Trientine dihydrochloride is indicated for the treatment of Wilson’s disease in patients intolerant to D-Penicillamine therapy, in adults, adolescents and children aged 5 years or older.

Clinical experience with Trientine dihydrochloride is limited and alternate dosing regimens have not been well-characterized; all endpoints in determining an individual patient's dose have not been well defined. Trientine dihydrochloride and penicillamine cannot be considered interchangeable. Trientine dihydrochloride should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.

Unlike penicillamine, Trientine dihydrochloride is not recommended in cystinuria or rheumatoid arthritis. The absence of a sulfhydryl moiety renders it incapable of binding cystine and, therefore, it is of no use in cystinuria. In 15 patients with rheumatoid arthritis, Trientine dihydrochloride was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment.

Trientine dihydrochloride is not indicated for treatment of biliary cirrhosis. 

Treatment should only be initiated by specialist physicians with experience in the management of Wilson’s disease.

Posology

The starting dose would usually correspond to the lowest recommended dose and the dose should subsequently be adapted according to the patient’s clinical response (see section 4.4).

Adults

The recommended dose is 750 - 1250 mg daily in 2 to 4 divided doses. This may be increased to a maximum of 2000 mg/day for adults.

The daily dose of Trientine dihydrochloride capsules should only be increased only when the clinical response is not adequate or the concentration of free serum copper is persistently above 20 mcg/dL. Optimal long-term maintenance dosage should be determined at 6-12 month intervals.

Special populations

Elderly

There is insufficient clinical information available for Trientine diydrochloride to determine whether there exist differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range as recommended for adults, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal impairment

There is limited information in patients with renal impairment. Therefore, the recommended dose in patients with renal impairment is the same as for adults. For specific precautions see section 4.4.

Hepatic impairment

There is limited information in patients with hepatic impairment. Therefore the recommended dose in patients with hepatic impairment is the same as for adults. For specific precautions see section 4.4.

Patients primarily presenting hepatic symptoms

The recommended dose in patients primarily presenting hepatic symptoms is the same as the recommended adult dose. It is advised, however, to monitor patients presenting with hepatic symptoms every two to three weeks after initiation of treatment with Trientine dihydrochloride capsules.

Patients primarily presenting neurological symptoms

Dose recommendations are the same as for adults. However, up titration should be done with moderation and consideration, and adapted according to the patient’s clinical response such as worsening of tremor as patients could be at risk of neurological deterioration at initiation of treatment (see section 4.4). It is further advised to monitor patients presenting with neurological symptoms every one to two weeks after initiation of treatment with Trientine diydrochloride capsules until target dose is reached.

Pediatric population

The dose is lower than for adults and depends on age and body weight. The dose should be adjusted according to clinical response; 500 – 750 mg/day in 2 to 4 divided doses have been used at initiation of therapy (see section 4.4). This may be increased to a maximum of 1500 mg/day for pediatric patients age 12 or under.

Children < 5 years

The safety and efficacy of Trientine diydrochloride capsules in children aged 0 to 5 years have not yet been established. No data are available.

Method of administration

For oral use.

Capsules should be swallowed whole with water and should not be opened or chewed.

It is important that Trientine dihydrochloride capsules is given on an empty stomach, at least one hour before meals or two hours after meals, and at least one hour apart from any other medicinal product, food or milk (see section 4.5).

When switching a patient from another trientine formulation, caution is advised because different trientine salts are available which may have a different trientine content (base) and a different bioavailability. Dose adjustment may be required (see section 4.2).

Trientine is a chelating agent which has been found to reduce serum iron levels. Iron supplementation may be necessary in some cases. Concomitant oral iron should be administered at a different time than trientine (see section 4.5).

The combination of trientine with zinc is not recommended. There are only limited data on concomitant use available and no specific dose recommendations can be made.

There is no evidence that calcium and magnesium antacids alter the efficacy of trientine but it is recommended to separate their administration (see section 4.5).

There is no advantage in using trientine and penicillamine in combination.

In patients who were previously treated with D-Penicillamine, lupus-like reactions have been reported during subsequent treatment with trientine, however it is not possible to determine if there is a causal relationship with trientine.

