Source: European Medicines Agency (EU) Revision Year: 2015 Publisher: Mitsubishi Tanabe Pharma Europe Ltd., Dashwood House, 69 Old Broad Street, London, EC2M 1QS, United Kingdom Tel: +44 (0)207 065 5000 Fax: +44 (0)207 065 5050 Email: info@mt-pharma-eu.com
The safety and efficacy of BindRen has not been studied in patients with:
Therefore, the use of BindRen is not recommended in patients with these disorders.
BindRen alone is not indicated for the control of hyperparathyroidism.
In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with BindRen. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with BindRen. In patients who develop severe constipation or other severe gastrointestinal symptoms, alternative treatment may need to be considered.
Caution should be exercised when treating patients with conditions which predispose to gastrointestinal haemorrhage, such as recent history of gastrointestinal haemorrhage, gastrointestinal ulcers, gastritis, diverticulosis, colitis and haemorrhoids.
Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. BindRen does not contain calcium, and has no effect on serum calcium concentrations on treatment for up to one year. Serum calcium concentrations should be monitored as a normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia.
BindRen did not induce any clinically relevant reduction in the absorption of vitamins A, D, E or K during clinical studies of up to one year. However, caution should be exercised when treating patients with a susceptibility to vitamin K or fat-soluble vitamin deficiencies, such as patients with malabsorption syndromes and patients treated with coumarin anticoagulants (e.g. warfarin). In these patients, monitoring of vitamin A, D and E concentrations or assessing vitamin K status through the measurement of coagulation parameters is recommended and the vitamins should be supplemented if necessary.
BindRen did not induce a clinically relevant reduction in folate absorption during clinical studies of up to one year. However, intestinal folate absorption may be impaired during long-term treatment of BindRen. In these patients, monitoring serum folate status and supplementation with folic acid should be considered.
Close monitoring of patients with hypothyroidism is recommended when levothyroxine is co-administered with BindRen (see section 4.5).
BindRen binds phosphate and bile acid, with the release of chloride which is available for systemic absorption. Changes in systemic ion balance with an increase in chloride and decrease in bicarbonate are therefore possible. However, BindRen did not induce any clinically relevant change in chloride and bicarbonate on treatment for up to one year.
BindRen is not absorbed from the gastrointestinal tract but may affect the bioavailability or absorption rate of other medicinal products. In addition, reduced bioavailability of other medicinal products by changes in enterohepatic circulation, for example, steroid hormones with potential impairment of the effectiveness of oral contraceptives, have been reported for medicinal products with a similar mechanism of action to BindRen. When administering any medicinal product where a reduction in the bioavailability could have a clinically relevant effect on safety or efficacy, the medicinal product should be administered at least 1 hour before, or 3 hours after taking BindRen. Concomitant treatment with medicinal products with a narrow therapeutic window requires close monitoring of drug concentrations or adverse reactions, on initiation or dose-adjustment of either BindRen or the concomitant medicinal product.
Interaction studies have been conducted in healthy volunteers. Interactions have not been studied at doses >9 g daily, and greater interaction effects at higher doses of BindRen cannot be excluded.
Single dose interaction studies demonstrated that the bioavailability of ciprofloxacin, warfarin and enalapril were not affected when co-administered with BindRen (6-9 g/day). BindRen lowered the bioavailability of digoxin by 16% and Cmax by 17%, and the Cmax of enalapril by 27%.
Due to the high in vitro binding potential between BindRen and levothyroxine, closer monitoring of thyroid stimulating hormone (TSH) levels in patients receiving BindRen and levothyroxine is recommended.
No in vivo data are available on the possible interaction of BindRen on the absorption of the immunosuppressant medicinal products mycophenolate mofetil, ciclosporin or tacrolimus. However, decreased blood concentrations have been reported for medicinal products with a similar mechanism of action to BindRen. Caution should be exercised when prescribing BindRen to patients receiving immunosuppressants.
Patients with seizure disorders were excluded from clinical trials with BindRen. Caution should be exercised when prescribing BindRen to patients also taking anti-seizure medicinal products.
BindRen is not absorbed and is not systemically available. No direct effects of BindRen are thus anticipated. However, other effects of BindRen may affect pregnant and breast-feeding women or influence fertility, see sections 4.4 and 4.5.
No data are available to assess the safety and efficacy in pregnant women. Patients that become pregnant and where a benefit/risk assessment confirms continued treatment with BindRen, supplementation of vitamins may be required, see section 4.4.
No data are available to assess the safety and efficacy in breast-feeding women. Patients that breast-feed and where a benefit/risk assessment confirms continued treatment with BindRen, supplementation of vitamins may be required, see section 4.4.
No data are available to assess the potential influence of BindRen on fertility.
BindRen has no or negligible influence on the ability to drive and use machines.
The Phase II and III clinical studies involving 1,410 patients with CKD Stage 5 on dialysis treated with BindRen for up to one year constituted the safety population. Patients received doses of up to 15 g per day, in three divided doses of 5 g.
Approximately 30% of patients experienced at least one adverse reaction. The most serious adverse reactions were gastrointestinal haemorrhage (uncommon) and constipation (common). The most frequently reported adverse reactions were nausea, dyspepsia and vomiting (all common). The frequency of adverse reactions increased with dose.
A tabulated list of frequencies was defined using the following convention: 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). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Uncommon: Gastroenteritis
Uncommon: Hyperparathyroidism
Common: Hypocalcaemia, decreased appetite
Uncommon: Folate deficiency, hypertriglyceridaemia, polydipsia
Rare: Vitamin K deficiency, calciphylaxis, electrolyte imbalance, fluid overload
Uncommon: Insomnia
Uncommon: Tremor, dizziness, headache, dysgeusia
Rare: Coronary artery disease
Uncommon: Haematoma, hypotension
Common: Constipation, abdominal pain, vomiting, abdominal distension, nausea, gastritis, dyspepsia, diarrhoea, flatulence, abdominal discomfort
Uncommon: Gastrointestinal haemorrhage, oesophagitis, faecaloma, dysphagia, change in bowel habit, dry mouth
Rare: Intestinal obstruction*
Uncommon: Hepatic enzymes increased
Uncommon: Urticaria, rash, pruritus, dry skin
Rare: Allergic dermatitis, guttae psoriasis
Uncommon: Muscle spasm, musculoskeletal pain, arthralgia, back pain, pain in extremities
Uncommon: Asthenia
* A single case with a fatal outcome
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 listed in Appendix V.
Not applicable.
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