Deflazacort Tablets 6 mg/12mg/24 mg/30 mg

Each uncoated tablet contains

Deflazacort 6 mg/12 mg/24 mg/30 mg.

Excipients q.s.

Tablets for oral administration.

6 mg/12 mg/24 mg/30 mg

4.1. Therapeutic indication

For asthma, rheumatoid arthritis when glucocorticosteriod therapy is warranted.

4.2.Posology and method of administration

Deflazacort is a glucocorticoid derived from prednisolone and 6mg of deflazacort has approximately the same anti-inflammatory potency as 5mg prednisolone or prednisone. Doses vary widely in different diseases and different patients. In more serious and lifethreatening conditions, high doses of deflazacort may need to be given. When deflazacort is used long term in relatively benign chronic diseases, the maintenance dose should be kept as low as possible. Dosage may need to be increased during periods of stress or in exacerbation of illness. The dosage should be individually titrated according to diagnosis, severity of disease and patient response and tolerance. The lowest dose that will produce an acceptable response should be used.

Adults

For acute disorders, up to 120 mg/day deflazacort may need to be given initially. Maintenance doses in most conditions are within the range 3-18 mg/day. The following regimens are for guidance only

Rheumatoid arthritis: The maintenance dose is usually within the range 3 - 18 mg/day. The smallest effective dose should be used and increased if necessary.

Bronchial asthma: In the treatment of an acute attack, high doses of 48-72 mg/day may be needed depending on severity and gradually reduced once the attack has been controlled. For maintenance in chronic asthma, doses should be titrated to the lowest dose that controls symptoms.

Other conditions: The dose of deflazacort depends on clinical need titrated to the lowest effective dose for maintenance. Starting doses may be estimated on the basis of ratio of 5mg prednisone or prednisolone to 6mg deflazacort.

Hepatic Impairment

In patients with hepatic impairment, blood levels of deflazacort may be increased. Therefore, the dose of deflazacort should be carefully monitored and adjusted to the minimum effective dose.

Renal Impairment

In renally impaired patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

Elderly

In elderly patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary. The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age.

Paediatric Population

There has been limited exposure of children to deflazacort in clinical trials. In children, the indications for glucocorticoids are the same as for adults, but it is important that the lowest effective dosage is used. Alternate day administration may be appropriate.

Doses of deflazacort usually lie in the range 0.25 - 1.5 mg/kg/day. The following ranges provide general guidance:

Juvenile chronic arthritis: The usual maintenance dose is between 0.25 - 1.0 mg/kg/day

Nephrotic syndrome: Initial dose of usually 1.5 mg/kg/day followed by down titration according to clinical need.

Bronchial asthma: On the basis of the potency ratio, the initial dose should be between 0.25 - 1.0 mg/kg deflazacort on alternate days.

Deflazacort withdrawal

In patients who have received more than physiological doses of systemic corticosteroids (approximately 9mg per day or equivalent) for greater than 3 weeks, 3 withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroids may be reduced rapidly to physiological doses. Once a daily dose equivalent to 9mg deflazacort is reached, dose reduction should be slower to allow the HPA-axis to recover. Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 48 mg daily of deflazacort, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

•  Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid greater than 48 mg daily of deflazacort (or equivalent),
• Patients repeatedly taking doses in the evening

4.3.Contraindications

Systemic infection unless specific anti-infective therapy is employed. Hypersensitivity to the active substance, deflazacort or any of the excipients. Patients receiving live virus immunisation.

4.4.Special warnings and precautions for use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine. Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity.

Adrenal suppression

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency which could be fatal, being tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy, any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy, they may need to be temporarily re-introduced. Patients should carry 'Steroid treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Anti-inflammatory/immunosuppressive effects and infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised. Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chicken pox should be advised to avoid close personal contact with chickenpox or herpes zoster and, if exposed, they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased. Patients should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed. Live vaccines should not be given to individuals with impaired responsiveness. The antibody response to other vaccines may be diminished.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Prolonged use of glucocorticoids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi or viruses. Use in active tuberculosis should be restricted to those cases of fulminating and disseminated tuberculosis in which deflazacort is used for management with appropriate antituberculosis regimen. If glucocorticoids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged glucocorticoid therapy, these patients should receive chemoprophylaxis. Tendonitis and tendon rupture are known class effect of glucocorticoids. The risk of such reactions may be increased by co-administration of quinolones. Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Special precautions

The following clinical conditions require special caution and frequent patient monitoring is necessary: -

• Cardiac disease or congestive heart failure (except in the presence of active rheumatic carditis), hypertension, thromboembolic disorders. Glucocorticoids can cause salt and water retention and increased excretion of potassium. Dietary salt restriction and potassium supplementation may be necessary.
• Gastritis or oesophagitis, diverticulitis, ulcerative colitis if there is probability of impending perforation, abscess or pyogenic infections, fresh intestinal anastomosis, active or latent peptic ulcer.
• Diabetes mellitus or a family history, osteoporosis, myasthenia gravis, renal insufficiency.
• Emotional instability or psychotic tendency, epilepsy. 
• Previous corticosteroid-induced myopathy.
• Liver failure.
• Hypothyroidism and cirrhosis, which may increase glucocorticoid effect.
• Ocular herpes simplex because of possible corneal perforation.

Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure, although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis. Glucocorticoids are known to cause irregular menstruation and leukocytosis, care should be taken with deflazacort.

Paediatric population

Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence which may be irreversible. Hypertrophic cardiomyopathy has been reported after systemic administration of glucocorticosteroids in preterm infants. In infants receiving administration of systemic glucocorticosteroids, echocardiograms should be performed to monitor myocardial structure and function.

Use in Elderly

The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions. Since complications of glucocorticoid therapy are dependent on dose and duration of therapy, the lowest possible dose must be given and a risk/benefit decision must be made as to whether intermittent therapy should be used.

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

• The same precautions should be exercised as for other glucocorticoids. Deflazacort is metabolised in the liver. It is recommended to increase the maintenance dose of deflazacort if drugs which are liver enzyme inducers are co-administered, e.g. rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide. For drugs which inhibit liver enzymes, e.g. ketoconazole it may be possible to reduce the maintenance dose of deflazacort.
• In patients taking estrogens, corticosteroid requirements may be reduced.
• The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, beta 2-agonists, xanthines and carbenoxolone are enhanced.
• The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
• In patients treated with systemic corticosteroids, use of non-depolarising muscle relaxants can result in prolonged relaxation and acute myopathy. Risk factors for this include prolonged and high dose corticosteroid treatment, and prolonged duration of muscle paralysis. This interaction is more likely following prolonged ventilation (such as in the ITU setting).
• The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.
• As glucocorticoids can suppress the normal responses of the body to attack by micro-organisms, it is important to ensure that any anti-infective therapy is effective and it is recommended to monitor patients closely. Concurrent use of glucocorticoids and oral contraceptives should be closely monitored as plasma levels of glucocorticoids may be increased. This effect may be due to a change in metabolism or binding to serum proteins. Antacids may reduce bioavailability; leave at least 2 hours between administration of deflazacort and antacids. 8
• Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

4.6.Fertility, pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, deflazacort does cross the placenta. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Breast-feeding

Corticosteroids are excreted in breast milk, although no data are available for deflazacort. Doses of up to 50 mg daily of deflazacort are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression but the benefits of breast feeding are likely to outweigh any theoretical risk.