Monitoring

Patients receiving Trientine diydrochloride capsules should remain under regular medical supervision and be monitored using all available clinical data for appropriate control of clinical symptoms and copper levels in order to optimise treatment. Frequency of monitoring is recommended to be at least twice a year. More frequent monitoring is advised during the initial phase of treatment and during phases of disease progression or when dose adjustments are made as to be decided by the treating physician (see section 4.2).

The aim of maintenance treatment is to maintain free copper levels in plasma (also known as non- ceruloplasmin plasma copper) and the urinary copper excretion within the acceptable limits.

The determination of serum free copper, calculated using the difference between the total copper and the ceruloplasmin-bound copper (normal level of free copper in the serum is usually 100 to 150 microgram/L), can be a useful index for monitoring therapy.

The measurement of copper excretion in the urine may be performed during therapy. Since chelation therapy leads to an increase in urinary copper levels, this may/will not give an accurate reflection of the excess copper load in the body but may be a useful measure of treatment compliance.

The use of appropriate copper parameter target ranges is described in clinical practice guidelines related to Wilson’s disease.

Like with all anti-copper agents, overtreatment carries the risk of copper deficiency, which is especially harmful for children and pregnant women (see section 4.6) since copper is required for proper growth and mental development. Therefore, monitoring for manifestations of overtreatment should be undertaken.

Patients with renal and/or hepatic impairment receiving trientine should remain under regular medical supervision for appropriate control of symptoms and copper levels. Close monitoring of renal and/or liver function is also recommended in these patients (see section 4.2).

Worsening of neurological symptoms may occur at the beginning of chelation therapy due to excess of free serum copper during the initial response to treatment. It is possible that this effect may be more evident in patients with pre-existing neurological symptoms. It is recommended to monitor patients closely for such signs and symptoms and to consider careful titration to reach the recommended therapeutic dose and to reduce dose when necessary.

Dose adjustments in the trientine dose should be considered in case of signs of reduced efficacy such as (persistent) increase in liver enzymes, and worsening of tremor. When trientine doses are adjusted this should be done in small steps. The trientine dose may also be reduced in case of side effects of trientine, such as gastrointestinal complaints and haematological changes. Trientine doses should be reduced to a more tolerable dose and may be increased again, once side effects have been resolved.

No interaction studies have been performed.

Zinc

There are insufficient data to support the concomitant use of zinc and trientine. The combination of trientine with zinc is not recommended as interaction of zinc with trientine is likely, thereby reducing the effect of both active substances.

Other anti-copper agents

No interaction studies have been performed on the concomitant administration of trientine with D- Penicillamine.

Food

No specific food interaction studies in humans have been performed with trientine. However as trientine is poorly absorbed following oral intake, food may inhibit absorption. The principal mechanism of action of trientine requires its systemic exposure (see section 5.1) so it is recommended that trientine be taken at least 1 hour before meals or 2 hours after meals and at least one hour apart from any other medicinal product, food, or milk to allow for maximum absorption and reduce the likelihood of the formation of complexes by metal binding in the gastrointestinal tract (see section 4.2).

Other products

Trientine has been found to reduce serum iron levels. Therefore, iron supplementation may be necessary in some cases. Concomitant oral iron or other heavy metals should be administered at a different time than trientine to prevent the formation of complexes (see section 4.4).

Although there is no evidence that calcium and magnesium antacids alter the efficacy of trientine, it is good practice to separate their administration (see section 4.4).

Pregnancy

Pregnancy Category C

There is a limited amount of data from the use of trientine in pregnant women.

Studies in animals have shown reproductive toxicity, which was probably a result of trientine-induced copper deficiency (see section 5.3). Trientine hydrochloride was teratogenic in rats at doses similar to the human dose. The frequencies of both resorptions and fetal abnormalities, including hemorrhage and edema, increased while fetal copper levels decreased when trientine hydrochloride was given in the maternal diets of rats.

Trientine should be used in pregnancy only after careful consideration of the benefits compared with the risks of discontinuing treatment in the individual patient. Factors to consider include the known risks associated with untreated or undertreated Wilson’s disease, risks associated with the stage of disease, the risk of those alternative treatments which are available and the possible effects of trientine (see section 5.3).

