Bovine Colostrum, Vitamin A, D, E, K & Zinc Powder

Each serve (3 g) of INSTAMUNE® provides:

Bovine Colostrum (with 30% IgG)-1000 mg Zinc-3.3 mg

Vitamin K-10 mcg

Vitamin A-1200 IU

Vitamin D-90 IU

Vitamin E-4 IU

Powder

90 grams per pack

4.1 Therapeutic indication

For children & adults to boost immunity.

4.2 Posology and method of administration

Recommended usage level:

Take one spoonful (3 g) with ½ cup of Milk/Water.

4.3 Contraindications

Known allergy to bovine colostrum or any of the ingredient of this product.

4.4 Special warnings and precautions for use

• Allergen Information: Product may contain Milk.
• This product shall be given only under medical advice by Physician / Certified Dietician / Nutritionist.
• This product is not to be used as a substitute for a varied diet.
• This product is not intended to diagnose, treat, cure or prevent any disease.

4.5 Drugs interactions

Bovine colostrum is generally well-tolerated, and no significant herb or drug interactions have been widely reported.

However, individuals with a known allergy to cow’s milk should avoid it.

4.6 Use in special populations

General Precautions: Due to the lack of comprehensive studies, it’s generally recommended to be cautious and it’s essential to consult with a healthcare provider before incorporating bovine colostrum into your diet during pregnancy or lactation.

4.7 Effects on ability to drive and use machines

There is no specific evidence to suggest that bovine colostrum has any direct effects on driving ability or use of machines. No effect anticipated.

4.8 Undesirable effects

• Colostrum is a high-protein, low fat and reduced lactose dairy product, as a result lactose-intolerant individuals generally experience no problems and some even report that colostrum helps with their condition. Colostrum used naturally contains low levels of lactose and during processing these are reduced further. If you can drink milk without any problem, then you can probably take colostrum.
• Some individuals may experience a mild gastrointestinal distress or a bloated feeling, which can be avoided by lowering the dose.
• If this reaction continues however then it is best to discontinue the colostrum treatment. However, as with all health supplements, it is always advisable to consult with your doctor in the first instance.

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

• Not to exceed the recommended daily usage.
• Overdosing on bovine colostrum is not well-documented, but taking it in excessive amounts could potentially lead to some side effects. Gastrointestinal Issues: High doses of bovine colostrum might cause nausea, bloating, diarrhea, or other digestive discomforts.
• In case of accidental overdose, contact a Healthcare Professional.

5.1 Pharmacodynamic properties

Bovine colostrum is a nutrient-rich fluid produced by cows in the first few days after giving birth. It’s packed with proteins, antibodies, and growth factors that help newborn calves thrive. For humans, bovine colostrum is often used in supplements due to its potential health benefits, such as boosting immunity, fighting infections, and promoting gut health.

This “early” milk has a nutrient profile and immunological composition significantly different from “mature” milk. In addition to macronutrients found in milk such as protein, carbohydrate, and fat, and micronutrients including vitamins and minerals, BC contain:

–Oligosaccharides,

–Growth factors,

– Antimicrobial compounds, &

– Immune-regulating constituents

either not present in milk or present in substantially lower concentrations.

Colostrum supports the human in two main ways.

1. Its multiple immune factors and natural antibiotics provide strong support for the immune system.

2.Its many growth factors offer a broad- spectrum boost to encourage optimum health and healing.

• The immunoglobulin, growth factors, antibodies play a role in prevention of infection that is in passive immunity.
• The vital nutrients help for tissue development, growth and energy.
• The growth factors present in the colostrum provide a novel treatment option for gastrointestinal conditions.

5.3 Pharmacokinetic properties

• Colostrum survives human GIT & works on mucosal surfaces: Bovine colostrum contains special glycoproteins and protease inhibitors which are extremely effective at protecting the destruction of colostrum’s active components (immunoglobulins and growth factors) by adult human digestive acids pancreatic enzymes and human stomach acids. This allows them to remain active as they pass into the bowel.
• The major benefit of immune factors from colostrum was shown to be their protective activity in the intestine on the walls of the bowel, and bronchials, (mucosal surfaces).
• The preservation of the biological activity of IgG (immunoglobulin) in the digestive secretions of adults receiving bovine immune colostrum orally indicates – passive enteral (intestinal) immunization for the prevention and treatment of acute intestinal diseases.
• Bovine colostrum has been shown to be safe, natural, effective & biologically transferable for human use.

6.1 Animal Toxicology or Pharmacology

Not available

Bovine Colostrum: Universal Donor of Colostrum to Human

• Only bovine colostrum has been shown to be safe, natural, effective & biologically transferable for human use.
• Colostrum is a nontoxic, non-allergenic food supplement that has no negative interactions with drugs, food, or other supplements.
• Bovine colostrum is not a drug: It is a safe, natural, non-allergenic food, taken by humans to treat and heal different conditions
• Help create new levels of vitality & well-being.

8.1 Incompatibilities

Not Applicable

8.2 Shelf-life

Refer on pack

8.3 Packaging information

Pack net weight:90 g Approximately Serving Size: 1 (3 g) No. of servings per pack: 30

8.4 Storage and handing instructions

Store below 30°C.

Protect from moisture.

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

• NOT FOR MEDICINAL USE.
• Not to be used as a substitute for a varied diet.
• Not intended to diagnose, treat, cure or prevent any disease.
• This product shall be given only under medical advice by Physician / Certified Dietician / Nutritionist.
• Not to exceed the recommended daily usage.

25th September 2024

Ferrous ascorbate, Folic Acid, Methylcobalamin and Zinc sulphate

Each Film-coated tablet contains:

Ferrous ascorbate equivalent to Elemental iron 100mg

Folic Acid IP 1.5mg

Methylcobalamin IP 1.5 mg

Zinc sulphate monohydrate eq. 22.5 mg

to Elemental Zinc

Excipients q.s.

Colour: Red Oxide of Iron and Titanium Dioxide IP

Film coated tablet

Ferrous Ascorbate 100 mg, Folic Acid 1.5 mg, Methylcobalamin 1.5 mg, Zinc Sulphate 22.5mg

4.1 Therapeutic indications

For the treatment of iron deficiency anemia.

4.2 Posology and method of administration

Adults

One tablet should be taken once daily by mouth.

Pediatric Population

There is no relevant use of Feronia HP Tablets in the pediatric population.

4.3 Contraindications

• Hypersensitivity to the active substances or any of the excipients.
• Paroxysmal nocturnal hemoglobinuria, hemosiderosis, haemochromatosis, active peptic ulcer, repeated blood transfusion, regional enteritis and ulcerative colitis.
• Feronia HP Tablets must not be used in the treatment of anemias other than those due to iron deficiency.
• Copper deficiency: Zinc may inhibit the absorption of Copper

4.4 Special warnings and precautions for use

CAUTION: Tablets are hygroscopic in nature. Exposure to humid conditions may soften the tablets affecting their appearance and shape. Cutting of strip should be avoided while dispensing/usage.

The label will state “Important warning: Contains Iron. Keep out of reach and sight of children, as overdose may be fatal”.

This will appear on the front of the pack within a rectangle in which there is no other information.

Some post-gastrectomy patients show poor absorption of iron. Care is needed when treating iron deficiency anemia in patients with treated or controlled peptic ulceration. Caution should be exercised when administering folic acid to patients who may have folate dependent tumors.

