Hyperphosphataemia in adult patients with chronic renal insufficiency under dialysis
treatment (haemodialysis, peritoneal dialysis).

The tablets must be taken orally with food and chewed. Do not swallow them whole.

Use
Velphoro is a chewable tablet that must be taken with meals. In order to increase phosphate
absorption from food, the daily dose should be divided between the meals of the day.
Patients do not need to drink more fluids than usual. The tablets must be chewed and must
not be swallowed whole. The tablets can be broken into small pieces. If you forget to take
one or more doses, the normal dose must be taken as usual with the next meal.

Initial dose
The recommended initial dose of Velphoro is 3 tablets (1,500 mg) per day.

Titration and maintenance
Serum phosphate levels must be monitored and the Velphoro dose increased or decreased
every 2–4 weeks in 500 mg increments (1 tablet) per day until an acceptable serum
phosphate level is attained. After that, the serum phosphate levels must be monitored
regularly.
In clinical practice, treatment takes place based on the need to check the serum phosphate
levels. Patients who respond to Velphoro usually reach the optimal serum phosphate level
using a daily dose of 1,500 to 2,000 mg (3–4 tablets).

Maximum daily dose
The maximum daily dose is 3,000 mg (6 tablets) per day.

Specific dosage instructions
Paediatric population
The efficacy and safety of Velphoro in children and adolescents under 18 years old has not
been studied.

Elderly patients
In clinical studies, Velphoro was administered to 248 patients aged ≥ 65. 73 of the patients
were ≥75 years old. No special posology or administration guidelines for elderly patients were
used in the study.

Patients with hepatic diseases
There are only limited clinical data on the use of Velphoro in patients with hepatic diseases.
Patients with elevated transaminases (≥3× ULN) were not investigated in the clinical study.
Velphoro should be administered with care in these patients (see “Special warnings and
precautions for use”).

Long-term experience with Velphoro is limited. In the pivotal clinical studies, the maximum
observation time was 55 weeks. It is recommended that the iron homeostasis be checked at
regular intervals in the case of long-term use.
There are only limited data on the use of Velphoro in patients with peritoneal dialysis (see
“Properties/Effects”).
Patients with a history of peritonitis, patients with clinically relevant diseases of the liver or
gastrointestinal tract or those who had had major gastrointestinal operations were not
investigated in clinical studies.
Velphoro should only be administered with caution in the aforementioned patient groups and
with strict monitoring of clinical status, serum electrolytes and iron homeostasis.
Velphoro can lead to a (reversible) discolouration of the teeth and tongue. There is often a
darkening of the stool in patients taking Velphoro. Velphoro does not affect the common
systems to test for occult blood in the stool.
Velphoro contains sucrose. Patients with a rare hereditary fructose intolerance, glucosegalactose
malabsorption or saccharase-isomaltase deficiency should not take this medicinal
product. It may be harmful to the teeth.

No interaction studies have been performed with dialysis patients.
Interaction studies have only been performed with healthy subjects.
Losartan, furosemide, digoxin, warfarin and omeprazole were studied in clinical studies on
interactions with other medicinal products. Concomitant administration of Velphoro did not
affect the bioavailability of these medicinal products. In in vitro studies, the adsorption of the
following medicinal products to Velphoro was observed: alendronate, doxycycline,
levothyroxine, atorvastatin, doxercalciferol and paricalcitol. These interactions can lead to a
decreased bioavailability of the medicinal products mentioned, which, apart from
doxercalciferol and paricalcitol, have not been studied in clinical trials. This means that
clinically relevant interactions cannot be ruled out.. Therefore, these medicinal products
should be administered at least 1 hour before or 2 hours after Velphoro. In addition, clinical
studies demonstrated no impact of Velphoro on iPTH lowering effect of oral Vitamin D
analogues(e.g. doxercalciferol, paricalcitol).
Medicinal products that are known to interact with iron (e.g. bisphosphonates, tetracycline,
levothyroxine, ciprofloxacin, mycophenolate, mycophenolate mofetil, integrase inhibitors and
complexing agents in general) should be administered at least 1 hour before or 2 hours after
Velphoro. For some medicinal products, it may be necessary to leave a longer period of time between taking Velphoro and taking the additional medicinal product (e.g. doxycycline). The Summary of Product Characteristics for the additional medicinal product should also be
consulted.
The effect of vitamin C on the resorption of iron from Velphoro has not been investigated.
Vitamin C should therefore generally be administered at least 1 hour before or 2 hours after
Velphoro.
In vitro studies with the following medicinal products revealed no significant interactions:
acetylsalicylic acid, cephalexin, cinacalcet, ciprofloxacin, clopidogrel, enalapril,
hydrochlorothiazide, metformin, metoprolol, nifedipine, pioglitazone, simvastatin and
quinidine.