Fertility

No data is available on Deflazacort and its effects on fertility.

4.7.Effects on ability to drive and use machines

The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Vertigo is a possible undesirable effect after treatment with deflazacort. If affected, patients should not drive or operate machinery.

4.8.Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitaryadrenal suppression correlates with the relative potency of the drug, dosage; timing of administration and the duration of treatment. The following CIOMS frequency rating is used: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), not known (cannot be estimated from the available data).

Endocrine disorders

Uncommon: Suppression of the hypothalamic-pituitary-adrenal axis, amenorrhoea, Cushingoid facies. Not known: Growth suppression in infancy, childhood and adolescence.

Metabolism and nutrition disorders

Common: Weight gain. Uncommon: impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, sodium and water retention with hypertension, potassium loss and hypokalaemic alkalosis when co-administered with beta 2-agonist and xanthines. Not known: Negative protein and calcium balance, increased appetite.

Infections and Infestations

Uncommon: Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis. Not known: candidiasis.

Musculoskeletal and connective tissue disorders

Uncommon: Osteoporosis, vertebral and long bone fractures. Rare: Muscle wasting. Not known: avascular osteonecrosis, tendonitis and tendon rupture when coadministered with quinolones, myopathy (acute myopathy may be precipitated by nondepolarising muscle relaxants, negative nitrogen balance.

Reproductive system and breast disorders

Not known: Menstrual irregularity.

Cardiac disorders

Not known: Heart failure, hypertrophic cardiomyopathy in preterm infants.

Nervous system disorders

Uncommon: Headache, vertigo.

Not known: restlessness, Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal, aggravation of epilepsy.

Psychiatric disorders

A wide range of psychiatric reactions including affective disorders such as: Uncommon: depressed and labile mood. Not known: irritable, euphoric, suicidal thoughts. Psychotic reactions including: Not known: mania, delusions, hallucinations, aggravation of schizophrenia Other reactions including: Uncommon: behavioural disturbances. Not known: anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

Eye disorders

Not known: Vision blurred, increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts especially in children, chorioretinopathy, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Gastrointestinal disorders

Uncommon: Dyspepsia, peptic ulceration, haemorrhage, nausea. Not known: perforation of peptic ulcer, acute pancreatitis (especially in children), candidiasis.

Skin and subcutaneous tissue disorders

Uncommon: hirsutism, striae, acne.

Rare: bruising.

Not known: Skin atrophy, telangiectasia.

General disorders and administration site conditions

Uncommon: Oedema.

Not known: impaired healing.

Immune system disorders

Uncommon: Hypersensitivity including anaphylaxis has been reported.

Blood and lymphatic system disorders

Not known: Leukocytosis.

Vascular disorders

Not known: Thromboembolism in particular in patients with underlying conditions associated with increased thrombotic tendency, rare incidence of benign intracranial hypertension.

Withdrawal symptoms and signs

Not known: Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight. This may occur in patients even without evidence of adrenal insufficiency.

Class effect

Pheochromocytoma crisis has been reported with other systemic corticosteroids and is a known class effect.

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

4.9. Overdose

It is unlikely that treatment is needed in cases of acute overdosage. The LD50 for the oral dose is greater than 4000 mg/kg in laboratory animals.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: corticosteroids for systemic use; Glucocorticoids. ATC code: H02AB13. Deflazacort is a glucocorticoid. Its anti-inflammatory and immunosuppressive effects are used in treating a variety of diseases and are comparable to other antiinflammatory steroids. Clinical studies have indicated that the average potency ratio of deflazacort to prednisolone is 0.69-0.89.

5.2 Pharmacokinetic properties

Absorption: Orally administered deflazacort appears to be well absorbed.

Distribution: The active metabolite D 21-OH achieves peak plasma concentrations in 1.5 to 2 hours. It is 40% protein-bound and has no affinity for corticosteroid-binding-globulin (transcortin).

Biotransformation: Orally administered deflazacort is immediately converted by plasma esterases to the pharmacologically active metabolite (D 21-OH). Metabolism of D 21-OH is extensive. The metabolite of D 21-OH is deflazacort 6- beta-OH.

Elimination: Its elimination plasma half-life is 1.1 to 1.9 hours. Elimination takes place primarily through the kidneys; 70% of the administered dose is excreted in the urine. The remaining 30% is eliminated in the faeces. Metabolism of D 21-OH is extensive; only 18% of urinary excretion represents D 21-OH. The metabolite of D 21-OH, deflazacort 6-beta-OH, represents one third of the urinary elimination.

Safety studies have been carried out in the rat, dog, mouse and monkey. The findings are consistent with other glucocorticoids at comparable doses. Teratogenic effects demonstrated in rodents and rabbits are typical of those caused by other glucocorticoids. Deflazacort was not found to be carcinogenic in the mouse, but studies in the rat produced carcinogenic findings consistent with the findings with other glucocorticoids.

Deflazacort, is an oxaline derivative of Prednisolone.

Figure: Structure of Deflazacort

IUPAC Name: (11β,16β)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4- dieno[17,16-d]oxazole-3,20-dione Molecular Formula: C₂₅H₃₁NO₆ Molecular Weight: 441.5 g/mol

1. Incompatibilities Not applicable.

2. Shelf-life

3. Packaging information

4. Storage and handing instructions

• Keep out of reach of children. Keep out of the sight and reach of children. Store in a dry place at a temperature not exceeding 25°C.

A patient information leaflet is available for this product.

Administration

Warn patients and/or caregivers to not stop taking Cortimax abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency.

Cortimax may be taken with or without food. Do not take Cortimax with grapefruit juice.

Tablets

Cortimax Tablets may be taken whole or crushed and taken immediately after mixing with applesauce.

Increased Risk of Infection

Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal. Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed.

Alterations in Cardiovascular/Renal Function

Inform patients and/or caregivers that Cortimax can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed.

Behavioral and Mood Disturbances

Advise patients and/or caregivers about the potential for severe behavioral and mood changes with Cortimax and encourage them to seek medical attention if psychiatric symptoms develop.

Decreases in Bone Mineral Density

Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of Cortimax, which can predispose the patient to vertebral and long bone fractures.

Ophthalmic Effects

Inform patients and/or caregivers that Cortimax may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks.

Vaccination

Advise patients and/or caregivers to bring immunizations up-to-date according to immunization guidelines prior to starting therapy with Cortimax. Live-attenuated or live vaccines should be administered at least 4 to 6 weeks prior to starting Cortimax. Inform patients and/or caregivers that they may receive concurrent vaccinations with use of Cortimax, except for live-attenuated or live vaccines.

Serious Skin Rashes

Instruct patients and/or caregivers to seek medical attention at the first sign of a rash.

Drug Interactions

Certain medications can cause an interaction with Cortimax. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment.

Deflazacort Suspension 6 mg/ 5 ml

Each 5 ml of suspension contains:

Deflazacort 6 mg

Excipients q.s.

Colour: quinolone yellow

Oral Suspension, 6 mg/ 5 ml

Cortimax Suspension: a bottle of 30 ml

Cortimax-XL Suspension: a bottle of 60 ml

4.1. Therapeutic indication

For asthma, rheumatoid arthritis when glucocorticosteriod therapy is warranted.

