Ranferon 12 Iron With Vitamins and Minerals Capsules

Ranferon®-12
(Iron with Vitamins and Minerals Capsules)

 

COMPOSITION

RANFERON 12 Capsules

Each Capsule contains:

Ferrous Fumarate BP 305 mg

(equivalent to 100 mg of elemental iron)

FoIic Acid BP 0.75 mg

Cyanocobalamin USP 5 mcg

Ascorbic Acid USP 75.0mg

Zinc Sulphate BP 5.0 mg

 

DESCRIPTION

RANFERON-12 Capsule formulation contains Ferrous fumarate, Folic Acid, Ascorbic acid, Cyanocobalamin (Vitamin B12) and Zinc Sulphate in concentrations required for therapeutic efficacy while at the same time offering a good tolerability profile.

 

PHARMACOLOGY

Medical Rational7

Nutritional anaemia is a world wide problem with the highest prevalence in developing countries. It is found especially among women of child bearing age, young children, during pregnancy and lactation and in the elderly. Nutritional anaemia is estimated to affect nearly two thirds of pregnant and one half of non pregnant women in developing countries. By far the most frequent cause of nutritional anaemia iron deficiency and less frequently, folate or vitamin B12 deficiency.

 

Pharmacodynamics1,2,4,5

Iron plays an essential role in oxygen transport (in haemoglobin) and oxidative metabolism, as well as various other metabolic processes. The iron content of body is normally kept constant by regulation of the amount absorbed to balance the amount lost.

If loss of iron from the body is increased and/or intake is inadequate, a negative iron balance may lead by degrees to depletion of body iron stores, iron deficiency and eventually to anaemia. Prophylactic iron supplements are required in pregnancy, menorrhagia, after gastrectomy and in the management of low birth weight infants.

Folic acid and cyanocobalamin are members of the vitamin B group with an essential role in various metabolic pathways. Their deficiency may lead to megaloblastic anaemias and severe neurological damage. Folic acid is essential in pregnant woman to protect against neural tube defects in the offspring.

Zinc is necessary for the proper functioning of over 200 metalloenzymes, including carbonic anhydrase, carboxypeptidase A, alcohol dehydrogenase, alkaline phosphatase, and RNA polymerase. It is also required to maintain structure in nucleic acids, proteins, and cell membranes. Physiological functions that are zinc dependent include cell growth and division, sexual maturation and reproduction, dark adaptation and night vision, wound healing, host immunity, taste acuity, and possibly olfactory acuity.

Ascorbic acid is a source of vitamin C, which may be beneficial during infection when vitamin C levels are believed to fall.

 

Pharmacokinetics2,6

Iron is irregularly and incompletely absorbed from the gastrointestinal tract, the main sites of absorption being the duodenum and jejunum. Maximum absorption is achieved when oral iron is administered on an empty stomach. The absorption of iron is enhanced in iron deficiency states. Only about 5 to 15 % of the iron ingested in food is normally absorbed.

Following absorption, the majority of iron is bound to transferrin and transported to the bone marrow where it is incorporated into haemoglobin; the remainder is contained within the storage forms, ferritin, haemosiderin or myoglobin, with smaller amounts occurring in haem-containing enzymes or in plasma bound to transferrin. Only a very small amount of iron is excreted, as the majority of the iron released after the destruction of haemoglobin molecule is recycled.

Folic acid is rapidly, absorbed mainly from the gastrointestinal tract, mainly from the duodenum and jejunum. Dietary folates are stated to have about half the bioavailability of crystalline folic acid. The naturally occurring folate polyglutmates are largely deconjugated and reduced by dihydrofolate reductase in the intestines to form 5-methyltetrahydrofolate, which appears in the portal circulation, where it is extensively bound to plasma proteins. Folic acid given therapeutically enters the portal circulation largely unchanged, since it is a poor substrate for reduction by dihydrofolate reductase.