There are no clinical data on the use of Velphoro during pregnancy.
Animal studies on reproductive and developmental toxicity have not demonstrated any
undesirable effects with respect to pregnancy, embryonic and foetal development, the birth
process or postnatal development.
Use with caution during pregnancy.

Breastfeeding
There are no clinical data on the use of Velphoro in breastfeeding mothers. The insignificant
absorption of iron from Velphoro makes excretion into breast milk unlikely. In order to decide
whether to continue breastfeeding or to continue the Velphoro therapy, the benefits for the
breastfed infant and the benefits of the Velphoro therapy for the mother must be weighed
against each other.

There are no studies on the effects of taking Velphoro on the ability to drive and use
machines.

The following undesirable effects have been reported in clinical studies with Velphoro.
Frequency of undesirable effects:
Very common: ≥1/10
Common: ≥1/100, <1/10
Uncommon: ≥1/1000, <1/100
Rare: ≥1/10,000, <1/1000
Velphoro was studied in two active substance-controlled pivotal studies. A total of n=778
haemodialysis patients and n=57 peritoneal dialysis patients were treated for up to a
maximum of 55 weeks. The dosage for these patients was between 250 mg iron/day and
3,000 mg iron/day.

Metabolism and nutrition disorders
Uncommon: hypercalcaemia, hypocalcaemia

Nervous system disorders
Uncommon: headache

Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnoea

Gastrointestinal disorders
Very common: diarrhoea*, faeces discoloured
Common: nausea, constipation, vomiting, dyspepsia, abdominal pain, flatulence,
discolouration of the teeth
Uncommon: abdominal distension (tightness in the abdomen), gastritis, abdominal discomfort,
dysphagia, gastro-oesophageal reflux disease (GORD), discolouration of the tongue, loss of
appetite

Skin and subcutaneous tissue disorders
Uncommon: pruritus, rash

General disorders and administration site conditions
Common: abnormal product taste
Uncommon: fatigue

Description of selected undesirable effects
*Diarrhoea11.6% of clinical study participants suffered from diarrhoea. In long-term studies of
over 55 weeks, the majority of diarrhoeal instances were minor (59.8%) and transient, and
occurred soon after the initiation of treatment. It caused 3.1% of the patients to discontinue
treatment.

To reports any side effect(s):
Saudi Arabia:

To report any side effect(s):

-The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

No instances of overdose with Velphoro are known. An overdose should be treated in
accordance with the common clinical practice.

Mechanism of action
The active substance of Velphoro is a mixture of polynuclear iron(III) oxyhydroxide
(pn-FeOOH), sucrose and starch. In the aqueous environment of the GI tract, phosphate
binding occurs through ligand exchange between hydroxyl groups and/or water and
phosphate ions through the physiological pH value of the GI tract.
Both serum phosphate levels and calcium phosphate products decrease due to reduced
phosphate absorption from food.

Clinical efficacy and safety
N=835 patients have been treated with Velphoro in clinical studies at a dosage of up to
3,000 mg iron/day.
Velphoro was studied in two pivotal studies: in a 6week,
open-label, randomised, activecontrolled (sevelamer hydrochloride), parallel-group, dose-finding study; and a 55week,
open-label, randomised, active-controlled (sevelamer carbonate) safety and efficacy study.

