Treatment of iron deficiency without anaemia and iron deficiency anaemia (IDA).

 

Prophylactic therapy of iron deficiency.

 

Prophylactic therapy of iron deficiency during pregnancy.

Posology

These tablets can be chewed or swallowed.

 

Treatment of iron deficiency anaemia in children over 12 years and adults:

100 mg to 300 mg iron (1 to 3 tablets) daily for 3 to 5 months until a normalisation of the haemoglobin (Hb) value is achieved. Afterwards, the therapy should be continued for several weeks with a dosage such as described for iron deficiency without anaemia to replenish the iron stores.

 

Treatment of iron deficiency anaemia in pregnancy:

200 mg to 300 mg iron (2 to 3 tablets) daily until a normalisation of the Hb value is achieved. Afterwards, the therapy should be continued at least until the end of the pregnancy with a dosage

such as described for iron deficiency without anaemia to replenish iron stores and to supplement the increased iron need during pregnancy.

 

Treatment and prevention of iron deficiency without anaemia in children over 12 years and adults:

100 mg (1 tablet) daily for 1 to 2 months. If a smaller dose is required for prevention, Feromenta® syrup can be used.

 

Paediatric population

Feromenta® chewable tablets are not recommended for children 12 years and younger. Feromenta® syrup and drops have a more suitable form and concentration for administration of the recommended dosages of this age group.

 

Method of administration

The daily dose can be divided into separate doses or can be taken at once. Feromenta® should be taken during or immediately after a meal.

 

Feromenta® chewable tablets can be chewed or swallowed whole.

Known hypersensitivity to iron (III)-hydroxide polymaltose complex (IPC) or to any of the excipients listed in section 6.1. Iron overload, such as haemochromatosis, haemosiderosis. Disturbances in iron utilisation, such as anaemia from lead poisoning, sidero-achrestic anaemia,thalassaemia. Anaemia not caused by iron deficiency, such as haemolytic anaemia or megaloblastic anaemia due to vitamin B12 deficiency.

Infections or tumour may cause anaemia. Since iron can be utilised only after correcting the primary disease, a benefit/risk evaluation is advisable.

 

During the treatment with Feromenta® there may be dark discolouration of the faeces, but this is of no clinical relevance.

 

The intake of Feromenta® is not expected to have an impact on the daily insulin management of diabetes patients. [Please enter the respective information according to the local label]

 

Feromenta® contains aspartame (E951) - a source of phenylalanine. May be harmful for people with phenylketonuria. (Not included in all formulations; consult local labelling).

Interactions IPC (with and without folic acid) with tetracycline or aluminium hydroxide were investigated in 3 human studies (crossover design, 22 patients per study). No significant reduction in the absorption of tetracycline was observed. The plasma tetracycline concentration did not fall below the level necessary for efficacy. Iron absorption from IPC was not reduced by aluminium hydroxide or tetracycline. Iron (III) hydroxide polymaltose complex can therefore be administered at the same time as tetracycline or other phenolic compounds, as well as aluminium hydroxide.

 

Studies in rats with tetracycline, aluminium hydroxide, acetylsalicylate, sulphasalazine, calcium carbonate, calcium acetate and calcium phosphate in combination with vitamin D3, bromazepam, magnesium aspartate, D-penicillamine, methyldopa, paracetamol and auranofin have not shown any interactions with IPC.

 

Similarly, no interactions with food constituents such as phytic acid, oxalic acid, tannin, sodium alginate, choline and choline salts, vitamin A, vitamin D3 and vitamin E, soya oil and soya flour were observed in in vitro studies with IPC. These results suggest that IPC can be taken during or immediately after food intake.

 

The haemoccult test (selective for Hb) for the detection of occult blood is not impaired, and therefore there is no need to interrupt the therapy.

 

Concomitant administration of parenteral and oral iron is not recommended since the absorption of oral iron would be inhibited.

Pregnancy

No data from clinical studies are available on the use of Feromenta® in pregnant women during the first trimester. To date, there have been no reports of serious adverse reactions after ingestion of Feromenta® in therapeutic doses for the treatment of anaemia in pregnancy. Animal data showed no evidence of risk to foetus and mother (see Section 5.3).