It is converted to the metabolically active form 5-methyltetrahydrofolate in the plasma and liver. The principal storage site is the liver; it is also actively concentrated in the cerebrospinal fluid. Folate undergoes enterohepatic circulation. Folate metabolites are eliminated in the urine and folate in excess of body requirements is excreted unchanged in the urine. Folate is distributed into breast milk. Folic acid is removed by haemodialysis.

Cyanocobalamin binds to intrinsic factor, a glycoprotein secreted by the gastric mucosa and is then actively absorbed from gastrointestinal tract. Absorption is impaired in patients with an absence of intrinsic factor, with a malabsorption syndrome or with disease or abnormality of the gut or after gastrectomy. Absorption from the gastrointestinal tract can also occur by passive diffusion; little of the vitamin present in food is absorbed in this manner although the process becomes increasingly important with larger amounts such as those used therapeutically.

Cyanocobalamin is extensively bound to specific plasma proteins (transcobalamines). Cyanocobalamin is stored in the liver, excreted in the bile and undergoes extensive enterohepatic recycling. Part of an administered dose is excreted in urine.

Cyanocobalamin diffuses across the placenta and also appears in breast milk.

Approximately 20 to 30 % of dietary zinc is absorbed, primarily from the duodenum and ileum. The amount absorbed is dependent on the bioavailability from food. Zinc is the most bioavailable from red meat and oysters. Phytates may impair absorption by chelation and formation of insoluble complexes at an alkaline pH. After absorption, zinc is bound in the intestine to the protein metallothionein. Endogenous zinc can be reabsorbed in the ileum and colon, creating an enteropancreatic circulation of zinc.

Zinc is stored primarily in red and white blood cell, but also in the muscle, bone skin, kidney, liver, pancreas, retina, and prostrate. Zinc is 60 % bound to albumin, 30 to 40 % bound to ᾳ-2-macroglobulin or transferring; and 1 % bound to amino acids, primarily histidine and cysteine. Peak plasma concentration is achieved within 2 hours. Zinc is primarily excreted in faeces and regulation of faecal losses is important in zinc homeostasis. Small amounts are lost in the urine and perspiration.

Ascorbic acid is readily absorbed from the gastrointestinal tract (jejunum) and widely distributed in the body tissues. Ascorbic acid is reversibly oxidised to dehydro ascorbic acid; some is metabolised to ascorbate-2-sulphate, which is inactive, and oxalic acid, which are excreted in the urine.

 

INDICATIONS

RANFERON – 12 CAPSULES are indicated for the treatment of iron deficiency anaemia.

 

DOSAGE AND ADMINISTRATION

RANFERON-12 CAPSULES are administered orally.

The usual recommended dose is one RANFERON-12 CAPSULE taken two or three times daily.

 

PRECAUTIONS

General2

Iron

Iron compounds should not be given to patients receiving repeated blood transfusions or to patients with anaemias not produced by iron deficiency unless iron deficiency is also present. Oral and parenteral therapies should not be used together. Care should be taken in patients with iron storage or iron absorption diseases such as haemaochromatosis, haemoglobinopathies or existing gastrointestinal diseases such as inflammatory bowel disease, intestinal strictures and diverticulae.

Liquid preparations containing iron salts should be diluted with water and swallowed through a straw to prevent discoloration of the teeth.

 

Vitamin B12 (Cyanocobalamin)

Cyanocobalamin or hydroxococobalamin should, if possible, not be given to patients with suspected vitamin B12 deficiency without first confirming the diagnosis. Regular monitoring of the blood is advisable. Use of doses greater than 10 mg daily may produce a haematological response in patients with folate deficiency; indiscriminate use may mask the precise diagnosis. Conversely, folate may mask vitamin B deficiency.

Cyanocobalamin should not be used for Leber’s disease or tobacco ambylopia since these optic neuropathies may degenerate further.

 

Folic Acid

Folic acid should never be given alone or with inadequate amounts of vitamin B12 for the treatment of undiagnosed megaloblastic anaemia, since folic acid may produce a haematopoietic response in patients with a megaloblastic anaemia due to vitamin B12 deficiency without preventing aggravation of neurological symptoms. This masking of the true deficiency state can lead to serious neurological damage, such as subacute combined degeneration of the spinal cord.

