidal reactions.

Treatment

There is no specific antidote, but in the event of overdose, gastric lavage as well as the administration of activated charcoal, may be useful. Close medical supervision and supportive therapy is recommended. Anticholinergic, Antiparkinson drugs may be helpful in controlling the extrapyramidal reactions.

5.1 Mechanism of action

Pantoprazole

Pantoprazole is a proton pump inhibitor (PPI) class of anti-secretory agent. Pantoprazole is a lipophilic weak base that crosses the parietal cell membrane and enters the acidic parietal cell canaliculus where it becomes protonated, producing the active metabolite sulfenamide. Sulfenamide forms an irreversible covalent bond with two sites of the H+/K+-ATPase enzyme located on the gastric parietal cell. Thus, Pantoprazole suppress the final step in gastric acid (Hydrochloric Acid - HCl) production by covalently binding to the H+/K+-ATPase enzyme (also called as proton pump) system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. The binding to the H+/K+-ATPase results in duration of anti-secretory effect that persists longer than 24 hours.

Domperidone

Domperidone is a dopamine receptor (D2) antagonist. Domperidone act predominantly on peripheral dopamine receptors and produces anti-emetic and gastro-kinetic effects. Domperidone does not readily cross the blood-brain barrier (BBB). Thus, in Domperidone users, especially in adults, extrapyramidal side effects are very rare (unlike metoclopramide). Anti-emetic effect of Domperidone is due to a combination of peripheral (gastro-kinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone (CTZ), which lies outside the BBB in the area postrema. Oral Domperidone also increases lower esophageal sphincter (LES) pressure, thus, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

5.2 Pharmacodynamic properties

With a single oral dose of 20 to 80 mg of Pantoprazole, a dose-dependent decrease in gastric acid secretion occurs. Following the initial oral dose of 40 mg Pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once-a-day dosing for 7 days, the mean inhibition was increased to 85%. Acid secretion had returned to normal within a week after the last dose of Pantoprazole; there was no evidence of rebound hypersecretion.

Pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since Pantoprazole binds to the enzyme distal to the receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (Acetylcholine, histamine and gastrin). The fasting gastrin values increase under Pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases.

Domperidone

Prokinetic effect : The prokinetic (gastro-kinetic) properties of Domperidone are related to its peripheral dopamine receptor blocking action.

Antiemetic effect : Domperidone produces antiemetic effect by blocking dopamine receptors (D2) peripherally. Inhibition of peripheral D2 receptor signaling prevents or relieves various GI symptoms, such as nausea and vomiting, and also relieves reflux and other symptoms associated with upper GI disorders.

5.3 Pharmacokinetic properties

Pantoprazole

Absorption

Like other PPIs, Pantoprazole is an acid-labile drug and therefore, administered orally in the form of gastro-resistant pellets. Absorption of Pantoprazole, therefore, begins in the intestine only after the pellets leave the stomach. After administration of a single or multiple oral doses of Pantoprazole 40 mg, the peak plasma concentration of Pantoprazole was achieved in approximately 2.5 hours, and Cmax was 2.5 mcg/ml. Peak serum concentration (Cmax) and area under the serum concentration time curve (AUC) increases in a dose-dependent manner (with dose range from 10 to 80 mg). Pantoprazole does not accumulate, and its pharmacokinetics are unaltered with multiple daily dosing. Pantoprazole undergoes little first-pass metabolism, resulting in an absolute bioavailability of approximately 77%.

Effect of antacid / food

Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of Pantoprazole with food may delay its absorption up to 2 hours or longer; however, the Cmax and the extent of Pantoprazole absorption (AUC) are not altered. Thus, Pantoprazole may be taken without regard to timing of meals.

Distribution

The apparent volume of distribution of Pantoprazole is approximately 11 to 23.6 liters, distributing mainly in extracellular fluid.

The plasma protein binding of Pantoprazole is about 98%, primarily to albumin.

Metabolism

Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the Pantoprazole metabolites have significant pharmacologic activity.

Excretion

Renal elimination represents the major route of excretion (about 80 %) for the metabolites of Pantoprazole, the rest is excreted with the faeces. There is no renal excretion of unchanged Pantoprazole. The main metabolite in both the serum and urine is desmethyl Pantoprazole which is conjugated with Sulphate. Following oral administration, the serum concentration of Pantoprazole declines biexponentially, with a terminal elimination half-life of approximately one hour.

Domperidone

Pharmacokinetics of Domperidone in sustained release formulation is not available. Conventional formulation of Domperidone (i.e. immediate release) has following pharmacokinetic properties :

Absorption

Domperidone is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 1 hour after dosing. The Cmax and AUC values of Domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. The low absolute bioavailability of oral Domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut and liver.

Distribution

Oral Domperidone does not appear to accumulate or induce its own metabolism. The peak plasma concentration (Cmax) of 18 ng/ml to 21 ng/ml occurs 1.5 hours (Tmax) after the oral dose. Domperidone is 91 to 93% bound to plasma proteins. Distribution studies with Domperidone have shown wide tissue distribution, but low brain concentration.

Metabolism

Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of Domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in Domperidone aromatic hydroxylation.

Excretion

After oral dose, Domperidone is excreted mainly by renal (31%) and biliary (66%) routes. The proportion of the drug excreted unchanged is small (10% of fecal excretion and approximately 1% of urinary excretion). The plasma half-life after a single oral dose is 7 to 9 hours in healthy subjects, but is prolonged in patients with severe renal insufficiency.

6.1 Animal toxicology or pharmacology

Pantoprazole

Carcinogenesis

In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with Pantoprazole doses of 0.5 to 200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface area basis of a 50 kg person dosed with 40 mg/day. In the gastric fundus, treatment with 0.5 to 200 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors in a dose-related manner. In the forestomach, treatment with 50 and 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell papillomas and malignant squamous cell carcinomas. Rare gastrointestinal tumors associated with Pantoprazole treatment included an adenocarcinoma of the duodenum with 50 mg/kg/day and benign polyps and adenocarcinomas of the gastric fundus with 200 mg/kg/day. In the liver, treatment with 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment with 200 mg/kg/day produced increased incidences of follicular cell adenomas and carcinomas for both male and female rats. In a 24-month carcinogenicity study, B6C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day of Pantoprazole, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment with 150 mg/kg/day produced increased incidences of hepatocellular adenomas and carcinomas in female mice. Treatment with 5 to 150 mg/kg/day also produced gastric-fundic ECL cell hyperplasia. A 26-week p53 +/-transgenic mouse carcinogenicity study was not positive.

Domperidone

Safety margins in in vitro proarrhythmic models (isolated Langendorff perfused heart) exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by 9- up to 45-fold. In in vivo models the no effect levels for QTc prolongation in dogs and induction of arrhythmias in a rabbit model sensitized for torsade de 13 pointes exceeded the free plasma concentrations in humans at maximum daily dose (10 mg administered 3 times a day) by more than 22-fold and 435-fold, respectively. In the anesthetized guinea pig model following slow intravenous infusions, there were no effects on QTc at total plasma concentrations of 45.4 ng/ml, which are 3-fold higher than the total plasma levels in humans at maximum daily dose (10 mg administered 3 times a day). At a high, maternally toxic dose (more than 40 times the recommended human dose), teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits. Development abnormalities observed in rats at a high exposure. Risk of carcinogenicity, mutagenicity or sensitisation cannot be excluded.

Each capsule of Pansa DSR contains 40 mg of Pantoprazole (in a gastro-resistant form) and 30 mg of Domperidone (in a prolonged release form) for oral administration in adults.

Pantoprazole

Pantoprazole Sodium is the Sodium salt form of Pantoprazole. Pantoprazole is a substituted Benzimidazole, proton pump inhibitor (PPI) class of anti-secretory agents which suppressesgastric acid production.

Molecular weight : 405.40 g/mol

Molecular formula : C₁₆H₁₄F₂N₃NaO₄S

Chemical name : Sodium; 5-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2- yl) methylsulfinyl] benzimidazol-1-ide Domperidone Domperidone is a dopamine receptor antagonist drug with antiemetic and gastrokinetic properties. Domperidone is white or almost white powder which is slightly soluble in water. Molecular weight : 425.90 g/mol Molecular formula : C22H24ClN5O2 Chemical name : 6-chloro-3-[1-[3-(2-oxo-3H-benzimidazol-1-yl)propyl]piperidin-4-yl]-1H-benzimidazol-2-one.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 capsules.

8.4 Storage and handling instructions

Store protected from moisture at a temperature not exceeding 25°C.

Keep out of reach of children.

• Instruct patients to take Pansa DSR Capsule exactly as prescribed by doctor. Do not change the dose or stop therapy without consulting to your doctor.
• Instruct patients to swallow Pansa DSR Capsule as a whole with water and not to open, chew or crush the capsules.
• 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 capsules per doses at the same time to make up for the missed dose.
• Pregnant women can use this medicine only if essential and in consultation with their doctor.
• 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. Pansa DSR Capsules and certain other medicines can interact with each other causing serious side effects.

04 July 2024

Pantoprazole & Domperidone Gastro-resistant Tablets (20 mg + 10 mg)

Each gastro-resistant tablet contains :

Pantoprazole Sodium IP

equivalent to Pantoprazole 20 mg

Domperidone Maleate IP

equivalent to Domperidone 10 mg

Excipients q.s.

Colours : Yellow Oxide of Iron & Titanium Dioxide IP

Tablets

4.1 Therapeutic indication

For the treatment of GERD not responding to pantoprazole.

4.2 Posology and method of administration

One tablet to be taken 1-3 times a day. The tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.

4.3 Contraindications

• known hypersensitivity to the active substance pantoprazole, domperidone or to substituted benzimidazoles or to any excipients listed in formulation.
• in patients with moderate or severe hepatic impairment
• renal impairment
• in patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.
• prolactin-releasing pituitary tumour (prolactinoma)
• co-administration with QT-prolonging drugs, at the exception of apomorphine
• co-administration with potent CY3A4 inhibitors (regardless of their QT prolonging effects) when stimulation of gastric motility could be harmful : gastro-intestinal haemorrhage, mechanical obstruction or perforation.

4.4 Special warnings and precautions for use

In patients with severe liver impairment the liver enzymes should be monitored regularly during treatment with pantoprazole, particularly on long-term use. In the case of a rise of the liver enzymes the treatment should be discontinued.

The use of pantoprazole as a preventive of gastroduodenal ulcers induced by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) should be restricted to patients who require continued NSAID treatment and have an increased risk to develop gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. high age (>65 years), history of gastric or duodenal ulcer or upper gastrointestinal bleeding.

Symptomatic response to pantoprazole may mask the symptoms of gastric malignancy and may delay diagnosis. In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded. Further investigation is to be considered if symptoms persist despite adequate treatment.

Pantoprazole may reduce the absorption of vitamin B12 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 or if respective clinical symptoms are observed.

In long-term treatment with pantoprazole, especially when exceeding 1 year, patients should be kept under regular surveillance.

Treatment with pantoprazole may lead to a slightly increased risk of gastrointestinalinfections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

For patients expected to be on prolonged pantoprazole treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically thereafter.

PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

PPIs are associated with very infrequent cases of Subacute Cutaneous Lupus Erythematosus (SCLE). If lesions occur, especially in sun exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping pantoprazole.

Increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, pantoprazole 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.

The risk of neurological side effects with domperidone is higher in young children. Overdosing may cause extra-pyramidal symptoms, but other causes should be taken into consideration.

Domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. Contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patient with underlying cardiac diseases such as congestive heart failure due to increased risk of ventricular arrhythmia.

4.5 Drugs interactions

Pantoprazole

Medicinal products with pH-dependent absorption pharmacokinetics

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with the absorption of other medicinal products where gastric pH is an important determinant of oral availability, e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole and other medicinal products such as erlotinib

HIV protease inhibitors

Co-administration of pantoprazole is not recommended with HIV protease inhibitors for which absorption is dependent on acidic intragastric pH such as atazanavir due to significant reduction in their bioavailability.

If the combination of HIV protease inhibitors with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g virus load) is recommended. A pantoprazole dose of 20 mg per day should not be exceeded. Dosage of the HIV protease inhibitor may need to be adjusted.