 

Studies in pregnant women after the first trimester have not shown any undesirable effect of Feromenta® on mothers and/or neonates. Therefore, a negative influence on the foetus is unlikely with the administration of Feromenta®.

 

Lactation

Human breast milk naturally contains iron, which is bound to lactoferrin. The amount of iron passing from IPC to the mother’s milk is unknown. It is unlikely that the administration of Feromenta® in women who are breast-feeding causes undesirable effects to the infant.

 

As a precautionary measure, women of childbearing age, and women during pregnancy and lactation should only use Feromenta® after consulting a medical doctor. A benefit/risk evaluation is advisable

No data available.

The safety and tolerability of Feromenta® has been evaluated in numerous clinical trials and published reports. The principal adverse drug reactions that have been reported in these trials, occurred in the following three system organ classes:

 

Table 1. Adverse Drug Reactions Detected in Clinical Trial

System Organ Clas	Very common (≥1/10)	Common (≥1/100, <1/10)	Uncommon (≥1/1,000, <1/100)
Gastrointestinal Disorders	Discoloured faeces1	Diarrhoea, nausea, dyspepsia	Vomiting, constipation, abdominal pain, tooth discolouration2
Skin and Subcutaneous Tissue Disorders			Rash, pruritus
Nervous System Disorders			Headache

1 “Discoloured faeces” were very commonly reported as an adverse event (23% of patients) and are a well-known ADR of oral iron medications.

2 “Tooth discolouration” was reported as an adverse event in 0.6% of the patients and is a known ADR of oral iron medications.

Notes: “Exanthema” was combined with “rash” and presented as “rash” in the table.

ADR = Adverse drug reaction.

Undesirable effects from post-marketing spontaneous reporting

No additional adverse drug reactions were identified

Laboratory abnormalities

No data available

 

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:

To report any side effect(s): - The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2340. o Hotline: 19999 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

 

In case of overdose, iron overload or intoxications are unlikely with Feromenta® due to the low toxicity of IPC (i.e., in mice or rats: lethal dose, 50% (LD50) >2,000 mg Fe/kg body weight) and controlled uptake of iron. No cases of accidental poisoning with fatal outcome have been reported

Pharmacotherapeutic group: Iron trivalent, oral preparations; Ferric oxide polymaltose complexes ATC-Code: B03AB05.

 

Mechanism of action

In IPC, the polynuclear iron(III)-hydroxide core is superficially surrounded by a number of non-covalently bound polymaltose molecules resulting in an overall average molecular weight of approximately 50 kDa. The polynuclear core of IPC has a structure similar to that of the physiological iron storage protein ferritin. Iron(III)-hydroxide polymaltose is a stable complex and does not release large amounts of iron under physiological conditions. Because of its size, the extent of diffusion of the iron(III)-hydroxide polymaltose complex through the membrane of the mucosa is about 40 times less than that of the hexaquo-iron(II) complex. Iron from IPC is taken up in the gut via an active mechanism.

 

Pharmacodynamic effects

The absorbed iron is bound to transferrin and is used for haemoglobin synthesis in the bone marrow or is stored, mainly in the liver, where it is bound to ferritin.

For pharmacodynamic drug interaction properties, see Section 4.5.

 

Clinical efficacy and safety

The efficacy of Feromenta® in normalising Hb and replenishing iron store levels has been demonstrated in numerous randomised, placebo or reference-therapy controlled clinical trials conducted in adults and children with varying iron status. These trials included over 3800 participants, of which approximately 2300 participants have received Feromenta®.

 

Adults and the elderly

In reference-drug controlled studies involving >300 Feromenta® treated adult patients, Feromenta® (100 to 200 mg iron/day) produced significant Hb increases, similar to those seen after 3 weeks to 6 months of treatments with ferrous sulfate or ferrous fumarate.