4.2.Posology and method of administration

Deflazacort is a glucocorticoid derived from prednisolone and 6mg of deflazacort has approximately the same anti-inflammatory potency as 5mg prednisolone or prednisone.

Doses vary widely in different diseases and different patients. In more serious and life-threatening conditions, high doses of deflazacort may need to be given. When deflazacort is used long term in relatively benign chronic diseases, the maintenance dose should be kept as low as possible. Dosage may need to be increased during periods of stress or in exacerbation of illness.

The dosage should be individually titrated according to diagnosis, severity of disease and patient response and tolerance. The lowest dose that will produce an acceptable response should be used.

There has been limited exposure of children to deflazacort in clinical trials.

In children, the indications for glucocorticoids are the same as for adults, but it is important that the lowest effective dosage is used. Alternate day administration may be appropriate.

Doses of deflazacort usually lie in the range 0.25 - 1.5 mg/kg/day.

The following ranges provide general guidance:

Juvenile chronic arthritis:  usual maintenance dose is between 0.25 - 1.0 mg/kg/day.

Nephrotic syndrome: Initial dose of usually 1.5 mg/kg/day followed by down titration according to clinical need.

Bronchial asthma: On the basis of the potency ratio, the initial dose should be between 0.25 - 1.0 mg/kg deflazacort on alternate days.

Hepatic Impairment

In patients with hepatic impairment, blood levels of deflazacort may be increased. Therefore, the dose of deflazacort should be carefully monitored and adjusted to the minimum effective dose.

Renal Impairment

In renally impaired patients, no special precautions other than those usually adopted in patients receiving glucocorticoid therapy are necessary.

Deflazacort withdrawal

In patients who have received more than physiological doses of systemic corticosteroids (approximately 9 mg/day or equivalent) for > 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids but there is uncertainty about HPA suppression, the dose of systemic corticosteroids may be reduced rapidly to physiological doses. Once a daily dose equivalent to 9 mg deflazacort is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it is considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 48 mg daily of deflazacort, or equivalent for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.
• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).
• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.
• Patients receiving doses of systemic corticosteroid > 48 mg daily of deflazacort (or equivalent),
• Patients repeatedly taking doses in the evening.

4.3. Contraindications

Systemic infection unless specific anti-infective therapy is employed. Hypersensitivity to the active substance, deflazacort or any of the excipients. Patients receiving live virus immunisation.

4.4. Special warnings and precautions for use

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine. Undesirable effects may be minimised by using the lowest effective dose for the minimum period, and by administering the daily requirement as a single morning dose or whenever possible as a single morning dose on alternate days. Frequent patient review is required to appropriately titrate the dose against disease activity.

Adrenal suppression

Adrenal cortical atrophy develops during prolonged therapy and may persist for years after stopping treatment. Withdrawal of corticosteroids after prolonged therapy must therefore always be gradual to avoid acute adrenal insufficiency which could be fatal, being tapered off over weeks or months according to the dose and duration of treatment. During prolonged therapy, any intercurrent illness, trauma or surgical procedure will require a temporary increase in dosage; if corticosteroids have been stopped following prolonged therapy, they may need to be temporarily re-introduced.

Patients should carry 'Steroid treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

Anti-inflammatory/immunosuppressive effects and infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked and may reach an advanced stage before being recognised.

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chicken pox should be advised to avoid close personal contact with chickenpox or herpes zoster and, if exposed, they should seek urgent medical attention. Passive immunisation with varicella zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased. Patients should be advised to take particular care to avoid exposure to measles and to seek immediate medical advice if exposure occurs. Prophylaxis with intramuscular normal immunoglobulin may be needed.

Live vaccines should not be given to individuals with impaired responsiveness. The antibody response to other vaccines may be diminished.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Prolonged use of glucocorticoids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi or viruses. Use in active tuberculosis should be restricted to those cases of fulminating and disseminated tuberculosis in which deflazacort is used for management with appropriate antituberculosis regimen. If glucocorticoids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged glucocorticoid therapy, these patients should receive chemoprophylaxis.

Tendonitis and tendon rupture are known class effect of glucocorticoids. The risk of such reactions may be increased by co-administration of quinolones. Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Corticosteroids should only be administered to patients with suspected or identified pheochromocytoma after an appropriate risk/benefit evaluation.

Special precautions

The following clinical conditions require special caution and frequent patient monitoring is necessary: -

• Cardiac disease or congestive heart failure (except in the presence of active rheumatic carditis), hypertension, thromboembolic disorders. Glucocorticoids can cause salt and water retention and increased excretion of potassium. Dietary salt restriction and potassium supplementation may be necessary.
• Gastritis or oesophagitis, diverticulitis, ulcerative colitis if there is probability of impending perforation, abscess or pyogenic infections, fresh intestinal anastomosis, active or latent peptic ulcer.
• Diabetes mellitus or a family history, osteoporosis, myasthenia gravis, renal insufficiency. • Emotional instability or psychotic tendency, epilepsy.
• Previous corticosteroid-induced myopathy.
• Liver failure.
• Hypothyroidism and cirrhosis, which may increase glucocorticoid effect.
• Ocular herpes simplex because of possible corneal perforation. Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids. Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure, although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently. Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis. Glucocorticoids are known to cause irregular menstruation and leukocytosis, care should be taken with deflazacort. Paediatric population Corticosteroids cause dose-related growth retardation in infancy, childhood and adolescence which may be irreversible. Hypertrophic cardiomyopathy has been reported after systemic administration of glucocorticosteroids in preterm infants. In infants receiving administration of systemic glucocorticosteroids, echocardiograms should be performed to monitor myocardial structure and function.

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

• The same precautions should be exercised as for other glucocorticoids. Deflazacort is metabolised in the liver. It is recommended to increase the maintenance dose of deflazacort if drugs which are liver enzyme inducers are co-administered, e.g. rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone and aminoglutethimide. For drugs which inhibit liver enzymes, e.g. ketoconazole it may be possible to reduce the maintenance dose of deflazacort.
• In patients taking estrogens, corticosteroid requirements may be reduced.
• The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics, beta 2-agonists, xanthines and carbenoxolone are enhanced.
• The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.
• In patients treated with systemic corticosteroids, use of non-depolarising muscle relaxants can result in prolonged relaxation and acute myopathy. Risk factors for this include prolonged and high dose corticosteroid treatment, and prolonged duration of muscle paralysis. This interaction is more likely following prolonged ventilation (such as in the ITU setting).
• The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication.
• As glucocorticoids can suppress the normal responses of the body to attack by micro-organisms, it is important to ensure that any anti-infective therapy is effective and it is recommended to monitor patients closely. Concurrent use of glucocorticoids and oral contraceptives should be closely monitored as plasma levels of glucocorticoids may be increased. This effect may be due to a change in metabolism or binding to serum proteins. Antacids may reduce bioavailability; leave at least 2 hours between administration of deflazacort and antacids.
• Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

4.6.Fertility, pregnancy and lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, deflazacort does cross the placenta. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and effects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate/lip in man. However, when administered for prolonged periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Breast-feeding

Corticosteroids are excreted in breast milk, although no data are available for deflazacort. Doses of up to 50 mg daily of deflazacort are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression but the benefits of breast feeding are likely to outweigh any theoretical risk.