 

Zinc sulphate

Prolonged administration of high doses of zinc supplements by mouth or parenterally leads to copper deficiency with associated sideroblastic anaemia and neutropenia. Zinc toxicity has occurred after the use of contaminated water in haemodialysis solutions. High serum zinc concentrations may be reduced by using a chelating drug such as sodium calcium edetate.

 

Ascorbic acid

Ascorbic acid is generally a safe drug for human use in normal doses. Excessive use of chewable ascorbic acid tablets has been reported to cause break down of tooth enamel.

 

Warnings1,5

Iron (any salt)

Caution is recommended in patients receiving repeated blood transfusions because the addition of high erythrocytic iron content may produce iron overload.

 

Zinc sulphate

Accumulation of zinc may occur in cases of renal failure. Ascorbic acid should be given with caution to patients with hyperoxaluria, which it may aggravate. It has been reported to cause hemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.

 

Contraindications1,3

RANFERON-12 CAPSULES are contraindicated in:

– Patients with porphyria cutanea tarda

– Anaemic conditions unless accompanied by iron deficiency (some conditions, such as hemolytic anemia or thalassemia, may cause excess storage of iron)

– Haemochromatosis or haemosiderosis, hyperoxaluria, glucose-6-phosphate dehydrogenase deficiency, or in iron overload

– Known hypersensitivity to any of the content of product

 

Carcinogenicity/Mutagenicity/Teratogenicity1,2,3,5

Iron

At therapeutic doses, no toxic effects are recognized after oral administration of iron salts to experimental animals. Mutagenicity tests in bacteria are not reported.

 

Vitamin B12 (Cyanocobalamin)

Long term animal studies to evaluate carcinogenic or mutagenic potential of cynocobalamin have not been performed.

 

Folic Acid

Folic acid is not mutagenic. Massive doses in rats and in rabbits (100 mg/kg upwards) produce precipitation of folate crystals in renal tubules, particularly proximal tubules and ascending limb of loop of Henle. Tubular necrosis is followed by recovery.

 

Zinc sulphate

Not applicable.

 

Ascorbic acid

There is no report of teratogenic effects of vitamin C (ascorbic acid) and little, if any evidence of carcinogenicity in vivo.

 

Pregnancy and Lactation1,5

Iron

Adequate, well-controlled studies in humans have not been done. Problems in humans have not been documented with normal daily-recommended amounts.

 

Vitamin B12 (Cyanocobalamin)

Adequate and well controlled studies have not been done in humans. Diagnostic testing should be postponed, if possible, until after delivery since cyanocobalamin crosses the placenta and is taken up by the fetus.

To avoid the possibility of radiation exposure to the fetus, in those circumstances where the patient’s pregnancy status is uncertain, a pregnancy test will help to prevent inadvertent administration of this preparation during pregnancy.

Cyanocobalamin is excreted in breast milk in very small concentrations. Although discontinuation of breast feeding is not essential, because of the potential risk to the infant from radiation exposure, temporary discontinuation of nursing is recommended for a short period of time.

 

Folic Acid

Problems in humans have not been documented with intake of normal daily recommended amounts. Folio acid crosses the placenta. However, adequate and well controlled studies in humans have not shown that folic acid causes adverse effect on the fetus.

Some studies have found that folic acid supplementation alone or in combination with other vitamins given before conception and during early pregnancy may reduce the incidence of neural tube defects in infants.

Folic acid is distributed into breast milk. However, problems in humans have not been documented with intake of normal daily recommended amounts.

 

Zinc sulphate

Problems in human have not been documented with intake of normal daily recommended amounts. However, adequate and well controlled studies in humans have not been done. The safety of zinc in human pregnancy has not been established.

Problems in human have not been documented with intake of normal daily recommended amounts. Zinc crosses the placenta and is present in breast milk.

 

Ascorbic acid
Studies have not been done in humans. Problems in humans have not been documented with intake of normal daily recommended amounts. Ascorbic acid crosses the placenta.

