HB SET Tablets (Ferrous ascorbate + Folic acid )

Table of Content

Anaemia is defined as a low haemoglobin concentration in blood, or less often, as a low haematocrit, the percentage of blood volume that consists of red blood cells.                            

Iron salts (e.g. ferrous ascorbate) are primarily required for the prophylaxis and treatment of iron deficiency anaemia. Iron is necessary for effective erythropoiesis, is a cofactor of several essential enzymes, including cytochromes, all of which are involved in electron transport. The ferrous form of inorganic iron is more readily absorbed. Ferrous ascorbate offers iron absorption of 43.7%.

Folic acid is required for synthesis of nucleoprotein, purine nucleotides and the metabolism of some amino acids, normal growth and cell reproduction, nucleoprotein synthesis and the maintenance of normal erythropoiesis.

Hb Set is indicated for the prevention and treatment of nutritional deficiency anaemia related to iron and folic acid. Hb Set is also indicated for the prevention and treatment of anaemia in pregnancy and lactation.

The dosage of Hb Set is one tablet per day, or as directed by the physician.

Hb Set is contraindicated in patients that are hypersensitive to ferrous ascorbate, folic acid, or to any other component of this formulation; and in patients with porphyria cutanea tarda, haemochromatosis and haemosiderosis, and haemolytic anaemia.

 

Composition

HB SET
Each film-coated tablet contains:
Ferrous ascorbate equivalent to
Elemental iron - 100 mg
Folic acid IP - 1.5 mg

Dosage Form

Tablets for oral use.

Description

Ferrous Ascorbate

Ferrous ascorbate is a synthetic molecule of iron and ascorbic acid. The ferrous form is absorbed thrice as much as the ferric form of iron. There is no dissociation of ferrous ascorbate on entering the gastrointestinal (GI) tract due to the stable chelate of iron with ascorbate.

Ascorbic acid reduces ferric iron to ferrous iron, which remains soluble even at neutral pH, and enhances the absorption of iron. It also inhibits the conversion of ferrous to ferric iron; this maintains the iron in highly soluble ferrous form, leads to increased absorption of iron and reduces the amount of free radicals generated, thereby minimizing adverse GI effects.

Ascorbic acid has been shown to inhibit the effect of phytates, phosphates and oxalates on iron absorption by the formation of soluble iron ascorbate complexes and by inhibiting the formation of insoluble iron complexes.

Folic Acid

Folate is a water-soluble vitamin. Folate is critically important for growth and, for this reason, it is required in increased amounts during pregnancy. The need for dietary folate remains elevated after pregnancy and during lactation because of the transfer of the mother's vitamins to the breast milk. Folic acid is the form of the vitamin used in folate supplements.

Pharmacology

Pharmacodynamics

Iron Salts
Iron salts are compounds used primarily for the prophylaxis and treatment of iron deficiency anaemia. The body stores iron in compounds called ferritin and haemosiderin since it is an essential component in the formation of haemoglobin. Adequate amounts of iron are necessary for effective erythropoiesis. Iron also serves as a cofactor of several essential enzymes, including cytochromes, all of which are involved in electron transport. Iron absorption is a variable of the existing body iron stores, the form and quantity in foods, and the combination of foods in the diet. The ferrous form of inorganic iron is more readily absorbed.

Folic Acid
Folic acid is required for synthesis of nucleoprotein, purine nucleotides and the metabolism of some amino acids, normal growth and cell reproduction, nucleoprotein synthesis and the maintenance of normal erythropoiesis.

It is converted in the liver and plasma to its metabolically active form, tetrahydrofolic acid, by dihydrofolate reductase, which then acts as an acceptor of one-carbon units. These are attached at several different positions to form six major congeners, each of which plays a specific role in intracellular metabolism. The coenzymes formed from folic acid are instrumental in the following intracellular metabolisms: Conversion of homocysteine to methionine, conversion of serine to glycine, synthesis of thymidylate, histidine metabolism, synthesis of purines, and the utilization or generation of formate.

Methyltetrahydrofolate is a methyl donor in the conversion of homocysteine to methionine. This reaction requires vitamin B12 as a cofactor. Individuals with an alanine to valine substitution in the gene for 5,10- methylenetetrahydrofolate reductase have elevated homocysteine and an elevated risk for coronary artery disease.