Fertility

No data is available on Deflazacort and its effects on fertility.

4.7.Effects on ability to drive and use machines

The effect of corticosteroids on the ability to drive or use machinery has not been systematically evaluated. Vertigo is a possible undesirable effect after treatment with deflazacort. If affected, patients should not drive or operate machinery.

4.8.Undesirable effects

The incidence of predictable undesirable effects, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage; timing of administration and the duration of treatment.

The following CIOMS frequency rating is 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 (<1/10 000), not known (cannot be estimated from the available data).

Endocrine disorders

Uncommon: Suppression of the hypothalamic-pituitary-adrenal axis, amenorrhoea, Cushingoid facies.

Not known: Growth suppression in infancy, childhood and adolescence.

Metabolism and nutrition disorders

Common: Weight gain.

Uncommon: impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, sodium and water retention with hypertension, potassium loss and hypokalaemic alkalosis when co-administered with beta 2-agonist and xanthines.

Not known: Negative protein and calcium balance, increased appetite.

Infections and Infestations

Uncommon: Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant tuberculosis.

Not known: candidiasis.

Musculoskeletal and connective tissue disorders

Uncommon: Osteoporosis, vertebral and long bone fractures.

Rare: Muscle wasting.

Not known: avascular osteonecrosis, tendonitis and tendon rupture when co-administered with quinolones, myopathy (acute myopathy may be precipitated by non-depolarising muscle relaxants, negative nitrogen balance.

Reproductive system and breast disorders

Not known: Menstrual irregularity.

Cardiac disorders

Not known: Heart failure, hypertrophic cardiomyopathy in preterm infants.

Nervous system disorders

Uncommon: Headache, vertigo.

Not known: restlessness, Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri), usually after treatment withdrawal, aggravation of epilepsy.

Psychiatric disorders

A wide range of psychiatric reactions including affective disorders such as:

Uncommon: depressed and labile mood.

Not known: irritable, euphoric, suicidal thoughts.

Psychotic reactions including:

Not known: mania, delusions, hallucinations, aggravation of schizophrenia

Other reactions including:

Uncommon: behavioural disturbances.

Not known: anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported.

Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.

Eye disorders

Not known: Vision blurred, increased intra-ocular pressure, glaucoma, papilloedema, posterior subcapsular cataracts especially in children, chorioretinopathy, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases.

Gastrointestinal disorders

Uncommon: Dyspepsia, peptic ulceration, haemorrhage, nausea.

Not known: perforation of peptic ulcer, acute pancreatitis (especially in children), candidiasis.

Skin and subcutaneous tissue disorders

Uncommon: hirsutism, striae, acne.

Rare: bruising.

Not known: Skin atrophy, telangiectasia.

General disorders and administration site conditions

Uncommon: Oedema.

Not known: impaired healing.

Immune system disorders

Uncommon: Hypersensitivity including anaphylaxis has been reported.

Blood and lymphatic system disorders

Not known: Leukocytosis.

Vascular disorders

Not known: Thromboembolism in particular in patients with underlying conditions associated with increased thrombotic tendency, rare incidence of benign intracranial hypertension.

Withdrawal symptoms and signs

Not known: Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death.

A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight. This may occur in patients even without evidence of adrenal insufficiency.

Class effect

Pheochromocytoma crisis has been reported with other systemic corticosteroids and is a known class effect.

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

It is unlikely that treatment is needed in cases of acute overdosage. The LD50 for the oral dose is greater than 4000 mg/kg in laboratory animals.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: corticosteroids for systemic use; Glucocorticoids.

ATC code: H02AB13.

Deflazacort is a glucocorticoid. Its anti-inflammatory and immunosuppressive effects are used in treating a variety of diseases and are comparable to other anti-inflammatory steroids. Clinical studies have indicated that the average potency ratio of deflazacort to prednisolone is 0.69-0.89.

5.2 Pharmacokinetic properties

Absorption: Orally administered deflazacort appears to be well absorbed.

Distribution: The active metabolite D 21-OH achieves peak plasma concentrations in 1.5 to 2 hours. It is 40% protein-bound and has no affinity for corticosteroid-binding-globulin (transcortin).

Biotransformation: Orally administered deflazacort is immediately converted by plasma esterases to the pharmacologically active metabolite (D 21-OH). Metabolism of D 21-OH is extensive. The metabolite of D 21-OH is deflazacort 6-beta-OH.

Elimination: Its elimination plasma half-life is 1.1 to 1.9 hours. Elimination takes place primarily through the kidneys; 70% of the administered dose is excreted in the urine. The remaining 30% is eliminated in the faeces. Metabolism of D 21-OH is extensive; only 18% of urinary excretion represents D 21-OH. The metabolite of D 21-OH, deflazacort 6-beta-OH, represents one third of the urinary elimination.

Safety studies have been carried out in the rat, dog, mouse and monkey. The findings are consistent with other glucocorticoids at comparable doses. Teratogenic effects demonstrated in rodents and rabbits are typical of those caused by other glucocorticoids. Deflazacort was not found to be carcinogenic in the mouse, but studies in the rat produced carcinogenic findings consistent with the findings with other glucocorticoids.

Deflazacort, is an oxaline derivative of Prednisolone.

 

Figure: Structure of Deflazacort

IUPAC Name: (11β,16β)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione Molecular Formula: C₂₅H₃₁NO₆

Molecular Weight: 441.5 g/mol

1.Incompatibilities

Not applicable.

2.Shelf-life

Refer on pack

3.Packaging information

Cortimax Suspension: a bottle of 30 ml

Cortimax-XL Suspension: a bottle of 60 ml

4. Storage and handing instructions

• Keep out of reach of children. Keep out of the sight and reach of children.
• Store in a dry place at a temperature not exceeding 25°C.

A patient information leaflet is available for this product.

Administration

• Warn patients and/or caregivers to not stop taking Cortimax abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency.
• Cortimax may be taken with or without food. Do not take Cortimax with grapefruit juice.

Increased Risk of Infection

Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal. Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed.

Alterations in Cardiovascular/Renal Function

Inform patients and/or caregivers that Cortimax can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed.

Behavioural and Mood Disturbances

Advise patients and/or caregivers about the potential for severe behavioral and mood changes with Cortimax and encourage them to seek medical attention if psychiatric symptoms develop.

Decreases in Bone Mineral Density

Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of Cortimax, which can predispose the patient to vertebral and long bone fractures.

Ophthalmic Effects

Inform patients and/or caregivers that Cortimax may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks.

Vaccination

Advise patients and/or caregivers to bring immunizations up-to-date according to immunization guidelines prior to starting therapy with Cortimax. Live-attenuated or live vaccines should be administered at least 4 to 6 weeks prior to starting Cortimax. Inform patients and/or caregivers that they may receive concurrent vaccinations with use of Cortimax, except for live-attenuated or live vaccines.

Serious Skin Rashes

Instruct patients and/or caregivers to seek medical attention at the first sign of a rash.

Drug Interactions

Certain medications can cause an interaction with Cortimax. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment.

Levocloperastine Fendizoate Oral Suspension

Each 5 ml oral suspension contains:

Levocloperastine Fendizoate 35.4 mg (equivalent to 20 mg of Levocloperastine Hydrochloride)

Excipients q.s.