Since anemia due to combined iron and vitamin B12 or folate deficiencies may be microcytic in type, patients with microcytic anemia resistant to therapy with iron alone should be screened for vitamin B12 or folate deficiency.

Accumulation of zinc may occur in cases of renal failure.

Pregnancy

Safety is not established in pregnant women; therefore Feronia HP is not recommended in pregnancy.

Lactation

Safety is not established in lactating women; therefore Feronia HP is not recommended during lactation.

Pediatric population

Feronia HP Tablets should be kept out of the reach of children.

4.5 Interaction with other medicinal products and other forms of interaction

• Iron reduces the absorption of penicillamine. Iron compounds impair the bioavailability of fluoroquinolones, levodopa, carbidopa, thyroxine and bisphosphonates.
• Absorption of both iron and antibiotic may be reduced if Feronia HP is given with tetracycline.
• Concurrent administration of antacids may reduce absorption of iron. Co- trimoxazole, chloramphenicol, sulphasalazine, aminopterin, methotrexate, pyrimethamine or sulphonamides may interfere with folate metabolism. Serum levels of anticonvulsant drugs may be reduced by administration of folate.
• Oral chloramphenicol delays plasma iron clearance, incorporation of iron into red blood cells and interferes with erythropoiesis.
• Some inhibition of iron absorption may occur if it is taken with cholestyramine, trientine, tea, eggs or milk.
• Administration of oral iron may increase blood pressure in patients receiving methyldopa.
• Coffee may be a factor in reducing iron bioavailability. Neomycin may alter the absorption of iron.
• The absorption of zinc may be reduced by calcium supplements, tetracyclines and phosphorus-containing compounds, agents which increase gastric pH, such as H2 blockers, may decrease zinc absorption while zinc may reduce the absorption of penicillamine, tetracyclines, fluoroquinolones.

Food

Studies of the co-administration of zinc with food performed in healthy volunteers showed that the absorption of zinc was significantly delayed by many foods (including bread, hard boiled eggs, coffee and milk). Substances in food, especially phytates and fibres, bind zinc and prevent it from entering the intestinal cells. However, protein appears to interfere the least.

4.6 Fertility, pregnancy and lactation

Pregnancy

Safety is not established in pregnant women; therefore Feronia HP is not recommended in pregnancy. Breast-feeding Safety is not established in lactating women; therefore Feronia HP is not recommended during lactation. Fertility No fertility data is available.

4.7 Effects on ability to drive and use machines

Feronia HP Tablets has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Very rare (<1/10,000)

Very rare (<1/10,000):

Rarely allergic reactions may occur.

Not known (cannot be estimated from the available data)

Not known: Gastrointestinal disorders Gastro-intestinal discomfort, anorexia, nausea, vomiting, constipation, diarrhea.

Not known: Renal and urinary disorders Darkening of the stools may occur. Blood amylase, lipase and alkaline phosphatase increased

Reporting of suspected adverse reactions

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

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

4.9 Overdose

Symptoms

Symptoms and signs of abdominal pain, vomiting and diarrhea appear within 60 minutes. Cardiovascular collapse with coma may follow. Some improvement may occur after this phase which, in some patients, is followed by recovery. In others, after about 16 hours, deterioration may occur involving diffuse vascular congestion, pulmonary edema, convulsions, anuria, hypothermia, severe shock, metabolic acidosis, coagulation abnormalities and hypoglycemia.

Management

Vomiting should be induced immediately, followed as soon as possible by parenteral injection of desferrioxamine mesylate, and then gastric lavage. In the meantime, it is helpful to give milk and/or 5% sodium bicarbonate solution by mouth.

Dissolve 2g desferrioxamine mesylate in 2 to 3ml of water for injections and give intramuscularly. A solution of 5g desferrioxamine in 50 to 100ml of fluid may be left in the stomach. If desferrioxamine is not available, leave 300ml of 1 % to 5 % sodium bicarbonate in the stomach. Fluid replacement is essential.

Recovery may be complicated by long-term sequelae such as hepatic necrosis, pyloric stenosis or acute toxic encephalitis which may lead to CNS damage.

Treatment of overdose should be with gastric lavage or induced emesis as quickly as possible to remove unabsorbed zinc. Heavy metal chelation therapy should be considered if plasma zinc levels are markedly elevated (> 10 mg/l).

Pediatric population

Acute overdose of oral iron requires emergency treatment. In young children 200-250mg/kg Ferrous Ascorbate is considered to be extremely dangerous.

5.1 Mechanism of Action/ Pharmacodynamic properties

Iron absorption occurs predominantly in the duodenum and upper jejunum. Iron is oxidized to the Fe3+ state no matter its original form when taken in orally. Gastric acidity as well as solubilizing agents such as ascorbate prevent precipitation of the normally insoluble Fe3+. Intestinal mucosal cells in the duodenum and upper jejunum absorb the iron. The iron is coupled to transferrin (Tf) in the circulation which delivers it to the cells of the body. A feedback mechanism exists that enhances iron absorption in people who are iron deficient. In contrast, people with iron overload dampen iron absorption. A number of dietary factors influence iron absorption. Ascorbate increase iron uptake in part by acting as weak chelators to help to solubilize the metal in the duodenum. Iron is readily transferred from these compounds into the mucosal lining cells.

Zinc supplementation improves immunity.

Zinc deficiency also has direct effects on the gastrointestinal tract such as impaired intestinal brush border, increased secretion in response to bacterial enterotoxins and perturbations in intestinal permeability. Zinc supplementation improves the transport of water and electrolytes across the intestinal mucosa in experimental zinc deficiency.

Zinc plays a fundamental role in cellular metabolism and is postulated to modulate host resistance to various infections.

5.2 Pharmacokinetic properties

Absorption

Iron is absorbed chiefly in the duodenum and jejunum. Folic Acid is absorbed mainly from the proximal part of the small intestine.

Distribution

The amounts of Folic Acid absorbed from normal diets are rapidly distributed in body tissues.

Biotransformation

Absorption being aided by the acid secretion of the stomach and being more readily affected when the iron is in the ferrous state.

Folic acid rapidly appears in the blood, where it is extensively bound to plasma proteins.

When larger amounts are absorbed, a high proportion is metabolized in the liver to other active forms of folate and a proportion is stored as reduced and methylated folate.

Elimination

Larger amounts of folate are rapidly excreted in the urine and about 4 to 5 micrograms is excreted in the urine daily.

Zinc is absorbed in the small intestine and its absorption kinetics suggest a tendency to saturation at increasing doses. Fractional zinc absorption is negatively correlated with zinc intake. It ranges from 30 to 60% with usual dietary intake (7-15 mg/d) and decreases to 7% with pharmacological doses of 100 mg/d.

In the blood, about 80% of absorbed zinc is distributed to erythrocytes, with most of the remainder being bound to albumin and other plasma proteins. The liver is the main storage for zinc and hepatic zinc levels are increased during maintenance therapy with zinc. The plasma elimination half-life of zinc in healthy subjects is around 1 hour after a dose of 45 mg. The elimination of zinc results primarily from fecal excretion with relatively little from urine and sweat. The fecal excretion is in the greatest part due to the passage of unabsorbed zinc but it is also due to endogenous intestinal secretion.

This Product (tablet) contains: Ferrous Ascorbate, Folic Acid, Methylcobalamin and Zinc sulphate as active ingredients, for the treatment of iron deficiency anemia.