Tetrahydrofolate assists in the conversion of serine to glycine by accepting a methylene group from serine. Pyridoxal phosphate is required as a cofactor. The resulting product, 5,10-methylenetetrahydrofolate, is an essential coenzyme in the synthesis of thymidylate. In this reaction, a methyl group is donated to deoxyuridylic acid to form thymidylic acid. This is a rate-limiting step in DNA synthesis. The megaloblastic changes produced by folic acid deficiency are secondary to the failure of thymidylate synthesis.

Tetrahydrofolate also acts as an acceptor of a formimino group from histidine to form formimino tetrahydrofolic acid and glutamic acid. Two steps in the synthesis of purine nucleotides require derivatives of folic acid. These derivatives, 5,10-methenyltetrahydrofolate and 10-formyltetrahydrofolate, donate carbons atoms to the growing purine ring. The utilization or generation of formate is assisted by tetrahydrofolate and 10-formyltetrahydrofolate.

Pharmacokinetics

Iron
Absorption
In case of iron-deficiency anaemia, the initial response of iron given orally is 1 week. Haemoglobin may increase 1.5 to 2.2 g/dl/week for the first 2 weeks and then 0.7 to 1.6 g/dl/week until normal haemoglobin levels are achieved. Reticulocyte count increases in 3 to 4 days and peaks in 7 to 10 days.

Given orally, subjects with normal iron stores absorb 10 - 35%; iron-deficient patients absorb 80 - 95%. The percent absorption is affected by the salt form, the amount administered, the dosing regimen, and the size of the iron stores. Oral iron is poorly absorbed by patients on continuous peritoneal dialysis. Vitamin C enhances absorption of non-haem iron. Ferrous iron is more bioavailable than ferric iron.

The absorption of a pharmacological dose of iron was assessed by determination of mucosal uptake, mucosal transfer and retention of 33 mg Fe (II) as ferrous sulphate and ferrous ascorbate in 11 subjects with normal iron stores and 9 subjects with iron deficiency. There was no difference in absorption between the two iron compounds in normal subjects. Absorption of ferrous ascorbate averaged 52% higher than ferrous sulphate in subjects with iron deficiency. The difference was the result of higher mucosal uptake, probably because the oxidation of Fe (II) in the alkaline milieu of the intestine, which leads to formation of non-absorbable Fe (III) complexes, was prevented.

For purposes of comparison, all studies currently refer to 40% absorption of the reference dose of ferrous ascorbate since it corresponds to that which is obtained in borderline iron-deficient populations.

Effects of Food
The main dietary enhancers of absorption of non-haem iron are muscle tissue (cysteine-containing proteins) and ascorbic acid. The main dietary inhibitors of absorption of non-haem iron are phytic acid, polyphenols, calcium and certain proteins.

Elimination
The elimination half-life of the parent compound is 6 hours. Excretion takes place in trace amounts through the kidneys and the faeces.

Folic acid
The therapeutic drug concentration of folic acid in a healthy adult ranges from 4 - 20 ng/mL. It appears in the plasma approximately 15 to 30 minutes after an oral dose; peak concentration is generally reached within 60 to 90 minutes.

Absorption
The bioavailability of folic acid ranges from 76% to 93%. Folic acid is absorbed by a carrier-mediated process primarily in the proximal part of the small intestine. There is little absorption in the distal jejunum and practically none in the distal ileum. Its absorption is reported to be impaired in patients with celiac disease in the proximal jejunum, but absorption is reported to be comparable to that for healthy individuals from the distal jejunum. Pregnancy does not appear to impair the absorption of folic acid.

Distribution
Folate derivatives are bound by plasma proteins. The greatest affinity for plasma protein-binding occurs with the non-methylated analogs. Other distribution sites include the liver (50%) and tissues. Once absorbed, folate and its derivatives are rapidly distributed to all body tissues. Normal serum, cerebrospinal fluid and erythrocyte levels of folate have been reported to be 5 - 15 ng/mL; 16 - 21 ng/mL and 0.175 - 0.316 mcg/mL, respectively. In general, folate serum levels below 5 ng/mL indicate folate deficiency, and levels below 2 ng/mL usually result in megaloblastic anaemia.