In a flavoured syrup base

Colour: Sunset Yellow FCF

Flavour: Mango

Oral suspension

20mg of Levocloperastine per 5ml

4.1 Therapeutic Indication

For the treatment of non-productive cough in adult patients

4.2 Posology and method of administration

Dose for Adults: 5 ml (20mg) three times daily.

4.3 Contraindications

• Known hypersensitivity to cloperastine or to any of the excipients.
• It should not be used in children under 2 years of age.
• Pregnant or breast-feeding women.
• Known hypersensitivity to antihistaminic agents.
• Patients receiving concomitant treatment with MAO inhibitors.
• Patients with hereditary fructose intolerance, glucose or galactose malabsorption, or sucrose isomaltase deficiency.
• Consumption of Alcohol is strictly contraindicated with Levocloperastine suspension.

4.4 Special warnings and precautions for use

Caution should be observed while prescribing Levocloperastine Fendizoate suspension to adults and children with hypertension, cardiovascular disease, uncontrolled diabetes mellitus, hyperthyroidism, seizures or in patients who are unusually hypersensitive to sympathomimetic amines.

Due to its mild anticholinergic activity, cloperastine should be administered with caution in patients with intraocular hypertension, narrow-angle glaucoma, prostatic hypertrophy, urine retention, hypertension, cardiac arrhythmia, myasthenia gravis, stenosing peptic ulcer or bowel obstruction affecting the oesophagus, intestine or bladder.

Persistent cough.

Caution is recommended in patients with chronic cough such as smoker's cough, pulmonary emphysema or asthma, as it inhibits the cough reflex and could therefore alter expectoration and increase airway resistance.

4.5 Drugs interactions

Levocloperastine Fendizoate suspension should not be concomitantly prescribed with sedatives or tranquilizers. Similarly, other antihistamine drugs should not be prescribed concomitantly.

As it has some antihistaminic activity, cloperastine can enhance the sedative effect of CNS

depressors such as anxiolytics, antipsychotic drugs, barbiturates, hypnotics, narcotics, sedatives, tranquilizers, some analgesics and alcohol.

Also due to this activity, cloperastine, antihistaminic agents and anticholinergic drugs (anti-parkinson's drugs, tricyclic antidepressants, MAO inhibitors, neuroleptic agents) can reciprocally increase their effects.

Expectorants and mucolytic drugs: Inhibition of the cough reflex could give rise to pulmonary obstruction in case of elevated volume or fluidity of bronchial secretions.

4.6 Use in special populations

Animal studies have not shown any evidence of damage to the foetus. In humans, its safety for use in pregnancy and lactation has not been established. Cloperastine should therefore not be used during pregnancy unless a doctor believes that the treatment's potential benefit for the mother exceeds all risks for the developing foetus or infant. As it is unknown whether the drug is excreted in human milk, its use during lactation is not recommended.

4.7 Effects on ability to drive and use machines

Levocloperastine can cause drowsiness, so caution is recommended when driving or using dangerous machinery. If drowsiness is noted at normal doses of cloperastine, do not drive or handle dangerous machinery.

4.8 Undesirable effects

Levocloperastine can produce minor and transient adverse reactions such as Dry mouth, GI effects, exhaustion, fainting, somnolence, sedation, clouding of consciousness, numbness, dizziness, headache, palpitations and allergic reaction.

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

No cases of overdose have been reported.

Intoxication can occur after ingesting quantities that are much higher than the therapeutic doses.

Overdose could cause symptoms such as drowsiness, anticholinergic symptoms, hallucinations, excitation, ataxia, lack of motor coordination and convulsions. In case of overdose, symptomatic and maintenance treatment is recommended. Vomiting should be induced or stomach lavage should be performed with saline serum.

5.1 Mechanism of action

Levocloperastine is a cough suppressant. Levocloperastine is a novel antitussive agent having dual mechanism of action, it acts on both the central bulbar cough centre and on peripheral receptors in the tracheobronchial tree.

As demonstrated in a number of animal models, Levocloperastine acts at the CNS level by inhibiting the bulbar cough centre. In addition to this primary mechanism of action, peripheral effects related to its antihistamine, anti-serotonergic and smooth muscle-relaxant properties also contribute to the overall efficacy of Levocloperastine in the treatment of cough, bronchospasm and related symptoms.

5.2 Pharmacodynamic properties

The therapeutic efficacy of DL-cloperastine in reducing the intensity and frequency of cough is well established, with efficacy similar to that of codeine and superior to that of dextromethorphan.

In clinical trials, levocloperastine had a faster onset of action and produced greater reductions in the intensity and frequency of cough compared with DL-cloperastine, codeine and levodropropizine.

The antitussive effects (reduction in intensity and frequency of cough) of levocloperastine were observed after the first day of treatment in patients of all ages. In children, levocloperastine reduced night-time awakenings and irritability; in adults, it was also effective in treating ACE inhibitor cough.

Levocloperastine was generally well tolerated. There was no evidence of clinically significant central adverse events, whereas drowsiness, dry mouth and nausea were reported with comparator agents (levodropropizine, codeine, DL-cloperastine).

Levocloperastine represents an effective alternative to currently used antitussive agents with the added advantage of faster onset of action and improved tolerability in all patient groups.

5.3 Pharmacokinetic properties

The product is absorbed from the gastrointestinal tract and mostly excreted in urine.

After administration of 10ml of oral suspension containing levocloperastine fendizoate, peak plasma concentrations of 10 μg/L were reached 2 to 4 hours after administration, with a lag-time of approximately 45 minutes before detection of the drug in the bloodstream, suggesting a gradual and protracted absorption from the intestine.

Oral bioavailability was >40% based on the ratio of area under the plasma concentrationtime curve (AUC) of unmodified drug calculated after oral and intravenous administration, while substantially higher values were obtained in excretion studies conducted with radiolabelling techniques (14C).

The half-life of levocloperastine is 0.80 hours (distribution half-life), 1.68 hours (elimination half-life), and 6.58 hours (terminal elimination half-life). The volumes of distribution (Vd) were found to be 80 ml/kg (terminal) and 57 ml/kg (at steady state), and the protein-bound fraction was high. Total body clearance was 7.5 L/hour.

In preclinical studies, levocloperastine demonstrated antitussive effects similar to those observed with codeine. In acute and repeated-dose toxicity studies, levocloperastine was well tolerated in rodents and dogs, with no clinically significant cardiovascular or gastrointestinal adverse events. The pharmacokinetic behaviour of levocloperastine, best described by a two-compartmental model with absorption phase, is similar to that of the racemic compound DL-cloperastine.

Administration of levocloperastine 1 to 9 mg/kg to guinea pigs dose-dependently inhibited cough induced by citric acid or ammonia vapour, showing an antitussive effect similar to that of codeine. The 50% effective dose (ED50) values for levocloperastine vs codeine were, respectively, 2.6 vs 3.6 mg/kg in the citric acid test, and 2.9 vs 3.1 mg/kg in the ammonia test. Activities of levocloperastine, DL-cloperastine and dextrocloperastine were similar in the citric acid-induced cough model, suggesting that the antitussive efficacy of cloperastine compounds is independent of their enantiomeric structure.

