Lagona is indicated for the treatment of:
- Adult patients with newly-diagnosed glioblastoma multiforme concomitantly with
radiotherapy (RT) and subsequently as monotherapy treatment.
- Children from the age of three years, adolescents and adult patients with malignant glioma,
such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression
after standard therapy.

Lagona should only be prescribed by physicians experienced in the oncological treatment of
brain tumours.
Anti-emetic therapy may be administered (see section 4.4).
Posology
Adult patients with newly-diagnosed glioblastoma multiforme
Lagona is administered in combination with focal radiotherapy (concomitant phase) followed
by up to 6 cycles of temozolomide (LAGONA) monotherapy (monotherapy phase).
Concomitant phase
Lagona is administered orally at a dose of 75 mg/m² daily for 42 days concomitant with focal
radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but
delay or discontinuation of Lagona administration should be decided weekly according to
haematological and non-haematological toxicity criteria. Lagona administration can be
continued throughout the 42 day concomitant period (up to 49 days) if all of the following
conditions are met:
- Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/l
- Thrombocyte count ≥ 100 x 10⁹/l
- Common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia,
nausea and vomiting).
During treatment a complete blood count should be obtained weekly. Lagona administration
should be temporarily interrupted or permanently discontinued during the concomitant phase
according to the haematological and non-haematological toxicity criteria as noted in Table 1.

a: Treatment with concomitant Lagona can be continued when all of the following conditions
are met: absolute neutrophil count ≥ 1.5 x 10⁹/l; thrombocyte count ≥ 100 x 109/l; CTC nonhaematological
toxicity ≤ Grade 1 (except for alopecia, nausea, vomiting).
Monotherapy phase
Four weeks after completing the Lagona + RT concomitant phase, Lagona is administered for
up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m² once
daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is
escalated to 200 mg/m² if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2
(except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 10⁹/l,
and the thrombocyte count is ≥ 100 x 10⁹/l. If the dose was not escalated at Cycle 2, escalation
should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m² per

day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and
discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.
During treatment a complete blood count should be obtained on Day 22 (21 days after the first
dose of Lagona). The dose should be reduced or administration discontinued according to
Table 3.

a: Lagona dose levels are listed in Table 2.
b: Lagona is to be discontinued if:
• Dose level -1 (100 mg/m²) still results in unacceptable toxicity
• The same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs
after dose reduction.
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant
glioma:
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy,
Lagona is administered orally at a dose of 200 mg/m² once daily for the first 5 days followed
by a 23 day treatment interruption (total of 28 days). In patients previously treated with
chemotherapy, the initial dose is 150 mg/m² once daily, to be increased in the second cycle to
200 mg/m² once daily, for 5 days if there is no haematological toxicity (see section 4.4)
Special populations
Paediatric population
In patients 3 years of age or older, Lagona is only to be used in recurrent or progressive
malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The
safety and efficacy of Lagona in children under the age of 3 years have not been established.
No data are available.
Patients with hepatic or renal impairment
The pharmacokinetics of Lagona were comparable in patients with normal hepatic function and
in those with mild or moderate hepatic impairment. No data are available on the administration
of Lagona in patients with severe hepatic impairment (Child's Class C) or with renal
impairment. Based on the pharmacokinetic properties of Lagona, it is unlikely that dose

reductions are required in patients with severe hepatic impairment or any degree of renal
impairment. However, caution should be exercised when Lagona is administered in these
patients.
Elderly patients
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of
Lagona is not affected by age. However, elderly patients (> 70 years of age) appear to be at
increased risk of neutropenia and thrombocytopenia (see section 4.4).
Method of administration
Lagona hard capsules should be administered in the fasting state.
The capsules must be swallowed whole with a glass of water and must not be opened or
chewed.
If vomiting occurs after the dose is administered, a second dose should not be administered that
day.

Opportunistic infections and reactivation of infections
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of
infections (such as HBV, CMV) have been observed during the treatment with Lagona (see
section 4.8).
Meningoencephalitis herpetic
In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been
observed in patients receiving Lagona in combination with radiotherapy, including cases of
concomitant steroids administration.
Pneumocystis jirovecii pneumonia
Patients who received concomitant Lagona and RT in a pilot trial for the prolonged 42-day
schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia
(PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant Lagona
and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count.
If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to
grade ≤ 1.
There may be a higher occurrence of PCP when Lagona is administered during a longer dosing
regimen. However, all patients receiving Lagona, particularly patients receiving steroids,
should be observed closely for the development of PCP, regardless of the regimen. Cases of
fatal respiratory failure have been reported in patients using Lagona, in particular in
combination with dexamethasone or other steroids.
HBV
Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has
been reported. Experts in liver disease should be consulted before treatment is initiated in