Metabolism
Folic acid is metabolized in the liver to 7,8-dihydrofolic acid and, eventually, to 5,6,7,8-tetrahydrofolic acid with the aid of a reduced diphosphopyridine nucleotide (DPNH) and folate reductases. This conversion occurs primarily in the liver and not to any significant degree during absorption through the intestinal mucosa. Tetrahydrofolic acid derivatives are distributed to all body tissues, but are stored primarily in the liver.

Excretion
The kidneys excrete 30% of folic acid. After a single oral dose of 100 mcg of folic acid in a limited number of normal adults, only a trace amount of the drug appeared in the urine. The other route of excretion is bile. Following oral administration, folic acid is found in concentrations ranging from 15 - 400 ng/mL in the bile, with peak levels occurring in approximately 120 minutes. Small amounts of orally administered folic acid have also been recovered in the faeces. Folic acid is also excreted in the milk of lactating mothers.

Indications

HB SET is indicated for the prevention and treatment of nutritional deficiency anaemia related to iron and folic acid. HB SET is also indicated for the prevention and treatment of anaemia in pregnancy and lactation.

Dosage and Administration

The dosage of HB SET is one tablet per day, or as directed by the physician.

Contraindications

HB SET is contraindicated in:

  • Patients hypersensitive to ferrous ascorbate, folic acid or to any other component of this formulation;
  • Patients with porphyria cutanea tarda, haemochromatosis and haemosiderosis, and haemolytic anaemia.

Warnings and Precautions

General

Do not exceed the recommended dose. The type of anaemia and the underlying cause or causes should be determined before starting therapy with this medication. Since the anaemia may be a result of a systemic disturbance, such as recurrent blood loss, the underlying cause or causes should be corrected, if possible.

Iron Salts
In general, people with a history of kidney disease, intestinal disease, peptic ulcer disease, enteritis, colitis, pancreatitis, hepatitis, who consume excessive alcohol, who plan to become pregnant, or who are over 55 years of age and have a family history of heart disease should consult a doctor and pharmacist before taking iron.

Individuals with blood disorders who require frequent blood transfusions are also at risk of iron overload and should not take iron supplements without direction by a qualified healthcare provider. Long-term use of high doses of iron can cause haemosiderosis that clinically resembles haemochromatosis. Iron overload is associated with several genetic diseases, including haemochromatosis. Accumulation of excess iron is being investigated as a potential contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

Folic Acid
Vitamin B12 deficiency that is allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord.

Folic acid in doses above 0.1 mg daily may obscure pernicious anaemia in that haematologic remission can occur while neurological manifestations remain progressive. This may result in severe nervous system damage before the correct diagnosis is made. Neurological manifestations will not be prevented with folic acid, and if not treated with vitamin B12, irreversible damage will result. Adequate doses of vitamin B12 may prevent, halt, or improve the neurological changes caused by pernicious anaemia.

Administration of folic acid alone is improper therapy for pernicious anaemia and other megaloblastic anaemias in which vitamin B12 is deficient. Doses of cyanocobalamin exceeding 10 mcg daily may produce a haematologic response in patients with folate deficiency. Indiscriminate administration may mask the true diagnosis.

Caution should be used in patients undergoing angioplasty since an intravenous loading dose of folic acid, vitamin B6, and vitamin B12, followed by oral administration taken daily after coronary stenting, might actually increase restenosis rates. Due to the potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents.