Levocloperastine (as well as dextrocloperastine and DL-cloperastine) exhibited spasmolytic activity in guinea-pigs via its antihistamine properties in vitro (inhibition of histamine-induced contraction in isolated tracheal rings) and in vivo (dose-dependent inhibition of bronchospasm induced by histamine aerosol). Similarly, serotonin-antagonist activity was demonstrated in vitro.

Unlike opioid antitussives, such as codeine, the CNS activity of levocloperastine is highly selective for the cough centre, thus avoiding central adverse effects such as sedation. This attenuation of CNS adverse effects is a differential feature of levocloperastine and is related to its specific stereoisomeric properties, since dextrocloperastine and DL-cloperastine, administered orally or intraperitoneally, induced sedative and stimulant effects of much greater magnitude (by approximately 50%) in tests of CNS function in rodents.

Both acute and repeated-dose toxicity studies found levocloperastine to be well tolerated in rodents and dogs. The 50% lethal dose (LD50) value of levocloperastine could not be calculated because the oral/intraperitoneal doses tested (up to 2000 mg/kg) did not cause death in any of the experimental animals. By comparison, the enantiomer dextrocloperastine was more toxic, with LD50 values of 466 mg/kg in the mouse and 1226 mg/kg in the rat after oral administration, and 155 and 177 mg/kg, respectively, after intraperitoneal administration.

In chronic toxicity studies, levocloperastine at dosages up to 75 mg/kg/day (corresponding to 45 times the therapeutic daily dosage in humans) for 6 months was considered 'safe' in rats and dogs. Mild adverse events (including vomiting, anorexia and transient biochemical/ histological signs of liver and kidney dysfunction) were observed only with dosages of 250 mg/kg/day following 6 months' treatment. Levocloperastine did not show mutagenic or carcinogenic effects in specific in vitro and in vivo studies.

Levocloperastine, the levorotatory isomer of DLcloperastine, is a centrally active, non-opioid antitussive agent with a chemical structure and pharmacological profile distinct from that of the racemate. It is devoid of central antinociceptive activities, does not cause addiction or dependence phenomena, and does not interfere with cardiovascular or gastrointestinal functions.

Cloperastine fendizoate is a N-oxyethylpiperidine. It is functionally related to a benzoate.

Structure of Cloperastine fendizoate

Molecular Formula: C₄₀H₃₈ClNO₅

Molecular Weight: 648.2 g/mol

8.1 Incompatibilities

None known.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A bottle of 100 ml.

8.4 Storage and handing instructions

Store in a cool place. Protect from light. Keep out of reach of children. Shake well before each use.

• You have been prescribed Soventus-DC Oral Suspension for the symptomatic relief of dry cough.
• It is usually taken for a short time, until the symptoms clear up.
• Measure the syrup with a special dose-measuring spoon or cup, not a regular table spoon.
• Drink extra fluids to help loosen the congestion and lubricate your throat while you are taking this medication.
• It should not be administered to patients with chronic cough or where cough is accompanied by excessive secretions.
• Inform your doctor if your cough lasts more than 7 days, comes back, or occurs with fever, rash or headache. These could be signs of a serious condition.

19-09-2024

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.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.

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

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.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.

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

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.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.

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

Saline Nasal Solution IP

Sodium Chloride IP 0.65% w/v

In an Aqueous Isotonic Solution

using Purified Water IP

Excipients q.s.

Benzalkonium Chloride IP 0.01% w/v

(As a preservative)

Nasal Spray

Sodium Chloride (0.65%w/v)

4.1 Therapeutic Indication

Naturally provides instant, soothing relief for dry, irritated nasal passages caused by colds, allergies, dry air, pollution, smoke, air travel, and the use of decongestants or steroidal sprays.

4.2 Posology and method of administration

Method of administration: Nasal use

• Clean nose by blowing.
• For children and adults: In erect posture, insert nozzle into nostril, squeeze bottle once & inhale spray.
• For infants/babies: tilt head far back while lying down or sitting. Turn bottle upside down. Allow 2-3 drops into nostril & spread.
• Repeat for other nostril

4.3 Contraindications

Maxtra-S Nasal Spray should not be used in the following conditions:

In case of hypersensitivity to the active substance or to any of the excipients listed in the formulation.

4.4 Special warnings and precautions for use

• The use of this Maxtra®-S Nasal Spray by more than one person may spread infection.
• Avoid if you are allergic to any of the ingredients in the formulation.
• Signs of an allergic reaction may include: rash, hives, itching, red-swollen-blistered or peeling skin with or without fever, wheezing, tightness in the chest or throat, trouble breathing, swallowing, unusual hoarseness or swelling of the mouth, face, lips, tongue or throat. Very severe nasal irritation.
• The product contains benzalkonium chloride which may cause irritation or swelling inside the nose, especially if used for a long time. Long term use may cause oedema of the nasal mucosa.
• Ensure that the container is undamaged and the contents clear in appearance before use. After use, discard any remaining solution.

4.5 Drugs interactions

None.

4.6 Use in special populations

Safe to use during pregnancy and lactation.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Usually do not occur, however rarely occurring side effects may include:

-if the inside of the nose is very dry and irritated, stinging may occur.

-allergic reactions

-sneezing

-cough

-nose irritation

-abnormal taste

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

None

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Decongestants and other nasal preparations, sodium chloride nasal spray

ATC code: R01AX10

The exact mechanism of action of saline nasal irrigation is unknown. One possibility is that the breakdown of the protective function of the nasal mucosa plays a role in upper respiratory conditions. Saline nasal irrigation may improve nasal mucosa function through several physiologic effects, including direct cleansing, removal of inflammatory mediators and improved mucociliary function, as suggested by increasing ciliary beat frequency.

5.2 Pharmacokinetic properties

Absorption

Sodium chloride distributes primarily to extracellular compartments, including plasma and interstitial fluid; sodium is maintained outside the cell via the Na+/K+-ATPase pump, which exchanges intracellular sodium for extracellular potassium. Penetration across the blood-brain barrier is low. Sodium chloride is excreted primarily in the urine, but it is also excreted in sweat and stool. In healthy patients at steady state with minimal sweat losses, sodium excreted in urine is roughly the same as dietary intake. Sweat sodium concentration is increased in children with cystic fibrosis, aldosterone deficiency, or pseudohypoaldosteronism.

No further information other than that which is included in the Summary of Product Characteristics.

6.1 Animal Toxicology or Pharmacology

No information provided.

Sodium chloride, also known as salt, common salt, table salt or halite, is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. It is listed on the World Health Organization Model List of Essential Medicine.

Molecular Weight : 58.44 g/mol.

8.1 Incompatibilities

None known.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

A bottle of 20 ml.

8.4 Storage and handing instructions

Store at temperature not exceeding 30°C. Protect from light and moisture. Keep out of reach of children. Shake well before each use.

Do not accept the pack if cap seal is broken on the bottle.

Close the cap tightly after use.

Preserve in tight container.

Alcohol Free Safe for Children Safe for repeated daily use

18-09-2024

Iron Sucrose Injection USP

Feronia-IV 50

Each ml contains: Ferric Hydroxide in Complex with Sucrose

equivalent to Elemental Iron……………………20 mg

Feronia-IV 100

Each ml contains:

Ferric Hydroxide in Complex with Sucrose

equivalent to Elemental Iron…………………. 20 mg

Solution for injection or infusion.