Coumarin anticoagulants (phenprocoumon or warfarin)

Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or INR. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding, and even death. Patients treated with pantoprazole and warfarin or phenprocoumon may need to be monitored for increase in INR and prothrombin time.

Methotrexate

Concomitant use of high dose methotrexate (e.g. 300 mg) and proton-pump inhibitors has been reported to increase methotrexate levels in some patients. Therefore in settings where high-dose methotrexate is used, for example cancer and psoriasis, a temporary withdrawal of pantoprazole may need to be considered. Other interactions studies

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4.

Interaction studies with medicinal products also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.

An interaction of pantoprazole with other medicinal products or compounds, which are metabolized using the same enzyme system, cannot be excluded.

Results from a range of interaction studies demonstrate that pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-glycoprotein related absorption of digoxin.

There were no interactions with concomitantly administered antacids.

Interaction studies have also been performed by concomitantly administering pantoprazole with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant interactions were found.

Medicinal products that inhibit or induce CYP2C19

Inhibitors of CYP2C19 such as fluvoxamine could increase the systemic exposure of pantoprazole. A dose reduction may be considered for patients treated long-term with high doses of pantoprazole, or those with hepatic impairment.

Enzyme inducers affecting CYP2C19 and CYP3A4 such as rifampicin and St John´s wort (Hypericum perforatum) may reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems.

Domperidone

The main metabolic pathway of domperidone is through CYP3A4. In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions. Concomitant use of the following substances is contraindicated

QTc-prolonging medicinal products

• anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)
• anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
• certain antipsychotics (e.g., haloperidol, pimozide, sertindole)
• certain antidepressants (e.g., citalopram, escitalopram)
• certain antibiotics (e.g. , erythromycin, levofloxacin, moxifloxacin, spiramycin)
• certain antifungal agents (e.g., pentamidine)
• certain antimalarial agents (in particular halofantrine, lumefantrine)
• certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)
• certain antihistaminics (e.g., mequitazine, mizolastine)
• certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)
• certain other medicines (e.g., bepridil, diphemanil, methadone)
• apomorphine, unless the benefit of the co-administration outweighs the risks, and only if the recommended precautions for co-administration are strictly fulfilled.

Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e :

• protease inhibitors
• systemic azole antifungals
• some macrolides (erythromycin, clarithromycin and telithromycin)

Concomitant use of the following substances is not recommended

Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides.

Concomitant use of the following substances requires caution in use

Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation : azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent CYP3A4 inhibitor).

The above list of substances is representative and not exhaustive.

Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs

With the combination of oral domperidone 10mg four times daily and ketoconazole 200mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10mg four times daily and oral erythromycin 500mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while Ketoconazole monotherapy (200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

4.6 Use in special populations

Pregnancy

Pantoprazole : There are no adequate and well-controlled studies in pregnant women. Domperidone : There are limited post-marketing data of its use in pregnant women. A study in rats has shown reproductive toxicity at a high, maternally toxic dose. Because animal reproduction studies are not always predictive of human response, Pansa D tablet should be used during pregnancy only if clearly needed.

Lactation

There is insufficient data on the excretion of pantoprazole in human milk but excretion into human milk has been reported. Domperidone is excreted in human milk and breast-fed infants receive less than 0.1% of the maternal weight-adjusted dose. Caution should be exercised in case of QTc prolongation risk factor in breast-fed infants.

A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from Pansa D therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the women.

Pediatric

Pansa D tablets are not recommended in children below 12 years of age.

Hepatic impairment

A daily dose of 20 mg pantoprazole should not be exceeded in patients with severe liver impairment. Domperidone is contraindicated in moderate or severe hepatic impairment. Hence, a Pansa D tablet is contraindicated in patients with moderate or severe hepatic impairment.

Renal impairment

In subjects with renal insufficiency (creatinine clearance<30 ml/min/1.73m2) the elimination half-life of domperidone was increased from 7.4 to 20.8 hours. Since very little unchanged drug (approx. 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency. However, on repeated administration, the dosing frequency of Pansa D should be reduced to once or twice daily depending on severity of the impairment.

4.7 Effects on ability to drive and use machines

Pansa D tablet has no or negligible influence on the ability to drive and use machines. Adverse drug reactions such as dizziness and visual disturbances may occur. If affected, patients should not drive or operate machines.

4.8 Undesirable effects

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: http://www.zuventus.co.in/safety.aspx

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

4.9 Overdose

Systemic exposure with up to pantoprazole 240 mg administered intravenously over 2 minutes, were well tolerated. As pantoprazole is extensively protein bound, it is not readily dialysable. Symptoms of overdosage with domperidone may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions. In the event of overdose, standard symptomatic treatment should be given immediately. Gastric lavage as well as the administration of activated charcoal may be useful. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Close medical supervision and supportive therapy is recommended. Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

5.1 Mechanism of Action

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. The binding to the (H+,K+)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours. Domperidone binds to dopamine receptor D2 (D2R) expressed by peripheral neurons; this inhibits dopamine binding and D2R-mediated signaling. Inhibition of peripheral D2R signaling prevents or relieves various gastrointestinal (GI) symptoms, such as nausea and vomiting, and may help relief reflux and symptoms of a variety of other upper GI disorders.

5.2 Pharmacodynamicproperties

Pantoprazole

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments have not been observed in humans. During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also Chromogranin A (CgA) increases due to decreased gastric acidity.

Domperidone

Domperidone does not readily cross the blood brain barrier. In domperidone users, especially in adults, extra pyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Studies have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion. When domperidone was administered in healthy subjects at up to 80 mg/day (i.e., more than twice the maximum recommended dosing) in QT study performed in accordance with ICH-E14 guidelines, no clinically relevant QTc effects were observed.

5.3 Pharmacokinetic properties

No known animal toxicology data

8.1 Incompatibilities

None

8.2 Shelf-life

24 Months.

8.3 Packaging information

A blister strip of 10 tablets.

8.4 Storage and handing instructions

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

Keep out of reach of children.

• Ask the patient to report any adverse events.
• Not to exceed the stated recommended daily dose.

14.05.2021

Ceftriaxone & Sulbactam for Injection IP

Monobact Kid

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 125 mg

Sulbactam Sodium IP equivalent to Sulbactam 62.5 mg

This pack contains Sterile Water for Injections IP 5 ml.

Monobact 375 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 250 mg

Sulbactam Sodium IP equivalent to Sulbactam 125 mg

This pack contains Sterile Water for Injections IP 5 ml.

Monobact 750 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 500 mg

Sulbactam Sodium IP equivalent to Sulbactam 250 mg

This pack contains Sterile Water for Injections IP 5 ml.

Monobact 1.5 gm

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 1000 mg

Sulbactam Sodium IP equivalent to Sulbactam 500 mg

This pack contains Sterile Water for Injections IP 10 ml.

Powder for solution for injection.

187.5 mg / 375 mg / 750 mg / 1.5 gm

4.1 Therapeutic indication

• Bacterial meningitis
• Infections of bones and joints
• Community acquired pneumonia
• Complicated skin and soft tissue infections
• Hospital acquired pneumonia
• Gonorrhoea
• Acute otitis media
• Syphilis
• Intra-abdominal infections
• Bacterial endocarditis
• Complicated urinary tract infections
• Surgical prophylaxis

4.2 Posology and method of administration

To be administered by deep intramuscular (I.M.) injection, slow intravenous (I.V.) injection, or as a slow I.V. infusion, after reconstitution with sterile water for injection (SWFI).

Dosage recommendations in adults

Usual Recommended Dose : 1.5 g to 3 g of Monobact Injection (1 g / 2 g ceftriaxone + 0.5 g / 1 g sulbactam) per day given once a day or in two equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. Also, the total dose of sulbactam should not exceed 4 grams per day

For Uncomplicated Gonococcal Infections : A single dose of 750 mg of Monobact Injection (500 mg ceftriaxone + 250 mg sulbactam) to be administered by I.M. route. For Preoperative Use (Surgical Prophylaxis): A single dose of 1.5 g of Monobact Injection (1g ceftriaxone + 0.5 g sulbactam) to be administered intravenously 30 minutes to 2 hours before surgery

The usual duration of therapy is 4 to 14 days. In complicated infections, longer therapy may be required. Or, as prescribed by the physician.

Dosage in adult patients with renal impairment and hepatic dysfunction

In patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the ceftriaxone dosage should not exceed 2 grams daily. Dose of sulbactam should be adjusted in patients with marked decrease in renal function (creatinine clearance of < 30 ml/min) and to compensate for reduced clearance less than 15ml/min, maximum dose of sulbactam should not exceed 1 gram per day.

Dosage recommendations in pediatric patients

For children with bodyweight above 50 kg or age over 12 years, the usual adult dosage should be administered. Although, ceftriaxone can be administered in neonates and infants, the safety and efficacy of this combination product (ceftriaxone + sulbactam injection) has not been established in children below 1 year of age. Thus, Monobact Injection is recommended only in pediatric patients 1 year of age or older.

Following doses in children are expressed in terms of ceftriaxone content of the formulation. Usual Recommended Dosage : 50 to 75 mg/kg/day, given in divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 2 grams. Sulbactam dose in children should not exceed 100 mg/kg/day.

Treatment of Meningitis : The initial therapeutic dose should be 100 mg/kg body weight. Thereafter, daily dose of 100 mg/kg may be administered once a day or in equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. The usual duration of therapy is 7 to 14 days depending on the type and severity of infection. Or, as prescribed by the physician

Geriatric patients

Dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 grams per day provided there is no severe renal and hepatic impairment.

Pharmaceutical precautions

Ceftriaxone-containing injection should not be mixed with other drugs in infusion bottle since compatibility has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Directions for reconstitution and dilution for use

Monobact comes in a composite pack containing one vial of dry powder and Sterile Water for Injections IP in ampoule. Each Monobact 1.5 gm pack contains 1 ampoule of 10 ml Sterile Water for Injections IP [SWFI]. Monobact 750 mg contains 1 ampoule of 5 ml Sterile Water for Injections IP, Monobact 375 mg and Monobact Kid packs contain 1 ampoule of 5 ml Sterile Water for Injections IP per pack. SWFI IP from the ampoule should be used to dissolve the dry powder present in the vial, just prior to the use. After adding the SWFI IP into the vial, agitate the vial gently until the powder dissolves completely into the solution.

Though, stability studies have shown that the solution is stable for 24 hrs at 25°C and up to days under 2°C to 8°C. It is advisable to use the solution immediately after reconstitution. Following are the recommendation for diluting the solution

4.3 Contraindications

• In patients with known hypersensitivity to ceftriaxone, cephalosporin class of antibiotics, or to tazobactam or to any component of the formulation.
• In hyperbilirubinemic neonates/preterm newborns : Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.
• Premature neonates : Ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).
• In neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium.
• Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated.

4.4 Special warnings and precautions

Test dose

Hypersensitivity

Before initiation of therapy, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated.

Clostridium difficile-associated diarrhea (CDAD)

CDAD has been reported with use of nearly all antibacterial agents, including ceftriaxone, 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. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Hemolytic anemia

An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class of antibacterial drugs including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.

Development of drug-resistant bacteria

Prescribing ceftriaxone in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of ceftriaxone may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pancreatitis

Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, and total parenteral nutrition). A cofactor role of ceftriaxone-related biliary precipitation cannot be ruled out.

Urolithiasis and post-renal acute renal failure

Ceftriaxone-calcium precipitates in the urinary tract have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of urolithiasis, and ureteral obstruction and post-renal acute renal failure. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of appropriate management. Ensure adequate hydration in patients receiving ceftriaxone. Discontinue ceftriaxone in patients who develop signs and symptoms suggestive of urolithiasis, oliguria or renal failure and/or the sonographic findings.

Gallbladder pseudolithiasis

Ceftriaxone-calcium precipitates in the gallbladder have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of gallbladder disease. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of conservative management. Discontinue ceftriaxone sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings.

Effect on prothrombin time

Alterations in prothrombin times have occurred in patients treated with ceftriaxone. Monitor prothrombin time during ceftriaxone treatment in patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

Altered laboratory tests

Positive direct Coombs' test and galactosemia test, false-positive test for urinary glucose and elevated lactate dehydrogenase (LDH).