Ferrous Ascorbate is an iron supplement used to treat or prevent low blood levels of iron (such as those caused by anemia or during pregnancy). Ascorbic acid (vitamin C) improves the absorption of iron from the stomach.

Molecular Formula- C₁₂H₁₄FeO₁₂ Molecular Weight: 406.08g/mol

Folic acid is used to treat anemia caused by folate deficiency. Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby.

Molecular Formula-C₁₉H₁₉N₇O₆

Molecular Weight- 441.4 g/mol

Zinc is an essential trace element for humans, animals, plants and for microorganisms and is necessary for prenatal and postnatal development. Zinc is also an essential nutrient element for coral growth as it is an important cofactor for many enzymes.

Molecular Formula-ZnSO₄

Molecular Weight- 179.47 g/mol

Methylcobalamin a form of vitamin B12.

Methylcobalamin is equivalent physiologically to vitamin B12, and can be used to prevent or treat pathology arising from a lack of vitamin B12 intake. Methylcobalamin is also used in the treatment of peripheral neuropathy, diabetic neuropathy, and as a preliminary treatment for amyotrophic lateral sclerosis.

Molecular formula: C63H91CoN13O14P

Molecular weight: 1344.405 g·mol−1

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

3 blister strips of 10 tablets each

8.4 Storage and handing instructions

Store at a temperature not exceeding 25°C. Protect from light.

Keep out of reach of children.

Patient Counselling Information

• WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor immediately.
• Feronia HP Tablet is given to fulfil your nutritional requirement and to prevent any related diseases.
• Avoid taking antacids 2 hours before or after taking Feronia HP Tablet as they may make it harder for your body to absorb the medicine.
• Let your doctor know if you are taking any other medications like antihypertensive, antibiotics, or medicines for heart disease or bone disorders.

Sept 2024

Ferrous Ascorbate, Folic Acid, Cyanocobalamin, Pyridoxine Hydrochloride & Cholecalciferol Tablets

Each film coated tablet contains:

Ferrous Ascorbate IP

equivalent to Elemental Iron 100 mg

Folic Acid IP 1.5 mg

Cyanocobalamin IP 7.5 mcg

(Vitamin B12)

Pyridoxine Hydrochloride IP 1.5 mg

(Vitamin B6)

Cholecalciferol IP 1000 IU (Vitamin D3) (As stabilized form) Excipients q.s. Colours: Lake of Sunset Yellow,

Lake of Erythrosine & Titanium Dioxide IP

Film coated tablet

Ferrous ascorbate (100mg), Folic Acid (1.5mg), Cyanocobalamin (7.5 mcg), Pyridoxine Hydrochloride (1.5 mg), Cholecalciferol IP (1000 IU)

4.1 Therapeutic indications

Treatment and prevention of anemia with multivitamin deficiency

4.2 Posology and method of administration

Adults

One tablet to be taken daily orally

Pediatric Population

There is no relevant use of Feronia-D3 Tablets in the pediatric population.

4.3 Contraindications

• Hypersensitivity to the active substances or any of the excipients.
• Paroxysmal nocturnal hemoglobinuria, hemosiderosis, haemochromatosis, active peptic ulcer, repeated blood transfusion, regional enteritis and ulcerative colitis.
• Hypercalcaemia and/or hypercalciuria
• Nephrolithiasis (Renal calculi)
• Hypervitaminosis
• Severe renal impairment

4.4 Special warnings and precautions for use

• CAUTION: Tablets are hygroscopic in nature. Exposure to humid conditions may soften the tablets affecting their appearance and shape. Cutting of strip to be avoided while dispensing /usage.
• Important warning: Contains Iron. Keep out of reach and sight of children, as overdose may be fatal.
• Some post-gastrectomy patients show poor absorption of iron. Care is needed when treating iron deficiency anemia in patients with treated or controlled peptic ulceration. Caution should be exercised when administering folic acid to patients who may have folate dependent tumors.
• Since anemia due to combined iron and vitamin B12 or folate deficiencies may be microcytic in type, patients with microcytic anemia resistant to therapy with iron alone should be screened for vitamin B12 or folate deficiency.
• Cholecalciferol should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of Cholecalciferol is not metabolised normally and other forms of vitamin D should be used. Cholecalciferol should not be taken by patients with a tendency to form calcium-containing renal calculi.
• Caution is required in patients receiving treatment for cardiovascular disease

Pediatric population

Feronia D3 Tablets should be kept out of the reach of children.

4.5 Interaction with other medicinal products and other forms of interaction

• Iron reduces the absorption of penicillamine. Iron compounds impair the bioavailability of fluoroquinolones, levodopa, carbidopa, thyroxine and bisphosphonates.
• Absorption of both iron and antibiotic may be reduced if Feronia D3 is given with tetracycline.
• Absorption of both iron and zinc are reduced if taken concomitantly. Concurrent administration of antacids may reduce absorption of iron. Co- trimoxazole, chloramphenicol, sulphasalazine, aminopterin, methotrexate, pyrimethamine or sulphonamides may interfere with folate metabolism. Serum levels of anticonvulsant drugs may be reduced by administration of folate.
• Oral chloramphenicol delays plasma iron clearance, incorporation of iron into red blood cells and interferes with erythropoiesis.
• Patients treated with cardiac glycosides may be susceptible to high calcium levels and should have ECG parameters and calcium levels monitored. It is recommended to reduce the dose or interrupt treatment if the calcium content in the urine exceeds 7.5 mmol/24 hours (300 mg/24 hours).
• Simultaneous administration of benzothiadiazine derivatives (thiazide diuretics) increases the risk of hypercalcaemia because they decrease the calcium excretion in the urine. The calcium levels in plasma and urine should therefore be monitored for patients undergoing long-term treatment.
• If Cholecalciferol is combined with metabolites or analogues of vitamin D careful monitoring of serum calcium levels is recommended.
• Some inhibition of iron absorption may occur if it is taken with cholestyramine, trientine, tea, eggs or milk.
• Administration of oral iron may increase blood pressure in patients receiving methyldopa.
• Coffee may be a factor in reducing iron bioavailability. Neomycin may alter the absorption of iron.
• Anti-convulsants e.g. phenytoin, phenobarbital, primidone may diminish the effect of Cholecalciferol due to hepatic enzyme induction.
• Rifampicin may reduce the effectiveness of Cholecalciferol due to hepatic enzyme induction.
• Isoniazid may reduce the effectiveness of Colecalciferol due to inhibition of the metabolic activation of Colecalciferol.
• Drugs leading to fat malabsorption, e.g. orlistat, liquid paraffin, cholestyramine, may impair the absorption of Cholecalciferol.
• The cytotoxic agent actinomycin and imidazole antifungal agents interfere with vitamin D activity.
• Concomitant use of glucocorticoids can decrease the effect of vitamin D.

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of Feronia D3 Tablets may be considered during pregnancy, if necessary.

The development of anemia despite prophylaxis with Feronia D3 Tablets calls for investigation. During pregnancy women should follow the advice of their medical practitioner as their requirements may vary depending on the severity of their disease and their response to treatment.

Breast-feeding

It is unknown whether Ferrous Ascorbate and Folic Acid / metabolites are excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Cholecalciferol and its metabolites are excreted in breast milk. Overdose in infants induced by nursing mothers has not been observed. However, when prescribing additional vitamin D to a breast-fed child the practitioner should consider the dose of any additional vitamin D given to the mother.

Fertility

No fertility data is available.