patients with positive hepatitis B serology (including those with active disease). During
treatment patients should be monitored and managed appropriately.
Hepatotoxicity
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with Lagona
(see section 4.8). Baseline liver function tests should be performed prior to treatment initiation.
If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide
including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver
function tests should be repeated midway during this cycle. For all patients, liver function tests
should be checked after each treatment cycle. For patients with significant liver function
abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity
may occur several weeks or more after the last treatment with temozolomide.
Malignancies
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid
leukaemia, have also been reported very rarely (see section 4.8).
Anti-emetic therapy
Nausea and vomiting are very commonly associated with Lagona.
Anti-emetic therapy may be administered prior to or following administration of Lagona.
Adult patients with newly-diagnosed glioblastoma multiforme
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is
strongly recommended during the monotherapy phase.
Patients with recurrent or progressive malignant glioma
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles
may require anti-emetic therapy.
Laboratory parameters
Patients treated with Lagona may experience myelosuppression, including prolonged
pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal
outcome. In some cases, exposure to concomitant medicinal products associated with aplastic
anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates
assessment. Prior to dosing, the following laboratory parameters must be met: ANC ≥ 1.5 x
10⁹/l and platelet count ≥ 100 x 10⁹/l. A complete blood count should be obtained on Day 22
(21 days after the first dose) or within 48 hours of that day, and weekly until ANC > 1.5 x 10⁹/l
and platelet count > 100 x 10⁹/l. If ANC falls to < 1.0 x 10⁹/l or the platelet count is < 50 x
10⁹/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose
levels include 100 mg/m², 150 mg/m², and 200 mg/m². The lowest recommended dose is 100
mg/m2.
Paediatric population
There is no clinical experience with use of Lagona in children under the age of 3 years.
Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).
Elderly patients (> 70 years of age)
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared
with younger patients. Therefore, special care should be taken when Lagona is administered in
elderly patients.

Male patients
Men being treated with Lagona should be advised not to father a child up to 6 months after
receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment (see
section 4.6).
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.

In a separate phase I study, administration of Lagona with ranitidine did not result in alterations
in the extent of absorption of temozolomide or the exposure to its active metabolite
monomethyl triazenoimidazole carboxamide (MTIC).
Administration of Lagona with food resulted in a 33 % decrease in C_max and a 9 % decrease in
area under the curve (AUC).
As it cannot be excluded that the change in C_max is clinically significant, Lagona should be
administered without food.
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H₂ receptor
antagonists, or phenobarbital did not alter the clearance of Lagona. Co-administration with
valproic acid was associated with a small but statistically significant decrease in clearance of
Lagona.
No studies have been conducted to determine the effect of Lagona on the metabolism or
elimination of other medicinal products. However, since Lagona does not undergo hepatic
metabolism and exhibits low protein binding, it is unlikely that it would affect the
pharmacokinetics of other medicinal products (see section 5.2).
Use of Lagona in combination with other myelosuppressive agents may increase the likelihood
of myelosuppression.
Paediatric population
Interaction studies have only been performed in adults.

Pregnancy
Pregnancy category: D.
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150
mg/m² Lagona, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3).
Lagona should not be administered to pregnant women. If use during pregnancy must be
considered, the patient should be apprised of the potential risk to the foetus.
Breast-feeding
It is not known whether Lagona is excreted in human milk; thus, breast-feeding should be
discontinued while receiving treatment with Lagona.
Lagona Hard Capsules
Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception to avoid
pregnancy while they are receiving Lagona.
Male fertility
Lagona can have genotoxic effects. Therefore, men being treated with it should be advised not
to father a child up to 6 months after receiving the last dose and to seek advice on
cryoconservation of sperm prior to treatment, because of the possibility of irreversible
infertility due to therapy with Lagona.

Lagona has minor influence on the ability to drive and use machines due to fatigue and
somnolence (see section 4.8).

Clinical trial experience
In patients treated with Lagona, whether used in combination with RT or as monotherapy
following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients
with recurrent or progressive glioma, the reported very common adverse reactions were
similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were
reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving
monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma
multiforme patients receiving Lagona concurrent with RT and also as monotherapy, and
commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly
or very commonly in both indications (Tables 4 and 5); the frequency of grade 3-4 laboratory
findings is presented after each table.
In the tables undesirable effects are classified according to System Organ Class and frequency.
Frequency groupings are defined according to 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). Within each frequency grouping, undesirable effects are
presented in order of decreasing seriousness.
Newly-diagnosed glioblastoma multiforme
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed
glioblastoma multiforme during the concomitant and monotherapy phases of treatment.

*A patient who was randomised to the RT arm only received Lagona + RT.
Laboratory results
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity
for most cytotoxic agents, including Lagona, was observed. When laboratory abnormalities and
adverse events were combined across concomitant and monotherapy treatment phases, Grade 3
or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8 % of the
patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events
were observed in 14 % of the patients who received Lagona.
Recurrent or progressive malignant glioma
In clinical trials, the most frequently occurring treatment-related undesirable effects were
gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions
were usually Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting
or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and
vomiting was 4 %.
Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive
malignant glioma and following the marketing of Lagona.