4.5 Drug interactions

Ceftriaxone

Amsacrine, Vancomycin, Fluconazole, and Aminoglycosides : Ceftriaxone is incompatible with these drugs.

Oral Contraceptives : Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment. Chloramphenicol : Caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.

Vitamin K Antagonist : Concomitant use of ceftriaxone with vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with ceftriaxone.

Sulbactam

Probenecid : Probenecid decreases the renal tubular secretion of sulbactam. Concurrent use of probenecid with sulbactam may result in increased and prolonged blood levels of sulbactam.

4.6 Use in special populations

Pregnancy

Animal studies have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Monobact Injection should be used during pregnancy only if clearly needed.

Lactation

Although sulbactam is distributed into breast milk in small amounts, no adverse effects have been seen in breast-fed infants and it is usually compatible with breast feeding. Low concentration of ceftriaxone is excreted in human milk. Therefore, caution should be exercised when Monobact Injection is administered to a nursing woman.

Pediatric patients

Safety and effectiveness of ceftriaxone has been established in pediatric patients. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Thus, ceftriaxone-containing preparations should not be administered to hyperbilirubinemic children. Safety and efficacy of Monobact Injection has not been established in children below 1 year of age.

4.7 Effects on the ability to drive and use machines

During treatment undesirable effects such as dizziness, headache, and convulsions may occur, which may influence the ability to drive and use machines. If affected by such events, patients should not drive or operate machinery.

4.8 Undesirable effects

Ceftriaxone-containing preparations are generally well tolerated. In clinical trials, the following adverse reactions were observed (related to ceftriaxone therapy or of uncertain etiology). Local Reactions : Injection site pain, induration, tenderness, phlebitis, warmth, tightness. Hypersensitivity : Rash, pruritus, fever or chills.

Infections and Infestations : Genital fungal infection. Hematologic : Eosinophilia, thrombocytosis, leukopenia. Less frequently reported were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.

Blood and Lymphatic Disorders : Granulocytopenia, coagulopathy. Gastrointestinal : Diarrhea/loose stools, nausea, vomiting, dysgeusia, pseudomembranous colitis.

Hepatic : Elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin.

Renal : Elevations of the blood urea nitrogen (BUN), creatinine and the presence of casts in the urine.

Central Nervous System : Headache, dizziness.

Dermatologic : Exanthema, allergic dermatitis, urticaria, edema; acute generalized exanthematous pustulosis (AGEP) and isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome / toxic epidermal necrolysis) have been reported.

Miscellaneous : Diaphoresis, flushing, increased blood creatinine.

Other rarely observed adverse reactions (< 0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.

Reporting of side effects

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

In the case of overdose nausea, vomiting, and diarrhea can occur. There is no specific antidote. Treatment should be supportive and symptomatic according the patient's clinical presentation.

5.1 Mechanism of action

Ceftriaxone

Ceftriaxone is a third generation cephalosporin class of beta-lactam antibiotic. Ceftriaxone inhibits bacterial cell wall synthesis and produces bactericidal effect. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gramnegative and Gram-positive bacteria.

Sulbactam

Beta-lactamases are the enzymes produced by certain bacteria to develop resistant to penicillin and cephalosporin class of beta-lactam antibiotics. Sulbactam inhibits action of these enzymes irreversibly. In particular, sulbactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance. The addition of sulbactam effectively extends the antibacterial spectrum of concurrently administered beta-lactam antibiotic (e.g., ceftriaxone) to include many bacteria normally resistant to it.

5.2 Pharmacodynamic properties

The combination of ceftriaxone and sulbactam is active against wide variety of beta-lactamase producing gram-positive and gram-negative bacteria. In addition, it demonstrates synergistic activity (reduction in MICs of combination therapy versus ceftriaxone alone) in a variety of organisms which are sensitive to ceftriaxone.

Monobact Injection has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections :

Gram-negative Bacteria

Acinetobacter calcoaceticus       Moraxella catarrhalis

Enterobacter aerogenes             Morganella morganii

Enterobacter cloacae                  Neisseria gonorrhoeae

Escherichia coli                           Neisseria meningitidis

Haemophilus influenzae             Proteus mirabilis

Haemophilus parainfluenzae      Proteus vulgaris

Klebsiella oxytoca                      Pseudomonas aeruginosa 

Klebsiella pneumoniae              Serratia marcescens

Gram-positive Bacteria

Staphylococcus aureus             Streptococcus pyogenes

Staphylococcus epidermidis      Viridans group streptococci

Streptococcus pneumoniae

Anaerobic Bacteria

Bacteroides fragilis Peptostreptococcus species

Clostridium species

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftriaxone. However, the efficacy of ceftriaxone in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-negative Bacteria

Citrobacter diversus     Salmonella species (including Citrobacter freundii Salmonella typhi)

Providencia species (including Providencia rettgeri) Shigella species

Gram-positive Bacteria

Streptococcus agalactiae

Anaerobic Bacteria

Porphyromonas (Bacteroides) melaninogenicus Prevotella (Bacteroides) bivius

5.3 Pharmacokinetic properties

Ceftriaxone

Absorption : Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 gram is about 81 mg/l and is reached in 2 to 3 hours after administration. The area under the plasma concentrationtime curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone (Cmax) levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively. An 8 to 15 % increase in Cmax is seen on repeated administration; steady state is reached in most cases within 48 to 72 hours depending on the route of administration.

Distribution : The volume of distribution of ceftriaxone is 7 to 12 litre. Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/l.

Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/l).

Metabolism : Ceftriaxone is not metabolized systemically; but is converted to inactive metabolites by the gut flora. Elimination : Plasma clearance of total ceftriaxone (bound and unbound) is 10 to 22 ml/min. Renal clearance is 5 to 12 ml/min. 50 to 60 % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40 to 50 % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.

Sulbactam

After a 30-minute infusion of 1g of sulbactam, a peak concentration of approximately 43 mcg/ml is obtained. Plasma protein binding is approximately 38%. The mean serum half-life of sulbactam is approximately 1 hour in healthy volunteers. Approximately 75 to 85% of sulbactam is excreted unchanged in the urine during the first 8 hours after administration to individuals with normal renal function.

6.1 Animal toxicology or pharmacology

Ceftriaxone

LD50 values after administration of ceftriaxone by intravenous route were in mice 1840 mg/kg, in rat 2240 mg/kg, and in rabbit 240 mg/kg. LD50 value reported after administration of ceftriaxone by oral route in mice and rats was >10,000 mg/kg. In a 2-week intravenous administration study, groups of eight male Füllinsdorf rats were administered 0, 25 or 60 mg/kg/day of ceftriaxone. Body weight gain was slightly depressed by 9.2 and 20.1% in the 25 and 60 mg/kg/day groups respectively. The average weight of the thyroid glands was increased in the treated groups by 11 to 14% in comparison to the control animals. A 50% reduction in plasma bilirubin in the treated rats was reported along with a decrease in the number of leucocytes. 11 Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies. Carcinogenicity studies on ceftriaxone were not conducted. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 g/day.

Sulbactam

Relevant data is not available.

Monobact is a combination of Ceftriaxone Sodium and Sulbactam Sodium available as dry powder for reconstitution.

Ceftriaxone

Ceftriaxone is a beta-lactam, third-generation cephalosporin antibiotic with bactericidal activity. Molecular Weight : 554.6g/mol.

Molecular Formula : C18H18N8O7S3.

Chemical Name : (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl] amino]- 3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Sulbactam sodium

Sulbactam is a β-lactamase inhibitor given in combination with β-lactam antibiotics to inhibit β- lactamase, an enzyme produced by bacteria that destroys antibiotic activity. Sulbactam sodium is a derivative of the basic penicillin nucleus. Molecular Weight : 255.22 g/mol.

Molecular Formula : C8H10NNaO5S.

Chemical Name : Sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia- 1-azabicyclo [3.2.0] heptane- 2- carboxylate 4,4- dioxide.

8.1 Incompatibilities

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute or to further dilute a reconstituted vial for I.V. administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same I.V. administration line. Ceftriaxone with sulbactam must not be administered simultaneously with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Monobact Kid : A vial of 187.5 mg with SWFI IP 5 ml.

Monobact 375 mg : A vial of 375 mg with SWFI IP 5 ml.

Monobact 750 mg : A vial of 750 mg with SWFI IP 5 ml.

Monobact 1.5 gm : A vial of 1.5 gm with SWFI IP 10 ml.

8.4 Storage and handling instructions

Store below 25°C. Protect from light. Do not freeze.

Keep out of reach of children. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

• Instruct patient to store medication as advised and not to expose the vial to moisture or direct light.
• When ceftriaxone with sulbactam 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 decrease the effectiveness of therapy and increase the likelihood that bacteria will develop antimicrobial resistance.
• 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 even as late as two months after the last dose of the antibiotic. If this occurs, instruct patients to contact their physician immediately.
• Instruct patient not to freeze the reconstituted solution and use it immediately after the preparation. Unused portion of solution, if any, should be discarded.

16 August 2024

Ketoprofen Plaster

Each plaster (7 cm X 10 cm) contains :

Ketoprofen IP 30 mg

Excipients q.s.

Medicated Transdermal Patch, 30 mg

4.1. Therapeutic indication

For the relief of musculoskeletal pain and inflammation.

4.2. Posology and method of administration

One patch to be applied for one day or as directed by the Physician.

Method of administration

Clean and dry the affected area before applying the patch. Remove the protective film and apply the adhesive part directly to the skin. If the patch is to be applied to very mobile joints such as the elbow or knee, a bandage can be applied to the joint when bent, to keep the patch in place.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in the formulation
• known hypersensitivity reactions, such as symptoms of asthma, allergic rhinitis to ketoprofen, fenofibrate, tiaprofenic acid, acetylsalicylic acid, or to other NSAID history of any photosensitivity reaction
• history of skin allergy to ketoprofen, tiaprofenic acid, fenofibrate, UV blockers or perfumes
• sun exposure, even in case of hazy sun, including UV light from solarium, should be avoided during the treatment and 2 weeks after its discontinuation.
• patients in whom substances with a similar mechanism of action (e.g. acetylsalicylic acid or other NSAIDs) cause attacks of asthma, bronchospasm or acute rhinitis, or cause nasal polyps, urticaria or angioedema. • active or suspected gastrointestinal ulcer or a history of gastrointestinal ulcer
• gastrointestinal bleeding or other active bleeding or bleeding disorders
• severe heart failure
• severe hepatic or renal dysfunction
• haemorrhagic diathesis and other coagulation disorders, or patients receiving anticoagulant therapy
• third trimester pregnancy
• children under 12 years of age
• The use on open wounds or on skin with pathological changes such as eczema, acne, dermatitis, inflammation or infection of any nature or on mucous membranes of body orifices is contraindicated.