4.7 Effects on ability to drive and use machines

Feronia D3 Tablets has no influence on the ability to drive and use machines. Cholecalciferol has no known side effects that are likely to affect the ability to drive and use or operate machines.

4.8 Undesirable effects

Very rare (<1/10,000)

Very rare (<1/10,000): Rarely allergic reactions may occur. Not known (cannot be estimated from the available data) Not known: Gastrointestinal disorders Gastro-intestinal discomfort, anorexia, nausea, vomiting, constipation, diarrhea. Not known: Renal and urinary disorders Darkening of the stools may occur. Rarely Hypercalcemia, Hypercalciuria

Reporting of suspected adverse reactions

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

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

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

4.9 Overdose

Symptoms

Symptoms and signs of abdominal pain, vomiting and diarrhea appear within 60 minutes. Cardiovascular collapse with coma may follow. Some improvement may occur after this phase which, in some patients, is followed by recovery. In others, after about 16 hours, deterioration may occur involving diffuse vascular congestion, pulmonary edema, convulsions, anuria, hypothermia, severe shock, metabolic acidosis, coagulation abnormalities and hypoglycemia.

Acute or chronic overdose of Cholecalciferol can cause hypercalcaemia, an increase in the serum and urinary concentrations of calcium. The symptoms of hypercalcaemia are not very specific and consist of nausea, vomiting, diarrhoea often in the early stages and later constipation, anorexia, fatigue, headache, muscle and joint pain, muscle weakness, polydipsia, polyuria formation of renal calculi, nephrocalcinosis, kidney failure, calcification of soft tissues, changes in ECG measurements, arrhythmias and pancreatitis. In rare and isolated cases there are reports that hypercalcaemia is fatal.

Management

Vomiting should be induced immediately, followed as soon as possible by parenteral injection of desferrioxamine mesylate, and then gastric lavage. In the meantime, it is helpful to give milk and/or 5% sodium bicarbonate solution by mouth.

Dissolve 2g desferrioxamine mesylate in 2 to 3ml of water for injections and give intramuscularly. A solution of 5g desferrioxamine in 50 to 100ml of fluid may be left in the stomach. If desferrioxamine is not available, leave 300ml of 1 % to 5 % sodium bicarbonate in the stomach. Fluid replacement is essential.

Recovery may be complicated by long-term sequelae such as hepatic necrosis, pyloric stenosis or acute toxic encephalitis which may lead to CNS damage.

A normalisation of hypercalcaemia due to vitamin D intoxication lasts several weeks. The recommendation for the treatment of hypercalcaemia is the avoidance of any further administration of vitamin D, including supplements, dietary intakes and the avoidance of sunlight. A low calcium or calcium-free diet can also be considered.

Rehydration and the treatment with diuretics e.g. furosemide to ensure adequate diuresis should be considered. Additional treatment with calcitonin or corticosteroids can also be considered.

Phosphate infusions should not be administered to lower hypercalcaemia of hypervitaminosis D because of the dangers of metastatic calcification.

Pediatric population

Acute overdose of oral iron requires emergency treatment. In young children 200-250mg/kg Ferrous Ascorbate is considered to be extremely dangerous.

5.1 Mechanism of Action/ Pharmacodynamic properties

Iron absorption occurs predominantly in the duodenum and upper jejunum. Iron is oxidized to the Fe3+ state no matter its original form when taken in orally. Gastric acidity as well as solubilizing agents such as ascorbate prevent precipitation of the normally insoluble Fe3+. Intestinal mucosal cells in the duodenum and upper jejunum absorb the iron. The iron is coupled to transferrin (Tf) in the circulation which delivers it to the cells of the body. A feedback mechanism exists that enhances iron absorption in people who are iron deficient. In contrast, people with iron overload dampen iron absorption. A number of dietary factors influence iron absorption. Ascorbate increase iron uptake in part by acting as weak chelators to help to solubilize the metal in the duodenum. Iron is readily transferred from these compounds into the mucosal lining cells.

Cholecalciferol is produced within the skin under the influence of UV radiation including sunlight. In its biologically active form, Cholecalciferol stimulates intestinal calcium absorption, incorporation of calcium into the osteoid, and release of calcium from bone tissue. In the small intestine it promotes rapid and delayed calcium uptake. The passive and active transport of phosphate is also stimulated. In the kidney, it inhibits the excretion of calcium and phosphate by promoting tubular resorption. The production of parathyroid hormone (PTH) in the parathyroids is inhibited directly by the biologically active form of Cholecalciferol. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active Cholecalciferol.

Elimination: Cholecalciferol and other forms of vitamin D are excreted in feces and urine.

• Iron participates in the second activation step of vitamin D, necessary to make this hormone functional.
• This conversion is done by a renal 25-hydroxyvitamin D 1α-hydroxylase (1α-OHase) enzyme which comprises a CYP-450, a ferredoxin, and a ferredoxin reductase.
• Therefore, less available iron could compromise production of the active form of vitamin D.

5.2 Pharmacokinetic properties

Folic Acid is absorbed mainly from the proximal part of the small intestine.

Distribution

The amounts of Folic Acid absorbed from normal diets are rapidly distributed in body tissues.

Biotransformation

Absorption being aided by the acid secretion of the stomach and being more readily affected when the iron is in the ferrous state.

Folic acid rapidly appears in the blood, where it is extensively bound to plasma proteins.

When larger amounts are absorbed, a high proportion is metabolized in the liver to other active forms of folate and a proportion is stored as reduced and methylated folate.

Elimination

Larger amounts of folate are rapidly excreted in the urine and about 4 to 5 micrograms is excreted in the urine daily.

The pharmacokinetics of Cholecalciferol have been widely studied and are well-known. Cholecalciferol from nutritional sources is almost completely absorbed from within the gastro-intestinal tract in the presence of dietary lipids and bile acids. Cholecalciferol is stored in fat cells and its biological half-life is approximately 50 days.

Cholecalciferol is metabolised by microsomal hydroxylase to form 25-hydroxycolecalciferol (25(OH)D3, calcidiol), the primary storage form of vitamin D3. 25(OH)D3 undergoes a secondary hydroxylation within the kidney to form the predominant active metabolite 1,25-hydroxycolecalciferol (1,25(OH)2D3, calcitriol). The metabolites circulate in the blood bound to a specific α -globin.

After a single oral dose of Cholecalciferol, the maximum serum concentrations of the primary storage form are reached after approximately 7 days. 25(OH)D3 is then slowly eliminated with an apparent half-life in serum of about 50 days. Cholecalciferol and its metabolites are excreted mainly in the bile and feces.

After high doses of Cholecalciferol, serum concentrations of 25(OH)D3 may be increased for months. Overdose-induced hypercalcemia may persist for weeks

This Product (tablet) contains: Ferrous Ascorbate, Folic Acid Cyanocobalamin, Pyridoxine and Cholecalciferol as active ingredients, for the treatment and prevention of Anemia with multivitamin deficiency.

Ferrous Ascorbate is an iron supplement used to treat or prevent low blood levels of iron (such as those caused by anemia or during pregnancy). Ascorbic acid (vitamin C) improves the absorption of iron from the stomach.

Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal bone mineralization and to prevent hypocalcemic tetany.

Folic acid is used to treat anemia caused by folate deficiency. Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby.