Ingestion of large amount of ascorbic acid daily throughout pregnancy may possibly harm the fetus.

Problems in humans have not been documented with intake of normal daily recommended amounts.

 

Paediatrics1

Iron

Iron supplementation is given to preterm infants after 2 months of age and to full term infants after 4 months of age, whether breast or formula fed. Problems in paediatrics have not been documented with intake of normal daily recommended amounts.

 

Vitamin B12 (Cyanocobalamin)

Although cyanocobalamin is used in children, there have been no specific studies evaluating safety and efficacy. When used in children, diagnostic benefit should be judged to out weight the potential risk of radiation.

 

Folic Acid

Problems in paediatrics have not been reported to occur with intake of normal daily recommended amounts.

 

Zinc sulphate

Problems in paediatrics have not been documented with intake of normal daily recommended amounts.

 

Ascorbic acid

Problems in paediatrics have not been documented with intake of normal daily recommended amounts.

 

Geriatrics1

lron

Problems in geriatrics have not been reported to occur with intake of normal daily recommended amounts. Some geriatric patients may require a larger than usual daily ingestion of bioavailable iron to correct an iron deficiency, because their ability to absorb iron has been diminished by reduced gastric secretions and achlorhydria.

 

Vitamin B12 (Cyanocobalamin)

Appropriate studies performed to date have not demonstrated geriatrics specific problems that would limit the usefulness of cyanocobalamin in the elderly.

 

Folic Acid

Problems in geriatrics have not been documented with intake of normal daily recommended amounts.

 

Zinc sulphate

Problems in geriatrics have not been documented with intake of normal daily recommended amounts. The elderly may be at risk of zinc deficiency due to poor food selection, decreased intestinal absorption of zinc, or medications, which may decrease absorption or increase urinary loss of zinc.

 

Ascorbic acid

Problems in geriatrics have not been documented with intake of normal daily recommended amounts.

 

Adverse Effects1,2,3

Iron

The astringent action of oral iron preparations sometimes produces gastrointestinal irritation and abdominal pain with nausea and vomiting. These irritant adverse effects are usually related to the amount of elemental iron taken rather than the type of preparation. Other gastrointestinal effects may include either diarrhoea or constipation.

Adverse effects may be reduced by giving it with or after food (rather on an empty stomach) or by beginning therapy with a small dose and increasing gradually. Modified release products are claimed to produce fewer side effects but this may only reflect the lower availability of iron from these preparations. Oral liquid preparations containing iron salts may blacken the teeth and should be drunk through a straw. The faeces of patients taking iron salts may be coloured black.

 

Vitamin B12 (Cyanocobalamin)

Allergic hypersensitivity reactions have occurred rarely following the parenteral administration of the vitamin B12 compounds cyanocobalamin and hydroxyocobalmin. Antibodies to hydroxyocobalmin transcobalamin II complex have developed during hydroxocobalamin therapy.

Arrthymias secondary to hyperkalaemia have occurred at the beginning of parenteral treatment with hydroxyocobalamine. lntranasal cyanocobalamin may cause rhinitis, nausea and headache.

 

Ascorbic acid

Withdrawal scurvy may occur after prolonged administration of 2 to 3 grams I day. Kidney stones (oxalate) or renal calcification are dose related. Other incidences are dizziness or faintness, diarrhea, flushing or redness of skin, headache, increase in urination, nausea or vomiting, stomach cramps. Very high doses of vitamin C may lead to disturbed water and electrolyte balance, increased red cell lysis, rebound scurvy and suppression of cobalamine activity.

 

Drug interactions1,2,3

Iron

Compounds containing calcium and magnesium, including antacids and mineral supplements, and bicarbonates, carbonates, oxalates, phosphates, egg, coffee tea (tannic acid) or whole grain breads and cereals may also impair the absorption of iron by the formation of insoluble complexes. Similarly the absorption of both iron salts and tetracyclines is diminished when taken together by mouth. If treatment with both drugs is required, a time interval of about 2 to 3 hours should be allowed between them. A suitable interval is also advised if an iron supplement is required in patients receiving trientine. Zinc salts may decrease the absorption of iron.