4.4. Special warnings and precautions for use

• The systemic bioavailability of ketoprofen applied via the transdermal route is significantly lower than that following oral administration. However, it is not possible to exclude completely the onset of systemic side effects, although it is much less likely that these side effects will occur at this level of plasma binding.
• Analgesics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs) can cause potentially serious hypersensitivity reactions, including anaphylactic reactions, even in subjects with no previous exposure to this type of drug. The risk of hypersensitivity reactions after the use of ketoprofen is greater in subjects who have already had this type of reaction after using other analgesics, antipyretics and non-steroidal anti-inflammatory drugs (NSAIDs).
• Administer with caution to patients with allergic conditions or a history of allergy. Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to aspirin and/or NSAIDs than the rest of the population.
• Treatment should be discontinued immediately upon development of any skin reaction including cutaneous reactions. There have been some reported cases of photosensitivity that occurred a few days, and in rare cases a few months, after the use of the drug. If symptoms of dermatitis are observed, discontinue treatment and keep the affected area away from sunlight.
• The recommended length of treatment should not be exceeded due the risk of developing contact dermatitis and photosensitivity reactions increases over time.
• It is recommended to protect treated areas by wearing clothing during all the application of the product and two weeks following its discontinuation to avoid the risk of photosensitisation.
• Special care should be taken for patients with Crohn’s disease or ulcerative colitis, chronic dyspepsia, history of bronchial asthma.
• Patients currently suffering from or with a previous history of gastrointestinal disease should be carefully monitored for digestive disorders, in particular gastrointestinal bleeding. In the rare cases where gastrointestinal bleeding or ulceration occur in patients receiving treatment with ketoprofen, treatment should be discontinued immediately. Like all NSAIDs, the drug can increase plasma urea nitrogen and creatinine.
• As with other inhibitors of prostaglandin synthesis, the drug may be associated with adverse effects on the renal system, which can lead to glomerular nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. As with other NSAIDs, the drug can cause transient small increases in some liver parameters, and also significant increases in SGOT and SGPT. In case of a relevant increase in such parameters, therapy must be discontinued.
• Ketoprofen should be used with caution in patients suffering from haematopoietic disorders, systemic lupus erythematosus or mixed connective tissue disorders. Like other NSAIDs, ketoprofen can mask the symptoms of infectious diseases. Caution should be exercised in patients with impairment of hepatic, renal or cardiac functions, as well as in patients and with other conditions predisposing to fluid retention. In such cases, the use of NSAIDs can cause a deterioration of renal function and fluid retention. Caution is also required in patients receiving diuretic therapy or those who are likely to be hypovolaemic, as there is an increased risk of nephrotoxicity. Caution should be exercised in the treatment of elderly patients, who are generally more prone to adverse events. The consequences of gastrointestinal bleeding and/or intestinal perforation, for example, are dose-dependent and are often more serious in the elderly; they can also occur without warning symptoms or previous history at any time during treatment.
• Elderly patients are more likely to be suffering from impaired renal, cardiovascular or hepatic function. As with any drug that inhibits prostaglandin and cyclo-oxygenase synthesis, the use of ketoprofen is not recommended in women who intend to become pregnant.
• The use of Ketoplast should be discontinued in women who have fertility problems or who are undergoing fertility investigations. Prolonged or repeated use of the product can cause sensitisation. Treatment must be stopped if hypersensitivity reactions occur. Do not use occlusive bandages. Hands should be washed thoroughly after each application of the product.

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

The low systemic bioavailability of ketoprofen from Ketoplast means that interaction with other medicaments is unlikely. However, the following interactions apply to NSAIDs in general.

Inadvisable combinations :

• Other NSAIDs, including high doses of salicylates (> 3 g/day) : the administration of several NSAIDs together can increase the risk of gastrointestinal ulcers and bleeding, through a synergistic effect.
• Oral anticoagulants, parenteral heparin and ticlopidine : increased risk of bleeding through inhibition of platelet function and damage to the gastrointestinal mucosa.
• Lithium (described with several NSAIDs) : NSAIDs increase plasma lithium levels (decreased renal excretion of lithium), which can reach toxic levels. This parameter therefore requires monitoring during the initiation, adjustment and withdrawal of treatment with ketoprofen.
• Methotrexate, used at high doses of 15 mg/week or more : increased haematological toxicity of methotrexate through a decrease in its renal clearance by antiinflammatory agents in general.
• Hydantoins and sulphonamides : the toxic effects of these substances can be increased.

Combinations requiring precautions :

• Methotrexate, used in low doses, less than 15 mg/week : increased haematological toxicity of methotrexate through a decrease in its renal clearance by antiinflammatory agents in general. Monitor blood count weekly during the first few weeks of this combination. Increase surveillance in the case of even a slight deterioration of renal function, and in the elderly.
• Diuretics, angiotensin converting enzyme inhibitors : treatment with NSAIDs is associated with the risk of acute renal failure in dehydrated patients (decreased glomerular filtration through reduced renal prostaglandin synthesis). Treatment with an NSAID may decrease their antihypertensive effect. If ketoprofen is prescribed together with a diuretic, it is essential to ensure that the patient is adequately hydrated and to monitor renal function at the start of the treatment.
• Pentoxifylline : increased risk of bleeding. Increase clinical monitoring and check bleeding time more often.
• Zidovudine : risk of increased red cell line toxicity through action on reticulocytes, with severe anaemia occurring one week after the start of NSAID treatment. Check complete blood count and reticulocyte count one or two weeks after starting treatment with NSAIDs.
• Sulphonylureas : NSAIDs can increase the hypoglycaemic effect of sulphonylureas by displacement from plasma protein binding sites.

Associations needing to be taken into account :

• Beta-blockers : treatment with an NSAID can decrease their antihypertensive effect through inhibition of prostaglandin synthesis.
• Cyclosporin and tacrolimus : nephrotoxicity can be enhanced by NSAIDs through renal prostaglandin mediated effects. During combination therapy, renal function must measured.
• Thrombolytics : increased risk of bleeding.
• Probenecid : plasma concentrations of ketoprofen can be increased; this interaction can be due to an inhibitory mechanism at the site of renal tubular secretion and of glucuronic conjugation and necessitates an adjustment of the ketoprofen dose.

4.6. Special Population

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy.

During the first and second trimester : As the safety of ketoprofen in pregnant women has not been evaluated, the use of ketoprofen during the first and second trimester of pregnancy should be avoided.

During the third trimester : During the third trimester of pregnancy, all prostaglandin synthetase inhibitors including ketoprofen may induce cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension) and renal dysfunction, which may progress to renal failure with oligo-hydroamniosis in the foetus. At the end of pregnancy, prostaglandin synthetase inhibitors including ketoprofen may lead to possible prolongation of bleeding time (both in mother and child), an anti-aggregating effect which may occur even at very low doses; and inhibition of uterine contractions resulting in delayed or prolonged labour. Therefore, ketoprofen is contraindicated during the third trimester of pregnancy.

If ketoprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

Breastfeeding

No data is available, on excretion of ketoprofen in human milk. Ketoprofen is not recommended in nursing mothers.

Paediatric population

Gastrointestinal bleeding, sometimes severe, and peptic ulcers have been observed in some paediatric patients treated with ketoprofen; the product should therefore be administered under the strict supervision of a physician, who should assess the necessary dosage regimen case by case. The safety and efficacy of cutaneous formulations of ketoprofen in children have not been estabilished.

4.7. Effects on ability to drive and use machines

The drug has a minor or moderate influence on the ability to drive and use machines, due to the possibility of dizziness or drowsiness occurring.

4.8. Undesirable effects

The prolonged use of products for topical administration may cause hypersensitivity phenomena. In such cases, the treatment should be discontinued and a suitable alternative therapy initiated.

Undesirable effects reported with ketoprofen systemic formulations

Although not associated with the topical use of ketoprofen, the following adverse events are reported for systemic use of ketoprofen : the most frequent adverse events are minor and transient, and consist of gastrointestinal effects such as indigestion, dyspepsia, nausea, constipation, diarrhoea, heartburn and various types of abdominal discomfort. Serious adverse reactions, all of which are very rare, include mainly cases of skin reactions (urticaria, erythema, exanthema, angioedema), gastrointestinal and respiratory tract reactions (bronchospasm, dyspnoea, laryngeal oedema), and occasional cases of allergic/anaphylactoid reactions, anaphylactic shock and mouth oedema. The majority of reactions that occurred in allergic/asthmatic patients and/or in patients with known hypersensitivity to NSAIDs have been serious.

Undesirable effects reported with ketoprofen topic formulations

The following MedDRAfrequency convention and system-organ classis used : Very common (≥1/10); Common (≥1/100 to < 1/10); Uncommon (≥1/1000 to < 1/100) ); rare (≥1/10 000 to < 1/1000); very rare (<1/10000)

Immune system disorders

Not known : anaphylactic shock, angioedema, hypersensitivity reactions.

Skin and subcutaneous tissue disorders

Uncommon : Local skin reactions such as erythema, eczema, pruritis, and burning sensations. Rare: photosensitisation and urticaria. Cases of more severe reactions such as bullous or phlyctenular eczema which may spread or become generalized have occurred rarely.

Renal and urinary disorders

Very rare : Cases of aggravation of previous renal insufficiency.

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 : http://www.zuventus.co.in/safety.aspx

5.1. Mechanism of action

Ketoprofen is an inhibitor of both the cyclo-oxygenase and lipoxygenase pathways. In addition, ketoprofen is a powerful inhibitor of bradykinin (a chemical mediator of pain and inflammation).

5.2. Pharmacodynamic properties

Inhibition of prostaglandin synthesis provides for potent anti-inflammatory, analgesic and antipyretic effects. Lipoxygenase inhibitors appear to attenuate cell-mediated inflammation and thus retard the progression of tissue destruction in inflamed joints. Ketoprofen stabilises the lysosomal membranes against osmotic damage and prevents the release of lysosomal enzymes that mediate tissue destruction in inflammatory reactions.

5.3. Pharmacokinetic properties

Absorption

Ketoprofen can be applied topically in effective concentrations, but with very low plasma concentrations of drug. Therapeutic levels in the affected tissues provide relief from pain and inflammation.

Distribution

Ketoprofen is 95-99% bound to plasma proteins. Significant levels of ketoprofen have been found in tonsillar tissue and in the synovial fluid following systemic administration.

Biotransformation

Ketoprofen is extensively metabolised : approximately 60-80% of the product administered systemically is found in the form of metabolites in the urine.

Elimination

Elimination is rapid and takes place essentially via the renal route : 50% of the product administered systemically is excreted in the urine within 6 hours.

There are no further preclinical data other than those already reported.

Ketoprofen is a non-steroidal anti-inflammatory drug with analgesic and anti pyretic properties. Ketoplast is shown to have inhibitory effects on prostaglandin and leukotriene synthesis, anti bradykinin activity as well as lysosomal membrane - stabilizing action.

The chemical name for Ketoprofen is 2 - (3 - benzoyl phenyl) - propionic acid with the following structural formula :

It is rapidly and well absorbed through skin and has a prolonged pharmacological action.

8.1. Incompatibilities

Not applicable

8.2. Shelf-life

36 months.

8.3. Packaging information

A pouch of 7 plasters.

8.4. Storage and handing instructions

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

Keep out of reach of children.

• KetoPlast should be applied on non-hairy area.
• Clean the application area with water & dry it before applying KetoPlast.
• Do not cut KetoPlast plaster. This may reduce the efficacy.
• Apply immediately upon removal from the protective pack.

03-02-2021

Marketed by :

5119, Oberoi Garden Estates, D-Wing, Chandivali, Andheri (E), Mumbai 400 072. Registered Trade Mark of Zuventus.

Ofloxacin & Metronidazole Suspension

Diof

Each 5 ml contains :

Ofloxacin IP 50 mg

Metronidazole Benzoate IP

equivalent to Metronidazole 100 mg

Excipients q.s.

Colour : Quinoline Yellow WS

In a flavoured syrup base

Diof-DS

Each 5 ml contains :

Ofloxacin IP 100 mg

Metronidazole Benzoate IP

equivalent to Metronidazole 200 mg

Excipients q.s.

Colour : Quinoline Yellow WS

In a flavoured syrup base

Suspension, Ofloxacin 50 mg / 100 mg and Metronidazole 100 mg / 200 mg

4.1 Therapeutic indication

For the treatment of diarrhea of mixed infection in adult patients only.

4.2 Posology and method of administration

Dose of Ofloxacin is 15 mg/kg/day and that of Metronidazole is 30 mg/kg/day in two divided doses. Therefore, New Normet suspension containing 100 mg of Ofloxacin and 200 mg of Metronidazole in each 5 ml is an appropriate combination.

Dosage: As advised by the physician.

Geriatric Use

• Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involves the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.
• In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended. Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage.

Pediatric Use

• Safety and effectiveness in pediatric patients and adolescents below the age of 18 years have not been established. Ofloxacin causes arthropathy (arthrosis) and osteochondrosis in juvenile animals of several species.
• Safety and effectiveness of metronidazole in pediatric patients have not been established, except for the treatment of amebiasis.

4.3 Contraindications

• Patients hypersensitivity to any fluoroquinolone antibacterials.
• Patients having history of epilepsy or tendon disorders or CNS disorder with a lowered seizure threshold should be avoided giving ofloxacin formulation.
• Ofloxacin shall not be prescribed to Adolescent, pregnant or breastfeeding women, since animal experiments do not entirely exclude the risk of damage to the growth-plate cartilage.
• In patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity because they more prone to haemolytic reactions when treated with quinolone antibacterial agents.
• Ofloxacin is not the drug of first choice in pneumonia, caused by Streptococcus pneumoniae or Chlamydia pneumonia, Methicillin resistant S. aureus. Ofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to ofloxacin.
• Metronidazole is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
• In patients with trichomoniasis, metronidazole is contraindicated during the first trimester of pregnancy.
• Use of metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks.
• Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole.