50mg/2.5 ml ampoule

100mg/5 ml ampoule

4.1. Therapeutic indications

1. Treatment of iron deficiency anemia in patients with chronic kidney disease (CKD).

2. Treatment of iron deficiency in the following indications:

• Where there is a clinical need to deliver iron rapidly to iron stores,
• In patients who cannot tolerate oral iron therapy or who are non-compliant,
• In active inflammatory bowel disease where oral iron preparations are ineffective. The diagnosis of iron deficiency must be based on appropriate laboratory tests (e.g. Hb, serum ferritin, transferrin saturation, serum iron, etc.).

4.2. Posology and method of administration

Monitor carefully patients for signs and symptoms of hypersensitivity reactions during and following each administration of Feronia-IV.

Feronia-IV should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where

full resuscitation facilities can be assured. The patient should be observed for adverse effects for at least 30 minutes following each Feronia-IV injection. Administration: Feronia-IV must only be administered by the intravenous route. This may be by a slow intravenous injection or by an intravenous drip infusion. Feronia-IV must not be used for intramuscular injection.

Adults and the elderly: The total cumulative dose of Feronia-IV, equivalent to the total iron deficit (mg), is determined by the haemoglobin level and body weight.

The dose for Feronia-IV must be individually determined for each patient according to the total iron deficit calculated with the following formula: Dosage Calculation:

Dose= (Body Weight) x (Target Hb in gm % - Actual Hb in gm %) x 2.4 + Depot iron mg.

• Below 35 kg body weight: target Hb = 13 gm % and depot iron = 15 mg/kg body weight
• 35 kg body weight and above: target Hb = 15 gm% and depot iron = 500 mg

The total amount of Feronia-IV required in mg is determined from above calculation.

Alternatively, the total amount of Feronia-IV required in ml is determined from the following formula or dosage table.

Treatment of iron deficiency

Chronic Iron Deficiency Anemia:

Dosage Calculation: Body Weight X (Target Hb in gm % - Actual Hb in gm %) x 2.4 + 500mg for iron store.

Acute Iron Deficiency Anemia:

Dosage Calculation: Body Weight x (Target Hb in gm % - Actual Hb in gm %)x 2.4

Dosage: The total single dose must not exceed 200 mg of iron given not more than three times per week. If the total necessary, dose exceeds the maximum allowed single dose, then the administration has to be split.

Intravenous drip infusion: Feronia-IV must be diluted only in sterile 0.9% m/V sodium chloride solution:

• 2.5 ml Feronia-IV (50 mg iron) in max. 50 ml sterile 0.9% m/V sodium chloride solution
• 5 ml Feronia-IV (100 mg iron) in max. 100 ml sterile 0.9% m/V sodium chloride solution
• 10 ml Feronia-IV (200 mg iron) in max. 200 ml sterile 0.9% m/V sodium chloride solution

For stability reasons, dilutions to lower Feronia-IV concentrations are not permissible.

Dilution must take place immediately prior to infusion and the solution should be administered as follows:

• 100 mg iron (5 ml Feronia-IV) in at least 15 minutes
• 200 mg iron (10 ml Feronia-IV) in at least 30 minutes

Intravenous injection: Feronia-IV may be administered by slow intravenous injection at a rate of 1 ml undiluted solution per minute and not exceeding 10 ml Feronia-IV (200 mg iron) per injection.

Injection into dialyser: Feronia-IV may be administered during a haemodialysis session directly into the venous limb of the dialyser under the same procedures as those outlined for intravenous injection.

Pediatric Patients

Recommended Treatment Regime in Pediatric Patients with Iron Deficiency Anemia

Using Iron Sucrose

1. Total cumulative dose (mg) = [Target Hb - Actual Hb] x weight (kg) x 2.4 + [15 x weight (kg)], Hb in g/dl.

Calculation of total iron deficit for initial repletion:

2. Dosing:

• Divide calculated total cumulate dose and give every 3-7 days until total dose is administered.
• Recommended maximum single dose is 300 mg or 7 mg iron/kg to prevent adverse effects

3. Administration:

Children (>1 month of age)

Dilute doses ≤ 100 mg 1:1 with NS. Infuse over 30 min

Dilute 200 mg in 200 ml NS. Infuse over 1 hr

Dilute 300 in 250 ml NS. Infuse over at least 1½ hr

NOTE: Do not mix Feronia - IV with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Feronia-IV 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Feronia-IV should be administered early during the dialysis session. The usual total treatment course of Feronia-IV is 1000 mg. Feronia-IV treatment may be repeated if iron deficiency reoccurs.

Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)

Administer Feronia-IV 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14-day period. There is limited experience with administration of an infusion of 500 mg of Feronia-IV, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Feronia-IV treatment may be repeated if iron deficiency reoccurs. Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)

Administer Feronia-IV in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Feronia-IV in a maximum of 250 mL of 0.9% NaCl. Feronia-IV treatment may be repeated if iron deficiency reoccurs.

Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatment

The dosing for iron replacement treatment in pediatric patients with HDD-CKD has not been established. For iron maintenance treatment: Administer Feronia-IV at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Feronia-IV treatment may be repeated if necessary.

Pediatric Patients (2 years of age and older) with NDD-CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatment

The dosing for iron replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For iron maintenance treatment: Administer Feronia-IV at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Feronia-IV treatment may be repeated if necessary.

4.3. Contraindications

The use of Feronia IV is contraindicated in the following conditions:

• Hypersensitivity to the active substance, to Feronia IV or any of its excipients
• Known serious hypersensitivity to other parenteral iron products
• Anaemia not caused by iron deficiency
• Evidence of iron overload or hereditary disturbances in utilisation of iron.

4.4.Special warnings and precautions for use

Parenterally administered iron preparations can cause hypersensitivity reactions including serious and potentially fatal anaphylactic/anaphylactoid reactions. Hypersensitivity reactions have also been reported after previously uneventful doses of

parenteral iron complexes.

The risk is enhanced for patients with known allergies including drug allergies, including patients with a history of severe asthma, eczema or other atopic allergy. There is also an increased risk of hypersensitivity reactions to parenteral iron complexes in patients with immune or inflammatory conditions (e.g. systemic lupus erythematosus, rheumatoid arthritis).

Feronia-IV should only be administered when staff trained to evaluate and manage anaphylactic reactions is immediately available, in an environment where full resuscitation facilities can be assured. Each patient should be observed for adverse effects for at least 30 minutes following each Feronia-IV injection. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately. Facilities for cardio respirator y resuscitation and equipment for handling acute anaphylactic/anaphylactoid reactions should be available, including an injectable 1:1000 adrenaline solution. Additional treatment with antihistamines and/or corticosteroids should be given as appropriate.

In patients with liver dysfunction, parenteral iron should only be administered after careful risk/benefit assessment. Parenteral iron administration should be avoided in patients with hepatic dysfunction where iron overload is a precipitating factor, in particular Porphyria Cutanea Tarda (PCT). Careful monitoring of iron status is recommended to avoid iron overload.

Parenteral iron must be used with caution in case of acute or chronic infection. It is recommended that the administration of iron sucrose is stopped in patients with ongoing bacteraemia. In patients with chronic infection a risk/benefit evaluation has to be performed, taking into account the suppression of erythropoiesis.

Hypotensive episodes may occur if the injection is administered too rapidly. Allergic reactions, sometimes involving arthralgia, have been more commonly observed when the recommended dose is exceeded.