If treatment with trientine is to be continued following a risk-benefit analysis, consideration should be given to reducing the dose of trientine to the lowest effective dose and monitoring compliance with the treatment regimen.

The pregnancy should be closely monitored in order to detect possible foetal abnormality and to assess maternal serum copper levels throughout the pregnancy. The dose of trientine used should be adjusted in order to maintain serum copper levels within the normal range. Since copper is required for proper growth and mental development, dose adjustments may be required to ensure that the foetus will not become copper deficient and close monitoring of the patient is essential (see section 4.4)

Babies born to mothers being treated with trientine should be monitored for serum copper and ceruloplasmin levels where appropriate.

Trientine dihydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding

There is limited clinical data suggesting that trientine is not excreted in breast milk. However, a risk to the newborns/infants cannot be excluded.

Because many drugs are excreted in human milk, caution should be exercised when Trientine dihydrochloride is administered to a nursing mother. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from trientine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

It is unknown whether trientine has an effect on human fertility.

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

Gastrointestinal disorders (26% of patients), musculoskeletal and connective tissue disorders (19.5% of patients) and nervous system disorders (14.3% of patients) were the most common reported events attributed to trientine.

Summary of the safety profile

Nausea can commonly occur on initial treatment and occasionally skin rash can occur. Duodenitis and severe colitis have been reported. Neurological deterioration can occur at the start of the treatment.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies are defined as: 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); not known (cannot be estimated from the available data).

Description of selected adverse reactions

There have been reports of neurological deterioration at the start of treatment in Wilson’s disease patients treated with copper chelators including trientine, with symptoms of, for example, dystonia, rigidity, tremor and dysarthria (see section 4.2).

Paediatric population

The study on a limited number of children in the age range of 5 to 17 years at the start of treatment indicate that frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed, appropriate biochemical analysis performed and symptomatic treatment given. There is no antidote.

In one reported case an overdose of 30 capsules did not produce any apparent adverse effects. In a second case, a large overdose of trientine (40 g) resulted in self-limiting dizziness and vomiting with no further clinical sequelae or significant biochemical abnormalities.

Chronic overtreatment can lead to copper deficiency and reversible sideroblastic anaemia. Overtreatment and excess copper removal can be monitored using values of urine copper excretion and of non-ceruloplasmin bound copper. Close monitoring is required to optimise the dose or adapt treatment if necessary (see section 4.4).

Pharmacotherapeutic group: Other alimentary tract and metabolism, various alimentary tract and metabolism products, ATC code: A16AX12

Mechanism of action

Trientine is a copper-selective chelator that enhances systemic elimination of divalent copper by forming a stable complex that is readily excreted by the kidneys. Trientine is a chelator with a polyamine-like structure and copper is chelated by forming a stable complex with the four constituent nitrogens in a planar ring. Thus, the pharmacodynamic action of trientine is dependent on its chemical property of chelating copper and not on its interaction with receptors, enzyme systems or any other biological system that might differ between species. Trientine may also chelate copper in the intestinal tract and so inhibit copper absorption.

Weiss 2013 conducted a multicentre, retrospective observational study to compare the efficacy and safety of trientine versus penicillamine (DPA) in patients with WD (n=380) treated at tertiary care centres in Germany and Austria, and additional patients from the EUROWILSON registry (n=25). The cohort consisted of outcomes for patients with WD treated with DPA (n=326) and trientine (n=141) for at least six months. The primary efficacy outcome was the change in hepatic and neurologic outcomes (i.e. clinical symptoms and tests) at 6, 12, 24, 36, and 48 months after initiation of the treatment regimen. Hepatic outcome measures were based on clinical symptoms, course of liver enzymes, and liver function tests. Patients with either of these clinical or biochemical signs of liver disease were considered symptomatic. The course of neurologic disease was evaluated by the physician.