Drug Interactions

Iron Salts

  • The administration of the following with iron salts results in decreased iron effectiveness: Aluminium hydroxide, aluminium phosphate, calcium , aluminium carbonate (basic), chloramphenicol, dihydroxyaluminium aminoacetate, dihydroxyaluminium sodium carbonate, magaldrate, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, methacycline, minocycline, oxytetracycline, rolitetracycline, sodium bicarbonate.
  • The administration of the following with iron salts results in decreased effectiveness of the following molecules: Cefdinir, cinoxacin, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, penicillamine, sparfloxacin, temafloxacin, trovafloxacin mesylate, levothyroxine.
  • The administration of the following with iron salts results in decreased effectiveness of the molecule as well as iron: Zinc (with decreased gastrointestinal absorption), acetohydroxamic acid, trientine (with decreased gastrointestinal absorption).
  • The administration of the following with iron salts results in reduced iron absorption/bioavailability: Esomeprazole, desferrioxamine, gossypol, lansoprazole, omeprazole, pantoprazole, rabeprazole, soybean, soy protein, vanadium, cholestyramine, colestipol, pancrelipase.
  • The administration of the following molecules with iron decreases the absorption of the molecules: Ciprofloxacin, ofloxacin, levofloxacin, tiludronate, risedronate, alendronate, etidronate, ibandronate, levodopa, methyldopa, levothyroxine, mycophenolic acid, minocycline, doxycycline, tetracycline, demeclocycline.
  • Allopurinol may increase iron storage in the liver and should not be used in combination with iron supplements.
  • Aminosalicylic acid may cause a malabsorption syndrome (weight loss, iron and vitamin depletion, steatorrhoea).
  • Aspirin and NSAIDs can cause mucosal damage and bleeding throughout the gastrointestinal tract. Chronic blood loss associated with the long-term use of these agents may contribute to iron deficiency anaemia. Since iron supplements may also irritate the gastrointestinal tract, patients should not use them concurrently with NSAIDs unless recommended by a physician.
  • Chloramphenicol can reduce the response to iron therapy in iron-deficiency anaemia.
  • Iron supplements and dimercaprol may combine in the body to form a harmful chemical.
  • Adequate dietary iron intake is recommended when taking H2 blockers like cimetidine, ranitidine, famotidine or nizatidine. Iron supplements are not usually required unless they are being used for another indication.

Folic Acid

  • The administration of the following with folic acids results in decreased effectiveness of the molecule: Fosphenytoin, phenytoin, pyrimethamine.
  • The administration of the following with folate results in reduced folate absorption: Aminosalicylic acid, antacids, antibiotics, aspirin, carbamazepine, cholestyramine, colestipol, cycloserine, cimetidine, famotidine, nizatidine, ranitidine, pancrelipase, sulfasalazine, triamterene.
  • The administration of the following with folate results in reduced serum folate levels: Oestrogens conjugated, oral contraceptives pills, methotrexate, methylprednisolone sodium succinate (noted in people with multiple sclerosis), intravenous pentamidine, phenobarbital and primidone, pyrimethamine.
  • Excessive use of alcohol increases the requirement for folic acid.
  • Chloramphenicol may antagonize some effects of folic acid on the blood (haematopoietic system). Limited data suggests that diuretics may increase excretion of folic acid.
  • Reduced vitamin B12 and, to a lesser extent, folate levels occur in some people with diabetes and can contribute to hyperhomocysteinaemia, which adds to the already increased risk of cardiovascular disease. The reduced folate levels seen in diabetics have been linked to metformin use in some cases, possibly as a result of reduced folic acid absorption. Symptomatic folate deficiency is unlikely to occur with metformin, but people with diabetes may need folic acid supplements to reduce hyperhomocysteinaemia.
  • Chronic cigarette smoking is associated with diminished folate status.
  • Folate-dependent enzymes have been inhibited in laboratory experiments by ibuprofen, naproxen, indomethacin and sulindac.
  • One study found that administration of folic acid to pregnant women might not interfere with the protective effect of the sulphadoxine/pyrimethamine combination when used for intermittent preventative treatment of malaria.
  • There is a general belief that folic/folinic acid supplements do not interfere with the therapeutic effects of trimethoprim. However, this view has been challenged, and failure of trimethoprim therapy has occurred rarely when folinic acid is given concurrently.

Pregnancy

Nutritional supplement doses of vitamins and minerals are generally considered safe during pregnancy.

Iron Salts
Pregnancy Category B
The use of iron supplements during pregnancy is considered an accepted and safe recommendation which benefits both the mother and the infant. Because of negative interactions of iron on intestinal absorption of other divalent minerals, supplemental iron doses should be as low as possible while fulfilling their purpose. It is not known if iron salts cross the placenta.

The incidence of foetal malformations was lower in the women who had taken iron during pregnancy compared to those who did not use supplemental iron. In addition, the women in the iron-treated group delivered infants with higher birth weights and also had a lower incidence of preterm births.