Paravenous leakage must be avoided because leakage of Feronia-IV at the injection site may lead to pain, inflammation, tissue necrosis and brown discoloration of the skin.

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

As with all parenteral iron preparations, Feronia-IV should not be administered concomitantly with oral iron preparations since the absorption of oral iron is reduced. Therefore, oral iron therapy should be started at least 5 days after the last injection of Feronia-IV.

4.6.Fertility, pregnancy and lactation

There are no adequate and well-controlled trials of iron sucrose in pregnant women. A careful risk/benefit evaluation is therefore required before use during pregnancy and Feronia-IV should not be used during pregnancy unless clearly necessary.

Iron deficiency anaemia occurring in the first trimester of pregnancy can in many cases be treated with oral iron. Treatment with Feronia-IV should be confined to second and third trimester if the benefit is judged to outweigh the potential risk for both the mother and the foetus.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Data on a limited number of exposed human pregnancies indicated no adverse effects of Feronia-IV on pregnancy or on the health of the foetus/newborn child. Non metabolised Feronia-IV is unlikely to pass into the mother's milk. No well-controlled clinical studies are available to date. Animal studies do not indicate direct or indirect harmful effects to the nursing child.

4.7.Effects on ability to drive and use machines

In the case of symptoms of dizziness, confusion or light headedness following the administration of Feronia IV, patients should not drive or use machinery until the symptoms have ceased.

4.8.Undesirable effects

The most frequently reported adverse drug reactions (ADRs) of iron sucrose in clinical trials were transient taste perversion, hypotension, fever and shivering, injection site reactions and nausea, occurring in 0.5 to 1.5% of the patients. Non-serious anaphylactoid reactions occurred rarely. In general, anaphylactoid reactions are potentially the most serious adverse reactions.

In clinical trials, the following adverse drug reactions have been reported in temporal relationship with the administration of iron sucrose, with at least a possible causal relationship:

Nervous system disorders

Common (≥ 1/100, < 1/10): transient taste perversions (in particular metallic taste). Uncommon (≥1/1000, < 1/100): headache, dizziness. Rare (≥1/10000, < 1/1000): paraesthesia, syncope, loss of consciousness, burning sensation.

Cardio-vascular disorders

Uncommon (≥ 1/1000, < 1/100): hypotension and collapse, tachycardia and palpitations.

Rare (≥1/10000, < 1/1000): hypertension.

Respiratory, thoracic and mediastinal disorders

Uncommon (≥1/1000, < 1/100): bronchospasm, dyspnoea.

Gastrointestinal disorders

Uncommon (≥1/1000, < 1/100): nausea; vomiting, abdominal pain, diarrhoea.

Skin and subcutaneous tissue disorders

Uncommon (≥ 1/1000, < 1/100): pruritus, urticaria, rash, exanthema, erythema.

Musculoskeletal, connective tissue and bone disorders

Uncommon (≥ 1/1000, < 1/100): muscle cramps, myalgia.

General disorders and administration site disorders

Uncommon (≥ 1/1000, < 1/100): fever, shivering, flushing, chest pain and tightness. Injection site disorders such as superficial phlebitis, burning, swelling. Rare (≥ 1/10000, < 1/1000): arthralgia, peripheral oedema, fatigue, asthenia, malaise, feeling hot, oedema.

Immune system disorders

Rare (≥ 1/10000, < 1/1000): anaphylactoid reactions. Moreover, in spontaneous reports the following adverse reactions have been reported: Isolated cases: reduced level of consciousness, light-headed feeling, confusion, angio-oedema, swelling of joints, hyperhidrosis, back pain, bradycardia, chromaturia.

Reporting of suspected adverse reactions

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

via email to: medico@zuventus.com

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

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

4.9 Overdose

Overdosage can cause acute iron overloading which may manifest itself as haemosiderosis. Overdosage should be treated, if required, with an iron chelating agent.

5.1 Pharmacodynamic properties

Mechanism of Action

Iron sucrose, the active ingredient of Feronia-IV, is composed of a polynuclear iron(III)-hydroxide core surrounded by a large number of non-covalently bound sucrose molecules. The complex has a weight average molecular weight (Mw) of approximately 43 kDa. The polynuclear iron core has a structure similar to that of the core of the physiological iron storage protein ferritin. The complex is designed to provide, in a controlled manner, utilisable iron for the iron transport and storage proteins in the body (i.e., transferrin and ferritin, respectively).

Following intravenous administration, the polynuclear iron core from the complex is taken up predominantly by the reticuloendothelial system in the liver, spleen, and bone marrow. In a second step, the iron is used for the synthesis of Hb, myoglobin and other iron-containing enzymes, or stored primarily in the liver in the form of ferritin.

5.2 Pharmacokinetic properties

In healthy adults administered intravenous doses of iron sucrose, its iron component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The iron component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating iron sucrose containing 100 mg of iron labelled with 52Fe/59Fe in patients with iron deficiency showed that a significant amount of the administered iron is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible iron trapping compartment. Following intravenous administration of Feronia-IV, iron sucrose is dissociated into iron and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of iron sucrose containing 1,510 mg of sucrose and 100 mg of iron in 12 healthy adults (9 females, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some iron was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of iron sucrose containing 500 to 700 mg of iron in 26 patients with anemia on erythropoietin therapy (23 females, 3 male; age range 16 to 60), approximately 5% of the iron was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of iron sucrose have not been studied.

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Feronia-IV, patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Feronia-IV at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Feronia-IV, the half-life of total serum iron was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr•μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Feronia-IV is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of iron sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Therapeutic class: Hematinic

Feronia-IV (iron sucrose injection, USP) is a brown, sterile, aqueous, complex of polynuclear iron (III)- hydroxide in sucrose for intravenous use.

Iron sucrose injection has a molecular weight of approximately 34,000 – 60,000 daltons

Structural formula: [Na2Fe5O8(OH) ⋅3(H2O)]n ⋅m(C12H22O11)

where: n is the degree of iron polymerization and m is the number of sucrose

molecules associated with the iron (III)-hydroxide.

Each mL contains 20 mg elemental iron as iron sucrose in water for injection.

1.Incompatibilities

Feronia-IV must not be mixed with other medicinal products except sterile 0.9% sodium chloride solution(NS) for dilution.

The diluted solution must appear as brown and clear.

Each ampoule of Feronia-IV is intended for single use only.

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

There is the potential for precipitation and/or interaction if mixed with other solutions or medicinal products. The compatibility with containers other than glass, polyethylene and PVC is not known.

2. Shelf-life

Refer on the pack.

3.Packaging information

Feronia-IV 50: A blister pack of 2.5 ml ampoule. Feronia-IV 100: A blister pack of 5 ml ampoule.

4.Storage and handing instructions

Ampoules or vials should be visually inspected for sediment and damage before use. Use only those containing a sediment free and homogenous solution.

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

Keep out of reach of children.

Store at controlled room temperature (15°C to 25°C). Do not refrigerate.

Prior History of Reactions to Parenteral Iron Products

Question the patients regarding any prior history of reactions to parenteral iron products.

Serious Hypersensitivity Reactions

Advise patients to report any symptoms of hypersensitivity that may develop during and following Feronia-IV administration, such as rash, itching, dizziness, light headedness, swelling, and breathing problems.

17th Sept. 2024