 

Placebo-controlled clinical trials in adults

In a randomised, single-blind, study treatment with Feromenta® 100 mg iron twice daily (with meals) for 8 weeks was compared to placebo in blood donors with normal Hb (≥135 g/L) and either normal (serum ferritin 50-150 ng/mL) or deficient (serum ferritin <20 ng/mL) iron stores. A significant rise in Hb (from 143 to 150 g/L; p=0.03) and repletion of body iron stores (rise in serum ferritin from 16.2 to 43.2 ng/mL; p=0.002) was seen in iron deficient (ID) subjects receiving Feromenta®.

 

In another 6 months, double-blind, randomized study, all subjects were males with iron deficiency defined as serum ferritin ≤30 ng/mL. Patients were randomised to receive Feromenta® tablets (200 mg iron/day), micro-capsulated ferrous sulfate (180 mg iron/day), or placebo. Iron was administered with meals and 50 mg ascorbic acid. At 6 months, treatment with Feromenta® resulted in an Hb increase (+3.3 g/L; p<0.05 versus placebo). The increase in serum ferritin was 27.4 ng/mL (p<0.05 versus placebo) in the Feromenta® group.

 

Short-term reference-controlled studies (<12 weeks duration)

In a double-blind, double-dummy study, 121 adults with iron deficiency anaemia (defined as Hb 85-120 g/L, MCH <28 pg and/or MCHC <33 g/dL) were randomised to receive Feromenta® (100 mg iron twice daily with meals) or standard dosing of ferrous sulfate (60 mg iron three times daily 30 minutes before meals)] for 9 weeks. In the per-protocol set, there was a significant increase in mean Hb from 107.4 g/L to 113.4 g/L at 3 weeks in the Feromenta® group (p=0.01). At 9 weeks, mean Hb level in the Feromenta® group was 120.3 g/L. In the intent-to-treat set, Hb values significantly increased from 108.9 g/L to 121.1 g/L in the Feromenta® group after 9 weeks.

 

Reference-controlled studies of ≥12 weeks duration

In a single centre, open-label, randomised, parallel-group study, treatment withFeromenta® drops or ferrous sulfate syrup, 100 mg iron twice daily for 12 weeks, was compared in 143 anaemic blood donors (Hb <136 g/L for men, Hb <120 g/L for women; serum ferritin <20 ng/mL). Hb, MCV, and MCH levels increased to a similar extent in both treatment groups. The increase in serum ferritin was 2.6 ng/mL in the Feromenta® group. The most common adverse effect was gastrointestinal tract intolerance occurring significantly less frequently with Feromenta® (44.7% ferrous sulfate group versus 8.6-17.5% with the Feromenta® groups; p<0.0001).

 

Feromenta® versus ferrous sulfate was evaluated in another 12 week randomised study. Study subjects were 145 blood donors with iron deficiency anemia (Hb <133 g/L for men, Hb <116 g/L for women). Feromenta® was administered with meals. With respect to normalisation of Hb values, a daily dose of Feromenta® 200 mg iron (100 mg twice daily) was shown to be more efficient than a 100 mg iron dose of Feromenta® (once per day). At the end of 12 weeks, normal Hb levels were reached by almost 80% of patients receiving either Feromenta® 200 mg iron/day (n=45), compared to 50% of patients receiving Feromenta® 100 mg iron/day (n=40).

 

Studies in adolescents

In a placebo-controlled study of 120 adolescents, aged 15 to 18 years, Feromenta® was shown to improve the iron status of adolescents with iron deficiency (with and without anaemia). Subjects were divided into 4 groups with 30 subjects per group: control placebo, control supplement, iron deficient (TSAT1 <16%; Hb ≥115 g/L for boys, Hb ≥105 g/L for girls), iron deficient and anaemic (Hb<105 g/L). The three active treatment groups received Feromenta® 100 mg iron/day, 6 days/week, for 8 months. At study-end, all three treatment groups demonstrated significant increases in iron parameters compared to the placebo group, including correction of iron deficiency and anaemia and improvement in iron parameters. No gastrointestinal adverse effects were reported.

