1. NAME OF THE MEDICINAL PRODUCT

Folavit 1 mg tablets Folavit 5 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Folavit 1 mg tablets Each tablet contains 1 mg folic acid. Excipients with known effect: each tablet contains 72,2 mg lactose (as monohydrate) and 8,3 mg sucrose. For the full list of excipients, see section 6.1.

Folavit 5 mg tablets Each tablet contains 5 mg folic acid. Excipients with known effect: each tablet contains 68,4 mg lactose (as monohydrate) and 8,3 mg sucrose. For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet

Folavit 1 mg tablets Light yellow or light yellow orange speckled, round, biconvex tablet of 7 mm with a score-line on one side. The tablet can be divided into two equal doses.

Folavit 5 mg tablets Yellow or yellow orange speckled, round, biconvex tablet of 7 mm with a score-line on one side. The tablet can be divided into two equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Folavit is indicated in adults and children.

- Reduction of side effects in patients receiving low-dose methotrexate therapy for rheumatoid arthritis, psoriasis and inflammatory bowel disease.

- Prevention or treatment of folate deficiency, which may cause macrocytic anemia. Folate deficiency is associated with elevated homocysteine levels. Various conditions can cause folate deficiency: - Inadequate dietary intake (e.g. malnutrition in the elderly) - Malabsorption (e.g. coeliac disease, bariatric surgery, inflammatory bowel disease, alcoholism) - Increased utilization (e.g. pregnancy, lactation, hemolytic anemia) - Increased loss (e.g. hemodialysis)

1 - Intake of medications (e.g. certain antiepileptic drugs, sulphasalazine, pemetrexed). Folic acid supplementation reduces the hematological toxicity of pemetrexed.

- Prevention of neural tube defects. Women at high risk include: - Previous pregnancy affected by a neural tube defect or woman or partner are affected by a neural tube defect themselves - Family history of neural tube defects - Use of antiepileptic drugs - Diabetes mellitus (type 1 and type 2) - Obesity - Malabsorption (e.g. coeliac disease, bariatric surgery) - Thalassemia or sickle cell anemia - Use of sulphasalazine - Use of proguanil

4.2 Posology and method of administration

Posology

- Reduction of side effects during low-dose methotrexate therapy: 5 to 10 mg once a week (24h after methotrexate intake, see section 4.5) or 1 mg daily. Other dosage regimens can be justified.

- Prevention or treatment of folate deficiency: 0,5-5 mg daily; higher doses may be necessary in some patients e.g. in malabsorption states. Folic acid doses > 1 mg/day should be avoided during treatment with certain antiepileptic drugs (see section 4.4 and 4.5).

- Reduction of side effects of pemetrexed therapy: 1 mg daily. At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed (unless prescribed otherwise) and daily dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed.

- Prevention of neural tube defects in women at high risk: 5 mg daily, starting at least 1 month before conception and continuing during the first trimester of pregnancy.

- Prevention of neural tube defects in women at no elevated risk: 0,5 mg daily, starting at least 1 month before conception and continuing during the first trimester of pregnancy.

Paediatric population

- Reduction of side effects low-dose methotrexate therapy: similar doses as adults.

- Prevention or treatment of folate deficiency:

- Neonates: 50 µg folic acid once daily - Children aged less than 1 year: 0,5 mg folic acid/kg once daily - Children aged 1 – 18 years: similar doses as adults.

Method of administration

Oral use.

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The tablets can be taken with or without food, with a glass of water.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Vitamin B12 deficiency unless simultaneous folic acid deficiency can be documented and administered with adequate amounts of cobalamine. Folic acid should never be given alone in the treatment of pernicious anemia and other vitamin B12 deficiency states (see section 4.4). - Megaloblastic anaemia of unknown origin, unless vitamin B12 deficiency can be excluded (see section 4.4). - Patients with malignant disease, unless prevention or treatment of folate deficiency associated hematological disorders is advisable (see section 4.4).