4.4 Special warnings and precautions for use

Ofloxacin

Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitisand Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects:

Fluoroquinolones, including ofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. Discontinue ofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Tendinopathy and Tendon Rupture: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. Discontinue ofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Peripheral Neuropathy: Fluoroquinolones, including ofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including ofloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible in some patients. Discontinue ooxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ofloxacin, in patients who have previously experienced peripheral neuropathy.

Central Nervous System Effects: Psychiatric Adverse Reactions: Fluoroquinolones, including ooxacin, have been associated with an increased risk of psychiatric adverse reactions, including toxic psychoses or hallucinations; agitation; delirium, confusion, disorientation, or disturbances in attention; nervousness or restlessness, memory impairment. If these reactions occur in patients receiving ofloxacin, the drug should be discontinued and appropriate measures instituted.

Central Nervous System Adverse Reactions: Fluoroquinolones have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pseudotumor cerebri), lightheadedness, or tremors.The effects of ofloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, ofloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures. Exacerbation of Myasthenia Gravis: Fluoroquinolones, including ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid ofloxcain in patients with known history of myasthenia gravis. The safety and efficacy of ofloxacin in pediatric patients and adolescents (under the age of 18 years), pregnant women, and lactating women have not been established.

Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones, including ofloxacin. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. This drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous incluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated. Other serious and sometimes fatal events, some due to hypersensitivity, and 

some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• fever, rash, severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome);
• vasculitis; arthralgia; myalgia; serum sickness;
• allergic pneumonitis;
• interstitial nephritis; acute renal insufficiency or failure;
• hepatitis; jaundice; acute hepatic necrosis or failure;
• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice or any other sign of hypersensitivity and supportive measures instituted.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ofloxacin tablets, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

General:

• Prescribing ofloxacin tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
• Adequate hydration of patients receiving ofloxacin should be maintained to prevent the formation of a highly concentrated urine.
• Administer ofloxacin with caution in the presence of renal or hepatic insufficiency/impairment. In patients with known or suspected renal or hepatic insufficiency/impairment, careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of ofloxacin may be reduced. In patients with impaired renal function (creatinine clearance ≤ 50 mg/mL), alteration of the dosage regimen is necessary.
• Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs.
• As with other quinolones, ofloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction).
• A possible interaction between oral hypoglycemic drugs (e.g., glyburide/glibenclamide) or with insulin and fluoroquinolone antimicrobial agents have been reported resulting in a potentiation of the hypoglycemic action of these drugs, sometimes resulting in coma or death. The mechanism for this interaction is not known. If a hypoglycemic reaction occurs in a patient being treated with ofloxacin, discontinue ofloxacin immediately and consult a physician. As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Torsades de pointes

Some quinolones, including ofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving quinolones, including ofloxacin. Ofloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.

Metronidazole

• Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Metronidazole for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions, such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, convulsive seizures).
• Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.
• Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued.
• Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking metronidazole.
• Cases of severe bullous skin reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalised exanthematous pustulosis (AGEP) have been reported with metronidazole. If symptoms or signs of SJS, TEN or AGEP are present, Metronidazole treatment must be immediately discontinued.
• Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Metronidazole should therefore, be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.

Psychotic Reaction with Disulfiram

Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks.

Interaction with Alcohol

Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headache, flushing, throbbing headache, rapid heartbeat, palpitation, sweating, thirst, chest pain, lightheadness, blurred vision, dizziness and difficulty in breathing. Rarely more severe reactions may include abnormal heart rhythm, heart attack, heart failure, unconsciousness, convulsions and even death. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole.

Central and Peripheral Nervous System Effects

Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy.

Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of metronidazole is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events.

Renal Impairment

Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended.

Fungal Superinfections

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candidacidal agent.

Use in Patients with Blood Dyscrasias

Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.

Drug-Resistant Bacteria and Parasites

Prescribing metronidazole in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites.

4.5 Drugs interactions

Ofloxacin

Antacids, Sucralfate, Metal Cations, Multivitamins

Quinolones form chelates with alkaline earth and transition metal cations. Administration of quinolones with antacids containing calcium, magnesium, or aluminum, with sucralfate, with divalent or trivalent cations such as iron, or with multivitamins containing zinc or with didanosine, may substantially interfere with the absorption of quinolones resulting in systemic levels considerably lower than desired. These agents should not be taken within the two-hour period before or within the twohour period after ofloxacin administration.

Caffeine

Interactions between ofloxacin and caffeine have not been detected.

Cimetidine

Cimetidine has demonstrated interference with the elimination of some quinolones. This interference has resulted in significant increases in half-life and AUC of some quinolones. The potential for interaction between ofloxacin and cimetidine has not been studied.

Cyclosporine

Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with some other quinolones. The potential for interaction between ofloxacin and cyclosporine has not been studied.

Drugs Metabolized by Cytochrome P450 Enzymes

Most quinolone antimicrobial drugs inhibit cytochrome P450 enzyme activity. This may result in a prolonged half-life for some drugs that are also metabolized by this system (e.g., cyclosporine, theophylline/methylxanthines, warfarin) when co-administered with quinolones. The extent of this inhibition varies among different quinolones.

Non-Steroidal Anti-Inflammatory Drugs

The concomitant administration of a non-steroidal anti-inflammatory drug with a quinolone, including ofloxacin, may increase the risk of CNS stimulation and convulsive seizures.

Probenecid

The concomitant use of probenecid with certain other quinolones has been reported to affect renal tubular secretion. The effect of probenecid on the elimination of ofloxacin has not been studied.

Theophylline

Steady-state theophylline levels may increase when ofloxacin and theophylline are administered concurrently. As with other quinolones, concomitant administration of ofloxacin may prolong the half life of theophylline, elevate serum theophylline levels, and increase the risk of theophylline-related adverse reactions. Theophylline levels should be closely monitored and theophylline dosage adjustments made, if appropriate, when ofloxacin is co-administered. Adverse reactions (including seizures) may occur with or without an elevation in the serum theophylline level.

Warfarin

Some quinolones have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. Therefore, if a quinolone antimicrobial is administered concomitantly with warfarin or its derivatives, the prothrombin time or other suitable coagulation test should be closely monitored.

Antidiabetic Agents (e.g., insulin, glyburide/glibenclamide)

Since disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concurrently with quinolones and an antidiabetic agent, careful monitoring of blood glucose is recommended when these agents are used concomitantly.

Interaction with Laboratory or Diagnostic Testing

Some quinolones, including ofloxacin, may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.

Metronidazole

Disulfiram

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.

Alcoholic Beverages

Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy.

Warfarin and other Oral Anticoagulants

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When FLAGYL is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.

Lithium

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.

Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.

Drugs that Inhibit CYP450 Enzymes

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.

Drugs that Induce CYP450 Enzymes

The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.

Drug/Laboratory Test Interactions

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

4.6 Use in special populations

Pregnancy

• There are, however, no adequate and well-controlled studies in pregnant women. Ofloxacin should be used during pregnancy only if the potential benefit justies the potential risk to the foetus.
• There are no adequate and well controlled studies of Metronidazole in pregnant women. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the foetus due to metronidazole.

Nursing Mothers

• Because of the potential for serious adverse reactions from ooxacin in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
• Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

4.7 Effects on ability to drive and use machines

Since there have been occasional reports of drowsiness/somnolence, impairment of skills, dizziness/vertigo and visual disturbances, which may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery); patients should advised not to drive or operate machinery if these symptoms occur. These effects may be enhanced by alcohol.

4.8 Undesirable effects

Ofloxacin

In clinical trials, the following events were considered likely to be drug-related in patients receiving multiple doses of ofloxacin: nausea, insomnia, headache, dizziness, diarrhea, vomiting, rash, pruritus, external genital pruritus in women, vaginitis, dysgeusia.

In clinical trials, the most frequently reported adverse events, regardless of relationship to drug, were: nausea, headache, insomnia, external genital pruritus in women, dizziness, vaginitis, diarrhea, vomiting.

In clinical trials, the following events, regardless of relationship to drug, occurred in 1 to 3% of patients: abdominal pain and cramps, chest pain, decreased appetite, dry mouth, dysgeusia, fatigue, fatulence, gastrointestinal distress, nervousness, pharyngitis, pruritus, fever, rash, sleep disorders, somnolence, trunk pain, vaginal discharge, visual disturbances, and constipation.

Additional events, occurring in clinical trials at a rate of less than 1%, regardless of relationship to drug, were :

The following laboratory abnormalities appeared in ≥1% of patients receiving multiple doses of ofloxacin. It is not known whether these abnormalities were caused by the drug or the underlying conditions being treated.

In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with other quinolones. The relationship of the drugs to these events is not presently established.

Metronidazole

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.co.in/drug-safety-reporting

4.9 Overdose

Symptoms-The most important signs to be expected following acute overdose are CNS symptoms such as confusion, dizziness, impairment of consciousness and convulsive seizures increases in QT interval as well as gastrointestinal reactions such as nausea and mucosal erosions.

Management-In the case of overdose steps to remove any unabsorbed ofloxacin e.g. gastric lavage, administration of adsorbants and sodium sulphate, if possible during the first 30 minutes, are recommended; antacids are recommended for protection of the gastric mucosa. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa. No specific antidote exists. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

5.1 Mechanism of Action

Ofloxacin inhibits bacterial DNA replication by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV. The nitro group of metronidazole acts as electron acceptor and is thus reduced to a chemically reactive drug form. This produces biochemical lesions in the cells, thus causing death. The major site of action is believed to be DNA, where it causes loss of the helical structure and inhibits synthesis.

5.2 Pharmacodynamic properties

Ofloxacin

Therapeutic doses of ofloxacin are devoid of pharmacological effects on the voluntary or autonomic nervous system. According to DIN 58 940, the following limits apply for ofloxacin:

Susceptible (S)≤ 1 mg/L, Intermediate (I) = 2 mg/L, Resistant (R) ≥ 4 mg/L.

Range of acquired bacterial resistance to ooxacin is as follows:

Normally susceptible

Aerobic Gram-positive micro-organisms: S. aureus - methicillin-sensitive (0.3-12.6%), S. pyogenes (2-5%) Aerobic Gram-negative micro-organisms: Acinetobacter spp (0.3-7.3%), Citrobacter spp. (3-15%), Enterobacter spp. (2-13%), E. coli (1-8%), H. influenzae (1%), Klebsiella spp. (1-10%), Moraxella spp. (0-0.2%), Morganella morganii (0- 6.9%), N. gonorrhoeae (25%) Proteus spp. (1-15%), Serratia marcescens (2-2.4%)

Others: Chlamydia spp, L. pneumophila

Intermediately susceptible

Aerobic Gram-positive micro-organisms: S. pneumoniae (70%), Providentia (17.1%)

Aerobic Gram-negative micro-organisms: E. faecalis (50%), P. aeruginosa (20-30%), Serratia spp. (20-40%)

Metronidazole

A potential for development of resistance exists against metronidazole. Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair.

Activity in Vitro and in Clinical Infections

• Gram-positive anaerobes: Clostridium species, Eubacterium species, Peptococcus species, Peptostreptococcus species.
• Gram-negative anaerobes: Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Fusobacterium species.

Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

• Gram-negative anaerobes: Bacteroides fragilis group (B. caccae, B. uniformis), Prevotella species (P. bivia, P. buccae, P. disiens)

5.3 Pharmacokinetic properties

6.1 Animal toxicology or pharmacology

Ofloxacin

Preclinical effects in conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, reproductive studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Joint toxicity was observed at exposure in the human therapeutic range in juvenile rats and dogs. Ofloxacin exhibits a neurotoxic potential and causes reversible testicular alterations at high doses.

Mutagenicity studies showed no evidence for mutagenicity of ofloxacin. However, like some other quinolones Ofloxacin is phototoxic in animals at exposure in the human therapeutic range. The phototoxic, photomutagenic and photocarcinogenic potential of ofloxacin is comparable with that of other gyrase inhibitors. Preclinical data from conventional genotoxicity studies reveal no special hazard to humans, carcinogen potential has not been investigated.