Molecular Formula-C₁₉H₁₉N₇O₆

Molecular Weight- 441.4 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

3 Blister strips of 10 tablets each

8.4 Storage and handing instructions

Store in a cool & dry place. Protect from moisture. Protect from light. Keep out of reach of children.

• WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor immediately.
• Feronia -D3 Tablet is given to fulfill your nutritional requirement and to prevent any related diseases.
• Avoid taking antacids 2 hours before or after taking Feronia-D3 Tablet as they may make it harder for your body to absorb the medicine.
• Let your doctor know if you are taking any other medications like antihypertensive, antibiotics, or medicines for heart disease or bone disorders.

25^th Sept 2024

Efonidipine Hydrochloride Ethanolate Tablets 10 mg / 20 mg / 40 mg

EFNOCAR-10

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 10 mg

Excipients q.s.

Colour: Titanium Dioxide IP

EFNOCAR-20

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 20 mg

Excipients q.s.

Colour: Titanium Dioxide IP

EFNOCAR-40

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 40 mg

Excipients q.s.

Colour: Titanium Dioxide IP

Film coated tablet

10/ 20/40 mg

4.1 Therapeutic Indication

Efonidipine is indicated for the management of

• Essential hypertension and renal parenchymal hypertension
• Angina

4.2 Posology and method of administration

Adults

• Essential hypertension and renal parenchymal hypertension: 20-40 mg orally once daily. A dose of up to 80 mg/day has been reported to be safe and effective in clinical trials.
• Angina: 40 mg/day.

Elderly

Efonidipine should be started with a low dose (20mg/day) and the patient's condition should be monitored. The dose should be halved in case the patient is intolerant to the higher dose.

In Children

Efonidipine is not recommended in infants and children as safety is not established in this group of patients.

4.3 Contraindications

• In patients with known hypersensitivity to Efonidipine or any other component of the formulation
• In pregnant women

4.4 Special warnings and precautions for use

• Should be administered with caution in patients with hepatic impairment.
• Should be administered with caution in patients with low BP and/or sinus node dysfunction.
• The drug should be withdrawn gradually to prevent rebound hypertension or worsening of angina.
• Administration of the drug may cause hypotension. Under such circumstances appropriate measures should be taken to either reduce the dose or withdraw the drug.
• Should not be taken with grapefruit juice as there may be excessive lowering of blood pressure.
• Dizziness may occur while taking antihypertensive agents. Hence, working on aerial platform, working with dangerous machinery and/or driving should be avoided.
• To be sold by retail on the prescription of Cardiologist / Nephrologist / Endocrinologist and Specialist in General / Internal medicine / Critical Care medicine only.

4.5 Drugs interactions

Concomitant administration of other antihypertensive agent/s may enhance the antihypertensive effect of efonidipine.

• Administration of calcium channel blockers (CCBs) with Cimetidine may cause elevated levels of CCBs.
• Increased levels of CCBs observed when taken concomitantly with grapefruit juice which may result in excessive lowering of blood pressure.
• Efonidipine when taken along with Tacrolimus may cause increased blood levels of Tacrolimus.

4.6 Use in special populations

Pregnancy

Efonidipine should not be administered in pregnant women.

Nursing Mothers

Efonidipine should not be administered in lactating women.

4.7 Effects on ability to drive and use machines

If patients taking Efonidipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

4.8 Undesirable effects

The common side effects are hot flushes, palpitations, facial flushing and headache. In addition, elevation in serum total cholesterol, ALT (SGPT), AST (SGOT) and BUN may occur.

Tabulated list of adverse reactions

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions

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

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

4.9 Overdose

In humans, experience with intentional overdose is limited. The stomach should be emptied by aspiration and gastric lavage if the patient reports immediately or up to two hours after overdosage.

Clinically significant hypotension due to Efonidipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

5.1 Mechanism of Action

Efonidipine, a new generation dihydropyridine (DHP) calcium channel blocker, inhibits both L-type and T-type calcium channels.

5.2 Pharmacodynamic properties

• Efonidipine exhibits antihypertensive effect through vasodilatation by blocking L-type and T-type calcium channels.
• Efonidipine has a negative chronotropic effect. Working on sino atrial node cells by inhibiting T-type calcium channel activation, Efonidipine prolongs the late phase-4 depolarization of the sino atrial node action potential and suppresses an elevated HR. The negative chronotropic effect of Efonidipine decreases heart rate, myocardial oxygen demand and increases coronary blood flow.
• Efonidipine increases coronary blood flow by blocking L & T-type calcium channels and attenuates myocardial ischaemia.
• By reducing synthesis and secretion of aldosterone, Efonidipine prevents hypertrophy and remodeling of cardiac myocytes.
• Efonidipine increases glomerular filtration rate without increasing intra-glomerular pressure and filtration fraction. This prevents hypertension induced renal damage.
• Efonidipine prevents Rho-kinase and NF-kB induced renal parenchymal fibrosis and provides long term renal protection.
• Efonidipine suppresses renin secretion from the Juxta Glomerular apparatus in the kidneys. •Efonidipine enhances sodium excretion from the kidneys by suppressing aldosterone synthesis and secretion from the adrenal glands. Aldosterone induced renal parenchymal fibrosis is suppressed by Efonidipine. •Efonidipine prevents NF-kB induced hypertrophy and inflammation in the renal vasculature and protects the kidneys.
• Efonidipine protects against endothelial dysfunction due to its anti-oxidant activity and by restoring nitric oxide bioavailability.
• Efonidipine has anti-atherogenic activity and protects the blood vessels from atherosclerosis.
• Efonidipine lowers blood pressure in cerebral resistance vessels and prevents hypertension induced brain damage.

5.3 Pharmacokinetic properties

Absorption

Peak plasma concentration is achieved in about 1.5 to 3.67 hours after administration. The bioavailability of Efonidipine is ~25% and half-life is approximately 4 hours.

Efonidipine 40mg when administered to healthy volunteers under fasting conditions shows the following pharmacokinetic profile:

The dissociation constant of Efonidipine from dihydropyridine receptors is very low (0.0042/min/nM), signifying very slow dissociation from the receptors. This explains the long duration of action of Efonidipine.

Metabolism

Efonidipine is primarily metabolized in the liver. The important metabolites are N-dephenylated Efonidipine (DPH), deaminated Efonidipine (AL) and N-debenzylated Efonidipine (DBZ). DBZ and DPH exhibit activity as calcium antagonists. The vasodilating properties of DBZ and DPH were about two-thirds and one-third respectively than that of the parent compound. Results suggest that the majority of the pharmacological effect after oral dosing of Efonidipine hydrochloride in man is due to unchanged compound and its metabolites make a small contribution to the pharmacological effect.

Elimination

Biliary route is the main pathway of excretion. No significant amount of unchanged drug is excreted in urine. In the urine collected for 24 h after an oral dosing, 1.1% of the dose was excreted as deaminated Efonidipine, and 0.5% as a pyridine analogue of deaminated Efonidipine.

6.1 Animal Toxicology or Pharmacology

The acute toxicology of efonidipine was studied in male and female mice, rats, and dogs following oral or intravenous administration. The intravenous LD, values in male mice and rats were 77 and 51 mg/kg, respectively. The oral LD, values for efonidipine in mice, rats, and dogs were higher than 1,500 mag. The signs of toxicity observed in mice and rats were depression of spontaneous movement, hypothermia, sedation, piloerection, lying, gasping, and clonic convulsion. The dogs developed mild diarrhea, soft stools, or a temporary decrease in food consumption.