In symptomatic hepatic patients, comparable rates of improvement were observed under first line d-penicillamine therapy (185 of 204; 90.7%) and first-line trientine therapy (25 of 27; 92.6%). In the same group, stable hepatic disease in terms of unchanged hepatic symptoms was observed for first-line d-penicillamine therapy treatment in 15 of 204 (7.4%) treatments versus 2 of 27 (7.4%) in the trientine group.  Stable hepatic disease under second-line therapy was reported for 4 of 16 (25%) d-penicillimine treatments and for 10 of 45 (22.2%) trientine treatments. No hepatic worsening was seen in chelation monotherapy for patients who presented without hepatic symptoms.  No statistically significant differences were found for the rate of improvement for first-line (d-penicillamine 77 of 114, 67.5% versus trientine 11 of 20, 55%) or second-line (d-penicillamine 3 of 13, 23.1% versus trientine 26 of 51, 51%) chelation therapy.

Stable neurologic disease was observed for first-line in the d-penicillamine group in 31 of 114 (27.2%) treatments versus 5 of 20 (25%) in the trientine group. Stable neurologic disease for second-line therapy was reported for 9 of 13 (69.2%) d- penicillamine treatments and for 17 of 51 (33.3%) trientine treatments. With second-line therapy, neurologic worsening was comparable between groups, with a trend favoring d-penicillamine (d-penicillamine: 1 of 13, 7.3%; trientine: 8 of 51, 15.7%).   A significantly higher rate of neurologic worsening was reported for first-line therapies of symptomatic neurologic patients treated with trientine (4 of 20; 20%) versus d-penicillamine (6 of 114; 5.3%) (p=0.042).

There were no differences between the treatments based on the number of overall discontinuations (p=0.36) with 142/326 (43.6%) discontinuing from d-penicillamine and 36/141 (25.5%) from trientine therapy.  Discontinuation as a result of adverse events was more frequent for d-penicillamine treatment than for trientine treatment with 94/326 (28.8%) of DPA treatments stopped because of adverse events versus 10/141 (7.1%) of trientine treatments (p=0.039).

Weiss 2018 conducted a multicentre, retrospective cohort study of medical records to evaluate the efficacy, safety and tolerability of trientine for at least 6 months as a second-line treatment in patients with WD (n=77). The study also included a prospective part which was a continuation of the retrospective study (n=52) to assess efficacy and quality of life (QoL) outcomes.

The efficacy endpoint was the clinical course of hepatic or neurological disease based on the Investigator’s scores at the time of initiating trientine (similar 5-point score as used in the Weiss 2013 study), and 6, 12, 24, 36, 48 months and at the last available time point while taking second line trientine and the time to discontinuation of trientine due to AE and/or inadequate response. Copper storage and metabolism were measured as surrogate endpoints at the time of initiation, and 6, 12, 24, 36, 48 months and at the last available time point after initiation of trientine.

A total of 77 patients were included in the intention to treat (ITT) population.  A total of 38 (49.4%) patients showed improved hepatic symptoms with 17 (22.1%) patients classified as ‘improved to normal’ and 21 (27.3%) patients classified as ‘improved but not normal’, 27 (35.1%) patients were ‘asymptomatic’ and 8 (10.4%) patients had ‘unchanged’ symptoms, and  4 (5.2%) patients had ‘worsened symptoms’.  A total of 11 (14.3%) patients showed improved neurological symptoms with 2 (2.6%) patients classified as ‘improved to normal’ and 9 (11.7%) patients classified with ‘improved but not normal’, 36 (46.8%) patients were ‘asymptomatic’ and 28 (36.4%) patients had ‘unchanged’ symptoms, and 2 (2.6%) patients had ‘worsened symptoms’.

Within the two years of observation, 12 (15.6%) of patients discontinued trientine and switched to another treatment option. At the individual last available observation, treatment with trientine was ongoing in 65 (84.4%) patients of the ITT population.

The Weiss 2019 study was a prospective study and a continuation of Weiss 2018 with an additional QoL objective. All patients had been enrolled in the retrospective study and were continued to be observed in the prospective study. The mean age was 42.3 ± 14.52 years.