4.4 Special warnings and precautions for use

- Folic acid treatment can mask a concurrent vitamin B12 deficiency, or the development of such, as it may resolve the megaloblastic anemia due to vitamin B12 deficiency. However, it does not prevent aggravation of neurological symptoms, which may result in irreversible nerve damage (see section 4.3). - Caution should be taken when treating patients which may have folate dependant tumour disease. Folic acid supplements may increase growth of already existing malignity (see section 4.3). - Folic acid supplementation should be avoided during treatment with fluorouracil or its prodrugs as it may increase fluorouracil toxicity (see section 4.5). - Folic acid supplementation should be avoided during treatment with raltitrexed as it may possibly interfere with the action of raltitrexed (see section 4.5). - Folic acid doses > 1 mg/day should be avoided during treatment with certain antiepileptic drugs in order to avoid decreased seizure control (see section 4.5) except for prevention of neural tube defects where 5 mg/day should be taken. - Folate deficiency due to high-dose (antitumoral) methotrexate, pyrimethamine or trimethoprim (dihydrofolate reductase inhibitors) should be treated with folinic acid instead of folic acid (see section 4.5). - This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of fructose intolerance, galactose intolerance, total lactase deficiency, sucrase- isomaltase insufficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

- Folic acid may increase toxicity of fluorouracil (pyrimidine analogue) and its prodrugs capecitabine and tegafur. Folic acid supplementation should be avoided. On the other hand, folinic acid may be used therapeutically in combination with fluorouracil (prodrugs) as adjuvant (see section 4.4). In this case, the dose of the cytostatic drug should be decreased. - Folic acid may interfere with the action of raltitrexed. Folic acid supplementation should be avoided (see section 4.4). - Intake of certain antiepileptic drugs may cause subnormal serum folate levels (in particular phenytoin, phenobarbital and primidone, possibly also carbamazepine and valproate). Conversely, if folic acid supplements are given to treat folate deficiency, the serum antiepileptic drug levels may fall, leading to decreased seizure control in some patients. Therefore, high dose folic acid supplementation (> 1 mg/day) should be avoided and levels of antiepileptic drugs (phenytoin, phenobarbital, primidone, pheneturide and carbamazepine) should be monitored in

3 case folic acid supplements are administered (see section 4.2). The antiepileptic drug dose should be adjusted if necessary. - High folic acid dose (i.e. dosage regimen of 5 to 10 mg folic acid once a week) should not be taken on the same day as methotrexate. Instead, it should be taken the day after methotrexate intake in order to avoid potential interference with methotrexate efficacy (see section 4.2). - Folate antagonists including high-dose (antitumoral) methotrexate, pyrimethamine and trimethoprim may cause hematological toxicity due to folate deficiency. Administration of folinic acid is the appropriate treatment (see section 4.4). - Treatment with cholestyramine or colestipol may interfere with folate absorption and cause folate deficiency. Folic acid supplements should be taken at least 1 h before or 4-6 h after cholestyramine or colestipol administration. - Treatment with sulphasalazine may cause folate deficiency. - Chronic alcoholism may cause folate deficiency. - Oral contraceptive use may cause reduced serum folate levels. - Treatment with triamterene may cause folate deficiency. Moreover, folic acid and triamterene may inhibit each other’s absorption. - Folic acid may increase the antidepressant action of fluoxetine.

Antibiotics may interfere with the microbiological assay for folic acid concentrations and may cause falsely low results.

4.6 Fertility, pregnancy and lactation

Pregnancy There are no known hazards to the use of folic acid in pregnancy. Pregnant women have higher folate requirements associated with the growth of fetal and maternal tissue and the active transfer of folate to the fetus. Periconceptional folic acid supplementation decreases the risk of a pregnancy affected by a neural tube defect.

Breastfeeding Folic acid is actively secreted in human breast milk. Breast milk folate concentrations are maintained at the expense of maternal folate reserves and are not affected by low maternal folate intake, unless women are severely folate deficient (see section 5.2). Folate requirements are increased during lactation. There are no known adverse events in breast fed infants whose mothers were receiving folic acid supplements.

Fertility There is no evidence for a negative effect of folic acid supplementation on male or female fertility.

4.7 Effects on ability to drive and use machines

Folavit has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of safety profile

Cases of hypersensitivity to folic acid, including anaphylactic reactions, have been reported.

Tabulated summary of adverse reactions

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The following adverse events have been reported in literature (case reports). The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

System Organ Class Frequency Adverse event Immune system disorders Not known Hypersensitivity Not known Anaphylactic reaction Gastrointestinal disorders Not known Nausea, vomiting, diarrhoea Skin and subcutaneous tissue Not known Fixed eruption, rash, pruritus, disorders erythema, urticaria, face angioedema

Description of selected adverse reactions

Hypersensitivity reactions have been reported and mostly affect the skin, although gastrointestinal disorders as part of the hypersensitivity reaction have occurred in some cases. Anaphylactic reaction after folic acid intake has also been reported.

