Composition PEAKRISE-XT

Dosage Form

Tablets for oral use.

Description

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.

Mean haemoglobin Significantly increased from 8.39 g/dl to 12.53 g/dl in 8 weeks2

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.

Clinical surveillance of all women using estrogen plus progestin therapy is important. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Daily Supplementation with iron & Folate leads to 73% reduction in anemia at term4

Maternal Zinc deficiency may compromise infant development & lead to poor birth outcomes5

Pharmacology

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.

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.

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

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.

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.

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.

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. Maternal Zinc deficiency may compromise infant development & lead to poor birth outcomes5

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

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

Dosage and Administration

The dosage of PEAKRISE-XT is one tablet per day, or as directed by the physician.

Contraindications

PEAKRISE-XT is contraindicated in :

• Patients hypersensitive to ferrous ascorbate, folic acid, Zinc Sulphate or to any other component of this formulation

• Patients with porphyria cutanea tarda, haemochromatosis and haemosiderosis, and haemolytic anaemia.

Warnings and Precautions

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.

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.

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.

• 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.

• 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.

• One study found that administration of folic acid to pregnant women might not interfere with the protective effect of the

• 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.

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

The use of iron supplements during pregnancy is considered an accepted and safe recommendation which benefits both the mother and the infant. Folate-dependent enzymes have been inhibited in laboratory experiments by ibuprofen, naproxen, indomethacin and sulindac.

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 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.

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 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

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.

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

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).

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 & Handling Instructions

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

Packaging Information

PEAKRISE-XT: Strip of 10 tablets.