A 13-week oral subacute toxicity study of efonidipine was performed in male or female rats and dogs. Increases in water consumption and urine volume were observed in male and female rats receiving efonidipine at 300 mg/kg/day. Urinalysis revealed a high concentration of Na+ and C1- in the rats receiving 100 or 300 mg/kg/day. Organ weight measurement revealed an increase in liver and heart weight in male animals receiving 10 mg/kg/day or more and in female animals receiving 30 mg/kg/day or more.

Thus, in this study, the noneffective dose level was 3 mg/kg/day in rats. The effects observed at 300 or 100 mg/kg/day in groups of male or female dogs included reversible hyperemia of the sclera. Pathological examination revealed a dose-induced increase in the absolute and relative heart weight in female dogs treated with the drug at 100 mg/kg/day or more. Thus, the maximum noneffective dose of efonidipine in dogs of either sex was estimated to be around 30 mg/kg/day.

An oral chronic toxicity study of efonidipine was carried out in rats and dogs. Efonidipine was administered to rats at a daily dose of 1.5, 7, or 30 mg/kg for one year.

Organ weight measurement revealed an increase or a tendency of increase in heart weight in male or female rats receiving 30 mg/kg/day. A decreased thyroid weight in the males and an elevated liver weight in the females were found in the 30 mg/kg/day group.

Therefore, the noneffective estimated oral dose of efonidipine in rats was 7 mg/kg/day. Efonidipine in a gelatin capsule containing 2.0, 6.5, or 20 mg/kg/day was administered to dogs once daily for one year. The estimated effective dose was ca 20 mg/kg/day and the noneffective dose was ca 6.5 mg/kg/day

Efonidipine is a novel dihydropyridine calcium channel blocker having anti-hypertensive and anti-anginal properties.

Chemical name: (±) -2 - [benzyl (phenyl) amino] ethyl 1, 4-dihydro-2 ,6-dimethyl- 5-(5,5-dimethyl-2-oxo-1 ,3,2-dioxaphosphorinan-2-yl) -4 - (3-nitrophenyl) -3-pyridinecarboxylate hydrochloride ethanol.

Molecular formula: C34H38 N3O7P • HCl •C2H6O

Molecular mass: 714.18 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 Blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store below 25°C. Protected from light & moisture.
• Keep out of reach of children.

Efnocar is a type of medicine known as a calcium channel blocker (CCB). It is used to treat high blood pressure (hypertension) and a type of chest pain called angina. It can be used by itself or with other medicines to treat these conditions. Do not use Efnocar if you are allergic to efonidipine (the active ingredient in Efnocar), or to the inactive ingredients.

Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies. Tell your doctor if you:

• ever had heart disease
• ever had liver problems
• are pregnant, or plan to become pregnant.
• are breast-feeding. Do not breast-feed while taking Efnocar.

You can stop breast-feeding or take a different medicine.

It may be easier to take your dose if you do it at the same time every day, such as with breakfast or dinner, or at bedtime.

While you are taking Efnocar do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor.

09/10/2024

Efonidipine Hydrochloride Ethanolate Tablets 10 mg / 20 mg / 40 mg

EFNOCAR-10

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 10 mg

Excipients q.s.

Colour: Titanium Dioxide IP

EFNOCAR-20

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 20 mg

Excipients q.s.

Colour: Titanium Dioxide IP

EFNOCAR-40

Each film coated tablet contains:

Efonidipine Hydrochloride Ethanolate 40 mg

Excipients q.s.

Colour: Titanium Dioxide IP

Film coated tablet

10/ 20/40 mg

4.1 Therapeutic Indication

Efonidipine is indicated for the management of

• Essential hypertension and renal parenchymal hypertension
• Angina

4.2 Posology and method of administration

Adults

• Essential hypertension and renal parenchymal hypertension: 20-40 mg orally once daily. A dose of up to 80 mg/day has been reported to be safe and effective in clinical trials.
• Angina: 40 mg/day.

Elderly

Efonidipine should be started with a low dose (20mg/day) and the patient's condition should be monitored. The dose should be halved in case the patient is intolerant to the higher dose.

In Children

Efonidipine is not recommended in infants and children as safety is not established in this group of patients.

4.3 Contraindications

• In patients with known hypersensitivity to Efonidipine or any other component of the formulation
• In pregnant women

4.4 Special warnings and precautions for use

• Should be administered with caution in patients with hepatic impairment.
• Should be administered with caution in patients with low BP and/or sinus node dysfunction.
• The drug should be withdrawn gradually to prevent rebound hypertension or worsening of angina.
• Administration of the drug may cause hypotension. Under such circumstances appropriate measures should be taken to either reduce the dose or withdraw the drug.
• Should not be taken with grapefruit juice as there may be excessive lowering of blood pressure.
• Dizziness may occur while taking antihypertensive agents. Hence, working on aerial platform, working with dangerous machinery and/or driving should be avoided.
• To be sold by retail on the prescription of Cardiologist / Nephrologist / Endocrinologist and Specialist in General / Internal medicine / Critical Care medicine only.

4.5 Drugs interactions

Concomitant administration of other antihypertensive agent/s may enhance the antihypertensive effect of efonidipine.

• Administration of calcium channel blockers (CCBs) with Cimetidine may cause elevated levels of CCBs.
• Increased levels of CCBs observed when taken concomitantly with grapefruit juice which may result in excessive lowering of blood pressure.
• Efonidipine when taken along with Tacrolimus may cause increased blood levels of Tacrolimus.

4.6 Use in special populations

Pregnancy

Efonidipine should not be administered in pregnant women.

Nursing Mothers

Efonidipine should not be administered in lactating women.

4.7 Effects on ability to drive and use machines

If patients taking Efonidipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

4.8 Undesirable effects

The common side effects are hot flushes, palpitations, facial flushing and headache. In addition, elevation in serum total cholesterol, ALT (SGPT), AST (SGOT) and BUN may occur.

Tabulated list of adverse reactions

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions

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

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

4.9 Overdose

In humans, experience with intentional overdose is limited. The stomach should be emptied by aspiration and gastric lavage if the patient reports immediately or up to two hours after overdosage.

Clinically significant hypotension due to Efonidipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

5.1 Mechanism of Action

Efonidipine, a new generation dihydropyridine (DHP) calcium channel blocker, inhibits both L-type and T-type calcium channels.

5.2 Pharmacodynamic properties

• Efonidipine exhibits antihypertensive effect through vasodilatation by blocking L-type and T-type calcium channels.
• Efonidipine has a negative chronotropic effect. Working on sino atrial node cells by inhibiting T-type calcium channel activation, Efonidipine prolongs the late phase-4 depolarization of the sino atrial node action potential and suppresses an elevated HR. The negative chronotropic effect of Efonidipine decreases heart rate, myocardial oxygen demand and increases coronary blood flow.
• Efonidipine increases coronary blood flow by blocking L & T-type calcium channels and attenuates myocardial ischaemia.
• By reducing synthesis and secretion of aldosterone, Efonidipine prevents hypertrophy and remodeling of cardiac myocytes.
• Efonidipine increases glomerular filtration rate without increasing intra-glomerular pressure and filtration fraction. This prevents hypertension induced renal damage.
• Efonidipine prevents Rho-kinase and NF-kB induced renal parenchymal fibrosis and provides long term renal protection.
• Efonidipine suppresses renin secretion from the Juxta Glomerular apparatus in the kidneys. •Efonidipine enhances sodium excretion from the kidneys by suppressing aldosterone synthesis and secretion from the adrenal glands. Aldosterone induced renal parenchymal fibrosis is suppressed by Efonidipine. •Efonidipine prevents NF-kB induced hypertrophy and inflammation in the renal vasculature and protects the kidneys.
• Efonidipine protects against endothelial dysfunction due to its anti-oxidant activity and by restoring nitric oxide bioavailability.
• Efonidipine has anti-atherogenic activity and protects the blood vessels from atherosclerosis.
• Efonidipine lowers blood pressure in cerebral resistance vessels and prevents hypertension induced brain damage.