Reproduction toxicity

Ofloxacin has no effect on fertility, peri- or postnatal development, and therapeutic doses did not lead to any teratogenic or other embryotoxic effects in animals. Ooxacin crosses the placenta and levels reached in the amniotic fluid are about 30% of the maximal concentrations measured in maternal serum.

Metronidazole

Metronidazole has been shown to be carcinogenic in the mouse and in the rat following chronic oral administration however similar studies in the hamster have given negative results. Epidemiological studies have provided no clear evidence of an increased carcinogenic risk in humans. Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects, while others studies were negative.

Ofloxacin is a synthetic broad-spectrum second-generation fluoroquinolone antibacterial agent. Metronidazole Benzoate is the benzoate ester of metronidazole, a synthetic nitroimidazole derivative with antiprotozoal and antibacterial activities.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Diof : A bottle of 60 ml.

Diof-DS : A bottle of 60 ml.

8.4 Storage and handling instructions

Store below 25°C. Protect from light. Do not freeze.

Keep out of reach of children.

Shake well before use.

• Your medicine contains Ofloxacin and Metronidazole which belong to a group of medicines called antibacterials.
• Do not take this medicine, if you are allergic to ofloxacin or metronidazole.

Signs of an allergic reaction include a rash, itching or shortness of breath.

• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
• If you have any further questions, ask your doctor or pharmacist.

19 July 2024

Ceftriaxone & Tazobactam for Injection

C-Tri XP KID 125 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 125 mg

Tazobactam Sodium IP equivalent to Tazobactam 15.625 mg

This pack contains Sterile Water for Injections IP 5 ml.

C-Tri XP 250 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 250 mg

Tazobactam Sodium IP equivalent to Tazobactam 31.25 mg

This pack contains Sterile Water for Injections IP 5 ml.

C-Tri XP 500 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 500 mg

Tazobactam Sodium IP equivalent to Tazobactam 62.5 mg

This pack contains Sterile Water for Injections IP 5 ml.

C-Tri XP 1 g

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 1.0 g

Tazobactam Sodium IP equivalent to Tazobactam 125 mg

This pack contains Sterile Water for Injections IP 10 ml.

Powder for solution for infusion.

125 mg / 250 mg / 500 mg / 1 gm

4.1 Therapeutic indication

• Bacterial meningitis
• Community acquired pneumonia
• Hospital acquired pneumonia
• Acute otitis media
• Intra-abdominal infections
• Complicated urinary tract infections (including pyelonephritis)
• Infections of bones and joints
• Complicated skin and soft tissue infections
• Gonorrhoea
• Syphilis
• Bacterial endocarditis
• Surgical prophylaxis

4.2 Posology and method of administration

C-Tri XP Injection to be administered by deep intramuscular (I.M.) injection, slow intravenous (I.V.) injection, or as a slow I.V. infusion, after reconstitution with sterile water for injection (SWFI).

Dosage Recommendations in Adults

Usual Recommended Dose : 1.125 g to 2.25 g of C-Tri XP Injection (1 g / 2 g ceftriaxone + 125 mg / 250 mg tazobactam) per day given once a day or in two equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. Tazobactam can be given up to 2 grams per day.

For Uncomplicated Gonococcal Infections : A single dose of 562.5 mg of C-Tri XP Injection (500 mg ceftriaxone + 62.5 mg tazobactam) to be administered by I.M. route. For Preoperative Use (Surgical Prophylaxis) : A single dose of 1.125 g of C-Tri XP Injection (1g ceftriaxone + 125 mg tazobactam) to be administered I.V. 30 minutes to 2 hours before surgery. The usual duration of therapy is 4 to 14 days. In complicated infections, longer therapy may be required.

Or, as prescribed by the physician.

Dosage in Adult Patients with Renal Impairment and Hepatic Dysfunction.

In patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the ceftriaxone dosage should not exceed 2 gram daily. Tazobactam should be used with care in patients with renal impairment or in hemodialysis patients. The I.V. dose and administration interval should be adjusted to the degree of renal function impairment.

Dosage Recommendations in Pediatric Patients

For children with bodyweight above 50 kg or age over 12 years, the usual adult dosage should be administered. Although, ceftriaxone can be administered in neonates and infants, the safety and efficacy of this combination product (ceftriaxone + tazobactam injection) has not been established in children below 2 years of age. Thus, C-Tri XP Injection is recommended only in children above 2 years of age.

Following doses in children are expressed in terms of ceftriaxone content of the formulation. Usual Recommended Dosage : 50 to 75 mg/kg/day, given in divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 2 grams. In children, tazobactam can be given up to 12.5 mg/kg body weight per dose.

Treatment of Meningitis : The initial therapeutic dose should be 100 mg/kg body weight. Thereafter, daily dose of 100 mg/kg may be administered once a day or in equally divided doses every 12 hours. The total daily dose of ceftriaxone should not exceed 4 grams. The usual duration of therapy is 7 to 14 days depending on the type and severity of infection. Or, as prescribed by the physician.

Pharmaceutical Precautions

Ceftriaxone-containing injection should not be mixed with other drugs in infusion bottle since compatibility has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Directions for reconstitution and dilution for use

Intramuscular injection : Contents of one vial should be dissolved in 0.45 ml of Sterile Water for Injections IP for C-Tri XP-KID 125 mg of injection, 0.9 ml of Sterile Water for Injections IP for C-Tri XP-250 mg injection, 1.8 ml of Sterile Water for Injections IP for C-Tri XP-500 mg injection and 3.6 ml of Sterile Water for Injections IP for C-Tri XP-1 g injection. The solution should be administered by deep intramuscular injection. Doses greater than 1 g (of Ceftriaxaone) should be divided and injected at more than one site.

Intravenous injection : Contents of one vial should be dissolved in 1.2 ml of Sterile Water for Injections IP for C-Tri XP-KID 125 mg of injection, 2.4 ml of Sterile Water for Injections IP for C-Tri XP-250 mg injection, 4.8 ml of Sterile Water for Injections IP for C-Tri XP-500 mg injection and 9.6 ml of Sterile Water for Injections IP for C-Tri XP-1 g injection. The solution should be administered over at least 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion.

Incompatibility / Interaction with Calcium-Containing Products

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute or to further dilute a reconstituted vial for I.V. administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same I.V. administration line.

Ceftriaxone with tazobactam must not be administered simultaneously with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition.

4.3 Contraindications

• In patients with known hypersensitivity to ceftriaxone,cephalosporin class of antibiotics, or to tazobactam or to any component of the formulation.
• In hyperbilirubinemic neonates/preterm newborns : Ceftriaxone can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.
• Premature neonates : Ceftriaxone is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).
• In neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing I.V. solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium.
• Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated.

4.4 Special warnings and precautions

Test Dose

Before therapy with ceftriaxone and tazobactam injection is instituted, a test dose is recommended to ascertain possibility of hypersensitivity to ingredients of injection. Serious acute hypersensitivity reactions may require the use of subcutaneous epinephrine and other emergency measures.

Hypersensitivity

Before initiation of therapy, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions (i.e., anaphylaxis) have been reported. In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated.

Clostridium Difficile-Associated Diarrhea (CDAD)

CDAD has been reported with use of nearly all antibacterial agents, including ceftriaxone, 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. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Hemolytic Anemia

An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class of antibacterial drugs including ceftriaxone. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on ceftriaxone, the diagnosis of a cephalosporin associated anemia should be considered and ceftriaxone stopped until the etiology is determined.

Development of Drug-Resistant Bacteria

Prescribing ceftriaxone in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of ceftriaxone may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Pancreatitis

Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge (preceding major therapy, severe illness, and total parenteral nutrition). A cofactor role of ceftriaxone-related biliary precipitation cannot be ruled out.

Urolithiasis and Post-Renal Acute Renal Failure

Ceftriaxone-calcium precipitates in the urinary tract have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of urolithiasis, and ureteral obstruction and post-renal acute renal failure. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of appropriate management. Ensure adequate hydration in patients receiving ceftriaxone. Discontinue ceftriaxone in patients who develop signs and symptoms suggestive of urolithiasis, oliguria or renal failure and/or the sonographic findings.

Gallbladder Pseudolithiasis

Ceftriaxone-calcium precipitates in the gallbladder have been observed in patients receiving ceftriaxone. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of gallbladder disease. The condition appears to be reversible upon discontinuation of ceftriaxone and institution of conservative management. Discontinue ceftriaxone sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings.

Effect on Prothrombin Time

Alterations in prothrombin times have occurred in patients treated with ceftriaxone. Monitor prothrombin time during ceftriaxone treatment in patients with impaired vitamin K synthesis or low vitamin K stores (e.g., chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

Altered Laboratory Tests

Positive direct Coombs' test and galactosemia test, false-positive test for urinary glucose and elevated lactate dehydrogenase (LDH).

4.5 Drug interactions

Ceftriaxone

Amsacrine, Vancomycin, Fluconazole, and Aminoglycosides : Ceftriaxone is incompatible with these drugs.

Oral Contraceptives : Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment.

Chloramphenicol : Caution is advised if concurrent administration of ceftriaxone with chloramphenicol is proposed.

Vitamin K Antagonist : Concomitant use of ceftriaxone with vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with ceftriaxone.

Tazobactam

Probenecid : When probenecid administered concomitantly with tazobactam, it prolongs the half-life of tazobactam by 71%. This is because probenecid inhibits tubular renal secretion of tazobactam. Probenecid should not be co-administered with tazobactam unless the benefit outweighs the risk.

4.6 Use in special populations

Pregnancy

Animal studies have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, C-Tri XP Injection should be used during pregnancy only if clearly needed.

Lactation

Low quantities of both ceftriaxone and tazobactam are excreted in human milk. Therefore, caution should be exercised when C-Tri XP Injection is administered to a nursing woman. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the woman and child.

Pediatric patients

Safety and effectiveness of ceftriaxone has been established in pediatric patients. In vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Thus, ceftriaxone-containing preparations should not be administered to hyperbilirubinemic children. Safety and efficacy of C-Tri XP Injection has not been established in children below 2 years of age.

Geriatric patients

Dosage adjustments are not necessary for geriatric patients with ceftriaxone dosages up to 2 grams per day provided there is no severe renal and hepatic impairment.

4.7 Effects on the ability to drive and use machines

During treatment with ceftriaxone and tazobactam combination, undesirable effects such as dizziness, headache, and convulsions may occur, which may influence the ability to drive and

use machines. If affected by such events, patients should not drive or operate machinery.

4.8 Undesirable effects

Ceftriaxone-containing preparations are generally well tolerated. In clinical trials, the following adverse reactions were observed (related to ceftriaxone therapy or of uncertain etiology).

Local Reactions : Injection site pain, induration, tenderness, phlebitis, warmth, tightness. Hypersensitivity : Rash, pruritus, fever or chills.

Infections and Infestations : Genital fungal infection.

Hematologic : Eosinophilia, thrombocytosis, leukopenia. Less frequently reported were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.

Blood and Lymphatic Disorders : Granulocytopenia, coagulopathy.

Gastrointestinal : Diarrhea/loose stools, nausea, vomiting, dysgeusia, pseudomembranous colitis.

Hepatic : Elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin.

Renal : Elevations of the blood urea nitrogen (BUN), creatinine and the presence of casts in the urine.

Central Nervous System : Headache, dizziness.

Genitourinary : Moniliasis, vaginitis.

Dermatologic : Exanthema, allergic dermatitis, urticaria, edema; acute generalized exanthematous pustulosis (AGEP) and isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome / toxic epidermal necrolysis) have been reported.

Miscellaneous : Diaphoresis, flushing, increased blood creatinine.

Other rarely observed adverse reactions (< 0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.

Reporting of side effects

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.co.in/drug-safety-reporting

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

4.9 Overdose

In the case of overdose nausea, vomiting, and diarrhea can occur. There is no specific antidote. Treatment should be supportive and symptomatic according the patient's clinical presentation.