 

Pregnant and breast-feeding women

 

The efficacy and safety of Feromenta® has been confirmed in an open-label, randomised controlled study including 80 pregnant women with iron-deficiency anemia (Hb ≤ 105 g/L, serum ferritin ≤ 15 ng/mL). Patients were randomised 1:1 to receive Feromenta® or ferrous sulfate (each 100 mg iron twice daily) during or after a meal for 90 days.

Mean (SD2) Hb increased in the Feromenta group from 96.4 (8.9) g/L at baseline to 103.0 (7.0) g/L, 110.5 (7.5) g/L, and 118.9 (5.3) g/L at day 30, 60 and 90, respectively. Mean serum ferritin at day 90 was 17.9 (3.9) ng/mL with Feromenta. Adverse events were significantly less frequent in the Feromenta group, occurring in 12 (29.3%) patients, than in the ferrous sulfate group (n=22; 56.4%; p=0.015). Patient adherence to treatment was significantly better in the Feromenta group. At day 90, the mean number of tablets/containers returned in the Feromenta group was significantly lower than mean number of tablets returned in the ferrous sulfate group (1.53 versus 2.97, respectively, p = 0.015).

 

A controlled trial of Feromenta® versus an untreated control group included 50 healthy, non-anemic breast-feeding mothers with normal blood count indices, serum ferritin levels above 30 ng/mL, and sufficient quantity of breast milk. The study assessed the efficacy and safety of Feromenta® in breast-feeding mothers and their children. 25 women were treated with Feromenta® (100 mg iron/day) for 3 months, while the remaining 25 women did not receive any iron treatment. In mothers treated with Feromenta®, mean Hb increased from 111±0.41 to 124±0.56 g/L, and serum ferritin increased from 44.53±1.12 to 67.55±1.2 ng/mL, (p<0.001 for all parameters) after 3 months. In the untreated mothers, mean Hb decreased from 111.5±0.35 to

91.1±0.38 g/L, and serum ferritin decreased from 44.95±1.69 to 19.03±1.54 ng/mL (p<0.001 for all parameters). Significant increases (p<0.001) in breast milk iron (12.3±0.1 and 20.4±0.26 μmol/L) and lactoferrin (3.75±0.05 to 3.96±0.03 g/L) were observed in the mothers treated with Feromenta®.

A similar trend was observed in breast-fed children after 3 months, showing a significant decrease in Hb (167.1±0.45 g/L at baseline versus 125.9±0.59 g/L) and serum ferritin levels (from 151.5±1.51 ng/mL to 95.99±1.44 ng/mL) when mothers were not treated with iron (p<0.001 for all parameters). Newborns from mothers that received Feromenta® treatment showed normal Hb levels and iron parameters after 3 months. No significant adverse events from Feromenta® treatment were reported in any of the mothers or children.

 

These results were confirmed in another study in breast-feeding mothers with mild iron deficiency anemia (IDA) at 7 to 12 weeks postpartum. 7 women were treated with Feromenta® at a dosage of 300 mg iron per day, reduced by half after 2.5 to 3 months of treatment. An additional 14 breast-feeding mothers were treated with IPC in combination with folic acid (Feromenta® Fol). At 3.5 to 4 months of treatment, the mothers’ haematological parameters increased to within the normal range (e.g., Hb increased from 91±2.1 to 121±1.6 g/L, serum ferritin from 6 (2-12) to 34 (28-61) ng/mL) and the iron and lactoferrin levels measured in breast-milk improved. Red blood cell indices also improved in the breast-fed infants with Hb increasing from 114.1±1.8 g/L at baseline to 124.3±2.9 g/L at end of study.