5.3 Pharmacokinetic properties

Absorption

Peak plasma concentration is achieved in about 1.5 to 3.67 hours after administration. The bioavailability of Efonidipine is ~25% and half-life is approximately 4 hours.

Efonidipine 40mg when administered to healthy volunteers under fasting conditions shows the following pharmacokinetic profile:

The dissociation constant of Efonidipine from dihydropyridine receptors is very low (0.0042/min/nM), signifying very slow dissociation from the receptors. This explains the long duration of action of Efonidipine.

Metabolism

Efonidipine is primarily metabolized in the liver. The important metabolites are N-dephenylated Efonidipine (DPH), deaminated Efonidipine (AL) and N-debenzylated Efonidipine (DBZ). DBZ and DPH exhibit activity as calcium antagonists. The vasodilating properties of DBZ and DPH were about two-thirds and one-third respectively than that of the parent compound. Results suggest that the majority of the pharmacological effect after oral dosing of Efonidipine hydrochloride in man is due to unchanged compound and its metabolites make a small contribution to the pharmacological effect.

Elimination

Biliary route is the main pathway of excretion. No significant amount of unchanged drug is excreted in urine. In the urine collected for 24 h after an oral dosing, 1.1% of the dose was excreted as deaminated Efonidipine, and 0.5% as a pyridine analogue of deaminated Efonidipine.

6.1 Animal Toxicology or Pharmacology

The acute toxicology of efonidipine was studied in male and female mice, rats, and dogs following oral or intravenous administration. The intravenous LD, values in male mice and rats were 77 and 51 mg/kg, respectively. The oral LD, values for efonidipine in mice, rats, and dogs were higher than 1,500 mag. The signs of toxicity observed in mice and rats were depression of spontaneous movement, hypothermia, sedation, piloerection, lying, gasping, and clonic convulsion. The dogs developed mild diarrhea, soft stools, or a temporary decrease in food consumption.

A 13-week oral subacute toxicity study of efonidipine was performed in male or female rats and dogs. Increases in water consumption and urine volume were observed in male and female rats receiving efonidipine at 300 mg/kg/day. Urinalysis revealed a high concentration of Na+ and C1- in the rats receiving 100 or 300 mg/kg/day. Organ weight measurement revealed an increase in liver and heart weight in male animals receiving 10 mg/kg/day or more and in female animals receiving 30 mg/kg/day or more.

Thus, in this study, the noneffective dose level was 3 mg/kg/day in rats. The effects observed at 300 or 100 mg/kg/day in groups of male or female dogs included reversible hyperemia of the sclera. Pathological examination revealed a dose-induced increase in the absolute and relative heart weight in female dogs treated with the drug at 100 mg/kg/day or more. Thus, the maximum noneffective dose of efonidipine in dogs of either sex was estimated to be around 30 mg/kg/day.

An oral chronic toxicity study of efonidipine was carried out in rats and dogs. Efonidipine was administered to rats at a daily dose of 1.5, 7, or 30 mg/kg for one year.

Organ weight measurement revealed an increase or a tendency of increase in heart weight in male or female rats receiving 30 mg/kg/day. A decreased thyroid weight in the males and an elevated liver weight in the females were found in the 30 mg/kg/day group.

Therefore, the noneffective estimated oral dose of efonidipine in rats was 7 mg/kg/day. Efonidipine in a gelatin capsule containing 2.0, 6.5, or 20 mg/kg/day was administered to dogs once daily for one year. The estimated effective dose was ca 20 mg/kg/day and the noneffective dose was ca 6.5 mg/kg/day

Efonidipine is a novel dihydropyridine calcium channel blocker having anti-hypertensive and anti-anginal properties.

Chemical name: (±) -2 - [benzyl (phenyl) amino] ethyl 1, 4-dihydro-2 ,6-dimethyl- 5-(5,5-dimethyl-2-oxo-1 ,3,2-dioxaphosphorinan-2-yl) -4 - (3-nitrophenyl) -3-pyridinecarboxylate hydrochloride ethanol.

Molecular formula: C34H38 N3O7P • HCl •C2H6O

Molecular mass: 714.18 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on pack

8.3 Packaging information

10 Blister strips of 10 tablets each

8.4 Storage and handing instructions

• Store below 25°C. Protected from light & moisture.
• Keep out of reach of children.

Efnocar is a type of medicine known as a calcium channel blocker (CCB). It is used to treat high blood pressure (hypertension) and a type of chest pain called angina. It can be used by itself or with other medicines to treat these conditions. Do not use Efnocar if you are allergic to efonidipine (the active ingredient in Efnocar), or to the inactive ingredients.

Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies. Tell your doctor if you:

• ever had heart disease
• ever had liver problems
• are pregnant, or plan to become pregnant.
• are breast-feeding. Do not breast-feed while taking Efnocar.

You can stop breast-feeding or take a different medicine.

It may be easier to take your dose if you do it at the same time every day, such as with breakfast or dinner, or at bedtime.

While you are taking Efnocar do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor.

09/10/2024

Calcium Fructoborate Capsules

Each serving per capsule contains:

Calcium Fructoborate equivalent to elemental Boron 6 mg

Ingredients:

Calcium Fructoborate, Bulking Agent [INS 460 (i)], Anticaking Agent [INS 553 (iii)], Antisticking Agent [INS 470 (i)], Ingredient of capsule shell [INS 464], Synthetic food colour [INS 102] & [INS 171]

Nutritional Information

* % RDA calculated as per ICMR Guidelines, 2020 for sedentary work men.

** % RDA values calculated as per FSSAI Labeling and Display Regulation 2020 for average adult.

# % RDA not established.

Capsule

6 mg (elemental Boron)

BoroflexTM is a Natural-identical form Calcium Fructoborate

100% Vegan and non-genetically modified (Non-GMO)

4.1 Therapeutic indication

Helps for bone and joint health.

4.2 Posology and method of administration

NUTRACEUTICAL

Target Consumer Group: Adults

Recommended usage: One capsule twice a day

Not to exceed the recommended daily dose.

Capsule should be swallowed whole & not to be opened, chewed or crushed.

4.3 Contraindications

Don't take this preparation if you are allergic to it or any ingredients contained in this preparation.

4.4 Special warnings and precautions for use

• It is Nutraceutical and Not for Medicinal Use.
• Allergen Information: Allergen free.
• This product is not intended to diagnose, treat, cure or prevent any disease.
• This product is not to be used as a substitute for a varied diet.

4.5 Drugs interactions

Boron is not known to have any clinically relevant interactions with medications.

• Fructoborates have positive synergic interactions with calcium, magnesium, zinc, iron, and copper.
• The amount of fructoborate should be increased when the amount of iodine, fluoride, and silicon from the body increases as well.
• Antagonism: Fructoborates are antagonized by silicon as orthosilicic acid, by iodine, and by fluoride.