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 the national reporting system.

4.9 Overdose

Overdose generally produces no symptoms. Even with doses as high as 15 mg per day, there have been no substantiated reports of side effects.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antianemic preparations - Folic acid and derivatives, ATC code: B03BB01.

Mechanism of action Folic acid (vitamin B9) is converted in the body to the biologically active form of folate. Folates function as cofactors for enzymes involved in numerous one-carbon transfer reactions that are important for the synthesis of RNA and DNA (formation of purine nucleotides and thymidylate), amino acid interconversions (e.g. conversion of homocysteine to methionine) and the process of methylation (production of the universal methyl donor S-adenosylmethionine). Different folate forms are involved in specific reactions.

Pharmacodynamic effects Folate is important for cell division and tissue growth. Therefore, folate deficiency adversely affects rapidly proliferating tissues such as bone marrow resulting in decreased production of blood cells. Folate deficiency may cause macrocytic megaloblastic anemia. S-adenosylmethionine donates its methyl group to methyltransferases for a wide range of substrates (e.g. DNA), all of which are regulators of important physiological processes.

5 Folate deficiency results in elevation of plasma homocysteine levels and insufficient production of S- adenosylmethionine with potential impairment of some methylation pathways. Folate deficiency during early pregnancy increases the risk of neural tube defects.

5.2 Pharmacokinetic properties

Absorption Folic acid is rapidly absorbed from the gastrointestinal tract, mainly from the duodenum and jejunum. It is estimated that food folates have about half the bioavalability of folic acid. Folic acid absorption involves active transport. After entering the intestinal cells, folic acid is reduced and methylated before entering the blood stream. Folic acid also enters the portal vein unchanged, with reduction and methylation taking place only once it reaches the liver. Passive diffusion across the cell membrane is limited, and occurs only at high doses. To a minor extent folate is also absorbed in the colon, and it is suggested that it may contribute significantly to total folate absorption.

Distribution The predominant form of folate in the circulation is 5-methyltetrahydrofolate. It is mainly bound to albumin. The principal storage site of folate is in the liver. The transport of folate to body tissues requires the involvement of folate transporters. Folate crosses the blood brain barrier, it is transported across the placenta and excreted into breast milk.

Biotransformation Folic acid is reduced and methylated to 5-methyltetrafolate in the liver, which is then transported to the bile and secreted in order to be reabsorbed via the intestines (enterohepatic cycle). The interconversion between different folate forms occurs through the folate-mediated one-carbon metabolic pathway.

Elimination Folic acid metabolites are eliminated in the urine and folate in excess of body requirements is excreted unchanged in the urine. The elimination also occurs via the faeces. Folic acid is removed by haemodialysis. Folate is secreted via breast milk. Folic acid supplementation in well-nourished lactating women does not affect breast milk folate concentration, whereas, in women with severe folate deficiency, supplementation increases the folate concentration of breast milk even before any improvement in maternal folate status is seen (see section 4.6).

Genetic polymorphism The C677T variant in the gene encoding methylenetetrahydrofolate reductase (MTHFR) is the most well-known genetic factor influencing folate status. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in an irreversible reaction. Homozygosity for the T allele is associated with reduced enzyme activity (up to 70% lower), around 20-25% lower serum folate and higher plasma total homocysteine concentrations compared with the 677CC genotype. The prevalence of MTHFR C677T polymorphism varies depending on the ethnicity and geographical region.

Renal impairment Chronic kidney disease may be associated with folic acid deficiency and hyperhomocysteinemia, especially amongst dialysis patients. Folic acid is removed by haemodialysis.

Hepatic impairment

6 Various liver diseases may be associated with folate deficiency. The degree of liver function impairment seems to be of little significance.

Weight Suboptimum plasma folate concentrations have been reported in obese women of childbearing age, which may be a possible contributor in increasing the risk of neural tube defects.

5.3 Preclinical safety data

Studies in animal models suggested that folic acid supplementation may promote the progression of established (pre)cancerous cells.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Starch, pregelatinized Sucrose Macrogol 4000 Stearic acid Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister packs: 18 months Containers: 9 months

6.4 Special precautions for storage

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Blister packs (Alu/PVC/PVdC/PVC) with 40 tablets. HDPE containers with LDPE cap with 250 or 1000 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 7. MARKETING AUTHORISATION HOLDER

To be completed nationally

8. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY} Date of latest renewal: {DD month YYYY}

10. DATE OF REVISION OF THE TEXT

MM/YYYY

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