Some agents, such as ascorbic acid and citric acid, may actually increase the absorption of iron. The response to iron may be delayed in patients receiving systemic chloramphenicol. Iron salts can also decrease the absorption of other drugs and thus reduce their bioavailability and clinical effect. Drugs so affected include bisphonates, entacapone, fluoroquinolones, levdopa, methyldopa, mycophenolate mofetil, etidronate, and peniciliamine. Iron salts may reduce the efficacy of levothyroxine. Pancreatin or pancrelipase may decrease iron absorption. Concurrent administration of medicinal iron with dimercaprol results in the formation of a toxic complex; if iron deficiency is present, its treatment should be postponed until therapy with dimercaprol has been discontinued for at least 24 hours; severe iron deficiency anaemia occurring during dimercaprol therapy should be managed with blood transfusion. Concurrent use not recommended as cimetidine may decrease absorption of non-haem iron. Iron supplements should be taken at least 2 hours before or after cimetidine.

Acetohydroxamic acid may impair iron absorption. Concurrent use of alcohol with iron for a prolonged time may result in iron toxicity.

 

Vitamin B12 (Cyanocobalamin)

Absorption of vitamin B12 from gastrointestinal tract may be reduced by neomycin, aminosalicylic acid, histamine H2-antagonists, and colchicines. Serum concentrations may be decreased by concurrent administration of oral contraceptives. Many of these interactions are unlikely to be of clinical significance but should be taken into account when performing assays for blood concentrations. Parenteral chloramphenicol may attenuate the effect of vitamin B12 in anaemia.

 

Folic Acid

Folate deficiency states may be produced by a number of drugs including analgesics (long term use), antiepileptic or anticonvulsants (hydantoin, carbamezapines), oral contraceptives or estrogen, antituberculous drugs, alcohol, and folic acid antagonists such as methatrexate, pyrimethamine, triamterene, trimethoprim, and sulfonamides (including sulfasalazine). In some instances, such as during methotrexate or antiepileptic therapy, replacement therapy with folinic acid or folic acid may become necessary in order to prevent megaloblastic anaemia developing; folate supplementation has reportedly decreased serum phenytoin concentrations in a few cases and there is a possibility that such an effect could also occur with barbiturate antiepileptics. Cholestyramine may interfere with absorption of folic acid. Antacids (aluminum or magnesium containing) may decrease the folic acid absorption by lowering the pH of the small intestine.

 

Zinc sulphite

The absorption of zinc may be reduced by iron supplements, penicillamine, phosphorus- containing preparations, and tetracyclines. Zinc supplements reduce the absorption of copper, fluoroquinolones, iron, penicillamine, and tetracyclines. Diuretics (thiazide) have been found to increase urinary zinc excretion. Fiber and phytates, found in bran, whole grain breads and cereals or phosphorus containing foods (milk or polutary) might reduce the zinc absorption.

 

Ascorbic acid

Concurrent use with anticoagulants has been reported to impair gastrointestinal absorption of anticoaglutants.

Concurrent use may result in metabolism of ascorbic acid to oxalate.
Ascorbic acid is incompatible in solution with aminophylline, bleomycin, erythromycin, lactobionate, nafcillin, nitrofurantoin sodium, conjugated estrogens, sodium bicarbonate, sulfafurazole diethanolamine, chloramphenicol sodium succinate, chlorthiazide sodium, and hydrocortisone sodium succinate.

Ascorbic acid increases the apparent half-life of acetaminophen and enhances iron absorption from the gastrointestinal tract.

 

Laboratory value interaction

Iron

• Presence of iron may give false-positive Orthotoluidine test.

• Iron salts may cause a decrease in bone uptake of technetium Tc 99m-labeled phosphates and phosphonates because of iron overload; bone scans with Tc 99m diphosphonates, taken 1 to 6 days after intramuscular iron dextran administration may show dense areas of activity in the buttock, following the contour of the iliac crest.