 

Paediatric population

 

In a double-blind, controlled study, the efficacy, tolerability and treatment compliance of Feromenta® treatment was compared with ferrous sulfate drops. Children, aged between 6 months and 2 years, with a diagnosis of iron deficiency anemia (Hb=80-110 g/L; MCV ≤70 fL, serum iron ≤30 mcg/dL, TIBC <470 mcg/dL, TSAT ≤15%, serum ferritin <7 ng/mL) received either Feromenta® (n=50) or ferrous sulfate (n=50), administered at 5 mg iron/kg body weight in one daily dose in the early morning. The results are summarized in table 1:

 

Table 1: Efficacy parameters before and after 12 weeks of Feromenta® treatment in children with IDA

Feromenta® Group (n=45)
	Baseline	12 Weeks
Hb (g/L)	101.3 ± 8.9	118.9 ± 5.8
MCV (fL)	64.13 ± 10.80	78.68 ± 12.67
Serum iron (mcg/dL)	25.28 ± 9.67	45.34 ± 12.38
Serum ferritin (ng/mL)	18.73 ± 3.32	46.38 ± 3.34
Transferrin (mg/dL)	215.73 ± 30.48	216.38 ± 22.34
Transferrin saturation (%)	10.80 ± 3.20	15.33 ± 3.45

Notes: Hb = Haemoglobin; MCV = Mean corpuscular volume

The efficacy of Feromenta® and ferrous sulfate supplementation on haematological parameters was evaluated in a 6 months, randomised, comparative clinical trial in 37 children (aged 8 months to 14 years, 22 male and 15 female) with IDA (Hb <115 g/L, Hct <35%, MCV <75 fL, ferritin <20 ng/mL). The children were randomised to treatment with 6 mg iron/kg body weight daily as Feromenta® syrup (n=17) or ferrous sulfate (n=20) for 3 months, followed by a dose of 3 mg/kg body weight daily for a further 3 months. Mean Hb increased in the Feromenta® group from 100 ± 6 g/L to 116 ± 7 g/L during the 6 month treatment period, whereas serum ferritin levels decreased from 22.6 ± 24.3 ng/mL to 11.8 ± 7.8 ng/mL.

 

Efficacy, tolerability, and acceptability of treatment with Feromenta® syrup (n=52) was compared to ferrous glycine sulfate syrup (n=51) in a randomised, open-label study in 103 children with IDA aged >6 months. Patients received 5 mg iron/kg/day for 4 months. Mean increases in Hb from baseline to months 1 and 4 with Feromenta® were 12 ± 9 g/L and 23 ± 13 g/L, respectively, (both p=0.001 vs. baseline). In the Feromenta group, 26.9% of the children reported gastrointestinal adverse events compared to 50.9 % in the comparator group (p=0.012). At months 1 and 4, the acceptance and willingness of the children to take the medication was significantly higher in the Ferrum Hausmann® group Feromenta® than in the comparator group.

 

The efficacy and safety in the prevention of anemia was assessed in an open-label study comparing 6-8 months of treatment with Feromenta® drops and ferrous gluconate syrup in 105 healthy children aged 4-6 months at enrolment. Patients were randomly assigned to receive either Feromenta® (n=52) or ferrous gluconate (n=53), at a dose of 7.5 mg iron/day from ages 4-6 months and at 15.0 mg iron/day for ages 6-12 months. Feromenta® was effective at preventing IDA in infancy. The number of children with Hb <110 g/L was 19.2% (5.7 % in comparator group, p<0.04) and the mean level of Hb was 116.8 ± 1.1 g/L at the age one year (120.4 ± 0.9 g/L in comparator group, p=0.014). There was no significant difference in serum iron, serum ferritin, mean corpuscular volume, mean corpuscular haemoglobin, red cell distribution, haematocrit and transferrin between both groups at 12 months. Gastrointestinal tract symptoms were 25% in the Feromenta® group (comparator 47%, p=0.025).

The efficacy of Feromenta® was also investigated in 68 preterm infants (gestational age ≤32 weeks). Subjects received Feromenta® at 5 mg iron/kg/day starting at either 2 weeks (n=32) or 4 weeks (n=36) of age. Haematological and iron status parameters were measured at 2, 4 and 8 weeks of age. As expected, a gradual decrease in iron status was observed in both groups; however, beginning supplementation at 2 weeks of age was shown to be significantly more effective than at 4 weeks of age with respect to iron status.