A 6week open-label randomised, active-controlled, dose-finding study with
haemodialysis patients suffering from hyperphosphataemia
A 6week randomised, open-label, active-controlled phase II dose-finding study was
conducted with 154 haemodialysis patients. Of these, 128 patients received Velphoro in a
fixed dose and 26 patients received a comparator product (sevelamer hydrochloride).
Velphoro showed a significant reduction in the serum phosphate level compared to the
baseline at doses of 1,000 mg iron/day to 2,500 mg iron/day. Overall, the reduction of the
serum phosphate in this dose range seemed to be comparable to that for treatment with
sevelamer hydrochloride (4,800 mg/day).

27week,open-label, randomised, active-controlled safety and efficacy study
(PACL05A)followed by a prolonged 28week extended safety study (PACL05B)
of dialysis patients with hyperphosphataemia
In study PACL05A, 1,055 patients (968 haemodialysis and 87 peritoneal dialysis) with
hyperphosphataemia were investigated. They received Velphoro (initial dose 1,000 mg
iron/day, 707 patients) or the comparator product sevelamer carbonate (initial dose 2.4 g,
348 patients).
Dose titration was possible for a period of 8 weeks at 2week intervals for efficacy and safety
reasons. The daily dose was able to be increased by 500 mg iron (Velphoro) and 2.4 g
(sevelamer) each time. The target phosphate range was defined as 0.81–1.78 mmol/L (2.5–
5.5 mg%). In the case of values outside of this target range or problems with tolerability, the
dose was adjusted. After week 8, the dose was kept constant until week 12. It was also
possible to reduce the dose during this period for reasons of tolerability.
From week 12, titrations for efficacy and safety reasons were possible again. The dose was
adjusted every four weeks.
After 24 weeks, 94 haemodialysis patients who were treated with Velphoro were randomised
again and received Velphoro for an additional 3 weeks either at its maintenance dose
(45 patients) or at a non-effective low dose (250 mg iron/day, 49 patients). At the end of this
3week period (week 27), a primary efficacy analysis was performed with regard to the
change in serum phosphorus compared to week 24. The Velphoro maintenance dose (1,000 to 3,000 mg iron/day) was shown to be significantly superior to the Velphoro control dose (250 mg iron/day) in terms of maintaining the phosphate-reducing effect.
The maximum daily dose of Velphoro was 3,000 mg iron/day and the minimum daily dose
was 1,000 mg iron/day.
The study also met the predefined secondary endpoint, which was to demonstrate the noninferiority
of Velphoro compared to the active comparator product (sevelamer carbonate)
after 12 weeks of treatment. The average change in the serum phosphate at week 12
compared to the baseline was 0.71 mmol/L in the Velphoro group and 0.79 mmol/L in the
sevelamer group.
After concluding PACL05A, 658 patients (597 haemodialysis and 61 peritoneal dialysis
patients) continued treatment in the original randomisation with either Velphoro (n=391) or
sevelamer carbonate (n=267) in the context of the 28week safety extension study(PACL05B).

The efficacy of Velphoro in terms of lowering serum phosphate levels was maintained during
the entire observation period. The average number of tablets to be taken in this part of the
study was around 4 tablets per day for the patients treated with Velphoro compared to
around 10 tablets per day for those on sevelamer.
Post-authorisation data

A prospective, non-interventional, post-authorisation safety study (VERIFIE) has been
conducted, evaluating the short- and long-term (up to 36 months) safety and effectiveness of
Velphoro in adult patients on haemodialysis (N=1,198) or peritoneal dialysis (N=160), who
were followed in routine clinical practice for 12 to 36 months (safety analysis set, N=1,365).
During the study, 45% (N=618) of these patients were concomitantly treated with phosphate
binder(s) other than Velphoro.