4.6 Use in special populations

Pregnant / lactating women, children & people with medical conditions should consult a Healthcare Professional before use.

4.7 Effects on ability to drive and use machines

No effect anticipated. There isn’t specific research directly linking boron supplementation to driving performance.

4.8 Undesirable effects

Generally recognized as safe (GRAS certified) by United States Food and Drug Administration (FDA). Generally well-tolerated; possible mild side effects include gastrointestinal discomfort, headaches, or skin reactions.

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.

5.1 Pharmacodynamic properties

Boron is a trace element found in various foods and available as a dietary supplement. It plays essential roles in the metabolism of plants, animals, and humans, and recent research suggests it may have been significant for the evolution of life on Earth. The World Health Organization recognizes boron as "probably essential" for humans. In food and beverages, boron appears as inorganic borates or as mono- or di-sugar-borate esters, such as calcium fructoborate.

Calcium fructoborate (CaFB) is a plant-based boron compound that enters cells via sugar transporters (GLUTs), facilitating the absorption of fructoboric acid. It acts as a catalyst for CO2 hydration, enhancing buffering capacity at physiological pH. CaFB modulates various cell signaling pathways, influencing inflammatory mediators and transcription factors, and exhibits antioxidant properties by reducing reactive oxygen species (ROS). Compared to traditional boric acid, CaFB has more complex mechanisms of action, including the formation of sugar borate esters (SBEs) that interact with key amino acids. SBEs are considered conditionally essential nutrients, potentially influencing metabolic processes and disorders like arthritis and diabetes. Additionally, CaFB demonstrates anti-inflammatory effects by regulating cytokine production and lowering inflammatory markers. Importantly, it exists as a non-toxic boron reservoir, allowing safe biological activity inside and outside cells. Overall, CaFB's diverse mechanisms distinguish it from conventional boron compounds.

5.2 Boron and Bone Health

Clinical studies suggest that boron may help reduce osteoarthritis symptoms by inhibiting inflammation. It plays a crucial role in bone growth and formation, potentially influencing osteoblast and osteoclast activity, serum steroid hormone levels, and calcium metabolism. Boron deficiency has been linked to abnormal limb development, delayed growth plate maturation, and decreased bone strength. Supplementation has shown to improve bone strength measures in animal studies.

Boron and Calcium Metabolism: Research indicates that boron deprivation leads to increased urinary excretion of calcium and magnesium and decreased levels of key hormones in postmenopausal women. Boron may positively influence calcium and vitamin D metabolism, reducing the risk of osteoporosis. A study found that 6 mg of boron supplementation per day for 60 days raised serum vitamin D levels by about 20% in vitamin D-deficient subjects. Additionally, a trial with female athletes and sedentary women showed that 3 mg/day of boron for 10 months reduced serum phosphorus and increased magnesium levels, potentially enhancing bone mineral density.

Boron and Arthritis: Lower boron intake has been associated with higher rates of arthritis. Studies have shown a negative correlation between soil boron levels and arthritis incidence. In areas with daily boron intakes of 1.0 mg or less, arthritis rates range from 20% to 70%, while in areas with 3–10 mg intake, rates drop to 0%–10%. A double-blind study indicated that 6 mg/day of boron significantly improved joint conditions and reduced pain in osteoarthritis patients after 8 weeks of supplementation compared to a placebo.

Stimulates Osteogenesis: Promotes osteoblast differentiation and reduces superoxide formation. Boosts testosterone, increases muscle mass, improves calcium absorption, and maintains bone density. Enhances the bioavailability of sex hormones and Vitamin D. Anti-oxidant Action: Acts as an anti-inflammatory by inhibiting oxidative bursts and improving free radical scavenging. Inhibits collagenase enzymes, protecting skin, joints, and bones.

Safety and Efficacy: Improves osteoarthritis symptoms and reduces inflammatory markers. Reduces knee discomfort and improves joint flexibility. Improves inflammatory and cardiovascular biomarkers. It reduces the use of painkillers.

Overall, boron appears to play a beneficial role in bone health, calcium metabolism, and potentially in reducing arthritis symptoms.

5.3 Pharmacokinetic properties

Absorption

Boroflex is water soluble and highly bioavailable. Most ingested boron is hydrolyzed to boric acid within the gastrointestinal tract. Fructoborates are absorbed in the small intestine. The body absorbs about 85%–90% of ingested boron.

Our bodies have no capability to synthesize them from fructose and boric acid. Studies have shown that Calcium Fructoborate (CaFB) absorbed from the gastrointestinal tract to the bloodstream in an intact form and time-dependent manner. Study results show that CaFB can be detected intact in blood following oral administration. Thus, it has been confirmed that CaFB could:

(a) have a distinct purpose and bioactivity of its own or

(b) serve as a controlled-release supply of Boron that does not convert back to Boric acid in tissues and blood

Some studies have identified three types of B-containing molecules of CaFB in aqueous solutions (the speciation of fructoborates is highlighted in Fig. 2): Free Boric Acid (5%), Diester (85%) and Monoester complex (10 %).

Figure: FBE speciation in the human metabolism

Subsequently, Fructoborate species may possess a biological role such as functioning as a coenzyme or cofactor (Fig.).

Metabolism of Fructoborates in enzymatic system

The biological and clinical benefits observed thus far for CaFB suggest that B-containing sugars are indeed unique and extraordinary participants in the realm of B-containing molecules. Studies have shown that CaFB is a good adjuvant in the treatment of osteoporosis, possibly the best in dietetic prevention of osteoporosis based on the large study group.

Storage

Fructoborates have been found in mice bone, heart, brain, liver, and muscle.

Excretion

In animal metabolism (mice), fructoborates are metabolized initially in fructoboric acid and then in boric acid and excreted mainly through urine.

6.1 Animal Toxicology or Pharmacology

Not available

Calcium fructoborate is a natural identical product with molecular composition Ca[(C₆H₁₀O₆)2B]2°4H₂O, identical with the calcium fructoborate molecule found in nature.

Sugar–borates (SBs) are mono- or di-sugar–borate esters (SBEs) comprised of one or two monosaccharide molecules linked to a boron (B) atom.

Using liquid- and solid-state 11B and 13C nuclear magnetic resonance (NMR) spectroscopy, the fructoborate anion structure was defined (figure-1).

Fructoborate anion structure

Three basic types of boron-containing molecules are found in aqueous solutions of Boroflex: free boric acid, the diester complex, and the monoester complex. The relative molar concentrations of these 3 types of boron-containing molecules were found to be approx. 5%, 85%, and 10 %, respectively.

8.1 Incompatibilities

None

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

1 Blister strip of 10 capsules

1 x 10 N Capsules

8.4 Storage and handing instructions

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

Keep out of reach of children

• Pregnant or nursing mothers, children, and people with medical conditions must consult a physician before taking this supplement
• Generally well-tolerated; possible mild side effects include gastrointestinal discomfort, headaches, or skin reactions.
• Long-term high doses may lead to toxicity, so adherence to recommended doses is crucial.
• Inform your healthcare provider about any medications or supplements you are currently taking, as CaFB may interact with certain drugs, especially those affecting bone health or hormone levels.
• Regular follow-up appointments with your healthcare provider are recommended to assess your response to the supplement and make necessary adjustments.
• Keep track of any changes in your symptoms, especially concerning bone and joint health.

27^th September 2024

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.