• Iron supplements may cause a decrease in tumour and/decreases uptake of Ga-67 gallium citrate due to competition for the same binding sites.

 

Vitamin B12 (Cyanocobalamin)

No technical interferences of this kind appear to have been reported.

 

Folic Acid

No effects of this kind appear to have been reported.

 

Zinc sulphate

Alteration in serum concentration of copper, high density lipoproteins (HDL) and Alkaline phosphatase.

 

Ascorbic acid

Ascorbic acid is a reactive substance in most redox systems and can give rise to false positive reactions in certain analytical tests for glucose, uric acid, creatinine, and occult blood.

 

OVERDOSAGE1,4,5

Iron

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

Symptoms and signs of abdominal pain, vomiting and diarrhoea 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 oedema, convulsions, anuria, hypothermia, severe shock, metabolic acidosis, coagulation abnormalities and hypoglycaemia.

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 2 g desferrioxamine mesylate in 2 to 3 ml of water for injections and give intramuscularly. A solution of 5 g desferfloxamine in 50 to 100 ml of fluid may be left in the stomach. If desferrioxamine is not available, leave 300 ml 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.

 

Vitamin B12 (Cyanocobalamin)

No cases of this kind have been described, and it is unlikely that any harm would result.

 

Folic Acid

No cases of this kind appear to have been reported, but even extremely high doses are unlikely to cause harm to the patient.

 

Zinc sulphate

In acute overdosage zinc sulphate is corrosive, due to the formation of zinc chloride by stomach acid; symptoms are corrosion and inflammation of the mucous membrane of the mouth and stomach; ulceration of stomach followed by perforation may occur.

Treatment consists of administration of milk (demulcents). Chelating agents such as sodium calcium edentate may be useful. The use of emetics or gastric lavage should be avoided.

 

Ascorbic acid

An intake of ascorbic acid as high as 10 g has been taken daily for 2 years by healthy people with no obvious side effects. Acute ingestion, even of massive doses, is unlikely to cause significant effects and treatment is unlikely to be needed.

 

STORAGE

Store below 25°C, protected from moisture.

 

PRESENTATION

Blister strip of 10 capsules; pack of 30’s, 120’s.

 

KEEP OUT OF REACH OF CHILDREN.

 

REFERENCES

1) Drug information for the Health Care Professionals USP Dl (Vol. 1) 1996; 16th Ed.:, 1114.16, 1507-9, 1781-86, 3037-3041.

2) Martindale – “The Complete Drug Reference” 2005; 34th Ed.: 1429, 1434-1436, 1458-1462.

3) Therapeutic Drugs Vol. 2 (1996): C342-C345; 178-182; F142-F145.

4) ABPI Compendium of Data Sheets and Summaries of Product Characteristics, PREGADAY Tablets, Celltech Pharmaceuticals Limited, UK. September 2001.

5) ABPI Compendium of Data Sheets and Summaries of Product Characteristics, Solvazinc, Provalis Healthcare, UK. January 2004.

6) ABPI Compendium of Data Sheets and Summaries of Product Characteristics, Cold and Flu Relief Hot Lemon, The Boots Company PLC, UK. July2001.

7) Park’s Text Book of Preventive and Social Medicine; 2000; Park and Park (Pub B. Bhanot Jabalpur, India.). 16th Ed.: 431-432.

8) Iron Deficiency Anaemia, Assessment, Prvention, and Control. A guide for programme managers (2001), WHO/NHD/01.3.

9) Robert E Rakel, 1994, Iron deficiency anemia in the textbook of Conn’s Current Therapy (published by WB Saunders Company, Philadelphia).

10) Nelson Textbook of Pediatrics, 14th edn. published by WB Saunders Company, Philadelphia.

Information Revised in November 2003 and Updated in June 2005.

 

MADE IN INDIA

RANBAXY LABORATORIES LIMITED

INDUSTRIAL AREA – 3

DEWAS – 455 001

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