In the safety analysis set, the most common undesirable effects were diarrhoea and
discoloured faeces, reported by 14% (N=194) and 9% (N=128) of patients, respectively. The
incidence of diarrhoea was highest in the first week and decreased with duration of use.
Diarrhoea was of mild to moderate intensity in most patients and resolved in the majority of
patients within 2 weeks. Discoloured (black) faeces is expected for an oral iron-based
compound, and may visually mask gastrointestinal bleeding. For 4 of the 40 documented
concomitant gastrointestinal bleeding events, Velphoro-related stool discolouration was
reported as causing an insignificant delay in diagnosis of gastrointestinal bleeding, without
affecting patient health. In the remaining cases, no delay in diagnosis of gastrointestinal
bleeding has been reported.

The results from this study showed that the effectiveness of Velphoro in a real-life setting
(including concomitant use of other phosphate binders in 45% of patients), was in line with
that observed in the phase 3 clinical study.

Velphoro works by binding phosphate in the GI tract, so systemic availability is not relevant to
the efficacy.

Absorption
The active substance of Velphoro, pnFeOOH is practically insoluble and is therefore not
absorbed. Its degradation products, mononuclear iron species, can, however, be released
from the surface of pnFeOOH and absorbed.
The iron absorption from Velphoro’s radioactively labelled active substance, 2,000 mg iron a
day, was examined in 16 patients with chronic kidney disease (8 predialysis and
8 haemodialysis patients) and in 8 healthy subjects with low iron reserves (serum ferritin
<100 mcg/L). In healthy subjects, the median uptake of radioactively labelled iron in the blood
on day 21 was 0.43% of the dose (min. 0.16% – max. 1.25%). In pre-dialysis patients, the
median uptake of radioactively labelled iron in the blood on day 21 was 0.06% of the dose
(corresponding to a median uptake of 1.2 mg of iron (minimum value 0.16 mg – maximum
value 8.8 mg of iron)). In haemodialysis patients, the median uptake was 0.02% of the dose
(corresponding to a median uptake of 0.4 mg of iron (minimum value 0 mg iron– maximum
value 0.8 mg of iron)). Blood concentrations of radioactively labelled iron were very low and
restricted to the erythrocytes.

Distribution
Due to the low solubility and the decomposition characteristics of Velphoro, no classical
pharmacokinetic studies have been carried out and the distribution of the medicinal product
has not been determined.

Biotransformation
The active substance of Velphoro, pnFeOOH, is not metabolised. The degradation products
of Velphoro, mononuclear iron species, can be absorbed, however. It can be assumed that
this iron goes into the physiological iron metabolism.
In vitro data suggest that the sucrose and starch components of the active medicinal
substance may be digested to form glucose and fructose or maltose and glucose. These
compounds can be absorbed into the blood.

Elimination
In animal studies with rats and dogs where the 59Fe Velphoro medicinal active substance was
administered orally, radioactively labelled iron was detected in faeces but not in urine.
On the basis of these preclinical studies, the excretion of the iron that is not absorbed (>99%
of the dose administered) is expected in the faeces.

Kinetics in special patient groups
No studies have been carried out in children or patients with reduced hepatic function.

Non-clinical data reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction and development.
Carcinogenicity studies were conducted in mice and rats.
A carcinogenic effect in mice was not clearly demonstrated. After two years of treatment,
membrane hyperplasia with the formation of diverticula/cysts was observed in the colon and
appendix of mice; however, this was regarded as a species-specific effect, as no
diverticula/cysts occurred in long-term studies with rats or dogs. In the case of rats, there was
a slightly increased incidence of benign Ccell adenoma in the thyroid glands of males who
had received sucroferric oxyhydroxide in the highest dose. The view is that this is most likely
an adaptive reaction to the pharmacological effect of the medicinal product.

Fertility
There are no data indicating the effects of Velphoro on human fertility. In animal studies, no
negative effects were observed on mating performance, fertility or litter parameters after
treatment with Velphoro.

Magnesium stearate
Silica (colloidalis anhydrica)

woodberry flavour
Neohesperidine dihydrochalcone.

Not applicable.

Store in the original package at temperatures not above 30°C.
Always keep the plastic bottle tightly closed in order to protect its contents from moisture.
Keep out of the reach of children.

HDPE bottles containing 90 chewable tablets

Please refer to section 6.3.