Folic Acid
Pregnancy Category A
Folic acid requirements are markedly increased during pregnancy and deficiency will result in foetal damage. Folic acid is recommended for women who are contemplating pregnancy or who are pregnant to avoid birth defects caused by folic acid deficiency. Folic acid crosses the placenta.

Studies in pregnant women have not shown that folic acid increases the risk of foetal abnormalities if administered during pregnancy. If the drug is used during pregnancy, the possibility of foetal harm appears remote. However, because studies cannot rule out the possibility of harm, folic acid should be used during pregnancy only if clearly needed.

It is recommended that all women capable of becoming pregnant consume folate in order to reduce the risk of the foetus developing a neural tube defect. Folic acid supplementation in higher than recommended doses is categorized as the FDA Pregnancy Category C.

Lactation

Iron Salts
Available evidence and/or expert consensus are inconclusive or are inadequate for determining infant risk when used during breastfeeding. The potential benefits of drug treatment have to be weighed against the potential risks before prescribing this drug during breastfeeding.

Folic Acid
Folic acid is excreted in human breast milk. During lactation, folic acid requirements are markedly increased; however, amounts present in human milk are adequate to fulfil infant requirements, although supplementation may be needed in low-birth-weight infants, in those who are breast-fed by mothers with folic acid deficiency, or in those with infections of prolonged diarrhoea. Most likely, it is safe to use during breastfeeding under the supervision of a qualified healthcare provider. Adverse effects in breastfed infants related to the intake of normal daily requirements of folic acid during lactation have not been documented. The potential benefits of drug treatment have to be weighed against the potential risks before prescribing this drug during breastfeeding.

Undesirable Effects

Iron Salts

Adverse reactions with iron therapy may include constipation, diarrhoea, nausea, vomiting, dark stools and abdominal pain. Adverse reactions with iron therapy are usually transient. Gastrointestinal upset, including nausea, vomiting, constipation, diarrhoea and dark stools, has been reported. Gastrointestinal side effects are relatively common and corrective bowel regimens such as increasing dietary fibre or over-the-counter medications might be recommended to balance these side effects.

Folic Acid

Folate appears to be well-tolerated in recommended doses. Stomatitis, alopecia, myelosuppression and zinc depletion have been reported.

Erythema, urticaria, skin flushing, rash, itching, nausea, bloating, flatulence, cramps, bitter taste, and diarrhoea have been reported. The colour of the urine may become more intense.

Irritability, excitability, general malaise, altered sleep patterns, vivid dreaming, overactivity, confusion, impaired judgment, increased seizure frequency, and psychotic behaviour have been reported. Very high doses can cause significant central nervous system side effects. Supplemental folic acid might increase seizures in people with seizure disorders, particularly in very high doses.

Folic acid may mask the symptoms of pernicious, aplastic or normocytic anaemias caused by vitamin B12 deficiency and may lead to neurological damage.

Anaphylaxis and bronchospasm have also been reported.

Overdosage

Iron Salts

The clinical course of acute iron overdosage can be variable. Initial symptoms may include abdominal pain, nausea, vomiting, diarrhoea, tarry stools, melena, haematemesis, hypotension, tachycardia, metabolic acidosis, hyperglycaemia, dehydration, drowsiness, pallor, cyanosis, lassitude, seizures, shock and coma.

Acute overdosage or iron accumulation symptoms may include arthritis, signs of gonadal failure (amenorrhoea, early menopause, loss of libido, impotence), and shortness of breath/dyspnoea. High doses may cause vomiting and diarrhoea, followed by cardiovascular or metabolic toxicity and death. It is unclear whether high levels are associated with cancer, coronary heart disease or myocardial infarction (MI or heart attack).

Folic Acid

Except during pregnancy and lactation, folic acid should not be given in therapeutic doses greater than 0.4 mg daily until pernicious anaemia has been ruled out. Patients with pernicious anaemia receiving more than 0.4 mg of folic acid daily who are inadequately treated with vitamin B12 may show reversion of the haematologic parameters to normal, but neurological manifestations due to vitamin B12 deficiency will progress. Doses of folic acid exceeding the RDA should not be included in multivitamin preparations; if therapeutic amounts are necessary, folic acid should be given separately.

Storage and Handling Instructions

Store in cool, dry and dark place. Keep out of reach of children.

Packaging Information

HB SET: Strip of 10 tablets.