5.1 Mechanism of action

Ceftriaxone

Ceftriaxone is a third generation cephalosporin class of beta-lactam antibiotic. Ceftriaxone inhibits bacterial cell wall synthesis and produces bactericidal effect. Ceftriaxone has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gramnegative and Gram-positive bacteria.

Tazobactam

Beta-lactamases are the enzymes produced by certain bacteria to develop resistant to antibiotics. Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases, which commonly cause resistance to penicillins and cephalosporins. Tazobactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance.

Rationale of the combination

Ceftriaxone is a third generation semi-synthetic parenteral cephalosporin that has excellent activity against variety of gram -ve organisms and some gram +ve organisms like Streptococcus pneumoniae, Staphylococcus aureus, H.influenzae, Neisseria meningitides and members of Enterobacteriaceae. Ceftriaxone is indicated in number of community and hospital acquired infections caused by the susceptible organisms both in adults and in children including neonates.

Tazobactam is penicillanic acid sulfone derivative with beta-lactamase inhibitory properties, having good affinity for a variety of both plasmid mediated and chromosomal beta lactamases produced by gram +ve and gram –ve bacteria which are originally sensitive to Ceftriaxone. Therefore, it enhances the activity of penicillins and cephalosporins against many resistant strains of bacteria. It is regarded as more potent than other β-lactamase inhibitors (like sulbactam).

Clinical role of Ceftriaxone can be compromised due to increasing proportion of extended spectrum β-lactamase (ESBL) producing bacteria which exhibit resistance to Ceftriaxone. To treat such infections Ceftriaxone can be combined with a beta lactamases inhibitor of better efficacy like Tazobactam. The combination of Ceftriaxone and Tazobactam will be effective not only against the beta lactamase producing organisms but also against the originally Ceftriaxone-susceptible bacteria.

5.2 Pharmacodynamic properties

The combination of ceftriaxone and tazobactam is active against wide variety of beta-lactamase producing gram-positive and gram-negative bacteria. In addition, it demonstrates synergistic activity (reduction in MICs of combination therapy versus ceftriaxone alone) in a variety of organisms which are sensitive to ceftriaxone.

C-Tri XP Injection has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections :

Gram-negative Bacteria

Acinetobacter calcoaceticus, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens

Gram-positive Bacteria

Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Viridans group streptococci

Anaerobic Bacteria

Bacteroides fragilis, Clostridium species, Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftriaxone. However, the efficacy of ceftriaxone in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-negative Bacteria

Citrobacter diversus, Citrobacter freundii, Providencia species (including Providencia rettgeri), Salmonella species (including Salmonella typhi), Shigella species

Gram-positive Bacteria

Streptococcus agalactiae

Anaerobic Bacteria

Porphyromonas (Bacteroides) melaninogenicus, Prevotella (Bacteroides) bivius

5.3 Pharmacokinetics

Ceftriaxone

Absorption : Following intramuscular injection, mean peak plasma ceftriaxone levels are approximately half those observed after intravenous administration of an equivalent dose. The maximum plasma concentration after a single intramuscular dose of 1 gram is about 81 mg/l and is reached in 2 to 3 hours after administration. The area under the plasma concentrationtime curve after intramuscular administration is equivalent to that after intravenous administration of an equivalent dose.

After intravenous bolus administration of ceftriaxone 500 mg and 1 g, mean peak plasma ceftriaxone (Cmax) levels are approximately 120 and 200 mg/l respectively. After intravenous infusion of ceftriaxone 500 mg, 1 g and 2 g, the plasma ceftriaxone levels are approximately 80, 150 and 250 mg/l respectively. An 8 to 15 % increase in Cmax is seen on repeated administration; steady state is reached in most cases within 48 to 72 hours depending on the route of administration.

Distribution : The volume of distribution of ceftriaxone is 7 to 12 litre. Ceftriaxone is reversibly bound to albumin. Plasma protein binding is about 95 % at plasma concentrations below 100 mg/l. Binding is saturable and the bound portion decreases with rising concentration (up to 85 % at a plasma concentration of 300 mg/l).

Metabolism : Ceftriaxone is not metabolized systemically; but is converted to inactive metabolites by the gut flora.

Elimination : Plasma clearance of total ceftriaxone (bound and unbound) is 10 to 22 ml/min. Renal clearance is 5 to 12 ml/min. 50 to 60 % of ceftriaxone is excreted unchanged in the urine, primarily by glomerular filtration, while 40 to 50 % is excreted unchanged in the bile. The elimination half-life of total ceftriaxone in adults is about 8 hours.

Tazobactam

Peak plasma concentration is attained immediately after completion of an I.V. infusion. Plasma protein binding of tazobactam is approximately 23%. Tazobactam is widely distributed in tissues and body fluids including intestinal mucosa, gall bladder, lung and bile.

Approximately 20% of a dose of tazobactam is metabolized to a single metabolite that has been found to be microbiologically inactive. Tazobactam is eliminated by the kidney via glomerular filtration and tubular secretion. Tazobactam and its metabolite are eliminated primarily by renal excretion, with 80% of the dose appearing as unchanged drug and the remainder of the dose appearing as the metabolite. In healthy subjects, plasma elimination half-life of tazobactam range from 0.7 to 1.2 hours following single or multiple doses.

6.1 Animal Toxicology or Pharmacology

Ceftriaxone

LD50 values after administration of ceftriaxone by intravenous route were in mice 1840 mg/kg, in rat 2240 mg/kg, and in rabbit 240 mg/kg. LD50 value reported after administration of ceftriaxone by oral route in mice and rats was >10,000 mg/kg. In a 2-week intravenous administration study, groups of eight male Füllinsdorf rats were administered 0, 25 or 60 mg/kg/day of ceftriaxone. Body weight gain was slightly depressed by 9.2 and 20.1% in the 25 and 60 mg/kg/day groups respectively. The average weight of the thyroid glands was increased in the treated groups by 11 to 14% in comparison to the control animals. A 50% reduction in plasma bilirubin in the treated rats was reported along with a decrease in the number of leucocytes. 11 Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with ceftriaxone. Ceftriaxone showed no potential for mutagenic activity in these studies. Carcinogenicity studies on ceftriaxone were not conducted. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose. Ceftriaxone produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 g/day.

Tazobactam

In an embryo-fetal study in rats, tazobactam administered at doses up 3000 mg/kg/day (approximately 19 times the recommended human dose based on body surface area comparison) did not produce maternal toxicity, or fetal toxicity or teratogenicity. Reproductive toxicity : In males, tazobactam had no effect on epididymal and testes weight or mating and fertility indexes. In females, tazobactam did not produce changes in the female estrus cycle length, days in cohabitation, mating index, fertility index, fetal body weight, or fetal gender ratio. In female rats that underwent caesarean section, the number of surviving offspring was reduced to a non-significant degree with the high-dose (640 mg/kg/day) of tazobactam. In high-dose females that were allowed to proceed to delivery without caesarean section, the number of implantations was significantly decreased, and this finding was accompanied by a significant increase in the number of still births and a non-significant decrease in the number of surviving offspring compared to control values. Tazobactam was shown to be negative for mutagenicity or clastogenesis in an Ames assay, a chromosomal aberration assay, and an in vivo micronucleus assay.

C-Tri XP is a combination of Ceftriaxone, a semi - synthetic third generation broad spectrum cephalosporin antibiotic along with a β- lactamase inhibitor Tazobactam. Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.

Ceftriaxone

Ceftriaxone is a beta-lactam, third-generation cephalosporin antibiotic with bactericidal activity.

Molecular Weight : 554.6g/mol.

Molecular Formula : C₁₈H₁₈N₈O₇S₃.

Chemical Name : (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino acetyl]amino]- 3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Tazobactam

Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Tazobactam is a β-lactamase inhibitor given in combination with β-lactam antibiotics to inhibit β-lactamase, an enzyme produced by bacteria that destroys antibiotic activity.

Molecular Weight : 322.28g/mol.

Molecular Formula : C₁₀H₁₁N₄NaO₅S.

Chemical Name : Sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4- thia-1- azabicyclo[3.2.0] heptane-2-carboxylate-4,4-dioxide.

8.1 Incompatibilities

8.2 Shelf-life

Refer to the pack.

8.3 Packaging information

C-Tri XP KID 125 mg : A vial of 140.625 mg with SWFI IP 5 ml.

C-Tri XP 250 mg : A vial of 281.25 mg with SWFI IP 5 ml.

C-Tri XP 500 mg : A vial of 562.5 mg with SWFI IP 5 ml.

C-Tri XP 1 g : A vial of 1.125 g with SWFI IP 10 ml.

8.4 Storage and handling instructions

Store below 30°C. Protect from light & moisture.

Keep out of reach of children. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Instruct patient to store medication as advised and not to expose the vial to moisture or direct light.

The medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of therapy and increase the likelihood that bacteria will develop antimicrobial resistance.

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 even as late as two months after the last dose of the antibiotic. If this occurs, instruct patients to contact their physician immediately.

Instruct patient not to freeze the reconstituted solution and use it immediately after the preparation. Unused portion of solution, if any, should be discarded.

13 August 2024

Cefixime, Cloxacillin & Lactic Acid Bacillus Tablets

Each film coated tablet contains:

Cefixime IP (as Trihydrate)

equivalent to Anhydrous Cefixime…………... 200 mg

Cloxacillin Sodium IP equivalent to Cloxacillin……………………...500 mg

(In Prolonged-release form)

Lactic Acid Bacillus …………………………90 million spores

Excipients q.s.

Colour: Titanium Dioxide IP

Appropriate overages of Lactic Acid Bacillus spores added.

Film coated tablet

Cefixime (200mg) Cloxacillin (500mg) & Lactic Acid Bacillus (90 million spores)

4.1 Therapeutic Indication

For the treatment of adult patients with upper & lower respiratory tract infections, skin and soft tissue infections.

4.2 Posology and Method of Administration

Adults: the recommended dosage is 1 tablet twice daily. The usual course of treatment is 7 days. This may be continued for up to 14 days if required.

4.3 Contraindications

Hypersensitivity to the penicillin, or to cephalosporin antibiotics or to any of the components listed in the formulation.

4.4 Special warnings and precautions for use

Cefixime

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 such as toxic epidermal necrolysis, Stevens-Johnson syndrome and drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in some patients on cefixime. When severe cutaneous adverse reactions occur, cefixime should be discontinued and appropriate therapy and/or measures should be taken. 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- sensitization 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.

Cloxacillin

Hematologic: During long-term therapy, renal, hepatic and hematopoietic functions should be checked periodically.

Hepatic: During long-term therapy, renal, hepatic and hematopoietic functions should be checked periodically.

Immune: Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients receiving penicillin or cephalosporin

therapy. These reactions are more apt to occur in individuals with a history or sensitivity to multiple allergens. Careful inquiry should be made concerning previous hypersensitivity to reactions to penicillins, cephalosporins or other allergens. If allergic or anaphylactic reactions occurs, discontinue treatment and administer the usual agents, e.g. antihistamines, pressor amines, corticosteroids.

Neurologic: The passage of any penicillin from blood into brain is facilitated by inflamed meninges and during cardiopulmonary bypass. In the presence of such factors, particularly in renal failure when high serum concentration can be attained, CNS adverse effects including myoclonia, convulsive seizures and depressed consciousness can be expected. Although this complication has not been reported with cloxacillin, it should be anticipated.

Renal: During long-term therapy, renal, hepatic and hematopoietic functions should be checked periodically.

4.5 Drugs interactions

Cefixime

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.

Cloxacillin

Probenecid: As with other penicillins, concurrent administration of probenecid enhances the serum concentration of cloxacillin.

4.6 Use in special populations

Pregnancy

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.

Lactation:

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

Cefixime

Acute generalized exanthematous pustulosis and Mouth ulceration has been reported with Cefixime use.

Blood and lymphatic system disorders: eosinophilia, hypereosinophilia, agranulocytosis, leucopenia, neutropenia, granulocytopenia, haemolytic anaemia, thrombocytopenia, thrombocytosis.

Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, nausea, vomiting, flatulence.

Hepatobiliary disorders: jaundice

Infections and infestations: pseudomembranous colitis

Investigations: aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased

Nervous system disorders: dizziness, headache, cases of convulsions have been reported with cephalosporins including cefixime, 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.