Fifty of the 51 patients (98.0%) treated with trientine were considered to have responded to treatment, while only one patient (2.0%) showed a mild worsening of disease at 12 months.  For neurological presentations, the neurological symptoms improved but not to normal in eight patients (15.7%), and improved to normal in one patient (2.0%). A total of 29 (56.9%) patients were asymptomatic over the duration of therapy. In 12 patients (23.5%) symptoms remained unchanged and there was one patient (2.0%) with worsening of neurological symptoms. The UWDRS neurologic subscale assessment was 11.3 ± 24.31 at baseline, 9.7 ± 23.85 at month 6 and 8.8 ± 22.86 at month 12 which indicated a neurological improvement.

The mean 24 h basal urine copper excretion was similar at month 6 and month 12 (4.011 µmol/24 h versus 4.452 µmol/24 h, respectively); the mean serum copper at baseline was 4.505 ± 3.4036 µmol/L, 4.648 ± 2.9990 µmol/L at month 6 and at 4.753 ± 3.6092 µmol/L at month 12; and the mean non-ceruloplasmin bound copper (NCC) concentration at month 6 was 1.1542 ± 0.92618 µmol/L and 0.9051 ± 0.88075 µmol/L at month 12.

The QoL data indicated that overall, the anxiety and depression improved during treatment with trientine. The other QoL indicators (mobility, self-care, usual activities and pain/discomfort) were stable and generally similar at month 6 and month 12.

Forty-one patients (18 male and 23 female) between the ages of 6 and 54 with a diagnosis of Wilson’s disease and who were intolerant of d-penicillamine were treated in two separate studies with trientine dihydrochloride. The dosage varied from 450 to 2400 mg per day. The average dosage required to achieve an optimal clinical response varied between 1000 mg and 2000 mg per day. The mean duration of trientine dihydrochloride therapy was 48.7 months (range 2-164 months). Thirty-four of the 41 patients improved, 4 had no change in clinical global response, 2 were lost to follow-up and one showed deterioration in clinical condition. One of the patients who improved while on therapy with trientine dihydrochloride experienced a recurrence of the symptoms of systemic lupus erythematosus which had appeared originally during therapy with penicillamine. Therapy with trientine dihydrochloride was discontinued. No other adverse reactions, except iron deficiency, were noted among any of these 41 patients.

One investigator treated 13 patients with trientine dihydrochloride following their development of intolerance to d-penicillamine. Retrospectively, the investigator compared these patients to an additional group of 12 patients with Wilson’s disease who were both tolerant of and controlled with d-penicillamine therapy, but who failed to continue any copper chelation therapy. The mean age at onset of disease of the latter group was 12 years as compared to 21 years for the former group. The trientine dihydrochloride group received d-penicillamine for an average of 4 years as compared to an average of 10 years for the non-treated group.

Various laboratory parameters showed changes in favor of the patients treated with trientine dihydrochloride. Free and total serum copper, SGOT and serum bilirubin all showed mean increases over baseline in the untreated group which were significantly larger than with the patients treated with trientine dihydrochloride. In the 13 patients treated with trientine dihydrochloride, previous symptoms and signs relating to d-penicillamine intolerance disappeared in 8 patients, improved in 4 patients, and remained unchanged in one patient. The neurological status in the trientine dihydrochloride group was unchanged or improved over baseline, whereas in the untreated group, 6 patients remained unchanged and 6 worsened. Kayser-Fleischer rings improved significantly during trientine dihydrochloride treatment.

The clinical outcome of the two groups also differed markedly. Of the 13 patients on therapy with trientine dihydrochloride (mean duration of therapy 4.1 years; range 1 to 13 years), all were alive at the data cutoff date, and in the non-treated group (mean years with no therapy 2.7 years; range 3 months to 9 years), 9 of the 12 died of hepatic disease.

Chelating Properties

Preclinical Studies

Studies in animals have shown that trientine dihydrochloride has cupriuretic activities in both normal and copper-loaded animals.