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of Lagona in 8 % and 4 %, respectively. Myelosuppression was predictable (usually within the first few cycles, with the nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC < 0.5 x 10⁹/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 10⁹/l), 9 % vs 3 %, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 neutropenia occurred in 8 % of female vs 4 % of male subjects and Grade 4 thrombocytopenia in 8 % of female vs 3 % of male subjects in the first cycle of therapy. In a study of 288 subjects with newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3 % of female vs 0 % of male subjects and Grade 4 thrombocytopenia in 1 % of female vs 0 % of male subjects in the first cycle of therapy.

Paediatric population

Oral Lagona has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of Lagona in children under the age of 3 years has not been established.

Post-Marketing Experience

The following additional serious adverse reactions have been identified during post-marketing exposure:

† Including cases with fatal outcome

^* Frequencies estimated based on relevant clinical trials.

Doses of 500, 750, 1,000, and 1,250 mg/m² (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.

Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O⁶position of guanine with additional alkylation also occurring at the N⁷ position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either Lagona + RT (n=287) or RT alone (n=286). Patients in the Lagona + RT arm received concomitant Lagona (75 mg/m²) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy Lagona (150 - 200 mg/m²) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis jiroveciipneumonia (PCP) prophylaxis was required during RT and combined Lagona therapy.

Lagona was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57 %) in the RT alone arm, and 62 patients of the 277 (22 %) in the Lagona + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank p < 0.0001 in favour of the Lagona arm. The estimated probability of surviving 2 years or more (26 % vs 10 %) is higher for the RT + Lagona arm. The addition of concomitant Lagona to RT, followed by Lagona monotherapy in the treatment of patients with newly-diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

Figure 1 Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms. However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] ≥ 70), progressive or recurrent after surgery and RT, were based on two clinical trials with oral Lagona. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the other was a randomised active-controlled trial of Lagona vs procarbazine in a total of 225 patients (67 % received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non-comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was 2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8 %.

In the randomised active-controlled trial, the PFS at 6 months was significantly greater for Lagona than for procarbazine (21 %vs 8 %, respectively – chi-square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for Lagona and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the Lagona arm (60 %) compared with the procarbazine arm (44 %) (chi-square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS ≥ 80.

Data on time to worsening of neurological status favoured Lagona over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for Lagona than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral Lagona in the treatment of patients with anaplastic astrocytoma at first relapse, the 6 month PFS was 46 %. The median PFS was 5.4 months. Median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35 % (13 CR and 43 PR) for the intent-to-treat population (ITT) n=162. In 43 patients stable disease was reported. The 6-month event-free survival for the ITT population was 44 % with a median event-free survival of 4.6 months, which was similar to the results for the progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression-free status was strongly associated with maintained or improved quality of life.

Paediatric population

Oral Lagona has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to Lagona is similar to adults.

Lagona is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O⁶ and N⁷ positions of guanine. Relative to the AUC of Lagona, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively. In vivo, the t_1/2 of MTIC was similar to that of Lagona, 1.8 hr.

Absorption

After oral administration to adult patients, Lagona is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of ¹⁴C-labelled Lagona, mean faecal excretion of ¹⁴C over 7 days post-dose was 0.8 % indicating complete absorption.

Distribution

Lagona demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that Lagona crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of Lagona was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t_1/2) in plasma is approximately 1.8 hours. The major route of ¹⁴C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of Lagona revealed that plasma Lagona clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m²per cycle both in children and in adults.

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

Lagona is an embryotoxic, teratogenic and genotoxic alkylating agent. Lagona is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of LAGONA, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.

Capsule content:

Lactose Anhydrous,

Colloidal silicon dioxide,

Sodium Starch Glycollate (Type A),

Tartaric Acid,

Stearic Acid,

Capsule shell, Size 0:

Lagona 5 mg hard capsules: gelatin, titanium dioxide (E 171). Yellow iron oxide (E 172), red iron oxide (E 172).

Lagona 20 mg hard capsules: gelatin, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172).

Lagona 100 mg hard capsules: gelatin, titanium dioxide (E 171), indigotine FD&C blue2 (E 132).

Lagona 140 mg hard capsules: Gelatin, titanium dioxide (E 171), indigotine FD&C blue 2 (E 132).

Lagona 180 mg hard capsules: Gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172).

Lagona 250 mg hard capsules: gelatin, titanium dioxide (E 171).

Printing ink

Shellac, dehydrated alcohol, Isopropyl alcohol, Butyl alcohol, propylene glycol, purified water, sodium ammonia solution, potassium hydroxide, black iron oxide (E 172).

Not applicable.

Bottle presentation

Store below 30 °C.

Store in the original bottle in order to protect from moisture.

Keep the bottle tightly closed.

Sachet presentation

Store below 30 °C.

HDPE Bottle presentation:

White opaque High Density Polyethylene Bottles with Polypropylene push lock assembly closure, with polyester coil containing 5 capsules.

Sachet presentation

Sachets composed of paper on linear low density polyethylene (outermost layer), aluminium and ethylene acrylic acid co-polymer (innermost layer).

Each sachet contains 1 hard capsule and is dispensed in a cardboard carton.

The carton contains 5 or 20 hard capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Lagona comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

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