Respiratory, thoracic and mediastinal disorders: dyspnoea

Renal and urinary disorders: Renal failure acute including tubulointerstitial nephritis as an underlying pathological condition

Immune system disorders, administrative site conditions, skin and subcutaneous tissue disorders: anaphylactic reaction, serum sickness-like reaction, drug rash with eaosinophilia and systemic symptoms, pruritus, rash, drug fever, arthralgia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angio-oedema, urticaria, pyrexia, face oedema, genital pruritus, vaginitis.

Cloxacillin

It may be expected the most common untoward reactions will be related to sensitivity. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and cephalosporins and in those with a history of allergy, asthma, hay fever or urticaria. All degrees of hypersensitivity, including fatal anaphylaxis, have been reported with penicillin.

Gastrointestinal: Nausea, vomiting, epigastric discomfort, flatulence and loose stools have been noted in some patients.

Hematologic: Eosinophilia, leucopenia, anemia, thrombocytopenia, thrombocytopenic, purpura, neutropenia and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Immune: Allergic reactions (rash, urticaria) including wheezing and sneezing have been reported.

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

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 (Gastric lavage) measures are recommended.

5.1 Mechanism of Action

Mechanism of action

Cefixime is a 3rd generation oral cephalosporin that has excellent activity against variety of Gram -ve organisms and a few Gram +ve organisms like streptococci spp. but, no activity against staphylococci. Cloxacillin is an acid resistant, β-lactamase resistant isoxazolyl penicillin with a spectrum of activity particularly against staphylococci and streptococci. Cloxacillin is resistant to degradation by penicillinase, thus useful against penicillinase-producing staphylococci.

In order to enhance the antibacterial coverage of cefixime against Gram +ve organisms, the addition of cloxacillin helps in Gram +ve coverage. Thus providing broader spectrum of antibiotic coverage.

Clinical evidence demonstrated the synergistic effect of cloxacillin and cefixime used in combination against S. pneumoniae and H. influenzae, the commonest causes of community-acquired pneumonia. Due to this synergistic activity dosage can be given in reduced frequency, thus increasing patient compliance. The usual dosage for this combination is 200 mg cefixime along with 500 mg cloxacillin to be given twice a day.

Lactobacillus preparations have been shown to offset the detrimental effects on the microflora produced with antibiotic administration. The normal bacterial flora of gut that is disturbed by the antibiotic is replenished by the addition of lactobacillus. Lactobacillus spores maintain or restore gut micro-ecology during or after antibiotic treatment. There is an increasing evidence for the effectiveness of probiotics with antimicrobial therapy in preventing or treating antibiotic associated diarrhea.

Pharmacodynamic properties

Cefixime: Cefixime has marked in vitro bactericidal activity against a wide variety of Gram-positive and Gram-negative organisms. As with other cephalosporins, bactericidal action of cefixime results from inhibition of cell-wall synthesis. 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 meticillin-resistant strains) are resistant to cefixime. In addition, most strains of Pseudomonas, Bacteroides fragilis, Listeria monocytogenes and Clostridia are resistant to cefixime. Cloxacillin: Cloxacillin exerts a bactericidal action against susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptides. Cloxacillin displays less intrinsic antibacterial activity and a narrower spectrum than penicillin G.

Lactobacillus: Lactobacillus is an aerobic gram-positive, ubiquitous inhabitant of the human oral cavity, vagina and gastrointestinal tract. It inhibits the colonization of pathogenic bacteria upon the intestinal epithelium. The inhibitory process known as 'competitive exclusion' can be expanded by the competition for the adherence sites of the intestinal mucosa between pathogens and lactobacilli and by the inhibitory substance.

5.2 Pharmacokinetic properties

Cefixime: The absolute oral bioavailability of cefixime is in the range of 22-54%. Absorption is not significantly modified by the presence of food. 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. Typically, the peak serum levels following the recommended adult or paediatric doses are between 1.5 and 3 mcg/mL. Little or no accumulation of cefixime occurs following multiple dosing. The pharmacokinetics of cefixime in healthy elderly (age > 64 years) and young volunteers (11-35) compared the administration of 400 mg doses once daily for 5 days. Mean C and AUC values were slightly greater in the elderly. Elderly patients may be given the same max dose as the general population.

Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine.

Serum protein binding is well characterised for human and animal sera; cefixime is almost exclusively bound to the albumin fraction, the mean free fraction being approximately 30%. Protein binding of cefixime is only concentration dependent in human serum at very high concentrations which are not seen 14 following clinical dosing. Transfer of C-labelled cefixime from lactating rats to their nursing offspring through breast milk was quantitatively small (approximately 1.5% of the mothers' body content of cefixime in the pup). No data are available on secretion of cefixime in human breast milk. Placental transfer of cefixime was small in pregnant rats dosed with labelled cefixime.

Cloxacillin: Cloxacillin is stable in an acid medium and is approximately 50% absorbed orally. After an oral dose of 500mg cloxacillin, a peak serum level of about 8 micrograms/mL is reached in about 1 hour. The serum level after i.m. cloxacillin is approximately twice that obtained when the same dose is given orally to fasting adults. Food in the stomach or small intestine reduces absorption and peak serum levels are approximately 50% those obtained after fasting. As with other penicillins, concurrent administration of probenecid enhances the serum concentration. Once absorbed, approximately 94% are bound to plasma proteins. After oral administration, roughly 20% of the dose is excreted in the urine, together with one or more active metabolites as yet unidentified. The half-life of elimination is about 30 minutes.

Lactobacillus: No pharmacokinetic data is available.

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

6.1 Animal Toxicology or Pharmacology

C Tax-O XL 200 is a combination of three medicines: Cefixime, Cloxacillin, and Lactobacillus.

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, 7 2-( Z)-[ O-(carboxy methyl) oxime] trihydrate.

Molecular weight: 507.50 as the trihydrate.

Chemical Formula: C₁₆H₁₅N₅O₇S₂.3H₂O The structural formula for cefixime is:

Cloxacillin is a semisynthetic penicillin antibiotic carrying a 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido group at position 6. It is a semi-synthetic penicillin antibiotic which is a chlorinated derivative of [oxacillin].

Molecular Weight: 435.9 g/mol

Molecular Formula:C₁₉H₁₈ClN₃O₅S

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

A strip of 10 tablets

8.4 Storage and handing instructions

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 for oral suspension or cefixime chewable 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.

July 2024

OMEGA-3 LIQUID

Nutritional Information:

Each Serving size of 5 ml contains:

• Total Omega-3………… 585 mg
• EPA ……………………. 255 mg
• DHA …………………….180mg

Ingredients: Water, Fructose, Fish Oil, Sunflower Oil, Mango Puree, Stabilizer [INS 414 & INS 415], Flavour - Mango & Peach, Antioxidant [INS 300, INS 301 & INS 307b], Preservative [INS 211] & Acidity regulator [INS 330].

Dosage Form: liquid

Dosage Strength: 585 mg of omega−3 fatty acids per 5ml.

4.1 Therapeutic indication

Usage: BRAINMAX^TM is a source of Omega-3 fatty acids, EPA & DHA, maintains good health, cognitive health and helps brain function. Supports development of the brain, eyes and nerves in children and adolescents.

4.2 Posology and method of administration

This product can be taken directly from the spoon or diluted with water, fruit juice or milk.

AGES 2-4 years: 1 teaspoon (5 ml) daily.

AGES 4-12 years: 1-2 teaspoons (5-10 ml) daily.

ADULTS: 2-4 teaspoons (10-20 ml) daily.

SHAKE WELL BEFORE USE.

4.3 Contraindications

BRAINMAX ^TM is contraindicated in patients known to be allergic to fish oil and ingredient of it.

4.4 Special warnings and precautions for use

• Allergen information: contains fish oil. BRAINMAXTM contain omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to BRAINMAXTM. BRAINMAXTM should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
• It’s a Nutraceutical. NOT FOR MEDICINAL USE. This product is not intended to diagnose, treat, cure or prevent any disease.
• Not to exceed the stated recommended daily usage. Once opened, store refrigerated & use within 90 days.
• Please consult your healthcare provider, if you are taking blood thinners or are diabetic.

4.5 Drug interactions

Anticoagulants or Other Drugs Affecting Coagulation

Because of the moderate increase in bleeding time (with the high dosage), patients receiving anticoagulant therapy must be monitored and the dosage of anticoagulant adjusted if necessary.

4.6 Use in special populations

For Pregnant or lactating woman, seek guidance from your Healthcare Professional before using this product.

4.7 Effects on ability to drive and use machines

Effects on ability to drive and use machines have not been studied. Nevertheless, BRAINMAX^TM is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

BRAINMAX^TM has no, or minor side effects. When used in recommended doses, no side effects have been reported with BRAINMAX^TM.

However, fish oil supplements can cause mild side effects, including:

• A fishy aftertaste, bad breath
• Heartburn, nausea or diarrhea
• Rash
• BRAINMAX^TM does contain fish. Therefore, people allergic to fish will show allergic reaction to BRAINMAX^TM.

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 are no special recommendations. Treatment should be symptomatic.

5.1 Mechanism of Action/Pharmacodynamic properties

BRAINMAX^TM contains essential fatty acids, omega-3 series polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) extracted from fish oil. They are essential to health and people must consume them through food. Omega-3 fatty acids are considered as a functional food because of its functional component mainly polyunsaturated fatty acids, which has positive impact on human health when consumed in a sufficient quantity.

Omega-3 fatty acids are essential nutrients that play crucial roles in human health, including in pediatric patients. Here are some key points regarding their use in pediatric populations:

1. Brain Development: Omega-3 fatty acids, especially DHA, are crucial for brain development in infants and young children. DHA supports neuronal growth, synaptogenesis, and cognitive function.

2. Visual Development: DHA is also essential for the development of the retina and visual acuity in infants, contributing to healthy vision.

3. Behavioural Disorders: Some studies suggest that omega-3 supplementation may help in managing symptoms of ADHD (Attention-Deficit/Hyperactivity Disorder) and other behavioural disorders by supporting cognitive function and reducing inflammation.

4. Cardiovascular Health: Omega-3 fatty acids can contribute to cardiovascular health by lowering triglyceride levels and potentially reducing the risk of cardiovascular diseases later in life.

5.3 Pharmacokinetic properties

During and after absorption, there are three main pathways for the metabolism of the omega-3 fatty acids:

- the fatty acids are first transported to the liver where they are incorporated into various categories of lipoproteins and then channeled to the peripheral lipid stores;

- the cell membrane phospholipids are replaced by lipoprotein phospholipids and the fatty acids can then act as precursors for various eicosanoids;

- the majority is oxidised to meet energy requirements.

The concentration of omega-3 fatty acids, EPA and DHA, in the plasma phospholipids corresponds to the EPA and DHA incorporated into the cell membranes.

Animal pharmacokinetic studies have shown that there is a complete hydrolysis of the ethyl ester accompanied by satisfactory absorption and incorporation of EPA and DHA into the plasma phospholipids and cholesterol esters.

6.1 Animal Toxicology

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, of repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. In addition, non-clinical literature data on safety pharmacology are indicating that there is no hazard for humans.

Nutritional Information:

Each Serving size of 5 ml contains:

• Total Omega-3………… 585 mg
• EPA ……………………. 255 mg
• DHA …………………….180mg

Ingredients: Water, Fructose, Fish Oil, Sunflower Oil, Mango Puree, Stabilizer [INS 414 & INS 415], Flavour - Mango & Peach, Antioxidant [INS 300, INS 301 & INS 307b], Preservative [INS 211] & Acidity regulator [INS 330].

8.1 Incompatibilities

None applicable

8.2 Shelf-life

Best before 24 months from manufacturing date.

8.3 Packaging information

Net Quantity: 150 ml

8.4 Storage and handing instructions

Store in a cool & dry place.

Once opened, store refrigerated & use within 90 days.

Keep out of reach of children.

• BRAINMAX^TM should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish
• If you are pregnant, nursing, taking any medications or have any medical condition, consult your doctor before use.
• Discontinue use and consult your doctor if any adverse reaction occurs.
• Please consult your healthcare provider, if you are taking blood thinners or are diabetic.

9^th July 2024