 

The influence of meals taken concomitantly with Feromenta® was examined in a randomised multicentre, double-blind comparative clinical trial in 113 infants and small children (aged 6 months to 4 years; 61% were less than 2 years old) suffering from IDA (Hb <110 g/L). Treatment consisted of 2.5 mg iron/kg body weight daily, given as Feromenta® drops, either with meals (Group A) or between meals (1 hour before or 2 hours after any food, Group B) for a duration of 90 days. Clinical symptoms evaluated were tiredness, apathy, anorexia and irritability with a score allocated to each symptom (0 = absent, 1 = moderate, 2 = marked). A global score (0–8) was obtained by summing the scored symptoms. There was a significant decrease of the global clinical score in both groups: Feromenta® administration with meals, from mean 2.70 to 0.74; Feromenta® administration between meals, from 2.67 to 0.98. Hb levels increased from

98.4 g/L to 111.9 g/L in the group that received Feromenta® with food for 90 days, and from 98.5 g/L to 111.0 g/L in the other group (both, p<0.05). This study confirms that Feromenta® can be administered simultaneously with meals without an impairment of its effectiveness.

 

Absorption

The iron of IPC is absorbed by a controlled mechanism. Serum iron increase after application does not correlate with total iron absorption measured as incorporation in Hb. Studies with radiolabelled IPC showed that there is a good correlation between the percentage of erythrocyte uptake (incorporation in Hb) and the absorption quantified by whole body count. The highest absorption of iron from IPC is in the duodenum and jejunum. As with other oral iron preparations, the relative absorption of iron from IPC, measured as incorporation in Hb, decreased with increasing doses of iron. A correlation between the extent of iron deficiency (i.e., serum ferritin levels) and the relative amount of iron absorbed was also observed (i.e., the higher the iron deficiency, the better the relative absorption). In contrast to ferrous salts, iron absorption from IPC has been shown to be increased in the presence of food when given to anaemic subjects.

 

Distribution

The distribution of iron from IPC after absorption has been shown in a study using twin-isotope technique (55Fe and 59Fe).

 

Biotransformation

The iron absorbed from IPC is used in the bone marrow for Hb synthesis or is stored, mainly in the liver, bound to ferritin.

 

Elimination

Iron that is not absorbed is excreted via the faeces.

 

Pharmacokinetics in special populations

No data available.

Nonclinical data established with IPC reveal no special hazard for humans based on conventional studies of single-dose and repeated dose toxicity, genotoxicity, or reproductive and developmental toxicity.

Carcinogenicity

No long-term studies of tumourigenic potential are available.

 

Mutagenicity

No genotoxic effects were observed for IPC in assays for gene mutation (in vitro bacterial assay) and chromosomal damage (human lymphocytes in vitro and rat micronucleus test in vivo).

 

Impairment of fertility

Fertility studies of IPC in animals did not reveal any effects on fertility or early embryonic development.

 

Teratogenicity

Embryo-foetal toxicity studies of IPC in animals did not reveal any foetal risk. Treatment of rats and rabbits with IPC during organogenesis did not induce any teratogenic or embryolethal effects. Based on these animal studies, there is no evidence of a risk during the first trimester.

No effects of IPC on pre- and post-natal development of offspring were observed in a study in rats, in which dams were treated from Day 6 after mating to Day 20 of lactation, inclusive.

 

Other

The LD50 for IPC, as determined in animal studies with mice or rats was greater than an orally administered dose of 2,000 mg of iron per kilogram body weight. The available preclinical data on toxicity after a single dose and repeated administration have yielded no further information that has not already been mentioned in other sections.

Aspartame NF: 1.50 mg.

Chocolate Essence Powder : 0.60 mg.

Polyethylene glycol MW 6000: 37.00 mg.

Purified Talc: 37.00 mg.

Ethanol 96 percent: 20.00 mg.

Emdex: 730.00 mg.

Citric acid anhydrous: 21.9 mg.

Not applicable.

24 Months / 2 Years.

Do not store above 30○ C and keep in the original package (i.e., outer carton) in order to protect from light.

30/pack.

Aluminum thin strip temper plain, dull side lacquer laminated to oriented polyamide film. Bright side lacquer laminated to PVC w/ hard tempered aluminum foil lid.

No special requirements.