Human Studies

Renal clearance studies were carried out with penicillamine and trientine dihydrochloride on separate occasions in selected patients treated with penicillamine for at least one year. Six-hour excretion rates of copper were determined off treatment and after a single dose of 500 mg of penicillamine or 1.2 g of trientine dihydrochloride. The mean urinary excretion rates of copper were as follows:

In patients not previously treated with chelating agents, a similar comparison was made:

These results demonstrate that trientine dihydrochloride is effective as a cupriuretic agent in patients with Wilson’s disease although on a molar basis it appears to be less potent or less effective than penicillamine. Evidence from a radio-labelled copper study indicates that the different cupriuretic effect between these two drugs could be due to a difference in selectivity of the drugs for different copper pools within the body.

Absorption

Following oral administration, trientine absorption is low and variable in patients with Wilson’s disease. Trientine is absorbed with Tmax occurring between 0.5 and 4 hours post-dose in healthy volunteers and patients. Exposure seems to be highly variable between subjects. The terminal half-life in plasma is approximately 13.5 h.

Distribution

Trientine has low human plasma protein binding and is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney in the rat.

Biotransformation

Trientine is acetylated in two major metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT). The extent of MAT and DAT’s contribution to the overall effect of Cufence on copper levels in Wilson’s Disease patients remains to be determined.

Trientine is metabolised by acetylation via spermidine/spermine N-acetyltransferase and not via N-acetyltransferase 2.

Elimination

Trientine and its metabolites are rapidly excreted in the urine.

Unabsorbed trientine is bound to intestinal copper and eliminated through faecal excretion.

Non-clinical data reveal no special hazard for humans based on a series of studies investigating cardiovascular safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to embryofoetal development.

Effects in non-clinical studies were largely consistent with induced copper deficiency in the plasma and liver of previously copper normative animals and as such could be attributed to the pharmacological action of trientine. The main toxicological findings associated with trientine, which were generally seen across all species examined, included body weight loss or lower body weight gain, altered urinary electrolytes, low plasma copper levels and various histopathological changes in the lungs (mainly interstitial pneumonitis). All effects were reversible with the exception of the lung findings; however the dose levels where these effects were observed are far in excess of those used clinically. Moreover, there was some doubt about the relationship to trientine, as the lung findings were also observed in most of the control dogs in the 26 week study. In dogs, ataxia, tremors, abnormal gait and underactivity were observed following administration of very high levels of trientine. Some functional neurological abnormalities were also identified, particularly in severly affected animals, however no associated nerve damage was observed. Electrocardiography was also unaffected.

In pregnant animals, high dose trientine associated with significant reductions in serum copper, revealed an early effect on embryo survival and a marginally lower foetal weight. There was no evidence of embryo-foetal toxicity at lower dose levels despite dose-related reductions in serum copper. These effects were observed only at exposures sufficiently in excess of maximum human exposure to indicate little relevance to clinical use.

No fertility data are available but estrous cyclicity was unaffected and reproductive organs were not identified as target organs in general repeat dose toxicity studies.

The OECD SIDS triethylenetetramine 2002 classifies the genotoxic profile of trientine as low priority/concern. Some positive in vitro mutagenicity data were obtained but in vivo test systems showed no mutagenic activity. No long term animal carcinogenicity trials have to date been performed with trientine via the oral route, but via the dermal route, there was no increases in cancers above baseline. Moreover, there is evidence to suggest that trientine actually reduces endogenous DNA damage in a strain of rat (Long-Evans Cinnamon) considered to represent an appropriate model of Wilson’s disease. This suggests a reduced carcinogenic risk for Wilson’s disease patients as a result of trientine therapy.

Trientine dihydrochloride is a known irritant, especially to mucus membranes, upper respiratory tract and skin, and induces skin sensitisation in guinea pigs, mice and man (OECD SIDS triethylenetetramine 2002).

Capsule content:

Stearic acid

Capsule shell:

Gelatin

Titanium dioxide (E171)

FD&C Yellow 6 (E110)

Not applicable.

Store in a refrigerator (2ºC-8ºC). Do not freeze.

Keep the container tightly closed. Store in the original container and retain the silica gel strip in the bottle in order to protect from moisture.

White HDPE bottle with polypropylene cap and induction heat seal liner with a strips of silica gel as desiccant..

Pack size: 1 bottle of 100 hard capsules

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